Thalassemia syndromes are common monogenic disorders that represent a significant global health issue. No systematic epidemiological and molecular investigations on thalassemias in Croatian population have been reported to date. This prospective study included 70 children with a presumptive diagnosis of thalassemia, and their 42 first-degree relatives. Molecular characterization was performed using direct sequencing and gap-PCR methods. We identified 46 (30 children and 16 first-degree relatives) β-thalassemia heterozygous carriers from 24 unrelated families, carrying eight different mutations and one hemoglobin variant. Five variants account for approximately 85% of all affected β-globin alleles: Hb Lepore-Boston-Washington (32,6%), HBB: c.93-21G>A (19,6%), HBB:c.315+1G>A (13,1%), HBB:c.92+1G>A (10,9%), and HBB:c.92+6T>C variant (8,7%). A need for more detailed genetic profiling of β-thalassemia carriers is emphasized since genetic modifiers can significantly impact their phenotype. Our study provides important new insights into the relevance of β-thalassemia heterozygosity in the pediatric clinical practice.

Based on a rich data set of recoveries donated by a debt collection business, recovery rates for non-performing loans taken from a single European country are modelled using linear regression, linear regression with Lasso, beta regression and inflated beta regression. We also propose a two-stage model: beta mixture model combined with a logistic regression model. The proposed model allows us to model the multimodal distribution we find for these recovery rates. All models are built using loan characteristics, default data and collections data prior to purchase by the debt collection business. The intended use of the models is to estimate future recovery rates for improved risk assessment, capital requirement calculations and bad debt management. They are compared using a range of quantitative performance measures under K-fold cross validation. Among all the models, we find that the proposed two-stage beta mixture model performs best.

The objective of this study was to perform a systematic review and meta-analysis of the articles that addressed the effect BA or carnosine supplementation on physical exercise (PE)-induced oxidative stress (OS). Before May 2018 we searched throughout PubMed, CAPES Periodic and SPORTDiscus human model peer review, randomized control studies with chronic BA or carnosine supplementation on PE-induced OS. A total of 128 citations were found. Only four articles met criteria for inclusion. All four studies used healthy young sedentary, recreationally active or athletic participants. After a chronic BA or carnosine supplementation, the studies evaluated PE-induced OS both immediately and several hours after exercise (0.5 to 48 h). In response to PE-induced OS, when compared to placebo, BA/carnosine supplementation increased total antioxidant capacity [TAC; Effect Size (ES) = 0.35, 95% Confidence Interval (CI) 0.06 to 0.65, p = 0.02] and glutathione (GSH; ES = 0.75, 95% CI 0.32 to 1.19, p = 0.0007) concentrations while decreased direct OS markers (ES = −1.19, 95% CI −1.48 to −0.80, p < 0.01) and superoxide dismutase (SOD) activity (ES = − 0.58, 95% CI −1.10 to −0.06, p = 0.03). BA or carnosine supplementation did not prevent the increase in indirect OS markers (ES: 0.06, 95% CI −0.38 to 0.500, p = 0.80). In humans, following PE-induced OS, initial treatment trials of BA or carnosine supplementation seemed to increase TAC and GSH concentrations, while decreasing SOD activity. Also, albeit mitigating the acute increase in direct OS markers (reactive nitrogen and oxygen species), treatment did not decrease measured values of indirect OS markers (peroxidation or molecule oxidation).

Methylation in the estrogen receptor alpha (ESRα) promoter is an epigenetic abnormality in breast cancer (BCa) and hypermethylation results in the loss of ER expression. We used pyrosequencing to investigate if there is a direct link between P0/P1 promoters of ESRα aberrant methylation and risk of progression of benign tumors to BCa. Results showed a significant elevated level of DNA methylation in ESRα P1 promoter (p = 0.0001) in fibroadenoma than ER-negative BCa tissues, and a 2-fold increased ESRα expression in fibrocystic, and fibroadenoma. In addition, the methylation level of HIN-1 and RASSF1A promoters were elevated in ER-positive when compared to ER-negative BCa (p-value <0.5). ANOVA Mixed Model revealed a significant interaction between RASSF1A with fibroadenoma and ER-positive BCa (p = 0.004). Tumors with unclassified molecular subtype (ER-positive, PR-negative, HER2-negative) had elevated levels of methylation (p = 0.046) in the P0 promoter compared with luminal B (ER-positive, PR-positive, HER2-positive) tumors. Tumors with grade 3 showed a borderline association with ESRα P1 promoter methylation when compared with grade 2 tumors (p = 0.056). These results showed a highly methylated ESRα P0 promoter in the initial stages of breast carcinogenesis while the methylation in the P1 promoter occurs at later stages of BCa with poor prognosis. Therefore, methylation of ESRα promoter and tumor-related genes could serve as potential biomarker for prediction of fibroadenoma that are at elevated risk of progressing to BCa.

Severe inherited alpha-1 antitrypsin deficiency (AATD) is an autosomal genetic condition linked to chronic obstructive pulmonary disease (COPD). The significance of heterozygous, milder deficiency variants (Pi*M, Pi*S, Pi*Z) is less clear. We studied AATD genotypes in 145 children (up to 72 months old) with assessed wheezing severity using the Pediatric Respiratory Assessment Measure (BCCH PRAM score). A control group of 74 children without airway obstruction was included. AAT concentration and Pi phenotype were determined from dry blood spot samples using nephelometry and real-time PCR; PiS and PiZ alleles were identified by isoelectrofocusing. Among the wheezers, the Pi*S allele incidence was 2.07% (3 cases) and Pi*Z allele was 6.9% (10 cases). The Pi*Z allele frequency was higher in wheezers compared to controls (44.8% vs. 20.27%) and the general Lithuanian population (44.8% vs. 13.6%) and was similar to adult COPD patients in Lithuania: Pi*S 10.3% vs. 15.8% and Pi*Z 44.8% vs. 46.1%. No association was found between AAT genotypes and wheezing severity. Finding that wheezer children exhibit a frequency of Z* and S* alleles like that found in adults with COPD suggests a potential genetic predisposition that links early wheezing in children to the development of COPD in adulthood. Larger cohort studies are needed to confirm this finding.

The blood counts of α thalassemia carriers (α-thal) are similar to those of β thalassemia carriers, except for Hgb A2 that is not elevated. The objective of this study was to determine whether mathematical formulas are effective for detecting suspected α-thal. The data were obtained from the database of the prevention program for detecting couples at risk for having a child with hemoglobinopathy. RBC indices were analyzed using mathematical formulas and the sensitivity and negative predictive value (NPV) calculated. Among 1334 blood counts suspected α-thal analyzed, only the Shine&Lal and the Support Vector Machine formulas revealed high sensitivity and NPV. Sensitivity was 85.54 and 99.33% and NPV 98.93 and 99.93%, respectively. Molecular defects were found in 291, 81 had normal α genes. Molecular analysis was not performed in 962. Based on these results, mathematical formulas incorporating one of these reliable formulas for detecting suspected α or β thalassemia carriers in the program of the automatic analyzers can flag these results and increase the awareness of the primary physicians about the carrier risk and send an alert with a recommendation for further testing.

Background: The Liver Imaging Reporting and Data System (LI-RADS) combines standardized terminology with a classification system for imaging findings in patients with HCC, therefore rendering diagnostic biopsy unnecessary in many cases. This retrospective study included 23 patients with a biopsy diagnosis of HCC, performed either before or after local interventional procedures, in order to evaluate the histopathologic changes induced by previous procedures and their potential influence on the response to immune therapy. Material and Methods: The study encompassed a cohort of patients diagnosed with Hepatocellular Carcinoma (HCC). Diagnosis was established through contrast-enhanced computer tomography or magnetic resonance imaging that identified LI-RADS-5 nodules in conjunction with historical liver disease and elevated alpha-fetoprotein (AFP) levels, or through histological examination confirming positivity for glypican3, heat shock protein70, and glutamine synthetase. The study detailed the liver disease etiology, LI-RADS scores, characteristics and dimensions of HCC nodules, serum AFP concentrations, Edmondson-Steiner grading, and the expression of programmed cell death ligand 1 (PD-L1) in the tumor cells. Results: Among the study's cohort of Hepatocellular Carcinoma (HCC) patients, a portion had not received any prior treatments, while the remainder experienced local HCC recurrence following trans-arterial chemoembolization or radiofrequency ablation. Observations indicated elevated alpha-fetoprotein (AFP) levels in those who had not undergone any previous interventions, showing statistical significance. The Edmondson-Steiner classification predominantly identified grade III differentiation across patients, irrespective of their treatment history. Furthermore, an increase in intra-tumoral programmed cell death ligand 1 (PD-L1) expression was noted in patients who had not been subjected to previous therapies. Conclusion: Liver biopsy offers valuable insights for patients with Hepatocellular Carcinoma (HCC), assisting in the tailoring of immune therapy strategies, particularly in cases of recurrence following prior local interventions.

FacioScapuloHumeral Dystrophy (FSHD) is one of the most prevalent inherited muscle disorders, and is linked to the inappropriate expression of the DUX4 transcription factor in adult muscles. The deregulated molecular network causing FSHD skeletal muscle dysfunction and pathology is still not well understood. It has been shown that the hypoxia response factor HIF1α is critically disturbed in FSHD and has a major role in DUX4 induced cell death. In this study, we further explore the relationship between DUX4 and HIF1α. We found that the DUX4 and HIF1α link differed according to the stage of myogenic differentiation and was conserved between human and mouse muscle. Furthermore, we found that HIF1α knock-down in a mouse model of DUX4 local expression exacerbated DUX4-mediated muscle fibrosis. Our data indicate that the suggested role of HIF1α in DUX4 toxicity is complex and that targeting HIF1α might be challenging in the context of FSHD therapeutic approaches.

Background: Diabetic patients are more likely to experience morbidity and mortality as a result of microvascular complications such as retinopathy, neuropathy, nephropathy, and stroke. There are many synthetic anti-diabetic agents available which are expensive and have undesirable pathological effects. Thus, it is essential to look for cost-effective, natural, and safe antidiabetic agents. The aim of this study was to screen phytoconstituent and evaluate the in-vitro and in-silico α-amylase inhibitory activity of ethanolic extract of Adhatoda vasica leaves. Method: The extraction of Adhatoda vasica leaves was performed with ethanol through Soxhlet extraction process. Different concentrations (0.1 mg/ml to 1 mg/ml) of ethanolic extract, Acarbose, and Sitagliptin, were prepared and all concentrations were evaluated for α-amylase inhibitory activity through the spectrophotometric method. Molecular docking (AutodockVina 1.2.0) and toxicity profiling (SToPToX web server) studies were performed. Results: The plant extract showed highest inhibition of α-amylase (56.763±0.0035) at a concentration of 1 mg/ml. This inhibitory activity was supported by the in-silico study. Vasicoline (C5) and quercetin (C9), active constitute of plant Adhatoda vasica, showed the best binding energy of 8.3 and 8.0 Kcal/mol respectively with α-amylase enzyme (PDBID: 4W93). Toxicity study revealed the safety profile of plant extract. Conclusion: It was concluded that Adhatoda vasica leaves possess some bioactive compounds which are responsible for controlling blood glucose levels and its identification, purification, and isolation may lead to the development of newer therapeutic agent with lesser side effects.

As a result of scientific technological advancements in medical diagnostics, treatment modalities of non-communicable and communicable diseases, and palliative care approaches, the life expectancy of women is soaring than men across the globe, due to the longer telomere length and other protective factors. The main symptoms of menopause broadly be divided into psychological somatovegetative and urogenital. Neglected menopausal symptoms can lead to debilitating comorbidities which may end up in mortalities. Fortunately, modern treatment and therapeutic formalities based on pharmaceutical preparations, as well as lifestyle- modifications have provided long-lasting relief for the pre-menopausal woman. This can be done as per her preference if she is knowledgeable, resourceful, and cheerful. Menarchae is the “ alpha” and menopause is the “omega” phase in the reproductive lifecycle of any woman. Reproductive health is essentially an integral part of women’s health. In this 4^th industial revolution era information technology and digital science go hand in hand to improve the quality of life of populations across the globe irrespective of their educational and professional status. Health literacy among disadvantageous sub populations increased. Positive attitudes, perception and evidence-informed knowledge on adolesecent girls about not only ‘period pains’ but menopausal symptoms as an inevitable phase in a woman’s reproductive health may make a better sense at the dawn of evidence based medicine even in a low middle income country like Sri Lanka. Hence, this timely communication strengthens by, Do not fear when menopause is near: The Importance of a Preparatory Time and Space to face the consequences of Menopaus. How to forget the fact that alpha and the omega are inevitable phases in woman’s reproductive health trajectory. Moreover, the importance of a preparatory time and space well in advance preferably in peri-menopausal time to prevent and control the inevitable health consequences. Moreover, to invest in menopause for a brighter future in the modern personalized medicine era based on global scientific evidence.

Recent studies have been able to detect α-synuclein (αSyn) seeding in formaldehyde-fixed paraffin-embedded (FFPE) tissues from patients with synucleinopathies using seed amplification assays (SAAs), but with relatively low sensitivity due to limited protein extraction efficiency. With the aim of introducing an alternative option to frozen tissues, we developed a streamlined protein extraction protocol for evaluating disease-specific seeding in FFPE human brain. We evaluated the protein extraction efficiency of different tissue preparations, deparaffinizations, and protein extraction buffers using formaldehyde-fixed and FFPE tissue of a single Lewy body disease (LBD) subject. Alternatively, we incorporated heat-induced antigen-retrieval and dissociation using a commercially available kit. Our novel protein extraction protocol has been optimized to work with 10 sections of 4.5-µm-thickness or 2-mm-diameter micro-punch of FFPE tissue that can be used to seed SAAs. We demonstrated that extracted proteins from FFPE still preserve seeding potential and further show disease-specific seeding in LBD and multiple system atrophy. To the best of our knowledge, our study is the first to recapitulate disease-specific αSyn seeding behavior in FFPE human brain, with structural validation. Our findings open new perspectives in re-evaluating archived human brain tissue, extending the disease-specific seeding assays to larger cohorts to facilitate molecular subtyping of synucleinopathies.

Gold nanoparticles have been increasingly used in several electronic, material fabrication, and biomedical applications. Several methods have been reported to prepare gold nanoparticles of various shapes and sizes with different photophysical properties. Although useful to prepare gold nanoparticles, most of the methods are not stable enough and under degradation if stored at room temperatures (up to 30 C) for a few days. In this paper, we report a novel environmentally friendly method to synthesize self-assembled gold nanoparticles by using leaf extract of Cannabis indica as a reducing agent. The nanoparticles were found to be stable for more than a month when stored at room temperature (30 C). They were able to form stable conjugates with bovine α-lactalbumin protein that may possess anti-cancerous properties.

Background: Body dysmorphic disorder (BDD) is a psychiatric disorder characterized by excessive preoccupation with imagined defects in appearance. Optical illusions induce illusory effects that distort the presented stimulus thus leading to ambiguous percepts. Using electroencephalography (EEG), we investigated whether BDD is related to differentiated perception during illusory percepts. Methods: 18 BDD patients and 18 controls were presented with 39 optical illusions together with a statement testing whether or not they perceived the illusion. After a delay period, they were prompted to answer whether the statement is right/wrong and their degree of confidence for their answer. We investigated differences of BDD on task performance and self-reported confidence and analysed the brain oscillations during decision-making using nonparametric cluster statistics. Results: Behaviorally, the BDD group exhibited reduced confidence when responding incorrectly, potentially attributed to higher levels of doubt. Electrophysiologically, the BDD group showed significantly reduced alpha power at mid-central scalp areas, suggesting impaired allocation of attention. Interestingly, the lower the alpha power of the identified cluster, the higher the BDD severity, as assessed by BDD psychometrics. Conclusions: Results evidenced that alpha power during illusory processing might serve as a quantitative EEG biomarker of BDD, potentially associated with reduced inhibition of task-irrelevant areas.

Background: Acute intermittent porphyria (AIP) is caused by haploinsufficiency of porphobilin-ogen deaminase (PBGD) enzymatic activity. Acute attacks occur in response to fasting and altera-tions in glucose metabolism, insulin resistance and mitochondrial turnover may be involved in AIP pathophysiology. Therefore, we investigated the metabolic pathways in PBGD-silenced hepatocytes and assessed the efficacy of an insulin-mimic, the α-lipoic acid (α-LA) as a potential therapeutic strategy. Methods: HepG2 cells were transfected with a siRNA targeting PBGD (siPBGD). Cells were cul-tured with low glucose concentration to mimic fasting and exposed to α-LA alone or with glu-cose. Results: At baseline, siPBGD cells showed lower expression of genes involved in glycolysis and mitochondrial dynamics along with reduced total ATP levels. Fasting further unbalanced gly-colysis by inducing ATP shortage in siPBGD cells and activated DRP1, which mediates mito-chondrial separation. Consistently, siPBGD cells in fasted state showed the lowest protein levels of Complex IV which belong to the oxidative phosphorylation (OXPHOS) machinery. α-LA up-regulated glycolysis and prompted ATP synthesis and triglyceride secretion, thus possibly providing energy fuels to siPBGD cells by improving glucose utilization. Finally, siPBGD exposed to α-LA plus glucose raised mitochondrial dynamics, OXPHOS activity and energy production. Conclusions: α-LA-based therapy may ameliorate glucose metabolism and mitochondrial dys-functions in siPBGD hepatocytes. Keywords: AIP, PBGD, glucose metabolism, mitobiogenesis, α-lipoic acid

3,4-dihydroxyphenylacetaldehyde (DOPAL) is the focus of the catecholaldehyde hypothesis for the pathogenesis of Parkinson disease and other Lewy body diseases. The catecholaldehyde is produced via oxidative deamination catalyzed by monoamine oxidase (MAO) acting on cytoplasmic dopamine. DOPAL is autotoxic, in that it can harm the same cells in which it is produced. Normally DOPAL is detoxified by aldehyde dehydrogenase (ALDH)-mediated conversion to 3,4-dihydroxyphenylacetic acid (DOPAC), which rapidly exits the neurons. Genetic, environmental, or drug-induced manipulations of ALDH that build up DOPAL promote catecholaminergic neurodegeneration. A concept derived from the catecholaldehyde hypothesis imputes deleterious interactions between DOPAL and the protein alpha-synuclein (S), a major component of Lewy bodies. DOPAL potently oligomerizes S, and S oligomers impede vesicular and mitochondrial functions, shifting the fate of cytoplasmic dopamine toward MAO-catalyzed formation of DOPAL—destabilizing vicious cycles. Direct and indirect effects of DOPAL and of DOPAL-induced misfolded proteins could “freeze” intra-neuronal reactions, plasticity of which is required for neuronal homeostasis. The extent to which DOPAL toxicity is mediated by interactions with S, and vice versa, are poorly understood. Because of numerous secondary effects such as augmented spontaneous oxidation of dopamine by MAO inhibition, there has been insufficient testing of the catecholaldehyde hypothesis in animal models. The clinical pathophysiological significance of genetics, emotional stress, environmental agents, and interactions with numerous proteins relevant to the catecholaldehyde hypothesis are matters for future research. The imposing complexity of intra-neuronal catecholamine metabolism seems to require a computational modeling approach to elucidate clinical pathogenetic mechanisms and devise pathophysiology-based, individualized treatments.

I wish to suggest a physiological function for alpha-synuclein (a-syn) that has the potential to explain its role in pathology. Intraneuronal proteinaceous Lewy Bodies (LBs), the pathological hallmark of Parkinson’s disease and other synucleinopathies, consist majorly of a-syn. Ample evidence suggests that LBs are not the result of simple amyloidosis of cytosolic a-syn. Benign soluble unstructured a-syn gets converted into toxic species which preferentially accumulates in LBs. But how these aberrant a-syn molecules are produced in the cytosol, is still not clear. The present hypothesis is an effort to relate a metabolic reaction specific to neuronal function, that is, phase transition, with the pathobiology of a-syn. During high frequency stimulation, which entails rapid phase transition reactions at the presynaptic compartment, aberrant interaction of a-syn with the membrane occasionally generates toxic a-syn molecules. My conjecture is that the physiological function of a-syn is to modulate membrane fluidity by a process wherein it goes through a conformation cycle driven by a flux of energy from mitochondria. It is the range of toxic a-syn produced during aberrant phase transition reaction that is responsible for pathology, not the normal a-syn that reenters the conformation cycle, thereby, resolving the paradox of the Janus-face of a-syn.

Our understanding and theoretical interpretation of observations in astrophysics and cosmology depends on our knowledge of the fundamental constants and their possible dependence on time and space. Atomic spectroscopy and radio astronomy give important information on the validity and stability of the fundamental constants. The possible dependence of the fine structure constant alpha on time and spatial direction is an active topic of research.Period doubling is a universal property of nonlinear dynamical systems, and the doubling is exact in principle. The value of the elementary charge squared can be calculated by the period doubling process from the Planck charge and thereby the value of alpha.If ‘old’ and ‘new’ electrons are identical, then the Planck charge, i.e. a set of natural constants, has remained constant over time. In this article we show that the value of alpha calculated from the Planck charge is 0.007 % smaller than the current accepted value of alpha.

Natural killer T cells (NKT) are a subset of T lymphocytes bridging innate and adaptive immunity. These cells recognize self and microbial glycolipids bound to non-polymorphic and highly conserved CD1d molecules. Three NKT cell subsets, type I, II and NKT-like expressing different antigen receptors (TCR) were described and TCR activation promotes intracellular events leading to specific functional activities. NKT can exhibit different functions depending on the secretion of soluble molecules and the interaction with other cell types. NKT cells act as regulatory cells in the defence against infections but, on the other hand, their effector functions can be involved in the pathogenesis of several inflammatory disorders due to their exposure to different microbial or self antigens, respectively. A deep understanding of the biology and functions of type I, II and NKT-like cells as well as their interplay with cell types acting in innate (Neuthrophils, Innate Lymphoid cells, Machrophages and Dendritic cells) and adaptive immunity (CD4+,CD8+ and Double Negative T cells) should be important to design potential immunotherapies for infectious and autoimmune diseases.

Stem cells can be used to treat diabetic mellitus and complications. ω3-docosahexaenoic acid (DHA) derived lipid mediators are inflammation-resolving and protective. This study found novel DHA-derived 7S,14R-dihydroxy-4Z,8E,10Z,12E,16Z,19Z-docosahexaenoic acid (7S,14R-diHDHA), a maresin-1 stereoisomer biosynthesized by leukocytes and related enzymes. Moreover, 7S,14R-diHDHA can enhance mesenchymal stem cell (MSC) functions in the amelioration of diabetic mellitus and retinal pericyte loss in diabetic db/db mice. MSCs treated with 7S,14R-diHDHA were delivered into db/db mice i.v. every 5 days for 35 days. Blood glucose levels in diabetic mice were lowered by 7S,14R-diHDHA-treated MSCs compared to control and untreated MSC groups, accompanied by improved glucose tolerance and higher blood insulin levels. 7S,14R-diHDHA-treated MSCs increased insulin+ β-cell ratio and decreased glucogan+ α-cell ratio in islets, as well as reduced macrophages in pancreas. 7S,14R-diHDHA induced MSC functions in promoting MIN6 β-cell viability and insulin secretion. 7S,14R-diHDHA induced MSC paracrine functions by increasing the generation of hepatocyte growth factor and vascular endothelial growth factor. Furthermore, 7S,14R-diHDHA enhanced MSC functions to ameliorate diabetes-caused pericyte loss in diabetic retinopathy by increasing their density in retina in db/db mice. Our findings provide a novel strategy for improving therapy for diabetes and diabetic retinopathy using 7S,14R-diHDHA-primed MSCs.

The main objective of this paper is to introduce a further extension of extended (p, q)-beta function by considering two Mittag-Leffler function in the kernel. We investigate various properties of this newly defined beta function such as integral representations, summation formulas and Mellin transform. We define extended beta distribution and its mean, variance and moment generating function with the help of extension of beta function. Also, we establish an extension of extended (p, q)-hypergeometric and (p, q)-confluent hypergeometric functions by using the extension of beta function. Various properties of newly defined extended hypergeometric and confluent hypergeometric functions such as integral representations, Mellin transformations, differentiation formulas, transformation and summation formulas are investigated.

Beta thalassemia is an inherited blood disorder that results in inefficient erythropoiesis due to genetic mutation that leads to reduction or absence of the hemoglobin beta-globulin protein. Approximately 8.5% of UAE residents suffer from β-thalassemia, a significant health and financial problem. The treatment options available for β-Thalassemia major are limited and associated with a wide range of complications. β-thalassemia gene therapy is emerging as a potential novel treatment option that eliminates the complications caused by the current long-term treatment modalities and the associated economic burden. This paper reviews the scientific literature related to emerging gene-therapy for β-Thalassemia by analyzing all the articles published from January 2010 to December 2023 in the English language on Databases like PubMed, Scopus, ProQuest, and CINAHL. The use of gene therapy has demonstrated promising outcomes for a permanent cure of β-Thalassemia. ZYNTEGLO (Betibeglogene autotemcel) is the only cell-based gene therapy which was approved by the FDA on 19th August, 2018. To conclude, Gene therapy is an innovative solution. It demonstrates a promising future, but does come with its own set-backs and is something that must be tackled in-order to revolutionize it in the medical world. FDA approved ZYNTEGLO is a potentially one-time curative treatment for β-Thalassemia. Although cutting-edge, its use is limited because of the high cost; a price of $2.8million per patient.

This paper provides the straight proof for the Riemann Hypothesis.The proof has been formulated with the modified version of Riemann Xi function ξ(s) , that shows the relationship with upper incomplete gamma function.

The high transmissibility, rapid evolution, and immune escape of SARS-CoV-2 variants can influence the course of infection and, in turn, morbidity and mortality in COVID-19, posing a challenge in controlling transmission rates and contributing to the emergence and spread of new variants. The factors that shape viral genetic variation are consequently essential for understanding the evolution and transmission of SARS-CoV-2, especially in vaccinated individuals where immune response plays a role in the progression and spread of this disease. This study assessed. In this context, we evaluated the impact of immunity induced by the CoronaVac vaccine (Butantan/Sinovac) on intra-host genetic diversity, analyzing 118 whole-genome sequences of SARS-CoV-2 from unvaccinated and vaccinated patients infected with the Gamma variant. Vaccination with CoronaVac favors negative selection at the intra-host level in different genomic regions and prevent greater genetic diversity of SARS-CoV-2, which may help reduce the emergence of new mutations, reinforcing the importance of vaccination in reducing virus transmission.

A panorama of the current historiography on the Supernova of 1054 is outlined. Shklovsky (1968) [1], and Murdin (1985) [2] show how the interpretation of this phenomenon converged on a Su-pernova event. Here we reconsider the historical data, assuming a Gamma-Ray Burst (GRB) as its source. A Supernova correlated with the GRB explains well the fading time observed by the an-cient Chinese astronomers, in daytime and in night time, while the GRB power-law explains the present X-rays and GeV emission of the Crab. On the ground of recent understanding of the first episode of binary driven Hypernova GRB (BDHN GRB) in terms of the collapse of a ten solar masses core, we propose the possible identification of the real Supernova event at earlier time than Chinese chronicles. This work allows a new understanding of the significance of historical astronomical observations, including a fireball, due to gamma-rays air shower observation, and a plague of acute radiation syndrome, documented with several thousands of victims in the Eura-sian area (Egypt, Iraq and Siria).

(1) Background: Gamma-aminobutyric acid (GABA) is one of the inhibitory neurotransmitters with beneficial effects including sedative property. However, despite various clinical trials, scientific evidence regarding the impact of orally ingested GABA, whether natural or synthesized through biological pathways, on sleep is not clear.; (2) Methods: The present study work evaluated GABA-A biding affinity of GABALAGEN(GBL), a low-molecular-weight collagen infused with GABA, through receptor binding assays. The sedative effects of GBL were investigated through electroencephalography (EEG) analysis in the electro foot shock (EFS) stress-induced sleep animal model and then we examined the expression orexin, GABAA receptor in the brain region using immunohistochemistry.; (3) Results: We found that on the binding assay, GBL displayed high affinity to GABAA receptor (IC50 value, 31.5µg/mL)). Also, after treatment of GBL, percent of total time of REM and NREM were significantly and dose-dependently increased compared to the Con group. Consistent with behavioral results, the GBL-treated groups showed that the expression of GABAA receptor immune-positive cells in the VLPO were markedly and dose-dependently increased compared to the Con group. Also, the GBL-treated groups showed that the expression of orexin immune-reactive cells in the LH were significantly decreased compared to the Con group.; (4) Conclusions: In conclusion, GBL showed efficacy and potential to be used as an anti-stress therapy to treat sleep deprivation through antagonism of GABA receptors and consequent inhibition of orexin activity.

Recent interest in preventing the development of osteoporosis has focused on the regulation of redox homeostasis. However, the action of lycopene (LYC), a strong natural antioxidant com-pound, on osteoporotic bone loss remains largely unknown. Here, we show that the administra-tion of LYC to OVX rats reduces body weight gain, improves lipid metabolism and preserves bone quality. In addition, LYC treatment inhibits ROS overgeneration in serum and bone marrow in OVX rats, and in BMSCs upon H2O2 stimulation, leading to inhibiting adipogenesis and pro-moting osteogenesis during bone remodeling. Mechanically, LYC may improve bone quality via an increase in the expressions of FoxO1 and Runx2, and a decrease in the expressions of PPARγ and C/EBPα in OVX rats and BMSCs. Collectively, these findings suggest that LYC attenuates osteoporotic bone loss through promoting osteogenesis and inhibiting adipogenesis via regula-tion of the FoxO1/PPARγ pathway driven by oxidative stress, presenting a novel strategy for os-teoporosis management.

The mechanism of immune activation and de-activation is very important. Host should trigger effective immunity against pathogen infection. And, host cannot trigger immunity against self-antigens that will lead to detrimental autoimmune disorders. Spleen and liver have opposite roles in mediating immune responses. Spleen is the organ involving in immune activation, and liver is the organ involving in immune de-activation. Sympathetic nerve system and parasympathetic nerve system have opposite roles in mediating immune responses. Sympathetic nerve system is involving in pro-inflammatory, and parasympathetic nerve system is involving in anti-inflammatory. ACTH and glucocorticosteroid have opposite roles in mediating immune responses. ACTH is involving in activating adaptive immunity with inhibiting innate immunity, and glucocorticosteroid is involving in activating innate immunity with inhibiting adaptive immunity. The molecular chaperons, heat shock proteins, which are induced by fever, have the vital roles in immune activation. On the contrary, IgD B cells and gamma-delta T cells are causing immune de-activation via the mechanism of clonal anergy. These mechanism can help us the know the work of immunological pathways better for better control of infectious diseases and autoimmune disorders.

Our aim was to determine the secondary antibody deficiency profiles of patients in a mesoregion of São Paulo state, Brazil, focusing on infectious diseases. Demographic characteristics, clinical and laboratory data were obtained from electronic files; infections were classified as organ-specific and graded as mild, moderate, life-threatening, and fatal. Non-Hodgkin lymphoma (NHL) accounted for 30% of patients, nephrotic syndrome (NS) 25%; chronic lymphocyte leukemia 20%, and multiple myeloma 15%. Patients with NS were younger than those in other groups, and hypo-γ-globulinemia was detected in 94.1%, IgG <400 mg/dL in 60.0%, IgA <40 mg/dL in 55.0%, and CD19 <20 cells/mm³ in 30.0%. One hundred and one infections were found; 82.1% were classified as mild or moderate, 7.9% as life-threatening, and 1.9% as fatal. Respiratory tract infections were more prevalent (41.5%), and pneumonia accounted for 19.8%. Lower levels of infections were found in patients with NS compared with NHL (P=0.0001). Most patients progressed to hypo-γ-globulinemia and secondary antibody deficiency after treatment with immunosuppressants, and mild and moderate infections were predominant. These therapies are increasing in patients with different diseases, therefore monitoring hypo-γ-globulinemia and infections may help to identify patients at high risk for severe complications, antibiotic prophylaxis or treatment, and immunoglobulin replacement

Three-quarters of a million babies are born extremely preterm (< 28 weeks’ gestation) world-wide with devastating outcomes: 20% die in the newborn period, a further 35% develop bronchopul-monary dysplasia (BPD) and 10% suffer from cerebral palsy. Pioglitazone, a Peroxisome Proliferator Activated Receptor Gamma (PPARγ) agonist, may reduce the incidence of BPD and improve neurodevelopment in extreme preterm babies. Pioglitazone exerts an anti-inflammatory action mediated through Nuclear Factor-kappa B repression. PPARγ signalling is underactive in preterm babies as adiponectin remains low during the neonatal pe-riod. In newborn animal models, pioglitazone is shown to be protective against BPD, necrotising en-terocolitis, and lipopolysaccharide-induced brain injury. Single Nucleotide Polymorphisms of PPARγ are associated with inhibited preterm brain development and impaired neurodevelop-ment. Pioglitazone was well tolerated by the foetus in reproductive toxicology experiments. Bladder cancer, bone fractures, and macular oedema seen rarely in adults may be avoided with a short treatment course. Other effects of pioglitazone including improved glycaemic control and lipid metabolism may provide added benefit in prematurity. Currently, there is no formulation of pioglitazone suited for administration to preterm babies A liquid formulation of pioglitazone needs to be developed before clinical trials. The potential benefits are likely to outweigh any anticipated safety concerns.

We investigate the impact of incoming nuclear data on the predictions of the neutron star (NS) stripping model for short gamma-ray bursts. The main area to which we pay attention is the NS crust. We show that the uncertain properties of the NS equation of state can significantly influence the stripping time tstr, the main dynamical parameter of the model. Based on the known time delay (tstr≈1.7s) between the peak of the gravitational wave signal GW170817 and the detection of gamma photons from GRB170817A, we obtain new restrictions on the nuclear matter parameters, in particular, the symmetry energy slope parameter: L&lt;114.5MeV. In addition, we study the process of nucleosynthesis in the outer and inner crusts of a low-mass NS. We show that the nucleosynthesis is strongly influenced by both the incoming nuclear data and the equation of state of the NS matter.

The details of the solar flare production mechanisms are not yet completely understood. One of the standing questions is the anisotropy of the X-ray flux, especially in strong flares. It can be studied indirectly by analysing the characteristics of flares at different positions on the visible disc. In this paper, the durations, peak and integral fluxes of strong (X-class) solar flares from cycles 22--25 are considered with respect to their apparent position on the Sun. It is found that there exists a significant north--south asymmetry in all three parameters, which also varies depending on the phase of the solar cycle (with general predominance of the south). This confirms the results of previous studies. A weaker and less significant east--west asymmetry is found as well, partly supported by literature. A previously undetected centre-to-limb asymmetry is reported (in favour of the limb) in all three parameters. All three asymmetries are enhanced during the solar minimum, which could hint at their connection to the large scale magnetic structuring of the Sun. The prevalence of strong solar flares near the limb at the solar minimum has clear space weather warning implications.

The dentate gyrus (DG) is part of the hippocampal formation and is essential for important cognitive processes such as navigation and memory. The oscillatory activity of the DG network is believed to play a critical role in cognition. DG circuits generate three main rhythms: theta, beta, and gamma, which participate in the specific information processing performed by DG neurons. In the temporal lobe epilepsy (TLE), cognitive abilities are impaired, which may be due to drastic alterations in the DG structure and network activity during epileptogenesis. The theta rhythm and theta coherence are especially vulnerable in dentate circuits; disturbances in DG theta oscillations and their coherence may be responsible for general cognitive impairments observed during epileptogenesis. Some researchers suggested that the vulnerability of DG mossy cells is a key factor in the genesis of TLE, but others did not support this hypothesis. The aim of the review is not only to present the current state of the art in this field of research but to help pave the way for future investigations by highlighting the gaps in our knowledge to completely appreciate the role of DG rhythms in brain functions. Disturbances in oscillatory activity of the DG during TLE development are described in detail that may be a diagnostic marker in the treatment of this disease.

Additive manufacturing or 3D printing applying polycaprolactone-(PCL)-based medical devices represents an important branch of tissue engineering, where the sterilization method is a key process for further safe application in vitro and in vivo. In this study, the authors intend to access the most suitable gamma radiation conditions to sterilize PCL-based scaffolds in a preliminary biocompatibility assessment, envisioning future studies for airway obstruction conditions. Three radiation levels were considered, 25 kGy, 35 kGy and 45 kGy and evaluated as to their cyto- and biocompatibility. All three groups presented biocompatible properties, indicating an adequate sterility condition. As for the cytocompatibility analysis, devices sterilized by 35 kGy and 45 kGy showed better results, with the 45 kGy showing overall improved outcomes. This study allowed to select the most suitable sterilization condition for PCL-based scaffolds, aiming at immediate future assays, by applying 3D-customized printing techniques to specific airway obstruction lesions of the trachea.

The brain rhythms are essential for information processing in neuronal networks. Oscillations recorded in different brain regions can be synchronized and have a constant phase difference, i.e. be coherent. Coherence between local field potential (LFP) signals from different regions in the brain may be correlated with the performance of cognitive tasks, from which it is concluded that these regions of the brain are involved in the task performance together. In this review, we discuss why coherence occurs and how it is coupled to the information transfer between different regions of the hippocampal formation. Coherence in theta and gamma frequency ranges is described since these rhythms are most pronounced during the hippocampus-dependent attention and memory. We review in vivo studies of interactions between different regions of the hippocampal formation in theta and gamma frequency bands. The kay provisions of the review: 1) coherence emerges from synchronous postsynaptic currents in principal neurons, occurring as a result of synchronization of neuronal spike activity; 2) synchronization of neuronal spike patterns in two regions of the hippocampal formation can be realised through induction or resonance; 3) coherence at a specific time point reflects the transfer of information between regions of the hippocampal formation, in particular, gamma coherence reflects the coupling of active neuronal ensembles. Overall, coherence is not an epiphenomenon, but an important physiological process that has certain generation mechanisms and performs important functions in information processing and transmission across the brain regions.

The discovery by the Large Area Telescope on board Fermi of variable gamma-ray emission from radio-loud narrow-line Seyfert 1 (NLSy1) galaxies revealed the presence of a possible third class of AGN with relativistic jets in addition to blazars and radio galaxies. Considering that NLSy1 are usually hosted in spiral galaxies, this finding poses intriguing questions about the nature of these objects and the formation of relativistic jets. We report on a systematic investigation of the gamma-ray properties of a sample of radio-loud NLSy1, including the detection of new objects, using 7 years of Fermi-LAT data with the new Pass 8 event-level analysis. In addition we discuss the radio-to-very-high-energy properties of the gamma-ray emitting NLSy1, their host galaxy, and black hole mass in the context of the blazar scenario and the unification of relativistic jets at different scales.

High redshift blazars are among the most powerful objects in the Universe. Although they represent a significant fraction of the extragalactic hard X-ray sky, they are not commonly detected in gamma-rays. High redshift (z>2) objects represent <10 per cent of the AGN population observed by Fermi so far, and gamma-ray flaring activity from these sources is even more uncommon. The characterization of the radio-to-gamma-ray properties of high redshift blazars represents a powerful tool for the study of the energetics of such extreme objects and the Extragalactic Background Light. This contribution will present results of multi-band campaigns, from radio to gamma-rays, on PKS 0836+710, PKS 2149-306, and TXS 0536+145. The latter is the highest redshift detection of a flaring gamma-ray blazar so far. At the peaks of their respective flares these sources reached an apparent isotropic gamma-ray luminosity of about 10^50 erg/s, which is comparable with the luminosity observed from the most powerful blazars. The physical properties derived from the multi-wavelength observations of these sources are then compared with those shown by the high redshift population.

A new generalization of extended beta function and its various properties, integral representations and distribution are given in this paper. In addition, we establish the generalization of extended hypergeometric and con uent hypergeometric functions using the newly extended beta function. The properties these extended and con uent hypergeometric functions such as integral representations, Mellin transformations, dif- ferentiation formulas, transformation and summation formulas are also investigated.

Background: Decision, whether to de-label patient with suspected BL hypersensitivity, is based on the risk stratification. The aim of the study was to prepare a characteristic of diagnostic risk groups and to create a model enabling the identification of the low-risk diagnostic group. Methods: We analyzed medical records of patients hospitalized due to suspected hypersensitivity to BL antibiotics. Based on the history data, patients were divided into three diagnostic risk groups, using the criteria proposed by Shenoy et al. Univariate and multivariate analysis model were used to create a diagnostic tool. Results: Among 263 patients referred for BL hypersensitivity diagnosis, 88 (33.5%) were qualified to group I, 129 (49%) to group II, and 46 (17.5%) to group III. There were significant differences between diagnostic risk groups regarding history of hypersensitivity to penicillins (p<0.001), cephalosporins (p<0.001), >1 BL (p<0.05), several episodes of BL hypersensitivity (p<0.001), medical intervention (p<0.001), documented hypersensitivity (p<0.001), time from drug intake to symptoms (p<0.001), time from hypersensitivity to diagnosis (p<0.001). 81 patients (30.8%) were de-labeled: 52 (59.8%) in group I, 27 (20.9%) in group II and 2 (4.3%) in group III. In univariate analysis, model of the low diagnostic risk group applied to the de-labeled part showed 90% specificity and 21.93% sensitivity. NPV and PPV were estimated at 72.04% and 49.53%, respectively. Multivariate model had high specificity but low sensitivity; its NPV was 76% with 68% PPV. Conclusions: The tool enabling the identification of low diagnostic risk patients based on anamnesis is not sensitive enough, to de-label patients on its basis.

Gender and biological sex have distinct impacts on the pathogenesis of type 2 diabetes (T2D). Estrogen deficiency is known to predispose female mice to T2D. In our previous study, we found that high-fat, high-sucrose diet (HFHSD) induces T2D in male mice through the miR-10b-5p/KLF11/KIT pathway, but not in females, highlighting hormonal disparities in T2D susceptibility. However, the underlying molecular mechanisms of this hormonal protection in females remain elusive. To address this knowledge gap, we utilized ovariectomized, estrogen-deficient female mice, fed them a HFHSD to induce T2D, and investigated the molecular mechanisms pathway in estrogen-deficient diabetic female mice, cell lines, and patients with T2D in female. Initially, female mice fed a HFHSD exhibited delayed onset of T2D, but ovariectomy-induced estrogen deficiency promptly precipitated T2D without delay. Intriguingly, insulin (INS) was upregulated, while insulin receptor (INSR) and protein kinase B (AKT) were downregulated in these estrogen-deficient diabetic female mice, indicating insulin-resistant T2D. These dysregulations of INS, INSR, and AKT were mediated by a miR-10a/b-5p-NCOR2 axis. Treatment of miR-10a/b-5p effectively alleviated hyperglycemia in estrogen-deficient T2D female mice, while β-estradiol temporarily reduced hyperglycemia. Consistent with the murine findings, plasma samples from female T2D patients exhibited significant reductions in miR-10a/b-5p, estrogen, and INSR, but increased insulin levels. Our findings suggest that estrogen protect against insulin-resistant T2D in females through miR-10a/b-5p/NCOR2 pathway, indicating the potential therapeutic benefits of miR-10a/b-5p restoration in female T2D management.

A surge of b-phenylethylamine (PEA), an endogenous monoamine found in traces in the human brain and naturally present in chocolate, has been commonly associated with romantic love earning it the nickname of “love molecule”. The origin of this association must be traced to a speculation dating back to the early eighties that has over time become something of a factoid, reaching a large diffusion through the sharing phenomenon of the Internet. What is disputed in this paper is the existence of any direct biochemical or physiological evidence of the role of PEA in any of the phases of romantic love in the human species. The actual and possible roles of PEA in human physiology are reviewed.

Hemoglobinopathies are a group of disorders in which the hemoglobin molecule has abnormal production or structure. The hemoglobin molecules in red blood cells (RBC) are impacted by the blood disease known as sickle cell disease (SCD), and Thalassemia is one of the major monogenic disorders that reduces hemoglobin production( Kohne et al ., 2011). This disorder results in a large number of red blood cells being destroyed, leading to anemia. India bears a huge burden of hemoglobinopathies; thalassemia is the most prevalent (Mondal SK et al., 2016). A key component of thalassemia prevention is a successful screening procedure to identify Thalassemia carriers. Effective screening programs have numerous obstacles, especially in environments with limited resources. Machine learning (ML) has been used to solve technical and domain-specific problems in a variety of prognostic and diagnostic medical jobs. In this work, we aimed to identify and analyze the most common mutation of β--thalassemia and sickle cell disease from the north Indian population by employing Machine learning-based algorithms. To accurately predict the carrier state from a simple blood test, and to predict pathogenic hemoglobin variants in a group of individuals, these results demonstrate the application of integrated bioinformatics and machine learning approaches. This study contributes to the validation of the models based on data from several individuals and hemoglobinopathies.

Background: Cutaneous melanoma arises from skin melanocytes and has a high risk of metastatic spread. Despite better prevention, earlier detection, and the development of innovative therapies melanoma incidence and mortality increase annually. Major clinical risk factors for melanoma include fair skin, an increased number of nevi, the presence of dysplastic nevi, and a family history of melanoma. However, several external inducers seem to be associated with melanoma susceptibility such as environmental exposure, primarily unprotected sun experience, alcohol consumption, and heavy metals. In recent years, epidemiological studies have highlighted a potential risk of β-hexachlorocyclohexane (β-HCH), the most studied organochlorine pesticide, on cancer induction including melanoma. Methods: We evaluated in vitro the impact of this pollutant on epidermal and dermal cells, attempting to describe mechanisms that could render cutaneous cells more prone to oncogenic transformation. Results: We demonstrated that β-HCH impacts melanocyte biology with a highly cell-type specific signature that involves perturbation of AKT/mTOR and Wnt/β-catenin signaling, and AMPK activation that converges in lowering energy reserve, cell proliferation, and pigment production. Conclusion: In conclusion, long-term exposure to persistent organic pollutants damages melanocyte metabolism in the function of the melanin content with a consequent reduction of melanogenesis indicating a potential augmented skin cancer risk.

We discuss the issues with tentative generalisations of the process matrix formalism from finite-dimensional mechanical systems all the way to quantum field theory. We present a detailed overview of possible open problems that arise when one attempts to move from particle ontology into the realm of field ontology, i.e., when one transitions from mechanics to field theory framework. These issues need to be addressed, and problems solved, if one aims to expand the scope of applicability of the process matrix formalism, and therefore its usefulness. This is far from a trivial and straightforward endeavour, but rather a task for a whole future research programme.

Background and Objectives: Stroke is a main leading cause for mortality and morbidity worldwide. Treat-ment of this pathology is still under development and its risk factors remain the main target to be reached. Therefore, we aim to determine the role of interleukin 1 beta in atheromatosis, as risk factor for stroke and the reole of this biomarker in stroke prognosis. Materials and Methods: The study conducted enrolled 56 patients diagnosed with ischemic stroke in the anterior (AVT) and posterior vascular territory (PVT). All patients had venous blood collected at admission and 7 days after the onset of the cerebral ischemia in order to determine plasma concentration for interleukin 1 beta. At the same time an extracranial carotid ultrasound was performed. Results: Interleukin 1 beta collected at admission was positively correlated with NIHSS at admission (Pearson index 0,424) and both measurements were corelated with carotid stenosis (Spearmen correlation index 0,529, respectively 0,653). Conclusion: Interleukin 1 beta could be a reliable biomarker for stroke prognosis and carotid atheromatosis development.

Beta-carotene is a fat-soluble antioxidant commonly found in foods such as fruits, vegetables, and palm oil. Despite various liquid chromatography methods are proposed to detect and measure the sera carotenoid level, a long retention time to elute this marker is needed. This study attempted to develop a rapid reverse phase method in eluding beta-carotene in human sera. The researchers managed to elute the antioxidant in 2.2 minutes by applying a combination of a C8 column, mobile phase comprising of acetonitrile mixed with methanol in 70:30 proportion, and an ultra-high performance liquid chromatography system. The outputs had a good calibration curve (R²=0.959) and low coefficient of variation (0.2%), suggesting this protocol is reliable. A column with a lower carbon chain such as C8 allows the beta-carotene molecule to flow through the column faster. Besides, selecting solvents with high elution strength coupled with an ultra-high performance liquid chromatography system which equipped with high pressure can force the beta-carotene through the column in a shorter duration compared to previous reported methods. Therefore, it is recommended to adopt this protocol in epidemiological studies where beta-carotene is screened as a dietary biomarker associated with disease of interest by using human sera in the population level.

As the globe becomes more urban, the question how much natural biodiversity can subsist in cities becomes increasingly urgent to answer, and also how is urban diversity structured? To contribute to an answer, we studied the metacommunity of bees in a North European metropolitan area. The system consisted of 13 sites in the city of Aarhus, Denmark, censused from April to September during one year. Bees were sampled monthly in pan traps and a set of traits was related to their presence. In total, 40 species were collected–29 solitary species (40% of all sampled individuals), ten Bombus species (28%), and Apis mellifera (32%). Most sampled bees were soil-nesting, pollen generalists, and relatively common. Habitat diversity within a set of concentric circles with trap as centre and radius from 50 m to 1000 m was related to bee a diversity per site (total bee spp. with and without honeybee, solitary bees, and bumblebees). The relationship was only significant within the 1,000 m circle, and solitary bee diversity did not even correlate with habitat diversity at this large spatial scale level. The bee-site (space) and bee-month (time) networks were analyzed with respect to nestedness, modularity, and spatio-temporal b diversity. The two networks were weakly nested and strongly modular, being composed of five and six modules of tightly linked bees. Total b diversity, b_TOTAL, is the sum of species turnover, b_TURN, and species loss/gain or nestedness, b_NEST; and for both space and time, b_TURN was more important than b_NEST. Furthermore, b_TOTAL was higher than season b_TOTAL. Thus, the urban bee metacommunity was well-structured in both space and time and the high b_TURN indicated, that the network was strongly modular. We suggest the main reason is the high spatio-temporal patchiness of habitats, sustaining many unique species.

Nowadays, we can observe a worldwide trend towards the development of synthetic biomaterials. Numerous researches have been carried out in order to better understand the cellular behavior involved in the inflammation and bone healing processes related to living tissues. The aim of this study is to evaluate the tissue behavior of two different types of biomaterials: synthetic nano-hydroxyapatite / beta-tricalcium phosphate and hydroxyapatite in non-critical bone defects in rat calvaria. Twenty four rats underwent surgery in which two 3 mm defects in each cavity were performed. The rats were divided into 2 groups: Group 1, using xenogen hydroxyapatite (Bio oss ™); Group 2, using synthetic nano-hydroxyapatite / beta-tricalcium phosphate (Blue Bone ™). Sixty days after the surgery, the calvaria bone defect was filled with biomaterial, the animals were sacrificed and marked with Masson's trichrome and PAS staining, and immunohistochemistry (TNF-α, MMP-9) and electron microscopy analyzes were performed. Histomorphometric analysis indicates a greater presence in the protein matrix in Group 2, in addition to higher levels of TNF-α, MMP-9. The ultrastructural analysis shows an association of material with fibroblasts in the tissue regeneration stage. Paired statistical data indicates that Blue Bone ™ can improve bone formation / remodeling when compared to biomaterials of xenogenous origin.

This review was carried out to identify different beta-lactamase resistance genes reported in published literature from Nigeria and to determine the proportion estimates of the important beta-lactamase resistance genes in Nigeria. Sixty-three (63) articles were included in this review based on the eligibility criteria. All the beta-lactamases reported were detected from the Gram-negative bacteria, most especially from Enterobacteriaceae (n=53). Thirty-six different beta-lactamase genes have been reported from Nigeria. These genes belong to the narrow-spectrum, AmpC, extended-spectrum, and carbapenemase beta-lactamase resistance genes. Eight (8) genes (bla_DHA, bla_CTXM-1, bla_CTXM-14, bla_GES-1, bla_VEB-1, bla_OXA-1, bla_OXA-2, and bla_TEM-1) were shared between animals and humans, 5 genes (bla_SHV-1, bla_SHV-2, bla_SHV-11, bla_SHV-12, and bla_NDM-1) were common to both humans and environment while none of the genes was unique to both animals and environment. Four genes including bla_CMY, bla_TEM-1, bla_AmpC, and internationally pandemic bla_CTXM-15 gene were unique to animals, humans, and the environment. No carbapenemase gene was reported from animals yet. The pooled proportion estimate of ESBL genes in Nigeria was 31% (95% CI: 26-36%, P<0.0001), while the estimate of bla_CTXM-15 gene in Nigeria was 46% (95% CI: 36-57%, P<0.0001). The proportion estimate of AmpC genes was 32% (95% CI: 11-52%, P<0.001), while the estimate for carbapenemases was 8% (95% CI: 5-12%, P<0.001). This study has provided information on the beta-lactamases distribution in Nigeria. This is necessary for a better understanding of molecular epidemiology of clinically important beta-lactamases especially the extended-spectrum beta-lactamases and carbapenemases in Nigeria.

Beta thalassemia major (β-TM) disorder characterized by the lack, or severe reduction in the production of hemoglobin β-globin chains. The standard protocol for the management of β-TM is blood transfusion and iron chelation therapy to reduce the iron overload state. The present study aimed to investigate the relationships between two iron regulatory hormones, hepcidin (HEPC) and erythroferrone (ERFE) levels and iron status parameters (ISPs) in Iraqi patients with β-TM. ISPs and hormones were measured in sixty patients and compared with thirty healthy controls. The results indicated significant changes in different iron status parameters, while ferritin (FRT) with the ~11 fold increase showed the most change. Significant reduction in HEPC and increase in ERFE levels were detected in patients as compared to the control group, while no direct correlation was identified with the other measured ISPs. Receiver operating characteristic (ROC) analysis showed that the z-score of the composite of ERFE+FRT has a full diagnostic ability for β-TM. In conclusion, our finding indicated the correlation between different ISPs, FRT as the leading predictor of iron overload and tow main iron regulatory hormones.

The stock beta coefficient literature extensively discusses the proper methods for the estimation of beta as well as its use in asset valuation. However, there are relatively few references with respect to the appropriate time horizon that investors should utilize when evaluating the risk-return relationship of a stock. We examine the appropriate time horizon for beta estimation differentiating our results by sector according to the Industry Classification Benchmark. We employ data from the NYSE and we estimate varying lengths of beta employing data from 30 to 250 trading days. The constructed beta series is then examined for the presence of breaks using the endogenous structural break literature. Results show evidence against the use of betas that employ more than 90 trading days of data provisional to the sector under study.

Cholesterol, a crucial component of cell membranes, influences various biological processes, including membrane trafficking, signal transduction, and host-pathogen interactions. Disruptions in cholesterol homeostasis have been linked to congenital and acquired conditions, including neurodegenerative disorders such as Alzheimer’s disease (AD). Previous research from our group has demonstrated that herpes simplex virus type I (HSV-1) induces an AD-like phenotype in several cell models of infection. This study explores the interplay between cholesterol and HSV-1-induced neurodegeneration. The impact of cholesterol was determined by modulating its levels with methyl-beta-cyclodextrin (MβCD) using the neuroblastoma cell lines SK-N-MC and N2a. We have found that HSV-1 infection triggers the intracellular accumulation of cholesterol in structures resembling endolysosomal/autophagic compartments, a process reversible upon MβCD treatment. Moreover, MβCD exhibits inhibitory effects at various stages of HSV-1 infec-tion, underscoring the importance of cellular cholesterol levels not only in the viral entry pro-cess but also in subsequent post-entry stages. MβCD also alleviated several features of AD-like neurodegeneration induced by viral infection, including lysosomal impairment and intracellu-lar accumulation of amyloid-beta peptide (Aβ) and phosphorylated tau. In conclusion, these findings highlight the connection between cholesterol, neurodegeneration, and HSV-1 infection, providing valuable insights into the underlying mechanisms of AD.

The extremely controversial conclusions about the function of human interferon-gamma (hIFNγ) C-terminus as well as the lack of a consistent model explaining its role in the receptor binding prompted us to scrutinize the interaction of hIFNγ with its extracellular receptor hIFNGR1 in different scenarios by means of molecular dynamics simulations. We find that the two molecules alone fail to form a stable complex but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity essay on cells depleted from surface sulfation confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling.

The field of epigenetics, which explores how heritable traits or stable alterations of cell functions occur without changes to the DNA sequence and how environmental factors affect gene expression, is rapidly advancing. Epigenetics plays a critical role in memory formation, learning, and cognitive functioning, effectively bridging genetics with environmental influence. Maternal behavior in rats, for instance, can modify the stress response of their offspring through epigenetic mechanisms such as histone acetylation and DNA methylation. Understanding neurodegenerative diseases like Parkinson's disease (PD) depends on comprehending the mechanisms of epigenetic regulation. Epigenetic modifications, which alter proteins and DNA structure without changing the DNA sequence, can activate or suppress gene expression, assisting organisms in adapting to environmental changes. These modifications may influence genes involved in inflammation, synaptic plasticity, and neuroprotection, potentially contributing to cognitive deficits in PD patients. MicroRNAs (miRNAs), histone modifications, and DNA methylation are the epigenetic mechanisms that significantly influence cell differentiation and maintain normal cellular activity. Understanding the intricate molecular processes of epigenetics could lead to more targeted and effective therapies. Despite numerous findings on how epigenetics affects cognitive alterations in PD patients, only some studies coordinate and integrate these results. Here, we summarize recent findings on how epigenetic changes impact gene expression linked to cognitive impairments in PD.

With the advancing energy transition, ice is a growing problem in wind turbine sector. The development of systems to detect and mitigate icing makes it necessary to understand its basic behavior and characteristics. This paper proposes a method for the continuous and full field measurement of the icing process of rotating blades, using a single line laser profile scanner. Inside of a climate chamber, a rotor is driven by a motor, while a system of nozzles provides a fine water dust, which leads to ice accumulating on simple NACA blades, that in turn is measured by a triangulation laser. The measurement data is cleared from outliers and presented as a surface in 3D space. An alpha shape is used to reconstruct and extract the volume of the ice between a reference and a measurement surface, using the corresponding Matlab function. Appropriate input parameters for the function and offsetting of the reference surface to improve the results are compared and discussed. The resulting system is able to detect thin changes in the ice layer in the range of sub millimeter thickness.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons and the buildup of misfolded alpha-synuclein proteins. While its exact cause remains unknown, several factors may influence its development. This review examines how factors like chronic constipation, head injuries, cholesterol and uric acid levels, pesticide exposure, smoking, NSAIDs, and caffeine intake may affect PD risk. Chronic constipation appears to be linked to a higher risk of PD, potentially serving as an early warning sign. Head injuries, especially mild-to-moderate ones, may also play a role in increasing PD risk. Surprisingly, higher levels of cholesterol seem to protect against PD, while lower levels of uric acid might increase the risk in the presence of some differences according to gender type. Exposure to certain pesticides is associated with a higher PD risk. NSAIDs, on the other hand, may or may not have a protective effect, with conflicting evidence. Interestingly, caffeine and tobacco smoking appear to lower the PD risk. Further studies are needed to fully understand the complex interplay between these factors and PD. It's also important to remember that these are just general trends, and individual risk factors will vary depending on a person's unique genetic makeup, medical history, and overall health.

(1) Background: Globally, about 600 million people are afflicted with diabetes, and one of its most prevalent complications is neuropathy, a debilitating condition. At present, the exploration of novel therapies for alleviating diabetic neuropathy-associated pain is genuinely captivating, considering that current therapeutic options are characterized by poor efficacy and significant risk of side effects. In the current research, we evaluated the antihyperalgesic effect of sildenafil (phosphodiesterase-5 inhibitor) – metformin (antihyperglycemic agent) combination and its impact on biochemical markers in alloxan-induced diabetic neuropathy in rats; (2) Methods: The study comprised a cohort of 70 diabetic rats and 10 non-diabetic rats which were submitted to hot, cold, and tactile stimulus tests. Morover, we investigated the influence of this combination on TNF-α, IL-6 nitrites and thiols levels in brain and liver tissues; (3) Results: The results demonstrated that all sildenafil-metformin combinations decreased the pain sensitivity in von Frey test, Hot-plate test and Cold-plate test. Furthermore, alterations in nitrites and thiols concentrations and pro-inflammatory cytokines (specifically TNF-α and IL-6) were noted following a 15-day regimen of various sildenafil-metformin combinations. (4) Conclusions: The combination of sildenafil and metformin has a synergistic effect in alleviating pain in alloxan-induced diabetic neuropathy rats. Additionally, the combination effectively decreased inflammation, inhibited the rise in NOS activity, and provided protection against glutathione depletion.

Gas gangrene refers to severe necrotizing syndromes in soft tissues of animals caused by Clos-tridium. Five species of histotoxic clostridia are responsible for myonecroses. These agents require a port of entry, such as skin punctures with needles contaminated with bacterial spores. The present case report describes the clinicopathological findings of gas gangrene in a male Quarter horse living in the Brazilian Amazon biome. Clinical examination revealed clinical signs of toxemia and an enlarged left limb. The anamnesis found the administration of medication to this limb. The animal died five hours after its arrival at the veterinary hospital. At necropsy, histopathological lesions characterized by intense muscle necrosis, liquefaction, and gas formation were observed, suggestive of Clostridium lesions, which were confirmed by multiplex PCR. C. septicum was the etiological agent identified.

Inflammation is a vital aspect of the body's immune response, appearing either as an acute reaction that swiftly develops (e.g., after injury or during an infection) or as a chronic condition that persists over a prolonged period, often linked with autoimmune disorders or cancer. This study introduces potential TNF-alpha inhibitors investigated by Molecular Docking investigation. They are Dactolisib with a binding energy of -10.1 kcal/mol, Nilotinib with -9.6 kcal/mol, Eltrombopag with -9.7 kcal/mol, Radotinib with -9.6 kcal/mol, and Nilotinib again with -9.7 kcal/mol. Additionally, Hypericin exhibited a notable binding energy of -9.9 kcal/mol, suggesting its potential as a natural TNF-alpha inhibitor. While these computational results are preliminary, they provide a foundation for further biological studies to confirm their efficacy. The significance of these findings extends to the scientific community, offering potential applications in the field of inflammatory diseases.

The protection of first responders from radioactive contamination of alpha emitters that may result from a radiological accident is of great complexity due to the short range of the alpha particle in air of a few cm. To overcome this issue, for the first time a system for near real-time measuring alpha particles remotely mounted on a UAS has been developed, tested and calibrated. The new system, based on an optical system adapted to be installed on the UAS in order to measure the UV-C fluorescent emitting by the alpha particle in air, has been tested and calibrated carried out by laboratory and in field experiments using UV-C leds and ²⁴¹Am sources. In experimental flights, the probability of detecting a point source was determined to be approximately 60%. In case of a surface extended source, a detection efficiency per unit surface activity of ten counts per second per MBq cm^-2 are calculated. A background count rate of UV-C around 26 ± 28 s^-1 for an integration time of 0.1 s was measured during flights, which leads to a decision threshold surface activity of 5 MBq cm^-2.

Antiphospholipid syndrome (APS) is a group of autoimmune diseases caused by antiphospholipid antibodies (aPLs) characterized by arteriovenous thrombosis and a morbid pregnancy. We deliberated a case report of seven cases to investigate whether inhibitors of tissue necrosis factor-α could reduce pregnancy dangers caused by APS. The seven patients are with increased tumor necrosis factor, poor improvement after receiving traditional inhibitory drugs. To address these situations, the tumor necrosis factor inhibitors were prescribed after getting the patient's informed consent, and the state of illness was carefully watched for. After treatment, symptoms of contractions and abdominal pain disappeared and the B ultrasound examination showed embryo survived with good obstetric outcomes. Subsequently, maternal and neonatal health is compromised. An intervention by the administration of TNF-α inhibitors was posited to be an effective way of reducing dangerous pregnancies like preterm pregnancies, premature deliveries, abortions and miscarriages. We reviewed outcomes from seven cases in an attempt to establish how TNF- α Inhibitors could save pregnancies. We focused on key pregnancy outcomes like birth weight, gestational weeks and preterm miscarriage to tell the outcomes of TNF- α Inhibitors in pregnancy. After careful evaluation of the results surrounding these aspects, we found that TNF- α Inhibitors could prolong gestational period. Other positive outcomes include the attainment of birth weights approach the threshold, zero incidence of preterm miscarriage.

Background: Deficiency of alpha-1 antitrypsin (AAT1) is a rare disorder that represents a significant health threat and early diagnostic a priority issue. We investigate the usefulness of the serum protein electrophoresis (SPE) as an opportunistic screening tool for AAT1 deficiency. Methods: For 6 months, all SPE carried out for any reasons were evaluated in our center. In those with less than 3% of Alpha-1 globulins, AAT1 concentrations were studied. The SERPINA1 gene was subsequently sequenced in those subjects displaying concentrations below 100 mg/dL. Results: Out of the total, 14 patients (0.3%) were identified with low AAT1 concentrations, 11 of them agreeing to enter the study. Of those, mutations in the SERPINA1 gene were discovered in 10 subjects (91%). Heterozygous mutations were detected in 7 patients; 3 had the c.1096G>A mutation (p.Glu366Lys; Pi*Z), 2 the c.863A>T mutation (p.Glu288Val; Pi*S), one the c.221_223delTCT mutation (p.Phe76del; Pi*Malton) having the last one the c.1066G>A (p.Ala356Thr) mutation not previously described. Finally one patient had the c.863A>T mutation in homozygosis whereas two double heterozygous patients c.863A> T/ c.1096G>A were detected. Conclusions: an altered result in the concentration of AAT1 anticipates a mutation in the SERPINA1 gene in a manner close to 91%. The relationship between a decrease in the Alpha-1 globulin band of the SPE and an alteration in the AAT1 concentration is direct in basal states of health. The SPE is presented as a highly sensitive test for opportunistic screening of AAT1 deficiency.

Glutamate dehydrogenase (GDH) interconverts glutamate to a-ketoglutarate and ammonia, interconnecting amino acid and carbohydrate metabolism. In humans, two functional GDH genes, GLUD1 and GLUD2, encode for hGDH1 and hGDH2, respectively. GLUD2 evolved from retro-transponsition of the GLUD1 gene in the common ancestor of modern apes. These two isoenzymes are involved in the pathophysiology of neoplastic, neurodegenerative, and metabolic disorders. The 3D structures of hGDH1 and hGDH2 have been experimentally determined; however, no information is available about the path of GDH2 structure changes during primate evolution. Here, we compare the structures predicted by the AlphaFold Colab method for the GDH2 enzyme of modern apes and their extinct primate ancestors. Also, we analyze the individual effect of amino acid substitutions emerging during primate evolution. Our most important finding is that the predicted structure of GDH2 in the common ancestor of apes was the steppingstone for the structural evolution of primate GDH2s. Two changes with a strong functional impact occurring at the first evolutionary step, Arg443Ser and Gly456Ala, had a destabilizing and stabilizing effect, respectively, making this step the most important one. Subsequently, GDH2 underwent additional modifications that fine-tuned its enzymatic properties to adapt to the functional needs of modern-day primate tissues.

Background: Despite hearing aids adequately compensate for hearing loss, a substantial proportion of the population leave their hearing difficulties untreated. Even though this is a well-known clinical issue, the optimal approach to address this issue during the hearing rehabilitation process is still unclear. Purpose: The present study aims to characterise behavioural and neurophysiological auditory and cognitive processing skills in experienced hearing aid users versus those with normal hearing, aimed at providing clinicians with the evidence required to adequately manage the expectations of their clients, thus indirectly reinforcing hearing-aid adoption within the adult population with hearing loss. Research design: Behavioural tests included auditory, cognitive, and speech-in-noise tasks; and neurophysiological testing included cortical auditory evoked potentials evoked by a /da/ stimulus presented at 65 dB SPL. The tests were selected based on previous literature supporting specific speech-understanding skills. Study sample: Ten participants (7 female, 21—68 years) with bilateral, mild-moderate to moderately-severe sensorineural hearing loss (HL), and 10 with clinically normal hearing (NH, 8 female, 19—62 years) participated in the study. Data collection and analysis: Behavioural data was analysed using multivariate analysis of variance (MANOVA) and neurophysiological analysis used measurements such as independent t-test, time-frequency analysis and inter-trial phase coherence. Results: The NH and HL groups presented similar scores in all the behavioural tasks. Time-frequency analysis revealed a statistically significantly reduction in alpha (8–12 Hz) synchronisation at the centro-frontal electrodes in the HL group – a brain activity pattern that has been associated with listening effort, inhibition and selective attention. Conclusions and significance: Results support the conclusion that hearing aids are effective in compensating for the audibility of their users, enabling them to perform at similar levels than their normal-hearing peers. However, the reduced alpha synchronisation observed in the HL population indicates that adequate audibility does not extend to improved neural responses. Future studies need to investigate the induced activity in speech understanding paradigms to explore the auditory processing differences at cortical level. The results are only from a small sample size but the findings have the potential to support clinicians in managing adequately the expectations of their clients in regards the benefits of hearing aid technologies.

The primary goal of this research is to examine the α-amylase inhibitory effect of phytoconstituents found in the roots of the Cyclea peltata plant. The extract will also be used to investigate the effect of root extract on α-amylase inhibition assay. The roots were gathered, processed, and extracted in petroleum ether before being kept at 4ºC. The extract was exposed to a preliminary phytochemical examination. The extract was employed in the α-amylase inhibition experiment at concentrations of 50, 100, 200, 400, 600, 800, and 1000 µg/ml with acarbose as a control. Molecular docking analysis was performed on the phytoconstituents cycleapeltine, cycleadrine, cycleacurine, cycleanorine, cycleahomine chloride, and acarbose on human pancreatic alpha-amylase 1B2Y. A preliminary phytochemical study revealed the presence of alkaloids, saponins, and terpenoids. The tests came back negative for flavonoids, steroids, and tannin. The root extract inhibited α-amylase at 69.42 ± 0.74 % at 1000 µg/ml and acarbose at 94.63 ± 0.57 %. The IC50 value was calculated and found to be 484.08 µg/ml for the extract and 42.47 µg/ml. The docking studies, revealed that cycleacurine (-4.751 Kcal/mol) has a comparable anti-diabetic effect to Acarbose (-6.713 Kcal/mol). Furthermore, the function groups –OH and –NH found in phytoconstituents interacted with the active site of 1B2Y similarly to acarbose. This provides evidence that the function groups –OH and –NH present in the phytoconstituents might inhibit alpha amylase.

The potato tuber moth PTM, Phthorimaea operculella, is one of the most economically important potato pests worldwide. In the present study, the potential of Steinernema feltiae and Steinernema carpocapsae for controlling PTM in potato tubers was evaluated compared to alpha-cypermethrin. Steinernema carpocapsae in both concentrations (12.6×10⁶IJs and 6.2×10⁶IJs) showed a lower number of emerged insects than alpha-cypermethrin (10 mg ai l^-1). Alpha-cypermethrin (20 mg ai l^-1) showed the highest efficacy against PTM (81.17%), S.carpocapsae (12.6×10⁶IJs), and alpha-cypermethrin (10 mg ai l^-1) showed similar efficacy (72.53%) while S. feltiae (6.2×10⁶IJs) showed the lowest efficacy (39.04%). The results showed that S.carpocapsae in both concentrations and S. feltiae (12.6×10⁶IJs) were efficient the same as alpha-cypermethrin (10 mg ai l^-1) having no environmental and health adverse impacts issued in the chemical insecticides usage. Both concentrations of alpha-cypermethrin and S. carpocapsae showed the least tuber damage with no significant differences, while it was as high as the control (59.26%) in both concentrations of S. feltiae. This promising finding introduces EPNs as a part of the potato tuber protection program in storage. Accordingly, EPNs can be considered as an appropriate alternative to synthetic chemicals for PTM control without any residue and health problems.

We consider the inverse function $z=g(w)$ of a (normalized) starlike function $w=f(z)$ of order $\alpha$ on the unit disk of the complex plane with $0<\alpha<1.$ Krzy{\. z}, Libera and Z\l otkiewicz obtained sharp estimates of the second and the third coefficients of $g(w)$ in their 1979 paper. Prokhorov and Szynal gave sharp estimates of the fourth coefficient of $g(w)$ as a consequence of the solution to an extremal problem in 1981. We give a straightforward proof of the estimate of the fourth coefficient of $g(w)$ together with explicit forms of the extremal functions.

New class of triazinoindole bearing thiosemicarbazide (1-25) was synthesized and evaluated for α-glucosidase inhibitory potential. All synthesized analogues exhibited excellent inhibitory potential having IC50 values ranging from 1.30 ± 0.01 to 35.80 ± 0.80 µM when compared with the standard acarbose having IC50 value 38.60 ± 0.20 µM. Among series the analogues 1 and 23 was found the most potent having IC50 values 1.30 ± 0.05 and 1.30 ± 0.01 µM respectively. Structure activity relationship (SAR) was mainly based upon by bring about difference of substituents on phenyl rings. To confirm the binding interactions, molecular docking study was performed. Synthesized analogues were characterized through HREI-MS, 1H and 13C-NMR analysis.

Background: This study aimed to describe the frequency and duration of sedentary bouts and assess the bidirectional cross-sectional associations between these characteristics and adiposity in elderly women. Methods: Data from 314 elderly community-dwelling women (mean age 66.6±6.5 years) from Czech Republic, Poland, and Slovakia were analyzed. Measures were collected in 2008–2017. Fat mass percentage (FM%) was used as an indicator of adiposity. The patterns of sedentary behaviour were monitored using an accelerometer, and ≥5, ≥10, ≥20, ≥30, ≥40, and ≥60 minute bouts were analyzed. The exponent alpha was also calculated to express the accumulation of sedentary time in bouts. We performed a multiple linear regression analysis to assess the bidirectional causal association between variables. Results: There was a significant association of FM% with time spent in bouts with a duration ≥5, ≥10, ≥20min (β ranging 0.11–0.28, p≤0.01) and the frequency of bouts with a length ≥5, ≥10, ≥20, and ≥30min (β ranging 0.03–0.74, p≤0.05) in fully-adjusted models. In contrast, a strong negative association was observed between FM% and alpha (bout distribution) in both directions (p≤0.001). Conclusions: Our results suggest that the sedentary characteristics such as bout duration, bout frequency, and distribution (alpha) are bidirectionally associated with adiposity and they should be considered in further research in older adults.

Interferon-gamma release assays (IGRAs) gained attention for diagnosing latent tuberculosis infection (LTBI) due to their higher specificity compared to the tuberculin skin test (TST). However, IGRA performance varied across different populations. This study evaluated the diagnostic performance of three IGRA assays (TBF-FIA, TBF-ELISA, and QFT-Plus) in Ghana, comparing them among individuals exposed and unexposed to MTB infection. Conducted in TB clinics across three regions, this prospective and cross-sectional study included healthy individuals with no known TB exposure (unexposed group) and patients with confirmed active TB (exposed group). Blood samples were tested using all three assays per manufacturers’ guidelines. The TBF-ELISA showed 3.4% higher sensitivity, but 4.6% lower specificity compared to QFT-Plus. The TBF-FIA had a sensitivity of 78.5%-87.3% and a specificity of 82.9%-90.0%. These findings indicated that while the three IGRA assays offered similar diagnostic accuracy, variations in specificity and limited data on point-of-care assays like TBF-FIA required further investigation.

Epigenetic changes regulate gene expression through histone modifications, chromatin remod-eling and proteins interpreter of these modifications. The PRC1 and PRC2 complexes shape gene repression via histone modifications. Specifically, the CBX protein family aids PRC1 recruitment to chromatin, impacting the progressive multistep process driving chromatin silencing. Among family members, CBX3 is a complex protein involved in aberrant epigenetic mechanisms that drive lung cancer progression. CBX3 promotes lung tumorigenesis by interacting with key pathways such as PI3K/AKT, Ras/KRAS, Wnt/β-catenin, MAPK, Notch, and p53, leading to in-creased proliferation, inhibition of apoptosis, and enhanced resistance to therapy. Given our current lack of knowledge, additional research is required to uncover the intricate mechanisms underlying CBX3 activity, as well as its involvement in molecular pathways and its potential biomarker evaluation. Specifically, the dissimilar roles of CBX3 could be reexamined in order to gain a greater insight into lung cancer pathogenesis. This review aims to provide a clear overview of the context-related molecular profile of CBX3, which could be useful for addressing clinical challenges and developing novel targeted therapies based on personalized medicine.

Gemcitabine (2',2'-difluoro-2'-deoxycytidine), a widely used anticancer drug, is considered as a gold standard in treating aggressive pancreatic cancers. Gamma-proteobacteria that colonize the pancreatic tumors contribute to chemoresistance against gemcitabine by metabolizing the drug to a less active, deaminated, form. The gemcitabine transporters of these bacteria are unknown to date. Furthermore, there is no complete knowledge on the gemcitabine transporters in Escherichia coli or any other related proteobacteria. In this study, we investigate the complement of gemcitabine transporters in E. coli K-12 and two common chemoresistance-related bacteria (Klebsiella pneumoniae, Citrobacter freundii). We find that E. coli K-12 has two high-affinity gemcitabine transporters with distinct specificity properties, namely NupC and NupG, whereas the gemcitabine transporters of C. freundii and K. pneumoniae include the NupC and NupG orthologs, indistinguishable functionally from their counterparts, and, in K. pneumoniae, one additional NupC variant, designated KpNupC2. All these bacterial transporters have higher affinity for gemcitabine than their human counterparts. The highest affinity (KM 2.5-3.0 μΜ) is exhibited by NupGs of the Bacteria-specific Nucleoside-H+ Symporter (NHS) family followed by NupCs (KM 10-13 μΜ) of the Concentrative Nucleoside Transporter (CNT) family, 15-100 times higher than the affinities reported for the human gemcitabine transporter hENT1/SLC29A1 which is primarily associated with gemcitabine uptake in the pancreatic adenocarcinoma cells. Our results offer a basis for further insight into the role of specific bacteria in drug availability within tumors and understanding the structure-function differences of bacterial and human drug transporters.

The saphenous vein is the conduit of choice for bypass grafting. Unfortunately, the hemodynamic stress associated with the arterial environment of the bypass vein graft leads to the development of intimal hyperplasia (IH), an excessive cellular growth and collagen deposition that results in restenosis and secondary graft occlusion. Hydrogen sulfide (H2S) is a ubiquitous redox-modifying gasotransmitter that inhibits IH. H2S is produced via the reverse trans-sulfuration pathway by 3 enzymes: cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST). However, the expression and regulation of these enzymes in the human vasculature remains unclear. Here, we investigated the expression of CSE, CBS and 3-MST in segments of native human saphenous vein and large arteries. Furthermore, we evaluated the regulation of these enzymes in vein segments cultured under static, venous (7 mmHg pressure) or arterial (100 mmHg pressure) pressure. CSE was expressed in the media, neointima and intima of the vessels and was negatively regulated by arterial shear stress. Adenoviral-mediated CSE overexpression or RNA interference-mediated CSE knock-down revealed that CSE inhibited primary human VSMC migration but not proliferation. We propose that high shear stress in arteriovenous bypass grafts inhibits CSE expression in both the media and endothelium, which may contribute to increased VSMC migration in the context of IH.

The successive steps of the oxidation mechanism of crocin, major compound of saffron, by the free OH• radical are investigated by the pulse radiolysis, steady-state (gamma) radiolysis methods and molecular simulations. The optical absorption properties of the transient species and their reaction rate constants are determined. The absorption spectrum of the oxidized radical of crocin resulting from the H-abstraction presents a maximum at 678 nm and a band at 441 nm, almost as intense as that of crocin. The spectrum of the covalent dimer of this radical contains an intense band at 441 nm and a weaker one at 330 nm. The final oxidized crocin, issued from radical disproportionation, absorbs weaker with a maximum at 330 nm. The molecular simulation results suggest that the OH• radical is electrostatically attracted by the terminal sugar and is scavenged predominantly by the neighbor methyl site of the polyene chain as in a sugar-driven mechanism. Based on detailed experimental and theoretical investigations, the antioxidant properties of crocin are highlighted.

The aim of this study was to investigate the possible role of 99mTc-sestamibi in the regulation of cancer cell proliferation and apoptosis. To this end, Te in vivo values of 99mTc-sestamibi uptake have been associated to the in-situ expression of both Ki67 and caspase-3. For in vitro investiga-tions BT-474 cells were incubated with three different concentration of 99mTc-sestamibi: 10µg/ml –1µg/ml – 0,1µg/ml. Expression of caspase-3 and Ki67, as well as the ultrastructure of cancer cells, were evaluated at T0 and after 24, 48, 72 and 120 hours after 99mTc-sestamibi incubation. Ex vivo data strengthened the known association between the sestamibi uptake and the Ki67 expression. Linear regression analysis showed a significant association between the sestamibi uptake and the number of apoptotic cells evaluated as caspase-3 positive breast cancer cells. As concern the in vitro data, a significant decrease of the proliferation index was observed in breast cancer cells incubated with high concentration of 99mTc-sestamibi (10µg/ml). Amazingly, a significant increase in caspase-3 positive cells in cultures incubated with 10µg/ml 99mTc-sestamibi was observed. This study suggested the possible role of sestamibi in the regulation of pathophysiological process involved in breast cancer.

Kim-Kim (Russ. J. Math. Phys. 2017, 24, 241-248) defined the degenerate Laplace transform and investigated some of their certain properties. Motivated by this study, in this paper, we introduce the degenerate Sumudu transform and establish some properties and relations. We derive degenerate Sumudu transforms of power functions, degenerate sine, degenerate cosine, degenerate hyperbolic sine, degenerate hyperbolic cosine, degenerate exponential function, and function derivatives. We also acquire a relationship between degenerate Sumudu transform and degenerate gamma function. Moreover, we investigate a scale preserving theorem for the degenerate Sumudu transform. Furthermore, we show that the degenerate Sumudu transform is the theoretical dual transform to the degenerate Laplace transform.

Diabetic retinopathy (DR), a prevalent complication of diabetes mellitus affecting a significant portion of the global population, has long been viewed primarily as a microvascular disorder. However, emerging evidence suggests that it should be redefined as a neurovascular disease with multifaceted pathogenesis rooted in oxidative stress and advanced glycation end products. The transforming growth factor-β (TGF-β) signaling family has emerged as a major contributor to DR pathogenesis due to its pivotal role in retinal vascular homeostasis, endothelial cell barrier function, and pericyte differentiation. However, the precise roles of TGF-β signaling in DR remain incompletely understood, with conflicting reports on its impact in different stages of the disease. Additionally, the BMP subfamily within the TGF-β superfamily introduces further complexity, with BMPs exhibiting both pro- and anti-angiogenic properties. Furthermore, TGF-β signaling extends beyond the vascular realm, encompassing immune regulation, neuronal survival, and maintenance. The intricate interactions between TGF-β and reactive oxygen species (ROS), non-coding RNAs, and inflammatory mediators have been implicated in the pathogenesis of DR. This review delves into the complex web of signaling pathways orchestrated by the TGF-β superfamily and their involvement in DR. A comprehensive understanding of these pathways may hold the key to developing targeted therapies to halt or mitigate the progression of DR and its devastating consequences.

Natural products play a crucial role in drug discovery, primarily due to their structural complexity. The prenylated flavanone, glabranin ((S)-5,7-dihydroxy-8-(3-methylbut-2-en-1-yl)-2-phenylchroman-4-one), isolated plant Dalea elegans, has demonstrated neuroprotective effects, attributed to its inhibition of GSK-3β as per our previous in silico studies. Given the enzyme's diverse functions and its potential as a target for neurodegenerative diseases, our group synthesized and evaluated an 11C-labeled derivative of glabranin. We present its in vitro biological activity, including IC50, neuronal uptake in Alzheimer’s-affected brain regions, key physicochemical properties, and animal studies. This study confirms [11C]FLA's interaction with GSK-3β in vitro, highlighting the potential of radiotracers in bioactive compound research.

Lithium has long been recognized for its therapeutic efficacy in the treatment of manic-depressive illness (MDI). Additionally, numerous reports highlight its protective properties against cell insults, with a remarkable majority of these effects documented in neurons. Utilizing the major mechanisms of its action, we bring insights that explain lithium's ability to preferentially promote survival in neurons. Specifically, we explore its interactions with magnesium at protein binding sites, with a particular focus on its impact on glycogen synthase kinase 3 beta (GSK3β). We propose that lower intracellular free magnesium levels in the brain, coupled with the higher expression of GSK3β, which is an enzyme whose activity is magnesium-dependent, amplify its impact on brain cells, promoting neuronal survival.

Exposure to environment polluting chemicals (EPCs), which are ligands of the aryl hydrocarbon receptor (AhR), is associated with the development of type 2 diabetes (T2D). This study explores the mechanisms by which AhR ligands contribute to β-cell failure in T2D. Incubation of rat RINm5F pancreatic β-cells with low-dose 2,3,7,8-tetrachlorodibenzodioxin (TCDD), the most potent AhR ligand, inhibited glucose-stimulated insulin secretion (GSIS). A single injection of TCDD in wild type mice reduced the size of Langerhans islets, but not in AhR liver knock-out mice (AhR-LKO). RNA-seq database analysis identified Serpine1, encoding for plasminogen activator inhibitor type-1 (PAI-1) as a TCDD-mediated secretory protein that are synthesized in an AhR-dependent manner in the liver. Elevated PAI-1 levels were shown to induce caspase 3/7-dependent apoptosis in RINm5F cells, suggesting a novel pathway through which EPCs exacerbate T2D. These findings support the hypothesis that chronic exposure to AhR ligands may directly inhibit GSIS in pan-creatic β-cells and indirectly induced β-cell apoptosis through increased PAI-1. This study provides new insights into the EPC-PAI-1 axis as a missing link between pancreatic β-cell failure and the progression of T2D and offers a potential target for therapeutic intervention.

Alzheimer’s disease (AD), the leading cause of dementia (50-70%), is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and significant neuropathological changes, including β-amyloid plaques and neurofibrillary tangles. This review synthesizes current understanding of the complex interplays that contribute to the pathogenesis of AD, while exploring the mechanisms underlying the formation of β-amyloid plaques and neurofibrillary tangles, with a focus on the amyloidogenic and non-amyloidogenic pathways, Tau protein hyperphosphorylation, and the resultant neurotoxicity. Furthermore, the study delves into mitochondrial dysfunction and oxidative stress as critical contributors to neuronal degeneration, highlighting the mitochondrial cascade hypothesis and its implications in both early (EOAD) and late-onset AD (LOAD). The study emphasizes the irreversible nature of the disease’s progression, detailing the pathological transformations from the preclinical to the severe stage, where lesions disseminate throughout the entire cortex.

The need for solvating and encapsulating hydro-sensitive molecules drives noticeable trends in the applications of cyclodextrins in pharmaceutical industry, food, polymer, materials, and agricultural science. Among them, β-cyclodextrin is one of the most used for the entrapment of phenolic acid compounds to mask the bitterness of wheat bran. In this regard, there is still a need for a good predictive model that assesses β-cyclodextrin bitterness masking capabilities for various phenolic compounds. This study uses a dataset of 20 phenolic acids docked to the β-cyclodextrin cavity to generate three different binding constants. The data from docking study were combined with topological, topographical and quantum-chemical features from the ligands in a machine learning-based structure-activity relationship study. Three different models for each binding constant were computed using a combination of Genetic Algorithm (GA) and Multiple Linear Regression (MLR) approaches. The developed ML/QSAR models showed a very good performance, with high predictive ability and correlation coefficients of 0.969 and 0.984, for training and test sets, respectively. The models revealed several factors responsible for a binding with cyclodextrin, showing positive contributions toward the binding affinity values, including such features as presence of six-membered rings in the molecule, branching, electronegativity values, and polar surface area.

Hepatocellular carcinoma (HCC) development is associated with altered modifications in DNA methylation, changing transcriptional regulation. Emerging evidence indicates that DNA methyltransferase 1 (DNMT1) plays a key role in carcinogenesis process. This study aimed to investigate how pirfenidone (PFD) modifies this pathway and the effect generated by the association between c-Myc expression and DNMT1 activation. Rats F344 were used for HCC development using 50 mg/kg of diethylnitrosamine (DEN) and 25 mg/kg of 2-aminofluorene (2-AAF). HCC/PFD group received simultaneous doses of 300 mg/kg of PFD. All treatments lasted 12 weeks. On the other hand, HepG2 cells were used to evaluate the effects of PFD in restoring DNA methylation in the presence of the inhibitor 5-Aza. Histopathological, biochemical, immunohistochemical, and western blot analysis were carried out and our findings showed that PFD treatment reduced the amount and size of tumors along with decreased Glipican-3, β-catenin, and c-Myc expression in nuclear fractions. Also, this treatment improved lipid metabolism by modulating PPARγ and SREBP1 signaling. Interestingly, PFD augmented DNMT1 and DNMT3a protein expression, which restores global methylation, both in our in vivo and in vitro models. In conclusion, our results suggest that PFD could slow down HCC development by controlling DNA methylation.

A new polymorph of anhydrous β-cyclodextrin (polymorph III) was obtained and characterized for the first time using powder X-ray diffraction, infrared spectroscopy and thermal analysis. Solution enthalpy and time of dissolution in water were determined by solution calorimetry for this polymorph and compared with those of dried commercial form of β-cyclodextrin (polymorph I), its amorphous form and 2-hydroxypropyl-β-cyclodextrin. Specific heat capacity of polymorphs I and III was determined by differential scanning calorimetry in the wide range of temperatures, which gives enthalpy and Gibbs energy of polymorphic transition at 298 K. Affinity of polymorph III and 2-hydroxypropyl-β-cyclodextrin for water was characterized by determination of their hydration isotherms, which gives the values of hydration Gibbs energy. Being energy-rich, the found new polymorph of β-cyclodextrin has a significantly higher dissolution rate and an in-creased affinity for water compared with the dried commercial form of β-cyclodextrin. Such properties make the new polymorph promising in industrial applications for guest inclusion in aqueous solutions and pastes and may be a desirable alternative for water-soluble β-cyclodextrin derivatives.

Following ischemic stroke, the degradation of myelin and other cellular membranes surpasses the lipid-processing capabilities of resident microglia and infiltrating macrophages. This imbalance leads to foam cell formation in the infarct and areas of secondary neurodegeneration, instigating sustained inflammation and furthering neurological damage. Given that mitochondria are the primary sites of fatty acid metabolism, augmenting mitochondrial biogenesis (MB) may enhance lipid processing, curtailing foam cell formation and post-stroke chronic inflammation. Previous studies have shown that the pharmacological activation of the β2-adrenergic receptor (β2-AR) stimulates MB. Consequently, our study sought to discern the effects of intensified β2-AR signal-ing on MB, the processing of brain lipid debris, and neurological outcome using a mouse stroke model. To achieve this goal, aged mice were treated with formoterol, a long-acting β2-AR ago-nist, daily for two and eight weeks following stroke. Formoterol increased MB in the infarct re-gion, modified fatty acid metabolism, and reduced foam cell formation. However, it did not re-duce markers of post-stroke neurodegeneration or improve recovery. Our findings suggest that boosting MB in myeloid cells is one component of a therapeutic avenue for improving brain lipid debris processing after stroke.

Multidrug-resistant (MDR) Pseudomonas aeruginosa infections represent major a public health concern and require comprehensive understanding of their genetic make-up. This study investigated the first occurrence of IMP-carrying MDR P. aeruginosa strains from Bulgaria. Whole genome sequencing identified a novel plasmid-mediated blaIMP-100 allele located in a In1300-like integron embedded in a novel putative transposon. Two other closely related chromosomal blaIMP variants IMP-13 and IMP-84 were also detected. The IMP-producers were resistant to last-line drugs including cefiderocol (CFDC) (2 out of 3) and susceptible to colistin. The blaIMP-13/84 cassettes were situated in a In320 integron inserted in a Tn5051-like transposon as previously reported. Lastly, the p47825-IMP plasmid rendered PAO1 transformant resistant to CFDC, suggesting a transferable CFDC resistance. A variety of virulence factors associated with adhesion, antiphagocytosis, iron uptake, quorum-sensing, as well as secretion systems, toxins, and proteases were confirmed, suggesting significant pathogenic potential consistent with the observed strong biofilm formation. Emergence of IMP-producing MDR P. aeruginosa is alarming as they remain unsusceptible even to last geneneration drugs like CFDC. Newly detected IMP-100 was even located in an CFDC-resistant XDR strain.

A morning lymphocytosis has been observed in patients under methylprednisolone (mPDN) treatment. We here determine prospectively the timing and magnitude of mPDN-induced lymphocytosis and study the effects of concomitant beta-blockers administration on lymphocyte count (L). L was measured before and 24 to 72 hours after initiating mPDN treatment in 20 patients with immune-mediated inflammatory disorders (IMID). After one week, patients with increased L were divided in two groups receiving, in addition to mPDN, either propranolol or a placebo; L was determined 4 days later. Lymphocyte subpopulations and mPDN plasma levels were determined in subsets of the patients. Values are expressed as median with 25%-75% interquartile range. A 73.4 % (37-305) increase of L was observed in 18/20 patients as soon as 48 (48-72) hours after initiating mPDN (32 mg; 16-32). Lymphocytosis (L ≥4,000/µL) was observed in 7 patients and hyperlymphocytosis (L ≥ 5,000/µL) in 4 of them. No significant changes in L variation were shown under propranolol. In conclusion, the morning lymphocytosis observed during mPDN treatment occurs in the very first days of mPDN administration. The lack of effect of propranolol does not support the role of an increased adrenergic tone.

: Supplement the use of ergogenic aids in cyclist’s directly have been improved the body metabolism and hemodynamic factors that are micro supplement in chancing reactions on the body muscle mass and limb muscle. Mostly knowing that, muscle power development progressive fast glycolytic and short time oxidative systems reactions. Sport competition intervals, therefore, during periods has been used specific drinks supported to cyclists. But, be obtained during should be long race times. Athletes directly needed some drug and fluid intake to prevented from metabolic breakdown rapidly the dynamic physiologic performance factors. Beta-alanine supplementation can be direct muscle performance development affects the anaerobic metabolism and capacity. It should be de-termined how the cyclists will use the competitive and training period intervals can increase the cyclists specific sprint and endurance race performance. Science cyclist International Road doses will be created in which, intervals can random effectively the investigate. This study random a cohort studies is examined the effects of beta-alanine supplementation on aerobic and anaerobic power output in specific cyclists. Therefore, we have been databases PubMed, Scopus and Medline initial search 10 August 2020 were created prospective effect the quality of bias work concluded effect size (ES) 95% confidence interval (CI) were used in participant. Participations (N=66) have age range 25 to 38 of the using beta-alanine in training periods to endurance muscle performance, aerobic power, anaerobic power, and sprint time trials. As a result of beta-alanine improved an-aerobic and aerobic power output on 4-week time-dependent trial performance condition. Signifi-cant values are obtained level factor alpha <0.05 and p-value analysis pre-post interactive stand-ardization.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The interferons (IFNs) were discovered in 1957, and recombinant IFN-β-1b was approved by the US Food and Drug Administration as the first disease-modifying therapy (DMT) for MS in 1993. Since that time, clinical trials and real-world observational studies have demonstrated the effectiveness of IFN therapies. The pivotal intramuscular IFN-β-1a phase 3 trial was the first to demonstrate that a DMT could reduce accumulation of sustained disability in MS. Patient adherence to treatment is higher with intramuscular IFN-β-1a, given once weekly, than with subcutaneous formulations requiring multiple injections per week. Moreover, subcutaneous IFN-β-1a is associated with an increased incidence of injection site reactions and neutralizing antibodies compared with intramuscular administration. In recent years, revisions to MS diagnostic criteria have improved clinicians’ ability to identify patients with MS and have promoted the use of magnetic resonance imaging (MRI) for diagnosis and monitoring. MRI studies show that treatment with IFN-β-1a, relative to placebo, reduces T2 and gadolinium-enhancing lesions and gray matter atrophy. Since the approval of intramuscular IFN-β-1a, several high-efficacy therapies have been approved for MS, though the benefit of these high-efficacy therapies should be balanced against the increased risk of serious adverse events. For some subpopulations of patients, including pregnant women, the safety profile of IFN-β formulations may provide a particular benefit. In addition, the antiviral properties of IFNs may indicate therapeutic opportunities for IFN-β in the treatment of viral infections such as COVID-19.

Bone innate ability to repair without scaring is surpassed by major bone damage. Current gold-standard strategies do not achieve a full recovery of bone biomechanical properties. To bypass these limitations, tissue engineering techniques based on hybrid materials made up of osteoprogenitor cells, like mesenchymal stem cells (MSCs), and bioactive ceramic scaffolds, like calcium phosphate-based (CaPs), are promising. Biological properties of the MSCs, are influenced by the tissue source. The aim of this study is to define the MSC source and construct (MSC and scaffold combination) most interesting for its clinical application in bone regeneration. iTRAQ generated the hypothesis that anatomical proximity to bone has a direct effect on MSC phenotype. MSCs were isolated from adipose tissue, bone marrow and dental pulp. MSCs were cultured both on plastic surface and on CaPs (hydroxyapatite and β-tricalcium phosphate) to compare their biological features. On plastic, MSCs isolated from dental pulp (DPSCs) were the MSCs with the highest proliferation capacity and the greatest osteogenic potential. On both CaPs, DPSCs are the MSCs with the greatest capacity to colonize bioceramics. Furthermore, results show a trend for DPSCs are the MSCs with the most robust increase in the ALP activity. We propose DPSCs as a suitable MSCs for bone regeneration cell-based strategies.What do you want to do ?New mailCopy

Substantial studies have focused on early detection of Alzheimer's disease (AD). Cerebral amyloid beta (Aβ), is hallmark of AD, can be observed in vivo via positron emission tomography imaging using amyloid tracer or cerebrospinal fluid assessment, but costly expensive. The current study aims to identify and compared predictability in magnetic resonance imaging (MRI) markers and neuropsychological markers to predict cerebral Aβ status in AD cohort using machine learning (ML) approaches. The predictability in candidate markers for cerebral Aβ status was examined by analyzing 724 participants from the ADNI-2 cohort. Demographic variables, structural MRI markers, and neuropsychological test scores were used as input in several ML algorithms to predict cerebral Aβ positivity. Out of five combination of candidate markers, neuropsychological markers with demographics showed the most cost-efficient result. A feature selection model could distinguish abnormal levels of Aβ with the predictability of 0.85, indicating the same performance with MRI-based models. The result has first to identified the predictability in MRI markers using ML approaches, and secondary to demonstrate the neuropsychological model with demographics could predict Aβ positivity, suggesting a more cost-efficient method for detecting cerebral Aβ status compared to MRI markers.

Clinical pathogens especially Gram-negative bacteria developing resistance to third-generation cephalosporins are making the clinical outcome more complicated and serious. This study was undertaken to evaluate the distribution of extended-spectrum beta-lactamases in Tamil Nadu regions in India. For this study, clinical samples were collected from five different hospitals located in Tamil Nadu and ESBL producing Gram-negative isolates were characterized. Minimal inhibitory concentration (MIC) was performed using cefotaxime and ceftazidime. The blaESBL producing genes were screened using multiplex PCR for the genes, CTX-M group-1,-2,-8,-9,-26. Conjugation studies were performed using E. coli AB1157 as a recipient for the isolates harbouring plasmid-borne resistance following broth-mating experiment. In total, 1500 samples were collected and 599 Gram-negative bacteria were isolated that included Escherichia coli (n=233), Klebsiella pneumoniae (n=182), Pseudomonas aeruginosa (n=79), Citrobacter spp. (n=30), Proteus mirabilis (n=28), Salmonella spp. (n=21), Acinetobacter baumannii (n=12), Serratia spp. (n=6), Shigella spp. (n=4), Morganella morganii (n=3) and Providencia spp. (n=1). MIC results showed that 358 isolates were resistant to cefotaxime and ceftazidime. Further, ESBL gene amplification results showed that 19 isolates had CTX-M group-1 gene including E. coli (n=16), K. pneumoniae (n=2) and P. aeruginosa (n=1) whereas one M. morganii isolate had CTX-M group-9 gene in their plasmid. Through conjugation studies, 12/20 isolates were found to be involved in the transformation of its plasmid-borne resistance gene. Our study highlighted the role of horizontal gene transfer in the dissemination of plasmid-borne blaCTX-M resistance genes among ESBL producing isolates.

By manipulating the various physico-chemical properties of amino acids, design of peptides with specific self-assembling properties has been emerging since more than a decade. In this context, short peptides possessing detergent properties (so-called “peptergents”) have been developed to self-assemble into well-ordered nanostructures that can stabilize membrane proteins for crystallization. In this study, the peptide with “peptergency” properties, called ADA8 extensively described by Zhang et al., is studied by molecular dynamics for its self-assembling properties in different conditions. In water, it spontaneously forms beta sheets with a β barrel-like structure. We next simulated the interaction of this peptide with a membrane protein, the bacteriorhodopsin, in the presence or absence of a micelle of dodecylphosphocholine. According to the literature, the peptergent ADA8 is thought to generate a belt of β structures around the hydrophobic helical domain that could help stabilize purified membrane proteins. Molecular dynamics is here used to challenge this view and to provide further molecular details for the replacement of detergent molecules around the protein. To our best knowledge, this is the first molecular mechanism proposed for ''peptergency''. In addition, our calculation approach should serve as a predicting tool for the design of beta peptergent with diverse amphipathic properties.

The main objective of this paper is to introduce k-fractional derivative operator by using the definition of k-beta function. We establish some results related to the newly defined fractional operator such as Mellin transform and relations to k-hypergeometric and k-Appell's functions. Also, we investigate the k-fractional derivative of k-Mittag-Leffler and Wright hypergeometric functions.

Type II diabetes is a major coronavirus disease comorbidity that can be prevented through a diet. Capsicum annuum (chili) consumption is often suggested, and using functional food cultivars is the most effective strategy. However, the general combining ability (GCA), specific combining ability (SCA), and heterotic effect of functional biochemicals (polyphenol content, antioxidant activities, and α-glucosidase inhibitory compounds) remain poorly known in C. annuum. This study aimed to estimate those parameters in C. annuum by using five different genotypes and their hybrid com-binations based on growth characteristics, yield, yield components, and fruit functional biochem-icals. The F1 and F1R progenies were obtained from crosses in a greenhouse and full diallel design. Each parent used in this study had a GCA advantage for each character. The hybrid combination of 074 x 005 and 435 x 367 displayed the best yield results. However, the results indicated the opposite regarding α-glucosidase inhibitory. The heterotic effect of functional biochemicals was observed for traits related to genotypes, polyphenol content, antioxidant activity, α-glucosidase inhibitory compounds, and similar properties related to yield and yield components, indicating their hybrid use in chili production.

Background: Mounting evidence supports the role of the endocannabinoid system in neurophysiology, includ-ing blood-brain barrier (BBB) function. Recent work has demonstrated that activation of endocannabinoid re-ceptors can mitigate insults to the BBB during neurological disorders, like traumatic brain injury, cortical spreading depression and stroke. As alterations to the BBB are associated with worsening clinical outcomes in these conditions, studies herein sought to examine the impact of endocannabinoid depletion on BBB integrity. Methods: Barrier integrity was investigated in vitro via bEnd.3 cell monolayers to assess endocannabinoid syn-thesis, barrier function, calcium influx, junctional protein expression, and proteome-wide changes. Results: In-hibition of 2-AG synthesis using DAGLα inhibition and siRNA inhibition of DAGLα led to loss of barrier in-tegrity via altered expression of VE-cadherin, which could be partially rescued by exogenous application of 2-AG. Moreover, the deleterious effects of DAGLα inhibition on BBB integrity showed both calcium and PKC (protein kinase C)-dependency. Conclusions: These data indicate that disruption of 2-AG homeostasis in brain endothelial cells, in the absence of insult, is sufficient to disrupt BBB integrity thus supporting the role of the endocannabinoid system in neurovascular disorders.

The paper deals with exploration of subsequences of polygonal numbers of different sides derived through step-by-step elimination of terms of the original sequences. Eliminations are based on special rules similarly to how the classic sieve of Eratosthenes was developed through the elimination of multiples of primes. These elementary number theory activities, appropriate for technology-enhanced secondary mathematics education courses, are supported by a spreadsheet, Wolfram Alpha, Maple, and the Online Encyclopedia of Integer Sequences. General formulas for subsequences of polygonal numbers referred to in the paper as polygonal number sieves of order k that include base-two exponential functions of k have been developed. Different problem-solving approaches to the derivation of such and other sieves based on the technology-immune/technology-enabled framework have been used. The accuracy of computations and mathematical reasoning is confirmed through the technique of computational triangulation enabled by using more than one digital tool. A few relevant excerpts from the history of mathematics are briefly featured.

This review provides an overview of the biotransformation of limonene and α-pinene, which are commonly found in wood residues and citrus fruit by-products, to produce high-value-added products. Essential oils derived from various plant parts contain monoterpene hydrocarbons, such as limonene and pinenes which are often considered waste due to their low sensory activity, poor water solubility, and tendency to autoxidize and polymerise. However, these terpene hydrocarbons serve as ideal starting materials for microbial transformations. Moreover, agro-industrial byproducts can be employed as nutrient and substrate sources, reducing fermentation costs, and enhancing industrial viability. Terpenes, being secondary metabolites of plants, are abundant in byproducts generated during fruit and plant processing. Microbial cells offer advantages over enzymes due to their higher stability, rapid growth rates, and genetic engineering potential. Fermentation parameters can be easily manipulated to enhance strain performance in large-scale processes. The economic advantages of biotransformation are highlighted by comparing the prices of substrates and products. For instance, R-limonene, priced at US$34/L, can be transformed into carveol, valued at around US$530/L. This review emphasises the potential of biotransformation to produce high-value products from limonene and α-pinene molecules, particularly present in wood residues and citrus fruit by-products. The utilisation of microbial transformations, along with agro-industrial byproducts, presents a promising approach to extract value from waste materials and enhance the sustainability of the antimicrobial, the fragrance and flavour industry.

In this paper, experiences of the last 20 years with the PERALS-technique are described. PERALS stands for Photo Electron Rejecting Alpha Liquid Scintillation. This LSC-technique was developed by Jack McDowell in the 70ies and is a powerful technique for the analyses of many natural alpha nuclides. The principle is based on a selective extraction of the radionuclide from the water phase by means of a complexing or ion pair reagent. The extractant contains also a suitable cocktail for the scintillation counting. Therefore, the extract can be analysed directly after the extraction step. After removing quenchers, such as oxygen, and the proper setting of a pulse shape discriminator, alpha pulses can be counted with a photomultiplier. The paper describes the development of robust analysis schemes for the determination of traces of polonium, radon, radium, strontium, thorium, uranium and other actinides in water samples (groundwater, rain water, river water, drinking water, mineral water, sea water).

1) Background: We analyzed the size structure, richness and diversity in eight permanent forest plots in the upper limit of the great Amazon basin located in the Ecuadorian parts of Cordilleras del Cóndor and Cutucú. Our hypothesis was that not all the forests of the eastern mountain ranges are homogeneous in characteristics, but rather present differences in their structure, richness and floristic diversity. In order to test this, our main objective was to classify the types of forests based on characteristics in diametric structure and species composition of the Amazonian forests of the eastern cordilleras in southern Ecuador, and also to determine the influence of critical edaphic-environmental and geomorphological factors. 2) Methods: Eight one-hectare permanent plots were installed in homogeneous and well-conserved forest stands. Four plots were located in the province of Zamora Chinchipe and four in the province of Morona Santiago. We identified and measured all trees> 10 cm at diameter breast height. For each plot, soil samples were taken, along with environmental and slope data. The multidimensional non-metric adjusted scaling (NMDS) was used to evaluate changes in climatic and geomorphological gradients. The relationship between the composition of the species at the plot level and the edaphoclimatic variables was tested using a canonical correspondence analysis (CCA). Finally, we modeled the change in species diversity (Fisher's alpha) in relation to the climatic gradients, altitudinal and geomorphological using a GLMM. 3) Results: Overall, we identified 517 species belonging to 76 families. We determined the existence of two different types of forest, the first one named Terra Firme, characterized by the presence of a larger number of species and individuals per plot, compared to the second type of forest, called Tepuy or Sandstones forest. Species richness was negatively correlated with soil phosphorus content and pH, mean annual temperature, annual precipitation and altitude. The CCA analysis showed differences in the species composition between the Terra Firme and Sandstone forests. The climatic seasonality and the concentration of cations in the soil influence the diversity of the Amazon forest communities of the southeastern cordilleras. The forests of Terra Firme, which are settled in more stable and nutrient-rich climatic areas, were more diverse. Sandstone forests are poor in nutrients and develop in areas with stronger seasonality

We introduce a new variation on the domination theme which we call vertex domination as reducing waste of time in transportation planning and optimization of transport routes. We determine the vertex domination number $\gamma_v$ for several classes of fuzzy graphs. The bounds is obtained for it. In fuzzy graphs, monotone decreasing property and monotone increasing property are introduced. We prove both of the vizing's conjecture and the Grarier-Khelladi's conjecture are monotone decreasing fuzzy graph property for vertex domination. We obtain Nordhaus-Gaddum (NG) type results for these parameters. The relationship between several classes of operations on fuzzy graphs with the vertex domination number of them is studied. Finally, we discuss about vertex dominating set of a fuzzy tree by using the bridges and $\alpha$-strong edges equivalence.