A self-immolative Kdn-glycoside substrate enables high-throughput screening for inhibitors of Kdnases.

Aspergillus fumigatus, a filamentous fungus, is an opportunistic pathogen and the major causative agent of the often-fatal disease, invasive aspergillosis (IA). Current treatments for IA are limited due to their high toxicity and/or the emergence of drug resistance; therefore, a need exists for the development of new therapeutics to treat IA. The Kdnase produced by A.

Mechanism-Based Allylic Carbasugar Chlorides That Form Covalent Intermediates with α- and β-Galactosidases.

Glycoside hydrolases have been implicated in a wide range of human conditions including lysosomal storage diseases. Consequently, many researchers have directed their efforts towards identifying new classes of glycoside hydrolase inhibitors, both synthetic and from natural sources. A large percentage of such inhibitors are reversible competitive inhibitors that bind in the active site often due to them possessing structural features, often a protonatable basic nitrogen atom, that mimic the enzymatic transition state.

Development of Tunable Mechanism-Based Carbasugar Ligands that Stabilize Glycoside Hydrolases through the Formation of Transient Covalent Intermediates.

Mutations in many members of the set of human lysosomal glycoside hydrolases cause a wide range of lysosomal storage diseases. As a result, much effort has been directed toward identifying pharmacological chaperones of these lysosomal enzymes. The majority of the candidate chaperones are active site-directed competitive iminosugar inhibitors but these have met with limited success.

A comparative study of the developability of full-length antibodies, fragments, and bispecific formats reveals higher stability risks for engineered constructs.

Engineered antibody formats, such as antibody fragments and bispecifics, have the potential to offer improved therapeutic efficacy compared to traditional full-length monoclonal antibodies (mAbs). However, the translation of these non-natural molecules into successful therapeutics can be hampered by developability challenges. Here, we systematically analyzed 64 different antibody constructs targeting Tumor Necrosis Factor (TNF) which cover 8 distinct molecular format families, encompassing full-length antibodies, various types of single chain variable fragments, and bispecifics.

An organic proton cage that is ultra-resistant to hydroxide-promoted degradation.

Alkaline polymer membrane electrochemical energy conversion devices offer the prospect of using non-platinum group catalysts. However, their cationic functionalities are currently not sufficiently stable for vapor-phase applications, such as fuel cells. Herein, we report 1,6-diazabicyclo[4.

Remote and low-cost intraocular pressure monitoring by deep learning of speckle patterns.

Significance: Glaucoma, a leading cause of global blindness, disproportionately affects low-income regions due to expensive diagnostic methods. Affordable intraocular pressure (IOP) measurement is crucial for early detection, especially in low- and middle-income countries.

Aim: We developed a remote photonic IOP biomonitoring method by deep learning of the speckle patterns reflected from an eye sclera stimulated by a sound source.

A Fluorogenic Disaccharide Substrate for α-Mannosidases Enables High-Throughput Screening and Identification of an Inhibitor of the GH92 Virulence Factor from .

Trimming of host glycans is a mechanism that is broadly employed by both commensal and pathogenic microflora to enable colonization. Host glycan trimming by the opportunistic Gram-positive bacterium has been demonstrated to be an important mechanism of virulence. While employs a multitude of glycan processing enzymes, the -mannosidase SpGH92 has been shown to be an important virulence factor.

Integrated room temperature single-photon source for quantum key distribution: publisher's note.

This publisher's note contains a correction to Opt. Lett.47, 1673 (2022)10.

Integrated room temperature single-photon source for quantum key distribution.

High-purity single-photon sources (SPS) that can operate at room temperature are highly desirable for a myriad of applications, including quantum photonics and quantum key distribution. In this work, we realize an ultra-bright solid-state SPS based on an atomic defect in hexagonal boron nitride (hBN) integrated with a solid immersion lens (SIL). The SIL increases the source efficiency by a factor of six, and the integrated system is capable of producing over ten million single photons per second at room temperature.

The influence of siblings on ethnically diverse children's gender typing across early development.

Most U.S. children grow up with siblings.

Glycoside hydrolase stabilization of transition state charge: new directions for inhibitor design.

Carbasugars are structural mimics of naturally occurring carbohydrates that can interact with and inhibit enzymes involved in carbohydrate processing. In particular, carbasugars have attracted attention as inhibitors of glycoside hydrolases (GHs) and as therapeutic leads in several disease areas. However, it is unclear how the carbasugars are recognized and processed by GHs.

A heme•DNAzyme activated by hydrogen peroxide catalytically oxidizes thioethers by direct oxygen atom transfer rather than by a Compound I-like intermediate.

Hemin [Fe(III)-protoporphyrin IX] is known to bind tightly to single-stranded DNA and RNA molecules that fold into G-quadruplexes (GQ). Such complexes are strongly activated for oxidative catalysis. These heme•DNAzymes and ribozymes have found broad utility in bioanalytical and medicinal chemistry and have also been shown to occur within living cells.

Structurally homologous sialidases exhibit a commonality in reactivity: Glycoside hydrolase-catalyzed hydrolysis of Kdn-thioglycosides.

Aspergillus fumigatus is one of the main causative agents of invasive aspergillosis, an often-lethal fungal disease that affects immunocompromised individuals. A. fumigatus produces a sialidase that cleaves the nine-carbon carbohydrate Kdn from glycoconjugates.

First-generation somatostatin receptor ligands and pregnancy: lesson from women with acromegaly.

Introduction: Few data are available on the risks of first-generation somatostatin receptor ligands (SRLs) during pregnancy in women treated for acromegaly. Current recommendations suggest the withdrawal of treatment at diagnosis of pregnancy. The aims of this literature review were to evaluate the teratogenic effects and the potential impact of SRLs on maternal and fetal outcomes by comparing acromegalic patients treated or not during pregnancy.

An Epoxide Intermediate in Glycosidase Catalysis.

Retaining glycoside hydrolases cleave their substrates through stereochemical retention at the anomeric position. Typically, this involves two-step mechanisms using either an enzymatic nucleophile via a covalent glycosyl enzyme intermediate or neighboring-group participation by a substrate-borne 2-acetamido neighboring group via an oxazoline intermediate; no enzymatic mechanism with participation of the sugar 2-hydroxyl has been reported. Here, we detail structural, computational, and kinetic evidence for neighboring-group participation by a mannose 2-hydroxyl in glycoside hydrolase family 99 -α-1,2-mannanases.

Clinical characteristics of familial hypocalciuric hypercalcaemia type 1: A multicentre study of 77 adult patients.

Objective: Familial hypocalciuric hypercalcaemia type 1 (FHH1), related to heterozygous loss-of-function mutations of the calcium-sensing receptor gene, is the main differential diagnosis for primary hyperparathyroidism. The aim of our study was to describe clinical characteristics of adult patients living in France with a genetically confirmed FHH1.

Design And Patients: This observational, retrospective, multicentre study included 77 adults, followed up in 32 clinical departments in France, with a genetic FHH1 diagnosis between 2001 and 2012.

The Diabetes and Emotional Health Handbook and Toolkit for Health Professionals Supporting Adults With Type 1 and Type 2 Diabetes: Formative Evaluation.

Background: Health professionals have expressed unmet needs, including lacking the skills, confidence, training, and resources needed to properly attend to the psychological needs of people with diabetes.

Objective: Informed by needs assessments, this study aimed to develop practical, evidence-based resources to support health professionals to address the emotional needs of adults with type 1 or type 2 diabetes.

Methods: We developed a new handbook and toolkit informed by formative evaluation, including literature reviews, stakeholder consultation and review, and a qualitative study.

Conformationally Controlled Reactivity of Carbasugars Uncovers the Choreography of Glycoside Hydrolase Catalysis.

Glycoside hydrolases (GHs) catalyze hydrolyses of glycoconjugates in which the enzyme choreographs a series of conformational changes during the catalytic cycle. As a result, some GH families, including α-amylases (GH13), have their chemical steps concealed kinetically. To address this issue for a GH13 enzyme, we prepared seven cyclohexenyl-based carbasugars of α-d-glucopyranoside that we show are good covalent inhibitors of a GH13 yeast α-glucosidase.

Directed evolution of a remarkably efficient Kdnase from a bacterial neuraminidase.

N-acetylneuraminic acid (5-acetamido-3,5-dideoxy-d-glycero-d-galacto-non-2-ulosonic acid), which is the principal sialic acid family member of the non-2-ulosonic acids and their various derivatives, is often found at the terminal position on the glycan chains that adorn all vertebrate cells. This terminal position combined with subtle variations in structure and linkage to the underlying glycan chains between humans and other mammals points to the importance of this diverse group of nine-carbon sugars as indicators of the unique aspects of human evolution and is relevant to understanding an array of human conditions. Enzymes that catalyze the removal N-acetylneuraminic acid from glycoconjugates are called neuraminidases.

The physical organic chemistry of glycopyranosyl transfer reactions in solution and enzyme-catalyzed.

Our understanding of the mechanisms of glycopyranosyl transfer that occur in solution, both for the chemical synthesis of complex structures and that for the cleavage of glycosidic bonds has allowed us to design biologically active molecules. Recent efforts on the reactivity of glycopyranosides, which are critical entities in all biological systems, coupled with the advent of modern spectroscopic instrumentation have allowed physical organic chemists to broaden our knowledge of glycosyl transfer reaction transition states, both in solution and for enzyme-catalyzed processes, and of critical high energy intermediates. This review details recent physical organic, kinetic and structural studies that have led to elucidation of several different mechanism for the transfer of glycopyranosyl moieties from various substrates to acceptors, such as water or a sugar hydroxyl group.

Synthesis of Sterically Congested 2,2'-Bi(Adamantyl)-Based Alcohol and Amines.

Sterically congested chiral alcohol and amines have gained tremendous attention in the design of asymmetric catalysts. Herein, the synthesis of a sterically congested bis-adamantane framework-based chiral alcohol, (1,2,3,4)-4-(2-adamantyl)adamantan-2-ol, and amine, (1,2,3,4)-4-(2-adamantyl)adamantan-2-amine, is described. Access to these sterically encumbered compounds is found via the preparation of an enantioenriched 4-adamantyladamantan-2-one intermediate, which was synthesized in 6 steps from adamantan-2-one.

Weight-loss with activation of brown fat: Suspect pheochromocytoma.

Introduction: Excess catecholamine stimulates heat production in brown adipose tissue (BAT). Activation of BAT can be detected in patients presenting pheochromocytoma.

Case Study: A 58-year-old female patient sought medical advice due to 13 kg weight loss over 2 years accompanied by sweating and high blood pressure.

Gestational diabetes and acromegaly: Single-centre experience of 14 pregnancies.

Introduction: The prevalence of gestational diabetes (GD) in women with acromegaly is rarely reported. The aims of this study were to evaluate the prevalence of GD in acromegalic women submitted to a systematic screening for GD and then to compare women with or without GD.

Patients And Methods: We studied 14 pregnancies in 11 women (34.

Medical therapy in patients with endogenous hypoglycaemia: Is euglycaemia achievable?

Context: While the only curative treatment for patients with endogenous hypoglycaemia related to inappropriate insulin or to insulin growth factor 2 (IGF2) secretion is surgery, medical treatment to normalize plasma glucose levels can be useful.

Objective: The aim of this prospective single centre study was to assess whether patients with endogenous hypoglycaemia, considered euglycaemic with medical treatments, experienced asymptomatic hypo- or hyperglycaemic excursions.

Patients And Methods: All patients with endogenous hypoglycaemia related to inappropriate insulin or to IGF2 secretion between 2012 and 2016 and considered normoglycaemic with medical treatment (absence of clinical hypoglycaemia and self-monitoring blood glucose in the normal range) were enroled and underwent a six-day continuous glucose monitoring (CGM) recording.