This study was conducted to establish olanzapine-induced hepatopathy in Wistar albino rats as a newer model to screen putative hepatoprotective agents namely silymarin.

Leukaemia-propagating cells are more frequent in high-risk acute B lymphoblastic leukaemia than in many malignancies that follow a hierarchical cancer stem cell model. It is unclear whether this characteristic can be more universally applied to patients from non-'high-risk' sub-groups and across a broad range of cellular immunophenotypes. Here, we demonstrate in a wide range of primary patient samples and patient samples previously passaged through mice that leukaemia-propagating cells are found in all populations defined by high or low expression of the lymphoid differentiation markers CD10, CD20 or CD34. The frequency of leukaemia-propagating cells and their engraftment kinetics do not differ between these populations. Transcriptomic analysis of CD34(high) and CD34(low) blasts establishes their difference and their similarity to comparable normal progenitors at different stages of B-cell development. However, consistent with the functional similarity of these populations, expression signatures characteristic of leukaemia propagating cells in acute myeloid leukaemia fail to distinguish between the different populations. Together, these findings suggest that there is no stem cell hierarchy in acute B lymphoblastic leukaemia.

References form the backbone of any medical literature. Presently, because of high inflation, it is very difficult for any library/organization/college to purchase all journals. The condition is even worse for an individual person, such as private practitioners. The solution lies in the free availability of full-text articles. Here, the authors share their experiences about the accessibility of free full-text articles.

Sentinel lymph node biopsy (SLNB) by dual-dye method (radioisotope plus blue) is the gold standard for axillary staging in patients with breast cancer, but in developing countries, logistic issues and financial constraint play a vital role. Recently, indocyanine green (ICG) has emerged as an alternative to radioisotope (technetium-99 [Tc-99]) for SLNB in breast cancer. This study compared the diagnostic performance of Tc-99 plus methylene blue (MB) dye versus ICG + MB dye SLNB.

Rapid thermokinetics associated with laser-based additive manufacturing produces strong bulk crystallographic texture in the printed component. The present study identifies such a bulk texture effect on elastic anisotropy in laser powder bed fused Ti6Al4V by employing an effective bulk modulus elastography technique coupled with ultrasound shear wave velocity measurement at a frequency of 20 MHz inside the material. The combined technique identified significant attenuation of shear velocity from 3322 ± 20.12 to 3240 ± 21.01 m/s at 45[Formula: see text] and 90[Formula: see text] orientations of shear wave plane with respect to the build plane of printed block of Ti6Al4V. Correspondingly, the reduction in shear modulus from 48.46 ± 0.82 to 46.40 ± 0.88 GPa was obtained at these orientations. Such attenuation is rationalized based on the orientations of [Formula: see text] crystallographic variants within prior columnar [Formula: see text] grains in additively manufactured Ti6Al4V.

The purpose of this meta-analysis is to compare the efficacy of MitraClip plus medical therapy versus medical therapy alone in patients with functional mitral regurgitation (FMR). FMR caused by left ventricular dysfunction is associated with poor prognosis. Whether MitraClip improves clinical outcomes in this patient population remains controversial.

Approximately one-quarter of the global population have latent tuberculosis infection (LTBI), and tuberculosis (TB) is accountable for more than 1.5 million deaths annually. Methotrexate, cyclosporine, and tumor necrosis factor inhibitors may be associated with increased risk of TB and LTBI reactivation, although data are limited on the risks of TB with use of newer biologics.

Yellow mosaic disease (YMD) in bitter gourd (Momordica charantia) is a devastating disease that seriously affects its yield. Although there is currently no effective method to control the disease, breeding of resistant varieties is the most effective and economic option. Moreover, quantitative trait locus (QTL) associated with resistance to YMD has not yet been reported. With the objective of mapping YMD resistance in bitter gourd, the susceptible parent "Punjab-14" and the resistant parent "PAUBG-6" were crossed to obtain F4 mapping population comprising 101 individuals. In the present study, the genotyping by sequencing (GBS) approach was used to develop the genetic linkage map. The map contained 3,144 single nucleotide polymorphism (SNP) markers, consisted of 15 linkage groups, and it spanned 2415.2 cM with an average marker distance of 0.7 cM. By adopting the artificial and field inoculation techniques, F4:5 individuals were phenotyped for disease resistance in Nethouse (2019), Rainy (2019), and Spring season (2020). The QTL analysis using the genetic map and phenotyping data identified three QTLs qYMD.pau_3.1, qYMD.pau_4.1, and qYMD.pau_5.1 on chromosome 3, 4, and 5 respectively. Among these, qYMD.pau_3.1, qYMD.pau_4.1 QTLs were identified during the rainy season, explaining the 13.5 and 21.6% phenotypic variance respectively, whereas, during the spring season, qYMD.pau_4.1 and qYMD.pau_5.1 QTLs were observed with 17.5 and 22.1% phenotypic variance respectively. Only one QTL qYMD.pau_5.1 was identified for disease resistance under nethouse conditions with 15.6% phenotypic variance. To our knowledge, this is the first report on the identification of QTLs associated with YMD resistance in bitter gourd using SNP markers. The information generated in this study is very useful in the future for fine-mapping and marker-assisted selection for disease resistance.

Background: In the United States (US), colorectal cancer (CRC) is the second leading cause of cancer-related deaths. With the majority of the US population covered by employer-based health plans, employers can play a critical role in increasing CRC screening adherence, which may help avert CRC-related deaths. Therefore, it is important for self-insured employers to consider the impact of appropriate utilization of CRC screening options. Objective: To evaluate the impact of increasing multitarget stool DNA [mt-sDNA (Cologuard®)] use among CRC screeners from the perspective of a US self-insured employer. Methods:A 5-year Markov model was developed to quantify the budget impact of increasing mt-sDNA from 6% to 15% among average-risk screeners using colonoscopy, fecal immunological test, and mt-sDNA. Data on direct medical costs were obtained from published literature, Medicare CPT codes, and the Healthcare cost and Utilization project. Indirect costs included productivity loss due to workplace absenteeism for CRC screening and treatment. Results: With a hypothetical population of 100,000 employees with screeners aged 50-64 years, compared to status quo, increased mt-sDNA utilization resulted in no differences in the numbers of cancers detected and the overall direct and indirect cost savings were ~$214,000 ($0.04 per-employee-per-month) over 5 years. Most of the savings were due to a reduction in the direct medical expenditure related to CRC screening, adverse events, and productivity loss due to colonoscopy screening. Similar results were observed in the model simulation among screeners aged 45-64 years. Conclusion: Increased utilization of mt-sDNA for CRC screening averts direct and indirect medical costs from a self-insured US employer perspective.

Non-structural protein (NS1) is a 350 amino acid long conserved protein in the dengue virus. Conservation of NS1 is expected due to its importance in dengue pathogenesis. The protein is known to exist in dimeric and hexameric states. The dimeric state is involved in its interaction with host proteins and viral replication, and the hexameric state is involved in viral invasion. In this work, we performed extensive structure and sequence analysis of NS1 protein, and uncovered the role of NS1 quaternary states in its evolution. A three-dimensional modeling of unresolved loop regions in NS1 structure is performed. "Conserved" and "Variable" regions within NS1 protein were identified from sequences obtained from patient samples and the role of compensatory mutations in selecting destabilizing mutations were identified. Molecular dynamics (MD) simulations were performed to extensively study the effect of a few mutations on NS1 structure stability and compensatory mutations. Virtual saturation mutagenesis, predicting the effect of every individual amino acid substitution on NS1 stability sequentially, revealed virtual-conserved and variable sites. The increase in number of observed and virtual-conserved regions across NS1 quaternary states suggest the role of higher order structure formation in its evolutionary conservation. Our sequence and structure analysis could enable in identifying possible protein-protein interfaces and druggable sites. Virtual screening of nearly 10,000 small molecules, including FDA-approved drugs, permitted us to recognize six drug-like molecules targeting the dimeric sites. These molecules could be promising due to their stable interactions with NS1 throughout the simulation.

We aimed to systematically analyze the literature on the use of transcatheter aortic valve replacement (TAVR) to treat active aortic valve infective endocarditis (AV-IE). Surgery is declined in one-third of patients with IE who meet indications because of prohibitive surgical risk. TAVR might be an alternative for selected patients with AV-IE as a bridge-to-surgery or stand-alone therapy. PubMed/MEDLINE, Embase, and Cochrane databases were searched (2002-2022) for studies on TAVR use in active AV-IE. Of 450 identified reports, six met inclusion criteria (all men, mean age 71 ± 12 years, median Society of Thoracic Surgeons (STS) score 27, EuroSCORE 56). All patients were prohibitive surgical risk candidates. Five out of six patients had severe, and one patient had moderate aortic regurgitation on presentation. Five out of six patients had prosthetic valve endocarditis after surgical valve replacement 13 years before (median), and one patient had TAVR a year before hospitalization. All patients had cardiogenic shock as the indication for TAVR. Four patients received balloon-expanding, and two patients received self-expanding TAVR after a median of 19 (IQR 9-25) days from diagnosis of IE. No death or myocardial infarction occurred, but one patient had a stroke within the first 30 days. The median event-free time was 9 (IQR 6-14) months including no death, reinfection, relapse IE, or valve-related rehospitalization. Our review suggests that TAVR can be considered as an adjuvant therapy to medical treatment for selected patients in whom surgery is indicated for treatment of acute heart failure due to aortic valve destruction and incompetence caused by infective endocarditis, but who have a prohibitive surgical risk. Nonetheless, a well-designed prospective registry is urgently needed to investigate the outcomes of TAVR for this off-label indication. No evidence exists for using the TAVR to treat infection-related surgical indications such as uncontrolled infection or control of septic embolization.

The goal of the current investigation was to develop a non-pressurized liquid bandage to promote the healing of wounds by using silver sulfadiazine. A three-factor three level box-behnken statistical design was employed to optimize the drug-loaded liquid bandage. Film-forming liquid bandage was developed by using ethyl-cellulose, dibutyl sebacate, and glycerol. For optimization, ethyl cellulose, dibutyl sebacate, and isopropyl myristate were taken as independent variables while tensile strength, water vapor absorption value, and drying time were taken as dependent variables. The film-forming liquid bandage was evaluated for various parameters like tensile strength, water vapor absorption value, drying time, viscosity, pH, in-vitro drug release studies, in-vivo wound healing studies, and stability studies. The optimized formulation was found with the tensile strength of 68.24 ± 0.24 MPa, water vapor absorption value of 2.00 ± 0.25 %, drying time of 1.75 ± 0.14 min, viscosity of 60 ± 0.5 cPs, pH of 6.0 ± 0.5 and good physicochemical properties with satisfactory film-forming ability. The in-vitro study shows that the release of test formulations was better than the marketed formulation. After 6 h of study, the liquid bandage and marketed formulation showed 41.02 % and 29.32 % of drug release respectively. Significant results were obtained for the in-vivo wound healing studies. Upon comparison with the control group (2.61 mm) and marketed formulation (1.44 mm), rats treated with the optimized formulation exhibited a noticeable improvement in wound contraction (0.8 mm). The liquid bandage after three months of stability testing was found to be stable with optimum. The film-forming liquid bandage was found to be an effective alternative to conventional topical preparations as it develops a thin polymeric layer on the wound and the skin around it and improves comfort for the patient by protecting the wound from external factors and physical harm.

New drugs are needed for the treatment of relapsed acute lymphoblastic leukemia and preclinical evaluation of the MEK inhibitor, selumetinib, has shown that this drug has excellent activity in those leukemias with RAS pathway mutations. The proapoptotic protein, BIM is pivotal in the induction of cell death by both selumetinib and glucocorticoids, suggesting the potential for synergy. Thus, combination indices for dexamethasone and selumetinib were determined in RAS pathway-mutated acute lymphoblastic leukemia primagraft cells in vitro and were indicative of strong synergism (combination index <0.2; n=5). Associated pharmacodynamic assays were consistent with the hypothesis that the drug combination enhanced BIM upregulation over that achieved by a single drug alone. Dosing of dexamethasone and selumetinib singly and in combination in mice engrafted with primary-derived RAS pathway-mutated leukemia cells resulted in a marked reduction in spleen size which was significantly greater with the drug combination. Assessment of the central nervous system leukemia burden showed a significant reduction in the drug-treated mice, with no detectable leukemia in those treated with the drug combination. These data suggest that a selumetinib-dexamethasone combination may be highly effective in RAS pathway-mutated acute lymphoblastic leukemia. An international phase I/II clinical trial of dexamethasone and selumetinib (Seludex trial) is underway in children with multiply relapsed/refractory disease.

A bacterium isolated from a hot-water spring identified as Bacillus thermoamylovorans BHK67 successfully produced a thermotolerant extracellular alkaliphilic lipase. The lipase was purified to homogeneity by anion exchange chromatography with 15-fold purification and 12.1% yield. The lipase appeared to be a hexameric protein as it possessed a single band of Mr 25kDa in SDS PAGE and 150kDa in Native PAGE. DLS analysis of purified Bacillus thermoamylovorans BHK67 lipase (BTL) also showed the molecular integrity, homogeneity and stability of the enzyme. The purified lipase showed maximum activity at pH 7.5 with a half-life of 10.5h at 55°C. Kinetic study of purified lipase by Lineweaver-Burk plot provided Km (7.7mM),Vmax (90.9U/mL/min),Kcat (227.3s-1) and Kspec (29.4mMs-1) for substrate p-nitrophenylpalmitate.The purified lipase also showed astonishing stability following exposure to ethanol, n-propanol, iso-propanol, n-butanol and DMSO. Amino acid characterization of BTL by MALDI-TOF-MS showed considerable resemblance with lysophospholipase L1 related esterase of Lactobacillus ozensis DSM 23829. Experimental coupled molecular modeling postulated a structure-activity correlation of BTL as a probable contender in degradation of xenobiotic compounds, biocatalysis, biotransformation of compounds, synthesis of optically active compounds, foodstuff industry, anticancer therapeutics etc.

The pool of quality control proteins (QC) that maintains protein-folding homeostasis (proteostasis) is dynamic but can become depleted in human disease. A challenge has been in quantitatively defining the depth of the QC pool. With a new biosensor, flow cytometry-based methods and mathematical modeling we measure the QC capacity to act as holdases and suppress biosensor aggregation. The biosensor system comprises a series of barnase kernels with differing folding stability that engage primarily with HSP70 and HSP90 family proteins. Conditions of proteostasis stimulation and stress alter QC holdase activity and aggregation rates. The method reveals the HSP70 chaperone cycle to be rate limited by HSP70 holdase activity under normal conditions, but this is overcome by increasing levels of the BAG1 nucleotide exchange factor to HSPA1A or activation of the heat shock gene cluster by HSF1 overexpression. This scheme opens new paths for biosensors of disease and proteostasis systems.

The abortive activity of topoisomerases can result in clastogenic and/or lethal DNA damage in which the topoisomerase is covalently linked to the 3'- or 5'-terminus of a DNA strand break. This type of DNA damage is implicated in chromosome translocations and neurological disease and underlies the clinical efficacy of an important class of anticancer topoisomerase 'poisons'. Tyrosyl DNA phosphodiesterase-1 protects cells from abortive topoisomerase I (Top1) activity by hydrolyzing the 3'-phosphotyrosyl bond that links Top1 to a DNA strand break and is currently the only known human enzyme that displays this activity in cells. Recently, we identified a second tyrosyl DNA phosphodiesterase (TDP2; aka TTRAP/EAPII) that possesses weak 3'-tyrosyl DNA phosphodiesterase (3'-TDP) activity, in vitro. Herein, we have examined whether TDP2 contributes to the repair of Top1-mediated DNA breaks by deleting Tdp1 and Tdp2 separately and together in murine and avian cells. We show that while deletion of Tdp1 in wild-type DT40 cells and mouse embryonic fibroblasts decreases DNA strand break repair rates and cellular survival in response to Top1-induced DNA damage, deletion of Tdp2 does not. However, deletion of both Tdp1 and Tdp2 reduces rates of DNA strand break repair and cell survival below that observed in Tdp1-/- cells, suggesting that Tdp2 contributes to cellular 3'-TDP activity in the absence of Tdp1. Consistent with this idea, over-expression of human TDP2 in Tdp1-/-/Tdp2-/-/- DT40 cells increases DNA strand break repair rates and cell survival above that observed in Tdp1-/- DT40 cells, suggesting that Tdp2 over-expression can partially complement the defect imposed by loss of Tdp1. Finally, mice lacking both Tdp1 and Tdp2 exhibit greater sensitivity to Top1 poisons than do mice lacking Tdp1 alone, further suggesting that Tdp2 contributes to the repair of Top1-mediated DNA damage in the absence of Tdp1. In contrast, we failed to detect a contribution for Tdp1 to repair Top2-mediated damage. Together, our data suggest that Tdp1 and Tdp2 fulfil overlapping roles following Top1-induced DNA damage, but not following Top2-induced DNA damage, in vivo.

The world is currently facing the COVID-19 pandemic, for which mild symptoms include fever and dry cough. In severe cases, it could lead to pneumonia and ultimately death in some instances. Moreover, the causative pathogen is highly contagious and there are no drugs or vaccines for it yet. The pathogen, SARS-CoV-2, is one of the human coronaviruses which was identified to infect humans first in December 2019. SARS-CoV-2 shares evolutionary relationship to other highly pathogenic viruses such as Severe Acute Respiratory Syndrome (SARS) and Middle East respiratory syndrome (MERS). We have exploited this similarity to model a target non-structural protein, NSP1, since it is implicated in the regulation of host gene expression by the virus and hijacking of host machinery. We next interrogated the capacity to repurpose around 2300 FDA-approved drugs and more than 3,00,000 small molecules of natural origin towards drug identification through virtual screening and molecular dynamics. Interestingly, we observed simple molecules like lactose, previously known anti-virals and few secondary metabolites of plants as promising hits. These herbal plants are already practiced in Ayurveda over centuries to treat respiratory problems and inflammation. Disclaimer: we would not like to recommend uptake of these small molecules for suspect COVID patients until it is approved by competent national or international authorities.

In this study, a bacterial carbonic anhydrase (CA) was purified from Corynebacterium flavescens for the CO2 conversion into CaCO3. The synthesized CaCO3 can be utilized in the papermaking industry as filler material, construction material and in steel industry. Herein, the CA was purified by using a Sephadex G-100 column chromatography having 29.00 kDa molecular mass in SDS-PAGE analysis. The purified CA showed an optimal temperature of 35 °C and pH 7.5. In addition, a kinetic study of CA using p-NPA as substrate showed Vmax (166.66 μmoL/mL/min), Km (5.12 mM), and Kcat (80.56 sec-1) using Lineweaver Burk plot. The major inhibitors of CA activity were Na2+, K+, Mn2+, and Al3+, whereas Zn2+ and Fe2+ slightly enhanced it. The purified CA showed a good efficacy to convert the CO2 into CaCO3 with a total conversion rate of 65.05 mg CaCO3/mg of protein. In silico analysis suggested that the purified CA has conserved Zn2+ coordinating residues such as His 111, His 113, and His 130 in the active site center. Further analysis of the CO2 binding site showed conserved residues such as Val 132, Val 142, Leu 196, Thr 197, and Val 205. However, a substitution has been observed where Trp 208 of its closest structural homolog T. ammonificans CA is replaced with Arg 207 of C. flavescens. The presence of a hydrophilic mutation in the CO2 binding hydrophobic region is a further subject of investigation.

Aspergillus species are known to cause damage to food crops and are associated with opportunistic infections in humans. In the United States, significant losses have been reported in peanut production due to contamination caused by the Aspergillus species. This study evaluated the antifungal effect and anti-aflatoxin activity of selected plant-based essential oils (EOs) against Aspergillus flavus in contaminated peanuts, Tifguard, runner type variety. All fifteen essential oils, tested by the poisoned food technique, inhibited the growth of A. flavus at concentrations ranging between 125 and 4000 ppm. The most effective oils with total clearance of the A. flavus on agar were clove (500 ppm), thyme (1000 ppm), lemongrass, and cinnamon (2000 ppm) EOs. The gas chromatography-mass spectrometry (GC-MS) analysis of clove EO revealed eugenol (83.25%) as a major bioactive constituent. An electron microscopy study revealed that clove EO at 500 ppm caused noticeable morphological and ultrastructural alterations of the somatic and reproductive structures. Using both the ammonia vapor (AV) and coconut milk agar (CMA) methods, we not only detected the presence of an aflatoxigenic form of A. flavus in our contaminated peanuts, but we also observed that aflatoxin production was inhibited by clove EO at concentrations between 500 and 2000 ppm. In addition, we established a correlation between the concentration of clove EO and AFB1 production by reverse-phase high-performance liquid chromatography (HPLC). We demonstrate in our study that clove oil could be a promising natural fungicide for an effective bio-control, non-toxic bio-preservative, and an eco-friendly alternative to synthetic additives against A. flavus in Georgia peanuts.

Coronaviral disease-19 is the global challenge for medical fraternity and public health sector. Need of social distancing has compelled physicians and surgeons to continue medical education through virtual mode like webinar.