To stabilize the Earth’s climate a large-scale transition is needed to non-carbon emitting renewable energy technologies like wind and solar energy. Although these renewable energy sources are now lower-cost than fossil fuels, their inherent intermittency make them unable to supply a constant load without storage. To address these challenges rechargeable electric batteries are currently the most promising option; however, their high capital costs limit current deployment velocities. To both reduce the cost as well as improve performance 3D printing technology has emerged as a promising solution. This literature review provides the state-of-the-art enhancements of battery properties with 3D printing including efficiency, mechanical stability, energy and power density, customizability and sizing, production process efficiency, material conservation and environmental sustainability as well as the progress in solid-state batteries. The principles, advantages, limitations, and recent advancements associated with the most common types of 3D printing are reviewed focusing on their contributions to the battery field. 3D printing batteries offer design flexibility, material flexibility, reduces pack weight, minimizes material waste, increases the range of applications and has the potential to reduce costs. As 3D printing technologies become more accessible, the prospect of cost-effective production for customized batteries is extremely promising.

Active vitamin D derivatives (VDDs) – 1α,25-dihydroxyvitamin D3/D2 and their synthetic analogs – are well-known inducers of cell maturation with the potential for differentiation therapy of acute myeloid leukemia (AML). However, their dose-limiting calcemic activity is a significant obstacle to using VDDs as an anticancer treatment. We have shown that different activators of the NF-E2-related factor-2/Antioxidant Response Element (Nrf2/ARE) signaling pathway, such as the phenolic antioxidant carnosic acid (CA) or the multiple sclerosis drug monomethyl fumarate (MMF), synergistically enhance the antileukemic effects of various VDDs applied at low concentrations in vitro and in vivo. This study aimed to investigate whether glutathione, the major cellular antioxidant and the product of the Nrf2/ARE pathway, can mediate the Nrf2-dependent differentiation-enhancing activity of CA and MMF in HL60 human AML cells. We report that glutathione depletion using L-buthionine sulfoximine attenuated the enhancing effects of both Nrf2 activators concomitant with downregulating vitamin D receptor (VDR) target genes and the activator protein-1 (AP-1) family protein c-Jun levels and phosphorylation. On the other hand, adding reduced glutathione ethyl ester to dominant negative Nrf2-expressing cells re-stored both the suppressed differentiation responses and the downregulated expression of VDR protein, VDR target genes, as well as c-Jun and P-c-Jun levels. Finally, using the transcription factor decoy strategy, we demonstrated that AP-1 is necessary for the enhancement by CA and MMF of 1α,25-dihydroxyvitamin D3-induced VDR and RXRα protein expression, transactivation of the vitamin D response element, and cell differentiation. Collectively, our findings suggest that glutathione mediates, at least in part, the potentiating effect of Nrf2 activators on VDDs-induced differentiation of AML cells, likely through the positive regulation of AP-1.

Introduction: Digitalis use in patients with severe heart failure is controversial. We assessed the effects of digitalis therapy on mortality in a large, observational study in recipients of cardiac resynchronization therapy (CRT). Methods: Consecutive patients receiving a CRT-defibrillator in three European tertiary referral centers were enrolled and followed for a median of 28 months. Digitalis use was assessed at the time of CRT implantation. Multivariate Cox-regression model and propensity score matching was used to determine all-cause mortality as primary endpoint. CRT-response (defined as improvement of ≥1 NYHA class), echocardiographic improvement (defined as improvement of LVEF of ≥ 5%), and ICD shocks were assessed as secondary endpoints. Results: The study comprised 552 CRT recipients with standard indications, including 219 patients (40%) treated with digitalis. Compared to patients without digitalis, they had more often atrial fibrillation, poorer LVEF and higher NYHA class (all p ≤ 0.002). Crude analysis of all-cause mortality demonstrated a similar relative risk of death for patients with and without digitalis (HR=1.14; 95% CI 0.88-1.5; p=0.40). After adjustment for independent predictors of mortality, digitalis therapy did not alter the risk for death (adjusted HR=1.04; 95% CI 0.75-1.45; p=0.82). Also, in comparison to 286 propensity score matched patients, mortality was not affected by digitalis intake (propensity adjusted HR=1.11; 95% CI 0.72-1.70; p=0.64). CRT response was predominant in digitalis non-users concerning both improvement of HF symptoms and LVEF (NYHA p<0.01; LVEF p<0.01) while patients on digitalis had more often ventricular tachyarrhythmias requiring ICD shock (p=0.01). Conclusions: Digitalis therapy had no effect on mortality but did negatively affect CRT response and susceptibility to ventricular arrhythmias requiring ICD shock treatment.

Low 25 OH vitamin D (25(OH)D) in preterm infants is a risk factor of bronchopulmonary dysplasia (BPD), but increased supplementation failed to demonstrate beneficial effect on BPD. In neonatal animal models, deficiency and excessive vitamin D exposure have been associated with increased mortality and lung histological alterations evocative of BPD. Our hypothesis is that 25(OH)D levels ≥ 120nmol/L is also a risk factor for BPD or death. This retrospective single-center cohort study included all infants born <31 weeks gestational age without major malformation with at least a determination of 25(OH)D <36 weeks corrected age and no determination <50 nmol/L. Routine 25(OH)D determination was performed at 1 month and monthly thereafter. A total of 175 infants were included. Infants with BPD or who died had a significantly lower term and weight, but a similar frequency of 25(OH)D ≥120nmol/L (50.5% vs 43.9%, p=0.53). The logistic regression identified weight (OR 0.997, 95%CI [0.995-0.998]) and term (OR 0.737, 95%CI [0.551-0.975]) as significantly associated with BPD or death; the occurrence of excessive 25(OH)D was not significantly associated (OR 1.029, 95%CI [0.503-2.093]). The present study did not demonstrate any significant association between excessive 25(OH)D after one month of age and BPD or death.

This paper presents a new method for the design of separable denominators 2-D IIR filters with nearly linear phase in the passband. The design method is based on a balanced-realization model reduction technique. The nearly linear-phase 2-D IIR filter is designed using 2-D model reduction from a linear-phase 2-D FIR filter, which serves as the initial filter. The structured controllability and observability Gramians $P^s$ and $Q^s$ serve as the foundation for this technique. These Gramians are block diagonal positive-definite matrices that satisfy 2-D Lyapunov equations. An efficient method is used to compute these Gramians by minimizing the traces of $P^s$ and $Q^s$ under linear matrix inequalities (LMI) constraints. The use of these Gramians ensures that the resulting 2-D IIR filter preserves stability and can be implemented using a separable denominator 2-D filter with fewer coefficients than the original 2-D FIR filter. Numerical examples show that the proposed method compares favorably with existing techniques.

Mitochondrial dysfunction plays a pivotal role in numerous complex diseases. Understanding the molecular mechanisms by which the “powerhouse of the cell” turns into the “factory of death” is an exciting yet challenging task that can unveil new therapeutic targets. The mitochondrial matrix protein CyPD is a peptidylprolyl cis-trans isomerase involved in the regulation of the permeability transition pore (mPTP). The mPTP is a multi-conductance channel in the inner mitochondrial membrane whose dysregulated opening can ultimately lead to cell death and whose involvement in pathology has been extensively documented over the past few decades. Moreover, several mPTP-independent CyPD interactions have been identified, indicating that CyPD could be involved in the fine regulation of several biochemical pathways. To further enrich the picture, CyPD undergoes several post-translational modifications that regulate both its activity and interaction to its clients. Here, we will dissect what is currently known about CyPD and critically review the most recent literature about its involvement in neurodegenerative disorders, focusing on Alzheimer’s Disease and Parkinson’s Disease, supporting the notion that CyPD could serve as a promising therapeutic target for the treatment of such conditions. Notably, significant efforts have been made to develop CyPD-specific inhibitors, which hold promise for the treatment of such complex disorders.

Middle East region experiences a high prevalence of hypovitaminosis D, yet most genetic studies on Vitamin D have focused on European populations. Furthermore, there is a lack of research on the genomic risk factors affecting the elderly population, who are more susceptible to health burden. We investigated the genetic determinants of 25-hydroxyvitamin D levels in elderly Lebanese individuals (n=199) through a whole exome-based genome-wide association study. We identified new loci with suggestive evidence of an association with Vitamin D levels, including rs141064014 in the MGAM gene (P-value of 4.40 × 10−06) and rs7036592 in PHF2 (P-value of 8.43 × 10−06). A meta-analysis of the Lebanese data and the largest European genome-wide association study confirmed consistence replication of numerous variants, including rs2725405 in SLC38A10 (P-value of 3.73 x 10-08). Despite the lower performance of European-derived polygenic risk scores compared to the European estimations, it still effectively predicted Vitamin D deficiency among elderly Lebanese individuals. Our findings provide novel insights into the genetic mechanisms of Vitamin D deficiency in Middle Eastern elderly populations, facilitating the development of personalized approaches for more effective management of hypovitaminosis D. Additionally, we demonstrated that whole exome-based genome-wide association study is an effective method for identifying genetic components associated with phenotypes.

For order-of-addition experiments, the response is affected by the addition order of the experimental materials. Consequently, the main interest focuses on creating a predictive model and an optimal design for optimizing the response. Van Nostrand (1995) proposed the pairwise-order (PWO) model for detecting PWO effects. Under the PWO model, the full PWO design is optimal under various criteria but is often unaffordable because of the large run size. In this paper, we consider the D-, A- and M.S.-optimal fractional PWO designs. We first present some results on information matrices. Then, a flexible and efficient algorithm is given for generating these optimal PWO designs. Numerical simulation shows that the generated design has an appealing efficiency in comparison with the full PWO design, though with only a small fraction of runs. Several comparisons with existing designs illustrate that the generated designs achieve better efficiencies, and the best PWO designs and some selected 100% efficient PWO designs generated by the new algorithm are reported.

(1) Background: The issue of human adaptation to the Arctic environmental factors is relevant. The adaptation can be assessed through dynamic monitoring of the functional state of a person during his/her stay there. The vitamin D level in blood is one of the markers of the functional reserves of the human body and can contribute to more successful adaptation in the Arctic. (2) Methods: The study involved 38 participants in the scientific and educational expeditionary project "Arctic Floating University-2021". Blood collection for determination of vitamin D content was carried out at the beginning of the expedition. A dynamic study was carried out for 20 days in the morning and in the evening during a marine scientific expedition to the Arctic. The main parameters of the functional state of the participants were assessed using instrumental psychophysiological, projective and questionnaire methods. Statistical methods: Mann-Whitney U-test, correlation analysis using the Spearman coefficient. (3) Results: It was found that at the beginning of the expedition, the functional state of participants with severe vitamin D deficiency is characterized by a shorter average duration of RR intervals and reduced SDNN values, which may indicate a higher level of regulatory mechanisms tension. The pronounced differences in the nature of the dynamic series of objective and projective working capacity parameters were manifested most clearly. According to the subjective questionnaire characteristics of well-being, activity and mood, no significant features of the participants with vitamin D deficiency were revealed. (4) Conclusion: The participants with vitamin D deficiency in blood are characterized by a reduced adaptive capacity during the expedition to the Arctic.

COVID-19 has emerged as deadly pandemic worldwide with no vaccine or suitable antiviral drugs to prevent or cure the disease. Because of the time-consuming process to develop new vaccines or antiviral agents, there has been a growing interest in repurposing some existing drugs to combat SARS-CoV-2. Vitamin D is known to be protective against acute respiratory distress syndrome (ARDS), pneumonia and cytokine storm. Recently it has been used as a repurposed drug for the treatment of H5N1 virus-induced lung injury. Circumstantial evidences indicate that people with low level of vitamin D are more susceptible to SARS-CoV-2. Although, vitamin D was suggested to interfere with viral replication, its interaction with any SARS-CoV-2 protein is unexplored yet. Beside this, ivermectin, a well-known anti-parasitic agent, exhibits potent anti-viral activities in vitro against viruses such as HIV-1 and dengue. Very recently, ivermectin has been found to reduce viral load of SARS-CoV-2 in vitro. We have analyzed available structures of SARS-CoV-2 proteins to identify probable binding partner(s) of vitamin D and ivermectin through knowledge-based docking studies and figured out possible implication of their binding in SARS-CoV-2 infection. Our observations suggest that the non-structural protein nsp7 possesses a potential site to house 25-hydroxyvitamin D3 (VDY) or the active form of Vitamin D, calcitrol. Binding of vitamin D with nsp7 likely to hamper the formation of nsp7-nsp8 complex which is required to bind with RNA dependent RNA polymerase (RdRP), nsp12 for optimal function. On the other hand, potential binding site of ivermectin has been identified in the S2 subunit of trimeric spike(S) glycoprotein of SARS-CoV-2. We propose that deeply inserted mode of ivermectin binding at three inter-subunit junctions may restrict large scale conformational changes of S2 helices which is necessary for efficient fusion of viral and host membrane. Our study, therefore, opens up avenues for further investigations to consider vitamin D and ivermectin as potential drugs against SARS-CoV-2.

The commitment of the EU to Corporate Social Responsibility (CSR) is projected in the EU law about annual reporting by businesses. Since EU member states further develop this framework by their own domestic laws, annual reporting with CSR information is not unified and just partially mandatory in the EU. Do all European businesses report CSR information and what public declaration to society do they provide with it? The main dual purpose of this paper is identifying the parameters of this annual reporting duty and studying the CSR information provided by the ten largest Czech companies in their annual statements for 2013-2017. Based on legislative research and the teleological interpretation, the current EU legislative framework with Czech particularities is presented and, via a case study exploring 50 annual reports, the data about the type, extent and depth of the CSR is dynamically and comparatively assessed. It appears that, at a minimum, large Czech businesses satisfy their legal duty and e-report on CSR in a similar extent, but in dramatically different quality. Employee matters and adherence to international standards are used as a public declaration to society more than the data on environmental protection, while social matters and R&D are played down.

It is widely known that vitamin D receptors have been found in neurons and glial cells and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical grey nuclei, and substantia nigra. The vitamin D helps the regulation of neurotrophin, neural differentiation and maturation, through the control operation of growing factors synthesis (ie NGF and GDNF), the trafficking of the septo-hyppocampal pathway, and the control of the synthesis process of different neuromodulators (such as Ach, DA, and GABA). Based on these assumptions, we have written this review in order to summarize the potential role of vitamin D in neurological pathologies. The work could be titanic, and might result very fuzzy and even incoherent, if we would not have conjectured to taper our first intentions and devoted our interests towards three mainstreams: demyelinating pathologies, vascular syndromes and neurodegeneration. Due to the lack of effective therapeutic options, a part from the disease modifying strategies, the role of different risk factors should be investigated in neurology, as far as their correction may lead to the improvement of the cerebral conditions. We have explored the relationships between the gene-environmental influence and long term vitamin D deficiency, as a risk factor for the development of different types of neurological disorders, along with the role and the rationale of therapeutic trials with vitamin D implementation.

This paper describes the first results of an Image Recognition Based Location (IRBL) for mobile application focusing on the procedure to generate a Database of range images (RGB-D). In an indoor environment, to estimate the camera position and orientation, a prior spatial knowledge of the surrounding is needed. In order to achieve this objective a complete 3D survey of two different environment (Bangbae metro station of Seoul and E.T.R.I. building in Daejeon – Republic of Korea) was performed using LiDAR (Light Detection And Ranging) instrument and the obtained scans were processed in order to obtain a spatial model of the environments. From this, two databases of reference images were generated using a specific software realized by the Geomatics group of Politecnico di Torino (ScanToRGBDImage). This tool allow to generate synthetically different RGB-D images) centered in the each scan position in the environment. Later, the external parameters (X, Y, Z, ω, φ, κ) and the range information extracted from the DB images retrieved, are used as reference information for pose estimation of a set of acquired mobile pictures in the IRBL procedure. In this paper the survey operations, the approach for generating the RGB-D images and the IRB strategy are reported. Finally the analysis of the results and the validation test are described.

Soil carbon (C) cycling under anoxic conditions is mechanistically linked to dissimilatory iron (Fe) reduction, which could be regulated by exogenous dissolved organic matter (DOM). However, the impact of complex exogenous DOM on soil microbial activity and C-Fe coupling in paddy soils remains underexplored. With a 100-day microcosm experiment, we determined that the molecular composition of DOM derived from organic fertilizers and biochar on paddy soil affects soil microbial community, Fe reduction, and C emissions. Our results indicated that biochar-DOM significantly promoted Fe reduction and accelerated CH₄ and CO₂ emissions, and organic manure-DOM increased soil CO₂ emissions, which was closely related to the molecular composition of exogenous DOM. DOM molecules with high aromaticity (AI_mod) and high DBE, including lignins-vascular plant-derived polyphenols, lignins-polycyclic aromatics (PA), and condensed aromatics-PA, promoted soil Fe reduction and CH₄ emissions by enriching soil Fe-reducing bacteria (FeRB), reducing methanotrophs, and facilitating r-strategists at the early stage of incubation. Conversely, DOMs with low AI_mod, low DBE and high H/C, such as lignins-highly unsaturated and phenolic compounds and proteins-aliphatic compounds, enhanced CO₂ emissions by facilitating recalcitrant C degradation and CH₄ oxidation at the late stage of incubation. In conclusion, our study highlights the importance of the molecular composition of DOMs derived from organic amendments in regulating soil Fe reduction and C emissions. The findings offer novel insights into the effective utilization of agricultural resources and the mitigation of soil C emissions.

The recent mountain pine beetle outbreaks have caused widespread mortality among lodgepole pine trees in western North America, resulting in a reduced population of surviving trees. While previous studies have focused on the cascading impacts of these outbreaks on the physiology and growth of the surviving trees, there remains a need for a comprehensive study into the interactions among various physiological traits and the growth in post-outbreak stands. Specifically, the relationship between chemical (primarily terpenes) and anatomical (mainly resin ducts) defences, as well as the allocation of non-structural carbohydrates (NSCs) to support these defence modalities, is poorly understood. To address these gaps, we conducted a field survey of surviving lodgepole pine trees in post-mountain pine beetle outbreak stands in western Canada. Our retrospective analysis targeted to determine correlations between the post-outbreak concentrations of monoterpenes, diterpenes, and NSCs in the phloem, and the historical resin duct characteristics and growth traits before and after the outbreak. We detected strong correlations between post-outbreak concentrations of monoterpenes and historical resin duct characteristics, suggesting a possible link between these two defence modalities. Additionally, we found a positive relationship between NSCs and the total concentrations of monoterpenes and diterpenes, suggesting that NSCs likely influence the production of these terpenes in lodgepole pine. Furthermore, historical tree growth patterns showed strong positive correlations with many individual monoterpenes and diterpenes. Interestingly, while surviving trees had enhanced anatomical defences after the outbreak, their growth patterns did not vary before and after the outbreak conditions. The complexity of these relationships emphasizes the dynamics of post-outbreak stand dynamics and resource allocation in lodgepole pine forests, highlighting the need for further research. These findings contribute to a broader understanding of conifer defenses and their coordinated responses to forest insect outbreaks, with implications for forest management and conservation strategies.

The cyclamen mite, Phytonemus pallidus, is one of the important pests in strawberry cultivation in Canada. This insect pest hides on young strawberry leaves that have not yet opened, which limits their control. In addition, the fight against the latter involves the use of synthetic chemicals that are not without effect on the environment, human health and beneficial organisms. We hypothesized that vectorization by bees could reduce the number of applications, product runoff and provide targeted control of these pathogens. To do this, field trials were conducted to evaluate the effectiveness of bumblebees Bombus terrestris in propagating Beauveria bassiana to control this pest. Our results showed that bumblebees were able to disseminate the inoculum on strawberry plants. Also, all the products used (B. bassiana and neem oil) were effective on P. pallidus. It should be noted that high mortality has been noted on this pest thanks to the application of this entomopathogen by spraying. In addition, neither of the two products tested had a significant effect on lady beetles C. septempunctata. These results therefore suggest the use of bee vectoring and neem essential oils in the sustainable management of strawberry mites.

Idiopathic pulmonary fibrosis (IPF) is a difficult to treat condition to treat with a high mortality rate. While preclinical models such as Bleomycin (Bleo)-induced fibrosis recapitulate some aspects of IPF, new models that more closely mimic the disease are warranted. We have developed and characterized a novel model in BALB/c mice using a transient overexpression of IL-6 combined with Bleo. This model’s transcriptomic signature was compared to published human IPF datasets. BALB/c females were treated with AdIL-6 in combination with Bleo (AdIL-6+Bleo) or control comparators, and underwent assessments of histopathology (ECM, α-SMA accumulation), collagen content and lung physiology (Elastance, EST). Flow cytometry was used to characterize T cell and Macrophage subsets, and T cell depletion studies (anti-CD4/CD8) were completed to assess T cells role in fibrosis. Bulk RNA sequencing generated gene signatures were compared to that of other rodent fibrosis models and published human datasets of IPF datasets. The AdIL-6+Bleo treatment resulted in robust fibrosis measures (day21), sustained fibrosis until at least day 50, a unique cytokine profile at day 7, and increased activated CD4+Tcells, CD8+Tcells, and CD16+MHChi/Clec7a/iNOS-/Arg1-/CD206- macrophages. T cell depletion markedly decreased fi-brotic responses and this population of macrophages. The Day 21 AdIL-6+Bleo transcriptome shared more genes with each of two human IPF datasets than Bleo alone in C57Bl/6 mice or other rodent models. We conclude that AdIL-6+Bleo in BALB/c mice offers a superior preclinical model for studying IPF mechanisms and potential therapeutic intervention.

The reaction mechanisms of C-S borylation of aryl sulfides catalyzed by the 1,4-benzoquinone (BQ), were investigated by employing M06-2X-D3/ma-def2SVP method and basis set. In this study, the SMD model was taken to simulate the solvent effect of 1,4-dioxane. Also, TD-DFT calculations of BQ and methyl(p-tolyl)sulfane were performed in SMD solvent model. The computational results indicated that BQ and methyl(p-tolyl)sulfane, serving as a photo-catalyst, would be excited under blue LED of 450 nm, aligning well with experimental observations. Additionally, the role of 3O2 was investigated, revealing that it could be activated to 1O2 from the released energy of 1[BQ+methyl(p-tolyl)sulfane]* or 3[BQ+ methyl(p-tolyl)sulfane]*→BQ+ methyl(p-tolyl)sulfane process. Then 1O2, bis(pinacolato)diboron, and methyl(p-tolyl)sulfane would through a series of reactions to yield the final product P. The Gibbs free energy surface show that path a2-2 is optimal and this path has less steps and lower energy barrier. The electron spin density isosurface graphs were employed to analyze structures and elucidate the single electron distribution. These computational results offer valuable insights into the studied interactions and related processes and shed light on the mechanisms governing C–S borylation from aryl sulfides and b2pin2 catalyzed by BQ and methyl(p-tolyl)sulfane.

The emergence of drug resistance inducing mutations in Hepatitis C virus (HCV) coupled with genotypic heterogeneity has made targeting NS3/4A serine protease difficult. In this work, we investigated the mutagenic variations in the binding pocket of Genotype 3 (G3) HCV NS3/4A and evaluated ligands for efficacious inhibition. We report mutations at 14 positions within the ligand-binding residues of HCV NS3/4A including H57R and S139P within the catalytic triad. We then modeled each mutational variant for pharmacophore-based virtual screening (PBVS) followed by covalent docking towards identifying a potential covalent inhibitor, i.e. cpd-217. The binding stability of cpd-217 was then supported by molecular dynamic simulation followed by MM/GBSA binding free energy calculation. The free energy decomposition analysis indicated that the resistant mutants alter the HCV NS3/4A-ligand interaction, resulting in an unbalanced energy distribution within the binding site leading to drug resistance. cpd-217 was identified to interact with all NS3/4A G3 variants with significant covalent docking scores. In conclusion, cpd-217 emerges as a potential inhibitor of HCV NS3/4A G3 variants that warrants further in vitro and in vivo studies. The study will pave the way for drug design and development of HCV G3 NS3/4A.

Aquaporins (AQPs) are a family of integral membrane proteins that selectively transport water and glycerol across the cell membrane. Because AQPs are involved in a wide range of physiological functions and pathophysiological conditions, AQP-based therapeutics may have broad potential for clinical utility, including disorders of water and energy balance. However, AQP modulators have not yet been developed as suitable candidates for clinical applications. In this study, to identify potential modulators of AQPs, we screened 32 natural products by measuring the water and glycerol permeability of mouse erythrocyte membranes using a stopped-flow light scattering method. None of the tested natural compounds substantially affected osmotic water permeability. However, several compounds considerably affected glycerol permeability. Stichoposide C increased the glycerol permeability of mouse erythrocyte membranes, whereas rhizochalin decreased it at nanomolar concentrations. Immunohistochemistry revealed that AQP7 was the main aquaglyceroporin in mouse erythrocyte membranes. We further verified the effects of stichoposide C and rhizochalin on aquaglyceroporins using human AQP3 expressing keratinocyte cells. Stichoposide C, but not stichoposide D, increased AQP3-mediated transepithelial glycerol transport, whereas the peracetyl aglycon of rhizochalin was the most potent inhibitor of glycerol transport among the tested rhizochalin derivatives. Collectively, stichoposide C and the peracetyl aglycon of rhizochalin might function as modulators of AQP3 and AQP7, and suggest the possibility of these natural products as potential drug candidates for aquaglyceroporin modulators

A class of semi-linear elliptic equations with critical Hardy-Sobolev exponent has been considered. This model is widely used in hydrodynamics and glaciology, gas combustion in thermodynamics, quantum field theory and statistical mechanics, as well as gravity balance problems in galaxies. The $\left( PS\right) _{c}$ sequence of energy functional has been investigated, and then the mountain pass lemma was used to prove the existence of at least one nontrivial solution. Also a multiplicity result has been obtained. Some known results have been generalized.

Background: Capmatinib and savolitinib, selective MET inhibitors, are widely used to treat various MET-positive cancers. In this study, we aimed to determine the effects of these inhibitors on MET-amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be MET-positive with copy number variation &gt; 10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Nest, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the MET signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Results: Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of MET and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in MET-amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in a MKN-45 GC cell xenograft model. Furthermore, combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 (HER2)- and MET-positive OE-33 cells. Conclusions: Therefore, targeting MET with savolitinib and capmatinib efficiently suppressed the growth of MET-amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on HER2- and MET-amplified GC cells.

Background and Objectives: High job strain is worsening the outcome in coronary artery disease, CAD. Severe dissatisfaction on workplace, imbalance between high demands , and low rewards, are affecting the quality of life, and diminishing the duration of life, especially in CAD patients. Our study included two samples : CAD patients (experimental group), and without CAD patients, but with traditional risk factors (control group). The main objective of the study was the role played by high sensitivity C reactive protein, hs CRP, and microalbuminuria, as mediators of job strain and CAD relationship. Secondary objectives were the following: identification of the most vulnerable patients( with significant job strain) and intervention towards this category, for cardiovascular events prevention (primary or secondary). Materials and Methods: The utilized methods were the following : clinical exam; electrocardiogram; echocardiogram; non contrast enhanced computed chest tomography; laboratory findings ( lipid profile, glycemia, hs CRP, microalbuminuria); type D scale, DS 14; depression questionnaire, PHQ-9; and satisfaction with work scale, SWWS. Results: The highest values for hs CRP and microalbuminuria were noticed in patients with the lowest Likert score, for both samples CAD, and without CAD patients. The highest job strain was noticed in females. More than half of CAD patients ,with low Likert scores, revealed myocardial infarction. Conclusions: Microalbuminuria and hs CRP were statistical significant in the study as intercessors, in job strain and CAD relationship. The most vulnerable patients for vascular events were females, in both groups : CAD and “CAD waiting desk”. In CAD sample, the vascular vulnerability was also increased by high job strain.

Understanding mechanisms of ageing remains a complex challenge for biogerontologists, but recent adaptations of evolutionary ageing theories offer a compelling lens in which to view both age-related molecular and physiological deterioration. Ageing is commonly associated with a progressive loss of biochemical processes and degeneration of molecular material, however, the mechanisms of diminishing function are not simply a result of aberrant expression of these pathways. Natural selection pressures are at their highest in youthful periods to select genes advantageous to maximising reproductive capacity. After sexual maturation, selective pressure diminishes, subjecting individuals to maladaptive pleiotropic gene function once beneficial for developmental growth, but pathogenic later in life. Due to this selective ‘shadowing’ in ageing, mechanisms to counter hyperfunctional genes are unlikely to evolve within a given species. These genetic ‘run-on’ programmes are not dysfunctional per se and, in fact, remain highly robust. Thus, interventions capable of optimising gene function during the ageing process represent as attractive therapeutic modalities. Caenorhabditis elegans offers a unique model to explore high-throughput screening of interventions to combat hyperfunctional pathways involved in ageing. However, the majority of research to date employ whole-life vs late-life pathway manipulation of developmental/growth-related systems to claim ageing attenuation, despite significant impairments in early-life fitness and discordance with healthspan. Here, we discuss data supporting hyperfunctional changes at a global molecular and functional level in C. elegans, and how classical lifespan-extension mutants alter these dynamics. We later discuss the relevance of such mutant models for exploring mechanisms of ageing, highlighting that post-reproductive gene manipulation represents a far more translatable approach for C. elegans research not routed within pleiotropic constraints. More so, lifespan has become a routine readout for quantifying ‘ageing’, however, we make the argument that a compression of gerospan vs lifespan extension is a more meaningful goal for anti-ageing regimes with current knowledge. Similarly, mechanisms governing lifespan are distinct from those regulating health, and slowing senescent pathology accumulation appears more applicable for the abstraction to human ageing.

In this paper, a class of semi-linear elliptic equations involving Hardy-Sobolev critical exponents has been investigated. This problem comes from the consideration of standing waves in the anisotropic Schr\"{o}dinger equation, also it is very important in the field of hydrodynamics, glaciology, quantum field theory and statistical mechanics. By a detailed estimation for the extremum function and using Mountain Pass Lemma with $\left( PS\right) _{c}$ conditions, the existence of positive solutions has been obtained. On the other hand, by establishing Pohozaev-type identity and using the properties of Bessel function, the nonexistence of positive solution also has been obtained. These results are extensions of E. Jannelli's research (\cite[Theorem 1.A-1.C]{EJ}).

Abstract: Background: Viral hepatitis B and C (HBV and HCV) pose significant public health challenges globally, particularly in Nigeria, where access to healthcare and treatment affordability are major concerns. This study aims to identify sociodemographic and clinical predictors of health insurance coverage among patients with HBV and HCV in Nigeria. Methods: A cross-sectional facility-based study was conducted at two secondary hospitals in Nasarawa State, Nigeria. Par-ticipants included patients diagnosed with HBV, HCV, or both and are > 18 years old. Data were collected using a structured questionnaire covering sociodemographic and clinical information, health insurance details, and economic impact. Logistic multivariate regression analysis was used to analyze the relationship between sociodemographic/clinical variables and health insurance status. Results: Out of 295 participants included in the final analysis, 67.1% had health insur-ance, primarily covering hepatitis screening and vaccination. Being aged 31-45 years (adjusted Odds Ratio [aOR]: 5.72, 95% Confidence Interval [CI]: 1.4 - 23.28, p = 0.02), having post-secondary education (aOR: 11.73, CI: 4.09 - 33.66, p < 0.001), and being HIV-positive (aOR: 2.86, CI: 1.02 - 8.02, p = 0.046) were significant predictors of health insurance coverage. Being unemployed significantly reduced the likelihood of having health insurance (aOR: 0.04, CI: 0.01 - 0.11, p < 0.001).Conclusions: This study reveals high insurance coverage among patients seeking viral hepatitis services in Nasarawa state, Nigeria and provides critical insights into the sociodemo-graphic predictors of health insurance coverage. It also highlights the need for the expansion health insurance benefit package that covers for viral hepatitis diagnosis and treatment, espe-cially for the younger adults, unemployed and less educated populations. This should be followed with adequate budgeting and policy implementation monitoring efforts, which are crucial for Nigeria's journey towards universal health coverage and elimination of viral hepatitis.

Using the h-index to assess individual researchers is not only unethical and unfair but also inaccurate and misleading. This index fails to offer a reliable measure of a researcher's impact based on their citation scores. Beyond statistical and conceptual considerations, authorship practices, especially in the case of multi-authored publications, give rise to significant problems that often go unnoticed. While some modifications of the h-index have been proposed to mitigate these weaknesses, the fundamental deficiencies persist. Most of these flaws have been effectively addressed by the c-score, a composite citation index. The c-score excludes self-citations, normalizes the number of citations by considering the number of authors in each paper, and takes into account first, single, and last authorship. This approach provides a more realistic measure of the impact of each individual researcher based on raw citations.

The efficiency and performance of Proton Exchange Membrane Fuel Cells (PEMFCs) are primarily influenced by ORR electrocatalysts. In recent years, atomically dispersed met-al-nitrogen-carbon (M-N-C) catalysts have gained significant attention due to their high active center density, high atomic utilization, and high activity. These catalysts are now considered the preferred alternative to traditional noble metal electrocatalysts. The unique properties of M-N-C catalysts are anticipated to enhance the energy conversion efficiency and lower the manufac-turing cost of the entire system, thereby facilitating the commercialization and widespread ap-plication of fuel cell technology. This article initially delves into the origin of performance and degradation mechanisms of Fe-N-C catalysts from both experimental and theoretical perspectives. Building on this foundation, the focus shifts to strategies aimed at enhancing the activity and durability of atomically dispersed Fe-N-C catalysts. These strategies encompass the use of bi-metallic atoms, atomic clusters, heteroatoms (B, S, and P), and morphology regulation to optimize catalytic active sites. The article concludes by detailing the current challenges and future pro-spects of atomically dispersed Fe-N-C catalysts.

This study aimed to evaluate the positive effect of autumn olive berries (AOB) extract on aging delay by improving the lipid metabolism of middle-aged C. elegans who became obese due to high glucose (GLU) diet. As a result of investigating the total phenol content and DPPH radical scavenging ability of freeze- or spray-dried AOB, freeze-dried AOB showed better antioxidant potential. Afterward, through HPLC analysis, it was confirmed that catechin was the main compound in the polyphenols of AOB. Therefore, we used freeze-dried AOB in subsequent in vivo experiments. AOB inhibited lipid accumulation in both the young adult and middle-aged groups in a concentration-dependent manner under both normal and 2% GLU conditions. Additionally, AOB inhibited ROS accumulation in a concentration-dependent manner under normal and 2% GLU conditions in the middle-aged worms. In particular, AOB also increased the number of body bending and egg production in middle-aged worms. To confirm the intervention of genetic factors related to lipid metabolism in the effect of AOB, body lipid accumulation was confirmed using worms deficient in the daf-16, atgl-1, aak-1, and akt-1. Regarding the effect of AOB on reducing lipid accumulation, the impact was nullified in daf-16 deficient worms under the 2% GLU condition and nullified in both daf-16 and deficient worms under fasting conditions. This means that AOB regulates lipogenesis and lipolysis by mediating daf-16 and atgl-1 in middle-aged worms. Our results suggest that AOB contributes to the aging delay effect by improving lipid metabolism in metabolic impaired middle-aged worms.

The utilization of titanium dioxide (TiO2) as a photocatalyst for the treatment of wastewater has attracted significant attention in the environmental field. Herein, we have prepared a NH2-MIL-125-derived TiO2@N-doped C Visible Light Catalyst through an in-situ calcination method. The nitrogen element in the organic connector is released through calcination, simul-taneously doping into the sample, thereby enhancing its spectral response to cover the visible region. The as-prepared TiO2@N-doped C catalyst exhibited preserved cage structure even after calcination, thereby alleviating the optical shielding effect and further augmenting its photo-catalytic performance by increasing the reaction sites between the catalyst and pollutants. The calcination time of the TiO2@N-doped C-450 °C catalyst was optimized to achieve a balance be-tween the TiO2 content and nitrogen doping level, ensuring efficient degradation rates for basic fuchsin (99.7%), Rhodamine B (89.9%), and tetracycline hydrochloride (93%) within 90 minutes.

In this paper we investigate in different scenarios the feasibility of using massive multiple-input multiple-output (mMIMO) with Reconfigurable Intelligent Surfaces (RISs) to boost the throughput and coverage performances with high energy efficiency, considering sub-6 GHz, mmWave and THz bands. With that objective, a centralized radio access network (C-RAN) suitable for beyond fifth generation (B5G) systems is considered, where we integrate the base stations (BSs) with multiple RISs and devices or user equipment. RISs with a large number of quasi-passive reflecting elements constitute a low-cost approach capable of shaping the radio wave propagation and improve wireless connectivity. We consider a scenario where multiple RISs are combined with mMIMO in the uplink in order to provide connectivity to Smart City (thousands of active low power devices) wirelessly, in the 3.6GHz and 28GHz bands. We also address a scenario where RISs are adopted with mMIMO in the downlink so as to offer connectivity to a Stadium with Pitch, (thousands of active user equipment) in the 28GHz band. Finally, we have also studied the connectivity at 100GHz of a Factory where several RIS panels replacing most of the BSs equipped with mMIMO assure improved throughput and coverage. We concluded that RISs are capable of improving the performance in any of these analyzed scenarios at the different frequency bands, justifying that they are a key enabling technology for 6G.

We define a spinor-Minkowski metric for SL(4,C). It is not a trivial generalization of the SL(2,C) metric and it involves the Minkowskian one. We define 4x4 version of the Pauli matrices and eight 4-component associated generalized eigenvectors that can be regarded as undotted covariant spinors. The 4-component spinors can be grouped into four categories. Each category transforms in its own way. The outer products of pairwise combinations of 4-component spinors can be associated with 4-vectors. Including the dotted covariant, undotted and dotted contravariant forms totally we have sixteen pairs of spinors. Eight of them live in the conjugate space which has no countepart in SL(2,C).

Based on the analysis of the spatial distribution of uranium grade in 348 boreholes of a uranium deposit in Xinjiang, the enrichment and spatial variation of uranium ore in two stopes of the deposit are discussed by using multifractal theory. The distribution characteristics of uranium ore of the two stopes are studied by multifractal parameters: the scaling exponent of mass , the scaling exponent of each sub-set and its corresponding fractal dimension , the fractal dimension D0 and information dimension D1. The differences of uranium distribution in two stopes can be well quantified by multifractal spectrum and multifractal parameters( , , ).10m×10m is defined as a fence unit, and the window sizes are respectively set, the singularity exponent of the two stopes are calculated by this element concentration-area(C-A) method. The results show that the multifractal theory and model can organically combine spatial structure information, scale change information and anisotropy information to obtain low-grade and weak mineral resources information, and can effectively distinguish complex and superimposed anomalies. This will provide a basis for local concentration and spatial variation rules of uranium distribution and the design of the parameters of leaching uranium mining well site.

A variety of bioactive substances present in fruits and vegetables processed products have health-promoting properties. Consumption of nutrient-rich plant-based products is essential to address undernutrition and micronutrient deficiencies. Preservation is paramount in manufacturing plant-based non-solid foods such as juices, purees, and sauces. Thermal processing has been widely used to preserve fruit and vegetable-based products by reducing enzymatic and microbial activities, thereby ensuring safety and prolonged shelf life. However, the nutritional value of products is compromised due to the deleterious effects of thermal treatments on essential nutrients and bioactive compounds. To prevent the loss of nutrients associated with thermal treatment, alternative technologies are being researched extensively. In studies conducted on non-solid food, UV-C treatment has been proven to preserve quality and minimize nutrient degradation. This review compiles information on the use of UV-C technology in preserving the nutritional attributes of non-solid foods derived from fruit and vegetables. Legislation, market potential, consumer acceptance, and limitations of UV-C are reviewed.

Pruning is an important part in controlling the branching, good fruit size, and prodctivity of fruit trees. and consequently, ‘Valencia’ orange trees were grown many years ago, the trees were suffering from a decline in productivity in the newly reclaimed lands after certain years of plantation. This study elucidated the effect of pruning severity on growth, yield and fruit quality of ‘Valencia’ orange trees. Four levels of pruning were applied on 35 years old ‘Valencia’ orange trees as follows: T1: Control (un-pruned), T2: Light pruning ( 25% of main branches were removed); T3: Moderate pruning (50% of main branches were removed) and T4: Heavy pruning: 75% of main branches were removed. The treatments were done in February 15th (for each season). The results indicated that pruning severity increased vegetative growth paraments such as shoot length and leaf area and decreased canopy volume of Valencia orange trees in comparison to control. Maximum yield was gained from 75% followed by 50% and 25% pruning severity treatment. The pruning treatments improve in fruit weight, size, firmness, juice content, TSS%, TSS/acid ratio and vitamin C content. In addition, pruning produced an increasing in fruit yield per tree as well as yield increasing %. Hence, it might be concluded that pruning at different severity applied in February can be used effectively on ‘Valencia’ orange trees to improve vegetative growth, fruit physical and chemical properties. Besides, increasing fruit yield by nearly 20% in comparison to control.

Type 2 diabetes mellitus may be complicated with chronic complications including diabetic neuropathy (DN). Timely diagnosis is crucial in treatment and maybe reversal of this complication. C reactive protein to albumin ratio (CAR) is considered as a marker of inflammation in various diseases that characterized with acute or chronic inflammation. Since diabetic neuropathy and type 2 diabetes mellitus are also associated with chronic, low grade inflammation, we aimed to study CAR levels of type 2 diabetic subjects with diabetic neuropathy and to compare to those in patients without diabetic neuropathy. Type 2 diabetic patients presented to our institutional outpatient clinics were divided into two according to the presence of DN. Subjects with DN were listed as DN group and others were as non-DN group. Characteristics and laboratory data, including CAR, in DN and non-DN groups were compared. Median CAR of the DN and non-DN groups were 2,19 (0,2-49)% and 0,56 (0,02-5,8)%, respectively (p&lt;0.001). CAR was significantly and positively correlated with age (r=0.15, p&lt;0.001), weight (r=0.19, p=0.01), BMI (r=0.11, p=0.03), waist circumference (r=0.10, p=0.046), fasting plasma glucose (r=0.14, p=0.004), serum creatinine (r=0.25, p&lt;0.001), triglyceride (r=0.17, p&lt;0.001), and LDL-cholesterol (r=0.13, p=0.001) levels. Moreover, CAR was inversely correlated with eGFR levels (r=-0.16, p&lt;0.001). The sensitivity and specificity of CAR (when higher than 1,02%) in predicting diabetic neuropathy were 78% and 73%, respectively (AUC: 0.84, p&lt;0.001, 95% CI: 0,82-0,87). Moreover, high CAR level was an independent risk factor of diabetic neuropathy (p&lt;0.001, OR: 1.34, 95% CI: 0.48-1.62). In conclusion, elevated CAR levels could be considered as a marker of diabetic neuropathy.

The chelating aluminum complex [2-(Me2NCH2)C2B10H10]AlX2 (X = Br 3, CH3 4) was synthesized using 2-dimethylaminomethyl-o-carboranyl lithium (2) with aluminum tribromide or dimethylaluminum bromide, resulting in a modest yield. Compound 4 was obtained by reacting compound 3 with CH3Li in toluene. All compounds were characterized by infrared (IR) spectroscopy, 1H, 11B, 13C nuclear magnetic resonance (NMR) spectroscopy, and X-ray crystallography. X-ray structural studies of CabNAlBr2 (3) and CabNAlMe2 (4) indicated that the Al atom was located at the center of a distorted tetrahedron. Crystal structures of the CabNAlBr2 (3) [a = 8.9360(3) Å, b = 12.0358(9) Å, c = 14.7730(4) Å, α = β = γ = 90°] and the CabNAlMe2 (4) [a = 8.9551(3) Å, b = 11.9126(9) Å, c = 14.7711(4) Å, α = β = γ = 90°] were obtained. The reactivity of aluminum complexes 3 and 4 with Lewis bases, such as H2O, pyridine, alkylamines, and arylamines, confirmed their rapid decomposition.

Background and Aim: Spontaneous bacterial peritonitis is a common infection in liver cirrhosis. This systematic review and meta-analysis provides detailed information on the prevalence of SBP among HBV and HCV-related liver cirrhosis globally. Methods: A systematic search for articles describing the prevalence of SBP in HBV, and HCV related cirrhosis was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. Our search returned ten (10) eligible articles involving 1,713 viral cirrhosis cases representing eight (8) countries. A meta-analysis was performed on our eligible studies using the random effect model. A protocol was registered with PROSPERO (CRD42022321790). Results: The pooled prevalence of SBP in HBV associated cirrhosis had the highest estimate [8.0% (95% CI, 2.7 – 21.0%; I2= 96.13%; p < 0.001)], followed by SBP in HCV associated liver cirrhosis [4.0% (95% CI, 1.3% – 11.5%; I2 = 88.99%; p < 0.001)]. China (61.8%, CI: 57.1 – 66.3%), the USA (50.0%, CI: 34.6 – 65.4%), and Holland (31.1%, CI: 21.6 – 42.5%) had the highest estimate for SBP in HBV associated liver cirrhosis, SBP in HCV associated liver cirrhosis and SBP in HBV+HCV associated liver cirrhosis respectively. There was a significant difference in the prevalence of SBP in viral hepatitis-associated liver cirrhosis with the year of sampling and method of SBP detection at P<0.001. There was an increase in SBP incidence at the beginning of 2016 across the liver cirrhosis in this study. Conclusion: The findings of this review revealed an increase in the incidence of SBP in viral hepatitis over the last decade, the latter could be due to the global increase in Bacterial resistance. This indicates a possible future rise in the global prevalence of SBP among HBV, and HCV-related liver cirrhosis.

We recently proposed that topological quantum computing might be based on $SL(2,\mathbb{C})$ representations of the fundamental group $\pi_1(S^3\setminus K)$ for the complement of a link $K$ in the $3$-sphere. The restriction to links whose associated $SL(2,\mathbb{C})$ character variety $\mathcal{V}$ contains a Fricke surface $\kappa_d=xyz -x^2-y^2-z^2+d$ is desirable due to the connection of Fricke spaces to elementary topology. Taking $K$ as the Hopf link $L2a1$, one of the three arithmetic two-bridge links [the Whitehead link $5_1^2$, the Berge link $6_2^2$, the double-eight link $6_3^2$] or the link $7_3^2$, the $\mathcal{V}$ for those links contains the reducible component $\kappa_4$, the so-called Cayley cubic. In addition, the $\mathcal{V}$ for the later two links contains the irreducible component $\kappa_3$, or $\kappa_2$, respectively. Taking $\rho$ to be a representation with character $\kappa_d$ ($d<4$), with $|x|,|y|,|z| \le 2$, then $\rho(\pi_1)$ fixes a unique point in the hyperbolic space $\mathcal{H}_3$ and is conjugate to a $SU(2)$ representation (a qubit). Even though details on the physical implementation remain open, more generally, we show that topological quantum computing may be developed from the point of view of three-bridge links, the topology of the $4$-punctured sphere and Painlev\'e VI equation. The $0$-surgery on the $3$ circles of the Borromean rings L6a4 is taken as an example.

Apis cerana and Apis mellifera, are very important honey species for agriculture in Asian countries. In recent decades, A. cerana populations have sharply declined in all Asian countries as a result of Sacbrood Virus infection and have now recovered to their original size. It can change the genetic structure of local populations of A. cerana. We used the nuclear gene Vitellogenin VG to assess the genetic structure of local populations of A. cerana and the signature of adaptive selection. We performed a population genetic analysis of the honey bees A. cerana from South Korea in comparison with A. cerana samples from Russia, Japan, Nepal, and China. The sequences of the gene VG of a closely related honey bee species, A. mellifera, from India and Poland were used as outgroup samples. A comparative analysis of northern and southern A. cerana populations was performed. The signatures of positive adaptive selection were found in the local population of A. cerana. We performed the Tajima's neutrality D test for A. cerana populations from different local populations based on the gene VG exon sequences. All A. cerana populations showed signs of population size expansion following the possible recent decline in population sizes. The local populations of A. c. koreana were subdivided according to their geographical distribution into southern, northern, and central Korean clusters. The gene VG exon sequences can be used as informative markers for monitoring the changes in genetic structure and adaptation to the environment processes in A. cerana populations.

The emergence of chemoresistance in neoplastic cells is one of the major obstacles in cancer therapy. Autophagy was recently reported as one of the mechanisms that promote chemoresistance in cancer cells by protecting from apoptosis and driving senescence. Thus, understanding the role of autophagy and its underlying signaling pathways is crucial for the development of new therapeutic strategies to overcome chemoresistance. We have previously reported that PKCη is a stress-induced kinase that confers resistance in breast cancer cells against chemotherapy by inducing senescence. Here we show that PKCη promotes autophagy induced by ER and oxidative stress and facilitates the transition from autophagy to senescence. We demonstrate that PKCη knockdown reduces both the autophagic flux and markers of senescence. Additionally, using autophagy inhibitors, such as chloroquine and 3-methyladenine, we show that PKCη and autophagy are required for establishing senescence in MCF-7 in response to oxidative stress. Different drugs used in the clinic are known to induce autophagy and senescence in breast cancer cells. Our study proposes PKCη as a target for therapeutic intervention, acting in synergy with autophagy-inducing drugs, to overcome resistance and enhance cell death in breast cancer.

The C/N ratio is an extremely important parameter in the composting process, which is directly responsible for the growth of microorganisms. A low C/N ratio contributes to higher emissions of greenhouse gases and odorous substances, such as ammonia (NH3), which is formed by nitrogen mineralization. Due to the highly toxic effects of ammonia, it is a particularly unwanted by-product that can disrupt the composting process because it poisons microorganisms and cause environmental issues. The activity of anammox bacteria, so far analyzed only in wastewater treatment processes, is a particularly efficient method of nitrogen removal, having an advantage over the conventional methods used previously. Our study proofs the presence of anammox bacteria during composting, what gives an opportunity to improve the process and reduce its impact on atmospheric pollution. Despite the aerobic nature of this process, the composted mass of waste presents conditions conducive to the development of these ammonia oxidizing bacteria, as well as other strains of microorganisms cooperating with them. This makes it possible to compost at a low C/N ratio; in addition, there is no need for additional energy supply through aeration, as the processes carried out by anammox bacteria do not require oxygen.

Scale invariance is expected in empty Universe models, while the presence of matter tends to suppress it. As shown recently, scale invariance is certainly absent in cosmological models with densities equal to or above the critical value ρ_c = 3(H₀)²/(8πG). For models with densities below ρc, the possibility of limited effects remains open. If present, scale invariance would be a global cosmological property. Some traces could be observable locally. For the Earth-Moon two-body system, the predicted additional lunar recession would be increased by 0.92 cm/yr, while the tidal interaction would also be slightly increased. The Earth-Moon distance is the most systematically measured distance in the Solar System, thanks to the Lunar Laser Ranging (LLR) experiment active since 1970. The observed lunar recession from LLR amounts to 3.83 (±0.009) cm/yr; implying a tidal change of the length-of-the-day (LOD) by 2.395 ms/cy. However, the observed change of the LOD since the Babylonian Antiquity is only 1.78 ms/cy, a result supported by paleontological data, and implying a lunar recession of 2.85 cm/yr. The significant difference of (3.83-2.85) cm/yr = 0.98 cm/yr, already pointed out by several authors over the last two decades, corresponds well to the predictions of the scale-invariant theory, which is also supported by several other astrophysical tests.

Here we report the effect of substrate, sonication process, and post-annealing on the structural, morphological, and optical properties of ZnO thin films grown in the presence of isopropyl alcohol (IPA) at temperature 30 – 65 ℃ by successive ionic layer adsorption and reaction (SILAR) method on both soda lime glass (SLG) and Cu foil. The X-ray diffraction (XRD) patterns confirmed the preferential growth (002) and (101) plane of wurtzite ZnO structure while grown on SLG and Cu foil substrate respectively. Both XRD and Raman spectra confirmed the ZnO and Cu-oxide phases of the deposited films. Scanning electron microscope (SEM) image of the deposited films shows compact and uniformly distributed grains for samples grown without sonication while using IPA at temperature 50 and 65 ℃. The post-annealing treatment improves the crystallinity of the films, further evident by XRD and transmission and reflection results. The estimated optical bandgaps are in the range of 3.37-3.48 eV for as-grown samples. Results revealed that high-quality ZnO thin films could be grown without sonication using IPA dispersant at 50 ℃, which is much lower than the reported results using the SILAR method. This study suggests that in the presence of IPA, the SLG substrate results in better c-axis oriented ZnO thin films than that of DI water, ethylene glycol, propylene glycol at the optimum temperature of 50 ℃. Air-annealing of the samples grown on Cu foils induced the formation of Cu_xO/ZnO junctions which is evident from the characteristic I-V curve including the structural and optical data.

Candida spp. are the most common cause of fungal infections worldwide. The taxonomy of Candida is controversial and has undergone recent changes due to novel genetically related species. Therefore, some complexes of cryptic species have been proposed. In clinical settings, the correct identification of Candida species is relevant since some species are associated with high resistance to antifungal drugs and increased virulence. This study aimed to identify the species of four Candida complexes (C. albicans, C. glabrata, C. parapsilosis, and C. haemulonii) by molecular methods. This is the first report of six cryptic Candida species in Honduras: C. dubliniensis, C. africana, C. duobushaemulonii, C. orthopsilosis, and C. metapsilosis, and it is also the first report of the allele hwp1-2 of C. albicans sensu stricto. It was not possible to demonstrate the existence of C. auris among the isolates of the C. haemulonii complex. We also propose a simple method based on PCR-RFLP for the discrimination of the multi-resistant pathogen C. auris within the C. haemulonii complex.

Concept Knowledge (C-K) theory has been used in engineering and science-based research for more than a decade. Design of an Information Technology (IT) artefact is mostly pragmatic in nature. Design Science Research (DSR) methodology applied and studied in many Information Systems (IS) research. Many sub design decisions involved through the design of an IT artefact from a concept (idea) to a working prototype. A DSR artefact is based on a combination of decisions made during several sub-design stages. Artefacts are built based on the selection of elements in each sub-design space. Recording the design decisions on each sub-design space would be beneficial for future researchers. By knowing the design decisions on each sub-design space, researchers would be able to try different combinations of the design. C-K theory provides the ability to capture the design processes’ several sub-design spaces. In this paper, we discuss the DSR research methodology by looking at the stages proposed in the literature, and the application of C-K theory in an IT-based DSR. This paper also proposed a C-K theory-based protocol called Concept Tree for tracking and reporting artefact design steps. The application of C-K theory in DSR is exhibited using the implementation of the Concept Tree for a prototype design IT artefact.

Hepatitis-C is one of the most common viral diseases caused by hepatitis C virus (HCV). It is responsible for millions of deaths each year in the developing world. The common dissemination paths of HCV include the use of contaminated water and transfusion of infected blood. Control of this virus has become a challenge for scientists and health professionals due to its versatility and adaptability in different host environments. Along with other problems, lack of efficient diagnosis, quantification and genotyping of viral strains are the major hindrances in a management of this notorious epidemic. The knowledge of HCV genotype and an amount of virus in patient’s blood are pre-requisites to determine the duration and method of treatment. In this review, we discuss the implications of HCV molecular diagnostic methods and their clinical applications. We conclude that while, several commercial and home-brewed methods are available for this purpose, and there is a visible vacuum for cost effective, robust, sensitive assays that can detect multiple viral genotypes in a single reaction. We are of the view that the level of sensitivity offered by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) technique is unequivocal as compared to other techniques. Therefore, researchers may explore further possibilities using this technique in the management of HCV.

In the present study, the performance of a 70 L photobioreactor, operating outdoors, was investigated using a purple bacterial strain as Rhodopseudomonas sp. S16-VOGS3 for producing poly-3-hydroxybutyrate (PHB). The novel photobioreactor was equipped with 5L-shaped rows; the bottom of every row was placed in a stainless-steel tank containing water with controlled temperature. The photofermentation trials were carried out under fed-batch mode and under a semi-continuous regimen using lactic acid as carbon source. The effect of the irradiance and the C/N ratio on the PHB accumulation was investigated, in order to evaluate the optimal bacterial growth. The results showed the feasibility of the prototype photobioreactor for the production of PHB by Rhodopseudomonas sp. S16-VOGS3 under the natural light/dark cycle. During the fed-batch growth (144 h long), the cumulative PHB increased quickly reaching the maximum value of 377 mg/L and decreased to 255 mg/L during the semi-continuous regimen (336 h long).

Cadmium is a highly toxic heavy metal for biological systems. Cupriavidus metallidurans CH34 is a model strain for heavy metal resistance and bioremediation. The aim of this study was to determine the role of the c-di-GMP pathway in the C. metallidurans CH34 response to cadmium in both planktonic and biofilm cells. Increasing cadmium concentrations correlates with an inhibition of biofilm formation and EPS production in C. metallidurans cells. Planktonic and biofilm cells showed similar tolerance to cadmium. During exposure to cadmium an acute decrease of c-di-GMP levels in planktonic and biofilm cells was observed. Transcription analysis by RT-qPCR showed that cadmium induced in planktonic cells and strongly induced in biofilm cells the expression of the urf2 gene and the mercuric reductase encoding merA gene, which belong to the Tn501/Tn21 mer operon. After exposure to cadmium the cadA gene involved in cadmium resistance was equally upregulated in both lifestyles. Bioinformatic analysis and null mutant complementation assays indicated that the protein encoded by the urf2 gene is a functional phosphodiesterase involved in the c-di-GMP metabolism. We propose to rename the urf2 gene as mrp gene for metal regulated phosphodiesterase. An increase of the second messenger c-di-GMP content by the heterologous expression of the constitutively active diguanylate cyclase PleD* correlated with an increase in biofilm formation and cadmium susceptibility. These results indicate that the response to cadmium in C. metallidurans CH34 involves a decrease in c-di-GMP content that inhibits the biofilm lifestyle.

Molecularly imprinted polymers (MIPs) were synthesized and applied for the selective extraction of oblongifolin C (OC) from fruit extracts of Garcinia yunnanensis Hu. A series of experiments and computational approaches were employed to improve the efficiency of screening for optimal MIP systems in the study. The molar ratio (1:4) was chosen at last based on the comparison of the binding energy of the complexes between the template (OC) and functional monomers using density functional theory (DFT) at the RI-PBE-D3-gCP/def2-TZVP level of theory. The binding characterization and the molecular recognition mechanism of MIPs were further explained using the molecular modeling method and NMR and IR spectra data. The reusability of this approach was demonstrated in over 20 batch rebinding experiments. 140.5 mg of OC (>95% purity) was obtained from the 5 g extracts with 2 g of MIPs with the best binding properties through gradient elution program from 35% to 70% methanol-water solution. At the same time, another structural analog, 46.5 mg of guttiferone K (GK) (>88% purity), was also obtained by the gradient elution procedure. Our results showed that the structural analogs could be separated from the crude extracts by the molecularly imprinted solid-phase extraction (MISPE) using a gradient elution procedure for the first time.

Abstract: Although the pathophysiology of fibromyalgia syndrome has been better understood in recent decades, a unified model of its pathogenesis and an effective therapeutic approach are still far from being realized. The main aim of this article will be to delve into the fundamental mechanisms of the pathophysiology of fibromyalgia conceptualized as stress intolerance syndrome. Using the biopsychosocial model of chronic pain syndromes, we will describe the potential role of the attachment system, C tactile fibers, and oxytocinergic system dysfunction in the pathophysiology of fibromyalgia syndrome and other central sensitivity syndromes. At the end of the article, the therapeutic implications of this new global and translational pathophysiological model will be briefly discussed.

Myo-inositol (MYO) and D-chiro-inositol (DCI) are the two most significant isomeric forms of inositol, playing a critical role in intracellular signaling. MYO is the most abundant form of inositol in nature; DCI is produced from MYO through epimerization by an insulin-dependent enzyme. Recently, it has been demonstrated that inositols may influence oocyte maturation, improve intracellular Ca2⁺ oscillation in the oocytes and have been proposed as potential interventions for restoring spontaneous ovulation. MYO concentration in human follicular fluid is considered a bioindicator of oocyte quality. In the ovary, DCI modulates the activity of aromatase thus regulating androgen synthesis. Under physiological conditions, MYO/DCI ratio is maintained at 40:1 in the plasma. In women with PCOS, MYO/DCI ratio lowers to 0:2:1, contributing to elevated androgen production. By regulating FSH signaling, MYO administration increases the number of high-quality embryos available for transfer in poor responder patients. Finally, by acting downstream to insulin signaling inositol administration during pregnancy may represent a novel strategy for counteracting gestational diabetes. These findings show that diet supplementation with inositols may be a promising strategy to address female infertility and sustain healthy pregnancy.

In this article we focus on kynurenic acid metabolism, a biochemical part of L-tryptophan catabolism, in processes related to memory and cognitive impairment and its subsequent relevance to neuropsychiatric disorders and the ageing process. Kynurenic acid is synthesised from L-kynurenine by kynurenine aminotransferases. Experimental pharmacological studies have shown that elevated levels of kynurenic acid in the brain are associated with impaired learning and that lowering kynurenic acid levels can improve these symptoms. The discovery of new compounds with the ability to block kynurenine aminotransferase opens up new therapeutic avenues against memory impairment and dementia. The newly developed Helix pomatia snail model of memory is being used for this pharmacological approach. In conclusion, diet, exercise and physical activity have a significant impact on the endogenous pharmacology of kynurenic acid and significantly modulate steady-state conditions and delay the events of the ageing process.

In this article we focus on kynurenic acid metabolism, a biochemical part of L-tryptophan catabolism, in processes related to memory and cognitive impairment and its subsequent relevance to neuropsychiatric disorders and the ageing process. Kynurenic acid is synthesised from L-kynurenine by kynurenine aminotransferases.Experimental pharmacological studies have shown that elevated levels of kynurenic acid in the brain are associated with impaired learning and that lowering kynurenic acid levels can improve these symptoms. The discovery of new compounds with the ability to block kynurenine aminotransferase opens up new therapeutic avenues against memory impairment and dementia. The newly developed Helix pomatia snail model of memory is being used for this pharmacological approach. In conclusion, diet, exercise and physical activity have a significant impact on the endogenous pharmacology of kynurenic acid and significantly modulate steady-state conditions and delay the events of the ageing process.

The purpose of this study is to examine how sales restrictions on gasoline-powered vehicles influence patent application behavior in automobile engine technology. This is achieved through a factorial analysis targeting structural changes in patent applications. We examine patterns in patent data from 1985 to 2019 using index decomposition based on the logarithmic mean Divisia index. The analysis utilizes patent data and focuses on one non-green (internal combustion engine vehicles) and three green automobile engine technologies (battery electric vehicle, hybrid electric vehicle, and full cell vehicle). Furthermore, the study focuses on four significant patent offices (China, Japan, the United States, and Germany) to examine global disparities. The analytical results reveal that a country’s green investment pattern changes depending on its growth stage. Intellectual property protection policies and encouragement of R&D will extend the scope of R&D activities in emerging nations where intellectual property markets are not well developed. Furthermore, different countries have distinct product development strategies when it comes to various forms of green automotive engine technologies. Green patents are likely to rise in industrialized nations for incentives such as tax breaks or subsidies for R&D spending on specific technological advancements and the extension of intellectual property protection.

Background/Objectives: Women's reproductive and overall well-being are intricately associated to vitamin D levels. In Morocco, vitamin D deficiency is a major issue for premenopausal women, yet little data exists on their dietary intake of this nutrient. This study explores vitamin D dietary intake, socio-demographic determinants, and its correlation with serum 25-hydroxyvitamin D [25(OH)D3] in premenopausal Moroccan women. Methods: A cross-sectional study was conducted with 355 women aged 18-49 in Meknes, Morocco, using validated questionnaires to assess dietary intake and sun exposure. Potential covariates such as physical activity and BMI were also assessed . Serum 25(OH)D was measured via chemiluminescence immunoassay. Chi-square tests and Spearman correlation were used to identify socio-demographic factors influencing vitamin D intake. Linear and multivariate regression analysis determined the main predictors of serum 25(OH)D levels. Results :The median (interquartile range) vitamin D dietary intake was 2.8 (2.7) µg/day , with less than 20% of women meeting the recommended 5 µg/day. Major dietary sources were fish (48%), dairy (24.3%), and meat (9.4%), with fortified foods contributing only for 7%. Lower intake was linked to younger age (p=0.004) and rural living (p=0.024). While no significant association was found between dietary intake and serum 25(OH)D ((β(SE): 0.155(0.094), p=0.340 ) , sun exposure positively predicted serum levels(β(SE): 0.343 (0.128), p=0.008) , and BMI negatively affected them (β(SE): -1.128 (0.337), p=0.001). Conclusions: Our findings highlight insufficient vitamin D intake among premenopausal Moroccan women, especially younger and rural women. Nutritional interventions are needed to address this deficiency, promoting better dietary habits, sun exposure, and healthy weight.

We investigated the effect of 0.6 MeV proton irradiation on the superconducting and normal state properties of thin-film YBa2Cu3O7−δ superconductors. A thin-film YBCO superconductor (≈ 567 nm thick) was subject to a series of proton irradiations with a total fluence of 7.6×1016p/cm2. Upon irradiation, Tc was drastically decreased from 89.3 K towards zero with a corresponding increase in its normal state resistivity above Tc. This increase in resistivity which indicates the increase of defects inside the thin-film sample can be converted to the dimensionless scattering rate. We found that the relation between Tc and dimensionless scattering rate obtained during proton irradiation approximates the generalized d-wave Abrikosov-Gor’kov theory better than the previous results obtained from electron irradiations. This is an unexpected result since the electron irradiation is known to be most effective to suppress superconductivity over other heavier ion irradiations such as proton irradiation. It suggests that the type of defects created by proton irradiation evolves from cascade defects (in bulk single crystals) to point-like defects (in thin-film single crystals) as the thickness decreases.

The nuclear hormone family of receptors regulates gene expression. The androgen receptor (AR) shuttles upon ligand binding and homodimerization from the cytosol into the nucleus to activate gene expression. Thyroid hormone receptors(TR), retinoic acid receptors (RAR), and the vitamin D receptor (VDR) are present in the nucleus bound to chromatin as a heterodimer with the retinoid X receptors (RXR) and repress gene expression. Ligand binding leads to transcription activation. The hormonal ligands for these receptors play crucial roles to ensure the proper conduct of very many tissues and exert effects on prostate cancer (PCa) cells. Androgens support PCa proliferation and deprivation alone or with chemotherapy is the standard therapy for PCa. RAR activation and 3,5,3'-triiodo-L-thyronine (T3) stimulation of TR support the growth of PCa cells. Ligand stimulation of VDR drives growth arrest, differentiation, and apoptosis of PCa cells. Often these receptors are explored as separate avenues to find treatments for PCa and other cancers. However, there is accumulating evidence to support receptor interactions and crosstalk of regulatory events whereby a better understanding might lead to new combinatorial treatments.

Certain micronutrients exhibit immunomodulatory effects. However, no intervention has yet investigated the effect of an individualized supplementation on the severity of upper respiratory tract infections (URI). Therefore, we investigated whether a personalized supplementation moderates the incidence and severity of URI. Selenium, zinc, and vitamin D was measured from 59 healthy participants ) in dried blood spots. Accordingly, a personalized supplement was provided with or without the respective micronutrients. We used WURSS-21 questionnaires to assess the disease status. The blood values converged during the intervention and micronutrients no longer differed at the end of the intervention period between treated and untreated volunteers. The incidence and severity of the illness did not significantly differ between the groups. However, when analyzing the WURSS-21 score by the intention to treat, the initially randomized treatment arm revealed a significantly higher score than the placebo arm. Upon acute administration, individualized combination of selenium, zinc and vitamin D does not reduce the number or contribute to a milder course of URIs. Therefore, supplementation in acute infectious situations seems questionable. Further studies must address the habitual diet in more detail to better understand the impact of individual micronutrient status on the prevention of URI.

This article examines the diagnosis of the Agricultural Innovation System (SIA) in the department of Tolima, Colombia, as part of a project led by the Colombian Ministry of Agriculture and Rural Development and the Technological University of Pereira (TUP), which also evaluated the National Agricultural Innovation System (NAIS) in regions such as Chocó, Bolívar, and Meta. A methodology was used that involved a survey with 58 questions on a Likert scale to 300 participants, evaluated with congruence and relevance indexes, identifying key variables in the operation of the Agricultural Innovation System (AIS). A survey was also applied to actors of the National Innovation System for Higher Education in Agriculture, A survey was also applied to map the participating actors in the regional agricultural innovation systems of Tolima to identify gaps in extension, innovation, development, sustainability, ICT, education and training. Among the conclusions, it stands out that the associativity subsystem presents the lowest lag and is close to a score of two on the scale of gaps, evaluation carried out among the five subsystems including extension, ICT, environmental aspects, and pub-lic policy. The department of Tolima shows low performance in innovation and ICT, while the extension is less lagging. In Chaparral there is a general lag, with innovation being the worst evaluated subsystem. Rovira obtains high scores in most subsystems, although innovation and ICT have lower scores. At the national and regional levels, innovation is low, and articulation among NARS actors is insufficient, which highlights the need to promote good practices, strategies, and projects.

This research emphasizes a meta-heuristic Modified Ant Lion Optimizer (MALO) optimization approach for simultaneous utilization of DSTATCOM devices and distributed Photovoltaic (PV) sources with network reconfiguration in a radial power distribution scheme. In a radial power distribution network with network reconfiguration majority of the research is based on Constant Power model analysis. However, it is noticed that load models have a substantial impact on the distributed PV sources and the D-STATCOM device's optimal size and position. The effect of the Constant Power (CP) and Polynomial (ZIP) with load growth load models for the simultaneous insertion of distributed PV sources and DSTATCOM devices with network reconfiguration examined in this research work for power system planning. The penetration levels of distributed PV sources considered for the investigation are 25%, 50%, 75%, and 100%. The principal objective of this research is to reduce network total power losses, enhance the voltage magnitude profile at all buses, and reduce the overall operating cost while adhering to equality and inequality constraints. The proposed algorithm verified on 118-node test systems. The investigation is carried out for planning network upgradation to a High Voltage Distribution System(HVDS) on 317 nodes in the rural Bangalore Electricity Supply Company Limited(BESCOM) radial distribution scheme. Simulated results obtained by this method are validated with the BAT algorithm and available techniques in the literature.

Multiple Sclerosis (MS) is a neurodegenerative disease that mainly affects young adults. The high prevalence of the disease and its impact on patients' quality of life led to priority being given to the etiopathogenesis of the disease to identify possible modifiable factors and consequent effective intervention strategies. Recent hypotheses suggest that the etiopathogenesis of MS is multifactorial and includes factors related to the immune system, neuroinflammation and neuro-degeneration. In this scenario, sleep has a close - although indirect - relationship with MS, through its relationship with each of those factors. In particular, the role of cytokines in immune system impairment and neuroinflammation, mitochondrial dysfunction and oxidative stress in neurodegeneration all are associated with sleep in different forms. Furthermore, melatonin in relation with vitamin D has a potential therapeutic effect in MS sleep-related problems. Given the growing interest of research in the mechanisms underlying MS and therapies able to alleviate MS-related symptoms at all stages of the disease, a more in-depth study of the role of sleep disturbances and the factors intrinsically related to sleep and MS could be useful both to investigate the etiopathogenetic factors of MS and to develop potential non-invasive intervention strategies for MS treatment.

DNA double-strand breakage is the most lethal damage to chromosomal DNA. It activates a series of cellular DNA damage response pathways, including DNA damage sensing, control of cell cycle arrest and apoptosis, and DNA repair. DNA damage response pathways are regulated by complex signaling machineries. Of the intracellular signaling cascades, diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid (PA). Because both DG and PA serve as second messengers, DGK activity induces a shift of signaling pathways from DG-mediated to PA-mediated cascades, thereby implicating DGK in the regulation of widely various functions. Reportedly, one member of the DGK family, DGKζ, is intimately involved in the regulation of stress responses through p53 and NF-κB. Stresses such as ischemia and infarction cause DGKζ downregulation. Experimental DGKζ depletion renders cells and mice vulnerable to various stressors such as chemotherapeutic agents and ionizing irradiation. Nevertheless, how DGKζ is involved in DNA repair, a critical event of DNA damage response for survival remains unknown. For this study, we examined how DGKζ depletion affects DNA repair mechanisms. We demonstrated that DGKζ depletion causes attenuation of Akt activation and DNA-PK protein expression upon DNA damage, which might engender downregulated BRCA1 protein synthesis and stability. Results suggest that DGKζ depletion attenuates BRCA1-mediated DNA repair machinery, thereby conferring vulnerability to DNA damage.

The post-hoc analysis presented here aimed to address the influence of endogenous vitamin D in the immunological mechanism underlying effective mite allergoid-immunotherapy (AIT). Previously, we have shown that one subpopulation of T regulatory cells results in phenotypically identifiable as functionally potentiated and memory cells in allergic children after 12 months of this immunoactive treatment. Indeed, AIT is the only known treatment able to reshape the detrimental immune response against the allergen into a not noxious one. Besides, VD is widely considered an immunoregulatory molecule endogenously produced and exogenously provided with foods and supplements that might interact with AIT mechanism and affect its outcome. Therefore, a post-hoc analysis of the clinical and immunological data of three different cohorts of allergic patients was performed. One cohort (N=70) was on standard symptoms-controlling pharmacological treatment while the other two (N=60 and N=35, respectively) were treated with AIT for 12 months. Among the first were observed a lower mean endogenous VD level (&lt;22 ng/ml) along with worse symptoms and higher use of medications. Remarkably, the comparison between two sub-cohorts of patients with serum VD above (N=32) or below (N=28) a cut-off value set at mean value (27 ng/ml) revealed that optimal improvement of all clinical and immune parameters was achieved (as expected by effective AIT), irrespective of the VD level. Notably, the third analysis, carried out on one cohort of AIT patients also taking concomitantly VD3 as food supplement (N=19), was distinguished by uppermost overall treatment outcome (amelioration of symptoms, lowest medications requirement, and reduction of total and allergen-specific IgE) as well as the increase of allergen-specific tolerogenic memory T regulatory cells. These findings suggest that endogenous VD level affects allergy severity and allergen immunotherapy effectiveness. Also, VD3 might be investigated as an add-on supplement to get the best out of immunotherapy in VD deficient/insufficient allergic patients. The immunogenic but low-allergenic mite allergoid used as bioactive agent might have contributed to minimize allergic and highlight immunological effects described here.

Like 18F-FDG, 99mTc-1-thio-D-glucose (99mTc-TG) also binds to GLUT receptors. The aim of this Phase I study was to evaluate the safety, biodistribution and dosimetry of 99mTc-TG. Twelve lym-phoma patients were injected with 729±102 MBq 99mTc-TG. Whole-body planar imaging was per-formed in 10 patients at 2, 4, 6 and 24 h after injection. In all 12 patients SPECT/CT (at 2 h) and SPECT (at 4 and 6 h) imaging was performed. Vital signs and possible side effects were monitored during imaging and up to 7 days after injection. 99mTc-TG injections were well tolerated and no side effects or alterations in blood and urine analyses data were observed. The highest absorbed dose was in the kidneys and urinary bladder wall, followed by the adrenals, prostate, bone mar-row, lungs, myocardium, ovaries, uterus, liver and gall bladder wall. 99mTc-TG SPECT/CT re-vealed foci of high activity uptake in the lymph nodes of all nine patients with known nodal le-sions. Extranodal lesions were detected in all nine cases. In one patient, a lesion in the humerus head, which was not detected by CT, was visualized using 99mTc-TG. Potentially, 99mTc-TG SPECT can be considered as an additional diagnostic method for imaging GLUT receptors in lymphoma patients.

Background: Nutritional rickets is still considered as a global health problem especially in low-resource countries and immigrant societies of developed countries. Generalized skeletal deformities including angular knee deformities as genu varum and genu valgum are prominent features of nutritional rickets. Angular knee deformities can cause gait difficulties. However, the true remodelling potential of the healed knee deformities is largely unknown to the pediatric and orthopedic community. Aims: The primary objective of this study protocol is to investigate the natural history of disease in regard to the remodelling potential of angular knee deformities in children and adolescents with healed nutritional rickets. And determine the potential patient- and deformity-related factors that are associated with a favorable deformity remodelling as age and sex of patients and type, severity, laterality of deformities etc. Methods: This will be a prospective observational analytical cohort natural history of disease study. A minimum of at least 140 knees with healed nutritional rickets and angular knee deformities will be observed at regular three-monthly intervals over a period of at least one year. We will report two outcome variables namely; clinical and radiological tibio-femoral angle. And independent patient and deformity-related variables as age, sex, deformity type, severity and laterality. Inferential statistics namely bivariate and multivariate analysis will be employed accordingly to identify the relation between outcome variables and the different independent variables. Ethics and dissemination: This protocol study has been approved by the institutional research ethics committee. Results will be presented at conferences and submitted to relevant international and society publications. Authors will also communicate the results to their scholarly networks and post them on scholarly networking sites. Conclusions: This study has the potential for improving the decision-making process as to which patients deserve conservative treatment and which deserve surgical deformity correction. Results are expected to have an impact on the clinical practice of pediatricians, orthopedic surgeons and family physicians alike.

Abstract: A primary action of vitamin D is regulation of gene transcription. Many cell types possess genes that make antimicrobial peptides (AMPS) (endogenous antibiotics), recently discovered to be regulated by vitamin D. Two examples are cathelicidin and beta defensins, both bioactive against many different bacteria, fungi, mycobacteria, parasites and viruses. The signal transduction pathway is triggered by sensing microorganisms via cell surface receptors, causing intracellular production of calcitriol (1,25(OH)2D) and vitamin D receptors, leading to upregulation of AMP production. Serum 25(OH)D concentrations required to sustain adequate AMP production to eradicate infections are unknown. Vitamin D3 is photosynthesized in skin in amounts ranging from 10,000 (250 mcg) to 25,000 (625 mcg) International Units (IU) from 7-dehydrocholesterol after whole-body exposure to one minimal erythemal dose (MED) of ultraviolet B (UVB) radiation, and is impacted by many factors including geographic localities, seasonal changes and skin pigmentation. We and others have reported extended daily oral dosing with these amounts of vitamin D3 safe. We routinely observe serum 25(OH)D concentrations below 20ng/ml on new admissions, which have been reported insufficient to sustain AMP production. In contrast serum 25(OH)D concentrations above 100ng/ml have been reported after serial UVB treatments for psoriasis. Little vitamin D naturally occurs in food, and insufficient sun exposure may be causing worldwide deficiency. We review evidence suggesting that higher daily intakes of vitamin D3 than the currently recommended 600 (15 mcg) IU/day may be necessary to sustain AMP production in the face of an overwhelming infection, particularly in non-Hispanic blacks, a high risk population suffering the worst outcomes from COVID-19. We propose that increased vitamin D supplementation could provide a safe and cost-effective way to protect all populations from infections, in particular those from pandemic COVID-19.

A literature review was conducted to summarize the frequency of the D-allele of the angiotensin-converting enzyme-1 in all countries with available data. Using an ecological study design limited to high income countries, we found that the country-level frequency of the D-allele was associated with increased COVID-19 incidence and mortality.

In this paper, we observe that if X is a set and (Bin(X), □) is the semigroup of binary systems on X, then its center ZBin(X) consists of the locally-zero-semigroups and that these can be modeled as (simple) graphs and conversely. Using this device we show that we may obtain many results of interest concerning groupoids by reinterpreting graph theoretical properties and at the same time results on graphs G may be obtained by considering them as elements of centers of the semigroups of binary systems (Bin(X), □) where X = V(G), the vertex set of G.

This paper proposed three-dimensional numerical simulation method by coupling of electrostatic and fluid fields to evaluating the performance of electrical sensor in the concentration measurement of gas/solid two-phase flow. Compared with the static numerical simulation, this real-time dynamic 3-D simulation method can research on a designed capacitance sensor combining the dynamic characteristics of the two-phase flows for concentration measurement. Several fluid-electrostatic models of transmission pipes with different sensor structures are built. Under different test positions and different particle concentrations, the flow characteristics and the corresponding electric signals can be obtained, and the correlation coefficient between the concentration values and the capacitance values are used for performance evaluation of the sensors. The effects of flow regimes on concentration measurement are also been investigated in this paper. To validate the results of simulation, an experimental platform with horizontal straight pipe for phase volume concentration measurement of solid/air two-phase flow is built, and the experimental results agree well with simulation conclusions. The simulation and test results show that the coupling models can give constructive reference opinions for the sensor design and collection of installation position in different transmission pipelines, which are very important for the practical process of pneumatic conveying system.

Islatravir (ISL) is the first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTtI) with novel modes of action. Data on ISL resistance is currently limited, particularly to HIV-1 non-B subtypes. This study aimed to assess prevalent nucleos(t)ide reverse transcriptase inhibitor (NRTI) resistance mutations in HIV-1 subtype C for phenotypic resistance to ISL. Prevalent single and combinations of NRTI resistance mutations were selected from a routine HIV-1 genotypic drug resistance testing database and introduced into HIV-1 subtype C-like pseudoviruses, which were then tested for ISL susceptibility. Single NRTI resistance mutations were susceptible or showed only a low level of resistance to ISL. This included thymidine analogue mutations (TAMs, i.e., M41L, D67N, K70R, T215FY, K219EQ) and non-TAMs (i.e., A62V, K65R, K70ET, L74IV, A114S, Y115F, M184V). Combinations of M184V with one or more additional NRTI resistance mutations generally displayed reduced ISL susceptibilities. This was more prominent for combinations that included M184V+TAMs, and particularly M184V+TAM-2 mutations. Combinations that included M184V+K65R did not impact significantly on ISL susceptibility. Our study suggests that ISL would be effective in treating people living with HIV (PLWH) failing tenofovir disoproxil fumarate (TDF)/lamivudine (3TC) or TDF/emtricitabine (FTC)-containing regimens but would be less effective in PLH failing zidovudine (AZT) with 3TC or FTC-containing regimens.

Breast cancer is currently the second leading cause of death worldwide, accounting for 15% of all deaths (8.2 million deaths). Approximately 20% of breast cancer diagnoses are triple-negative breast cancer (TNBC), a type of cancer that lacks receptors for estrogen (ER negative), progesterone (PR negative), and human epidermal growth factor receptor 2 (HER2/neu negative). Consequently, TNBC doesn’t respond to hormonal or targeted therapies, making it challenging to treat due to its rapid growth, metastasis, and high recurrence rate within the first three years of therapy. Alternative chemotherapies are needed to address this problem. Pharmacological dose of vitamin C (high-dose VC) has been identified as a potential treatment for some cancer cells. The present study aimed to evaluate whether VC has a therapeutic effect on TNBC using MDA-MB-231 cells as the model. MTT assay, Hoechst 33342 staining, Nuclear ID Red/Green staining, Rhodamine 123 staining, and Western blot analysis were employed to test the hypothesis that pharmacological dose of VC can kill TNBC cells. Upregulation of Apaf-1, caspases -3, -6, -7, -8, and -9, inhibition of matrix metalloproteinases (MMP-2 and MMP-9), reduction in cell cycle protein expression, and enhancement of tumor suppressor proteins such as p53 and p21 indicated that pharmacological dose of VC has promising anti-cancer properties in the treatment of TNBC.

Soil carbon is newly refined as ~32,000 Gt C (gigatonnes) over ten times previous totals. Soil organic carbon (SOC) of ~22,000 Gt C plus plants at ~2,400 Gt C in both above- and below-ground stocks hold 99% of Earth’s biomass. Occupying a topographic surface area of 25 Gha with mean depth 21 m, soil has more organic carbon than all plants, oceans, fossil fuels, or the atmosphere combined. Soils are both the greatest biotic carbon store and the most active CO2 source. Basic inventory is required for proper understanding and utilization of Earth’s natural resources, especially with increasing soil degradation and species loss. Values are raised considerably, the disparity due to lack of full soil depth survey, neglect of terrain and of other omissions. Herein new totals are determined for mineral soils, permafrost, and peats (of all forms and ages), to full depth (easily doubling shallow values) and allowing for terrain that is ignored in all terrestrial models (doubling most values again), plus SOC in recalcitrant glomalins (~30%) and friable saprock (+26%). Additionally, soil inorganic carbon (SIC), aquatic sediments and dissolved fractions are factored in. Soil biota (e.g. fungi, bacteria and earthworms) are similarly upgraded. Primary productivity, also upped for terrain, is confirmed at 220 Gt C/yr on land supported by C/O isotope fluxes. Priority issues of species extinction, humic topsoil loss, and excess atmospheric CO2 are all remedied by SOC restoration and biomass recycling via (vermi-)compost for use in 100% organic husbandry and adoption of wider practices of Permaculture based upon scientific observation of Nature.

Color distortion in an image poses a challenge for classification and regression when the input data consists of pictures. Because of that, a new algorithm for color standardization of photos is proposed, which serves as a base for a deep neural network regression model. This approach utilizes a custom color template, which was developed based on an initial series of studies and digital imaging. Using the equalized histogram of R, G, B channels from the digital template and its photo, a color mapping strategy is computed. By applying this approach, the histograms are adjusted, and the colors of photos taken with a smartphone are standardized. The proposed algorithm has been developed for a series of photos where the entire surface roughly maintains a uniform color, and the differences in color between the photographs of individual objects are minor. The optimized approach was validated in the colorimetric determination procedure of vitamin C. The dataset for deep neural network in the regression variant was formed from photos of samples under two separate lighting conditions. For the concentration range of vitamin C from 0 to 87.72 µg·mL-1, the RMSE for the test set ranged between 0.75 and 1.95 µg·mL-1, in comparison to the non-standardized variant, where this indicator was at the level of 1.48-2.29 µg·mL-1. The consistency of the predicted concentration results with actual data expressed using R2 was between 0.9956 and 0.9999, for each of the standardized variants. This approach allows for the removal of light reflections on the shiny surface of solutions, which is a common problem in liquid samples. The color matching algorithm has a universal character, and its application scope is not limited.

A 23-month-old neutered male dog of unknown ancestry presented with a history of progressive neurological signs that included anxiety, cognitive impairment, tremors, seizure activity, ataxia, and pronounced visual impairment. The clinical signs were accompanied by global brain atrophy. Due to progression in the severity of disease signs, the dog was euthanized at 26 months of age. Examination of tissues collected at necropsy revealed dramatic intracellular accumulations of autofluorescent inclusions in the brain, retina, and cardiac muscle. The inclusions were immunopositive for subunit c of mitochondrial ATP synthase, and their ultrastructural appearances were similar to those of lysosomal storage bodies that accumulate in some of the neuronal ceroid lipofuscinosis (NCL) diseases. The also dog exhibited widespread neuroinflammation. Based on these findings, the dog was deemed likely to have suffered from a form of NCL. A whole genome sequence analysis of the proband’s DNA revealed a homozygous C to T substitution that altered the intron 3 – exon 4 splice site of CLN6. Other mutations in CLN6 cause NCL diseases in humans and animals including dogs. CLN6 protein was undetectable with immunolabeling in the tissues of the proband. Based on the clinical history, fluorescence and electron-microscopy, immunohistochemistry, and molecular genetic findings, the disorder in this dog is classified as an NCL resulting from the absence of CLN6 protein. Screening the dog’s genome for a panel of breed-specific polymorphisms indicated that its ancestry included numerous breeds, with no single breed predominating. This suggests that the CLN6 disease variant is likely to be present in other mixed breed dogs and at least some of the ancestral breeds.

Dysregulation of the Cyclin-dependent kinase 8 (CDK8) activity has been associated to many diseases including the colorectal and breast cancer. As usual in the CDK family, the activity of CDK8 is controlled by a regulatory protein called cyclin C (CycC). But while human CDK family members are generally activated in two steps that is, the binding of the cyclin to CDK and the phosphorylation of a residue in the CDK activation loop, CDK8 does not require the phosphorylation step to be active. Another peculiarity of CDK8 is its ability to be associated to CycC while adopted an inactive form. These specificities raise the question of the role of CycC in the complex CDK8-CycC, which appears to be more complex than for the other members of CDK family. Through MD simulations and binding free energy calculations, we investigated the effect of CycC on the structure and dynamics of CDK8 on the one hand, and the structural molecular basis of the protein-protein interaction between the two partners on the other hand. We found that CycC has a stabilizing effect on CDK8 and identified specific interaction hotspots within its interaction surface compared to other human CDK/Cyc pairs. Targeting these specific interaction hotspots could be a promising approach in terms of specificity, to effectively disrupt the interaction between CDK8. The simulation of the conformational transition from the inactive to the active form of CDK8 suggests that the residue Glu99 of the CycC may assume the role of the missing phosphorylation step in the activation mechanism of CDK8. In a more general view, these results point the importance of keeping the CycC in computational studies when studying the human CDK8 protein in both the active and the inactive form.

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a specific subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1's mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was safe and well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is safe and well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest.

This research aims to deepen the understanding of the relationship between conductivity and morphology in polypyrrole (PPy) via a comparison of the bipolaron to polaron ratios with a focus on the C-H deformation area. PPy samples were synthesized with different surfactants: sodium dodecyl sulfate (SDS), cetyltrimethylammonium bromide (CTAB), and tween 80 (TW). The study revealed that SDS significantly altered the bipolaron and polaron in C-H deformation region and showed higher conductivity than other surfactants. Notably, the morphological shifts to a sheet-like structure when using ammonium sulfate (APS) contrasted with the particle-like form observed with ferric chloride (FeCl3). These results showed that if the oxidant changed, the bi-polaron and polaron ratios in C-H deformation were unrelated to PPy morphology. However, this work showed a consistent relationship between SDS use, the bipolaron and polaron ratios in the C-H deformation, and the conductivity properties. Moreover, the natural positive charge of PPy and negatively charged SDS molecules may lead to an electrostatic interaction between PPy and SDS. This work assumes that this interaction might cause the transformation of polaron to bipolaron in the C-H deformation region, resulting in improved conductivity of PPy. This work offers more support for the future investigation of PPy characteristics.

(1) Background: Hepatitis C virus (HCV) screening mostly uses a one-assay anti-HCV testing approach, which has a higher probability of false-positive results in populations with low HCV prevalence. (2) Methods: In this investigation, 17,926 participants, were screened for HCV, and the reactives were tested using a two-assay anti-HCV approach: Elecsys ElectroChemiLuminescence (ECL) and a ChemiLuminescence ImmunoAssay (CLIA), respectively. A recombinant immunoblot assay (RIBA) was performed to confirm anti-HCV positivity. Statistical analysis was performed. (3) Results: A total of 350 specimens resulted reactive in the ECL screening, of which CLIA retesting showed that 292 (83.4%) were anti-HCV reactive (283 positive, 9 indeterminate, none negative by RIBA), but 58 (16.6%) were not anti-HCV reactive (15 positive, 12 indeterminate, 31 negative by RIBA). The two-assay strategy significantly improved the positive predictive value (PPV: 95.00%) with χ2: 7.59(p&lt;0.01) then the PPV assessed by one assay (PPV: 90.6%) with χ2: 34.51 (p&lt; 0.001). The ROC curve defined a sensibility and specificity for the dual approach of: 99.66% and 100.00%. (4) Conclusions: Compared with a one-assay testing strategy, the two-assay testing strategy may significantly reduce false positives in anti-HCV testing and identify inactive HCV infection in low seroprevalence populations.

Avian metapneumovirus subgroup C (aMPV/C) causes respiratory diseases and egg dropping in chickens and turkeys, resulting in severe economic losses to the poultry industry worldwide. Integrin β1 (ITGB1), a transmembrane cell adhesion molecule, is present in various cells and mediates numerous viral infections. Herein, we demonstrate that ITGB1 is essential for aMPV/C infection in cultured DF-1 cells, as evidenced by the inhibition of viral binding by EDTA blockade, Arg-Ser-Asp (RSD) peptide, monoclonal antibody against ITGB1, and ITGB1 short interfering (si) RNA knockdown in cultured DF-1 cells. Simulation of the binding process between the aMPV/C fusion (F) protein and avian-derived ITGB1 using molecular dynamics showed that ITGB1 may be a host-factor for benefiting aMPV/C attachment or internalization. Transient expression of avian ITGB1 rendered porcine and feline non-permissive cells (DQ cells and CRFK cells, respectively) susceptible to aMPV/C infection. Replication kinetic of aMPV/C in siRNA-knockdown cells revealed that ITGB1 plays an important role in aMPV/C infection at the early stage (attachment and internalization). aMPV/C was also able to infect efficiently human non-small cell lung cancer (A549) cells. This may be due to a consequence of the similar structures of both metapneumovirus F protein-specific motifs (RSD for aMPV/C and RGD for human metapneumovirus) recognized by ITGB1. Overexpression of avian-derived ITGB1 and human-derived ITGB1 in A549 cells enhanced aMPV/C infectivity. Taken together, this study demonstrated that ITGB1 acts as an essential receptor for aMPV/C attachment and internalization into host cells in which facilitates aMPV/C infection.

Stabilization of a G-quadruplex (G4) in the promotor of the c-MYC proto-oncogene leads to inhibition of gene expression, and it thus represents a potentially attractive new strategy for cancer treatment. However, most G4 stabilizers show little selectivity among the many G4s present in the cellular complement of DNA and RNA. Intriguingly, a crescent-shaped cell-penetrating thiazole peptide, TH3, preferentially stabilizes the c-MYC G4 over other promotor G4s, but the mechanisms leading to this selective binding remain obscure. To investigate these mechanisms at the atomic level, we performed an in silico comparative investigation of the binding of TH3 and its analogue TH1 to the G4s from the promotors of c-MYC, c-KIT1, c-KIT2, and BCL2. Molecular docking and molecular dynamics simulations, combined with in-depth analyses of non-covalent interactions and bulk and per-nucleotide binding free energies, revealed that both TH3 and TH1 can induce the formation of a sandwich-like framework through stacking with both the top and bottom G-tetrads of the c-MYC G4 and the adjacent terminal capping nucleotides. This framework produces enhanced binding affinities for the c-MYC G4 relative to other promotor G4s, with TH3 exhibiting an outstanding binding priority. Van der Waals interactions were identified to be the key factor in complex formation in all cases. Collectively, our findings fully agree with available experimental data. Therefore, the identified mechanisms leading to specific binding of TH3 towards the c-MYC G4 provide valuable information to guide the development of new selective G4 stabilizers.

Background: Although lower extremity revascularization is commonly performed in hemodialysis patients, poor prognosis remains a major problem. Protein-energy wasting is reportedly associated with chronic inflammation and advanced atherosclerosis in hemodialysis patients. We investigated the association between the geriatric nutritional risk index (GNRI) as a surrogate marker of protein-energy wasting, C-reactive protein (CRP), and their joint roles in the prediction of amputation and/or mortality. Methods: We enrolled 800 patients successfully underwent lower extremity revascularization. Patients were divided into low, middle and high tertile (T1, T2 and T3) according to GNRI and CRP levels, respectively. Results: Amputation-free survival rates for 8 years were 47.0%, 56.9%, and 69.5% in T1, T2, and T3 of the GNRI, and 65.8%, 58.7%, and 33.2% for T1, T2, and T3 of CRP, respectively (p<0.0001 for both). Declined GNRI [adjusted hazard ratio (aHR) 1.78, 95% confidence interval (CI) 1.24-2.59, p=0.0016 for T1 vs. T3] and elevated CRP (aHR 1.86, 95%CI 1.30-2.70, p=0.0007 for T3 vs. T1) were independent predictors of amputation and/or mortality. In the combined setting of both variables, the risk was 3.77-fold higher (95% CI 1.97-7.69, p<0.0001) in the T1 of GNRI with T3 of CRP than in the T3 of GNRI with T1 of CRP. Conclusions: Patients with pre-procedural decreased GNRI and elevated CRP levels frequently experienced amputation and/or mortality, and a combination of both variables could more accurately stratify the risk.

Our recent work has focused on the application of infinite group theory and related algebraic geometric tools in the context of transcription factors and microRNAs. We were able to differentiate between “healthy" nucleotide sequences and disrupted sequences that may be associated with various diseases. In this paper, we extend our efforts to the study of messenger RNA metabolism, showcasing the power of our approach. We investigate (i) mRNA translation in prokaryotes and eukaryotes, (ii) polyadenylation in eukaryotes, which is crucial for nuclear export, translation, stability, and splicing of mRNA, (iii) miRNAs involved in RNA silencing and post-transcriptional regulation of gene expression, and (iv) the identification of disrupted sequences that could lead to potential illnesses. To achieve this, we employ (a) infinite (finitely generated) groups fp, with generators representing the r+1 distinct nucleotides and a relation between them [e.g., the consensus sequence in the mRNA translation (i), the poly(A) tail in item (ii), and the miRNA seed in item (iii)], (b) aperiodicity theory, which connects “healthy groups" fp to free groups Fr of rank r and their profinite completion F^r, and (c) the representation theory of groups fp over the space-time-spin group SL2(C), highlighting the role of surfaces with isolated singularities in the character variety. Our approach could potentially contribute to the understanding of the molecular mechanisms underlying various diseases and help develop new diagnostic or therapeutic strategies.

Mutations in the LMNA gene (encoding lamin A/C proteins) cause several human cardiac diseases, including dilated cardiomyopathies (LMNA-DCM). The main clinical risks in LMNA-DCM patients are sudden cardiac death and progressive left ventricular ejection fraction deterioration, and therefore most human and animal studies have sought to define the mechanisms through which LMNA mutations provoke cardiac alterations, with particular focus on cardiomyocytes. To investigate if LMNA mutations also cause vascular alterations that might contribute to the etiopathogenesis of LMNA-DCM, we generated and characterized Lmnaflox/floxSM22αCre mice, which constitutively lack lamin A/C in vascular smooth muscle cells (VSMCs), cardiac fibroblasts, and cardiomyocytes. Like mice with whole body or cardiomyocyte-specific lamin A/C ablation, Lmnaflox/floxSM22αCre mice recapitulated the main hallmarks of human LMNA-DCM, including ventricular systolic dysfunction, cardiac conduction defects, cardiac fibrosis, and premature death. These alterations were associated with hyperactivation of Smad3 and elevated expression of the proapoptotic protein caspase 3 in the heart. Lmnaflox/floxSM22αCre mice also exhibited perivascular fibrosis in the coronary arteries, and a switch of aortic VSMCs from the ‘contractile’ to the ‘synthetic’ phenotype. Ex vivo wire myography in isolated aortic rings revealed impaired maximum contraction capacity and an altered response to vasoconstrictor and vasodilator agents in Lmnaflox/floxSM22αCre mice. To our knowledge, our results provide the first evidence of phenotypic alterations in VSMCs that might contribute significantly to the pathophysiology of some forms of LMNA-DCM. Future work addressing the mechanisms underlying vascular defects in LMNA-DCM may open new therapeutic avenues for these diseases.

Proposed fundamental laws of biology and a model of health and disease underscore the importance of the lymphatic system. The lymphatics are responsible for two of the laws of biology and the fulcrum of health and disease balancing proliferation with regeneration through the immune system. It is responsible for protection from the environment and repair of senile and damaged tissue. Life is constantly bombarded by forces that increase entropy. Lymphatics provide negative entropy to maintain health. Lymphatics help maintain cellular homeostasis removing products of metabolism. Using these principles, the role of lymphatics is investigated in salt sensitivity hypertension, cardiorenal system, the new pillar of heart failure and kidney disease - Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors, and brain diseases. The realization of organ lymphatics in maintenance of health and disease opens the avenue to new therapeutics. This is the unrealized potential of lymphatic study.

A twelve-week feeding trial was conducted to investigate the effect of dietary supplementation of a functional immunostimulant mixture (FIM; nucleotides, β-glucan and vitamins C and E) on growth, feed utilization, innate immunity, digestive enzyme activity, hematological parameters, intestinal morphology and inflammatory gene expression of olive flounder, Paralichthys olivaceus. A fish meal-based basal diet (control) was formulated and three other diets were prepared by incorporating 0.5, 1.0 and 1.5% FIM into the basal diet (HB0.5, HB1.0 and HB1.5, respectively). Five replicate groups of fish (26.3 ± 0.1 g) were fed one of the experimental diets. Inclusion of 1.5% FIM in the diet significantly enhanced growth and feed utilization. Significantly higher plasma hemoglobin, hematocrit, total protein levels and lower plasma glucose level were observed in HB1.5 group. Total immunoglobulin content, lysozyme, nitroblue tetrazolium, myeloperoxidase, superoxide dismutase, glutathione peroxidase and catalase activities and immune-related gene expressions of toll-like receptor and perforin were significantly increased at highest inclusion level. FIM supplementation significantly increased villus height and goblet cell counts. Anti-inflammatory gene expression was significantly upregulated at a 1.5% level. Dietary supplementation of 1.5% of FIM could improve growth and feed utilization, immune, hematological and histomorphological parameters of olive flounder.

G-protein coupled receptors (GPCRs), one of the largest superfamilies of cell-surface receptors, are heptahelical integral membrane proteins that play critical roles in virtually every organ system. G-protein-coupled receptors operate in membranes rich in cholesterol, with an imbalance in cholesterol level within the vicinity of GPCR transmembrane domains affecting the structure and/or function of many GPCRs, a phenomenon that has been linked to several diseases. These effects of cholesterol could result in indirect changes by altering the mechanical properties of the lipid environment or direct changes by binding to specific sites on the protein. There are a number of studies and reviews on how cholesterol modulates class A GPCRs, however, this area of study is yet to be explored for class C GPCRs, which are characterized by a large extracellular region and often form constitutive dimers. This review highlights specific sites of interaction, functions, and structural dynamics involved in the cholesterol recognition of the class C GPCRs. We summarize recent data from some typical family members to explain the effects of membrane cholesterol on the structural features and functions of Class C GPCRs and speculate on their corresponding therapeutic potential.

The study aimed to determine the relationship between glucose, C-peptide, BDNF, and leptin between mother and fetus and neonatal weight. Methods: In the prospective observational cohort study, we included 66 women with T1DM. According to the z-score for neonatal weight, patients were divided into Healthy weight neonates (n=42) and Overweight neonates (n=24). The maternal blood samples were taken during pregnancy and cesarean section when the umbilical vein blood sample was also withdrawn. The maternal vein sera were analyzed for fasting glucose, CRP, leptin, BDNF, TSH, FT3, and FT4. The umbilical vein sera were analyzed for glucose, C-peptide, leptin, TSH, FT3, FT4, and BDNF concentration. The neonatologist measured the skinfold thickness on the third day of neonatal life. Results: A strong correlation was confirmed between maternal and umbilical vein glucose concentration and maternal glucose and C-peptide in umbilical vein blood. A negative correlation was found between the concentration of BDNF in the umbilical vein and glucose in maternal blood. A strong correlation was seen between BMI and maternal blood leptin concentration, neonatal fat body mass, and umbilical vein blood leptin concentration. Increased odds for Overweight neonates were BMI, BDNF, and TSH in the first trimester of pregnancy. Maternal leptin concentration decreased the odds of Overweight neonates. Conclusions: Maternal glucose concentrations affect the fetus’s glucose, C-peptide, and BDNF concentrations. Leptin levels increase in maternal blood due to increased body mass index, and in the neonate, its fat body mass is responsible for increased leptin concentrations.

pH is the major factor that makes producers in aquaponics frustrated, since the main three organisms (aquatic animal, plant, and microbes) in the system with different preferences. Yet, amending the growing environment with additional C is a potential method to improve the growth of shrimp and plants as well as the establishment of microbe. A detailed study of the effects of pH and additional C on aquaponics under saline conditions has not been investigated. In this study, the effect of pH and additional C on the growth performance of shrimp (Litopenaeus vannamei) and five edible plants in marine aquaponic systems using the nutrient film technique (NFT) was evaluated. The results indicated that at both pH 6.5 treatments, plants grew better; nevertheless, the growth performance of plants in pH 7.5 with additional C was improved and showed a similar yield to lower pH treatments. On the other hand, shrimp growth was little affected by pH and additional C. A higher impact of imbalanced ionic composition on shrimp performance may have contributed to this trend. Hence, we suggest that only if the ionic composition is managed can make RO water a suitable source of water for shrimp-based aquaponic. In spite of this, more research is required.

Blackcurrant juice (Ribes nigrum L.) was subjected to supercritical carbon dioxide (SCCD) at 10, 30 and 60 MPa for 10 min at 45°C as well as thermally treated at 45°C and 85°C for 10 min to determine the stability, antioxidant capacity (AC) and bioaccessibility (BAc) of vitamin C, total anthocyanins and their individual monomers. An in vitro gastrointestinal digestion model completed with dialysis was used to assess BAc. The use of SCCD at each of the pressures applied improved the stability of vitamin C, total anthocyanins, and AC before in vitro digestion. As a result of digestion, L-ascorbic acid was oxidized to L-dehydroascorbic acid, and finally, the total content of vitamin C, anthocyanins, and AC decreased. SCCD did not significantly improve the BAc of vitamin C and total anthocyanins. The highest BAc of vitamin C was noted in fresh juice (FJ) (40%) and after mild heat treatment at 45°C (T45) (46%). The highest BAc of total anthocyanins was also noted in the FJ (4.4%). The positive effect of the application of SCCD on the BAc of the delphinidin-3-O-glycosides was observed compared to T45 and thermal pasteurization at 85°C (T85). Moreover, cyanidins were generally more bioaccessible than delphinidins in all samples. AC after digestion was higher in SCCD samples compared to thermally treated measured using ABTS+• and DPPH• assays, whereas in dialysate similar trends were observed only for AC measured using the ABTS+• assay. This phenomenon was justified by the formation of individual metabolites detected by UPLC-PDA-MS / MS in the model experiment with delphinidin-3-O-rutinoside. The protocatechuic acid which is well known as a strong antioxidant was detected in the model experiment after digestion. Further research is needed to better understand the metabolic pathway of anthocyanins and the possible uses of SCCD to improve the health properties of fruit products.

Preproenkephalin (PPE) is a precursor molecule for multiple endogenous opioid peptides Leu-enkephalin (ENK) and Met-ENK, which are involved in a wide variety of modulatory functions in the nervous system. Despite the functional importance of ENK in the brain, the effect of brain-derived factor(s) on PPE expression is unknown. We report the dual effect of neural epidermal growth factor (EGF)-like-like 2 (NELL2) on PPE gene expression. In cultured NIH3T3 cells, transfection of NELL2 expression vectors induced an inhibition of PPE transcription intracellularly, in parallel with downregulation of protein kinase C signaling pathways and extracellular signal-regulated kinase. Interestingly, these phenomena were reversed when synthetic NELL2 was administered extracellularly. The in vivo disruption of NELL2 synthesis resulted in an increase in PPE mRNA level in the rat brain, suggesting that the inhibitory action of intracellular NELL2 predominates the activation effect of extracellular NELL2 on PPE gene expression in the brain. Biochemical and molecular studies with mutant NELL2 structures further demonstrated the critical role of EGF-like repeat domains in NELL2 for regulation of PPE transcription. These are the first results to reveal the spatio-specific role of NELL2 in the homeostatic regulation of PPE gene expression.

The open-bundle structure of cytochrome c’ as an unfolding intermediate was determined by small-angle neutron scattering experiment (SANS). The four-α-helix bundle structure of Cyt c’ at neutral pH was transited to an open-bundle structure (at pD ~13), which is a joint-clubs consisting of four clubs (α-helices) connected by short loops. The compactly folded structure of Cyt c’ (radius of gyration, Rg = 18 Å for the Cyt c’ dimer) at neutral or mildly alkaline pD transitioned to a remarkably larger “open-bundle” structure at pD ~13 (Rg = 25 Å for the Cyt c’ monomer). Cyt c’ adopts an unstructured random coil structure at pD = 1.7 (Rg = 25 Å for the Cyt c’ monomer). Numerical partial scattering function analysis (joint-clubs) and ab initio modelling gave structures similar to the “open-bundle”, which retains the α-helices but loses the bundle structure.

Although automated Acute Lymphoblastic Leukemia (ALL) detection is essential, it is challenging due to the morphological correlation between malignant and normal cells. The traditional ALL classification strategy is arduous, time-consuming, often suffers inter-observer variations, and necessitates experienced pathologists. This article has automated the ALL detection task, employing deep Convolutional Neural Networks (CNNs). We explore the weighted ensemble of deep CNNs to recommend a better ALL cell classifier. The weights are estimated from ensemble candidates' corresponding metrics, such as accuracy, F1-score, AUC, and kappa values. Various data augmentations and pre-processing are incorporated for achieving a better generalization of the network. We train and evaluate the proposed model utilizing the publicly available C-NMC-2019 ALL dataset. Our proposed weighted ensemble model has outputted a weighted F1-score of 88.6%, a balanced accuracy of 86.2%, and an AUC of 0.941 in the preliminary test set. The qualitative results displaying the gradient class activation maps confirm that the introduced model has a concentrated learned region. In contrast, the ensemble candidate models, such as Xception, VGG-16, DenseNet-121, MobileNet, and InceptionResNet-V2, separately produce coarse and scatter learned areas for most example cases. Since the proposed ensemble yields a better result for the aimed task, it can experiment in other domains of medical diagnostic applications.

ANGPTL3 is an important regulator of lipid metabolism. Its inhibition in people with hypercholesteremia reduces plasma lipid levels dramatically. Genome-wide association studies have associated ANGPTL3 variants with lipid traits. Irisin, an exercise modulated protein, has been associated with lipid metabolism. Intracellular accumulation of lipids impairs insulin action and contributes to metabolic disorders. In this study, we evaluate the impact of ANGPTL3 variants on levels of irisin and markers associated with lipid metabolism and insulin resistance. ANGPTL3 rs1748197 and rs12130333 variants were genotyped in a cohort of 278 Arab individuals from Kuwait. Levels of irisin and other metabolic markers were measured by ELISA. Significance of association signals was assessed using Bonferroni-corrected P-values and empirical P-values. The study variants were significantly associated with low levels of c-peptide and irisin. Levels of c-peptide and irisin were mediated by interaction between carrier genotypes (GA+AA) at rs1748197 and measures of IL13 and TG, respectively. While levels of c-peptide and IL13 were directly correlated in individuals with reference genotype, they were inversely correlated in individuals with carrier genotype. Irisin correlated positively with TG which is strong in individuals with carrier genotypes. These observations illustrate ANGPTL3 as a potential link connecting lipid metabolism, insulin resistance and cardioprotection.

Many neonates undergoing whole body hypothermia (WBH) following moderate to severe perinatal asphyxia suffer from renal impairment. While recent data suggest a WBH-related reno-protection, the differences in serum creatinine (Scr) patterns to reference patterns were not yet reported. We therefore aimed to document Scr trends and patterns in asphyxiated neonates undergoing WBH, and compared these to centiles reference Scr dataset of non-asphyia neonates. Using a systematic review strategy, reports on Scr trends (mean ± SD, or median and range) were collected (day 1-7) in WBH cohorts, and compared to centiles of an earlier reported reference cohort of non-asphyxia cases. Based on 13 papers on asphyxia+WBH cases, a pattern on postnatal Scr trends in asphyxia+WBH cases was constructed. Compared to the reference cohort, mean or median Scr values at birth (>90th centile) and the first two days of WBH (>75th centile) remained clinical relevantly higher in asphyxia+WBH cases, with a subsequent decline to reach at best high or high normal creatinine values (all >50th centile, but mainly >75th centile) from day 4 onwards. Such patterns are valuable to anticipate average changes in renal clearance capacity relevant for pharmacotherapy, but do not yet cover the relevant inter-patient variability observed in WBH cases.

Niemann-Pick type C (NPC) disease is a childhood autosomal recessive inherited rare neuro-degenerative disease, characterized by the accumulation of cholesterol and glycosphingolipids, implicating the autophagy-lysosome system. Inhibition of soluble epoxide hydrolase (sEH), an enzyme that metabolizes epoxy fatty acids (EpFAs) to 1,2-diols, exerts beneficial effects in mod-ulating inflammation and autophagy, critical features of the NPC disease. This study aimed to evaluate the effects of UB-EV-52 a sEH inhibitor (sEHi) in the Npc mouse model by administering for 4 weeks (5 mg/kg/day). Behavioral and cognitive assays (open field test (OF), elevated plus maze (EPM), novel object recognition test (NORT) and object location test (OLT) demonstrated that treatment produced an improvement in short- and long-term memory as well as in spatial memory. Moreover, the treatment with UB-EV-52 increased body weight and the lifespan by 25% and re-duced gene expression of the inflammatory markers (i.e. Il-1β and Mcp1) and improved oxidative stress (OS) markers (iNOS and Hmox1) in the treated Npc mice group. Regarding the autophagic markers, we surprisingly found significantly reduced levels of the ratio LC3B-II/LC3B-I and a significant reduction of brain protein levels of lysosomal-associated membrane protein-1 (LAMP-1) in Npc mice treated group compared to non-treated. Lipid profile analysis showed a significant reduction in lipid storage in the liver and some slight changes in brain tissue in treated Npc mice compared to non-treated groups. Thus, Our results suggest that the pharmacological inhibition of sEH ameliorates most of NPC’s characteristic traits in mice, demonstrating that sEH can be considered a potential therapeutic target for this condition.

Course-based Undergraduate Research Experiences (CUREs) provide the same benefits as individual, mentored faculty research while expanding the availability of research opportunities. One important aspect of CUREs is student’s engagement in collaboration. We developed a partnership with the Caenorhabditis elegans (C. elegans) database, WormBase, in which students submitted annotations of published manuscripts to the website. This activity provided students with a collaborative research activity that benefitted the greater scientific community and enhanced students’ understanding of molecular genetics during the COVID-19 pandemic. WormBase relies on community annotators to read published articles and input phenotypic data. Students submitted a total of nine annotations directly to WormBase, which were curated by WormBase to ensure correctness and to reduce overlap from redundant annotations. Due to the stress on students during this time of crisis, qualitative data were collected in lieu of quantitative pre-post analyses. Students described their learning experiences in terms of interactions with the scientific community and the “real world”, content knowledge and competencies, and changes in perspectives and use of resources. Students also reported that this activity was helpful in their understanding of critical molecular genetics concepts. Most students reported on cognitive processes that represent mid-level Bloom’s categories. The shift to online learning during the COVID-19 pandemic created an immediate need for meaningful, collaborative experiences in CUREs. By partnering with WormBase, students gained insight into the scientific community and contributed as community members. We describe possible modifications for future courses, potential expansion of the WormBase collaboration, and future directions for quantitative analysis.

There are limited proven therapies for the treatment of COVID-19. Vitamin C’s antioxidant, anti-inflammatory and immunomodulating effects, make it a potential therapeutic candidate, both for the prevention and amelioration of COVID-19 infection, and as an adjunctive therapy in the critical care of COVID-19, supporting anti-inflammatory treatment. This literature review focuses on vitamin C deficiency in respiratory infections including COVID-19; the mechanism of action in infectious disease and adrenal function supporting the anti-inflammatory actions of glucocorticosteroids: its role in preventing and treating colds and pneumonia and its role in treating sepsis and COVID-19. The evidence to date indicates that oral vitamin C (2-8g/d) may reduce incidence and duration of respiratory infections and intravenous vitamin C (2-24g/d) has been shown to reduce mortality, Intensive Care Unit and hospital stays, time on mechanical ventilation in severe respiratory infections. Further trials are urgently warranted. Given the favourable safety profile and low cost of vitamin C, and frequency of vitamin C deficiency in respiratory infections it may be worthwhile testing patients’ vitamin C status and treating accordingly with intravenous use within ICUs and orally with doses between 2 and 8g/day in hospitalised and infected persons.

Emerging pollutants as pharmaceuticals have been focusing international attention for few decades. Ciprofloxacin (CIP) is a common drug widely found in effluents from hospitals, industrial and different wastewater treatment plants, as well as rivers. In this work, the lab-scale 3D-BER system was established, and more than 90% of the antibiotic CIP removal from the Low C/N wastewater. Best results were obtained with current intensity, and different C/N ratio significantly improve the removal of CIP and nitrates, when the ideal conditions were; C/N = 1.5-3.5, pH =7.0-7.5, and I = 60 mA. The highest removal efficiency of CIP = 94.20 %, NO3--N= 95.53 % and total nitrogen (TN) = 84.27 %, respectively. In this novel system, the autotrophic-heterotrophic denitrifying bacteria played vital role for the removal of CIP and enhanced denitrification process. Thus, autotrophic denitrifying bacteria uses CO2 and H2 as carbon sources to reduce nitrates to N2. This system has the assortment and prosperous community revealed at the current intensity of 60 mA, and the analysis of bacterial community structure in effluent samples fluctuates under different condition of C/N ratios. According to the results of LC-MS/MS analysis, the intermediate products were proposed after efficient biodegradation of CIP. Microbial community on biodegrading was mostly found at phylum, and class level was dominantly responsible for the NO3--N and biodegradation of CIP. This work can provide some new insights towards the biodegradation of CIP and the efficient removal of nitrates from low C/N wastewater treatment by the novel 3D-BER system.

Among the many approaches to COVID-19 prevention, the possible role of diet has so far been somewhat marginal. Nutrition is very rich in substances with a potential beneficial effect on health and some of these could have an antiviral action or in any case be important in modulating the immune system and in defending cells from the oxidative stress associated with infection. This short review draws the attention on some components of Citrus fruits and especially of the orange (Citrus sinensis), well known for its vitamin content, but less for the function of its flavonoids. Among the latter, hesperidin has recently attracted the attention of researchers, because it binds to the key proteins of the SARS-CoV-2 virus. Several computational methods, independently applied by different researchers, showed that hesperidin has a low binding energy both with the coronavirus "spike" protein, and with the main protease that transforms the early proteins of the virus (pp1a and ppa1b) into the complex responsible for viral replication. The affinity of hesperidin for these proteins is comparable if not superior to that of common chemical antivirals. The preventive efficacy of vitamin C, at dosage attainable by diet, against viral infections is controversial, but recent reviews suggest that this substance may be useful in case of increased stress on the immune system. Finally, the reasons that suggest undertaking appropriate research on the Citrus fruits addition in the diet, as a complementary prevention and treatment of COVID-19, are discussed.