Alcohol effects on hepatic lipid metabolism through various mechanisms, leading synergistically to an accumulation of fatty acids (FA) and triglycerides. Obesity, as well as, the dietary fat [saturated fatty acids (FA) versus poly-unsaturated fatty acids (PUFA)] may modulate the hepatic fat. Alcohol inhibits adenosine monophosphate activated kinase (AMPK). AMPK activates peroxisome proliferators activated receptor a (PPARα) and leads to a decreased activation of sterol regulatory element binding protein 1c (SRABP1c). The inhibition of AMPK, and thus of PPARα results in an inhibition of FAs oxidation. This ß-oxidation is further reduced due to mitochondrial damage induced through cytochrome P4502E1 (CYP2E1) driven oxidative stress. Furthermore, the synthesis of FAs is stimulated through an activation of SHREP1. In addition, alcohol consumption leads to a reduced production of adiponectin in adipocytes due to oxidative stress and to an increased mobilization of FAs from adipose tissue and from the gut as chylomicrons. On the other side, the secretion of FAs via very low density lipoproteins (VLDL) from the liver is inhibited by alcohol. Alcohol also affects signal pathways such as early growth response 1 (Egr-1) associated with the expression of tumour necrosis factor  (TNF), and the mammalian target of rapamycin (mTOR) a key regulator of autophagy. Both have influence the pathogenesis of alcoholic fatty liver. Alcohol-induced gut dysbiosis is contributing to the severity of ALD by increasing metabolism of ethanol in the gut and promoting intestinal dysfunction. Moreover, pathogen associated molecular paterns (PAMPS) via specific Toll-like receptors (TLR) bacterial overgrowth is leading to the translocation of bacteria. Endotoxins, and toxic ethanol metabolites enter the enterohepatic circulation reaching the liver, inducing the activation of the nuclear factor kappa-B (NFB) pathway. Pro-inflammatory cytokines released in the process contribute to inflammation and fibrosis. In addition, cellular apoptosis is inhibited in the favor of necrosis.

The aim of this pilot study was to investigate whether single nucleotide polymorphisms (SNP) in the gene encoding the catalytic subunit of glutamate cysteine ligase (GCLC) are associated with the risk and clinical features of psoriasis. A total of 944 unrelated individuals, including 474 patients with a diagnosis of psoriasis and 470 healthy controls, were recruited for the study. Six common SNPs in the GCLC gene were genotyped using the MassArray-4 system. Polymorphisms rs648595 (OR=0.56 95%CI 0.35-0.90, Pperm=0.017) and rs2397147 (OR=0.54 95%CI 0.30-0.98, Pperm=0.05) were associated with susceptibility to psoriasis in males. In the male group, diplotype rs2397147-C/C×rs17883901-G/G was associated with decreased risk of psoriasis (FDR-adjusted P=0.014), whereas diplotype rs6933870-G/G×rs17883901-G/G (FDR-adjusted P=0.045) showed association with increased disease risk in females. Joint effects of SNPs with tobacco smoking (rs648595 and rs17883901) and alcohol abuse (rs648595 and rs542914) on the risk of psoriasis were observed (Pperm≤0.05). Furthermore, we found multiple sex-independent associations between GCLC gene polymorphisms and various clinical features such as earlier disease onset, the psoriatic triad, and specific localizations of skin lesions. The present study is the first to show that polymorphisms of the GCLC gene are significantly associated with the risk of psoriasis and related to its clinical features.

Autism Spectrum Disorder etiopathogenesis is still unclear and no effective preventive and treatment measures have been identified. Research has focused on the potential role of neuroinflammation and kynurenine pathway. Here we review the nature of these interactions. Pre-natal or neonatal infections would induce microglial activation, with secondary consequences on behavior, cognition and neurotransmitter networks. Peripherally, higher levels of pro-inflammatory cytokines and anti-brain antibodies have been identified. Increased frequency of autoimmune diseases, allergies, and recurring infections have been demonstrated both in autistic patients and in their relatives. Genetic studies, also, have identified some important polymorphisms in chromosome loci related to human leukocyte antigen (HLA) system. The persistence of immune-inflammatory deregulation would lead to mitochondrial dysfunction and oxidative stress, creating a self-sustaining cytotoxic loop. Chronic inflammation activates kynurenine pathway with increase in neurotoxic metabolites and excitotoxicity, causing long-term changes in glutamatergic system, trophic support and synaptic function. Furthermore, overactivation of kynurenine’s branch induces depletion of melatonin and serotonin worsening ASD symptoms. In this scenario, kynurenine pathway appears as a pharmacological target to treat and prevent ASD. Thus, in genetically predisposed subjects aberrant neurodevelopment may derives from a complex interplay between inflammatory process, mitochondrial dysfunction, oxidative stress and kynurenine pathway overexpression. To validate previous hypothesis a new translational research approach is necessary.

ORF6 is responsible for suppressing the immune response of cells infected by the SARS-CoV-2 virus. It is also the most toxic protein of SARS-CoV-2, and its actions are associated with the viral pathogenicity. Here we study in silico and in vitro the structure of the protein, its interaction with RAE1, and the mechanism of action behind its high toxicity. We show both computationally and experimentally that SARS-CoV-2 ORF6, embedded in the membranes of the endoplasmic reticulum, binds to RAE1 and sequesters it in the cytoplasm, thus depleting its availability in the nucleus and impairing nucleocytoplasmic mRNA transport. This negatively affects the cellular genome stability by compromising the cell cycle progression into the S-phase and by promoting the accumulation of RNA-DNA hybrids. Understanding the multiple ways in which ORF6 affects DNA replication may also have important implications for elucidating the pathogenesis of SARS-CoV-2 and developing therapeutic strategies to mitigate its deleterious effects on host cells.

In this paper, we will use the maximum likelihood estimation (MLE) and the Bayes methods to perform estimation procedures for the reliability of stress-strength ℜ=P[X>Y] based on independent adaptive progressive censored samples that were taken from the Chen distributions. An approximate confidence interval of ℜ is constructed using a variety of classical techniques, such as the normal approximation of the MLE, the normal approximation of the log-transformed MLE, and the percentile bootstrap (Boot-p) procedure. The Bayesian estimation of ℜ is obtained based on the balanced loss function, which comes in two versions here, the symmetric balanced squared error (BSE) loss function and the asymmetric balanced linear exponential (BLINEX) loss function. When estimating ℜ using the Bayesian approach, all the unknown parameters of the Chen distributions are assumed to be independently distributed and to have informative gamma priors. Further, a mixture of Gibbs sampling algorithm and Metropolis-Hastings algorithm is used to compute the Bayes estimate of ℜ and the associated highest posterior density credible interval. In the end, simulation research are used to assess the general overall performance of the proposed estimators and a real data set is provided to exemplify the theoretical results.

Soccer is the leading cause of all sports-related ocular injuries in Europe and Israel and leads to blindness at a disproportionately high rate, especially among children (Thompson et al., 2019). With soccer being the most popular sport in the world, it is surprising the only solution to ocular injuries are sports glasses which can cause direct damage to the eye and impair peripheral vision by 15%, calling for an alternative (Smith & Jones, 2020). This work, based on an imported facial model, focuses on both the qualitative and quantitative aspects of building a personalized, low-cost (through optimizing material needed), superior apparatus to conventional sports glasses. The quantitative side examines a modified and model-validated (through a SRS of thirty unique extrapolated points) multivariate linear regression equation, based on horizontal and vertical rotation angles (n=60) trained with residual and computer simulation data, that can accurately extrapolate and quantify ocular impact from all horizontal and vertical rotation angles and a modified Hertzian Contact Stress Equation to determine the thickness of the apparatus using the elasticity modulus, impact force, and geometrical facial and soccer-ball features. The qualitative side examines where firstly, ocular impact is most prevalent, and secondly, where most impact is seen from rotating the ball horizontally and vertically through analysis of Pearson’s Correlation Coefficient at the supraorbital, medial canthus, infraorbital, and lateral canthus regions from both regression equations as well as a cost-benefit analysis for comparison with conventional sports glasses. The findings discovered in this work lay the groundwork for future research to build a customized low-cost ocular injury prevention device which can simultaneously ensure complete ocular safety while enhancing athletic performance for over 250,000,000 players (Johnson & Garcia, 2022).

The Mediator is composed of multiple subunits conserved from yeast to humans and plays a central role in transcription. The tail components are not required for basal transcription but are required for response to different stresses. While some stresses are familiar such as heat, desiccation, and starvation, others are exotic, yet yeast can elicit a successful stress response. MCHM is a hydrotrope that induces growth arrest in yeast. We found that a naturally occurring variation in the Med15 allele, a component of the Mediator tail, altered the stress response to many chemicals in addition to MCHM. Med15 contains two polyglutamine repeats (polyQ) of variable lengths that change the gene expression of diverse pathways. Med15 protein existed in multiple isoforms and its stability was dependent on Ydj1, a protein chaperone. The protein level of the Med15 with longer polyQ tracts was lower and turned over faster than the allele with shorter polyQ repeats. MCHM sensitivity via variation of Med15 was regulated by Snf1 in a Myc tag dependent manner. Tagging Med15 with Myc altered its function in response to stress. Genetic variation in transcriptional regulators magnifies genetic differences in response to environmental changes. These polymorphic control genes are master variators.

There are many features of homeostasis worth investigating such as how it works (information pathways, set point processing), where its command and control processors are located in the cell, the language used and how homeostasis interacts with all effectors (all aspects of an organism's functional maintenance and development such as cell differentiation). All are necessary and valid inquiries, but this paper examines the implications of ignoring it as a factor of disease causation. Alternatively when properly understood the homeostasis profile becomes a rational explanation for any individual’s range of health; where some areas are very resistant to disease (resilient) and other areas of homeostasis are dysfunctional leading to minor, moderate or very susceptible tendencies to disease (a lack of resilience in homeostasis). An understanding of this phenomenon, its interactions with gene expression (epigenetics) is necessary in order to evaluate the solutions for acute and chronic diseases. By this method diseases can be defined more precisely as specific susceptibilities in homeostasis, leading to a method to restore specific homeostasis functions.

In this work, we study a boundary control problem for the evolutionary Stokes equations, under mixed boundary conditions, in two and three dimensions. The Stokes equation is a valuable tool in cardiovascular biomechanics, especially for modeling blood flow in low-velocity and high-viscosity conditions. Its application in the microvasculature, the design of medical devices, and the study of cardiovascular diseases helps improve the understanding and treatment of various pathological conditions. We provide a comprehensive theoretical framework to address the analysis and the derivation of a system of first-order optimality conditions that characterizes the solution of the control problem. Finally, solution-finding algorithm is proposed and illustrated with some simulations.

The pathophysiology of many mood disorders is closely related with abnormal stress response associated with the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis and cortisol overproduction. The hippocampus, key structure of the limbic system responsible for both cognitive and emotional spheres, is selectively vulnerable to excess of glucocorticoids (GCs) inducing neuroinflammation and neurodegeneration. The antiGC therapy of psychiatric diseases, in particular depressive disorders, may be a useful additional treatment. Among other approaches, targeting glucocorticoid receptors, abounded in the hippocampus, is regarded as highly promising. However, though the preclinical data provide firm evidence to the concept of antiGC therapy for stress-related diseases, clinical studies still are at the proof-of-concept stage. Noteworthy, chronic GC excess is associated not only with mood diseases, but also with cognitive decline, metabolic disorders, diabetes. Potentially, antiGC (HPA axis modifying) therapy may alleviate affective symptoms, cognitive disturbances, GC and insulin resistance and adverse side effects of conventional drugs through beneficial effects on hippocampal dysfunction and neurodegeneration, neuroinflammation, and neurogenesis. Since stress/GC-associated neuroinflammation-mediated pathology of the limbic system and, specifically, the hippocampus, is a general feature typical for many brain diseases, the concept of antiGC therapy may be extended, tested and validated in a wider spectrum of cerebral pathologies.

Polycyclic aromatic hydrocarbons (PAHs) have been reported to cause oxidative stress in metabolic processes. This study aimed to evaluate the relationship between exposure to PAHs, including benzo[a]pyrene (BaP) and 1-nitropyrene (1-NP), in the atmosphere and oxidative stress levels in the human body. This study included 44 Korean adults who lived in Cheongju, South Korea. Atmospheric BaP and 1-NP concentrations and urinary 6-hydroxy-1-nitropyrene (6-OHNP), N-acetyl-1-aminopyrene (1-NAAP), and 1-hydroxypyrene (1-OHP) concentrations were measured. The oxidative stress level was assessed by measuring urinary thiobarbituric acid reactive substances (TBARS) and 8-hydroxydeoxyguanosine (8-OHdG) concentrations. Urinary TBARS and 6-OHNP concentrations significantly differed between winter and summer. BaP exposure was significantly associated with urinary 8-OHdG concentrations in summer. However, atmospheric 1-NP did not show a significant correlation with oxidative stress marker concentrations. Urinary 1-NAAP concentration was a significant determinant for urinary 8-OHdG concentration in summer. Oxidative stress in the body increases in proportion to inhalation exposure to BaP, and more 8-OHdG is produced in the body as the amount of 1-NP, which is metabolized to 1-AP or 1-NAAP, increases.

Congenital Disorders of Glycosylation (CDG) are a heterogenous group of primarily autosomal recessive mendelian diseases caused by disruptions in the synthesis of lipid linked oligosaccha-rides and their transfer to proteins. CDGs affect multiple organ systems and vary in presentation, even within families. Here we describe a chemically induced mouse mutant, tvrm76, with early onset photoreceptor degeneration. The recessive mutation was mapped to Chromosome 9 and as-sociated with a missense mutation in the Dpagt1 gene encoding UDP-N-acetyl-D-glucosamine:dolichyl-phosphate N-acetyl-D-glucosaminephosphotransferase (EC 2.7.8.15). The mutation is predicted to cause a substitution of aspartic acid with glycine at residue 166 of DPAGT1. Increased expression of Ddit3, and elevated levels of HSPA5 (BiP) sug-gest the presence of early-onset endoplasmic reticulum (ER) stress. These changes were associated with induction of photoreceptor apoptosis in tvrm76 retinas. Mutations in human DPAGT1 cause Myasthenic Syndrome 13 and severe forms of Congenital Disorder of Glycosylation Type Ij. In contrast, Dpagt1tvrm76 homozygous mice present with congenital photoreceptor degeneration without overt muscle or muscular junction involvement. Our results suggest the possibility of DPAGT1 mutations in human patients that present primarily with retinitis pigmentosa with little or no muscle disease. Variants in DPAGT1 should be considered when evaluating cases of non-syndromic retinal degeneration.

The changing dynamics in climate is the primary and important determinant of agriculture productivity. The effects of this changing climate on overall productivity in agriculture can be understood when we study the effects of individual components contributing to the changing climate on plants and crops. Elevated CO₂ (eCO₂) and drought due to high variability in rainfall is one of the important manifestations of the changing climate. There is a considerable amount of literature that addresses climate effects on plant systems from molecules to ecosystems. Of particular interest is the effect of increased CO₂ on plants in relation to drought and water stress. As it is known that one of the consistent effects of increased CO₂ in the atmosphere is increased photosynthesis, especially in C₃ plants, it will be interesting to know the effect of drought in relation to elevated CO₂. The potential of elevated CO₂ ameliorating the effects of water deficit stress is evident from literature suggesting that these two are agents are brothers in arms protecting the plant from stress rather than partnering in crime, specifically water deficit when in isolation. The possible mechanisms by which this occurs will be discussed in this minireview. Interpreting the effects of short-term and long-term exposure of plants to elevated CO₂ in the context of ameliorating the negative impacts of drought will show us the possible ways by which there can be effective adaption to crops in the changing climate scenario.

Lettuce is a salt-sensitive crop and has a threshold electrical conductivity of 1.3–2.0 mS cm-1 and above that is considered detrimental. As there has been very little information on the physio-logical response of different critical stages of lettuce under different salt stress (SS), the current study is focused on investigating the effects of SS on the critical physiological traits influencing the carbon assimilation in different growth stages of lettuce. The experiment was conducted in deep-water culture hydroponic system in a greenhouse condition. Four levels of sodium chloride salt treatments (EC: 20, 16, 8, and 1.8 mS cm-1) were applied. During both growth stages (day 11 (GS1) and day 19 (GS2) after salt treatment), the leaf transpiration rate, stomatal conductance, and intercellular CO2 were severely decreased. However, the carbon assimilation rate remained unchanged under SS. Similarly, the water use efficiency increased under the SS. It is concluded that the increasing SS increased stomatal and non-stomatal limiting factors during GS1 suggesting the enhanced limitation in photosynthetic activity while no such trend was observed during GS2. The decreased gm with increased SS at GS1 and GS2 suggested that SS induced the irreversible decrease of gm, which in turn can be responsible for the transient reduction in the Vcmax and Jmax during GS2. Taken together, the evidence from this research recommends that varying the SS levels can significantly affect the physiological performance of lettuce at both growth stages.

Studies have shown that aerosols generated from flavored e-cigarettes contain Reactive Oxygen Species (ROS), promoting oxidative stress-induced damage within pulmonary cells. Our lab investigated the ROS content of e-cigarette vapor generated from disposable vape bars, a product exempt from the Federal Drug Enforcement Agency’s (FDA) 2020 flavor ban. Specifically, we analyzed vape bars belonging to multiple flavor categories (Tobacco, Minty Fruit, Fruity, Minty/Menthol, Desserts, and Drinks), manufactured by various vendors and of various nicotine concentrations (0-6.8%). Aerosols from these flavored vape bars were generated by a single puff aerosol generator and individually bubbled through a fluorogenic solution to detect and semi-quantify ROS in H2O2 equivalents generated by the vape bars. We compared and contrasted the ROS levels generated by each flavor as an indirect determinant of oxidative stress potential by these disposable vape bars. Our results showed that ROS concentration (μM) of aerosols produced from the vape bars varied significantly between different flavors and a function of nicotine concentration. Likewise, our results suggest that flavoring chemicals and nicotine concentration play a role in alerting ROS production in e-cigarette aerosols. Our study provides insight into the differential health effects of flavored disposable vape bars and the need for their regulation.

Pandemics caused by viruses have threatened lives of thousands of people. Viral infection is a complex and diverse process, and substantial studies have been complemented in understanding the biochemical and molecular interactions between viruses and hosts. However, the physical microenvironment where infections implement is often less carefully considered, and the role of mechanobiology in viral infection remains elusive. Mechanobiology focuses on sensation, transduction and response to intracellular and extracellular physical factors by tissues, cells and extracellular matrix. The intracellular cytoskeleton and mechanosensors have been proved to be extensively involved in virus life cycle. Furthermore, innovative methods in vivo and in vitro are being utilized to elucidate how extracellular factors including stiffness, forces and topography in regulating viral infection. Our current review covers how physical factors from different sources coordinate virus infection. We further discuss how this knowledge can be harnessed in future research on cross-fields of mechanobiology and virology.

The Covid-19 pandemic has severely tested the mental health of frontline health care workers. A repeated cross-sectional study can provide information on how their mental health evolved during the various phases of the pandemic. The intensivists of a COVID-19 hub hospital in Rome were investigated with a baseline survey during the first wave of the pandemic in April 2020 and were contacted again in December 2020, during the second wave. 152 of the 205 eligible workers responded to an online questionnaire designed to measure procedural justice, occupational stress (effort/reward imbalance), sleep quality, anxiety, depression, burnout, job satisfaction, happiness, and turnover intention. Workers reported a further increase in workload and compassion fatigue, which had already risen during the first wave, and a marked reduction in the time devoted to meditation and mental activities. A low level of confidence in the adequacy of safety procedures and the need to work in isolation, together with an increased workload and lack of time for meditation were the most significant predictors of occupational stress in a stepwise linear regression model. Occupational stress was, in turn, a significant predictor of insomnia, anxiety, low job satisfaction, burnout, and intention to leave the hospital. The number of workers manifesting symptoms of depression increased significantly to exceed 60%. Action to prevent occupational risks and enhance individual resilience cannot be postponed.

Despite the important role that the GH/IGF-I axis plays in vascular homeostasis, these kind of growth factors barely appear in articles addressing the neovascularization process. Currently, the vascular endothelium has turned to be considered as an authentic gland of internal secretion due to the wide variety of released factors and functions with local effect, including the paracrine/autocrine production of GH or IGF-I, for which the endothelium has specific receptors. In this comprehensive review, it will be described the evidence involving these proangiogenic hormones in arteriogenesis dealing with the arterial occlusion and making of them a potential therapy. It will be analyzed all those elements triggering the local and systemic production of GH/IGF-I and their possible role both in physiological and pathological conditions. The whole evidence will be combined with important data from the GHAS trial, in which GH or placebo were administrated to patients suffering from critical limb ischemia with no option for revascularization. We postulate that GH, alone or in combination, should be considered as a promising therapeutic agent for helping in the approach of the ischemic disease.

The pleiotropic biochemical and antioxidant functions of Vitamin C (Vit C) have recently sparked interest in its application in intensive care. Vit C protects important organ systems such as the cardiovascular, neurologic and renal system during inflammation and oxidative stress. Vit C also influences the systems of coagulation and inflammation and its application might prevent the development of organ damage. The current evidence of Vit C’s effect on the pathophysiological reactions during various acute stress events, such as sepsis, shock, trauma, burn and ischemia-reperfusion injury imposes the question, if the application of Vit C might be especially beneficial for cardiac surgery patients, who are routinely exposed to ischemia/reperfusion and subsequent inflammation, systematically affecting different organ systems. This review covers current knowledge about the role of Vit C in cardiac surgery patients with focus on its influence on organ dysfunctions. The relationships between Vit C and clinical health outcomes are reviewed with special emphasis on its application in cardiac surgery. Additionally, this review pragmatically discusses evidence regarding the administration of Vitamin C in every day clinical practice, tackling the issues of safety, monitoring, dosage and most the appropriate application strategy.

The importance of predicting the exposure to environmental hazards is highlighted by issues like global climate change, public health problems caused by environment stresses, and property damages and depreciations. Several approaches have been used to assess potential exposure and achieve optimal results under various conditions, for example, for different scales, groups of people, or certain points in time. Micro-simulation tools are becoming increasingly important in human exposure assessment, where each person is simulated individually and continuously. This paper describes an agent-based model (ABM) framework that can dynamically simulate human exposure levels, along with their daily activities, in urban areas that are characterized by environmental stresses such as air pollution and heat stress. Within the framework, decision making processes can be included for each individual based on rule-based behavior to achieve goals under changing environmental conditions. The ideas described in this paper are implemented in a free and open source NetLogo platform. A simplified modeling scenario of the ABM framework in Hamburg, Germany, further demonstrates its utility in various urban environments and individual activity patterns, and portability to other models, programs and frameworks. The prototype model can potentially be extended to support environmental incidence management by exploring the daily routines of different groups of citizens and compare the effectiveness of different strategies. Further research is needed to fully develop an operational version of the model.

Contact with nature is suggested to be as an important resource for human health and well-being. Stress alleviation and reduction of mental fatigue are main instances of improvement of human health and well-being in contact with nature. Although the term restoration experience in contact with nature has been used repeatedly for concepts of stress alleviation and reduction of mental fatigue, these refer to different sets of theories and research studies. In this paper, by reviewing the nature-health related theories of Biophilia, Stress Recovery Theory, Attention Restoration Theory and Supportive Environment Theory (SET), the similarities and differences between these two concepts have been discussed. Moreover, the measurement approach instruments based on different study methodologies and aims are provided. This paper could provide information for future studies with focus on factors to be of benefit for restoration experience in design and planning of natural landscape environments with the aim of health and well-being development.

This review describes the positive effects of growth hormone on the cardiovascular system. We analyze why the vascular endothelium is a real internal secretion gland, whose inflammation is the first step for developing atherosclerosis, as well as the mechanisms by which GH acts on the vascular endothelium improving its dysfunction. We also report how GH acts on coronary arterial disease and heart failure, and on peripheral arterial disease inducing the generation of new collateral vessels able to bypass a major artery occlusion. We include some preliminary data from a trial in which GH or placebo is given to elder people suffering from critical limb ischemia, showing the effects of the hormone on plasma markers of inflammation, and stating that the administration of GH in short periods of time is safe and effective even in diabetic patients. We also analyze how Klotho may have strong relationships with GH, inducing, after being released from the damaged vascular endothelium, the pituitary secretion of GH to repair the damaged tissue. Lastly, we show how GH induces wound healing by increasing the blood flow to the ischemic tissue. In summary, we postulate that short-time GH administration is useful for treating cardiovascular diseases.

Bare slope instability is a prevalent concern. The root system of, herbaceous vegetation enhances the shear strength of shallow–slope soil. Indoor experiments were conducted on rootless undisturbed soil (RUS) and undisturbed soil with a root system (USRS) using a triaxial compression apparatus to analyze the slope stability of composite soil with a Tagetes erecta root system. Significance tests and correlation analysis of the factors affecting shear performance were conducted using R software. The slope reinforcement, effect by the plant root system was simulated under 24 working conditions using the MIDAS finite element method. The results revealed the influence of the–root content (RC), moisture content (MC), and stress on the shear strength of USRS, the contribution degree, and the variables’ influences on slope stability. Both RUS and USRS exhibited strain hardening during shearing. The internal friction angle (φ) and cohesion (c) of USRS were negatively and positively correlated with the RC and MC (root burial depth), respectively, and a good fit was obtained for the relationship. The maximum deviatoric stress during shear failure was 1.29 times higher for USRS than for RUS. The RC (root depth) was positively correlated with the slope safety coefficient and the slope of the line under different working conditions, whereas the slope gradient was negatively correlated with the slope safety coefficient. The reinforcement effect by the root system resulted in a 13.2% increase in the safety coefficient and improved stability of slopes with a gradient larger than 1.5%. This article investigated the mechanism of the root–soil system and, the effects of different influencing factors on the shear strength of the soil, and slope stability. The findings provide new insights into shallow slope stability in practical slope protection projects.

The evolutionary success of land plants largely relies on their ability to cope with constant environmental fluctuations, which negatively impact their reproductive fitness and trigger adaptational responses to biotic and abiotic stresses. In this challenging scenario, comprehensive research efforts so far aimed at depicting the roles of well-known phytohormones, mainly auxins, along with brassinosteroids, jasmonates, and abscisic acid, although the signaling networks coordinating the crosstalk among them remains vaguely understood. Accordingly, this review focuses on the Arabidopsis Amidase Signature (AS) superfamily members, highlighting the hitherto relatively underappreciated functions of AMIDASE1 (AMI1) and FATTY ACID AMIDE HYDROLASE (FAAH), as crucial coordinators of the growth-defense response trade-off by modulating auxin and ABA homeostasis.

In the seasonally frozen regions, during the grouting of prestressed bridge ducts in low-temperature environments, incompletely cured grout materials undergo volumetric changes due to the freeze-thaw cycling, resulting in structural cracks along the prestressing ducts of the bridge, thereby diminishing the bridge's operational lifespan. To investigate the frost heaving characteristics of grout materials under freeze-thaw cycles and propose potential enhancements, this study was devised to conduct frost heaving stress tests on grout materials. Through this research, we gained insights into how various additives affect the frost heaving stress characteristics of grout materials under freeze-thaw cycles. Incorporating analyses of free water content, setting time, compressive strength, as well as macroscopic examinations such as XRD and SEM, this study delves into the mechanisms for enhancing frost heaving characteristics of grout materials. Furthermore, it proposes a research approach that utilizes multiple admixtures to improve the frost heaving properties of grout materials. Through frost heaving stress tests and other macroscopic experiments, the study investigates the influence of these combined admixtures on frost heaving stress in grout materials and elucidates the underlying improvement mechanisms. The results indicate that reducing the water-cement ratio, incorporating calcium formate, sulfoaluminate cement, air-entraining agents, and carbamide all have a positive impact on mitigating frost heaving stress in grout materials. However, the improvement mechanisms differ, and employing a single measure alone is insufficient to effectively reduce frost heaving stress while meeting performance criteria such as compressive strength, setting time, and flowability. Free water content emerges as a crucial indicator determining the magnitude of frost heaving stress in grout materials, with 11.5% of free water content representing the critical threshold for frost heaving in grout materials. Utilizing composite admixtures can simultaneously decrease free water content, lower the freezing point of free water, and alleviate frost heaving deformation, resulting in more efficient reduction of frost heaving stress. When the admixture content reaches 9.9%, frost heaving stress is eliminated, and the comprehensive performance parameters including compressive strength, setting time, and flowability meet the specified requirements.

Maintenance of integrity and function of the gastric mucosa (GM) requires a high regeneration rate of epithelial cells during the whole life span. The health of the gastric epithelium highly depends on redox homeostasis, antioxidant defense and activity of detoxifying systems within the cells as well as robustness of blood supply. Bioactive products of lipid peroxidation, in particular second messengers of free radicals, the bellwether of which is 4-hydroxynonenal (HNE), are important mediators in physiological adaptive reactions and signaling but they are also thought to be implicated in the pathogenesis of numerous gastric diseases. Molecular mechanisms and consequences of increased production of HNE and its protein adducts in response to stressors during acute and chronic gastric injury are well studied. However, several important issues related to the role of HNE in gastric carcinogenesis, tumor growth and progression, the condition of GM after eradication of Helicobacter pylori, or the relevance of antioxidants for HNE-related redox homeostasis in GM still need more studies and new comprehensive approaches. In this regard, preclinical studies and clinical intervention trials are required, which should also include the use of state-of-the-art analytical techniques such as HNE determination by immunohistochemistry and ELISA as well as modern mass-spectroscopy methods.

Implant-supported-screw-retained prostheses are really popular. Some of the most frequent complications have been mechanical complications. These include abutment screw loosening or even screw fracture. Using an intermediate abutment can offer several advantages. However, little literature has been found regarding how this affects the mechanical behavior of dental restorations. This study focuses on understanding the mechanical behavior of implant-supported restorations with a transepithelial component compared to those with a direct implant-supported restoration. It was carried out by using the Finite Element Method (FEM) and was experi-mentally validated. The results showed that in the case of transepithelial-supported restoration, the prosthetic screw mounted over the transepithelial component suffers higher stress than the one screwed directly to the implant. After applying a cyclic fatigue load, it is experimentally proven that, in the transepithelial-supported restorations, the fuse changes from being the screw that goes to the implant, to being the upper one. As a conclusion we can say that the use of an intermediate abutment in dental restoration not only provides better protection to the rest of the dental restoration but also allows easier repair in the event of a fracture. This can potentially lead to more efficient procedures and improved patient outcomes.

A widely accepted concept is that boys are more susceptible than girls to oxidative stress related complications of prematurity, including bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), and periventricular leukomalacia (PVL). We aimed to quantify the effect size of this male disadvantage by performing a systematic review and meta-analysis of cohort studies exploring the association between sex and complications of prematurity. Risk ratios (RRs) and 95% CIs were calculated by a random-effects model. Of 1365 potentially relevant studies, 41 met the inclusion criteria (625680 infants). Male sex was associated with decreased risk of hypertensive disorders of pregnancy, fetal distress, and C-section, but increased risk of low Apgar score, intubation at birth, respiratory distress, surfactant use, pneumothorax, postnatal steroids, late onset sepsis, any NEC, NEC>stage 1 (RR 1.12, CI 1.06-1.18), any IVH, severe IVH (RR 1.28, CI 1.22-1.34), severe IVH or PVL, any BPD, moderate/severe BPD (RR 1.23, CI 1.18-1.27), severe ROP (RR 1.14, CI 1.07-1.22), and mortality (RR 1.23, CI 1.16-1.30). In conclusion, preterm boys have higher clinical instability and greater need for invasive interventions than preterm girls. This leads to a male disadvantage in mortality and short-term complications of prematurity.

Ascending aorta aneurysm (AsAA) is a complex disease, currently defined an inflammatory disease. In the sporadic form, AsAA has, indeed, a complex physiopathology with a strong inflammatory basis, significantly modulated by genetic variants in innate/inflammatory genes, acting as independent risk factors and as largely evidenced in our recent studies performed during the last 10 years. Based on these premises, here, we want to revise the impact of reactive oxygen species (ROS) and oxidative stress on AsAA pathophysiology and consequently on the onset and progression of sporadic AsAA. This might consent to add other important pieces in the intricate puzzle of the pathophysiology of this disease with the translational aim to identify biomarkers and targets to apply in the complex management of AsAA, by facilitating the AsAA diagnosis currently based only on imaging evaluations, and the treatment exclusively founded on surgery approaches.

Research on healthy ageing shows that lifespan reductions are often caused by mitochondrial dysfunction. Thus, it is very interesting that the deletion of mitochondrial matrix peptidase LonP1 was observed to abolish embryogenesis, while deletion of the mitochondrial matrix peptidase ClpP prolonged survival. To unveil the targets of each enzyme, we documented the global proteome of LonP1^+/- mouse embryonal fibroblasts (MEF), for comparison with ClpP^-/- depletion. Proteomic profiles of LonP1^+/- MEF generated by label-free mass spectrometry were further processed with the STRING webserver Heidelberg for protein interactions. ClpP was previously reported to degrade Eral1 as a chaperone involved in mitoribosome assembly, so ClpP deficiency triggers accumulation of mitoribosomal subunits and inefficient translation. LonP1^+/- MEF also showed Eral1 accumulation, but no systematic effect on mitoribosomal subunits. In contrast to ClpP^-/- profiles, several components of the respiratory complex I membrane arm were accumulated, whereas the upregulation of numerous innate immune defense components was similar. Overall, LonP1 as opposed to ClpP appears to have no effect on translational machinery, instead it shows enhanced respiratory dysfunction; this agrees with reports on the human CODAS syndrome caused by LonP1 mutations.

Stress plays a central role in functioning for all life forms. As humans, we experience stress in a multitude of ways through various types of stimuli. Due to the constancy of stressors in our lives, the nervous system has learned to allosterically adapt to the stimuli, but when the body cannot adapt, chronic stress can have morphological and degenerative impacts on neuroanatomy and cognitive function that may or may not be reversible. This literature review aimed to identify the specific neuroanatomical structures impacted most by the long-term effects of chronic stress and the subsequent relationship the morphological changes had on cognitive function in rodent models. We examined articles published from PubMed, Google Scholar, and Science Direct, while focusing the search on anatomical and neurodegenerative effects associated with chronic stress stimuli. The degenerative effects of various types simulated physiological chronic stress showed the most impact on neurogenesis and neuronal development, brain plasticity, and spatial learning and memory with association to the hippocampus. The hippocampus, amygdala, prefrontal cortex, and hypothalamic-pituitary-adrenal axis (HPA) all had reversible and non-reversible morphological alterations, which also had a direct impact on the brain’s cognitive abilities. While studies regarding chronic stress are still being conducted, future research may be able to further highlight why stressful stimuli can particularly impact these structures and the tangential impacts that it may have on related or adjacent structures.

Reduced autonomic responses have been reported in horses of advanced age, predisposing them to compromised well-being. Maintained physical exertion tends to preserve autonomic function in geriatric horses. However, the impact of structured exercise regimens on autonomic modulation in geriatric horses has yet to be elucidated. A study was conducted to compare the autonomic modulation in geriatric horses with different activity levels: living sedentarily (SEL), retaining unstructured activities (RAT) and practising a structured exercise regimen (SER). The study observed heart rate variability (HRV) and found that the minimum and mean heart rate decreased in SER horses at 10–12 weeks, with no changes in SEL or RAT horses over the study period. Beat-to-beat (RR) intervals showed no differences in SEL horses, temporal fluctuation at 8–10 weeks in RAT horses and an increase at 10–12 weeks in SER horses. HRV was higher in SER than in RAT horses, as well as in SER horses to a lesser extent. Geriatric horses engaging in a structured exercise regimen demonstrated better autonomic regulation, reflecting lower stress than those retaining unstructured activities or living sedentarily. These results carry welfare implications for developing health management in geriatric horses.

Optic nerve disorders encompass a wide spectrum of conditions characterized by the loss of retinal ganglion cells (RGCs) and subsequent degeneration of the optic nerve. The etiology of these disorders can vary significantly, but emerging research highlights the crucial role of oxidative stress, an imbalance in the redox status characterized by an excess of reactive oxygen species (ROS), in driving cell death through apoptosis, autophagy, and inflammation. This review provides an overview of ROS-related processes underlying four extensively studied optic nerve diseases: glaucoma, Leber's hereditary optic neuropathy (LHON), anterior ischemic optic neuropathy (AION), and optic neuritis (ON). Furthermore, we present preclinical findings on antioxidants, with the objective of evaluating the potential therapeutic benefits of targeting oxidative stress in the treatment of optic neuropathies.

A unified critical state model has been developed for both clean sand and silty sand using the modified Cam-clay model (MCC). The main feature of the proposed model is a new critical state line equation in the e-ln(p) plane that is capable of handling both straight and curved test results. With this feature, the error in calculating plastic volumetric strain is eliminated in theory. Another crucial feature of the model is the transformed stress tensor based on the SMP (spatially mobilized plane) criterion, which takes into account the proper shear yield and failure of soil under three-dimensional stresses. Additionally, the proposed model applies the intergranular void ratio with the fines influence factor for silty sand. Only eight soil parameters are required for clean sand, and a total number of twelve soil parameters are needed for silty sand.

The APOE locus has garnered significant clinical interest because of its association with Alzheimer's disease (AD) and longevity. This genetic association appears across multiple genes in the APOE locus. Despite the apparent differences between AD and longevity, both conditions share a commonality of aging-related changes in mitochondrial function. This commonality is likely due to accumulative biological effects, partly exerted by the APOE locus. In this study, we investigated changes in mitochondrial structure/function-related markers using oxidative stress-induced human cellular models and postmortem brains (PMBs) from individuals with AD and normal controls. Our results reveal a range of expressional alterations, either up- or down-regulated, in these genes in response to oxidative stress. In contrast, we consistently observed an upregulation of multiple APOE locus genes in all cellular models and AD PMBs. Additionally, the effects of AD status on mitochondrial DNA copy number (mtDNA CN) varied depending on APOE genotype. Our findings imply a potential coregulation of APOE locus genes, possibly occurring within the same topologically associating domain (TAD) of the 3D chromosome conformation. The coordinated expression of APOE locus genes could impact mitochondrial function, contributing to the development of AD or longevity. Our study underscores the significant role of the APOE locus in modulating mitochondrial function and provides valuable insights into the underlying mechanisms of AD and aging, emphasizing the importance of this locus in clinical research.

Shot peening has become a well-established technique for the introduction of beneficial compressive Residual Stresses (RS) into the near-surface layers of metallic materials for the purpose of preventing or suppressing fatigue crack nucleation and growth. Ti-alloys are widely used to fabricate compressor blades of aeroengines. Titanium blades that may be susceptible to different modes of damage under cyclic loading (high cycle fatigue, fretting fatigue) are often subjected to shot peening to extend their safe operating time. The control and monitoring of residual stresses in titanium blades is of great importance to assure the safety of aeroengines. The techniques for residual stress evaluation include mechanical methods (material removal) as well as physical methods such as X-ray diffraction. Perhaps the most common and practically accessible form of the latter is the method. Conventional laboratory X-ray diffractometers typically probe samples to the depths up to ~20 µm that correspond to 1x...5x the average grain size for typical metals and alloys. The limitations of the method have been identified and reviewed in the literature, motivating the use of other semi-destructive approaches to evaluate the residual stresses in deeper layers and at more sharply defined locations. In the present report we present a case study of the comparison between non-destructive and semi-destructive evaluation techniques, namely the X-ray diffraction method against the mechanical and FIB-DIC ring-core drilling applied to the samples of VT6 (Russian designation of Ti-6Al-4V) titanium alloy after shot peening with 1 mm steel balls. Mechanical drilling of circular holes of ~2 mm diameter with laser speckle interferometry monitoring of strains gives a rough spatial resolution of a few millimeters, while the Korsunsky FIB-DIC method of Ga-ion beam micro-ring core milling within FIB-SEM with Digital Image Correlation (DIC) deformation analysis delivers spatial resolution down to a few micrometers. Good agreement has been found between the X-ray and FIB-DIC estimates of RS variation profiles as a function of depth in shot peened titanium alloy samples. Some advances in the FIB-DIC method are presented and discussed in terms of the acceleration of data acquisition and interpretation.

SLM Additive Manufacturing has demonstrated great potential for aerospace applications when structural elements of individual design and/or complex shape need to be promptly supplied. 3D-printable AlSi10Mg (RS-300) alloy is widely used for the fabrication of different structures in aerospace industry. The importance of the evaluation of residual stresses that arise as a result of complex 3D-printing process thermal history is widely discussed in literature, but systematic assessment remains lacking for their magnitude, spatial distribution, and comparative analysis of different evaluation techniques. In this study we report the results of a systematic study of residual stresses in a 3D-printed double tower shaped samples using several approaches: the contour method, blind hole drilling laser speckle interferometry, X-ray diffraction, and Xe pFIB-DIC micro-ring-core milling analysis. We show that a high level of tensile and compressive residual stresses is inherited from SLM 3D-printing and retained for longer than 6 months. The stresses vary over a significant proportion of the material yield stress. All residual stress evaluation techniques considered returned comparable values of residual stresses even regardless of dramatically different dimensional scales from millimeters for the Contour Method down, laser speckle interferometry and XRD and down to small fractions of a mm (70 μm) for Xe pFIB-DIC ring-core drilling. The use of residual stress evaluation is discussed in the context of optimizing the printing strategy to enhance the mechanical performance and long-term durability.

The effect of stress on task performance is complex, too much or too little negatively affects performance; and there exists an optimal level of stress to drive optimal performance. Task difficulty and external affective factors are distinct stressors that impact cognitive performance. Neuroimaging studies showed that mood affects working memory performance and the correlates are changes in haemodynamic activity in the prefrontal cortex (PFC). We investigate the interactive effects of affective states and working memory load (WML) on working memory task performance and haemodynamic activity using functional near-infrared spectroscopy (fNIRS) neuroimaging on the PFC of healthy participants. We seek to understand if haemodynamic responses could tell apart workload related stress from situational stress arising from external affective distraction. We found that the haemodynamic changes towards affective stressor and workload related stress were more dominant in the medial and lateral PFC respectively. Our study reveals distinct affective state-dependent modulations of haemodynamic activity with increasing WML in n-back tasks, which correlate with decreasing performance. The influence of negative affect on performance is greater at higher WML, and haemodynamic activity showed evident changes in temporal, and both spatial and strength of activation differently with WML.

Natural products have a significant role in the development of new drugs, being relevant the pentacyclic triterpenes extracted from Olea europaea. Anticancer effect of uvaol, a natural triterpene, has been scarcely studied. The aim of this study was to understand the anticancer mechanism of uvaol in HepG2 cell line. Cytotoxicity results showed a selectivity effect of uvaol with higher influence in HepG2 than WRL68 cells used as control. Uvaol presented anti-migratory capacity in HepG2, supported by the morphological changes and higher HSP-60 expression. This compound also induced arrest in G0/G1 phase and an increase in apoptosis rate. These results are supported by decreased Bcl-2 expression and down-regulation of AKT/PI3K signaling pathway. A reduction in reactive oxygen species levels in HepG2 cells was observed. Altogether, results showed anti-proliferative and pro-apoptotic effect of uvaol on hepatocellular carcinoma, constituting an interesting challenge in the development of new treatments against this type of cancer.

The present study aimed to analyze novel mechanisms underlying Nrf2-mediated anti-apoptosis in periodontal ligament stem cells (PDLSCs) in the periodontitis oxidative microenvironment. We created an oxidative stress model with H2O2-treated PDLSCs. Herein, we used real-time PCR, western blotting, TUNEL staining, fluorogenic assay and transfer genetics to confirm the degree of oxidative stress and apoptosis as well as the Nrf2 function. Surprisingly, we demonstrated that with up-regulated ROS and MDA levels, the effect of oxidative stress was obvious under H2O2 treatment. Anti-oxidative molecules were changed after the H2O2 exposure, whereby the anti-oxidative signaling of Nrf2 was activated with the increase of its downstream effectors, HO-1, NQO1 and γ-GCS. Additionally, the apoptosis levels gradually increased with oxidative stress and changes in the caspase-9, caspase-3, Bax and c-Fos levels, but not with caspase-8 and down-regulated Bcl-2. The enhanced antioxidant effect could not resist the occurrence of apoptosis. Furthermore, Nrf2 overexpression effectively improved the anti-oxidative levels and increased cell proliferation. At the same time, overexpression effectively restrained TUNEL staining and decreased the molecular levels of caspase-9, caspase-3, et al, but not that of caspase-8. By contrast, silencing the expression Nrf2 levels had the opposite effect. Collectively, Nrf2 alleviates PDLSCs via its effects on anti-oxidative and anti-intrinsic apoptosis by the activation of anti-oxidative enzymes.

Compressive residual stresses in thin films can inhibit crack propagation under normal or sliding contact loading, with associated enhancement of the coating apparent toughness, load bearing capacity and wear resistance. This study investigates the influence of residual stress distributions on the thin film/substrate adhesion using a nanoindenter coupled with scanning electron microscope (SEM) investigations of indentation induced failure modes. Reactive and un-reactive magnetron sputtering with ion plating was used to coat a (100) silicon substrate with aluminum nitride (AlN) with and without an aluminum (Al) adhesion layer. The presence of an Al bond layer gives additional interfacial tensile stress because of the difference in thermal expansion coefficient. Additionally, a different magnitude of residual stresses in the AlN coating was achieved by changing the applied bias voltage onto the substrate. Wafer curvature method and incremental focused ion beam (FIB) milling, combined with high-resolution in situ scanning electron microscopy (SEM) imaging and full field strain analysis by digital image correlation (DIC), were used to measure the average and in-depth stress residual stress distribution in the produced coatings. The adhesion energy was then quantified by using a nanoindentation based model. Results demonstrate that the additional tensile residual stress in the aluminum adhesion layer decrease significantly the coating adhesion, even in presence of a higher compressive stress state in the AlN top-layer. Therefore, the coatings without Al-layer showed better adhesion because of a more homogeneous compressive residual stress in comparison with the coating having Al layer, even though both groups of coatings are produced under same bias voltage. Results are discussed, and some general suggestions are made on the correlation between coating/substrate property combination and the adhesion energy of multilayer stacks. The results suggested that Al bond-layer and inhomogeneous residual stresses affected the adhesion of AlN negatively to a substrate like silicon.

Reef-dwelling calcifiers face numerous environmental stresses associated with anthropogenic carbon dioxide emissions, including ocean acidification and warming. Photosymbiont-bearing calcifiers, such as large benthic foraminifera, are particularly sensitive. To gain insight into their resistance and adaptive mechanisms to climate change, Amphistegina lobifera from the Gulf of Aqaba were cultured under elevated pCO2 (492, 963, and 3182 ppm) fully-crossed with elevated temperature (28°C and 31°C) for two months. Differential protein abundances in host and photosymbionts amongst treatments were investigated alongside physiological responses and microenvironmental pH variations. Over 1000 proteins were identified, of which one-third varied significantly between treatments. Thermal stress induced protein depletions, along with reduced holobiont growth. Elevated pCO2 caused only minor proteomic alterations and color changes. However, combined stressors reduced pore sizes and increased microenvironmental pH, indicating adaptive modifications to gas exchange. Notably, substantial proteomic variations at moderate-pCO2 and 31°C indicate cellular stress, while stable physiological performance at high-pCO2 and 31°C is scrutinized by putative decreases in test stability. Our experiment shows that the effects of climate change can be missed when stressors are assessed in isolation, and that physiological responses should be assessed across organismal levels to make more realistic predictions for the fate of reef calcifiers.

Protein glycation is usually referred to as an array of non-enzymatic post-translational modifications, formed by reducing sugars and carbonyl products of their degradation. Resulting advanced glycation end products (AGEs) represent a heterogeneous group of covalent adducts, known for their pro-inflammatory effects in mammals, and impacting on pathogenesis of metabolic diseases and ageing. In plants, AGEs are the markers of tissue ageing and response to environmental stressors, the most prominent of which is drought. Although water deficit enhances protein glycation in leaves, its effect on seed glycation profiles is still unknown. Moreover, the effect of drought on biological activities of seed protein in mammalian systems is still unstudied in respect of glycation. Therefore, here we address the effects of a short-term drought on the patterns of seed protein-bound AGEs and accompanying alterations in pro-inflammatory properties of seed protein in the context of seed metabolome dynamics. A short-term drought, simulated as polyethylene glycol-induced osmotic stress and applied at the stage of seed filling, resulted in dramatic suppression of primary seed metabolism, although secondary metabolome was minimally affected. This was accompanied with significant suppression of NF-kB activation in human SH-SY5Y neuroblastoma cells after a treatment with protein hydrolyzates, isolated from the mature seeds of drought-treated plants. This effect could not be attributed to formation of known AGEs. Most likely, the prospective anti-inflammatory effect of short-term drought is related to antioxidant effect of unknown secondary metabolite protein adducts, or down-regulation of unknown plant-specific AGEs due to suppression of energy metabolism during seed filling.

Healthcare workers' stress, burnout, and job dissatisfaction were exacerbated by the Covid-19 pandemic, whose mid-term negative effects are still present. The aim of this study was to investigate in healthcare workers the effect of the dimensions of burnout (Psychophysical exhaustion, Relational deterioration, and Professional inefficacy) on Career satisfaction. These relationships were evaluated by considering the direct and mediated effects of Disillusion. For these purposes, the Link Burnout Questionnaire (LBQ) and the Career Satisfaction Scale (Occupational Stress Indicator - OSI) were administered to 295 healthcare professionals working at three Italian public hospitals in Cagliari, Italy. The analyses were conducted using the Partial Least Square Structural Equation Model (PLS-SEM) method. Findings highlight that healthcare workers were in a condition of work distress, high risk of burnout, and career dissatisfaction. Also recognized was the direct negative effect of burnout dimensions on career satisfaction. Finally, the mediated negative effect of Disillusion in the relationship between burnout and career satisfaction was identified. This study emphasizes the relevance of the dimension of Disillusion, and its “bright side” Fulfilment, in healthcare workers, specifically referring to the disregarded relationship between burnout and career satisfaction.

In the face of climate change, bringing more useful alleles and genes from wild relatives of wheat is crucial to develop climate-resilience varieties. We used two populations of backcrossed recombinant inbred lines (BIL1 and BIL2), developed using two intra-specifically diverse Aegilops tauschii accessions from lineage 1 and lineage 2, respectively, and backcrossing to common wheat cultivar ‘Norin 61’. The study aimed to identify quantitative trait loci (QTL) associated with heat stress (HS) tolerance. The two BILs were evaluated under heat stress environments in Sudan for phenology, plant height (PH), grain yield (GY), biomass (BIO), harvest index (HI), and thousand kernel weight (TKW). Grain yield was significantly correlated with BIO and TKW under HS; therefore, stress tolerance index (STI) was calculated for these traits as well as for GY. A total of 16 heat tolerant lines were identified based on GY and STI-GY. The QTL analysis performed using inclusive composite interval mapping identified a total of 40 QTLs in BIL1 and 153 QTLs in BIL2 across all environments. We detected 39 QTLs associated with GY-STI, BIO-STI, and TKW-STI in both populations (14 in BIL1 and 25 in BIL2). The QTL associated with STI were detected on chromosomes 1A, 3A, 5A, 2B, 4B, and all the D-subgenomes. We found that QTL detected only under HS for GY on chromosome 5A, TKW on 3B and 5B, PH on 3B and 4B, and grain filling duration on 2B. The higher number of QTLs identified in BIL2 for heat stress tolerance suggests the importance of assessing the effects of intraspecific variation of Ae. tauschii in wheat breeding as it could modulate the heat stress responses/adaptation. Our study provides useful genetic resources for uncovering heat-tolerant QTLs for wheat improvement for heat stress environments.

8-oxoguanine glycosylase 1 (OGG1), which was initially identified as the enzyme that catalyzes the first step in the DNA base excision repair pathway, is now known also as a modulator of gene expression. What is important for cancer, is that OGG1 acts as a modulator of NFκB-driven gene expression. Specifically, oxidant stress in the cell transiently halts the enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, including NFκB, to their cognate sites to enable expression of cytokines and chemokines, with ensuing recruitment of inflammatory cells. Recently, we highlighted chief aspects of OGG1 involvement in regulation of gene expression, which have a significance in lung cancer development. However, OGG1 has also been implicated in the molecular underpinning of acute myeloid leukemia. In general, the capacity of cancer cells to adapt to oxidative stress depends on molecular systems such as the interface of OGG1 with NFκB, which bestows a cancer cell with the molecular mechanism of transformation of its microenvironment to enable adaptation and survival of malignant clones.

Understanding the energy metabolism and its regulation is one of the clues to metabolic engineering of stress-resistant lignocellulose-converting microbial strains, including also the promising ethanologen Zymomonas mobilis. Z. mobilis is an obligately fermentative, facultatively anaerobic bacterium, carrying an active respiratory chain with a low energy-coupling efficiency. Its respiration does not supply energy to aerobically growing culture on sugary media, yet oxidative phosphorylation has been demonstrated in non-growing cells with ethanol. In the present work we show that in respiring, non-growing Z. mobilis cells, receiving regular small amounts of ethanol, oxidative phosphorylation significantly contributes to the maintenance of their viability. Accordingly, no improvement of viability is seen in the NADH dehydrogenase (ndh)-deficient respiratory mutant, unable to oxidize ethanol. The ethanol effect is hampered also by the protonophoric uncoupler CCCP, or the inhibitor of ATP synthase, DCCD. At higher concentrations (6% v/v) ethanol causes stress that slows down culture growth. By monitoring the activity of several respiratory gene promoters in aerobically growing culture under ethanol stress with the green fluorescent protein reporter system, we demonstrate downregulation of these promoters, in particular the ndh promoter. We speculate that the decrease of the respiratory chain activity mitigates the production of reactive oxygen species.

Cryopreserved semen is widely used in Assisted Reproductive Technologies (ART) enabling the conservation and broad use of genetically superior semen. The quality of semen post-thawing determines the success of ART and despite the great advances in cryopreservation methods, the quality of frozen/thawed semen is still sub-optimal. Post-thawing spermatozoa endure oxidative stress (OS) due to the high levels of reactive oxygen and nitrogen species, which are produced during the freezing/thawing process, and the depletion of antioxidants. To counteract this depletion, supplementation of sperm preparation medium with antioxidants has been widely applied. Melatonin is a hormone with diverse biological roles and a potent antioxidant, with an ameliorative effect on spermatozoa. In the present study, the effect of melatonin on bovine spermatozoa was evaluated during in vitro sperm handling and under oxidative conditions in terms of sperm quality parameters and antioxidant capacity. Melatonin (100 μΜ) improved the kinematic parameters of spermatozoa, enhanced viability and reinforced the antioxidant status of spermatozoa by increasing cellular GSH levels and inhibiting iNOS protein expression.

There is an increasing interest in biomarkers of nitric oxide dysregulation and oxidative stress to guide management and identify new therapeutic targets in patients with chronic obstructive pulmonary disease (COPD). We conducted a systematic review and meta-analysis of the association between circulating metabolites within the arginine (arginine, citrulline, ornithine, asymmetric, ADMA, and symmetric, SDMA dimethylarginine), transsulfuration (methionine, homocysteine, and cysteine) and folic acid (folic acid, vitamin B6, and vitamin B12) metabolic pathways and COPD. We searched electronic databases from inception to 30 June 2023 and assessed the risk of bias and the certainty of evidence. In 21 eligible studies, compared to healthy controls, patients with stable COPD had significantly lower methionine (standardized mean difference, SMD=-0.50, 95% CI -0.95 to -0.05, p=0.029) and folic acid (SMD=-0.37, 95% CI -0.65 to -0.09, p=0.009), and higher homocysteine (SMD=0.78, 95% CI 0.48 to 1.07, p˂0.001) and cysteine concentrations (SMD=0.34, 95% CI 0.02 to 0.66, p=0.038). Additionally, COPD was associated with significantly higher ADMA (SMD=1.27, 95% CI 0.08 to 2.46, p=0.037), SDMA (SMD=3.94, 95% CI 0.79 to 7.08, p=0.014), and ornithine concentrations (SMD=0.67, 95% CI 0.13 to 1.22, p=0.015). In subgroup analysis, the SMD of homocysteine was significantly associated with the biological matrix assessed and the forced expiratory volume in the first second to forced vital capacity ratio, but not with age, study location, or analytical method used. Our study suggests the presence of significant alterations in metabolites within the arginine, transsulfuration, and folic acid pathways which can be useful for assessing nitric oxide dysregulation and oxidative stress and identifying novel treatment targets in COPD. (PROSPERO registration number: CRD42023448036)

Transcription factors are diverse intracellular proteins facilitating cellular responses to inducing factors via gene expression. Regulatory signalling cascades from the membrane proteins (sensors) to transcription factors (effectors) are paramount to accurate phenotypic display against external factors. This review examines several transcription factors germane to Cryptococcus (C.) neoformans adaptation and survival for human infection. These opportunistic pathogenic single-cell yeasts (fungi) possess several gene duplications and peculiar membrane proteins due to adaptive phenotypes and morphological plasticity. Consequently, hundreds of responsible pleiotropic genes have been studied to understand how these genes are induced, regulated, and coordinated. However, these findings are sparsely converged and interlinked, making it cumbersome to relate one gene to the other or group them by their functions. We reviewed several wide-ranging transcriptional analysis works associated with C. neoformans into comparable phenotypic traits that necessitate adaptation, survival, and human infection. We present a robust work that addresses several transcription factors and their inducing factors. Lastly, we converge, link, and group several of these factors according to their multifunctional expression pattern. We also provide adequate information on certain genes critical to this fungus, which could be explored pharmaceutically in drug targeting for more effective antifungal management.

Climate change may cause organisms to seek thermal refuge from rising temperatures, either by shifting their ranges or seeking microrefugia within their existing ranges. We evaluate the potential for thermal stratification to provide refuge for two fish species in the San Francisco Estuary (SFE): Chinook Salmon (Oncorhynchus tshawytscha) and Delta Smelt (Hypomesus transpacificus). We compiled water temperature data from multiple monitoring programs to evaluate spatial, daily, hourly, intra-annual, and inter-annual trends in stratification using generalized additive models. We used our data and models to predict the locations and periods of time that the bottom of the water column could function as thermal refuge for salmon and smelt. Periods in which the bottom was cooler than surface primarily occurred during the peak of summer and during the afternoons, with more prominent stratification during warmer years. Although the SFE is often exceedingly warm for fish species and well-mixed overall, we identified potential for thermal refugia in a long and deep terminal channel for Delta Smelt, and in the periods bordering summer for Chinook Salmon. Thermal stratification may increase as the climate warms, and pockets of cooler water at depth, though limited, may become more important for at-risk fishes in the future.

Rates of gestational cannabis use have increased despite limited evidence for its safety in fetal life. Recent animal studies demonstrate that prenatal exposure to 9-tetrahydrocannabinol (9-THC, the psychoactive component of cannabis) promotes intrauterine growth restriction (IUGR), culminating in postnatal metabolic deficits. Given IUGR is associated with impaired hepatic function, we hypothesized that 9-THC offspring would exhibit hepatic dyslipidemia. Pregnant Wistar rat dams received daily injections of vehicular control or 3 mg/kg 9-THC i.p. from embryonic day (E) 6.5 through E22. Exposure to 9-THC decreased the liver to body weight ratio at birth, followed by catch-up growth by three weeks of age. At six months, 9-THC-exposed male offspring exhibited increased visceral adiposity and higher hepatic triglycerides. This was instigated by augmented expression of enzymes involved in triglyceride synthesis (ACC, SCD, FABP1, and DGAT2) at three weeks. Furthermore, the expression of hepatic DGAT1/DGAT2 was sustained at six months, concomitant with mitochondrial dysfunction (i.e., elevated p66shc) and oxidative stress. Interestingly, decreases in miR-203a-3p and miR-29a/b/c, both implicated in dyslipidemia, was also observed in these 9-THC-exposed offspring. Collectively, these findings indicate that prenatal 9-THC exposure results in long-term dyslipidemia associated with enhanced hepatic lipogenesis. This is attributed by mitochondrial dysfunction and epigenetic mechanisms.

Plant diseases cause losses of approximately 16% globally. Thus, management measures must be implemented to mitigate losses and guarantee food production. In addition to traditional management measures, resistance induction and biological control have gained ground in agriculture due to their enormous potential. Endophytic fungi colonize plant tissues internally and have the potential to act as biological control agents, as elicitors in the process of resistance induction and in attenuating abiotic stresses. In this review, we list the action of this group of microorganisms as potential agents which can act in controlling plant diseases and describe several examples in which endophytes were able to reduce the damage caused by pathogens and adverse conditions. This is due to their arsenal of molecules generated during the interaction by which they form a kind of biological shield in the plant. Studies on these microorganisms have grown due to the existing diversity and the multiple benefits they can offer. Finally, considering that endophytic fungi can be an important tool in managing diseases due to the large amount of biologically active substances produced, bioprospecting this class of microorganisms is tending to increase and generate valuable products.

Almond (Prunus dulcis (Mill.) D.A.Webb) is one of the largest nut crops in the world. Recently, phenolic compounds, mostly stored in almond skin, have been associated with much of the health-promoting behavior associated with their intake. The almond skin enriched fraction obtained from cold-pressed oil residues of the endemic Moroccan Beldi ecotypes is particularly rich in chlorogenic acid. In this study, both almond skin extract (AE) and chlorogenic acid (CHL) supplements, similar to traditional positive control resveratrol, significantly increased the replicative life-span of yeast compared to the untreated group. Our results showed that AE and CHL significantly reduced the production of reactive oxygen and nitrogen species (ROS/RNS), most likely due to their ability to maintain mitochondrial function during aging, as indicated by the maintenance of normal mitochondrial membrane potential in treated groups. This may be associated with the observed activation of the anti-oxidative stress response in treated yeast, which results in activation at both gene expression and enzymatic activity levels for SOD2 and SIR2, the latter being an upstream inducer of SOD2 expression. Interestingly, the differential gene expression induction of mitochondrial SOD2 gene at the expense of the cytosolic SOD1 gene confirms the key role of mitochondrial function in this regulation. Furthermore, AE and CHL have contributed to the survival of yeast under UV-C-induced oxidative stress, by reducing the development of ROS / RNS, resulting in a significant reduction in cellular oxidative damage as evidenced by decreased membrane lipid peroxidation, protein carbonyl content and 8-oxo-guanine formation in DNA. Together, these results demonstrate the interest of AE and CHL as new regulators in the replicative life-span and control of the oxidative stress response of yeast.

Pneumonia is a severe lower respiratory tract infection that is a common complication and a major cause of mortality of the vitamin C-deficiency disease scurvy. This suggests an important link between vitamin C status and lower respiratory tract infections. Due to the paucity of information on the vitamin C status of patients with pneumonia, we assessed the vitamin C status of 50 patients with community-acquired pneumonia and compared these with 50 healthy community controls. The pneumonia cohort comprised 44 patients recruited through the Acute Medical Assessment Unit (AMAU) and 6 patients recruited through the intensive care unit (ICU); mean age 68 ± 17 years, 54% male. Clinical, microbiological and haematological parameters were recorded. Blood samples were tested for vitamin C status using HPLC with electrochemical detection and protein carbonyl concentrations, a marker of oxidative stress, using ELISA. Patients with pneumonia had depleted vitamin C status compared with healthy controls (23 ± 14 µmol/L vs 56 ± 24 µmol/L, P <0.001). The more severe patients in the ICU had significantly lower vitamin C status than those recruited through AMAU (11 ± 3 µmol/L vs 24 ± 14 µmol/L, P = 0.02). The total pneumonia cohort comprised 62% with hypovitaminosis C and 22% with deficiency, compared with only 8% hypovitaminosis C and no cases of deficiency in the healthy controls. The pneumonia cohort also exhibited significantly elevated protein carbonyl concentrations compared with the healthy controls (P < 0.001), indicating enhanced oxidative stress in the patients. We were able to collect subsequent samples form 28% of the cohort (mean 2.7 ± 1.7 days; range 1-7 days). These showed no significant differences in vitamin C status or protein carbonyl concentrations compared with baseline values (P = 0.6). Overall, the depleted vitamin C status and elevated oxidative stress observed in the patients with pneumonia indicates an enhanced requirement for the vitamin during their illness. Due to the important roles that vitamin C plays in the immune system, low vitamin C status is possibly both a cause and a consequence of the disease. Therefore, these patients would likely benefit from additional vitamin C supplementation to restore their blood and tissue levels to optimal. This may decrease oxidative stress and aid in their recovery.

We conducted many model simulations to understand the causes of the damages of coronavirus (COVID-19) to lung tissue and constructed a diagram showing apparent viral reproduction, immune response and damage accumulation curves. We found that lung damages include virus-caused damage, tissue damage caused by immune responses and tissue damage caused by accumulated wastes. The virus-caused damage is proportional to the phase lag between the viral reproduction curve and the delayed adaptive immune response curve, while waste-induced damage is attributed to imbalance in removing viral, cellular and metabolic by-products. We found that treatment strategies should slow down viral reproduction and speed up immune response, and improve blood micro-circulation in the lungs. Consistent with the strategies, measures are taken to void direct lung infection, strengthen innate responses, promote immune responses, dilute viral concentration in lung tissue, maintain waste removal balance, protect heart and kidneys, control other infections, avoid allergic reactions and other inflammation, etc. We show that medical, dietary, emotional, lifestyle, environmental, mechanical factors, etc. may be simultaneously used to mitigate lung damages and prove that multiple factor health optimization method is magnitudes more powerful than a single factor treatment. Such a method does not depend on molecular specificity and can be used in parallel to antiviral drugs.

The burdens of malnutrition, protein and micronutrient deficiency, and obesity cause enormous costs to society. Crop nutritional quality has been compromised by the emphasis on edible yield and through the loss of biodiversity due to the introduction of high-yielding uniform cultivars. Heirloom crop cultivars are traditional cultivars grown for a long time (> 50 years), and whose heritage has been preserved by regional, ethnic or family groups. Heirlooms are recognized for their unique appearance, names, uses and historical significance. They are gaining in popularity because of their unique flavors and cultural significance to local cuisine, and their role in sustainable food production for small-scale farmers. As a contrast to modern cultivars, heirlooms may offer a welcome alternative in certain markets. Recently, market channels have emerged for heirloom cultivars in the form of farmer-breeder-chef collaborations and seed savers organizations. There is therefore urgent need to know more about the traits available in heirloom cultivars, particularly for productivity, stress tolerance, proximate composition, sensory quality and flavor. This information is scattered and the intention of this review is to document some of the unique characteristics of heirloom cultivars that may be channeled into breeding programs for developing locally adapted high value cultivars.

Fixed offshore wind turbines continue to be developed for high latitude areas where not only wind and wave loads need to be considered, but also moving sea ice. Current rules and regulations for the design of fixed offshore structures in ice-covered waters do not adequately consider effects of ice loading and its stochastic nature on fatigue life of the structure. Ice crushing on such structures results in ice-induced vibrations, which can be represented by loading the structure using a variable-amplitude loading (VAL) sequence. Typical offshore load spectra are developed for wave and wind loading. Thus, a combined VAL spectrum is developed for wind, wave, and ice action. To this goal, numerical models are used to simulate the dynamic ice-, wind-, and wave-structure interaction. The stress time-history at an exemplarily selected critical point in an offshore wind energy monopile support structure is extracted from the model and translated into a VAL sequence, which can then be used as a loading sequence for the fatigue assessment or fatigue testing of welded joints of offshore wind turbine support structures. This study presents the approach to determine combined load spectra and standardized time series for wind, wave, and ice action.

Background: Fullerenes and metallofullerenes can be considered promising nanopharmaceuticals themselves and as a basis for chemical modification. As reactive oxygen species homeostasis plays a vital role in cells, the study of their effect on genes involved in oxidative stress and anti-inflammatory response is of particular importance. Methods: Human fetal lung fibroblasts were incubated with aqueous dispersions of C60, C70, and Gd@C82 in concentrations of 5 nM and 1.5 µM for 1, 3, 24, and 72 hours. Cell viability, intracellular ROS, NOX4, NFκB, PRAR-γ, NRF2, heme oxygenase 1, and NAD(P)H quinone dehydrogenase 1 expression have been studied. Results &amp; conclusion: The aqueous dispersions of C60, C70, and Gd@C82 fullerenes are active participants in ROS homeostasis. Low and high concentrations of AFDs have similar effects. C70 was the most inert substance, C60 was the most active substance. All AFDs have both a “prooxidant” and “antioxidant” effect, but with a different balance. Gd@C82 was a substance with more pronounced antioxidant and anti-inflammatory properties, while C70 had more pronounced “prooxidant” properties.

Study Objective: This study examined office workstation types’ impact on objective health-related metrics including stress, physical activity (PA), and sleep quality. We propose a sensor-based sleep quality index (SB-SQI) to fill a needed gap for objective sleep quality measurement over short timescales. Methods: We monitored 231 office workers using chest-worn sensors for 72 hours, yielding 11,736 hours of usable data from 163 participants (mean age 43.4, 56% women). SB-SQI was based on a validated algorithm estimating sleep-onset latency, total sleep time, and sleep efficiency, using the scoring method from the Pittsburg Sleep Quality Index (PSQI). We examined the relationships between SB-SQI, office workstation type (open-bench seating, cubicle, and private office), work-hours stress (standard deviation of heart rate variability), and after-work PA (relative duration of moderate-to-vigorous activity). Results: The sensor-derived poor-sleep ratio of the private office workers was higher than with other office workstation types (81% vs. 66.1%, p = 0.023). PSQI revealed a similar but insignificant trend with a lower effect-size. Among good-sleepers, open-bench seating workers had 22% (p = 0.018) less stress during work hours than others. A significant association between work-hours stress and after-work hours PA (r = 0.331, p = 0.000) was observed irrespective of office workstation type, with the highest PA level observed for open-bench seating workers. Conclusions: Office workstation type had a significant impact on work-hours stress, affecting PA after work hours, which influenced sleep quality. SB-SQI could be more sensitive than PSQI in determining the impact of office workstation types on sleep quality.

Extracellular vesicles (EVs), such as exosomes or oncosomes are released with molecules unfavorable for survival from cells. In addition, accumulating evidence has shown that tumor cells often eject anti-cancer drugs such as chemotherapeutics and targeted drugs within EVs, a novel mechanism of drug resistance. The EV-releasing, drug resistance phenotype is often coupled with cellular dedifferentiation and transformation, cells undergoing epithelial-mesenchymal transition (EMT) and taking on a cancer stem cell phenotype. Recent studies have shown that the release of EVs is also involved in immunosuppression. The concept of the resistance-associated secretory phenotype (RASP) is reviewed herein.

This paper presents an approach to the two-dimensional analysis of elastic isotropic deep beams using the finite difference method (FDM). Deep beams are subjected to in-plane loading and present a shear span to height ratio of less than 2.50; consequently, Euler-Bernoulli beam theory and Timoshenko beam theory do not apply. Deep beams analysis is generally conducted using numerical methods such as the finite element method and to a lesser extent the FDM; the strut-and-tie model and the stress field method are also widely utilized. Analytical approaches usually make use of the Airy stress function, where stresses are formulated in terms of the stress function; however, the exact solution of this function satisfying all of the boundary conditions can hardly be found, even for simple cases. In this paper, deep beams were analyzed using the FDM. The FDM is an approximate method for solving problems described with differential equations. The FDM does not involve solving differential equations; equations are formulated with values at selected nodes of the structure. Therefore, the deep beam was discretized with a two-dimensional grid, and additional nodes were introduced at the boundaries and at positions of discontinuity (openings, brutal change of material properties, non-uniform grid spacing), the number of additional nodes corresponding to the number of boundary conditions at the node of interest. The introduction of additional nodes allowed us to apply the governing equations at boundary nodes and satisfy the boundary and continuity conditions. An Airy stress function approach and a displacement potential function approach were considered in this study whereby strong formulations of equations (equilibrium, kinematic, and constitutive) were set. Stress and stability analyses were carried out with this model; furthermore, deep beams of varying stiffness, layered beams, and beams having openings were analyzed. For slender beams, the results obtained with the Airy stress function approach showed good agreement with those of the Euler-Bernoulli beam theory, and for deep beams, the shapes of stress distributions were in good agreement with a proper understanding of the behavior of structures. On the other hand, the displacement potential function approach delivered unsatisfactory results, probably due to the use of an inefficient equation solver; a more powerful tool will be needed in future research for this purpose.

The tryptophan (TRP)-kynurenine (KYN) metabolic pathway is a main player of TRP metabolism through which more than 95% of TRP is catabolized. The pathway is activated by acute and chronic immune responses leading to a wide range of illnesses including cancer, immune diseases, neurodegenerative diseases, and psychiatric disorders. The TRP-KYN pathway synthesizes multifarious metabolites including oxidants, antioxidants, neurotoxins, neuroprotectants, and immunomodulators. The immunomodulators are known to facilitate the immune system towards a tolerogenic state, resulting in chronic low-grade inflammation (LGI) that is commonly present in obesity, poor nutrition, exposer to chemicals or allergens, prodromal stage of various illnesses, and chronic diseases. KYN, kynurenic acid, xanthurenic acid, and cinnabarinic acid are aryl hydrocarbon receptor ligands that serve as immunomodulators. Furthermore, TRP-KYN pathway enzymes are known to be activated by the stress hormone cortisol and inflammatory cytokines, and genotypic variants were observed to contribute to inflammation and thus various diseases. The tryptophan 2,3-dioxygenase, the indoleamine 2, 3-oxygenases, and the kynurenine-3-monooxygenase are main enzymes in the pathway. This review article discusses the TRP-KYN pathway with special emphasis on its interaction with the immune system and the tolerogenic shift towards chronic LGI and overviews the major symptoms, pro- and anti-inflammatory cytokines, and toxic and protective KYNs to explore the linkage between chronic LGI, KYNs, and major psychiatric, including depressive disorder, bipolar disorder, substance use disorder, post-traumatic stress disorder, schizophrenia, and autism spectrum disorder.

The skeletal muscle plays a critical role in regulating systemic blood glucose homeostasis. Impaired skeletal muscle glucose homeostasis associated with type 2 diabetes mellitus (T2DM) has been observed to significantly affect the whole-body glucose homeostasis, thereby resulting in other diabetic complications. T2DM does not only affect skeletal muscle glucose homeostasis, but it also affects skeletal muscle structure and functional capacity. Given that T2DM is a global health burden, there is an urgent need to develop therapeutic medical therapies that will aid in the management of T2DM. Prediabetes is a prominent risk factor of T2DM that usually goes unnoticed in many individuals as it is an asymptomatic condition. Hence, research on prediabetes is essential because establishing diabetic biomarkers during the prediabetic state would aid in preventing the development of T2DM, as prediabetes is a reversible condition if it is detected in the early stages. Literature predominantly documents the changes in skeletal muscle during T2DM, but the changes in skeletal muscle during prediabetes remain unknown. In this review, we seek to review the existing literature on prediabetic and T2DM associated changes in skeletal muscle function.

8-Hydroxydeoxyguanosine (8-OHdG) was the most widely used oxidative stress biomarker of the free radical-induced oxidative damage product of DNA, which may allow a premature assessment of various diseases. This paper designed a label-free, portable biosensor device to direct detect 8-OHdG by plasma coupled electrochemistry on transparent and conductive indium tin oxide (ITO) electrode. We reported a flexible printed ITO electrode made from particle-free silver and carbon inks. After inkjet printing, the working electrode was sequentially assembled by gold nanotriangles (AuNTAs) and platinum nanoparticles (PtNPs). This nanomaterial-modified portable biosensor showed excellent electrochemical performance for 8-OHdG detection from 10 μg/mL to 100 μg/mL by our self-developed constant voltage source integrated circuit system. This work demonstrated a portable biosensor for simultaneously integrating nanostructure, electroconductivity, and biocompatibility to construct advanced biosensors for oxidative damage biomarkers. The proposed nanomaterial modified ITO-based electrochemical portable device was a potential biosensor to approach 8-OHdG point-of-care testing (POCT) in various biological fluid samples, such as saliva and urine samples.

Antimicrobial resistance (AMR) has been a serious threat to human health, and combination therapy is proved to be an economic and effective strategy to fight the resistance. However, the abuse of drug combinations would conversely accelerate the spread of AMR. In our previous work, it had been concluded that the mutant selection indexes (SIs) of one agent against a specific bacterial strain are closely related to the proportions of two agents in a drug combination. To discover probable correlations, predictors and laws for further proposing feasible principles and schemes guiding the AMR-preventing practice, here three aspects were further explored. First, the power function (y=ax^b, a > 0) correlation between the SI (y) of one agent and the ratio value (x) of two agents in a drug combination was further established based on the mathematical and statistical analyses for those experimental data, and two rules a₁ × MIC₁ = a₂ × MIC₂ and b₁ + b₂ = -1 were discovered from both equations of y=a₁x^b1 and y=a₂x^b2 respectively for two agents in drug combinations. Simultaneously, it was found that one agent with larger MPC alone for drug combinations show greater potency for narrowing itself MSW and preventing the resistance. Second, a new concept as mutation-preventing selection index (MPSI) was proposed and used for evaluating the mutation-preventing potency difference of two agents in drug combinations, and the positive correlation between the MPSI and the mutant prevention concentration (MPC) or minimal inhibitory concentration (MIC) was subsequently established. Inspired by this, the significantly positive correlation, contrary to previous reports, between the MIC and the corresponding MPC of antimicrobial agents against pathogenic bacteria was established using one hundred and eighty-one of data pairs reported. These results together of above three aspects indicate that the MPCs in alone and combination are very important indexes for drug combinations to predict the mutation-preventing effects and the trajectories of collateral sensitivity, and while the MPC of an agent can be roughly calculated from its corresponding MIC. Subsequently, the former conclusion was further verified and improved by the antibiotic exposure to forty-three groups designed as different drug concentrations and various proportions. The results further proposed that the C/MPC for the agent with larger proportion in drug combinations can be considered as a predictor and is the key to judge whether the resistance and the collateral sensitivity occur to two agents. Based on these above correlations, laws, and their verification experiments, some principles were proposed, and a diagram of the mutation-preventing effects and the resistant trajectories for drug combinations with different concentrations and ratios of two agents was presented. Simultaneously, the reciprocal of MPC alone (1/MPC), proposed as the stress factors of two agents in drug combinations, together with their SI in combination, is the key to predict the mutation-preventing potency and control the trajectories of collateral sensitivity. Finally, a preliminary scheme for antimicrobial combinations preventing the AMR was further proposed for subsequent improvement research and clinic popularization, based on the above analyses and discussion. Moreover, some similar conclusions were speculated for triple or multiple drug combinations.

Previous studies reported the physical, transcriptomics and metabolomics changes in in-vitro acute heat stressed bovine granulosa cells. Granulosa cells exhibited transient proliferation senescence, oxidative stress, increased rate of apoptosis, and decline in steroidogenic activity. This study performs joint integration and network analysis of metabolomics and transcriptomics data to further narrow down and elucidate the role of differentially expressed genes, important metab-olites and relevant cellular and metabolic pathways in acute heat-stressed granulosa cells. Among significant (Raw P-value <0.05) metabolic pathways where metabolites and genes did converge, this study found Vitamin B6 metabolism, Glycine, serine and threonine metabolism, Phenylalanine metabo-lism, Arginine biosynthesis, Tryptophan metabolism, Arginine and proline metabolism, Histidine metabolism, and Glyoxylate and dicarboxylate metabolism. Important significant convergent bio-logical pathways included, ABC transporters and Protein digestion and absorption, while func-tional signaling pathways included cAMP, mTOR, and AMPK signaling pathways together with Ovarian steroidogenesis pathway. Among caner pathways, the most important pathway was Central carbon metabolism in cancer. Through multiple analysis query, Progesterone, Serotonin, citric acid, Pyridoxal, L-Lysine, Succinic acid, L-Glutamine, L-Leucine, L-Threonine, L-Tyrosine, Vitamin B6, Choline, and CYP1B1, MAOB, VEGFA, WNT11, AOX1, ADCY2, ICAM1, PYGM, SLC2A4, SLC16A3, HSD11B2 and NOS2 appeared to be important enriched metabolites and genes, respectively. These genes, metabolites, metabolic, cellular and cell signaling pathways com-prehensively elucidate the mechanisms underlying the intricate fight between death and survival in acute heat-stressed bovine granulosa cells, and essentially help further our understanding and future quest of research in this direction.

The fatigue life of welded joints under cyclic loading is a complex process that can be roughly divided into fatigue crack initiation, crack propagation and final fracture. Usually, these phases are evaluated separately. Several methods are available to estimate the extent of the different phases in welded components, such as stress-based fatigue concepts for crack initiation or linear elastic fracture mechanics for crack propagation; however, distinguishing these phases in welded components is a complex procedure and often relies on assumptions such as transition crack sizes. The objective of this study is to investigate the relationship between fatigue crack initiation and propagation in welded joints using artificially notched specimens with welded joints characteristics of different notch acuity (different radii and opening angle). The experiments show that the investigated relationship basically depends on the notch acuity, the load level and the stress ratio.

Wernicke-Korsakoff syndrome (WKS) is induced by thiamine deficiency (TD) and mainly related to alcohol consumption. Frontal cortex dysfunction has been associated to impulsivity and disinhibition in WKS patients. The pathophysiology involves oxidative stress, excitotoxicity and inflammatory responses leading to neuronal death, but the relative contributions of each factor (alcohol and TD, isolate or in interaction) to these phenomena are still poorly understood. A rat model was used by forced consumption of 20% (w/v) alcohol for 9 months (CA), TD hit (TD diet + pyrithiamine 0.25 mg/kg, i.p. daily injections the last 12 days of experimentation; TDD), and both combined treatments (CA+TDD). Motor and cognitive performance and cortical damage were examined. CA caused hyperlocomotion as a possible sensitization of ethanol-induced excitatory effects and recognition memory deficits. In addition, CA+TDD animals showed a disinhibited-like behavior, which appears to be dependent on TDD. Also, combined treatment led to more pronounced alterations in nitrosative stress, lipid peroxidation, apoptosis and cell damage markers. Correlations between injury signals and disinhibition suggest that CA+TDD disrupts behaviors dependent on the frontal cortex. Our study sheds light on the potential disease-specific mechanisms, reinforcing the need for neuroprotective therapeutic approaches along with preventive treatments for the nutritional deficiency in WKS.

Environmental studies, metabolic research, and state of the art neurobiology point towards the reduced amount of natural day and sunlight exposure of the developing child’s organism as the consequence of increasingly long hours spent indoors online as the single unifying source of a whole set of health risks identified worldwide, as is made clear in this review of the current literature. Over exposure to digital environments, from abuse to addiction, now concerns even the youngest (ages 0 to 2), and triggers, as argued on the basis of clear examples herein, a chain of interdependent negative and potentially long-term metabolic changes. This leads to a deregulation of the serotonin and dopamine neurotransmitter pathways in the developing brain, currently associated with online activity abuse and/or internet addiction, and akin to that found in severe substance abuse syndromes. A general functional working model is proposed under the light of evidence brought to the forefront in this review.

The beating heart is subject to intrinsic mechanical factors, exerted by contraction of the myocardium (stretch and strain) and fluid forces of the enclosed blood (wall shear stress). The earliest contractions of the heart occur already in the 10-somite stage in the tubular as yet unsegmented heart. With development the looping heart becomes asymmetric providing varying diameters and curvatures resulting in unequal flow profiles. These flow profiles exert various wall shear stresses and as a consequence different expression patterns of shear responsive genes. In this paper we investigate the morphological changes of the heart after changes the blood flow by ligation of the right vitelline vein in a model chicken embryo and analyze the extended expression in the endocardial cushions of the shear responsive gene Tgfbeta receptor III. A major phenomenon is the diminished endocardial-mesenchymal transition resulting in hypoplastic (even absence of) atrioventricular and outflow tract endocardial cushions, that might be lethal in early phases. The surviving embryos exhibit several cardiac malformations including ventricular septal defects and malformed semilunar valves related to a malposition of the aortopulmonary septum and the enclosed neural crest cells. We discuss the results in the light of the interactions between several shear stress responsive signaling pathways including Vegf, Notch, Pdgf, Klf2, eNos, Endothelin and Tgfβ/Bmp/Smad.

Heat stress due to climate warming can significantly affect the synthesis of sex hormones in male adolescents, which can impair the ability of the hypothalamus to secrete gonadotropin-releasing hormone on the hypothalamic-pituitary-gonadal axis, which leads to a decrease in luteinizing hormone and follicle-stimulating hormone, which ultimately negatively affects spermatogenesis and testosterone synthesis. For optimal spermatogenesis, the testicular temperature should be 2–6°C lower than body temperature. Heat stress directly affects the testes, damaging them and re-ducing testosterone synthesis. Additionally, chronic heat stress abnormally increases the level of aromatase in Leydig cells, which increases estradiol synthesis while decreasing testosterone, lead-ing to an imbalance of sex hormones and spermatogenesis failure. Low levels of testosterone in male adolescents lead to delayed puberty and incomplete sexual maturation, negatively affect height growth and bone mineral density, and can lead to a decrease in lean body mass and an in-crease in fat mass. In order for male adolescents to acquire healthy reproductive capacity, it is recommended to provide sufficient nutrition and energy, avoid exposure to heat stress, and pro-vide foods and supplements to prevent or repair testosterone reduction, germ cell damage, and sperm count reduction caused by heat stress so that they can enter a healthy adulthood.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations to the dystrophin gene - resulting in deficiency of dystrophin protein, loss of myofiber integrity in skeletal and cardiac muscle, and eventual cell death and replacement with fibrotic tissue. Pathologic cardiac manifestations occur in nearly every DMD patient, with development of cardiomyopathy - the leading cause of death - inevitable by adulthood. As early cardiac abnormalities are difficult to detect, timely diagnosis and appropriate treatment modalities remain a challenge. There is no cure for DMD – treatment is aimed at delaying disorder progression and alleviating symptoms. A comprehensive understanding of the pathophysiological mechanisms is crucial to development of targeted treatments. While established hypotheses of underlying mechanisms include sarcolemmal weakening, upregulation of pro-inflammatory cytokines, and perturbed ion homeostasis, mitochondrial stress has recently come into focus as a potential key contributor. Several experimental compounds targeting the skeletal muscle pathology of DMD are in development, but effects of such agents on cardiac function remain unclear. Synergistic integration of small molecule- and gene-target-based drugs with metabolic, immune, or ion balance-enhancing compounds into a combinatorial therapy offers potential for treating dystrophin deficiency-induced cardiomyopathy, making it crucial to understand the underlying mechanisms driving the disorder.

Transcranial direct current stimulation (tDCS) is acknowledged for its non-invasive modulation of neuronal activity in psychiatric disorders. However, its application in insomnia research yields varied outcomes depending on different tDCS types and patient conditions. Our primary objective is to elucidate its efficiency and uncover the underlying mechanisms in insomnia treatment. We hypothesized that anodal prefrontal cortex stimulation activates glutaminergic projections from the infralimbic cortex (IL) to ventrolateral preoptic area (VLPO) to promote sleep. After administering 0.06 mA of electrical currents for 8 minutes, our results indicate significant non-rapid eye movement (NREM) enhancement in naïve mice within the initial 3 hours post-stimulation, persisting up to 16-24 hours. In the insomnia group, tDCS enhanced NREM sleep bout numbers during acute stress response and improved NREM and REM sleep duration in subsequent acute insomnia. Sleep quality, assessed through NREM delta powers, remains unaffected. Interference of the IL-VLPO pathway, utilizing designer receptors exclusively activated by designer drugs (DREADDs) with the cre-DIO system, partially blocked tDCS's sleep improvement in stress-induced insomnia. This study elucidated that the activation of the IL-VLPO pathway mediates tDCS's effect on stress-induced insomnia. These findings support the understanding of tDCS effects on sleep disturbances, providing valuable insights for future research and clinical applications in sleep therapy.

Germplasm is a long-term resource management mission and investment for civilization. For both food and nutritional health, the present changing environmental scenario has become an urgent universal concern. Multiple excellent studies have been previously performed, although the advancement and innovation of practices will require the exploration of the potentiality of crop germplasm. In this study, we emphasized (i) germplasm activates, current challenges and ongoing trends of the crop germplasm, and (ii) how the system biology will be helpful to understand the complex traits such as water use efficiency (WUE), and nitrogen use efficiency (NUE) to mitigate challenges for sustainable development under growing food requirement and climate change conditions. We focused on a vision for transforming PGR into a bio-digital resource system, for the development of climate-smart crops for sustainable food production. Moreover, this review attempted to address current challenges, research gaps and describe the advanced integrated strategies that could provide a platform for future crop improvement research.

The objective of the study was to examine the effects of perceived stress on depression and subsequently to examine the effects of depression on alcohol use disorders. The data were obtained by an electronic questionnaire survey during the coronavirus disease 2019 (COVID-19) pandemic (n=1523 Slovak college students). Descriptive, regression and correlation analysis were used in the analytical processing, while the analyses included students' scores in three diagnostic tools (Perceived Stress Scale (PSS), Patient Health Questionnaire for depression (PHQ 9) and Alcohol Use Disorders Identification Test (AUDIT)), as well as gender and income characteristics. The PSS identified an increased level of perceived stress in female students, in contrast, the AUDIT showed an increased level of alcohol use disorders in male students. Differences in mental and behavioural disorders between the gender and income categories were significant in most of the analysed cases. In terms of gender-income characteristics, it was possible to confirm a significant positive effect of the PSS score on the PHQ 9 score, as well as a significant positive effect of the PHQ 9 score on the AUDIT score. As a result, efforts to reduce stress will be reflected in a reduction of depressive disorders as well as a reduction of excessive alcohol consumption among students.

Decades of research suggest that Mindfulness-Based Stress Reduction (MBSR) training supports a greater capacity to live with chronic medical conditions and contributes to lowering stress levels. This paper introduces a model for a Mindfulness-Based Recovery from Stroke (MBRfS) for promoting stroke recovery, informed by the lived experience of the author (a stroke survivor and certified MBSR instructor), the research literature regarding MBSR training, and the specific challenges of stroke recovery. Four themes emerged from the autoethnographic analysis that informed the proposed model: Readiness to accept the stroke event and the acquired brain injury; Navigating uncertainties of stroke recovery with awareness and self-responsibility for outcomes; Trusting the inherent wisdom of the body as a stroke recovery “teacher”; and Increased capacity to integrate complex emotions with self-compassion, and a sense of wholeness. A four component MBRfS model is offered, which consists of an integration amongst a modified MBSR framework, emergent attitudinal themes, and insights from the autoethnographic vignettes. The MBRfS model offers a path for providing participants with a supportive experience within stroke recovery. Recommendations and suggestions for future studies are offered to support the development of MBRfS for stroke survivors and their caregivers, as well as contributing to health care providers.

Tumor cells exhibit a resistance-associated secretory phenotype involving extracellular vesicles (EVs) and heat shock proteins (HSPs). This response occurs in response to cell stress and cancer therapeutics. HSPs are stress-responsive molecular chaperones promoting proper protein folding, while also being released from cells with EVs as well as in free form as alarmins. We have here investigated the secretory phenotype of castration-resistant prostate cancer (CRPC) cells using proteome analysis. We have also examined the roles of the key co-chaperone CDC37 in stressome release, epithelial-to-mesenchymal transition (EMT), and tumor progression. A number of HSP family members and their common receptor CD91/LRP1 were enriched at high levels in CRPC cell-derived EVs among over 700 other protein species. The small EVs (30 to 200 nm in size, potentially exosomes) were released even in a non-heated condition from the prostate cancer cells, whereas EMT-coupled release of EVs (200 to 500 nm, likely ectosomes) with associated HSP90α was increased after heat shock stress (HSS). Lactate dehydrogenase, a marker of membrane leakage/damage of cells, was also released upon HSS from the prostate cancer cells. During this stress response, intracellular CDC37 was also transcriptionally inducible by heat shock factor 1, and knockdown of CDC37 decreased EMT-coupled release of EVs. Triple knockdown of CDC37, HSP90α, and HSP90β was required for efficient reduction of the chaperone trio and to reduce tumorigenicity of the CRPC cells in vivo. Taken together, the data indicated that CDC37 and HSP90 are essential for stressome release and for tumorigenesis in resistant cancer.

In recent years, numerous topologies of single phase and three phase Field Excited Flux-Switching Machine (FEFSM) have been developed for several applications. Comparative study of three types of single-phase low-priced Field Excited Flux-Switching Machine (FEFSM) is presented in this paper. Both the conventional 8S/4P sub-part rotor design and 6S/3P salient rotor design have an overlapped winding arrangements between armature coil and field excitation coil that depicts high copper losses as well as results in increased size of motor. Additionally, FEFSM with salient structure of the rotor have high flux strength in the stator-core that has much impact on high iron losses. Copper consumption and iron loss being a crucial proportion in total machine losses. Therefore a novel topology of single phase modular rotor field excited FSM with 8S/6P configuration is proposed, which enable non-overlap arrangement between armature coil and FEC winding that facilitates devaluation in the copper losses. The proposed modular rotor design acquires reduced iron losses as well as reduced active rotor mass comparatively to conventional rotor design. It is very persuasive to analyze the best range of speed for these rotors to avoid cracks and deformation, the maximum tensile strength (can be measured with principal stress in research) of the rotor analysis is conducted using JMAG. A deterministic optimization technique is used to enhance the performance of 8S/6P modular rotor design. The electromagnetic performance of conventional sub-part rotor design, F1-A3-3P design and proposed novel-modular rotor design are analyzed by 3D-Finite Element Analysis (3D-FEA), includes flux linkage, flux distribution, flux strength, back-EMF, cogging torque, torque characteristics, iron losses and efficiency.

Mitochondrial functions are essential for life, critical for development, maintenance of stem cells, adaptation to physiological changes, responses to stress and aging. The complexity of mitochondrial biogenesis requires coordinated nuclear and mitochondrial gene expression, owing to the need of stoichiometrically assemble the OXPHOS system for ATP production. It requires, in addition, the import of thousands of proteins from the cytosol to keep optimal mitochondrial function and metabolism. Moreover, mitochondria require lipid supply for membrane biogenesis, while it is itself essential for the synthesis of membrane lipids. To achieve mitochondrial homeostasis, multiple mechanisms of quality control have evolved to ensure that mitochondrial function meets cell, tissue and organismal demands. Herein, we give an overview of mitochondrial mechanisms that are activated in response to stress, including mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response (UPR^mt). We then discuss the role of these stress responses in aging, with particular focus on Caenorhabditis elegans. Finally, we review observations that point to the mitochondrial PHB (prohibitin) complex as a key player in mitochondrial homeostasis, being essential for mitochondrial biogenesis and degradation, and responding to mitochondrial stress. Understanding how mitochondria responds to stress and how such responses are regulated is pivotal to combat aging and disease.

This paper presents a demonstration of the feasibility of fabricating micro-cantilever harvesters with extended stress distribution and enhanced bandwidth by exploiting an M-shaped two-degrees-of-freedom design. The measured mechanical response of the fabricated device displays the predicted dual resonance peak behavior with the fundamental peak at the intended frequency. This design has the features of high energy conversion efficiency in a miniaturized environment where the available vibrational energy varies in frequency. It makes such a design suitable for future large volume production of integrated self powered sensors nodes for the Internet-of-Things.

This paper presents an approach to the elastic analysis of beams subjected to Saint-Venant torsion using Green’s theorem and the finite difference method (FDM). The Saint-Venant torsion of beams, also called free torsion or unrestrained torsion, is characterized by the absence of axial stresses due to torsion; only shear stresses are developed. A solution to this torsion problem consists of finding a stress function that satisfies the governing equation and the boundary conditions. The FDM is an approximate method for solving problems described with differential equations; it does not involve solving differential equations, equations are formulated with values at selected nodes of the structure. In this paper, the beam’s cross-section was discretized using a two-dimensional grid and additional nodes were introduced on the boundaries. The introduction of additional nodes allowed us to apply the governing equations at boundary nodes and satisfy the boundary conditions. Beams with solid sections as well as multiply connected cross-sections were analyzed using this model; shear stresses and localized stresses at reentrant corners, torsion constant, and warping displacements were determined. Furthermore, beams with thin-walled closed sections, single-cell or multiple-cell, were analyzed using the Prandtl stress function whereby a linear distribution of the shear stresses over the thickness was considered; closed-form solutions for shear stresses and torsion constant were derived. The results obtained in this study showed good agreement with the exact results for rectangular cross-sections, and the accuracy was increased through a grid refinement. For thin-walled closed sections, the shear stresses obtained at the centerline using the closed-form solutions were in agreement with the values using Bredt’s analysis but the maximal values in the cross-section, which did not necessarily occur at the position with the smallest thickness, were higher; in addition, the results using the closed-form solutions were in good agreement with those using FDM.

Alpha-methyl-p-tyrosine (AMPT; also referred as metyrosine) is an approved medication for the treatment of pheochromocytoma. As a tyrosine hydroxylase inhibitor AMPT may be a potential candidate for the treatment of diseases involving catecholamine alterations. However, only small-scale clinical trials have tested AMPT repurposing in few other illnesses. Chronic fatigue syndrome (CFS) is an heterogenous disorder with genetically associated vulnerability of catecholamine metabolism (e.g. catechol O-methyltransferase polymorphisms) holding an important impact of environmental factors. The current case report compiles genetic and longitudinal biochemical data for over a year follow-up of one patient sequentially diagnosed with sustained overstress, neurasthenia, CFS, and POTS (postural orthostatic tachycardia syndrome) over a 10-year period, and reports patient’s symptom improvement in response to low-medium doses of AMPT.

Preeclampsia, a hypertensive disease of pregnancy of unknown etiology, is intensely studied as a model of cardiovascular (CVD) disease not only due to multiple shared pathologic elements, but also because changes that develop over decades in CVD disease appear and resolve within days in preeclampsia. Those affected by preeclampsia and their offspring experience increased lifetime risks of CVD. At the systemic level, preeclampsia is characterized by increased cellular, membrane, and blood levels of cholesterol, however, cholesterol dependent signaling such as canonical Wnt/βcatenin, Hedgehog, and endothelial nitric oxide synthase is downregulated indicating a cholesterol deficit with upregulation of cholesterol synthesis and efflux. Hypoxia related signaling in preeclampsia also appears paradoxical with increased Hypoxia Inducible Factors (HIF) in the placenta but measurably increased oxygen in maternal blood in placental villous spaces. This review addresses the molecular mechanisms by which excessive systemic cholesterol and deficient cholesterol dependent signaling may arise from the effects of dietary lipid variance causing the cellular hypoxia which characterizes preeclampsia.

The cytokine-producing nucleotide-binding domain leucine-rich repeat and pyrin-containing receptor 3 (NLRP3) inflammasome is generally recognized to play a central role in the immune response to vaccination and NLRP3 activity is known to be increased by both aluminum adjuvants and by oxidative stress. Thus, the presence of oxidative stress may place individuals at higher risk for exaggerated or prolonged inflammatory responses and related side effects from vaccination. We here examine the relationship between oxidative stress and NLRP3 inflammasome activity, particularly in the context of aluminum-adjuvanted vaccines, and its implications for subpopulations of individuals with restricted antioxidant capacity.

The indole-3-pyruvic acid pathway is the major route for auxin biosynthesis in higher plants. Tryptophan aminotransferases (TAA1/TAR) and members of the YUCCA family of flavin-containing monooxygenases catalyze the conversion of L-tryptophan via indole-3-pyruvic acid into indole-3-acetic acid (IAA). It has been described that locally produced jasmonic acid (JA) in response to mechanical wounding, triggers de novo-formation of IAA through the induction of two YUCCA genes, YUC8 and YUC9. Here, we report the direct involvement of a small number of basic helix-loop-helix transcription factors of the MYC family in this process. We show that the JA-mediated regulation of YUC8 and YUC9 gene expression depends on the abundance of MYC2, MYC3, and MYC4. In support of this observation, seedlings of myc knockout mutants displayed a strongly reduced response to JA-mediated IAA formation. In addition, transactivation assays provided experimental evidence for the binding of the MYC transcription factors to a particular tandem G-box motif abundant in the promoter regions of YUC8 and YUC9, but not in those of the other YUCCA genes. Moreover, we clearly demonstrate that YUC8ox and YUC9ox overexpressing plants show less damage after spider mite infestation, thereby underlining a role of auxin in plant responses toward biotic stress cues.

To understand great disparities in disease outcomes between CIVID-19 patients, we explore infection and host responses in kinetics. From existing data, we deduced a model that the lungs are damaged by rapidly rising flow resistance as a result of retaining white blood cells in lung tissues. The retention of white blood cells is initially triggered by viral infection but aggravated by injuries caused by low temperature. Lungs are initially damaged by fluid leakage, rapidly followed by extruding blood into alveolar spaces. The step of blood extruding is predicted to take place in a very short time. Our simulations show that as little as 0.1% retention of white blood cells in the lungs can lead to their failure in 5 to 10 days. The small degrees of imbalance implies that this imbalance could be corrected by a large number of factors that are known to reduce flow resistance. The model implies that the top priority is maintaining blood micro-circulation and preserving organ functions in the entire disease course, especially after the virus has spread the whole lungs. From exploring a large number of hypothetical infection modes, we propose preventive, mitigating and treatment strategies for ultimately ending the pandemic. The first strategy is avoiding exposures that could result in widespread damages to lungs and taking post exposure mitigating measures that would reduce disease severity. The second strategy is reducing death rate and disability rate from the current levels to one tenth for infected patients by using multiple factors health optimization method. The double reduction strategies are expected to generate a series of chain reactions that favor mitigating or ending the pandemic. Some reactions include a big reduction of the amount of viral discharges from infected patients into the air, the avoidance of panic, chronic stress and emotional distress, and cross-infections which are expected in quarantines. The double reductions would have a final effect of ending the pandemic.

An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Intriguingly, despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of stress response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.

Fatigue-related subchondral bone injury of the third metacarpal/ metatarsal (McIII/ MtIII) bone is a common cause of wastage and welfare concern in racehorses. Better understanding of bone health and strength would improve animal welfare and be of benefit for the racing industry. Porosity index (PI) of bone is an indirect measure of osseous pore size and number and is therefore an interesting indicator of bone strength. MRI of compact bone using traditional methods even with short echo times fails to generate enough signal to assess bone architecture as the water protons are tightly bound. Ultrashort echo time (UTE) sequences aim to increase the amount of signal detected in the equine McIII/MtIII condyle. Cadaver specimens were imaged using a novel dual-echo UTE MRI technique and PI was calculated and validated against quantitative CT-derived bone mineral density (BMD). BMD and PI are inversely correlated in the equine distal Mc/ MtIII with a mean r value of -0.29. The r value is significantly different between fore- and hindlimbs. Further work is needed to assess how correlation patterns behave in different areas of the bone and to evaluate PI in horses with and without clinically relevant stress injury.

We previously showed that mice with knockout in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) gene encoding the PGC-1a protein and nuclear factor erythroid 2 like 2 (NFE2L2) gene, showed some features of the age-related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC-1a in AMD pathogenesis we used young (3-month) and old (12-month) mice with knockout in the PPARGC1A gene and age-matched wild-type (WT) animals. An immunohistochemical analysis showed age-dependent different expression of markers of oxidative stress defense, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3-month animals, but proteins of antioxidant defense also contributed to that discrimination. A bioinformatic analysis showed that PGC-1a might coordinate the interplay between genes encoding proteins involved in antioxidant defense, senescence and autophagy in the aging retina. These data support importance of PGC-1a in AMD pathogenesis and confirm the utility of mice with PGC-1a knockout as an animal model to study AMD pathogenesis.

Oxidative stress (OS) is involved in the pathogenesis of retinal neurodegenerative diseases like age-related macular degeneration (AMD) and diabetic retinopathy (DR) and an important target of therapeutic treatments. New therapeutics are tested in vivo despite limits in transferability and ethical concerns. Retina cultures using human tissue can deliver critical information and significantly reduce the number of animal experiments along with increased transferability. We cultured up to 32 retina samples derived from one eye, analyzed models’ quality, induced OS, and tested efficiency of antioxidative therapeutics. Bovine, porcine, rat, and human retinae were cultured in different experimental settings for 3-14 d. OS was induced by high-glucose or hydrogen peroxide (H2O2) and treated by Scutellarin, pigment epithelium-derived factor (PEDF), and/or granulocyte macrophage-colony stimulating factor (GM-CSF). Tissue morphology, cell viability, inflammation, and glutathione level were determined. Retina samples showed only moderate necrosis (23.83±5.05 increased to 27.00±1.66 AU PI-staining over 14 d) after 14 days in culture. OS was successfully induced (reduced ATP content of 288.3±59.9 vs. 435.7±166.8 nM ATP in controls); antioxidants reduced OS-induced apoptosis (from 124.20±51.09 to 60.80±319.66 cells/image after scutellarin-treatment). Enhanced mammalian animal and human retina cultures allow reliable, highly transferable research on OS-triggered age-related diseases and pre-clinical testing during drug development.

We examined special roles of the Central Nervous System (CNS) in an attempt to resolve the puzzle that chronic diseases cannot be cured by medicine. By exploring a skill-learning model, we found that the CNS is able to remember certain information reflecting biochemical and cellular (B&C) processes in the body. From the skill using ability, we found that the CNS is able to control basic B&C processes that drive and power the skill. From the ability to adjust forces and force direction of a physical act, we found that the CNS is able to adjust B&C processes that drive the physical act. From this adjustment capability, we further inferred that the CNS must also store information on the baseline B&C processes. As a whole, we found that the CNS can maintain information on baseline B&C processes, up-regulate or down-regulate the processes, and make comparisons in performing its regulatory functions. We found that chronic diseases are the results of deviated baseline B&C processes. Per the proved hypothesis, the CNS maintains deviated baseline B&C processes, and thus protects the body states of fully developed diseases. We then used the three CNS roles to explain that cancer progresses with increasing malignancy, cancer quickly returns after a surgery, cancer cells repopulate after chemotherapy and radiotherapy, cancer develops drug resistance inevitably, immune cells rebound after suppression, generally poor benefits of cancer drugs such as beta-blockers, etc. We further showed that long-term exercises generally push most, if not all, baseline B&C processes in diametrical opposing directions against the diseased B&C processes, implying that exercises play unique roles in reversing chronic diseases. Finally, we proposed several strategical approaches to resetting the CNS’ state memory as the essential condition for curing chronic diseases.

The literature on the causation of multiple sclerosis (MS), both genetic and environmental, extends over hundreds of years, with no firm conclusions on the exact role of autoimmunity and lifestyle. The epidemiology of MS was the basis for this review, but with a new, extensive examination of genes pertaining to each disorder, and disease of first, and second, degree relatives of those with MS. The author’s motivation was to discover some relationship between MS, and notable familial conditions, as the heredity of MS is concluded to be 30%, and the disorders had a chronic and/or idiopathic nature. This investigation hoped to further understand the randomness of MS- who acquires it, and what symptoms develop- after the author’s decades of observing several incidences of multiple members developing MS in a single family. Online databases for the human genome were used to link genes to MS, and symptoms, including excessive depression, fatigue and suicide rates, in coordination with linking genes for specific familial conditions including seizures, stroke, mental illness, bowel disorders, and thyroid conditions. Interesting associations were found, notably a cluster of Th2 cytokines, known to cure the animal model of MS, important receptors for neurotransmitters and hormones, a gene specific to Epstein Barr Virus, and potential genes for mitochondrial dysfunction. The results surprised the author, showing polygenic regions of chromosome 2 and 5, especially a cluster at loci 5q31-q33, may be dysregulated. The conclusion agrees with past hypotheses MS results not from a single gene, but from various genes, including those expressed in glial cells. The individual theories to the causation of MS, starting with Charcot may be explained by multiple pathways converging into a single disease outcome. In coordination with a sunlight factor, chromosome 2 appears to mediate the immune system, and inflammation, through ultraviolet radiation producing vitamin D3 in the skin, but additionally through peptides formed in the melanocyte stimulating and concentrating hormone class. The impact of stress in MS could be primary, given the loci of several stress-related and stress-modulated genes on these chromosomes, and calls for more appreciation of, and greater care for, the MS patients’ state of mind.

The aggregate aftermath of persistent inflammation in patients with inflammatory bowel disease (IBD) places them at increased risk for the advancement to colitis-associated colorectal cancer (CACRC). CACRC is preceded by IBD, the highly heterogenous, pharmacologically incurable, pertinacious, reverting/worsening, and immune-mediated inflammatory pathologies of the colon and rectum. The molecular and immunological basis of CACRC is highly correlated with the length/duration and stringency/severity of colon inflammation predisposed by the exogenous/free hemoglobin alpha chain (HbαC) the byproduct of infiltrating immune cells, extravasated erythrocytes, and macrophage erythrophagocytosis. The exogenous free HbαC prompts oxygen-free radical-arbitrated DNA damage (DNAD) through increased cellular reactive oxygen species (ROS) exacerbated by decreased tissue antioxidant defenses. Mitigation of Fenton reaction via pharmaceutical therapy would attenuate the ROS, promote apoptosis, DNAD repair, and subsequent prevent the incidence of CACRC. Three pharmaceutical options that attenuate hemoglobin toxicity include haptoglobin, deferoxamine, and flavonoids (vitamins C/E). Haptoglobin’s clearance rare from plasma is inversely correlated with its size; the smaller the size, the faster the clearance. Thus, the administration of Hp1-1 may prove to be beneficial. Furthermore, deferoxamine’s hydrophilic structure limits its ability to cross cell membranes. Thus, it may be beneficial if administered intracellularly to avoid the higher plasma concentrations and longer incubation periods associated with extracellular administration. Finally, the effectiveness of flavonoids and natural herb antioxidants is associated with high reactivity of hydroxyl substituents. Multiple analyses are currently underway to assess the clinical context of CACRC and outline the molecular basis of HbαC-induced ROS pathogenesis by exposing colonocytes and/or colonoids to HbαC. These cells are then treated with haptoglobin, deferoxamine (DFO), and flavonoids in order to separate free HbαC and measure their impact on hydroxyl radical formation therapies. The molecular pathogenesis of sporadic colorectal cancer (SCRC) i.e., “inflammation-dysplasia-carcinoma” progression sequence is well described, but the immunopathogenesis of CACRC herein reviewed is broadly still in prodromal stage/phase to be validated and understood. Therefore this timely review outlines the molecular and immunological basis of disease pathogenesis and the pharmaceutical intervention as a protective measure for CACRC.

Methane (CH4), produced endogenously in animals and plants, has recently been suggested to play a role in cellular physiology, potentially influencing the signaling pathways and regulatory mechanisms involved in nitrosative and oxidative stress responses. In addition, it has been proposed that supplementation of CH4 to organisms may be beneficial for the treatment of several diseases, including ischemia, reperfusion injury, and inflammation. However, it is still unclear if and how CH4 is produced in mammalian cells without the help of microorganisms, and how CH4 might be involved in physiological processes in humans. In this study, we provide first proof of the principle that CH4 is formed non-microbially in the human body by applying isotopically labeled methylated sulfur compounds, such as dimethyl sulfoxide (DMSO) and methionine, as carbon precursors to confirm cellular CH4 formation. A volunteer applied isotopically labeled (2H and 13C) DMSO on the skin, orally, and to blood samples. Monitoring of stable isotope values of CH4 convincingly showed the conversion of the methyl groups, as isotopically labeled CH4 was formed during all experiments. Based on these results, we consider several hypotheses about endogenously formed CH4 in humans, including physiological aspects and stress responses involving reactive oxygen species (ROS). While further and broader validation studies are needed, the results may unambiguously serve as a proof of concept for the endoge-nous formation of CH4 in humans by a radical-driven process. Furthermore, these results might encourage follow up studies to decipher the potential physiological role of CH4 and its bioactiv-ity in humans in more detail. Of particular importance is the potential to monitor CH4 as an ox-idative stress biomarker if the observed large variability of CH4 in breath air is an indicator for physiological stress responses and immune reactions. Finally, the potential role of DMSO as a radical scavenger to counteract oxidative stress caused by ROS might be considered in the health sciences. DMSO has already been investigated for many years, but its potential positive role for medical use remained highly uncertain.

Background. Epidemiological and clinical studies demonstrated that excessive salt intake causes severe hypertension and exacerbated organ derangement such as chronic kidney disease (CKD). In this study, we focused on evaluating histological and gene-expression findings in the kidney using stroke-prone spontaneously hypertensive rats (SHRSP) with high-salt intake and thromboxane A2/ prostaglandin H2 receptor (TPR) blocker ONO-8809. Methods. SHRSP aged 6 weeks were divided into three groups eating normal chow containing 0.4% NaCl, 2.0%NaCl, or 2.0%NaCl +ONO-8809 (0.6mg/kg p.o. daily). Histological analyses with immunohistochemistry and a gene-expression assay with a DNA kidney microarray were performed after 8 weeks. Results. The following changes were observed with high-salt intake. Glomerular sclerotic changes were remarkably observed in the juxtaglomerular cortex areas. ED1, MCP-1, nitrotyrosine, and HIF-1α staining areas were increased in the glomeruli and interstitial portion. Tbxa2r which encodes TPR, Prcp, and Car7 were significantly underexpressed in the kidney. The plasma 8-isoprostane level was significantly elevated, and was attenuated with ONO-8809 treatment. Conclusion. TXA2 and oxidative stresses exaggerated renal dysfunction in salt-loading SHRSP, and ONO-8809 as a TPR blocker suppressed these changes. Therefore, ONO-8809 is a candidate drug to prevent CKD for hypertensive patients associated with high-salt intake.

Retinal apoptosis plays a critical role in the progression of diabetic retinopathy (DR), a common diabetic complication. Currently, the tight control of blood glucose levels is the standard approach to prevent or delay the progression of DR. However, prevalence of DR among diabetic patients remains high. Focusing on natural nutrients or herbal medicines that can prevent or delay the onset of diabetic complications, we administered an ethanol extract of the aerial portion of Osteomeles Schwerinae (OSSCE), a Chinese herbal medicine, over a period of 17 weeks to spontaneously diabetic Torii (SDT) rats. OSSCE was found to ameliorate retinal apoptosis through the regulation of advanced glycation end products (AGEs) accumulation, oxidative stress, and mitochondrial function via inhibition of NF-κB activity, in turn through the downregulation of PKCδ, P47phox, and ERK1/2. We further demonstrated in 25 mM glucose-treated human retinal microvascular endothelial cells (HRMECs) that hyperoside (3-O-galactoside-quercetin), quercitrin (3-O-rhamnoside-quercetin), and 2''-O-acetylvitexin (8-C-(2''-O-acetyl-glucoside)-apigenin) were the active components of OSSCE that mediated its pharmacological action. Our results provide evidence that OSSCE is a powerful agent that may directly mediate a delay in development or disease improvement in patients of DR.

From a differential geometric perspective, information geometry (IG) aims to characterise the structure of statistical geodesic models. The research done for this paper offers a novel method for modelling the information geometry of a queuing system. From the perspective of IG, the manifold of the transient M/M/infinity queue is described in this context. The Fisher Information matrix (FIM) as well as the inverse of (FIM), (IFIM) of transient M/M/infinity QM are devised. In addition to that, new results that uncovered the significant impact of stability of QM on the existence of (IFIM) are obtained. Moreover, the Geodesic equations of motion of the coordinates of the underlying transient are obtained. Also, it is revealed that stable QM is developable (i.e., has a zero Gaussian curvature) and has a non-zero Ricci Curvature Tensor (RCT). Novel stability dynamics of transient M/M/iInfinity queue manifold is revealed by discovering the mutual dual impact between the behaviour of (RCT) and the stability(instability) phases of M/M/Infinity QM. Furthermore, a new discovery that presents the significant impact of stability of queue manifold and the continuity of the unique representation between M/G/1 queue manifold and Ricci Curvature Tensor (RCT). The information matrix exponential (IME) is devised. Also, it is shown that stability of the devised (IME) enforces the instability of M/M/ Infinity QM. More interestingly, novel relativistic info-geometric queueing theoretic links are revealed .

The pulsatile flow rate (PFR) in the cerebral artery system and shunt ratios in bifurcated arteries are two patient-specific parameters which may affect the hemodynamic characteristics on the pathobiology of cerebral aneurysms (CAs). Accordingly, a systematic study was employed to investigate the effects of the two parameters on hemodynamic characteristics in two internal carotid artery sidewall aneurysms (i.e., ICASA-1 and ICASA-2) models. Numerical results indicate larger PFRs can cause higher WSS in some local regions of the aneurysmal dome that may increase the probability of small/secondary aneurysms generation than under smaller PFRs. The low WSS and relatively high oscillatory shear index (OSI) could appear under a smaller PFR, which has the potential to cause aneurysmal sac growth and rupture. However, the variances in PFRs and bifurcated shunt ratios have rare impacts on the time-average pressure distributions on the aneurysmal sac, although a higher PFR can contribute more to the pressure increase in ICASA-1 dome due to the relatively stronger impingement by the redirected blood stream than in ICASA-2. Simulation results also present the variances of shunt ratios have rare impacts on the hemodynamic characteristics in sacs, mainly because the bifurcated location is not close enough to the sac in present models. Furthermore, it has been found that the vortex location plays a major role in the temporal and spatial distribution of the WSS on the luminal wall, varying significantly with the cardiac period.

Cisplatin (CDDP), carboplatin (CP), and oxaliplatin (OXP) are three platinating agents clinically approved worldwide for use against a variety of cancers. They are canonically known as DNA damage inducers; however, that is only one of their mechanisms of cytotoxicity. CDDP mediates its effects through DNA damage-induced transcription inhibition and apoptotic signalling. In addition, CDDP targets the endoplasmic reticulum (ER) to induce ER-stress, the mitochondria via mitochondrial DNA damage leading to ROS production, and the plasma membrane and cytoskeletal components. CP acts in a similar fashion to CDDP by inducing DNA damage, mitochondrial damage, and ER stress. Additionally, CP is also able to upregulate micro-RNA activity, enhancing intrinsic apoptosis. OXP, on the other hand, at first induces damage to all the same targets as CDDP and CP, yet it is also capable of inducing immunogenic cell death via ER stress and can decrease ribosome biogenesis through its nucleolar effects. In this comprehensive review, we provide detailed mechanisms of action for the three platinating agents, going beyond their nuclear effects to include their cytoplasmic impact within cancer cells. In addition, we cover their current clinical use and limitations, including side effects and mechanisms of resistance.