Preclinical characterization of the Omicron XBB.1.5-adapted BNT162b2 COVID-19 vaccine.

As SARS-CoV-2 evolves, increasing in potential for greater transmissibility and immune escape, updated vaccines are needed to boost adaptive immunity to protect against COVID-19 caused by circulating strains. Here, we report features of the monovalent Omicron XBB.1.

Discovery of First Branched-Chain Ketoacid Dehydrogenase Kinase (BDK) Inhibitor Clinical Candidate PF-07328948.

Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator of branched-chain amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From a starting point with potential idiosyncratic toxicity risk, modification to a benzothiophene core and discovery of a cryptic pocket allowed for improved potency with 3-aryl substitution to arrive at PF-07328948, which was largely devoid of protein covalent binding liability. This BDK inhibitor was shown also to be a BDK degrader in cells and in vivo rodent studies.

Structural basis for CCR6 modulation by allosteric antagonists.

The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation. Here, we present two inactive CCR6 structures in ternary complexes with different allosteric antagonists, CCR6/SQA1/OXM1 and CCR6/SQA1/OXM2.

Small molecule branched-chain ketoacid dehydrogenase kinase (BDK) inhibitors with opposing effects on BDK protein levels.

Branched chain amino acid (BCAA) catabolic impairments have been implicated in several diseases. Branched chain ketoacid dehydrogenase (BCKDH) controls the rate limiting step in BCAA degradation, the activity of which is inhibited by BCKDH kinase (BDK)-mediated phosphorylation. Screening efforts to discover BDK inhibitors led to identification of thiophene PF-07208254, which improved cardiometabolic endpoints in mice.

Indian Perspective of Burnout Among Plastic Surgeons.

 Over the last decade, the term has become familiar term in all walks of life, particularly medicine. Emotional exhaustion, depersonalization, and a low sense of personal accomplishment make up the triad. At least a third of plastic surgeons are having burnout according to the western literature.

Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4.

A series of small-molecule YEATS4 binders have been discovered as part of an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such as and demonstrate excellent potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit good physical properties and in vitro safety profiles. A new X-ray crystal structure confirms direct binding of this chemical series to YEATS4 at the lysine acetylation recognition site of the YEATS domain.

Management of Posttraumatic Posterior Elbow Defects by Nonmicrosurgical Reconstruction.

 Reconstruction of posterior defects is challenging due to the quality and uniqueness of the excess skin at the elbow that is durable, thick, pliable, and without much subcutaneous tissue. The goal of reconstruction is to cover the elbow defects with a durable skin cover that will facilitate full passive range of motion. In this era of microsurgery, free tissue transfer is feasible for almost any defect.

Nuances of Arteriovenous Fistula Creation for Vascular Access in Hemodialysis.

With rising incidence and increased life expectancy of patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), the number of patients requiring hemodialysis has increased substantially. Vascular access is the lifeline for a patient on hemodialysis (HD), and an arteriovenous fistula (AVF) is the undisputed gold standard for HD access. An effective and long-lasting fistula serves to increase the life expectancy of ESRD patients and improves their quality of life.

Post-CABG Deep Sternal Wound Infection: A Retrospective Comparative Analysis of Early versus Late Referral to a Plastic Surgery Unit in a Tertiary Care Center.

 Deep sternal wound infections (DSWI) following median sternotomy are initially treated by the cardiothoracic surgeons and are referred to a plastic surgical unit late in the course of time.  This is a retrospective review done in a tertiary care teaching institute from January 2005 to June 2018 and the data of 72 patients who had DSWI out of 4,214 patients who underwent median sternotomy for coronary artery bypass grafting (CABG) was collected with respect to the duration between CABG and presentation of DSWI as well as time of referral to a plastic surgery unit. We defined early referral as < or equal to 15 days from presentation and late referral as > 15 days.

Toward the assembly and characterization of an encoded library hit confirmation platform: Bead-Assisted Ligand Isolation Mass Spectrometry (BALI-MS).

The ability to predict chemical structure from DNA sequence has to date been a necessary cornerstone of DNA-encoded library technology. DNA-encoded libraries (DELs) are typically screened by immobilized affinity selection and enriched library members are identified by counting the number of times an individual compound's sequence is observed in the resultant dataset. Those with high signal reads (DEL hits) are subsequently followed up through off-DNA synthesis of the predicted small molecule structures.

BNT162b vaccines protect rhesus macaques from SARS-CoV-2.

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD-foldon).

Burnout among Plastic Surgery Residents in India: An Observational Study.

 Burnout syndrome can be defined as emotional exhaustion, depersonalization, and perceived lack of personal accomplishment, all of which lead to decreased effectiveness at work. The Medscape burnout and depression report of 2018 suggests that the burnout range across various specialties ranges from 23 to 48%. There are no studies to assess the burnout among plastic surgery residents in India.

PF-07059013: A Noncovalent Modulator of Hemoglobin for Treatment of Sickle Cell Disease.

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke.

The Reach of the Gastrocnemius Musculocutaneous Flap: How High Is High?

Background: Gastrocnemius muscle and musculocutaneous flaps are very versatile and one of the commonly used flaps for lower extremity reconstruction. There is significant literature available on the use of these flaps. However, we feel that the potential of the gastrocnemius musculocutaneous (GMC) flaps has not yet been fully explored in terms of increasing their reach, viability and arc of rotation.

The Anterior Interosseus Artery Perforator Flap: Anatomical Dissections and Clinical Study.

Background: Reconstruction of upper extremity deformities continues to be a challenge to the reconstructive surgeon. Various loco regional, distant and free flaps are available for reconstruction. However, each has its own set of advantages and disadvantages.

Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain.

Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes.

Limb salvage with microvascular free fibula following primary bone sarcoma resection.

Background: Extremity sarcomas are challenging to manage. Total eradication of tumour has to be balanced with restoration of limb function to prevent mortality and morbidity. Disease-free survival with maximum limb function is the ultimate goal in these patients.

Binding site elucidation and structure guided design of macrocyclic IL-17A antagonists.

Interleukin-17A (IL-17A) is a principal driver of multiple inflammatory and immune disorders. Antibodies that neutralize IL-17A or its receptor (IL-17RA) deliver efficacy in autoimmune diseases, but no small-molecule IL-17A antagonists have yet progressed into clinical trials. Investigation of a series of linear peptide ligands to IL-17A and characterization of their binding site has enabled the design of novel macrocyclic ligands that are themselves potent IL-17A antagonists.

Inhibiting complex IL-17A and IL-17RA interactions with a linear peptide.

IL-17A is a pro-inflammatory cytokine that has been implicated in autoimmune and inflammatory diseases. Monoclonal antibodies inhibiting IL-17A signaling have demonstrated remarkable efficacy, but an oral therapy is still lacking. A high affinity IL-17A peptide antagonist (HAP) of 15 residues was identified through phage-display screening followed by saturation mutagenesis optimization and amino acid substitutions.

Transcriptional Profiling of a Selective CREB Binding Protein Bromodomain Inhibitor Highlights Therapeutic Opportunities.

Bromodomains are involved in transcriptional regulation through the recognition of acetyl lysine modifications on diverse proteins. Selective pharmacological modulators of bromodomains are lacking, although the largely hydrophobic nature of the pocket makes these modules attractive targets for small-molecule inhibitors. This work describes the structure-based design of a highly selective inhibitor of the CREB binding protein (CBP) bromodomain and its use in cell-based transcriptional profiling experiments.

Probing the enzyme kinetics, allosteric modulation and activation of α1- and α2-subunit-containing AMP-activated protein kinase (AMPK) heterotrimeric complexes by pharmacological and physiological activators.

AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that serves as a pleotropic regulator of whole body energy homoeostasis. AMPK exists as a heterotrimeric complex, composed of a catalytic subunit (α) and two regulatory subunits (β and γ), each present as multiple isoforms. In the present study, we compared the enzyme kinetics and allosteric modulation of six recombinant AMPK isoforms, α1β1γ1, α1β2γ1, α1β2γ3, α2β1γ1, α2β2γ1 and α2β2γ3 using known activators, A769662 and AMP.