Preparation of azide biosynthetic surrogates of myo-Inositol

As a prelude to biomolecular incorporation studies, practical routes to a series of four regioisomeric azido-deoxy derivatives of inositol that mimic the natural myo-stereochemistry are described. Starting from commercially available myo-inositol, the regioselective and stereoselective introduction of azide functionality was achieved at the C-2, C-3, C-4 and C-5 positions via azide displacement of the corresponding O-sulfonates of suitably protected scyllo-, chiro-, epi- and neo-inositols, respectively. Notably, a final one-pot acetolysis method conveniently allowed for rapid access to pentaacetate azido-deoxy inositols. Investigations on the metabolic incorporation of these myo-inositol azide surrogates in both acetate and free alcohol forms are in progress

Triazolophostins: a library of novel and potent agonists of IP3 receptors.

IP3 receptors are channels that mediate the release of Ca(2+) from the intracellular stores of cells stimulated by hormones or neurotransmitters. Adenophostin A (AdA) is the most potent agonist of IP3 receptors, with the β-anomeric adenine contributing to the increased potency. The potency of AdA and its stability towards the enzymes that degrade IP3 have aroused interest in AdA analogs for biological studies. The complex structure of AdA poses problems that have necessitated optimization of synthetic conditions for each analog. Such lengthy one-at-a-time syntheses limit access to AdA analogs. We have addressed this problem by synthesizing a library of triazole-based AdA analogs, triazolophostins, by employing click chemistry. An advanced intermediate having all the necessary phosphates and a β-azide at the anomeric position was reacted with various alkynes under Cu(i) catalysis to yield triazoles, which upon deprotection gave triazolophostins. All eleven triazolophostins synthesized are more potent than IP3 and some are equipotent with AdA in functional analyses of IP3 receptors. We show that a triazole ring can replace adenine without compromising the potency of AdA and provide facile routes to novel AdA analogs.A. M. V. thanks the University Grants Commission (UGC) India for a Senior Research Fellowship (SRF) during this work. K. M. S. thanks the Department of Science and Technology (DST) India for Swarnajayanti Fellowship, Ramanujan Fellowship and for financial support. C. W. T. and V. K. were supported by the Wellcome Trust, Biotechnology and Biological Sciences Research Council, and the German Academic Exchange Service (V. K.).This is the final published version. It first appeared at http://dx.doi.org/10.1039/C5OB00440

Integron Gene Cassettes: A Repository of Novel Protein Folds with Distinct Interaction Sites

Mobile gene cassettes captured within integron arrays encompass a vast and diverse pool of genetic novelty. In most cases, functional annotation of gene cassettes directly recovered by cassette-PCR is obscured by their characteristically high sequence novelty. This inhibits identification of those specific functions or biological features that might constitute preferential factors for lateral gene transfer via the integron system. A structural genomics approach incorporating x-ray crystallography has been utilised on a selection of cassettes to investigate evolutionary relationships hidden at the sequence level. Gene cassettes were accessed from marine sediments (pristine and contaminated sites), as well as a range of Vibrio spp. We present six crystal structures, a remarkably high proportion of our survey of soluble proteins, which were found to possess novel folds. These entirely new structures are diverse, encompassing all-α, α+β and α/β fold classes, and many contain clear binding pocket features for small molecule substrates. The new structures emphasise the large repertoire of protein families encoded within the integron cassette metagenome and which remain to be characterised. Oligomeric association is a notable recurring property common to these new integron-derived proteins. In some cases, the protein-protein contact sites utilised in homomeric assembly could instead form suitable contact points for heterogeneous regulator/activator proteins or domains. Such functional features are ideal for a flexible molecular componentry needed to ensure responsive and adaptive bacterial functions.13 page(s

Sequential matching problem

Kurzfassung in englisch We present sequential matching problem (SMP) as the problem of finding maximal matchings in a sequence of bipartite graphs, with a strategy of making maximum number of common edges in two consecutive matchings. One application of SMP is the problem of assigning workers to jobs in different time shifts with a goal of minimizing total number of unnecessary switches between jobs. We analyze various algorithmic techniques for this NP-complete problem. We also analyze the Mixed Integer Programming (MIP)problem formulation with huge number of variables and their solution by branch and price method, a column generation scheme with branch and bound, of implicit pricing of nonbasic variables to generate new columns. We then discuss special branching rules, pricing problems, implementation issues, and computational results. Finally we analyze a simpler version of SMP with only two bipartite graphs which is still NP-complete, and an algorithm to augment the common edges in the maximum matchings

Treatment features in acute rhinosinusitis with severe evolution in children

Universitatea de Stat de Medicină şi Farmacie „Nicolae Testemiţanu”, Chişinău, Republica MoldovaIntroducere. Patologia rinosinuzală ocupă una din primele locuri în structura morbidității copiilor. Se disting 3 forme clinico-evolutive: ușoară, moderată și severă, iar prevalența rinosinuzitei acute este de 6-15% din populație cu o incidență de 135 cazuri la 1000 locuitori pe an, afectând sever calitatea vieții pacienților. Scopul lucrării. Evaluarea metodelor de diagnostic și tratament a rinosinuzitei acute la copii pentru optimizarea conduitei diagnostic-terapeutice. Ne-am propus să realizăm un studiu retrospectiv privitor la tratamentul rinosinuzitei acute cu evoluție severă la copii. Material și metode . S-a efectuat o cercetare axată pe analiza asupra tratamentului aplicat la pacienții cu rinosinuzite acute cu evoluție severă spitalizați pe parcursul anilor 2018-2023 și relevarea datelor obținute. Au fost utilizate date din literatura de specialitate cu referire la rinosinuzita acută la copii și datele statistice acumulate pe parcursul anilor 2018-2023 în cadrul secției ORL a Clinicii “Emilian Coțaga”. Rezultate. S-au înregistrat 226 pacienți cu diagnosticul de rinosinuzită acută cu evoluție severă pe parcursul anilor 2018-2023. 67% din pacienți s-au adresat după eșecul terapiei ambulatorii, iar circa 29% au reprezentat pacienții care s-au adresat primar. . 93% au prezentat afectarea mai multor sinusuri. Prevalența genului M/F este de 2:1. Recidivă s-a înregistrat la aprox. 37% Din numărul total de pacienți 34% au fost internați ca urmare a complicațiilor orbitale. La aproximativ 93% pacienți s-a realizat drenarea sinusurilor afectate, iar la 7% s-a administrat tratament conservativ. La majoritatea pacienților internați s-a înregis trat o îmbunătățire vădită după puncția și drenarea sinusu rilor, având o durată a spitalizării în medie de 7-14 zile. Con cluzii. Evaluarea statistică a ratei de vindecare și succesului intervenției chirurgicale denotă faptul că asigurarea unei drenări cât mai precoce asigură o bună evoluție a patologiei rinosinuzale acute cu evoluție severă și evitarea maximală a recidivei și cronicizării în timp la pacienții din categoria pe diatrică.Background . The rhinosinusal pathology holds an important place in children’s morbidity. There are 3 clinical types: mild, moderate and severe, and the prevalence of acute rhi nosinusitis is 6-15% of the population with an incidence of 135 cases per 1000 inhabitants per year, severely affecting the patients’ quality of life. Objective of the study . Eval uation of diagnostic and treatment methods of acute rhi nosinusitis in children to perform the therapeutic method. We proposed to make a retrospective study regarding the treatment of acute rhinosinusitis with severe evolution in children. Material and methods . A research based on the analysis of the treatment applied to patients with acute rhinosinusitis with severe evolution hospitalized during the years 2018-2023 and the presenting of the obtained data was carried out. Data from the literature with reference to acute rhinosinusitis in children and the statistical data during the years 2018-2023 in the ENT department of the “Emilian Coțaga” Clinic were used. Results. 226 patients were registered with the diagnosis of acute rhinosinusitis with severe evolution during the years 2018-2023. 67% of the patients came after the failure of initial therapy, and about 29% represented the patients who came for the first time. 93% of the patients had affected more than one sinus. The M/F gender prevalence was 2:1. Recurrence was recorded in approx. 37% of the patients .34% were hospitalized because of orbital complications. Drainage of the affected sinuses was performed in approximately 93% of patients, and conservative treatment was administered to 7%. In most hospitalized patients, a clear improvement was registered after sinus drainage, with an average hospitalization duration of 7-14 days. Conclusions. The statistical evaluation of the recovery rate and the success of the surgical method shows that providing a drainage as early as possible ensures a good evolution of the acute rhinosinusal pathology with severe clinical form and the maximum avoidance of recurrence and chronicity over time in pediat ric patients

RETAIN: Interactive Tool for Regression Testing Guided LLM Migration

Large Language Models (LLMs) are increasingly integrated into diverse applications. The rapid evolution of LLMs presents opportunities for developers to enhance applications continuously. However, this constant adaptation can also lead to performance regressions during model migrations. While several interactive tools have been proposed to streamline the complexity of prompt engineering, few address the specific requirements of regression testing for LLM Migrations. To bridge this gap, we introduce RETAIN (REgression Testing guided LLM migrAtIoN), a tool designed explicitly for regression testing in LLM Migrations. RETAIN comprises two key components: an interactive interface tailored to regression testing needs during LLM migrations, and an error discovery module that facilitates understanding of differences in model behaviors. The error discovery module generates textual descriptions of various errors or differences between model outputs, providing actionable insights for prompt refinement. Our automatic evaluation and empirical user studies demonstrate that RETAIN, when compared to manual evaluation, enabled participants to identify twice as many errors, facilitated experimentation with 75% more prompts, and achieves 12% higher metric scores in a given time frame.Preprin

Nasal permeability in inflammatory rhinosinusal diseases in children

Introduction: Rhinosinusal inflammatory diseases constitute a current problem of contemporary rhinology. Rhinitis, sinusitis seriously affect the physiological functions of the nose, including the most important of them, the respiratory function. However, in the specialized literature nasal breathing and its role in achieving the physiological status of the nose is insufficiently elucidated. Material and methods: Under our supervision were 80 children with rhinosinusal pathology aged between 6 and 15 years, who were divided into two groups. Group 1 included 40 children (22 boys and 18 girls) with chronic hypertrophic rhinitis, and group 2 consisted of 40 patients (21 boys and 19 girls) with chronic rhinosinusitis. At the same time, 30 healthy children (17 boys and 13 girls) formed the control group. In order to assess nasal permeability, we used acoustic rhinometry, a non-invasive and highly accurate method, which reveals conclusive data about the volume and geometry of the nasal fossae by measuring the minimum cross-sectional area. Results: The results obtained showed that nasal permeability was affected in both groups of patients, slightly prevalent in patients with chronic hypertrophic rhinitis where MCSA (minimum crosssectional area) values were MCSA-1 = 0.215 ± 0.012, and MCSA-2 = 0.325 ± 0.041. At the same time, in patients with chronic rhinosinusitis the MCSA-1 values were 0.241 ± 0.018, and MCSA-2 = 0.385 ± 0.067. In the control group, the MCSA-1 and MCSA-2 values were significantly higher, 0.410 ± 0.055 and 0.520 ± 0.050, respectively. These differences are statistically significant and indicate a decrease in nasal permeability in rhinosinusitis inflammations. Conclusions: Thus, nasal permeability, assessed by acoustic rhinometry, was statistically reduced in inflammatory rhinological diseases, both in chronic sinusitis and in hypertrophic rhinitis. At the same time, in patients with chronic hypertrophic rhinitis, the indices of the minimum transverse areas were lower, which means a more pronounced impairment in these patients. In both study groups, nasal permeability was reduced compared to healthy children

Chemical glycosylations for the synthesis of building units of post-translational modifications

In chemical glycosylation reactions, a glycosyl donor couples with a glycosyl acceptor through glycosidic linkage. Most of the products end up with a mixture due to the formation of a stereogenic center at the anomeric carbon. Activation with a suitable Lewis acid and introduction of the non‐participating protecting group on donor and acceptor results in a selective product. Herein, we used a suitably protected donor and acceptor which produced an orthogonally protected building block with α‐selectivity. We used also a donor for the synthesis of modified phosphoribosylated amino acid. The formation of glycoside products can be used to synthesize complex biologically important organic molecules