Proinsulin C-peptide is a major source of HLA-DQ8 restricted hybrid insulin peptides recognized by human islet-infiltrating CD4 T cells.

Type 1 diabetes (T1D) is an autoimmune disease that develops when T cells destroy the insulin-producing beta cells that reside in the pancreatic islets. Immune cells, including T cells, infiltrate the islets and gradually destroy the beta cells. Human islet-infiltrating CD4 T cells recognize peptide epitopes derived from proinsulin, particularly C-peptide.

Semisynthesis of A6-A11 lactam insulin.

Insulin replacement therapy is essential for the management of diabetes. However, despite the relative success of this therapeutic strategy, there is still a need to improve glycaemic control and the overall quality of life of patients. This need has driven research into orally available, glucose-responsive and rapid-acting insulins.

The impact of funding disruptions on large-scale teen pregnancy prevention research projects.

To advance the field of teen pregnancy prevention, new interventions must be developed and tested. The federal Teen Pregnancy Prevention program (TPP) funds the evaluation of promising interventions. We report on a funding disruption to 21 TPP Tier 2B research grantees across the US that was unusual for its ideological causation, sudden timing, severity, and ultimately court decisions compelling the agency to reverse the decision.

An Engineered Nanosugar Enables Rapid and Sustained Glucose-Responsive Insulin Delivery in Diabetic Mice.

Glucose-responsive insulin-delivery platforms that are sensitive to dynamic glucose concentration fluctuations and provide both rapid and prolonged insulin release have great potential to control hyperglycemia and avoid hypoglycemia diabetes. Here, biodegradable and charge-switchable phytoglycogen nanoparticles capable of glucose-stimulated insulin release are engineered. The nanoparticles are "nanosugars" bearing glucose-sensitive phenylboronic acid groups and amine moieties that allow effective complexation with insulin (≈95% loading capacity) to form nanocomplexes.

Optimization of Spray Drying Process Parameters for the Preparation of Inhalable Mannitol-Based Microparticles Using a Box-Behnken Experimental Design.

Inhalation is used for local therapy of the lungs and as an alternative route for systemic drug delivery. Modern powder inhalation systems try to target the required site of action/absorption in the respiratory tract. Large porous particles (LPPs) with a size >5 μm and a low mass density (usually measured as bulk or tapped) of <0.

The effect of substance P and its common in vivo-formed metabolites on MRGPRX2 and human mast cell activation.

The tachykinin neuropeptide substance P (SP) is the canonical agonist peptide for the neurokinin 1 receptor (NK R). More recently, it has also been shown to activate the Mas-related G protein-coupled receptor X2 (MRGPRX2) receptor on mast cells (MCs), triggering degranulation and release of inflammatory mediators. SP undergoes rapid C-terminal truncation in vivo by a number of proteases to generate the metabolites SP(1-9)-COOH and in particular SP(1-7)-COOH.

Copper Outdiffusion from Copper-Plated Solar Cell Contacts during Damp Heat Exposure.

Plated copper (Cu) contacts for silicon (Si) solar cells are an attractive alternative material to conventional screenprinted silver, but there are unresolved questions on the long-term integrity of plated contact structures. In this work, we perform characterization on plated Cu contacts from encapsulated cells that were degraded during extended exposure to damp heat (DH) stress. First, using energy-dispersive X-ray spectroscopy, we find evidence of Cu outdiffusion upward through capping layers made of both tin and silver applied with light-induced plating, resulting in a layer of Cu on the outer contact surface.

An introduction to the core data for cefiderocol with reflections for a possible role within UK clinical practice.

The video in this section is a copy of a recorded webinar organized by Shionogi to launch cefiderocol to the UK market in September 2020. Dr Andreas Karas presents the key clinical data for this new antibiotic for MDR Gram-negative infections, followed by reflections from Professor Jonathan Edgeworth on the potential use of the new agent in UK clinical practice. Included in the latter is a case study example of a compassionate use case using cefiderocol.

Modular Synthesis of Trifunctional Peptide-oligonucleotide Conjugates Native Chemical Ligation.

Cell penetrating peptides (CPPs) are being increasingly used as efficient vectors for intracellular delivery of biologically active agents, such as therapeutic antisense oligonucleotides (ASOs). Unfortunately, ASOs have poor cell membrane permeability. The conjugation of ASOs to CPPs have been shown to significantly improve their cellular permeability and therapeutic efficacy.

The Chemical Synthesis of Insulin: An Enduring Challenge.

The pancreatic peptide hormone insulin, first discovered exactly 100 years ago, is essential for glycemic control and is used as a therapeutic for the treatment of type 1 and, increasingly, type 2 diabetes. With a worsening global diabetes epidemic and its significant health budget imposition, there is a great demand for new analogues possessing improved physical and functional properties. However, the chemical synthesis of insulin's intricate 51-amino acid, two-chain, three-disulfide bond structure, together with the poor physicochemical properties of both the individual chains and the hormone itself, has long represented a major challenge to organic chemists.

Endosomal escape cell-penetrating peptides significantly enhance pharmacological effectiveness and CNS activity of systemically administered antisense oligonucleotides.

Antisense oligonucleotides (ASOs) are an emerging class of gene-specific therapeutics for diseases associated with the central nervous system (CNS). However, ASO delivery across the blood-brain barrier (BBB) to their CNS target cells remains a major challenge. Since ASOs are mainly taken up into the brain capillary endothelial cells interface through endosomal routes, entrapment in the endosomal compartment is a major obstacle for efficient CNS delivery of ASOs.

A meta-analysis of DaVinci Si versus Xi in colorectal surgery.

Background: The aim of this meta-analysis was to evaluate whether adoption of DaVinci Xi had any impact upon intra- and postoperative metrics in colorectal surgery.

Methods: The Pubmed, CINAHL, Cochrane Library and MEDLINE (Ovid) databases were systematically searched. Operating time as well as docking and surgeon console times were the primary endpoints.

Phenotype Driven Analysis of Whole Genome Sequencing Identifies Deep Intronic Variants that Cause Retinal Dystrophies by Aberrant Exonization.

Purpose: To demonstrate the effectiveness of combining retinal phenotyping and focused variant filtering from genome sequencing (GS) in identifying deep intronic disease causing variants in inherited retinal dystrophies.

Methods: Affected members from three pedigrees with classical enhanced S-cone syndrome (ESCS; Pedigree 1), congenital stationary night blindness (CSNB; Pedigree 2), and achromatopsia (ACHM; Pedigree 3), respectively, underwent detailed ophthalmologic evaluation, optical coherence tomography, and electroretinography. The probands underwent panel-based genetic testing followed by GS analysis.

Structure-Activity Relationships of Daptomycin Lipopeptides.

Daptomycin is a calcium-dependent cyclic lipodepsipeptide derived from the soil saprotroph , and its antibiotic properties make it a key agent for treatment of drug-resistant Gram-positive infections. It is most commonly used clinically for the treatment of Gram-positive skin and skin structure infections (SSSI), bacteremia, and right-sided endocarditis infections associated with , including methicillin resistant (MRSA). It has also been used "off-label" for Enterococcal infections.

The Antimicrobial Activity of Cannabinoids.

A post-antibiotic world is fast becoming a reality, given the rapid emergence of pathogens that are resistant to current drugs. Therefore, there is an urgent need to discover new classes of potent antimicrobial agents with novel modes of action. is an herbaceous plant that has been used for millennia for medicinal and recreational purposes.

Long-Term Antibiotic Prophylaxis in Urology and High Incidence of Infections in Surgical Adult Patients.

Clostridioides infections are the main cause of antibiotic-related diarrhea. Most of them come in the form of healthcare-associated Clostridioides infections (HA-CDI). The aim of the study was to analyze HA-CDI epidemiology and the relationship between antibiotic consumption and CDI epidemiology at St Luke's Provincial Hospital in Tarnow, Poland.

The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study.

Antibiotics have served humankind through their use in modern medicine as effective treatments for otherwise fatal bacterial infections. Teixobactin is a first member of newly discovered natural antibiotics that was recently identified from a hitherto-unculturable soil bacterium, , and recognized as a potent antibacterial agent against various Gram-positive bacteria, including methicillin-resistant (MRSA) and vancomycin-resistant enterococci. The most distinctive characteristic of teixobactin as an effective antibiotic is that teixobactin resistance could not be evolved in a laboratory setting.

1,3-Dichloroacetone: A Robust Reagent for Preparing Bicyclic Peptides.

The chemical synthesis of cyclic peptides is a well-established area of research. This has been further expanded by development of bio-orthogonal reactions that enable access to peptides of greater structural complexity. One approach utilizes 1,3-dichloroacetone to selectively link free cysteine side-chains with an acetone-like bridge via an S2 reaction.

Structure of micelle bound cationic peptides by NMR spectroscopy using a lanthanide shift reagent.

[Tm(DPA)] was used to generate multiple, paramagnetic nuclear Overhauser effect NMR spectra of cationic peptides when weakly bound to a lipopolysaccharide micelle. Increased spectral resolution combined with a marked increase in the number of distance restraints yielded high resolution structures of polymyxin and MSI-594 in the liposaccharide bound state.

Total Chemical Synthesis of a Nonfibrillating Human Glycoinsulin.

Glycosylation is an accepted strategy to improve the therapeutic value of peptide and protein drugs. Insulin and its analogues are life-saving drugs for all type I and 30% of type II diabetic patients. However, they can readily form fibrils which is a significant problem especially for their use in insulin pumps.

Synthesis and structure-activity relationships of teixobactin.

The discovery of antibiotics has led to the effective treatment of bacterial infections that were otherwise fatal and has had a transformative effect on modern medicine. Teixobactin is an unusual depsipeptide natural product that was recently discovered from a previously unculturable soil bacterium and found to possess potent antibacterial activity against several Gram positive pathogens, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci. One of the key features of teixobactin as an antibiotic lead is that resistance could not be generated in a laboratory setting.

The impact of backbone N-methylation on the structure-activity relationship of Leu -teixobactin.

Antimicrobial resistance is a serious threat to global human health; therefore, new anti-infective therapeutics are required. The cyclic depsi-peptide teixobactin exhibits potent antimicrobial activity against several Gram-positive pathogens. To study the natural product's mechanism of action and improve its pharmacological properties, efficient chemical methods for preparing teixobactin analogues are required to expedite structure-activity relationship studies.

Evaluation of the Educational Environment of a Cadaver Course in Robotic Colorectal Surgery: A Cross-sectional Study.

Background: The educational environment is a crucial metric of medical education that affects the course participants' motivation, achievement, happiness and success. The aim of this study was to evaluate the educational environment of a cadaver course in robotic colorectal surgery by comparing the perceptions of the participating residents to those of the participating surgeons.

Methods: This was a cross-sectional study carried out in 2017.