B-cell lymphoid malignancies is a heterogeneous group of hematologic cancers, where Bruton's tyrosine kinase (BTK) inhibitors have received FDA approval for several subtypes. The first-in-class covalent BTK inhibitor, ibrutinib, binds to the C481 amino acid residue to block the BTK enzyme and prevent the downstream signaling. Resistance to covalent BTK inhibitors can occur through mutations at the BTK binding site (C481S) but also other BTK sites and the phospholipase C gamma 2 (PLCγ2) resulting in downstream signaling. To bypass the C481S mutation, non-covalent BTK inhibitors, such as pirtobrutinib, were developed and are active against both wild-type and the C481S mutation. In this review, we discuss the molecular and genetic mechanisms which contribute to acquisition of resistance to covalent and non-covalent BTK inhibitors. In addition, we discuss the new emerging class of BTK degraders, which utilize the evolution of proteolysis-targeting chimeras (PROTACs) to degrade the BTK protein and constitute an important avenue of overcoming resistance. The moving landscape of resistance to BTK inhibitors and the development of new therapeutic strategies highlight the ongoing advances, that are being made towards the pursue of cure of B-cell lymphoid malignancies.

There are currently worldwide efforts to reduce sugar intake due to the various adverse health effects linked with the overconsumption of sugars. Artificial sweeteners have been used as an alternative to nutritive sugars in numerous applications; however, their long-term effects on human health remain controversial. This led to a shift in consumer preference towards non-caloric sweeteners from natural sources. Thaumatins are a class of intensely sweet proteins found in arils of the fruits of the West-African plant Thaumatococcus danielli. Thaumatins’ current production method through aqueous extraction from this plant and uncertainty of the harvest from tropical rainforests limits its supply while the demand is increasing. Despite successful recombinant expression of the protein in several organisms, no large-scale bioproduction facilities exist. We present preliminary process design, process simulation, and economic analysis for a large-scale (50 metric tons/year) production of thaumatin II variant by several different molecular farming platforms.

Tuberculosis (TB) is a contagious disease, caused by Mycobacterium tuberculosis (MTB) that has infected and killed a lot of people in the past. At present treatments against TB are available at a very low cost. Since these chemical drugs have many adverse effects on health, more attention is now given on the plant-derived phytochemicals as potential agents to fight against TB. In this study, 5 phytochemicals, 4-hydroxybenzaldehyde, benzoic acid, bergapten, psoralen, and p-hydroxybenzoic acid, are selected to test their potentiality, safety, and efficacy against two potential targets, the MTB RNA polymerase and enoyl-acyl carrier protein (ACP) reductase, the InhA protein, using various tools of in silico biology. The molecular docking experiment, drug-likeness property test, ADME/T-test, P450 SOM prediction, pharmacophore mapping, and modeling, solubility testing, DFT calculations, and PASS prediction study had confirmed that all the molecules had the good potentiality to inhibit the two targets. However, two agents, 4-hydroxybenzaldehyde and bergapten were considered as the best agents among the five selected agents and they also showed far better results than the two currently used drugs, that function in these pathways, rifampicin (MTB RNA polymerase) and isoniazid (InhA protein). These two agents can be used effectively to treat tuberculosis.

Background: Infections caused by E. coli cause considerable disease burden and range from frequently occurring and relatively innocent urinary tract infection (UTI) to severe bloodstream infection (BSI). The incidence of infections caused by ESBL-producing E. coli (ESBL-PEc) is increasing, justifying surveillance and development of preventive strategies in several domains. Faecal carriage is universal and believed to be the most important reservoir for E. coli from which infections can originate. It is currently unknown to what extent Dutch E. coli carriage strains in the community reflect isolates causing disease. In this study, we will perform comparative genomics to infer the population structures of human-derived ESBL-PEc from community- and hospital-acquired infections and from community-based faecal carriage samples in the Netherlands. Furthermore, we will describe the molecular epidemiology of E. coli isolates causing invasive disease (BSI). Methods: This study uses four different microbiological data sources: 1) ESBL-PEc from patients with community-acquired UTI tested in primary care between May and November 2017, 2) ESBL-PEc from urine cultures obtained from patients hospitalized between January 2014 and December 2016, 3) E. coli from blood cultures obtained from patients hospitalized between January 2014 and December 2016, and 4) ESBL-PEc from faecal samples collected in a national population- prevalence study performed between January 2014 and January 2017. Clinical epidemiological data was collected from all patients and all isolates were subjected to whole genome sequencing. Discussion: The EPIGENEC study (EPIdemiology and GENetics of E. coli) will describe the molecular epidemiology of E. coli BSI and assess the genomic population structure of ESBL-PEc strains from community-acquired and nosocomial infections, and of ESBL-PEc reflecting community-based faecal carriage. Information from these studies may assist in optimizing surveillance strategies and determining targets and potential impact of future new preventive measures.

The development of microbial products for cancer treatment has been in the spotlight in recent years. In order to accelerate the lengthy and expensive drug development process, in silico screening tools are systematically employed, especially during the initial discovery phase. Moreover, considering the steadily increasing number of molecules approved by authorities for commercial use, there is a demand for faster methods to repurpose such drugs. Here we present a review on virtual screening web tools, publicly available databases of molecular targets and libraries of ligands, with the aim to facilitate the discovery of potential anticancer drugs based on microbial products. We provide an entry-level step-by-step description of the workflow for virtual screening of microbial metabolites with known protein targets, as well as two practical examples using freely available web tools. The first case presents a virtual screening study of drugs developed from microbial products using Caver Web, a web tool that performs docking along a tunnel. The second case comprises a comparative analysis between a healthy isocitrate dehydrogenase 1, a mutant that results in cancer, using the recently developed web tool PredictSNP^Onco. In summary, this review provides the basic and essential background information necessary for virtual screening experiments, which may accelerate the discovery of novel anticancer drugs.

As the interface between human and machine becomes blurred, hydrogel incorporated electronics and devices have emerged to be a new class of flexible/stretchable electronic and ionic devices due to their extraordinary properties, such as soft, mechanically robust and biocompatible. However, heat dissipation in these devices could be a critical issue and remains unexplored. Here, we report the experimental measurements and equilibrium molecular dynamics simulations of thermal conduction in polyacrylamide (PAAm) hydrogels. The thermal conductivity of PAAm hydrogels can be modulated by both the crosslinking density and water content in hydrogels. The crosslinking density dependent thermal conductivity in hydrogels varies from 0.33 to 0.51 Wm^-1K^-1, giving a 54% enhancement. We attribute the crosslinking effect to the competition between the increased conduction pathways and the enhanced phonon scattering effect. Moreover，water content can act as filler in polymers which lead to nearly 40% enhancement in thermal conductivity in PAAm hydrogels with water content vary from 23 to 88 wt%. Furthermore，we find the thermal conductivity of PAAm hydrogel is insensitive to temperature in the range of 25 ^oC – 40 ^oC. Our study offers fundamental understanding of thermal transport in soft materials and provides design guidance for hydrogel-based devices.

Precise HDV-RNA detection and quantification are pivotal for accurate diagnosis and monitoring of response to newly approved treatment. We evaluate the performance of three assays: Hepatitis Delta RT-PCR system, EurobioPlex HDV assay, and the RoboGene HDV RNA Quantification kit 2.0, testing 151 HBsAg-positive samples, 90 HDV-RNA negative and 61 HDV-RNA positive. We also evaluated serial dilutions of the WHO international standard for HDV, PEI 7657/12. Finally, all HDV-RNA positive samples were genotyped using a next-generation sequencing strategy. Qualitative results indicated a 100% concordance between tests. Quantitative results correlated well between tests, r2=0.703 (Vircell-vs-Eurobio), r2=0.833 (Vircell-vs-RoboGene), r2=0.835 (Robogene-vs-Eurobio). Bias index was 2.083 (Vircell-vs-Eurobio), -1.283 (Vircell-vs-RoboGene), and -3.36 (Robogene-vs-Eurobio). Using the WHO IS, Vircell overestimated the viral load by 0.98 log IU/mL, Eurobio by 1.46 log IU/mL, and RoboGene underestimated it by 0.98 log IU/mL. Fifty-nine samples were successfully genotyped (Genotype 1, n=52; Genotype 5, n=7; Genotype 6, n=1), with similar results in terms of correlation and bias. The three assays demonstrate promising performance. Their accuracy, reflected in concordance rates and quantitative analysis, makes them suitable for clinical practice. However, in the absence of assay harmonization, quantitative HDV RNA monitoring should be performed in the same laboratory and assay to avoid variability.

Cyanobacteria are an ancient lineage of slow-growing photosynthetic bacteria and a prolific source of natural products with diverse chemical structures and potent biological activities and toxicities. The chemical identification of these compounds remains a major bottleneck. Strategies that can prioritize the most prolific strains and novel compounds are of great interest. Here, we combine chemical analysis and genomics to investigate the chemodiversity of secondary metabolites based on their pattern of distribution within some cyanobacteria. Planktothrix being a cyanobacterial genus known to form blooms worldwide and to produce a broad spectrum of toxins and other bioactive compounds, we applied this combined approach on four closely related strains of Planktothrix. The chemical diversity of the metabolites produced by the four strains was evaluated using an untargeted metabolomics strategy with high-resolution LC-MS. Metabolite profiles were correlated with the potential of metabolite production identified by genomics for the different strains. Although, the Planktothrix strains present a global similarity in term biosynthetic cluster gene for microcystin, aeruginosin and prenylagaramide for example, we found remarkable strain-specific chemo-diversity. Only few of the chemical features were common to the four studied strains. Additionally, the MS/MS data were analyzed using Global Natural Products Social Molecular Networking (GNPS) to identify molecular families of the same biosynthetic origin. In conclusion, we present an efficient integrative strategy for elucidating the chemical diversity of a given genus and link the data obtained from analytical chemistry to biosynthetic genes of cyanobacteria.

The study of the change in entropy during the formation of stars in collapsing molecular clouds is an important area of research in astrophysics. As the cloud decreases in size, the presence of gases leads to an increase in entropy. However, the extent of this change in entropy is influenced by the amount of space available for the gases. In this scientific investigation, I conduct a detailed analysis of entropy on a small scale within the contracting cloud, following the principles of the second law of thermodynamics. Initially, my focus is on a turbulent cloud composed of N particles with a mass of M, which collapses under the force of gravity. It becomes clear that in order for the collapse to occur, gravitational energy must overcome other pressure forces that oppose it. This process results in the rapid movement of particles within the cloud, ultimately leading to a change in entropy

Polymers' controlled pyrolysis is an economical and environmentally friendly solution to prepare activated carbon. However, due to the experimental difficulty in measuring the dependence between tissues and pyrolysis parameters at high temperatures, the unknown pyrolysis mechanism hinders access to the target products with desirable morphologies and performances. In this study, we investigate the pyrolysis process of polystyrene under different heating rates and temperatures employing reactive molecular dynamics (ReaxFF-MD) simulations. A clear profile of the generation of pyrolysis products determined by the temperature and heating rate is constructed. It is found that the heating rate affects the type and amount of pyrolysis intermediates and their timing, and low-rate heating helps yield more diverse pyrolysis intermediates. While the temperature affects the pyrolytic tissues of the final equilibrium products, either too low or too high a target temperature is detrimental to generating large areas of graphitized tissue. The established theoretical evolution process matches experiments well, thus contributing to preparing target activated carbons by referring to the regulatory mechanism of pyrolytic tissues.

The aim of this study was the reconstruction of SARS-CoV-2 evolutionary dynamics in time and space in Italy and Europe between February and June 2020. The cluster analysis showed that pure Italian clusters were observed mainly after the lockdown and distancing measures were adopted. Lineage B and B.1 spread between late January and early February 2020, from China to Veneto and Lombardy, respectively. Lineage B.1.1 most probably evolved within Italy and spread from central to south Italian regions, and to European countries. The lineage B.1.1.1 entered Italy only in the second half of March and remained localized in Piedmont until June 2020. In conclusion, the reconstructed ancestral scenario suggests a central role of China and Italy in the widespread diffusion of the D614G variant in Europe in the early phase of the pandemic and more dispersed exchanges involving several European countries from the second half of March 2020.

The aim of this study was to investigate the relationship between postprandial glycemic levels based on flash-monitoring and the production of intestinal hydrogen (H2) and methane (CH4) gases based on measurement of the amount of these gases in exhaled air. We studied 14 subjects with type 2 diabetes mellitus (T2DM) and 10 individuals without diabetes (control) with 3 food-load tests with simultaneous determination of gases in exhaled air and assessment of glucose levels. In 15.4% of patients with T2DM, there was a non-significant increase in exhaled H2. How-ever, all subjects in the control group had significant increase in exhaled H2. Moreover, the level of H2 in exhaled breathafter food load in patients with T2DM was lower than in normoglycemic subjects. Also, in normoglycemic subjects there was an inverse correlation between maximum glucose rise and maximum H2 in exhaled air after food load. At the same time in patients with T2DM the level of CH4 in exhaled air directly correlated with the parameters of postprandial glycemia in the test with lactulose. Confirmation of a causal relationship between decreased H2 production, increased intestinal CH4 production, and more severe postprandial glycemia may identify new therapeutic targets in the correction of postprandial glycemia in patients with T2DM.

Most malignant ovarian germ cell tumors (MOGTCs) have a very good prognosis and can be cured by chemotherapy, with yolk sac tumors (OYSTs) having the worse prognosis among MOGCTs. These tumors are rare and can benefit in the next future from specific therapeutic strategies after failure of platinum-based first-line and salvage regimens. In collaboration with EORTC SPECTA, we have developed a project to explore the molecular characteristics of OYST. The pilot part of the project was performed using retrospective samples and ten OYST patients including relapsed and disease free patients. The molecular analysis was performed using FoundationOne CDx. For each patient, the following variables are described in the molecular report provided by FMI (Fondation Medicine Incorporation): alteration type (SNV, deletion), actionable gene alteration, therapies approved in EU (patient's tumor type and other tumor types), tumor mutational burden (TMB) and microsatellite instability (MSI) status. A total of 10 patients with OYST diagnosed between 2007 and 2017 were analyzed. Four patients (40%) had a molecular alteration, according to the FMI test. A subset of three patients (33.3% of all patient) harbored targetable (KRAS, KIT, ARID1A) oncogenic mutations. Two patients at relapse harbored a targetable mutation. In this retrospective study, we were able to identify clinically relevant molecular alterations for all relapsed patients with molecular analysis. Dedicated studies are needed to demonstrate if they could benefit from specific therapeutic strategies after failure of platinum-based first-line and salvage regimens and if the presence of a molecular alteration could be linked to patients’ outcome.

The novel coronavirus disease 19 (COVID-19) has resulted in an estimated 20 million excess deaths and the recent resurgence of COVID-19 in China is predicted to result in up to 1 million deaths over the next few months. With vaccines unable to halt transmission it is important to continue our quest for safe, effective, affordable drugs that will be available to all countries. Drug repurposing is one of the strategies being explored in this context. Recently, out of 7,817 approved drugs, 214 candidates were systematically down-selected using a combination of 11 filters including approval status, assay data against SARS-CoV-2, pharmacokinetic, pharmacodynamic and toxicity profiles. These drugs were subjected in this study to virtual screening against various targets of SARS-CoV-2 followed by molecular dynamic studies of the best scoring ligands against each target. The chosen molecular targets were Spike receptor binding domain, Nucleocapsid protein RNA binding domain, and key non-structural proteins 3, 5, 12, 13 and 14. Four drugs approved for other indications — alendronate, cromolyn, natamycin and treprostinil — look sufficiently promising from our in silicostudies to warrant further in vitro and in vivo investigations as appropriate to ascertain their extent of anti-viral activities.

An important stage in SARS-CoV-2 life cycle is the fusion of spike(S) protein with the ACE2 host-cell receptor. Therefore, to explore conserved features in S protein dynamics and to identify potentially novel regions for drugging, we measured variability derived from 791 viral genomes and studied its properties by MD simulation. The findings indicated that S2 subunit (HR1, CH, and CD domains) showed low variability, low fluctuations in MD, and displayed a trimer cavity. By contrast, the RBD domain, which is typically targeted in drug discovery programmes, exhibits more sequence variability and flexibility. Interpretations from MD suggest that the monomer is in constant motion showing transitions up-to-down state, and the trimer cavity may function as a 'bouncing spring' that may facilitates S protein interactions with ACE2. Feasibility of trimer cavity for potential drug target was examined by SBVS screening. Several hits that have already been validated or suggested to inhibit the SARS-CoV-2 virus in cell systems were identified; in particular, the data suggest an action mechanism for such molecules including Chitosan and macrolide types. These findings identify a novel binding-site formed by the S protein, that might assist in future drug discovery programmes aimed at targeting the CoV family of viruses.

The emergence of diverse infections worldwide, which is a serious global threat to human existence, necessitate the urgent development of novel therapeutic candidates that can combat these diseases with efficacy. Isatin, a secondary metabolite from tryptophan is considered a privileged scaffold and favorable pharmacophore with a unique structural moiety and varied chemical and biological properties resulting in its widespread applications by medicinal chemists. Molecular hybridization is one of the most common and important techniques use in the synthesis of their bioactive hybrids in drug discovery. This review containing published articles from 2005 to 2022 focuses on isatin hybrids which have been synthesized and reported in the literature alongside a discussion on their biological properties. The purpose of this review is to set up the direction for the design and development of isatin-hybrids with tailored biological properties as effective therapeutic candidates inspired by nature.

Telomeres are specialized structures at the ends of linear chromosomes that protect them from degradation and fusion. Telomere replication is a complex process that involves both DNA polymerases and a specialized enzyme called telomerase. Telomerase is a ribonucleoprotein complex that synthesizes telomeric DNA by using an internal RNA template. However, telomerase alone cannot fully replicate the telomeric DNA, and requires the cooperation of other factors, such as shelterin, CST, and DNA repair proteins. Moreover, telomere replication is tightly regulated by various mechanisms, such as cell cycle checkpoints, telomere length homeostasis, and telomere position effect. Dysregulation of telomere replication can lead to genomic instability, cellular senescence, and cancer. Therefore, understanding the molecular details of telomere replication is crucial for elucidating the role of telomeres in aging and disease.

Molecular motors play a vital role in the transport of material within the cell. A family of motors of growing interest are burnt bridge ratchets (BBRs). BBRs rectify spatial fluctuations into directed motion by creating and destroying motor-substrate bonds. It has been shown that the motility of a BBR can be optimized as a function of the system parameters. However, the amount of energy input required to generate such motion and the resulting efficiency has been less well characterized. Here, using a deterministic model, we calculate the efficiency of a particular type of BBR, namely a polyvalent hub interacting with a surface of substrate. We find that there is an optimal burn rate and substrate concentration that leads to optimal efficiency. Additionally, the substrate turnover rate has important implications on motor efficiency. We also consider the effects of force-dependent unbinding on the efficiency and find that under certain conditions the motor works more efficiently when bond breaking is included. Our results provide guidance for how to optimize the efficiency of BBRs.

Habituation is the most ancient and fundamental form of learning. As a firewall that protects our brain from sensory overload, it is indispensable for higher cognitive processes. Studies in humans and animal models provide a growing body of evidence that habituation is affected in autism and related monogenic neurodevelopmental disorders (NDDs). An integrated application of habituation assessment in NDDs and their animal models has currently unexploited potential for fundamental neuroscience and medical care.With the aim to gain mechanistic insights, we systematically retrieved genes that have been demonstrated in the literature to underlie habituation. We identified 258 evolutionarily conserved genes across species, describe the biological processes they converge on, and highlight regulatory pathways and drugs that may alleviate the habituation deficits associated with their dysregulation. We also summarize current habituation paradigms and extract the most decisive arguments from the literature that support the crucial role of habituation for cognition in health and disease. We conclude that habituation is a conserved, quantitative, cognition- and disease-relevant process that can connect preclinical and clinical work, and hence is a powerful tool to advance research, diagnostics,’’ and treatment of NDDs.

The construction of molecular robotic-like objects that imitate living things is an important challenge for current chemists. Such molecular devices are expected to perform their duties robustly to carry out mechanical motion, process information, and make independent decisions. Dissipative self-organization plays an essential role in meeting these purposes. To produce a micro-robot that can perform the above tasks autonomously as a single entity, a function generator is required. Although many elegant review articles featuring chemical devices that mimic biological mechanical functions have been published recently, the dissipative structure, which is the minimum requirement, has not been sufficiently discussed. This article aims to show clearly that dissipative self-organization is a phenomenon involving autonomy, robustness, mechanical functions, and energy transformation. Moreover, the author details the recent experimental results of an autonomous light-driven molecular device that achieves all of these features. In addition, a chemical model of cell-amplification is also discussed to focus on the generation of hierarchical movement by dissipative self-organization. By reviewing this research, it may be perceived that mainstream approaches to synthetic chemistry have not always been appropriate. In summary, the author proposes that the integration of catalytic functions is a key issue for the creation of autonomous microarchitecture.

Alzheimer's disease (AD), which is characterized by the development of β-amyloid plaques and neurofibrillary tangles in the brain parenchyma, can result in synaptic and neuronal loss. Clinical signs, including deteriorating memory deficiency, may lead to catastrophic effects for the elderly. Research on brain imaging and its application in the study of AD has advanced extraordinarily over the past 30 years. However, widely used imaging methods are only capable of identifying structural or metabolic alterations at the anatomical level in the brain and can only be utilized for drawing inferential distinctions. As a disease with a complex pathophysiological mechanism, AD has many different molecular pathological features and molecular biomarkers. Therefore, molecular imaging for AD pathology indicators provides a practical method for the early diagnosis and impartial assessment of AD. The present review discusses the pathogenesis of AD, as well as the detection methods and principles of molecular imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) techniques. Meanwhile, various tracers and probes applied in molecular imaging that detect Aβ deposits, tau protein accumulation, and neurotransmitters are also reviewed. Molecular pathological tracers provide the possibility to accurately quantify brain changes through molecular imaging.

The purpose of this article is to highlight the new advancements in molecular and diagnostic genetic testing as well as properly classify all ovarian cancers. In this article we address statistics, histopathological classification, molecular pathways implicated in ovarian cancer, genetic screening panels and details about the genes, and also candidate genes. We hope to bring new information in the medical field as to better prevent and diagnose ovarian cancer.

Natural products from plants such as, chemopreventive agents attract huge attention because of their low toxicity and high specificity. The rational drug design in combination with structure based modeling and rapid screening methods offer significant potential for identifying and developing lead anticancer molecules. Thus, the molecular docking method plays an important role in screening a large set of molecules based on their free binding energies and proposes structural hypotheses of how the molecules can inhibit the target. Several peptide based therapeutics have been developed to combat several health disorders including cancers, metabolic disorders, heart-related, and infectious diseases. Despite the discovery of hundreds of such therapeutic peptides however, only few peptide-based drugs have made it to the market. Moreover, until date the activities of cyclic peptides towards molecular targets such as protein kinases, proteases, and apoptosis related proteins have never been explored. In this study we explore the in silico kinase and protease inhibitor potentials of cyclosaplin as well as study the interactions of cyclosaplin with other cancer-related proteins. Previously, the structure of cyclosaplin was elucidated by molecular modeling associated with dynamics that was used in the current study. Docking studies showed strong affinity of cyclosaplin towards cancer-related proteins. The binding affinity closer to 10 indicated efficient binding. Cyclosaplin showed strong binding affinities towards protein kinases such as EGFR, VEGFR2, PKB and p38 indicating its potential role in protein kinase inhibition. Moreover, it displayed strong binding affinity to apoptosis related proteins and revealed the possible role of cyclosaplin in apoptotic cell death. The protein-ligand interactions using LigPlot displayed some similar interactions between cyclosaplin and peptide-based ligands especially in case of protein kinases and a few apoptosis related proteins. Thus, the in silico analyses gave an insight of cyclosaplin as a potential apoptosis inducer and protein kinase inhibitor.

Vienna Atomic Line Database (VALD) contains data on atomic and molecular energy levels and parameters of spectral lines required for stellar spectra analysis. Hundreds of millions lines for fine spectral synthesis and for opacity calculations are collected in present version of VALD (VALD3). Critical evaluation of the data and the diversity of extraction tools support high popularity of VALD among users. The data model of VALD3 incorporates obligatory links to the bibliography making our database more attractive as publishing platform for data producers. The VALD data quality and completeness are constantly improving allowing better reproduction of stellar spectra. To illustrate continuous evolution of the data content we present a comparative analysis of the recent experimental and theoretical atomic data for Fe-group elements, which will be included in the next VALD release. This release will also include a possibility for extracting the line data with full isotopic and hyperfine structures.

Sarcoidosis is a multisystemic disease of unknown etiology characterized by the formation of granulomas in various organs, especially lung and mediastinal hilar lymph nodes. The clinical course and manifestations are unpredictable: spontaneous remission can occur in approximately two thirds of patients; up to 20% of patients have chronic course of the lung disease (called Ad-vanced Pulmonary Sarcoidosis) resulting in progressive loss of lung function, sometimes life-threatening that can lead to respiratory failure and death. The immunopathology mechanism leading from granuloma formation to the fibrosis in APS still remains elusive. Recent studies have provided new insights into the genetics factors and immune components involved in the clinical manifestation of the disease. In this review we aim to summarize the clinical-prognostic charac-teristics and molecular pathways which are believed to be associated with the development of APS

To improve the wear resistance of polyimide (PI), surface modification was developed. In this study, the tribological properties of graphene (GN), graphene oxide (GO), and KH550-grafted graphene oxide (K5-GO) modified PI were evaluated by molecular dynamics (MD) at the atomic level. The findings indicated that the addition of nanomaterials can significantly enhance the friction performance of PI. The friction coefficient of PI composites decreased from 0.253 to 0.232, 0.136, and 0.079 after coating GN, GO and K5-GO, respectively. Among them, the K5-GO/PI exhibited the best surface wear resistance. Importantly, the mechanism behind the modification of PI was thoroughly revealed by observing the wear state, analyzing the changes of interfacial interactions, interfacial temperature, and relative concentration.

The commercial cultivation of microalgae began in the 1960s and Chlorella was one of the first target organisms. The species has long been considered a potential source of renewable energy, an alternative for phytoremediation, and more recently, as a growth and immune stimulant. However, Chlorella vulgaris, which is one of the most studied microalga, has never been comprehensively profiled chemically. In the present study, comprehensive profiling of the Chlorella vulgaris metabolome grown under normal culture conditions was carried out, employing tandem LC-MS/MS to profile the ethanolic extract and GC-MS for fatty acid analysis. The fatty acid profile of C. vulgaris was shown to be rich in omega-6, -7, -9, and -13 fatty acids, with omega-6 being the highest, representing more than sixty percent (>60%) of the total fatty acids. This is a clear indication that this species of Chlorella could serve as a good source of nutrition when incorporated in diets. The profile also showed that the main fatty acid composition was that of C₁₆-C₁₈ (>92%), suggesting that it might be a potential candidate for biodiesel production. LC-MS/MS analysis revealed carotenoid constituents comprising violaxanthin, neoxanthin, lutein, β-carotene, vulgaxanthin I, astaxanthin, and antheraxanthin, along with other pigments such as the chlorophylls. In addition to these, amino acids, vitamins, and simple sugars were also profiled, and through mass spectrometry-based molecular networking, 48 phospholipids were putatively identified.

Developing clinically meaningful nanomedicines for cancer therapy requires the drugs to be effective, safe, simple, cheap, and easy to store. In the present work, we report that a simple cationic Fe(III)-rich salt of [FeIIICl(TMPPH2)][FeIIICl4]2 (Fe-TMPP) exhibits a superior anticancer performance toward a broad spectrum of cancer cell lines, including breast, colorectal cancer, liver, pancreatic, prostate, and gastric cancers, with half maximal inhibitory concentration (IC50) values in the range of 0.098−3.97 μM (0.066−2.68 μg mL−1), and comparable to the best-reported medicines. Fe-TMPP can forms stand-alone nanoparticles in water without the need for extra surface modification or organic-solvent-assisted antisolvent precipitation. Critically, Fe-TMPP is TME-responsive (TME = tumor microenvironment), and can only elicit its function in the TME with overexpressed H2O2, converting H2O2 to the cytotoxic •OH to oxidize the phospholipid of the cancer cell membrane, causing ferroptosis, a programmed cell death process of cancer cells.

Andalusia is a Spanish region that is home to numerous minority varieties due to its diversity and territorial extension, offering the local viticulture the possibility of diversifying its wine production. The molecular identification of 98 specimens from six areas with a winemaking tradition in Andalusia was carried out between the years 2020 and 2022. Thirteen microsatellite markers were used in this study, including the nine recommended by the OIV. 31 different genotypes were obtained, 20 of which corresponded to profiles of already described varieties (11 of them are of minority cultivation in Andalusia: 'Rojal Tinto', 'Beba', 'Zurieles', 'Rome', 'Hebén', 'Mollar Cano', 'Listán Prieto', 'Listán del Condado', 'Jarrosuelto', 'Negra Dorada' and 'Mantúo de Pilas'), while the other 11 profiles did not match with previously identified varieties. This profiles were integrated into the database of the IFAPA “Rancho de la Merced” Germplasm Bank. The eco-geographical groups of the new identified genotypes were determined through analysis of genetic diversity. The presence of the Grapevine Fanleaf Virus, the Grapevine Fleck Virus and the Grapevine Leafroll associated Viruses was also analyzed using an ELISA test due to the necessity of having certifiable clones of the new varieties for their potential interest in being authorized for its cultivation in Spain.

Levan is a fructan-type exopolysaccharide, which is produced by many microbes from sucrose via extracellular levansucrases. The hydrocolloid properties of levan depend on its molecular weight, while it is unknown why and to which extent levan is functionally diverse in dependence of its size. The aim of our study was to get deeper insights into the size-dependent, functional variability of levan. For this purpose, levans of different sizes were produced using the water kefir isolate Gluconobacter albidus TMW 2.1191 and subsequently rheologically characterized. Three levan types could be identified, which are similarly branched, but significantly differ in their molecular size and rheological properties among each other. The smallest levan (< 107 Da) produced without adjustment of the pH exhibited Newton-like flow behavior up to a specific concentration of 25% (w/v). On the contrary, larger levans (> 108 Da) produced at pH ≥ 4.5 were shear-thinning and showed a gel like behavior at ≥ 5% (w/v). A third (intermediate) levan variant was obtained via production in buffers at pH 4.0 and exhibited the properties of a viscoelastic fluid at ≥ 5% (w/v). Our study reveals that the variable size and composition of levan are controllable and more decisive for its functionality than the amount of exerted levan.

: Early and accurate detection of infectious diseases is a key step for surveillance, epidemiology, and control, notably timely disease diagnosis, patient management and follow-up. In this study, we aimed to develop hand-held ultra-fast duplex PCR assays coupled to amplicon detection by lateral flow (LF) immunoassay to deliver a rapid, and simple molecular diagnostic test for con-comitant detection and identification of the main Leishmania parasites encountered in Tunisia and the Old World. We selected two DNA targets to amplify L. major/L. tropica and L. infantum/L. tropica group of species DNAs, respectively. We optimized the experimental conditions of a du-plex ultra-fast PCR. The amplification is performed by a portable Palm convection PCR machine within 18 min and the products are detected by a LF cassette within 10 minutes. The test allows the identification of the infecting species according to the position and number of test lines re-vealed. Tested on a selection of DNAs of representative Leishmania strains of the three studied species (N=37), the ultra-fast duplex PCR-LF showed consistent, stable, and reproducible results. The analytical limit of detection of the test was 0.4pg for L. major, 4pg for L. infantum and 40pg for L. tropica.

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

In bilaterians organism, the signaling of pyramidal neurons (PyrNs) is linked to the relative (prevalent) molecular chirality and physiological, perceptual, cognitive, and psychological functions and dysfunctions, providing the coupling of the central nervous system downstream and upstream evolutionary and developmental processes. The most apparent and discriminating morphological specificity of PyrNs is the geometry of the cell body. However, the question "why/how PyrNs soma gains the shape of quasi-tetrahedral symmetry" has never been explicitly articulated. If the basic function of PyrNs is sensory space perception, supporting the orientation, and movement coordination, then the pyramidal shape of soma is the best evolutionary-selected geometry to perform sensory-motor coupling. In biology, the impact of chiral symmetry (handedness) is evident at all levels of biological organization, from the prevalent symmetry of biological molecules to the morphology and function of bilateral organisms. How the tetrahedral symmetry of biomolecules is linked to the morphology and functions of bilateral organisms remains a challenging question. Cell chirality represents an intermediate point connecting two poles of biochirality. In this holistic perspective, examining the PyrNs' morphology-circuitry-function link is crucial to understanding the complex interaction between genetic, epigenetic, and environmental factors in the evolution of the CNS. The predictive power of our hypothesis can be partially expressed by the statement that the most integral and reliable biomarker of the neurodegenerative (including aging) and mental (including all variants of psychiatric illness) disorders would be the detection of the hemispheric asymmetry of D-amino acids (D-AAs) level in pyramidal neurons (PyrNs).

When liquids are confined into nanometer-scale slit, the induced layering-like film structure allows the liquid to sustain non-isotropic stresses and thus being load-bearing. Such anisotropic characteristics of liquid under confinement arise naturally from the liquids’ wave number dependent compressibility that does not need solidification to take place as a prerequisite. In other words, liquids under confinement can still remain fluidity with molecules being (sub-)diffusive. However, the extensively prolonged structural relaxation time can cause hysteresis of stress relaxation of confined molecules in response to the motions of confining walls and thereby yield the quasi-static stress tensor history-dependent. In this work, by means of molecule dynamics, the discrepancy of stress tensor of a highly confined key base-oil component, i.e. 1-decene trimer, is captured after its relaxation from being compressed and decompressed. The results indicate that among the effects (e.g. confinement, molecular structure, and film density) that can potentially affect confined stress tensor, the ordering status of the confined molecules plays a predominant role.

Molecular engineering research is the fundamental way and the only way for the development of biomaterials. Based on molecular engineering, the biocompatibility of natural conformation and polymer biomaterials was studied. In this paper, we discuss that natural conformation is the basis of protein biological function, and that the synergistic action of peptide chain and side group is the motive force for protein to construct natural conformation and complete biological function. On the basis of the influence of the adsorption of polymer biomaterials on the natural conformation of proteins, the relationship between biocompatibility of biomaterials and protein conformation is further explained. Studies have shown that bismuth molecular materials can only be applied in the market and have their functionality if they have good biocompatibility. Therefore, the biocompatibility evaluation of new materials has important practical significance.

Proper regulation of microtubules (MTs) is critical for the execution of diverse cellular processes, including mitotic spindle assembly and chromosome segregation. There are a multitude of cellular factors that regulate the dynamicity of MTs and play critical roles in mitosis. Members of the Kinesin-8 family of motor proteins act as MT-destabilizing factors to control MT length in a spatially and temporally regulated manner. In this review, we focus on recent advances in our understanding of the structure and function of the Kinesin-8 motor domain, and the emerging contributions of the C-terminal tail of Kinesin-8 proteins to regulate motor activity and localization.

Clofazimine and Arbidol have both been reported to be effective in vitro SARS-CoV-2 fusion inhibitors. Both are promising drugs repurposed for treatment of COVID-19 and have been used in several previous and ongoing clinical trials. Small-molecule binding to expressed constructs of the trimeric S2 segment of Spike and the full-length SARS-CoV-2 spike protein were measured using a Surface Plasmon Resonance (SPR) binding assay. We demonstrate that Clofazimine, Toremifene, Arbidol and other Arbidol derivatives bind to the S2 segment of the Spike protein. Clofazimine provided the most reliable and highest quality SPR binding data to S2 over the conditions explored. A molecular docking approach was used to identify the most favorable binding sites on the S2 segment in the prefusion conformation, highlighting two possible small-molecule binding sites for fusion inhibitors. Results from molecular docking and modeling the structure-activity-relationship (SAR) of a newly reported series of Clofazimine derivatives supports the proposed Clofazimine binding site on the S2 segment. When the proposed Clofazimine binding site is superimposed with other experimentally determined coronavirus structures in structure-sequence alignments, the changes in sequence and structure may rationalize the broad-spectrum antiviral activity of Clofazimine in closely related coronavirus such as (SARS-CoV, MERS, hCoV-229E, hCoV-OC43).

Reducing carbohydrates digestion by having low glycaemic index (GI) foods has been linked to weight loss. Inhibiting related enzymes is an alternative way to decrease carbohydrate digestion. RCM-107, an eight-herb formula that is modified from the RCM-104, has indicated significant weight-loss action in clinical trials. However, no research has been conducted to study its effect on the activity of porcine pancreatic alpha-amylase (PPA), which is involved in carbohydrate absorption. In this paper, we used fluorescence PPA inhibition assay to investigate the inhibitory effects of RCM-107 and the individual herbs present in this herbal mixture on amylase activity. Subsequently, molecular docking predicted the key active compounds that may be responsible for the enzyme inhibition. According to our results, both the RCM-107 formula and several individual herbs displayed α-amylase inhibitory effects. Also, marginal synergistic effects of RCM-107 were also detected. In addition, alisol B, (-)-epigallocatechin-3-gallate (EGCG) and plantagoside have been predicted as the key active compounds that may be responsible for the α-amylase inhibition effect of RCM-107 according to inter-residue contact analysis. Finally, Glu233, Gln63, His305, Asp300 and Tyr151 are predicted to be markers of important areas with which potential amylase inhibitors would interact.

Benzazoles, such as benzoxazoles and benzothiazoles, are compounds with important biological and pharmacological activities and important intermediaries in synthesis. This report presents the synthesis of a butanamide derived from linking 5-chloro-2-aminobenzoxazole and 2-aminobenzothiazole via 4-chlorobutanoyl chloride. The corresponding compound N-(benzothiazol-2-yl)-4-((5-chlorobenzoxazol-2-yl)aminobutanamide was obtained 76 % yield global using accessible starting materials and methodology in two reaction steps. Furthermore, we made docking studies of this compound on 3-TOP protein to explore its potential as an antidiabetic agent.

We research the interaction between six representative carbon-based nanoparticles (CBNs) and 20 standard amino acids through all-atom molecular dynamics simulations. The six carbon-based nanoparticles are fullerene(C60), CNT55L3, CNT1010L3, CNT1515L3, CNT2020L3, and two-dimensional-graphene(Graphene33). Their curvatures decrease sequentially, and all of CNT are single-walled carbon nanotubes. We have observed that as the curvature of CBNs decreases, the adsorption effect of 20 amino acids with them has an increasing trend. In addition, we also used multi-dimensional clustering to analyze the adsorption effects of 20 amino acids on six carbon-based nanoparticles. We observed that the π-π interaction still plays an extremely important role in the adsorption of amino acids on carbon-based nanoparticles. Individual long-chain amino acids and “Benzene-like” Pro also have a strong adsorption effect with carbon-based nanoparticles.

Abies beshanzuensis, an extremely endangered species, attracts serious concerns on genetic diversity recovery and population protection. However, little genetic information was known about it till now. In this study, intra-/intergenomic ITS variation, secondary structure, and molecular phylogeny of A.beshanzuensis were determined by nrDNA-ITS marker, and results indicated that, ITS region featured rich polymorphism in ITS1 and highly conservative in 5.8S/ITS2 among intra-/inter-genome, implying rich genetic diversities and the occurrence of non-concerted evolution in ITS region. Predicated 5.8S structure possessed Helices-Loops with 3 motifs (M1/M2/M3) and 5 helices B4-B8, and ITS2 could form conservative Clover-like structure with 5 ribotypes, manifesting genetically structural generalities and individualities. Thirteen ITS pseudogenes were also identified from 76 samples (or clones). Molecular phylogeny revealed that, A.beshanzuensis shared genetically closer relationships with A.fanjingshanensis, A.chensiensis, A.yuanbaoshanensis among genus Abies. The available original data provided rich genetic information on ITS sequence, structure and molecular phylogeny of A.beshanzuensis, which not only updated the databases of ITS sequences as well as secondary structures essential for phylogenetic reference and DNA barcoding analyses, but also contributed to deep exploration of population diversities, origin and evolution as well theoretical direction for population recovery and protection of A.beshanzuensis.

Bulbophyllum is one of the largest genera and presents some of the most intricate taxonomic problems in the family Orchidaceae, including species of ornamental and medical importance. The lack of knowledge regarding the characterization of Bulbophyllum chloroplast (cp) genomes has imposed current limitations on our study. Here, we reported the complete cp genomes of seven Bulbophyllum species, including B. ambrosia, B. crassipes, B. farreri, B. hamatum, B. shanicum, B. triste and B. violaceolabellum, and compared with related taxa to provide a better understanding of their genomic information on taxonomy and phylogeny. A total of 28 Bulbophyllum cp genomes exhibit typical quadripartite structures with lengths ranging from 145,092 bp to 165,812 bp and GC content of 36.60% to 38.04%. Each genome contained 125–132 genes, encompassing 74–86 protein-coding genes, 38 tRNA genes, and eight rRNA genes. The genome arrangements, gene contents and length were similar with differences observed in ndh gene composition. A total of 18–49 long repeats and 38–80 simple sequence repeats (SSRs) were detected and the single-nucleotide (A/T) was dominant in Bulbophyllum cp genomes, with an obvious A/T preference. An analysis of relative synonymous codon usage (RSCU) revealed Leucine (Leu) was the most frequently used codon, while cysteine (Cys) was the least used. Six highly variable regions including ndhF-trnLUAG, trnTUGU-trnLUAA, trnFGAA-ndhJ, rps15-trnNGUU, rbcL-accD and psbI-trnSGCU were identified based on the ranking of the Pi values, had the potential to serve as DNA markers for species identification and phylogeny of the genus Bulbophyllum. Phylogenetic analysis based on the complete cp genome sequences and 68 protein-coding genes strongly supported 28 Bulbophyllum species can be divided into four branches and sects. Brachyantha, Cirrhopetalum, Leopardinae defined by morphology were non-monophyly. Our results enriched the genetic resources of Bulbophyllum species, providing valuable information to illustrate the complicated taxonomy, phylogeny and evolution process of the genus.

Colorectal cancer is a major threat to the society causing the death through metastasis to several patients with stage IV. Computational tools provide a relatively quick procedure in order to evaluate several molecules for their drug activity. Prenylated flavonoids are well known for their anticancer properties even in colon cancer. Here, we provided altered structures of chalcones, based on theoretical studies that are showing better binding affinities to several colon cancer related proteins. Using molecular docking and dynamics, alongside with density function theory and ADMET studies we are representing two new derivatives of Xanthohumol prenylated flavonoids having promising results against this disease.

Oral mucositis (OM) is one of the common adverse events associated with cancer treatment that decreases quality of life and affects treatment outcome. However, the medications used to manage OM are generally only palliative, and our knowledge of the syndrome is limited. The etiology of the syndrome is thought to be complex and multifactorial. We investigated the trends and characteristics of OM and estimated molecular initiating events (MIEs) associated with the development of the syndrome using FDA Adverse Event Reporting System. The study of trends and characteristics suggested that OM is significantly more likely to occur in females and nonelderly patients and is likely to be induced by protein kinase inhibitors such as afatinib and everolimus. Next, we used Toxicity Predictor, an in-house quantitative structure–activity relationship system, to estimate OM-associated MIEs. The results revealed that agonist activity of human pregnane X receptor, thyroid-stimulating hormone-releasing hormone receptor, and androgen receptor may be associated with OM development. Our study findings are expected to help avoid the risk of OM induction during the drug discovery process and clinical use of antineoplastic agents.

Lupinus mutabilis Sweet (Fabaceae), “tarwi” or “chocho”, is an important grain legume in the Andean region. In Peru, studies on tarwi have been mainly focused on morphological features, however, the have not been molecularly characterized. Currently, it is possible to explore genetic parameters of plants with reliable and modern methods like genotyping-by-sequencing (GBS). We here for the first time used single nucleotide polymorphisms (SNPs) markers to infer the genetic diversity and population structure of 89 accessions of tarwi from nine Andean regions of Peru. A total of 5922 SNPs distributed along all chromosomes of tarwi were identified. STRUCTURE analysis revealed that this crop is grouped into two clusters. A dendrogram was generated using the UPGMA clustering algorithm and, similar to the principal coordinate analysis (PCoA), it showed two groups that correspond to the geographic origin of the tarwi samples. AMOVA showed a reduced variation between clusters (7.59 %) and indicated that variability within populations is 92.41 %. Population divergence (Fst) between clusters 1 and 2 revealed low genetic difference (0.019). We also detected a negative Fis for both populations, demonstrating that, similar to other Lupinus species, tarwi also depends on cross-pollination. SNPs markers were powerful and effective for the genotyping process in this germplasm. We hope that this information is the beginning of the path towards a modern genetic improvement and conservation strategies of this important Andean legume.

Polo-like kinase 1 (PLK1) plays a pivotal role in cell division regulation and emerges as a promising therapeutic target for cancer treatment. Consequently, the development of small-molecule inhibitors targeting PLK1 has become a focal point in contemporary research. The adenosine triphosphate (ATP)-binding site and the polo-box domain in PLK1 present crucial interaction sites for these inhibitors, aiming to disrupt the protein's function. However, designing potent and selective small-molecule inhibitors can be challenging, requiring a deep understanding of protein-ligand interaction mechanisms at these binding sites. In this context, our study leverages the fragment molecular orbital (FMO) method to explore these site-specific interactions in-depth. Through the FMO approach, we used the FMO method to elucidate the molecular mechanisms of small-molecule drug binding to these sites to design PLK1 inhibitors that are both potent and selective. Our investigation further entailed a comparative analysis of various PLK1 inhibitors, each characterized by distinct structural attributes. This comparison enhanced our understanding of the structure-activity relationships of these inhibitors, underscoring the efficacy of the FMO method in identifying critical binding features and predicting binding modes for small-molecule ligands. Furthermore, Our research spotlighted "hot spot" residues instrumental for selective and robust PLK1 binding. Our findings offer profound insights, priming the rational design of innovative potential PLK1 inhibitors with significant implications for developing anticancer therapeutics.

In this study, we investigate the structural changes, electronic properties, and charge redistribution within azo-bithiophene (Azo-BT) chemisorbed monolayers under different light stimuli using density functional theory and molecular dynamics simulations. We consider two types of switches, Azo-BT and BT-Azo, with different arrangements of the Azo and BT blocks counting from the anchor thiol group. The chemisorbed monolayers of pure cis- and trans-isomers with a surface concentration of approximately 2.7 molecules per nm2 are modeled on a gold surface using classical all-atom molecular dynamics. Our results reveal significant shrinkage of the BT-Azo layer under UV illumination, whereas the thicknesses of the Azo-BT layer remain comparable for both isomers. This difference in behavior is attributed to the ordering of the trans-molecules in the layers, which is more pronounced for Azo-BT, leading to a narrow distribution of the inclination angle to the gold surface. Conversely, both layers consisting of cis-switches exhibit disorder, resulting in similar brush heights. To study charge transfer within the immobilized layers, we analyze each snapshot of the layer and calculate mean charge transfer integrals using Nelsen’s algorithm for a number of interacting neighboring molecules. Combining these integrals with reorganization energies defined for the isolated molecules, we evaluate the charge transfer rates and mobilities for electron and hole hopping within the layers at room temperature based on Marcus’ theory. This research offers new perspectives for the innovative design of electrode surface modifications and provides insights into controlling charge transfer within immobilized layers using light triggers. Additionally, we identify molecular properties that are enhanced through specific molecular design, which contributes to the development of more efficient molecular switches for various electronic applications.

Allergen immunotherapy (AIT) with aeroallergens is the only disease modifying treatment for patients with different allergic conditions. Despite the effectiveness of AIT has been evidenced in both randomized controlled trials and real word studies, it remains underused in less than 10% of subjects with allergic rhinitis (AR) and/or asthma (A). We aimed to determine the current eligibility for house dust mite (HDM) AIT by means of a Precision Allergy Molecular Diagnosis (PAMD@) model in a selected cohort of youngsters with different allergic phenotypes according to the available evidence. A complex response to both HDM and storage mite allergens was depicted regardless of the subjects´ basal atopic condition. No solely specific IgE binding responses to Der p 1, Der p 2 and/or Der p 23 were found in the studied cohort. Despite patients with A and atopic dermatitis showed significantly higher serum titers to 6 mite allergens than subjects with AR, no specific molecular profile could be regarded as disease specific. Given the increasing complexity of specific IgE responses to the local prevailing aeroallergens, the identification and presence of such molecules are needed in commercially available AIT in the era of precision medicine.

Quercetin (QUA), a flavonoid compound, is ubiquitously found in plants and has demonstrated a diverse range of biological activities. The primary objective of the present study is to assess the potential antiemetic properties of QUA using an in vivo and in silico approach. In this experiment, emesis was induced in 4-day-old chicks by orally administering copper sulfate pentahydrate (CuSO4.5H2O) at a dose of 50 mg/kg (orally). Domperidone (6 mg/kg), ondansetron (5 mg/kg), and hyoscine (21 mg/kg) were treated as positive controls (PCs), and distilled water was employed as a negative control (NC). QUA was administered orally at two distinct doses (25 and 50 mg/kg). Additionally, QUA (50 mg/kg) and PCs were administered separately or in combination to assess their antagonistic or synergistic effects on the chicks. The binding affinity of QUA and referral ligands towards 5HT3, D2, D3, and M1–M5 receptors was estimated, and ligand-receptor interactions were visualized through various computational tools. In vivo findings indicate that QUA (25 and 50 mg/kg) has a significant effect on reducing the number of retches (16.50 ± 4.65 and 10.00 ± 4.19 times) and increasing the chick latency period (59.25 ± 4.75 and 94.25 ± 4.01 seconds), respectively. Additionally, QUA (50 mg/kg) in combination with domperidone and ondansetron exhibited superior antiemetic effects, reducing the number of retches and increasing the onset of emesis-inducing time. Furthermore, it is worth noting that QUA demonstrated the strongest binding affinity towards the D2 receptor with a value of -9.7 kcal/mol through the formation of hydrogen and hydrophobic bonds. In summary, the study found that QUA exhibited antiemetic activity in chicks, potentially by interacting with the D2 receptor pathway.

The emergence of multi-drug resistant bacteria has severely increased the burden on the global health system, and such pathogen infections are considered a great threat to human well-being. Antimicrobial peptides, due to their potent antimicrobial activity and low possibility of inducing resistance, are increasingly becoming the focus of much interest. Herein, a novel dermaseptin peptide, named Dermaseptin-SS1 (SS1), was identified from a skin secretion-derived cDNA library of the South/Central American tarsier leaf frog, Phyllomedusa tarsius, using a ‘shotgun’ cloning strategy. Chemically-synthesised peptide SS1 was found to be broadly effective against Gram-negative bacteria with low haemolytic activity in vitro. A designed synthetic analogue of SS1, named peptide 14V5K, showed a lower salt sensitivity with more rapid bacteria-killing compared to SS1. Both peptides employed the membrane-targeting mechanism to kill Escherichia coli. The antiproliferative activity of SS1 and its analogues, against lung cancer cell lines, was found to be significant.

Traditional medicine is one of the main bases for studying and discovering natural sources of phytometabolites with antiviral properties. This research aims to demonstrate that the medicinal plants used as a treatment of viral diseases in the La Libertad region have, in fact, antiviral ac-tivity. The study evaluated the ethnobotany of the 8 most widely used medicinal plants in the region (Azadirachta indica A. Juss. “paraíso”, Caesalpinia spinosa (Molina) Kuntze “tara”, Citrus limon (L.) Osbeck “limón”, Clinopodium pulchellum (Kunth) Govaerts “panizara”, Cordia lutea Lam. “overo”, Ocimum basilicum L. “albahaca”, Schinus molle L. “molle”, and Taraxacum campylodes G.E. Haglund “diente de león”). The phytometabolites responsible for the antiviral activity were identified by LC-MS and evaluated in silico against the viral proteins NS2B/NS3 (DENV-2), NS5B (HCV), and ICP27 (HSV-1) using molecular docking in Autodock Vina and UCSF Chimera. The presence of five polyphenols (chlorogenic acid, gallic acid, caffeic acid, rosmarinic acid, and rutin) was found and, in the in silico test, the antiviral activity of chlorogenic acid stood out against DENV-2 and HCV, rutin against HCV and HSV-1, rosmarinic acid against DENV-2 and HCV. Therefore, it is verified that the medicinal plants studied have antiviral activity, which supports their use in traditional medicine

Rapeseed (Brassica napus L.) is one of the most important oil crops in China. Improving oil production of rapeseed is an important way to ensure the safety of edible oil in China. Oil production is an important index to reflect the quality of rapeseed and is determined by oil content and yield. Applying nitrogen is an important way to ensure a high yield. However, increasing nitrogen application would decrease oil content. Thus, it is critical to screen elite germplasm resources with stable or improved oil content under high nitrogen and to investigate the molecular mechanisms of nitrogen regulation of oil accumulation. In this paper, we review the effects of nitrogen levels on rapeseed yields and oil content, aiming to reveal the mechanisms of nitrogen regulation in oil accumulation and thereby provide a theoretical basis for breeding varieties with high oil content.

The application of graph theory in chemical and molecular structure research far exceeds people's expectations, and it has recently grown exponentially. In the molecular graph, atoms are represented by vertices and bonded by edges. Closed forms of multiplicative degree-based topological indices which are numerical parameters of the structure and determine physico-chemical properties of the concerned molecular compound. In this article, we compute and analyze many multiplicative degree-based topological indices of silicon-carbon Si₂C₃-I[p,q] and Si₂C₃-II[p,q].

The major arboviruses belong mainly to the families Bunyaviridae, Togaviridae, and Flaviviridae amongst which chikungunya virus and dengue virus have emerged as a global public health problem. The main objective of the study was to develop a specific, sensitive, and cost-effective molecular multiplex RT-PCR and RT-qPCR assay for the rapid and simultaneous detection of CHIKV and the four serotypes of DENV for arbovirus surveillance. Specific primers of all virus were designed, one step multiplex RT-PCR (mRT-PCR) and RT-qPCR (mRT-qPCR) was developed using reference strains of CHIKV and DENV serotypes. The specificity of the test for all the viruses was confirmed by sequencing. The standard curves showed a high correlation coefficient, R2= 0.99, for DENV-2 and DENV-3; R2= 0.98, for DENV-4 and CHIKV; R2= 0.93, for DENV-1. The limits of detection were calculated to be 10-2 copies/µL for all viruses. The specificity and sensitivity of the newly developed mRT-PCR and mRT-qPCR were validated using positive serum samples collected in India and Burkina Faso. The sensitivity of mRT-PCR and mRT-qPCR are 91%, and 100% respectively. The specificity of both assays was 100% specific. mRT-PCR and mRT-qPCR assays are low cost and a combination of both will be a useful tool for arbovirus surveillance.

Background: COVID-19, a member of corona virus family is spreading its tentacles across the world due to lack of drugs at present. Associated with its infection are cough, fever and respiratory problems causes more than 15% mortality worldwide. It is caused by a positive, single stranded RNA virus from the enveloped coronaviruse family. However, the main viral proteinase (Mpro/3CLpro) has recently been regarded as a suitable target for drug design against SARS infection due to its vital role in polyproteins processing necessary for coronavirus reproduction.Objectives: The present in silico study was designed to evaluate the effect of Eucalyptol (1,8 cineole), a essential oil component from eucalyptus oil, on Mpro by docking study.Methods: In the present study, molecular docking studies were conducted by using 1-click dock and swiss dock tools. Protein interaction mode was calculated by Protein Interactions Calculator.Results: The calculated parameters such as RMSD, binding energy, and binding site similarity indicated effective binding of eucalyptol to COVID-19 proteinase. Active site prediction further validated the role of active site residues in ligand binding. PIC results indicated that, Mpro/eucalyptol complexes forms hydrophobic interactions, hydrogen bond interactions and strong ionic interactions.Conclusions: Therefore, eucalyptol may represent potential treatment potential to act as COVID-19 Mpro inhibitor. However, further research is necessary to investigate their potential medicinal use.

In this theoretical study we report on molecular electrostatic potential (MEP) of titled molecules confined by repulsive potentials of cylindrical symmetry mimicking a topology. Our calculations show that the spatial restriction significantly changes the picture of MEP of molecules in quantitative and qualitative sense. In particular, the drastic changes of MEP as a function of the strength of spatial confinement are observed for the BrCN molecule. This preliminary study is the first step in the investigations of the behavior of MEP of molecular systems under the orbital compression.

Eukaryotic cells contain membranes with various curvatures, from the near-plane plasma membrane to the highly curved membranes of organelles, vesicles, and membrane protrusions. These curvatures are generated and sustained by curvature-inducing proteins, peptides, and lipids, and describing these mechanisms is an important scientific challenge. In addition to that, some molecules can sense membrane curvature and a thereby be trafficked to specific locations. The description of curvature-sensing is another fundamental challenge. Curved lipid membranes and their interplay with membrane-associated proteins can be investigated with molecular dynamics (MD) simulations, given the right tools. Various methods for simulating curved membranes with MD are discussed here, including tools for setting up simulation of vesicles, and methods for sustaining membrane curvature. The latter are divided into methods that exploit scaffolding virtual beads, methods that use curvature-inducing molecules, and methods applying virtual forces. The variety of simulation tools allow the researcher to closely match the conditions of experimental studies of membrane curvatures.

The chemical feedback between building blocks in templated polymerization of diblock copolymers and their consecutive micellization was studied for the first time by means of coarse-grained molecular dynamics simulations. Using a stochastic polymerization model, we were able to reproduce the experimental findings on the effect of chemical feedback on the polymerization rates at low and high solution concentrations. The size and shape of micelles were computed using a newly development software in python conjugated with graph theory. In full agreement with the experiments, our simulations revealed that micelles formed by the templated micellization are more spherical and have lower radius of gyration than those formed by the traditional two-step micellization method. Understanding the underlying mechanisms in templated reaction/assembly of polymers will help for rational design of new synthetic supramolecular materials.

The details of antigen-antibody interactions and the identification of epitopes are critical for the development of monoclonal antibody drugs. Ab42 is a native human-derived anti-CFH monoclonal antibody. In this study, the interaction between antigen pCFH and antibody (Ab42) was theoretically demonstrated by molecular docking and MD simulation, combined with free energy calculation and computational alanine scanning (CAS), and key amino acids and epitopes were identified. Experimental alanine scanning (EAS) was then carried out to verify the results of the calculation, and our results indicated that Ab42 antibody forms hydrogen bonds and interacts hydrophobically with pCFH through the Tyr315, Ser100, Gly33, and Tyr53 residues on its CDR, while the main pCFH epitopes are located at the six sites of Pro441, Ile442, Asp443, Asn444, Ile447, and Thr448. In conclusion, this study has explored the mechanism of antigen-antibody interaction from both theoretical and experimental aspects, and our results have important theoretical significance for the design and development of relevant antibody drugs.

The amino acid composition of the active site in an enzyme is influential on its substrate selectivity. For CYP2E1, the role of PHE residues in the formation of effective orientations for its activity toward aromatic substrates remains unclear. In this study, molecular docking and molecular dynamics analysis were performed toward the interactions between PHEs in the active site of human CYP2E1 and various aromatic compounds as confirmed CYP2E1 substrates. The results indicated that the orientation of 1-methylpyrene (1-MP) in the active site was highly modulated by the PHEs, PHE478 contributing to the binding free energy most significantly. Furthermore, by building a random forest model the relationship between each of 19 molecular descriptors of PCB congeners (from molecular docking, quantum mechanics, and physicochemical properties) and established human CYP2E1-dependent mutagenicity of a series of polychlorinated biphenyls (PCBs), which have been proven to be human carcinogens and endocrinal disrupters, was investigated. The presence of PHEs did not appear to significantly modify the electronic or structural feature of each bound ligand (PCB), instead, the flexibility of the molecular conformation of PHEs contributed substantially to the effective binding energy and orientation. It is supposed that PHE residues adjust their own conformation to permit a suitable space for the ligand binding and form an orientation favorable for a biochemical reaction. This study has provided some insights into the role of PHEs in guiding the interactive adaptation of the active site of human CYP2E1 for the binding and metabolism of aromatic substrates.

The Chagas disease (CD) is an endemic infectious disease in a large part of Latin America. This disease is characterized by the fact of being caused by the parasite Trypanosoma cruzi. Some symptoms of this disease are cardiopathies and gastrointestinal problems. Therefore, the commonly used treatment consists of nitro drugs such as benznidazole and nifurtimox, which target the nitroreductase enzyme that docks to the coenzyme flavin mononucleotide (FMN) and an oxidation-reduction reaction is generated. From this reaction, the nitro chemical function of benznidazole and nifurtimox is reduced to amine. This amine in turn interacts with the parasite´s DNA. In vitro tests experimentally help in the study of the parasite resistance to the drug benznidazole. This fact could explain how nonsynonymous mutations in the nitroreductase (NTR) enzyme do not allow the anchorage of the FMN coenzyme and as a consequence the parasite susceptibility to benznidazole decreases as the drug cannot be reduced. The structural relations from the hybrid Quantum Mechanics-Molecular Mechanics (QM/MM) allow to detect the small changes generated in the system, considering a charge distribution associated with the structure, angle changes, interaction distances, potential surface calculations between the wildtype enzyme and the mutation found.

The exploration of alternative antimalarial therapeutics is a requisite for the emergence of resistance against Artemisinin. Considering the required cost and time length of classical small molecule drug discovery process, phytochemical screening of traditionally used medicinal plant which are repertoire of active compounds with antimalarial activity has become popular. To investigate the antimalarial property of traditionally used medicinal plants, a number of Erythrina spp have been reviewed systematically where less studied E. fusca has been selected for further analysis. Phytochemical investigation yielded five compounds namely; Phaseolin, Phytol, β-amyrin, Lupeol, and Stigmasterol. In-vitro antimalarial drug sensitivity HRP-II ELISA was carried out against chloroquine (CQ) sensitive 3D7 and CQ-resistant Dd2 strains. Extracts showed significant antimalarial activity against 3D7 and Dd2 strains (IC₅₀ 4.94 – 22 µg/mL) and these compounds have been reported here for the first time. Molecular docking analysis showed high binding energy (−9.0 ± 0.32 kcal/mole) indicating high degree of interaction between Phaseolin and 14 clinically important Plasmodium falciparum proteins at the active site. Stable interaction was also observed between ligand and protein from molecular dynamics simulation analysis with high free energy (−75.156 ± 11.459) that substantiates the potential of Phaseolin as an antimalarial drug candidate.

The emergence of SARS/MERS drug resistant COVID-19 with high transmission and mortality has recently been declared a deadly pandemic causing economic chaos and significant health problems. Like all coronaviruses, SARS-CoV-2 is a large virus that has many druggable components within its proteome. In this study, we focused on repurposing approved and investigational drugs by identifying potential drugs that are predicted to effectively inhibit critical enzymes within SARS-CoV-2. We shortlisted seven target proteins with enzymatic activities known to be essential at different stages of the virus life cycle. For virtual screening, the energy minimization of a crystal structure or modeled protein was carried out using Protein Preparation Wizard (Schrödinger LLC, 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs (n=5903) that are already approved by worldwide regulatory bodies including the FDA, using the ZINC database. Screening was performed against viral targets using three sequential docking modes (i.e. HTVS, SP and XP). Our in-silico virtual screening identified ~290 potential drugs based on the criteria of energy, docking parameters, ligand and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. A top lead from each target group was further subjected to molecular dynamics simulation (MDS) using the Desmond module to validate the efficacy of the screening pipeline. All of the simulated hit-target complexes were predicted to strongly interact and with highly stable binding. Thus, we have identified a number of approved and investigational drugs with high likelihood of inhibiting a variety of key SARS-CoV-2 proteins. Follow-up studies will continue to identify inhibitors suitable for combination therapy based on drug-drug synergy to thwart resistance. In addition, the screening hits that we have identified provide excellent probes for understanding the binding properties of the active sites of all seven targets, further enabling us to derive consensus molecules through computer-aided drug design (CADD). While infections are expanding at a rampant pace, it must be recognized that resistance will grow commensurately through either genetic shift and/or genetic drift to all small molecule drugs identified. Vaccines should provide a more permanent solution through prevention, but resistivity is still a possible scenario. Nevertheless, a persistent multi-target drug development program is essential to curb this ongoing pandemic and to keep reemergence in check.

Chromoblastomycosis (CBM) and phaeohyphomycosis (FEO) are infections caused by melanized filamentous fungal agents, primarily found in tropical and subtropical regions. Both infections pose significant challenges for the correct identification of the causative agent due to their morphological similarity, making conventional methods of morphological analysis highly subjective. Therefore, molecular techniques are necessary for the precise determination of these species. In this regard, this study aimed to contribute to a new methodology based on PCR-RFLP for the identification of agents causing CBM and FEO. Sequences from the ITS region were used to identify potential restriction enzyme sites in silico, followed by in vitro validation using the selected restriction enzymes. The obtained results were compared with species identification through morphological analyses and sequencing. The results demonstrated that the PCR-RFLP applied in this study accurately identified two major agents of chromoblastomycosis, Fonsecaea pedrosoi and Fonsecaea monophora, as well as Cladophialophora bantiana and Exophiala dermatitidis, both causative agents of phaeohyphomycosis. In this context, the proposed assay can complement current methods for identifying these species, aiding in diagnosis, and contributing to the proper management of these infections.

ATP Synthase is an essential molecule in cell and molecular biology. It is responsible for the production of ATP during cellular respiration, a molecule that provides the energy required to drive a number of cellular processes. In this paper, I explore the rotational physics of ATP Synthase’s rotor, a part of the protein that spins during the production of ATP. Firstly, I discuss some elementary rotational kinematics of the rotor. I then derive two alternate formulations for the total linear acceleration of the rotor. Finally, I derive formulas for the moment of inertia, angular momentum, net torque, and kinetic energy of the rotor. Through this, I hope to provide a theoretical and mathematical insight into the mechanics of ATP Synthase during the production of ATP.

A major public health emergency has been created by the COVID-19 pandemic, which is brought on by the SARS-CoV-2 virus. Due to its crucial function in viral replication, the primary protease (Mpro) of the virus is a prime target for therapeutic research. In this study, we used molecular modeling and molecular dynamics simulations to examine the potential therapeutic uses of Mpro inhibitors for the treatment of COVID-19. Using induced fit docking and molecular dynamics simulations, we confirmed the top compounds after screening a library of compounds for their ability to bind to Mpro. Simulation interaction diagrams were used to investigate protein-ligand interactions, and MM-GBSA was used to determine binding energies. The Swiss ADME server was used to predict ADME properties. According to our findings, numerous substances are strong COVID-19 medication candidates since they have excellent ADME features and high binding affinities. This work serves as a foundation for additional experimental research and drug development initiatives aimed at Mpro.

The Herpotrichiellaceae family is an important group of dematiaceous filamentous fungi, associated with a variety of pathogenic fungal species causing Chromoblastomycosis (CBM) and Phaeohyphomycosis (PHM), both with polymorphic clinical manifestations and worldwide incidence. Currently, the identification of this family and determination of the causative agent is challenging due to the subjectivity of morphological identification methods, necessitating the use of molecular techniques to complement diagnosis. In this context, genetic sequencing of the Internal Transcribed Spacer (ITS) has become the norm due to a lack of alternative molecular tools for identifying these agents. Therefore, this study aimed to develop PCR-Multiplex methodologies to address this gap. Sequences from the ITS and Large subunit (LSU) of ribosomal DNA were used, and after manual curation and in vitro analyses, primers were synthesized for the identification of the aforementioned targets. The primers were optimized and validated in vitro, resulting in two PCR-Multiplex methodologies: one for identifying the Herpotrichiellaceae family and the bantiana clade, and another for determining the species Fonsecaea pedrosoi and Fonsecaea monophora. Ultimately, the assays developed in this study aim to complement other identification approaches for these agents, reducing the need for sequencing, improving the management of these infections, and enhancing the accuracy of epidemiological information.

The outbreak of Coronavirus, as well as its emerging potential consequences, has become a global challenge worldwide, demanding effective and controlled therapeutic strategies. Potential drug candidates could achieve that with minimal toxicity. The current investigation selected 2-Deoxy-D-glucose prescribed by Defense Research and Development Organization (DRDO), India. The derivative and modified form was tested through in silico analysis against COVID-19 main protease complex with N3 inhibitor. The derived form of 2-Deoxy-D-glucose was generated by replacing the hydroxy group with a hydrogen atom, and Cypate 2-Deoxy-D-glucose was chosen as a derivative against the COVID-19 main protease complex. A molecular docking approach was adopted to identify the stable and competent form among the modified and derivative forms of 2-Deoxy-D-glucose based on binding energy. By further promoting the stabilized complex, these compounds' toxicity was also scrutinized through ADMET analysis to predict the potential candidate. The current investigation suggested that the modified version of 2-Deoxy-D-glucose was more stable with minimal toxicity against COVID-19 main protease.

Mutation in the ethionamide (ETH) activating enzyme, EthA, is the main factor determining resistance to this drug, used to treat TB patients infected with MDR and XDR Mycobacterium tuberculosis isolates. Many mutations in EthA of ETH resistant (ETH-R) isolates have been described but their roles in resistance remain uncharacterized, partly because structural studies on the enzyme are lacking. Thus, we took a two-tier approach to evaluate two mutations (Y50C and T453I) found in ETH-R clinical isolates. First, we used a combination of comparative modeling, molecular docking, and molecular dynamics to build an EthA model in complex with ETH that has hallmark features of structurally characterized homologs. Second, we used free energy computational calculations for the reliable prediction of relative free energies between the wild type and mutant enzymes. The ΔΔG values for Y50C and T453I mutant enzymes in complex with FADH₂-NADP-ETH were 3.34 (+/−0.55) and 8.11 (+/−0.51) kcal/mol, respectively, compared to the wild type complex. The positive ΔΔG values indicate that the wild type complex is more stable than the mutants, with the T453I complex being the least stable. These are the first results shedding light on the molecular basis of ETH resistance, namely reduced complex stability of mutant EthA.

In this paper, we introduce a simple yet powerful and working version of the molecular dynamics code using the Python 3.9 language. The code contents are published in the link given in the appendix 1. The structure and components of the program is given in detail using flowcharts and code snippets. The program consists of major features like velocity verlet integrator, thermostats, COM removal, input and output modules, virial, pressure, and other thermodynamic quantities estimation etc. The author believes that this program will be helpful to graduate students who perform research in molecular dynamics simulations who intend to write their own code instead of the sophisticated open source packages.

The diffusion process of water molecules within a polyetherimide (PEI) glassy matrix has been analyzed by combining the experimental analysis of water sorption kinetics performed by FTIR spectroscopy with theoretical information gathered from Molecular Dynamics simulations and with the expression of water chemical potential provided by a non-equilibrium lattice fluid model able to describe the thermodynamics of glassy polymers. This approach allowed to construct a convincing description of the diffusion mechanism of water in PEI providing molecular details of the process related to the effects of the cross- and self-hydrogen bondings established in the system on the dynamics of water mass transport.

Silybum Marianum, is a plant belonging to the family Asteraceae. For many centuries it has been used a natural remedy for many diseases like Liver and Biliary tract diseases. It is effective as an anti-oxidant and is used in a variety of diseases. This study was conducted to check the effects of Silybum Marianum on PARP protein (4UND protein).The Molecular Docking techniques was chosen to check the effects of different chemical constituents of Silybum marianum on DNA damaging protein. For this purpose, different PARP inhibitor drugs were taken as standard. The Molecular Docking of the chemical constituents of Silybum marianum was performed using 4UND protein with the help of PyRx software along with BIOVIA Drug Discovery studio software. The result of molecular docking showed that some of the chemical constituent have higher binding affinity than standard PARP inhibitor drugs.

The global polyvinyldene flouride market is estimated to reach $937,278.5 thousand by 2019, therefore to develop new membranes and gain pioneering ideas, which could create innovative business opportunities, a fundamental knowledge about membrane properties fabricated from recent commercially available PVDF polymers is highly mandatory. In this study, we successfully prepared nine non-woven supported PVDF membranes using a phase inversion precipitation method starting from a 15 wt% PVDF solution in N-methyl-2-pyrrolidone. Various membrane morphologies were obtained by using (1) PVDF polymers with diverse molecular weight in a range from 300.000 Da to 700.000 Da and (2) different temperatures of the coagulation bath (20, 40, and 60 ±2°C) used for the films precipitation. Environmental Scanning Electron Microscope (ESEM) was used for surface and cross-section morphologies characterization. Atomic Force Microscope (AFM) was employed to investigate surface roughness, while Contact Angle (CA) instrument was used for membranes wettability studies. Fourier Transform Infrared Spectroscopy (FTIR) results show that the fabricated membranes are formed by a mixture of TGTG’ chains in α phase crystalline domains and all-TTTT trans planar zigzag chains characteristic to β phase. Moreover, generated results indicate that the phases content and membrane morphologies depend on the polymer molecular weight and conditions used for the membranes preparation. The diversity of fabricated membranes could be applied by the End User Industries for different applications.

Most existing cancer therapies negatively affect normal tissue as well as cancerous tissue. A potentially effective strategy for treating cancer that precludes off-target damage and could be an option for most patients would involve targeting one or more mutations that are ubiquitous in the given patient’s tumor(s). To effect this strategy, one would employ multi-region sequencing of a patient’s primary tumor and metastases to seek out mutations that are shared between all or at least most regions. Once the target or targets are known, one would ideally rapidly generate a molecular switch for at least one of said ubiquitous mutations that can distinguish the mutated DNA, RNA, or protein from the wild-type version and subsequently trigger a therapeutic response. I propose that the therapeutic response involve the replication of an oncolytic virus or intracellular bacterium, as any mutation can theoretically be detected by a vector that enters the cell - and automatic propagation could be very helpful. Moreover, the mutation “signal” can be easily enhanced through transcriptional and translational (if the target is an intracellular protein) enhancement. Importantly, RNA may make the best target for the molecular switches in terms of amplification of the signal and ease of targeting.

The COVID-19 pandemic has had a substantial impact on global health, notably the virus's association with autoimmune illnesses. Autoimmune illnesses occur when the immune system of the body targets healthy cells, causing damage and inflammation. The potential impact of COVID-19 on autoimmune disorders, the hazards of COVID-19 vaccinations for persons with autoimmune diseases, and the potential risks of COVID-19 vaccines are all discussed in this essay. COVID-19 can cause autoimmune illnesses by causing inflammation, organ and tissue damage, and molecular mimicry, in which the immune system mistakenly assaults healthy cells for the virus. However, not everyone infected with COVID-19 develops autoimmune disorders. While some research has found a link between COVID-19 and autoimmune illnesses, this does not always suggest causation. Other factors, such as genetics and environment, may also play a role in the emergence of autoimmune illnesses. COVID-19 can aggravate existing autoimmune disorders by causing the immune system to attack healthy cells, making management more difficult and increasing the risk of consequences. People with autoimmune disorders, on the other hand, may not be at a higher risk of severe COVID-19 than the general population. Some research has found that persons with autoimmune disorders are more likely to have severe COVID-19, whereas others have found no difference. COVID-19 vaccinations may represent dangers to persons with autoimmune illnesses since they contain antigens that can activate the immune system. Furthermore, due to their already overactive immune systems, some vaccines may not perform as well for people with autoimmune disorders, and some people with autoimmune diseases may have severe reactions to immunizations, producing inflammation and other symptoms. COVID-19 may not be any more hazardous to those with autoimmune illnesses than it is to the general population. The connection between COVID-19 and autoimmune disorders is complicated and under investigation. While some research implies that people with autoimmune disorders have a higher risk of severe COVID-19, others demonstrate no difference in death rates between them and the general population. There are also counterarguments that COVID-19 can induce and exacerbate autoimmune disorders, as well as worries about COVID-19 vaccine hazards for people who have autoimmune diseases. More research is required to completely understand the influence of COVID-19 on autoimmune illnesses, as well as the dangers and benefits of vaccinations for these people.

Antarctica is one of the most inhospitable continents on the planet, with lichens and mosses being the most common terrestrial organisms in ice-free areas. Antarctica is represented by only two species of Angiosperms, Deschampsia antarctica Desv. (Poaceae) and Colobanthus quitensis (Kunth) Bartl. (Caryophyllaceae). In this study, we characterized fungi isolated from the leaves of this grass species. The fungi were isolated from 4 individual plants from Half Moon Island (246 leave fragments investigated), and 7 from King George Island - Keller Peninsula (with 111 leave fragments investigated) Antarctica. Neoascochyta paspali, Phaeosphaeria elongata, Pyrenophora cf. chaetomioides and Alternaria sp. were associated with the plant and identified through analysis of the sequences of the internal transcribed spacer region (ITS) of the rDNA and nuclear ribosomal large subunit rRNA gene (LSU) as well as macro and micro-morphological characteristics. The isolates showed a better growth rate ranging from 10–20°C. An interesting result was that the fungi are already recognize as both plant pathogens and endophytic fungi. The results demonstrate that D. antarctica is an interesting fungal source. Those species might provide important information about the relationship on the endemic Antarctic biota.

The natural products and conventional chemotherapeutic drugs are believed to increase the cure rates of anti-cancer treatment while reducing their toxicity. The current study investigates the cytotoxic and apoptogenic effects of bioactive compounds from Monotheca buxifolia on Hep G2 cell lines. The effect on the viability of Hep G2 cells was evaluated by MTT assay; Morphological changes were studied, the apoptotic activity was demonstrated through Annexin-V-FITC/ PI, a molecular dynamics simulation study was conducted to explore the binding pattern of the compounds in the active site of the PPRAδ protein. The isolated compounds lauric acid, oleanolic acid, and bis(2-ethylhexyl) phthalate inhibited the growth of hepatocellular cancer cells, as determined by MTT assay and annexin V-FITC/PI. The IC50 value for lauric acid was 56.4584 ± 1.20 µg/ml, that for oleanolic acid was 31.9421 ± 1.03 µg/ml, and that for bis(2-ethylhexyl) phthalate was 83.8019 ± 2.18 µg/ml. After 24 h of treatment, 29.5% of Hep G2 cells treated with lauric acid, 52.1% of those treated with oleanolic acid, and 22.4% of those treated with bis(2-ethylhexyl) phthalate were apoptotic. Morphological assay and Hoechst staining microscopy revealed the morphological alterations of cell membrane accompanied by nuclear condensation after treatment. The high fluctuation indicates the high potency and adopting various interactions, and vice versa, the oleanolic acid showed highly residues fluctuation, which remains stable in the active site of PPARδ protein and involved in various interactions while remaining locally fluctuated in the binding site the other two compounds. In conclusion, a significant apoptogenic effect was exhibited by lauric acid, oleanolic acid, and bis(2-ethylhexyl) phthalate against HepG2 cells in inducing apoptosis. Our findings indicate that these bioactive compounds hold promise as potential therapeutic for hepatocellular carcinoma.

Atypical Polypoid Adenomyoma (APA) is a benign uterine lesion that occurs in women of reproductive age. The histological pattern is characterized by irregular epithelial proliferation and muscular stroma. Our work consists of a systematic review of the literature, including the description and analysis of a case study, and assesses the main immunohistochemical and molecular markers that contribute to making a differential diagnosis against endometrial adenocarcinoma. This allows offering patients conservative treatment compared to the radical management required for endometrial cancer, due to the significant physical and psychological consequences that one procedure or another can have on women's health. The goal of this research is to carry out an adequate diagnosis of APA by providing the necessary information to guide clinical management, establish patient prognosis, and minimize the emotional impact associated with the disease, all in combination with clinical and histopathological findings and complementary imaging tests. In conclusion, an appropriate immunohistochemical and molecular approach, along with the presumptive histological diagnosis, determine the correct classification of the lesion as APA and not as other malignant pathologies, which allows establishing a treatment protocol adjusted to the biological reality of this pathology.

Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that involve in regulation of cell proliferation, survival, and development. FGFR alterations including amplifications, fusions, rearrangements, and mutations can result downstream activation of tyrosine kinases leading to tumor development. Targeting those FGFR alterations has shown to be effective in cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid neoplasms and there are currently four FGFR inhibitors approved by the Food and Drug Administration (FDA). There have been developments of multiple agents targeting FGFR pathway including selective FGFR inhibitors, ligand traps, monoclonal antibodies, and antibody drug conjugates. However, most of these agents have variable and low responses with some intolerable toxicities and acquired resistances. This review will summarize previous clinical experiences and current developments of agents targeting FGFR pathway and discuss future directions of FGFR targeting agents.

In this paper we present methodology for precise calibration of Molecular Beam Epitaxy (MBE) growth process and achieving run to run stability of growth parameters. We present the analysis of the influence of fluxes stability during the growth of long wavelength quantum cascade laser structures designed for the range λ ~ 12–16 µm on wavelength accuracy with respect to desired emission wavelength. The active region of the lasers has a complex structure of nanometer thickness InxGa1-xAs/InyAl1-yAs superlattice. As a consequence, the compositional and thickness control of the structure via bulk growth parameters is rather difficult. To deal with this problem we employ methodology based on double-superlattice test structures, that precede the growth of the actual structures. The test structures are analyzed by high-resolution X-ray diffraction which allows to calibrate the growth of the complex active region of quantum cascade laser structures. We also study theoretically the effect of individual flux changes on emission wavelength and gain parameters of the laser. The results of simulations allow for determination of flux stability tolerance, preserving acceptable parameters of the laser and provide means of emission wavelength control. The proposed methodology was verified by the growth of laser structures for emission at around 13.5 μm.

A large amount of steel slag (SS) and CO2 are generated in the steelmaking process. The indirect CO2 capture using SS is a promising way for co-treatment of the wastes. Ammonium salt solution is widely used to extract Ca2+ from the SS since it is recyclable. Several works have focus on improving the carbonation rate by adjusting various parameters (e.g., temperature and pH). However, there is little detail information about the associating behaviors and interaction strength between the various ions in the ammonia solution during the carbonation process. In this work, the Ca2+–CO32-–NH4+–Cl-–H2O system was established by using Material studio software. The effects of temperature and concentration of CO32- on CaCO3 growth were explored at the atomic scale by calculating the binding energy, mean square displacement, and diffusion coefficient between particles. Furthermore, the microstructure, bonding characteristics, and occurrence behavior of each particle were studied though molecular dynamics simulation methods. The results showed that with the increase of temperature (20–80 ℃), the binding ability and diffusion coefficients of Ca2+ and CO32- increase in the system, which is beneficial to the formation of CaCO3 clusters. With the increase of the concentration of CO32- (15–25 vol.%), the binding ability and diffusion coefficient of Ca2+ and CO32- in the system are enhanced, which is beneficial to the formation of CaCO3 clusters.

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

Inhibitory activity of 14 phosphonic analogues of phenylglycine, substituted in aromatic ring by fluorine and chlorine, was determined towards porcine aminopeptidase N. The obtained data served as a basis for studying their interaction with the enzyme as modelled by the use of Schrödinger Release 2018 program. The observed linearity between modelled Gibbs free energy differences and inhibitory constants indicated the usefulness of this program. The obtained binding mode was compared with this modelled for bovine lens leucine aminopeptidase. Although both enzymes differ in the number of zinc ions present in the active site, they are considered to exhibit similar activity towards substrates and inhibitors. Our studies seem to support that supposition since the modes of binding of the studied inhibitors are quite similar. Additionally, inhibitory activity of the phosphonic analogues of phenylglycine towards barley aminopetpidase was determined showing that this enzyme could be considered as neutral aminopeptidase.

This study comprehensively investigates Al2O3's mechanical properties, focusing on fracture toughness, surface energy, Young's modulus, and crack propagation. The density functional theory (DFT) is employed to model the vacancies in Al2O3, providing essential insights into this material’s structural stability and defect formation. The DFT simulations reveal a deep understanding of vacancy-related properties and their impact on mechanical behavior. In conjunction with molecular dynamics (MD) simulations, the fracture toughness and crack propagation in Al2O3 are explored, offering valuable information on material strength and durability. The surface energy of Al2O3 is also assessed using DFT, shedding light on its interactions with the surrounding environment. The combination of DFT and MD simulations provides a robust framework for a comprehensive understanding of Al2O3's mechanical properties, with implications for material science and engineering applications.

We have synthesized quinoxaline analogs (1-25), characterized by 1HNMR and HREI-MS and evaluated for thymidine phosphorylase inhibition. Among the series, nineteen analogs showed better inhibition when compared with the standard inhibitor 7-Deazaxanthine (IC50 = 38.68 ± 4.42 µM). The most potent analog among the series is analog 25 with IC50 value 3.20 ± 0.10 µM. Sixteen analogs 1, 2, 3, 4, 5, 6, 7, 12, 13, 14, 15, 16, 17, 18, 21and 24 showed outstanding inhibition which is many folds better than the standard 7-Deazaxanthine. Two analogs 8 and 9 showed moderate inhibition. A structure- activity relationship has been established mainly based upon the substitution pattern on the phenyl ring. The binding interactions of the active compounds were confirmed through molecular docking studies.

Bufadienolides-like chemicals, which mostly composed the active ingredient of Chansu, had been widely discovered to possess anti-inflammatory, tumor-suppressing and antipain activity, but the mechanisms of action were not clearly illuminated. In this research, in order to explore the potential mechanism of bufadienolides-like chemicals on breast cancer, a serious of bioinformatics analysis, included (1) differentially expressed genes identification combined with gene set variation analysis, (2) tissue specific co-expression network construction, (3) differentially regulated sub-networks detection with disease phenome, (4) hub gene selection and it’s relation to survival probability, and (5) similar small molecule detection were performed with gene expression profiles of bufadienolides-like chemicals. Results indicated bufadienolides-like chemicals had the most same target with valproic, estradiol and etc, could disturbed the pathways in RNA splicing, apoptotic process, cell migration, extracellular matrix organization, adherens junction organization, synaptic transmission, Wnt signaling, AK-STAT signaling, BMP signaling pathway and unfolded protein response, and had the potential ability to be used as anticancer, hormones and vasoprotectives agents.

Molecularly imprinted polymers (MIPs) can often bind target molecules with high selectivity and specificity. When used as MIPs, conductive polymers may have unique binding capabilities; they often contain aromatic rings, which have a great tendency to undergo covalent and hydrogen bonding interactions with similarly structured target (or template) molecules. In this work, an electrochemical method was used to optimize the synthetic self-assembly of poly(aniline-co-metanilic acid) and testosterone, forming testosterone-imprinted polymers (TIPs) on sensing electrodes. The linear sensing range for testosterone ranged from 0.1 to 100 pg/mL, and the limit of detection was as low as ~pM. Random urine samples were collected and diluted 1000 fold to measure testosterone concentration using the above TIP sensors in comparison with a commercial ARCHITECT ci 8200 system. The testosterone concentrations in the tested samples were in the range of 0.33± 0.09 to 9.13±1.33 ng/mL. The mean accuracy of the TIP-coated sensors was 90.3 ±7.0 %.

Brucella abortus is a facultative intracellular Gram-negative bacterium that causes chronic persistent infections in humans and livestock. In this study, conventional bio-typing, multiple-locus variable-number tandem repeat analysis (MLVA), and whole-genome sequencing-single-nucleotide polymorphism (WGS-SNP) were used to investigate the molecular epidemiology characteristics of Brucella abortus strains in China and their relationships to world lineages. A total of 100 strains were collected from 1953 to 2013, suggesting that B. abortus circulated in China in the past five decades. Moreover, most strains were mainly distributed in the northwest area. During this period, seven biovars were found, indicating that B. abortus displayed a high diversity of biovars and that the main epidemic areas are in the northern provinces. Strains have high genetic diversity, and bruce07 is the most helpful locus for genotyping of this population. Moreover, 17 MLVA-11 genotypes were found; 13 of them are of known genotypes and four are unassigned genotypes, indicating that B. abortus in this study had several geographic origins. Still, strains from unassigned genotypes may originate from China. Many shared MLVA-16 genotypes were observed in strains from the same provinces in Northern China, which confirmed a brucellosis outbreak within northern regions. WGS-SNP analysis showed that eight Chinese strains formed a ladder-like phylogram (C. Ⅶ) with strains from nine countries, including Uganda, Iraq, Russia, Georgia, Spain, Italy, Egypt, Mongolia, and China; strains were introduced to these countries from a single source. Notably, Chinese strains were closely related to strains from Russia and Mongolia; frequent animal (cattle) trade and exchanges may promote this process. We will provide new and insightful information for strength surveillance and control of B. abortus brucellosis in China.

In this research, atomistic molecular dynamics simulations are combined with mesoscopic phase-field computational methods in order to investigate phase-transformation in polycrystalline Aluminum microstructure. In fact, microstructural computational modeling of engineering materials could help to optimize their mechanical properties for industrial applications (e.g. directional solidification for turbine blades). As a result, a multiscale modeling approach is developed to find a relation between manufacturing variables (e.g. temperature) and microstructural properties of crystalline materials (e.g. grain size), which could be used to develop an advanced manufacturing process for sensitive applications. The results show that atomistic modeling of grain growth could be used as a first-principle approach in order to study phase transformation's kinetics, which could capture morphology of polycrystalline materials more accurately. On the other hand, phase-field mesoscopic approach needs less computational efforts, but still it relies on semi-empirical data to capture accurate phase transformation regimes, which makes this approach suitable for rapid examining of new manufacturing conditions as well as its effects on microstructural properties of polycrystalline materials.

PPR is a highly contagious viral disease and one of the deadliest affecting wild goats, sheep and small ruminants, however goats are generally more sensitive. The causative agent is the Peste des Petits Ruminants virus (PPRv) which is a single-stranded RNA virus of negative polarity belonging to the Paramyxoviridae family. In February 2020, an active outbreak of PPR was re-ported in a herd of a transhumant farmer in the village of Ngainth Pathé (department of Kounguel, Kaffrine region,Senegal). Of the ten (10) swabs collected from goats, eight (8) came back positive by real-time PCR. The most positive sample was amplified, purified and amplicon sent for sequencing. Phylogenetic analysis showed that the sequence of the PPR virus obtained belonged to lineage IV. These results confirm those found in the latter countries and reinforce the hypothesis of the importance of animal mobility between these neighboring countries. In perspective, following the discovery of this lineage IV in Senegal, a study on its dispersion is underway throughout the national territory. The results that will emerge from this study, asso-ciated with detailed data on animal movements and epidemiological data, will provide appro-priate and effective information to improve PPR surveillance and control strategies with a view to its eradication.

Avipoxvirus (APV), a linear dsDNA virus belonging to the subfamily Chordopoxvirinae of the family Poxviridae, infects more than 278 species of domestic and wild birds. It is responsible for causing the avian pox disease, which is characterized by its cutaneous and diphtheric forms. With a high transmission capacity, it can cause high economic losses and damage to the ecosys-tem. Several diagnostic methods are available and vaccination of birds can be an effective pre-ventive measure. To update the molecular characterization and phylogenetic analysis of viruses isolated in Portugal between 2017 and 2023, ten APV-positive samples were analyzed. A P4b gene fragment was amplified by PCR and the nucleotide sequence of the amplicons was deter-mined by Sanger sequencing. The sequences obtained were aligned using ClustalW, and a max-imum likelihood phylogenetic tree was constructed. With this study, it was possible to verify that the analyzed sequences are distributed in subclades A1, A2, B1, and B3. Since some of them are quite similar to others from different countries and obtained in different years, it is possible to conclude that there have been several viral introductions in Portugal. Finally, it was possible to successfully update the data on avipoxviruses in Portugal.

Cysteine cathepsins, a class of proteinaceous enzymes, regulate a wide variety of metabolic processes in human including protein breakdown and turnover and immune functions. Eleven cysteine cathepsins have been identified so far and a wide array of studies related to identifying their specific functions, regulation and distribution patterns in tissues have been conducted. However, in recent past, the association of cysteine cathepsins in occurrence and progression of cancers have been identified and this has caused unrest in scientists triggering them to investigate the physiology, biochemical pathways and interactions of these cathepsins in cancer metastasis and therefore has become a noteworthy topic of intensive research. This review focusses and collects together the published work on molecular functional and structural characterization studies that have been done so far on in vitro expression of genes encoding for cysteine cathepsins in the Escherichia coli bacterial expression system. Accordingly, it was found out that all cathepsins except for cathepsins K, C, H, X and W have been expressed this way and the majority of them were found to be expressed in E. coli BL21(DE3) pLysS expression host via pET3 expression vector. In addition, it was also noted that in most of the expression studies, the substrate that was used to validate the enzymatic activity of the recombinant enzyme that was produced was a cysteine residue along with a benzyloxy-carbonyl salt. Through this review, the authors suggest that there is a very high need that all cysteine cathepsins need to be characterized both structurally and functionally on a molecular platform to better understand their interactions including the biochemical pathways. It is also momentous that the mass production of the recombinant forms of these enzymes are facilitated via expression in such bacterial expression systems and in turn, would also provide a strong platform for the development and progression of studies related to human physiology including oncological studies such as cancer metastasis. Moreover, as per biochemical features of the enzymes that could be identified, the production of efficient inhibitors or inducers as per the necessity to improve health and promote wellbeing among the mankind could be facilitated.

Aurora kinase A (AURKA) is a normal cell proliferation-inducing enzyme encoded by AURKA gene, with over-expression observed in different types of malignancies. Hence, the goal is to find potential inhibitors against AURKA. In this study, molecular docking, Standard Precision and Extra Precision methods were employed. After the docking study, the ligands showed an extremely low binding score which suggested very high binding affinity of the ligands. Furthermore, Quantum polarized ligand docking (QPLD) was performed to predict the binding status of the molecules. Based on the binding affinity, the top four compounds were chosen for further analysis. The docked complexes were further analyzed in explicit water conditions using 100 ns molecular dynamics simulations and binding free energy calculation. Then, density functional theory (DFT) calculation was used to calculate the molecular properties of the molecules. Finally, systems biology experiments validated the molecular docking and molecular dynamics simulation studies and indicated that quercetin, kaempferol, luteolin and rutin could inhibit the AURKA. The results show that, these four molecules have high binding affinity to the AURKA and significant interactions (LEU139, GLU211and ALA213) were also identified with the hinge region of Aurora kinase A. Thus, LEU139, GLU211, and ALA213 were identified as the crucial protein mechanisms.

The protein extract of Ulva australis hydrolyzed with alcalase and flavourzyme investigated multi-functional properties, including total antioxidant capacity (TAC), collagenase inhibitory and antibacterial activities. The #5 fraction (SP5) and #7 fraction (SP7) of U. australis hydrolysate from cation-exchange chromatography showed significantly high TAC, collagenase inhibitory and antibacterial effects against Propionibacterium acnes, and only Q3 fraction from anion-exchange chromatography showed high multi-functional activities. The eight peptides among 42 peptides identified by MALDI-TOF/MS and Q-TOF/MS/MS were selected from the results to screen molecular docking on target proteins, and were synthesized. Thr-Gly-Thr-Trp (TGTW) showed ABTS [2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)] radical scavenging activity. Effect TAC as Trolox equivalence was dependent on the concentration of TGTW. The Asn-Arg-Asp-Tyr (NRDY) and Arg-Asp-Arg-Phe (RDRF) possessing collagenase inhibitory activity increased according to the increase of concentration and the IC50 values of them were 0.95 mM and 0.84 mM, respectively. Peptides, RDRF and His-Ala-Val-Tyr (HAVY) showed anti-P. acnes effects with IC50 values of 8.57 mM and 13.23 mM, respectively. These results suggest that the U. australis hydrolysate could be a resource for the application of effective nutraceuticals and cosmetics.

Whole-genome sequencing has advanced our understanding of the population structure of the pathogenic species complex Cryptococcus gattii, which has allowed for the phylogenomic specification of previously described major molecular type groupings and novel lineages. Recently, isolates collected in Mexico in the 1960s were determined to be genetically distant from other known molecular types and were classified as VGVI. We sequenced four clinical isolates and one veterinary isolate collected in the southwestern U.S. and Argentina during 2012-2021. Phylogenomic analysis groups these genomes with those of the Mexican VGVI isolates, expanding VGVI into a clade and establishing this molecular type as a clinically important population. These findings also potentially expand the known Cryptococcus ecological range with a previously unrecognized endemic area.

Metamorphosis is a critical process for most anurans to transition from water to land. The appearance of air-breathing lungs occurs during the change in oxygen medium from water to air. Revealing the structural construction and molecular switches of lung organogenesis is essential to understand the realization of air-breathing function. In this study, histology and transcriptomics were combinedly conducted to explore these issues in Microhyla fissipes lungs during metamorphosis. During the pro-metamorphic phase, histological structure improving of the alveolar wall was accompanied by robust substrate metabolism and protein turnover. The lungs, at the metamorphic climax phase, are characterized by an increased number of cilia in the alveolar epithelial cells and collagenous fibers in the connective tissues, corresponding to the transcriptional upregulation of cilia and extracellular matrix-related genes. The post-metamorphic lungs strengthen the contracting function, as suggested by the thickened muscle layer and the upregulated expression of genes involved in muscle contraction. The blood–gas barrier is fully developed in adult lungs whose transcriptional features are tissue growth and differentiation regulation and immunity. Importantly, significant transcriptional switches of pulmonary surfactant protein and hemoglobin facilitate air-breathing. Our results illuminated four key steps of lung development for amphibians to transition from water to land.

A cryptic invader of the genus Persicaria is recently increasing in the damper, northern parts of La Palma and Gran Canaria in the Canary Islands (Spain) and locally behaves as an invasive species. Examination of historical herbarium specimens showed this species to be present in Gran Canaria since the 1960’s and the same probably applies to La Palma. Up to now, this species had been assigned to the Old World weed P. maculosa. However, morphologically these plants clearly correspond with P. hydropiperoides, a common and widespread weed native to the New World, and morphologically similar indeed to P. maculosa. Diagnostic features for these two species, as well as for another similar species (P. decipiens, originally described from the Canary Islands), are compared, thoroughly discussed and copiously illustrated. The current distribution, ecology and naturalization status of P. hydropiperoides in the Canary Islands are also assessed. The variability of P. hydropiperoides is discussed, more precisely the taxonomic position of a southern ‘race’ of it that is sometimes referred to as a distinct species, P. persicarioides. In addition to our morphology-based study, a molecular phylogenetic analysis has been conducted on the nuclear ITS region and the plastid DNA region trnL-F.

The conformational state of the activation loop (A-loop) is pivotal for the activation of most protein kinases. Hence, the characterization of the conformational dynamics of the A-loop is important to increase our understanding of the molecular processes related to diseases and to support the discovery of small molecule kinase inhibitors. Here, we carry out a combination of Molecular Dynamics (MD) and Essential Dynamics (ED) analyses to fully map the effects of phosphorylation, ADP, and conformation disrupting (CD) inhibitors (i.e., CD532 and MLN8054) on the dynamics of the A-loop of Aurora-A. MD revealed that the stability of the A-loop in an open conformation is enhanced by single phospho-Thr-288, while paradoxically, the presence of second phosphorylation at Thr-287 decreases such stability and renders the A-loop more fluctuant in time and space. Moreover, we found that such post-translational modification has a significant effect on the direction of A-loop motions. ED analysis suggests that the presence of the phosphate moiety induces the dynamics of Aurora-A to sample two distinct energy minima, instead of a single large minimum, as in unphosphorylated Aurora-A states. This suggests that the conformational distributions of Aurora-A with both single and double phospho-threonine modifications are remarkably different from the unphosphorylated state. In the closed states, binding of CD532 and MLN8054 inhibitors has the effect of increasing the distance of the N- and C-lobes of the kinase domain of Aurora-A, and the angle analysis between those two lobes during MD simulations showed that the N- and C-lobes are kept more open in presence of CD532, compared to MLN8054. As the A-loop is a common feature of Aurora protein kinases, our studies provide a general description of the conformational dynamics of this structure upon phosphorylation and different ligands binding.

Acid lime [Citrus aurantifolia (Christm.) Swingle] is a fruit crop, enriched with high commercial value and is cultivated in 60 out of 75 districts representing all geographical landscapes of Nepal. Lack of high yielding cultivars is probably one of the main reason for its extremely reduced productivity which warrants a deep understanding of genetic diversity in existing germplasm. Hereby, we aim to access the genetic diversity of acid lime germplasm cultivated at 3-different ecological gradients of eastern Nepal employing PCR-based Inter-Simple Sequence Repeats markers (ISSR). Altogether, 21 polymorphic ISSR markers were used to assess the genetic diversity in 60 acid lime cultivars sampled from different geographical locations. Analysis of binary data matrix was performed on the basis of bands obtained, scoring of the data was done accordingly, and principal coordinate analysis and phenogram were constructed using different computer algorithms. ISSR profiling yielded 234 amplicons, of which 87.18% were found to be polymorphic. The number of amplified fragments ranged from 7-18 with amplicon size ranging from 250-3200 bp. The NTSYS based Cluster analysis using UPGMA algorithm taking Dice Similarity coefficient separated 60 accessions into 2-major and 3-minor clusters. The genetic diversity analysis revealed the highest for Terai and the lowest for High-hill zone. Cluster I comprised of accessions from High-hill and Mid-hill regions revealing the close genetic relationship, whereas cluster II comprised of accessions from all three agro-ecological zones and the exotic varieties. Furthermore, our results revealed the accessions harvested from different geographical gradients were not genetically distinct, but highest diversity was observed in Terai accessions in comparison to the regions belonging to the High and Mid-hills. Thus, our data indicate that the ISSR provides a better option for evaluating the genetic diversity of Nepalese Acid Lime cultivars and furnished significant information, assisting parental selection in current and future breeding programs and germplasm conservation which ultimately may help to provide a technological breakthrough for the farmers of the developing country like Nepal.

On the primitive Earth, both L- and D-amino acids would have been present. However, only L-amino acids are essential blocks to construct proteins in modern life. To study the relative stability of D-amino acid substituted peptides, a variety of computational methods were applied. Ten prebiotic amino acids (Gly, Ala, Asp, Glu, Ile, Leu, Pro, Ser, Thr, and Val) were previously determined by multiple meteorite, spark discharge, and hydrothermal vent studies. Some previously reported early Earth polypeptide analogs were focused on in this study. Tripeptides composed of only Asp, Ser, and Val exemplified that different positions (i.e., N-terminus, C-terminus, and middle) made a difference in the minimal folding energy of peptides, while the chemical classification of amino acid (hydrophobic, acidic, or hydroxylic) did not show a significant difference. Hierarchical cluster analysis for dipeptides with all possible combinations of the proposed ten prebiotic amino acids and their D-amino acid substituted derivatives generated five clusters. Primordial simple polypeptides were modeled to test the significance of molecular fluctuations, secondary structure occupancies, and folding energy differences based on these clusters. We found peptides with α-helices, long β-sheets, and long loops are usually less sensitive to D-amino acid replacements in comparison to short β-sheets. Intriguingly, amongst 129 D-amino acid residues, mutation sensitivity profiles presented that the ratio of more to less stable residues was about 1. In conclusion, some combinations of a mixture of L- and D-amino acids can potentially act as essential building blocks of life.