BTN3A3 evasion promotes the zoonotic potential of influenza A viruses.

Spillover events of avian influenza A viruses (IAVs) to humans could represent the first step in a future pandemic1. Several factors that limit the transmission and replication of avian IAVs in mammals have been identified. There are several gaps in our understanding to predict which virus lineages are more likely to cross the species barrier and cause disease in humans1. Here, we identified human BTN3A3 (butyrophilin subfamily 3 member A3)2 as a potent inhibitor of avian IAVs but not human IAVs. We determined that BTN3A3 is expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts primarily at the early stages of the virus life cycle by inhibiting avian IAV RNA replication. We identified residue 313 in the viral nucleoprotein (NP) as the genetic determinant of BTN3A3 sensitivity (313F or, rarely, 313L in avian viruses) or evasion (313Y or 313V in human viruses). However, avian IAV serotypes, such as H7 and H9, that spilled over into humans also evade BTN3A3 restriction. In these cases, BTN3A3 evasion is due to substitutions (N, H or Q) in NP residue 52 that is adjacent to residue 313 in the NP structure3. Thus, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.

Effect of salinity stress and surfactant treatment with zinc and boron on morpho-physiological and biochemical indices of fenugreek (Trigonella foenum-graecum).

Micronutrient application has a crucial role in mitigating salinity stress in crop plants. This study was carried out to investigate the effect of zinc (Zn) and boron (B) as foliar applications on fenugreek growth and physiology under salt stress (0 and 120 mM). After 35 days of salt treatments, three levels of zinc (0, 50, and 100 ppm) and two levels of boron (0 and 2 ppm) were applied as a foliar application. Salinity significantly reduced root length (72.7%) and shoot length (33.9%), plant height (36%), leaf area (37%), root fresh weight (48%) and shoot fresh weight (75%), root dry weight (80%) and shoot dry weight (67%), photosynthetic pigments (78%), number of branches (50%), and seeds per pod (56%). Fenugreek's growth and physiology were improved by foliar spray of zinc and boron, which increased the length of the shoot (6%) and root length (2%), fresh root weight (18%), and dry root weight (8%), and chlorophyll a (1%), chlorophyll b (25%), total soluble protein content (3%), shoot calcium (9%) and potassium (5%) contents by significantly decreasing sodium ion (11%) content. Moreover, 100 ppm of Zn and 2 ppm of B enhanced the growth and physiology of fenugreek by reducing the effect of salt stress. Overall, boron and zinc foliar spray is suggested for improvement in fenugreek growth under salinity stress.

Bridging the Gap in Understanding Bone Metastasis: A Multifaceted Perspective.

The treatment of patients with advanced cancer poses clinical problems due to the complications that arise as the disease progresses. Bone metastases are a common problem that cancer patients may face, and currently, there are no effective drugs to treat these individuals. Prostate, breast, and lung cancers often spread to the bone, causing significant and disabling health conditions. The bone is a highly active and dynamic tissue and is considered a favorable environment for the growth of cancer. The role of osteoblasts and osteoclasts in the process of bone remodeling and the way in which their interactions change during the progression of metastasis is critical to understanding the pathophysiology of this disease. These interactions create a self-perpetuating loop that stimulates the growth of metastatic cells in the bone. The metabolic reprogramming of both cancer cells and cells in the bone microenvironment has serious implications for the development and progression of metastasis. Insight into the process of bone remodeling and the systemic elements that regulate this process, as well as the cellular changes that occur during the progression of bone metastases, is critical to the discovery of a cure for this disease. It is crucial to explore different therapeutic options that focus specifically on malignancy in the bone microenvironment in order to effectively treat this disease. This review will focus on the bone remodeling process and the effects of metabolic disorders as well as systemic factors like hormones and cytokines on the development of bone metastases. We will also examine the various therapeutic alternatives available today and the upcoming advances in novel treatments.

Role of APOC3 3238C/G polymorphism in HIV-associated neurocognitive disorder.

Apolipoprotein not only have a role in cholesterol metabolism but also play a role in normal brain function. Apolipoprotein gene polymorphisms are known risk factors for a number of mental and neurological disorders. The expression of brain apolipoproteins is significantly altered in several brain disorders. Therefore, we assed ApoC33238 C/G polymorphism in a total of 248 patient infected with HIV (45 with HAND, 89 without HAND, 114 without ART) and 134 healthy controls using PCR-RFLP. ApoC3 3238CG, 3238 GG genotypes and 3238G allele showed a non-significant increased risk for severity of HAND (P = 0.16, OR = 1.83; P = 0.32, OR = 2.78; P = 0.10, OR = 1.65) while comparing individuals with and without HAND. ApoC3 3238 GG genotype and 3238G allele revealed an increased risk for disease progression when compared between HIV patients with and without ART (P = 0.55, OR = 1.76; P = 0.65, OR = 1.12) though risk could not reach statistical significance. ApoC3 3238 GG genotype and 3238G allele were associated with the reduced risk of acquiring HIV infection when comparing HIV patients who are not on ART with healthy controls (P = 0.05, OR = 0.29; P = 0.04, OR = 0.66). In HIV patients on ART,ApoC3 3238 GG genotype showed an increased susceptibility to development of HAND (P = 0.48, OR = 2.24) when comparing alcohol drinkers and non-drinkers however risk could not reach statistical significance. In conclusion, the genotype ApoC33238GG displayed an inclination of risk for the severity of HAND and HIV disease progression. The polymorphism of APOC3 3238C/G may have a role to reduce the risk for acquisition of HIV infection. ApoC33238GG genotype in presence of alcohol may increase susceptibility to development of HAND.

Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin.

The bone microenvironment is composed of niches that house cells across variable oxygen tensions. However, the contribution of oxygen gradients in regulating bone and blood homeostasis remains unknown. Here, we generated mice with either single or combined genetic inactivation of the critical oxygen-sensing prolyl hydroxylase (PHD) enzymes (PHD1-3) in osteoprogenitors. Hypoxia-inducible factor (HIF) activation associated with Phd2 and Phd3 inactivation drove bone accumulation by modulating osteoblastic/osteoclastic cross-talk through the direct regulation of osteoprotegerin (OPG). In contrast, combined inactivation of Phd1, Phd2, and Phd3 resulted in extreme HIF signaling, leading to polycythemia and excessive bone accumulation by overstimulating angiogenic-osteogenic coupling. We also demonstrate that genetic ablation of Phd2 and Phd3 was sufficient to protect ovariectomized mice against bone loss without disrupting hematopoietic homeostasis. Importantly, we identify OPG as a HIF target gene capable of directing osteoblast-mediated osteoclastogenesis to regulate bone homeostasis. Here, we show that coordinated activation of specific PHD isoforms fine-tunes the osteoblastic response to hypoxia, thereby directing two important aspects of bone physiology: cross-talk between osteoblasts and osteoclasts and angiogenic-osteogenic coupling.

Probing the binding of morin with alpha-2-macroglobulin using multi-spectroscopic and molecular docking approach : Interaction of morin with α2M.

Alpha-2-macroglobulin (α2M) is an essential antiproteinase that is widely distributed in human plasma. The present study was aimed at investigating the binding of a potential therapeutic dietary flavonol, morin, with human α2M using a multi-spectroscopic and molecular docking approach. Recently, flavonoid-protein interaction has gained significant attention, because a majority of dietary bioactive components interact with proteins, thereby altering their structure and function. The results of the activity assay exhibited a 48% reduction in the antiproteolytic potential of α2M upon interaction with morin. Fluorescence quenching tests unequivocally confirmed quenching in the fluorescence of α2M in the presence of morin, conforming complex formation and demonstrating that the binding mechanism involves a dynamic mode of interaction. Synchronous fluorescence spectra of α2M with morin showed perturbation in the microenvironment around tryptophan residues. Furthermore, structural changes were observed through CD and FT-IR, showing alterations in the secondary structure of α2M induced by morin. FRET further supports the results of the dynamic mode of quenching. Moderate interaction is shown by binding constant values using Stern-Volmer's fluorescence spectroscopy. Morin binds to α2M at 298 K with a binding constant of 2.7 × 104 M-1, indicating the strength of the association. The α2M-morin system was found to have negative ΔG values, which suggests that the binding process was spontaneous. Molecular docking also reveals the different amino acid residues involved in this binding process, revealing that the binding energy is -8.1 kcal/mol.

Exploring the interaction of myricetin with human alpha-2-macroglobulin: biophysical and in-silico analysis.

Myricetin (MYR) is a bioactive secondary metabolite found in plants that is recognized for its nutraceutical value and is an essential constituent of various foods and beverages. It is reported to exhibit a plethora of activities, including antioxidant, antimicrobial, antidiabetic, anticancer, and anti-inflammatory. Alpha-2-macroglobulin (α2M) is a major plasma anti-proteinase that can inhibit proteinases of both human and non-human origin, regardless of their specificity and catalytic mechanism. Here, we explored the interaction of MYR-α2M using various biochemical and biophysical techniques. It was found that the interaction of MYR brings subtle change in its anti-proteolytic potential and thereby alters its structure and function, as can be seen from absorbance and fluorescence spectroscopy. UV spectroscopy of α2M in presence of MYR indicated the occurrence of hyperchromism, suggesting complex formation. Fluorescence spectroscopy reveals that MYR reduces the fluorescence intensity of native α2M with a shift in the wavelength maxima. At 318.15 K, MYR binds to α2M with a binding constant of 2.4 × 103 M-1, which indicates significant binding. The ΔG value was found to be - 7.56 kcal mol-1 at 298.15 K, suggesting the interaction to be spontaneous and thermodynamically favorable. The secondary structure of α2M does not involve any major change as was confirmed by CD analysis. The molecular docking indicates that Asp-146, Ser-172, Glu-174, and Tyr-180 were the key residues involved in α2M-MYR complex formation. This study contributes to our understanding of the function and mechanism of protein and flavonoid binding by providing a molecular basis of the interaction between MYR and α2M.

Nutritional Composition, Fatty Acids Profile, Mineral Content, Antioxidant Activity and Acute Toxicity of the Flesh of Helix aspesra Müller.

Humans consume snail flesh as part of their diet. To assess its nutritional value and toxicity, chemical analyses were conducted to confirm the presence of protein, total and reduced carbohydrates, fat, fatty acid composition and mineral components. Furthermore, an acute toxicity study was carried out to determine the safety of Helix aspersa Müller snail flesh. H. aspersa Müller snail flesh exhibits a high nutritional content, a good ω3/ω6 ratio and higher levels of unsaturated fatty acids. Various minerals have been found in the flesh of H. aspersa Müller. Around 76.91 kcal, or 3.84% of the energy of a daily meal of 2000 kcal, are present in 100 g of this flesh. The evaluation of the antioxidant capacity indicated that the flesh's extracts contained a large quantity of antioxidant biomolecules. Administration of the aqueous extract of H. aspersa Müller flesh didn't cause death in laboratory rats, indicating that the lethal dose 50 is greater than 2000 mg·kg-1 body weight. The consumption of the flesh of H. aspersa Müller is highly recommended for human consumption due to its high concentration of nutrients and essential elements, as well as unsaturated fats, and due to its safety.

Design, Synthesis, In Vitro Biological Evaluation and In Silico Molecular Docking Study of Benzimidazole-Based Oxazole Analogues: A Promising Acetylcholinesterase and Butyrylcholinesterase Inhibitors.

Alzheimer's disease (AD) is a degenerative neurological condition that severely affects the elderly and is clinically recognised by a decrease in cognition and memory. The treatment of this disease has drawn considerable attention and sparked increased interest among the researchers in this field as a result of a number of factors, including an increase in the population of patients over time, a significant decline in patient quality of life, and the high cost of treatment and care. The current work was carried out for the synthesis of benzimidazole-oxazole hybrid derivatives as efficient Alzheimer's inhibitors and as a springboard for investigating novel anti-chemical Alzheimer's prototypes. The inhibition profiles of each synthesised analogue against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes were assessed. All the synthesized benzimidazole-based oxazole analogues displayed a diverse spectrum of inhibitory potentials against targeted AChE and BuChE enzymes when compared to the reference drug donepezil (IC50 = 2.16 ± 0.12 M and 4.50 ± 0.11 µM, respectively). The most active AChE and BuChE analogues were discovered to be analogues 9 and 14, with IC50 values of 0.10 ± 0.050 and 0.20 ± 0.050 µM (against AChE) and 0.20 ± 0.050 and 0.30 ± 0.050 µM (against BuChE), respectively. The nature, number, position, and electron-donating and -withdrawing effects on the phenyl ring were taken into consideration when analysing the structure-activity relationship (SAR). Molecular docking studies were also carried out on the active analogues to find out how amino acids bind to the active sites of the AChE and BuChE enzymes that were being studied.

Phytochemical, Morphological and Genetic Characterisation of Anacyclus pyrethrum var. depressus (Ball.) Maire and Anacyclus pyrethrum var. pyrethrum (L.) Link.

The present study is based on a multidisciplinary approach carried out for the first time on Anacyclus pyrethrum var. pyrethrum and Anacyclus pyrethrum var. depressus, two varieties from the endemic and endangered medicinal species listed in the IUCN red list, Anacyclus pyrethrum (L.) Link. Therefore, morphological, phytochemical, and genetic characterisations were carried out in the present work. Morphological characterisation was established based on 23 qualitative and quantitative characters describing the vegetative and floral parts. The phytochemical compounds were determined by UHPLC. Genetic characterisation of extracted DNA was subjected to PCR using two sets of universal primers, rbcL a-f/rbcL a-R and rpocL1-2/rpocL1-4, followed by sequencing analysis using the Sanger method. The results revealed a significant difference between the two varieties studied. Furthermore, phytochemical analysis of the studied extracts revealed a quantitative and qualitative variation in the chemical profile, as well as the presence of interesting compounds, including new compounds that have never been reported in A. pyrethrum. The phylogenetic analysis of the DNA sequences indicated a similarity percentage of 91%. Based on the morphological characterisation and congruence with the phytochemical characterisation and molecular data, we can confirm that A. pyrethrum var. pyrethrum and A. pyrethrum var. depressus represent two different taxa.

Exploring Medicinal Herbs' Therapeutic Potential and Molecular Docking Analysis for Compounds as Potential Inhibitors of Human Acetylcholinesterase in Alzheimer's Disease Treatment.

Background and Objectives: Alzheimer's disease (AD) stands as a pervasive neurodegenerative ailment of global concern, necessitating a relentless pursuit of remedies. This study aims to furnish a comprehensive exposition, delving into the intricate mechanistic actions of medicinal herbs and phytochemicals. Furthermore, we assess the potential of these compounds in inhibiting human acetylcholinesterase through molecular docking, presenting encouraging avenues for AD therapeutics. Materials and Methods: Our approach entailed a systematic exploration of phytochemicals like curcumin, gedunin, quercetin, resveratrol, nobiletin, fisetin, and berberine, targeting their capability as human acetylcholinesterase (AChE) inhibitors, leveraging the PubChem database. Diverse bioinformatics techniques were harnessed to scrutinize molecular docking, ADMET (absorption, distribution, metabolism, excretion, and toxicity), and adherence to Lipinski's rule of five. Results: Results notably underscored the substantial binding affinities of all ligands with specific amino acid residues within AChE. Remarkably, gedunin exhibited a superior binding affinity (-8.7 kcal/mol) compared to the reference standard. Conclusions: These outcomes accentuate the potential of these seven compounds as viable candidates for oral medication in AD treatment. Notably, both resveratrol and berberine demonstrated the capacity to traverse the blood-brain barrier (BBB), signaling their aptitude for central nervous system targeting. Consequently, these seven molecules are considered orally druggable, potentially surpassing the efficacy of the conventional drug, donepezil, in managing neurodegenerative disorders.

Supracellular measurement of spatially varying mechanical heterogeneities in live monolayers.

The mechanical properties of tissues have profound impacts on a wide range of biological processes such as embryo development (1,2), wound healing (3-6), and disease progression (7). Specifically, the spatially varying moduli of cells largely influence the local tissue deformation and intercellular interaction. Despite the importance of characterizing such a heterogeneous mechanical property, it has remained difficult to measure the supracellular modulus field in live cell layers with a high-throughput and minimal perturbation. In this work, we developed a monolayer effective modulus measurement by integrating a custom cell stretcher, light microscopy, and AI-based inference. Our approach first quantifies the heterogeneous deformation of a slightly stretched cell layer and converts the measured strain fields into an effective modulus field using an AI inference. This method allowed us to directly visualize the effective modulus distribution of thousands of cells virtually instantly. We characterized the mean value, SD, and correlation length of the effective cell modulus for epithelial cells and fibroblasts, which are in agreement with previous results. We also observed a mild correlation between cell area and stiffness in jammed epithelia, suggesting the influence of cell modulus on packing. Overall, our reported experimental platform provides a valuable alternative cell mechanics measurement tool that can be integrated with microscopy-based characterizations.

Molecular interaction of cryptophycin 52 with Caspase 8 for the management of lung cancer during coronavirus outbreak : A computational study.

It has been seen that, during COVID-19 outbreak lung cancer (LC) patients are noted as a high-risk population which make a more challenging to treatment of the LC patients. The active form of caspase-8 is involved in lung carcinogenesis in both humans and mice. In this study, the virtual screening was performed among 200 compounds retrieved from several resources for the searching of potent lead against Caspase 8 (Casp8). Cryptophycin 52 was found to have a strong inhibiting efficacy based on the free energy of binding with the active site of Casp8. The lowest binding energy was found to be -8.05 kcal/mole and was further analyzed for molecular dynamic simulation. Casp8 enzyme was determined to interact with cryptophycin 52 through twelve amino acid residues, specifically ARG260, SER316, GLY318, ASP319, THR337, VAL354, PHE355, PHE356, ILE357, GLN358, ALA359 and CYS360 along with six hydrogen bond particular, ILE357:N-UNK1: O7, UNK1: O14-PHE355:O, UNK1: C25-PHE355:O, UNK1: C35-THR337:O, UNK1: H65-HE355:O and UNK1: C25-PHE356. In addition, MD simulations for 50ns were performed for optimization, flexibility estimation and assessment of Casp8-cryptophycin 52 complex stability. This complex was seen as reasonably stable according to the RMSD, RMSF, and radius of gyration graph. Results obtained indicate cryptophycin 52 may be a lead compound with significant anti-cancer ability against Casp8. Further experimental work, however, is expected to support the compound's anti-cancer viewpoint.

Management of diabetic ulcers of the dorsum of the foot and distal leg ulcers.

OBJECTIVE: Diabetic foot ulceration of toes, forefoot and heel have been extensively studied; however, the dorsum of the foot and the distal leg have rarely been addressed. The objective of this study was to assess diabetic ulcers of the dorsum of the foot and of the distal leg (DUDFDLs) as primary sites, or extended lesions from other foot locations, with regard to possible causes, management and outcomes. METHOD: This was a retrospective study conducted in Jabir Abu Eliz Diabetic Centre (JADC) in Khartoum from January 2018 to August 2019. All patients with a primary DUDFDL, or one extending from a plantar or heel ulcer, were included. RESULTS: A cohort of 102 patients with DUDFDLs were studied; 74 (72.5%) were male and 28 (27.5%) were female, with a male-to-female ratio of 2.6:1, and a mean age of 57±12 years. The ulcer was a primary DUDFDL in 38 patients and a secondary ulcer in 64 patients. The outcome in 38 patients with primary DUDFDL was healing without amputation in 26 cases (68.4%), amputation of toes in 12 cases (31.6%), and no major amputation or death. Of the 64 patients presenting with secondary DUDFDL extending from the plantar surface, there was extension to the dorsum of the foot through the forefoot ulcer in 54 patients and through the ankle joint to the distal leg in 10 patients. For the plantar ulcers extending to the dorsum, five cases healed without amputation (9.3%), minor amputation was necessary in 29 cases (53.7%), major amputation in 14 cases (25.9%) and six patients died (11.1%). For the distal leg ulcers with extension through the ankle joint, five healed without amputation and five required minor amputation. CONCLUSION: Primary DUDFDLs had a favourable outcome. Dorsum extension of diabetic foot ulcer from the plantar aspect of the foot carries a high risk for major limb amputation and death.

Chemical Composition and Anti-Urolithiatic Activity of Extracts from Argania spinosa (L.) Skeels Press-Cake and Acacia senegal (L.) Willd.

Ethnobotanical studies have reported the traditional medicinal uses of Acacia senegal (L.) Willd. and Argania spinosa (L.) Skeels against kidney stone formation and other chronic kidney diseases. The present work is undertaken to study the litholytic activity and the inhibiting activity of calcium oxalate crystallization by bioactive compounds identified in Argania spinosa (L.) Skeels press-cake (residue of Argan oil) and in Acacia senegal (L.) Willd. The litholytic activity was studied in vitro on cystine and uric acid stones using a porous bag and an Erlenmeyer glass. The study of the inhibiting activity of calcium oxalate crystallization, was based on temporal measurements of the optical density, registered at a 620 nm wavelength for 30 min using an ultraviolet−visible spectrophotometer. The silylation method was performed to identify phytochemicals, followed by gas chromatography coupled with mass spectrophotometry (GC/MS) analysis. The results show significant litholytic activity of Argania Spinosa press-cake hydro-ethanolic extract on uric acid and cystine stones, respectively, with dissolution rates (DR) of 86.38% and 60.42% versus 3.23% and 9.48% for the hydro-ethanolic extract of Acacia senegal exudate. Furthermore, the percentages of nucleation inhibition are 83.78% and 43.77% (p ˂ 0.05) for Argania spinosa and Acacia senegal, respectively. The results point to the detection of 17 phytochemicals in Argania spinosa press-cake extract, the majority of which are phenolic acids and have potent anti-urolithiatic action.

Increased S1P expression in osteoclasts enhances bone formation in an animal model of Paget's disease.

Paget's disease (PD) is characterized by increased numbers of abnormal osteoclasts (OCLs) that drive exuberant bone formation, but the mechanisms responsible for the increased bone formation remain unclear. We previously reported that OCLs from 70% of PD patients express measles virus nucleocapsid protein (MVNP), and that transgenic mice with targeted expression of MVNP in OCLs (MVNP mice) develop bone lesions and abnormal OCLs characteristic of PD. In this report, we examined if OCL-derived sphingosine-1-phosphate (S1P) contributed to the abnormal bone formation in PD, since OCL-derived S1P can act as a coupling factor to increase normal bone formation via binding S1P-receptor-3 (S1PR3) on osteoblasts (OBs). We report that OCLs from MVNP mice and PD patients expressed high levels of sphingosine kinase-1 (SphK-1) compared with wild-type (WT) mouse and normal donor OCLs. SphK-1 production by MVNP-OCLs was interleukin-6 (IL-6)-dependent since OCLs from MVNP/IL-6-/- mice expressed lower levels of SphK-1. Immunohistochemistry of bone biopsies from a normal donor, a PD patient, WT and MVNP mice confirmed increased expression levels of SphK-1 in OCLs and S1PR3 in OBs of the PD patient and MVNP mice compared with normal donor and WT mice. Further, MVNP-OCLs cocultured with OBs from MVNP or WT mice increased OB-S1PR3 expression and enhanced expression of OB differentiation markers in MVNP-OBs precursors compared with WT-OBs, which was mediated by IL-6 and insulin-like growth factor 1 secreted by MVNP-OCLs. Finally, the addition of an S1PR3 antagonist (VPC23019) to WT or MVNP-OBs treated with WT and MVNP-OCL-conditioned media (CM) blocked enhanced OB differentiation of MVNP-OBs treated with MVNP-OCL-CM. In contrast, the addition of the SIPR3 agonist, VPC24191, to the cultures enhanced osterix and Col-1A expression in MVNP-OBs treated with MVNP-OCL-CM compared with WT-OBs treated with WT-OCL-CM. These results suggest that IL-6 produced by PD-OCLs increases S1P in OCLs and S1PR3 on OBs, to increase bone formation in PD.

CXCR4 expression in the bone marrow microenvironment is required for hematopoietic stem and progenitor cell maintenance and early hematopoietic regeneration after myeloablation.

The bone marrow (BM) microenvironment/niche plays a key role in regulating hematopoietic stem and progenitor cell (HSPC) activities; however, mechanisms regulating niche cell function are not well understood. In this study, we show that niche intrinsic expression of the CXCR4 chemokine receptor critically regulates HSPC maintenance during steady state, and promotes early hematopoietic regeneration after myeloablative irradiation. At steady state, chimeric mice with wild-type (WT) HSPC and marrow stroma that lack CXCR4 show decreased HSPC quiescence, and their repopulation capacity was markedly reduced. Mesenchymal stromal cells (MSC) were significantly reduced in the BM of CXCR4 deficient mice, which was accompanied by decreased levels of the HSPC supporting factors stromal cell-derived factor-1 (SDF-1) and stem cell factor (SCF). CXCR4 also plays a crucial role in survival and restoration of BM stromal cells after myeloablative irradiation, where the loss of BM stromal cells was more severe in CXCR4-deficient mice compared to WT mice. In addition, transplantation of WT donor HSPC into CXCR4-deficient recipient mice demonstrated reduced HSPC homing and early hematopoietic reconstitution. We found that CXCR4 signaling attenuates irradiation-induced BM stromal cell loss by upregulating the expression of the antiapoptotic protein Survivin via the PI3K pathway. Our study suggests that SDF-1-CXCR4 signaling in the stromal microenvironment cells plays a crucial role in maintenance of HSPCs during homeostasis, and promotes niche regeneration and early hematopoietic reconstitution after transplantation. Modulation of CXCR4 signaling in the HSPC microenvironment could be a means to enhance hematopoietic recovery after clinical hematopoietic cell transplantation.

Sodium-glucose cotransporter-2 Inhibitors in Heart Failure: An Updated Systematic Review and Meta-analysis of 13 Randomized Clinical Trials Including 14,618 Patients With Heart Failure.

ABSTRACT: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors showed benefit in patients with heart failure. In this updated meta-analysis, we evaluate the therapeutic efficacy and safety of SGLT-2 inhibitors in patients with heart failure. Different electronic databases were searched to find relevant articles. RevMan 5.4 was used for pooling data using a random/fixed-effects model, complemented by several sensitivity and subgroup analyses. A total of 13 randomized clinical trials including 14,618 patients with heart failure were included in analysis among 6797 studies screened. The overall mortality rate was 12.45% in the SGLT-2 group and 14.67% in the placebo group with 18% lower odds of overall mortality [odds ratio (OR), 0.82; confidence interval (CI), 0.75-0.91] in the SGLT-2 group. Odds of cardiovascular mortality was 18% lower (OR, 0.82; CI, 0.74-0.92) in the SGLT-2 group. The odds of hospitalization for heart failure (HHF) was 38% lower during the study period (OR, 0.62; CI, 0.56-0.68) in the SGLT-2 group. In addition, a benefit was seen for composite outcome HHF or mortality and considering subgrouping based on diabetes status, gender, and age groups. Although genital infection was significantly higher in the SGLT-2 group, the occurrence of severe adverse events, hypoglycemia, urinary tract infection, bone fracture, volume depletion, and other renal events did not differ between the 2 groups. Thus, SGLT-2 inhibitors improved cardiovascular outcomes among patients with heart failure with no significant difference in adverse events. Clinical benefit was comparable in diabetic and nondiabetic individuals, males and females, people in younger and older age groups with underlying heart failure, and HF with reduced ejection fraction.

Interaction of organophosphate pesticide chlorpyrifos with alpha-2-macroglobulin: Biophysical and molecular docking approach.

Organophosphate class of pesticides causes neurotoxicity and carcinogenicity in humans. Once inside the human body, these pesticides often interact with plasma proteins, such as alpha-2-macroglobulin (α2M) which is the key anti-proteinase. Our work focuses on the structural and functional alteration of α2M by chlorpyrifos (CPF), a member of organophosphates. We explored the binding interaction between alpha-2-macroglobulin and CPF by using UV absorption and fluorescence spectroscopy (steady state and synchronous), circular dichroism and molecular docking approach. The functional activity of α2M was analyzed by anti-proteinase trypsin inhibitory assay which showed dose-dependent decrease in alpha-2-macroglobulin antiproteolytic potential. UV absorption studies and fluorescence quenching experiments suggested the formation of a complex between α2M and CPF. The CD spectra suggested a reduction in the beta helical (ß helix) content of α2M. Analysis of thermodynamic parameters suggested the process is spontaneous and endothermic with the ΔG and ΔH values being -5.501 kJ/mol, 11.49 kJ/mol, respectively. CPF binds with Ile-1390, Pro-1391, Leu-1392, Lys-1393, Val-1396, Lys-1397, Arg-1407, Thr-1408, Glu-1409, Val-1410, Asp-282, Glu-281 of α2M as suggested by molecular docking.

Modeling and optimization by particle swarm embedded neural network for adsorption of methylene blue by jicama peroxidase immobilized on buckypaper/polyvinyl alcohol membrane.

Jicama peroxidase (JP) immobilized functionalized Buckypaper/Polyvinyl alcohol (BP/PVA) membrane was synthesized and evaluated as a promising nanobiocomposite membrane for methylene blue (MB) dye removal from aqueous solution. The effects of independent process variables, including pH, agitation speed, initial concentration of hydrogen peroxide (H2O2), and contact time on dye removal efficiency were investigated systematically. Both Response Surface Methodology (RSM) and Artificial Neural Network coupled with Particle Swarm Optimization (ANN-PSO) approaches were used for predicting the optimum process parameters to achieve maximum MB dye removal efficiency. The best optimal topology for PSO embedded ANN architecture was found to be 4-6-1. This optimized network provided higher R2 values for randomized training, testing and validation data sets, which are 0.944, 0.931 and 0.946 respectively, thus confirming the efficacy of the ANN-PSO model. Compared to RSM, results confirmed that the hybrid ANN-PSO shows superior modeling capability for prediction of MB dye removal. The maximum MB dye removal efficiency of 99.5% was achieved at pH-5.77, 179 rpm, ratio of H2O2/MB dye of 73.2:1, within 229 min. Thus, this work demonstrated that JP-immobilized BP/PVA membrane is a promising and feasible alternative for treating industrial effluent.