The interaction of methotrexate with the human C5a and its potential therapeutic implications.

Methotrexate (MTX) is an antimetabolite drug that mimics folate and inhibits dihydrofolic acid reductase, resulting in the impairment of malignant growth in actively proliferating tissues. MTX is approved by the FDA for primarily treating non-Hodgkin lymphoma, lymphoblastic leukemia, and osteosarcoma. In addition, MTX is also prescribed as a preferred anti-rheumatic medication for the management of rheumatoid arthritis, including psoriasis, indicating that MTX has a multipronged mechanism of action.

Evaluation of effect of various drinks on tooth surface morphology under scanning electron microscope.

Aim And Objectives: The study aimed to evaluate and compare the effect of various beverages carbonated drinks, i.e., thumps up, fresh fruit juice (apple and pomegranate) and packaged fruit juice (apple and pomegranate) on tooth surface morphology under scanning electron microscope.

Structure of Designer Antibody-like Peptides Binding to the Human C5a with Potential to Modulate the C5a Receptor Signaling.

C5a is an integral glycoprotein of the complement system that plays an important role in inflammation and immunity. The physiological concentration of C5a is observed to be elevated under various immunoinflammatory pathophysiological conditions in humans. The pathophysiology of C5a is linked to the "two-site" protein-protein interactions (PPIs) with two genomically related receptors, such as C5aR1 and C5aR2.

A Rationally Designed Synthetic Antiviral Peptide Binder Targeting the Receptor-Binding Domain of SARS-CoV-2.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus, is the causative agent responsible for the spread of the COVID19 pandemic across the globe. The global impact of the COVID19 pandemic, the successful approval of vaccines for controlling the pandemic, and the further resurgence of COVID19 necessitate the exploration and validation of alternative therapeutic avenues targeting SARS-CoV-2. The initial entry and further invasion by SARS-CoV-2 require strong protein-protein interactions (PPIs) between the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptors expressed on the cell surfaces of various tissues.

Conformational variants of the ternary complex of C5a, C5aR1, and G-protein.

The complement component fragment 5a (C5a) binds and activates two complement receptors like C5aR1 and C5aR2, which play a significant role in orchestrating the proinflammatory function of C5a in tissues through the recruitment of heterotrimeric G-proteins and β-arrestins. Dysregulation of the complement induces excessive production of C5a, which triggers aberrant activation of the C5a-C5aR1-G-protein and C5a-C5aR2-β-arrestin signalling axes in tissues, contributing to the pathology of numerous immune-inflammatory diseases. Thus, understanding the interaction of C5a with C5aR1 and C5aR2, as well as the interaction of G-protein and β-arrestins, respectively, with C5a-C5aR1 and C5a-C5aR2, holds tremendous therapeutic value.

A rationally engineered small antimicrobial peptide with potent antibacterial activity.

Antimicrobial resistance (AMR) is a silent pandemic declared by the WHO that requires urgent attention in the post-COVID world. AMR is a critical public health concern worldwide, potentially affecting people at different stages of life, including the veterinary and agriculture industries. Notably, very few new-age antimicrobial agents are in the current developmental pipeline.

Ternary model structural complex of C5a, C5aR2, and β-arrestin1.

Complement component fragment 5a (C5a) is one of the potent proinflammatory modulators of the complement system. C5a recruits two genomically related G protein-coupled receptors (GPCRs), like C5aR1 and C5aR2, constituting a binary complex. The C5a-C5aR1/C5aR2 binary complexes involve other transducer proteins like heterotrimeric G-proteins and β-arrestins to generate the fully active ternary complexes that trigger intracellular signaling through downstream effector molecules in tissues.

Neutraligands of C5a can potentially occlude the interaction of C5a with the complement receptors C5aR1 and C5aR2.

The complement system is central to the rapid immune response witnessed in vertebrates and invertebrates, which plays a crucial role in physiology and pathophysiology. Complement activation fuels the proteolytic cascade, which produces several complement fragments that interacts with a distinct set of complement receptors. Among all the complement fragments, C5a is one of the most potent anaphylatoxins, which exerts solid pro-inflammatory responses in a myriad of tissues by binding to the complement receptors such as C5aR1 (CD88, C5aR) and C5aR2 (GPR77, C5L2), which are part of the rhodopsin subfamily of G-protein coupled receptors.

Mitochondrial metabolic determinants of multiple myeloma growth, survival, and therapy efficacy.

Multiple myeloma (MM) is a plasma cell dyscrasia characterized by the clonal proliferation of antibody producing plasma cells. Despite the use of next generation proteasome inhibitors (PI), immunomodulatory agents (IMiDs) and immunotherapy, the development of therapy refractory disease is common, with approximately 20% of MM patients succumbing to aggressive treatment-refractory disease within 2 years of diagnosis. A large emphasis is placed on understanding inter/intra-tumoral genetic, epigenetic and transcriptomic changes contributing to relapsed/refractory disease, however, the contribution of cellular metabolism and intrinsic/extrinsic metabolites to therapy sensitivity and resistance mechanisms is less well understood.

Therapeutic implications of mitochondrial stress-induced proteasome inhibitor resistance in multiple myeloma.

The connections between metabolic state and therapy resistance in multiple myeloma (MM) are poorly understood. We previously reported that electron transport chain (ETC) suppression promotes sensitivity to the BCL-2 antagonist venetoclax. Here, we show that ETC suppression promotes resistance to proteasome inhibitors (PIs).

C5aR2 receptor: The genomic twin of the flamboyant C5aR1.

The complement fragment C5a is one of the most potent proinflammatory glycoproteins liberated by the activation of the biochemical cascade of the complement system. C5a is established to interact with a set of genomically related transmembrane receptors, like C5aR1 (CD88, C5aR) and C5aR2 (GPR77, C5L2) with comparable affinity. The C5aR1 is a classical G-protein-coupled receptor (GPCR), whereas C5aR2 is a nonclassical GPCR that tailors immune cell activity potentially through β-arrestins rather than G-proteins.

Modified Inguinal Lymph Node Dissection in Groin-Negative Patients of Penile Cancer: Our Experience.

Cancer of the penis is an important health problem in India, causing significant morbidity. Involvement of locoregional lymph nodes is the most significant prognostic factor for patients with penile cancer. In this study, we reviewed clinical data of all patients who underwent modified inguinal lymph node dissection as a means to diagnose micro-metastasis in inguinal lymph nodes, and analysed the outcomes.

Therapeutic ureteroscopy for urolithiasis in children younger than 60 months of age.

Purpose: The management of urinary tract calculi has evolved dramatically in children with the development of smaller and more durable endoscopic equipment. The indications for therapeutic ureteroscopy in children have significantly expanded with the availability of smaller caliber endoscopes and Holmium:YAG laser. In this paper, we review our experience of the management of urolithiasis and report outcomes of therapeutic ureterorenoscopy (URS) in children younger than 60 months.

Perception, knowledge, and practice of endodontists and general dental practitioners toward evidence-based practice and factors associated with it-A cross-sectional study.

Background: Evidence-based practice is the cornerstone of dentistry and especially endodontics. Diagnosis, treatment planning, and treatment with recent advancement based on evidence would be a great help for the patent satisfaction and treatment prognosis; hence, the aim of present study was to explore difference between perception, knowledge, and practice of endodontists and general dental practitioners (GDPs) towards evidence-based practice and factors associated with it.

Materials And Methods: The present study is a cross-sectional descriptive questionnaire study conducted among specialists in the subject of conservative and endodontic dentistry and GDPs working in private clinics in Modinagar city, Uttar Pradesh.

Knowledge, attitude, and practice of general dental practitioners toward following proper standards of endodontic practice and use of latest technology in Dehradun: A cross-sectional study.

Background: Choosing latest technology for the treatment improves the chances of favorable prognosis and saves the time of the clinician; hence, the aim of the study was to explore their knowledge, attitude, and practice (KAP) toward following proper standards of endodontic practice and use of latest technology.

Materials And Methods: The present study was a cross-sectional, descriptive questionnaire study conducted among general dental practitioners (GDPs). The survey was conducted among 156 GDPs.

Functional defects in TcdB toxin uptake identify CSPG4 receptor-binding determinants.

is a major nosocomial pathogen that produces two exotoxins, TcdA and TcdB, with TcdB thought to be the primary determinant in human disease. TcdA and TcdB are large, multidomain proteins, each harboring a cytotoxic glucosyltransferase domain that is delivered into the cytosol from endosomes via a translocation domain after receptor-mediated endocytosis of toxins from the cell surface. Although there are currently no known host cell receptors for TcdA, three cell-surface receptors for TcdB have been identified: CSPG4, NECTIN3, and FZD1/2/7.

Epitopes and Mechanism of Action of the Clostridium difficile Toxin A-Neutralizing Antibody Actoxumab.

The exotoxins toxin A (TcdA) and toxin B (TcdB) are produced by the bacterial pathogen Clostridium difficile and are responsible for the pathology associated with C. difficile infection (CDI). The antitoxin antibodies actoxumab and bezlotoxumab bind to and neutralize TcdA and TcdB, respectively.

Nascent peptide assists the ribosome in recognizing chemically distinct small molecules.

Regulation of gene expression in response to the changing environment is critical for cell survival. For instance, binding of macrolide antibiotics to the ribosome promotes translation arrest at the leader open reading frames ermCL and ermBL, which is necessary for inducing the antibiotic resistance genes ermC and ermB. Cladinose-containing macrolides such as erythromycin (ERY), but not ketolides such as telithromycin (TEL), arrest translation of ermCL, whereas either ERY or TEL stall ermBL translation.

Small molecule inhibitors of Clostridium difficile toxin B-induced cellular damage.

Clostridium difficile causes life-threatening diarrhea through the actions of its homologous toxins TcdA and TcdB on human colonocytes. Therapeutic agents that block toxin-induced damage are urgently needed to prevent the harmful consequences of toxin action that are not addressed with current antibiotic-based treatments. Here, we developed an imaging-based phenotypic screen to identify small molecules that protected human cells from TcdB-induced cell rounding.

Negamycin interferes with decoding and translocation by simultaneous interaction with rRNA and tRNA.

Negamycin (NEG) is a ribosome-targeting antibiotic that exhibits clinically promising activity. Its binding site and mode of action have remained unknown. We solved the structure of the Thermus thermophilus ribosome bound to mRNA and three tRNAs, in complex with NEG.

Molecular basis for erythromycin-dependent ribosome stalling during translation of the ErmBL leader peptide.

In bacteria, ribosome stalling during translation of ErmBL leader peptide occurs in the presence of the antibiotic erythromycin and leads to induction of expression of the downstream macrolide resistance methyltransferase ErmB. The lack of structures of drug-dependent stalled ribosome complexes (SRCs) has limited our mechanistic understanding of this regulatory process. Here we present a cryo-electron microscopy structure of the erythromycin-dependent ErmBL-SRC.