Conformational changes induced by K949A mutation in the CRISPR-Cas12a complex drives an effective target-binding mechanism.

The CRISPR/Cas system is a potential tool for genome editing, yet it faces challenges due to off-target activity caused by mismatches at specific positions. However, Off-target activity can be minimized by optimal design of guide RNA (gRNA) but there remains a possibility of unintended cleavage, highlighting the role of the Cas nuclease in off-target recognition and binding the target site. This study focuses on comparing the conformational dynamics and stability of Wildtype, RR, RVR, RRm and RVRm variants of AsCas12a with gRNA-DNA bound complexes.

Histone Deacetylase Inhibitors orchestrate epigenetic signalling and alter the nucleoporins and nuclear envelope in cervical cancer.

Histone Deacetylases inhibitors (HDACi) modulate the acetylation profile of lysines on the histone tails to facilitate DNA accessibility to transcription factors. While the phenotypes caused by HDAC inhibition on cancer cells have been studied extensively, the nuclear geometry and expression signatures modulated by these enzymes have not been well understood.This work attempts to understand the functional implication of HDAC inhibitor treatment (NaB and MS275) on cervical cancer cells.

Exploration of structural space of Cus17 lectin with glycans using molecular docking and simulation studies.

The Cus17 phloem protein, in the case of species, plays an important role in the phloem-based defense of the plant. Cus17 can bind to various carbohydrates present on insect exoskeletons or fungal cells. The recent experimental structure of chitotriose bound Cus17 elucidates the carbohydrate interacting residues of Cus17.

A Strain-Specific Clumping Mechanism Enables ST88 to Circumvent the Host Neutrophil Response.

Community-associated methicillin-resistant strains often demonstrate enhanced virulence, with different strains eliciting varied immune responses in humans. The factors that enable some strains to evade killing by immune cells remain unclear. Here, we describe studies designed to understand intracellular survival assays that revealed that while a well-characterized MRSA ST8 strain (USA300) was susceptible to phagocytic clearance, a genotypically similar MRSA ST88 strain (LVP-7) effectively evaded neutrophil killing.

Adaptive laboratory-evolved MRSA with PPEF manifests cross-susceptibility to oxacillin and hypersensitivity to ciprofloxacin.

Emerging resistance to current antibiotics is a global threat to human health. Therefore, comprehending the mechanism behind antibiotic resistance holds paramount importance. In the pursuit of finding new antibacterial agents, our group has developed a small molecule, PPEF (2'-(4-ethoxyphenyl)-5-(4-propylpiperazin-1-yl)-1H,1'H-2,5'-bibenzo(d)imidazole), having bisbenzimidazole as a pharmacophore, targeting bacterial type IA topoisomerase, a novel drug target in bacteria.

Tracing the function expansion for a primordial protein fold in the era of fold-based function prediction: β-trefoil.

The incredibly narrow protein fold bottleneck, which separates the billions of unique proteins on one side to deliver diverse biological functions on the other, arises from folds that tolerate mutations during evolution. One such fold, called the β-trefoil, is present in functionally diverse proteins including cytokines involved in the immune system such as interleukin-1. The unrecognizable sequence-level diversity, even among paralogs of interleukin-1 within the same chromosomal locus, suggests the resilience of this fold to mutational onslaught.

Computational analysis of promoter features associated with contrasting expression patterns of human genes under normal and disease conditions.

The promoter region plays a critical role in regulating gene expression, particularly in complex vertebrate genomes. However, promoters associated with contrasting gene expression patterns have not been comprehensively characterized. In this study, we systematically analyzed multiple features of human promoter sets corresponding to contrastingly expressed gene sets or transcripts (PCeGs).

Recent Developments in the Application of Artificial Intelligence and Machine Learning in Early Screening and Diagnosis of Autism.

Autism Spectrum Disorder (ASD or Autism) is a neurodevelopmental disorder that is characterized by challenges in social communication skills and the presence of restricted and repetitive behaviors during early childhood. ASD poses a significant public health challenge with increasing prevalence rates worldwide. Early diagnosis and intervention are critical for improving outcomes in children with ASD.

Bipartite Graph Analysis of the Virus-Host Protein Interaction Network to Identify Key Proteins Mediating the Infection.

Viruses depend on the host cells for replication and manipulate host cellular processes to assemble their components. Therefore, studying viral infections at the cellular level involves exploring interactions between viral and host proteins. These interactions can be structured as a bipartite network, where one set of nodes represents host proteins, another set represents viral proteins, and the edges symbolize the interactions between these two sets of nodes.

HSP90 and the cancer transcriptome: a comprehensive review of inhibitors and mechanistic insights.

This review summarizes the structure, function, expression, and inhibitors of HSP90, the chaperone, in cancers. It systematically investigates the effects of HSP90 inhibitors, including AUY922, B11B021, CCT-018159, D7-gedunin, geldanamycin, and gedunin, across a range of cancer cell lines (HCC151, HT29, MCF7, PC3, VCAP, and A375) and a normal HA1E cell line, using data from the CLUE database. Our analysis reveals that treatment with these HSP90 inhibitors induces significant stress responses in tumor cells, initiating intrinsic and extrinsic apoptotic pathways.

Identifying trials run in India, registered with ClinicalTrials.gov, is not straightforward.

Clinical trial registries are invaluable resources for many stakeholders. However, these registries often require customized methodologies to identify studies of interest. To determine what steps it would take to catalog every trial that has run in India, in this study, we examined the records held by the registry of the United States, ClinicalTrials.

Biological and genomic characterization of a cypovirus isolated from golden muga silkworm, Antheraea assamensis Helfer (Lepidoptera: Saturniidae).

A potential viral pathogen, cypovirus causing cytoplasmic polyhedrosis in the Indian golden muga silkworm, Antheraea assamensis Helfer, was isolated and characterized. Electron microscopy analysis confirmed the presence of typical occlusion bodies with icosahedral virions embedded in polyhedral matrices. The viral genome was dsRNA totaling approximately 24.

Investigation of Anti-Cancer Properties of Novel Curcuminoids in Leukemic Cells and Dalton Lymphoma Ascites Model.

Leukemia, one of the major causes of cancer death, ranks 11th worldwide among cancer-related deaths. The current treatment of leukemia faces challenges recently due to a high burden of side effects. It is well established that curcumin has anticancer and tumor-suppressing activities in several cancers in addition to leukemia.

Construction and characterization of cloning vector and temperature sensitive vectors for Gordonia sp. IITR100.

Gordonia spp. are Gram-positive, non-sporulating bacteria which have several industrial as well as environmental applications. In order to enhance their potential, metabolic engineering is required which often involves genome manipulation.

Clinical trial registration in India: 12% of drug regulatory trials are not registered, as required by law.

Background: Amongst other things, the drug regulator, Central Drugs Standard Control Organization (CDSCO), is responsible for regulating clinical trials that underlie drug approvals in India. Since 2009, CDSCO has mandated that all regulatory clinical trials be registered with the Clinical Trials Registry - India (CTRI). In this study, we aimed to determine whether regulatory trials, for which CDSCO had given permission, were registered with CTRI as required.

Toll-like receptor 4 pathway evolutionary trajectory and functional emergence.

Introduction: Toll-like receptors 4 (TLR4) recognize lipopolysaccharides (LPS) from bacteria as their conventional ligands and undergo downstream signaling to produce cytokines. They mediate the signaling either by the TIRAP-MyD88 complex or by the TRAM-TRIF complex. The MyD88 pathway is common to all other TLRs, whereas the TRAM-TRIF complex is largely exclusive to TLR4.

Development and experimental validation of a machine learning model for the prediction of new antimalarials.

A large set of antimalarial molecules (N ~ 15k) was employed from ChEMBL to build a robust random forest (RF) model for the prediction of antiplasmodial activity. Rather than depending on high throughput screening (HTS) data, molecules tested at multiple doses against blood stages of Plasmodium falciparum were used for model development. The open-access and code-free KNIME platform was used to develop a workflow to train the model on 80% of data (N ~ 12k).

Renal and Peripheral Blood Transcriptome Signatures That Predict Treatment Response in Proliferative Lupus Nephritis-A Prospective Study.

Mechanisms contributing to non-response to treatment in lupus nephritis (LN) are unclear. We characterised the transcriptome of paired peripheral blood mononuclear cells (PBMCs) and renal tissues in LN before and after cyclophosphamide (CYC) treatment and identified markers that predicted treatment response. Total RNA isolated from paired PBMCs (n = 32) and renal tissues (n = 25) of 16 proliferative LN before CYC treatment, 6 months post-treatment, and during renal flare, was sequenced on Illumina Novaseq-6000 platform.

Global transcriptome profiling of ST09 treated breast cancer cells identifies miR-197-5p/GPX3 antioxidant axis as a regulator of tumorigenesis.

ROS (Reactive Oxygen Species) has a dual role in tumorigenesis. Some cancers have high ROS conditions, and others have low ROS. TNBC thrives on high ROS compared to other Breast Cancer subtypes.

Ectopic overexpression of DNA-/RNA-binding Alba proteins misregulates virulence gene homeostasis during asexual blood development.

Alba domain-containing proteins are ubiquitously found in archaea and eukaryotes. By binding to either DNA, RNA, or DNA:RNA hybrids, these proteins function in genome stabilization, chromatin organization, gene regulation, and/or translational modulation. In the malaria parasite , six Alba domain proteins PfAlba1-6 have been described, of which PfAlba1 has emerged as a "master regulator" of translation during parasite intra-erythrocytic development (IED).

Establishing a General Atomistic Model for the Stratum Corneum Lipid Matrix Based on Experimental Data for Skin Permeation Studies.

Understanding the permeation of drugs through the intercellular lipid matrix of the stratum corneum layer of skin is crucial for effective transdermal delivery. Molecular dynamics simulations can provide molecular insights into the permeation process. In this study, we developed a new atomistic model representing the multilamellar arrangement of lipids in the stratum corneum intercellular space for permeation studies.

Loss of correlated proteasomal subunit expression selectively promotes the 20S state which underlies luminal breast tumorigenicity.

Why cancer cells disproportionately accumulate polyubiquitinated proteotoxic proteins despite high proteasomal activity is an outstanding question. While mis-regulated ubiquitination is a contributing factor, here we show that a structurally-perturbed and sub-optimally functioning proteasome is at the core of altered proteostasis in tumors. By integrating the gene coexpression signatures of proteasomal subunits in breast cancer (BrCa) patient tissues with the atomistic details of 26S holocomplex, we find that the transcriptional deregulation induced-stoichiometric imbalances perpetuate with disease severity.

Design, Synthesis and in vitro Evaluation of Primaquine and Diaminoquinazoline Hybrid Molecules Against the Malaria Parasite.

In this study, we built on the known inhibitory potential of diaminoquinazolines (DAQs) against different stages of Plasmodium development and designed a convenient two-step synthesis to combine DAQ with primaquine (PQ) pharmacophore. The PQ-DAQ hybrids displayed potent in vitro activities in the low nanomolar range (IC 135.20-398.

Structural Basis for the Essential Role of Ca in the Lytic Activity of Staphylococcus aureus PlyGRCS Endolysin Targeting Methicillin-Resistant Staphylococcus aureus.

Staphylococcus aureus causes a wide range of infections, from mild skin conditions to severe, life-threatening diseases. Bacteriophage endolysins exhibit a selective capacity to degrade the peptidoglycan layer of Gram-positive bacteria, making promising biotherapeutic agents against antibiotic-resistant infections. PlyGRCS, a specific endolysin derived from S.

Evolution of sequence, structural and functional diversity of the ubiquitous DNA/RNA-binding Alba domain.

The DNA/RNA-binding Alba domain is prevalent across all kingdoms of life. First discovered in archaea, this protein domain has evolved from RNA- to DNA-binding, with a concomitant expansion in the range of cellular processes that it regulates. Despite its widespread presence, the full extent of its sequence, structural, and functional diversity remains unexplored.