Browse Articles

Differential transport pathways of saturated and unsaturated fatty acid esters in male mouse hepatocytes

Preoperative ANemiA among elderly undergoing Major Abdominal surgery (PANAMA) is associated with early postoperative morbidity and worse quality of life outcomes

Photoredox/Cr-catalyzed enantioselective radical-polar crossover transformation via C-H functionalization

Watershed: a more efficient sampling unit for mountain camera traps

Optical time-lapsed in situ mechanochemical studies on metal halide perovskite systems

Single inhaler with beclometasone, formoterol, and glycopyrronium versus triple therapies in adults with uncontrolled asthma: a systematic review and meta-analysis

Molecular basis for azetidine-2-carboxylic acid biosynthesis

Abstract Azetidine-2-carboxylic acid (AZE) is a long-known plant metabolite. Recently, AZE synthases have been identified in bacterial natural product pathways involving non-ribosomal peptide synthetases. AZE synthases catalyse the intramolecular 4-exo-tet cyclisation of S-adenosylmethionine (SAM), yielding a highly strained heterocycle. Here, we combine structural and biochemical analyses with quantum mechanical calculations and mutagenesis studies to reveal catalytic insights into AZE synthases. The cyclisation of SAM is facilitated by an exceptional substrate conformation and supported by desolvation effects as well as cation-π interactions. In addition, we uncover related SAM lyases in diverse bacterial phyla, suggesting a wider prevalence of AZE-containing metabolites than previously expected. To explore the potential of AZE as a proline mimic in combinatorial biosynthesis, we introduce an AZE synthase into the pyrrolizixenamide pathway and thereby engineer analogues of azabicyclenes. Taken together, our findings provide a molecular framework to understand and exploit SAM-dependent cyclisation reactions.

A single-phase seven-level switched capacitor with common ground inverter and improved phase-shift modulation technique

Abstract Lately, transformer-less Researchers in the fields of power electronics and renewable energy have taken notice of photovoltaic inverters because of their great efficiency, low cost, and small size. However, higher efficiency typically results in more components, making the inverter costly and bulky. This article proposes a single-phase seven-level transformer-less with common ground topology. The proposed topology utilizes 10 switches, 4 capacitors and 1 diode. This article also suggests an improved Phase Shift (PS) Modulation Technique which reduces overall losses. When implemented with improved Phase Shift (PS), the total highest attainable efficiency of the proposed topology is 98.05% at 15 W. The THD% of voltage harmonics is reduced to 15.29% from 17.20% and for current harmonics is reduced to 5.07% from 10.15%. The reliability of the proposed inverter has also been analyzed. The simulation as well as hardware results have been presented to validate the performance of the proposed inverter.

OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma

Real world study on combining local interventions with systemic therapy in unresectable hepatocellular carcinoma

Fucosylated haptoglobin promotes inflammation via Mincle in sepsis: an observational study

Meta-analysis of the association between overexpression of RAD51 family genes and prognosis and clinical features in breast cancer

Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation

Study on the heating law of thermal effect of HIFU on tissue based on piezoelectric ceramic voltage and vibration frequency

Atlas of multilineage stem cell differentiation reveals TMEM88 as a developmental regulator of blood pressure

Abstract Pluripotent stem cells provide a scalable approach to analyse molecular regulation of cell differentiation across developmental lineages. Here, we engineer barcoded induced pluripotent stem cells to generate an atlas of multilineage differentiation from pluripotency, encompassing an eight-day time course with modulation of WNT, BMP, and VEGF signalling pathways. Annotation of in vitro cell types with reference to in vivo development reveals diverse mesendoderm lineage cell types including lateral plate and paraxial mesoderm, neural crest, and primitive gut. Interrogation of temporal and signalling-specific gene expression in this atlas, evaluated against cell type-specific gene expression in human complex trait data highlights the WNT-inhibitor gene TMEM88 as a regulator of mesendodermal lineages influencing cardiovascular and anthropometric traits. Genetic TMEM88 loss of function models show impaired differentiation of endodermal and mesodermal derivatives in vitro and dysregulated arterial blood pressure in vivo. Together, this study provides an atlas of multilineage stem cell differentiation and analysis pipelines to dissect genetic determinants of mammalian developmental physiology.

Development of an mPBPK machine learning framework for early target pharmacology assessment of biotherapeutics

Abstract Development of antibodies often begins with the assessment and optimization of their physicochemical properties, and their efficient engagement with the target of interest. Decisions at the early optimization stage are critical for the success of the drug candidate but are constrained due to the limited knowledge of the antibody and target pharmacology. In the present work, we propose a machine learning-based target pharmacology assessment framework that utilizes minimal physiologically based pharmacokinetic (mPBPK) modeling and machine learning (ML) to infer optimal physicochemical properties of antibodies and their targets. We use a mPBPK model previously developed by our group that incorporates a multivariate quantitative relationship between antibodies’ physicochemical properties such as molecular weight (MW), size, charge, and in silico + in vitro derived descriptors with their PK properties. In this study, we perform a high-throughput exploration of virtual antibody drug candidates with varying physicochemical properties (binding affinity, charge, etc.), and virtual target candidates with varying characteristics (baseline expression, half-life, etc.) to unravel rules for antibody drug candidate selection that achieve favorable drug-target interaction, which is defined by target occupancy (TO) percentage. We identified that variations in the antibody dose and dosing scheme, target form (soluble or membrane-bound), antibody charge, and site of action had a significant effect on the TO and selection criteria for antibody drug candidates. By unraveling new design rules for antibody drug properties that are dependent on ML-based TO assessment, we deliver a first-in-class ML-based target pharmacology assessment framework toward better understanding of the biology-specific PK and ADME processes of antibody drug candidate proteins and reduce the overall time for drug development.

Grand canyons on the Moon

Complete chloroplast genomes of 13 species of the Impatiens genus for genomic features and phylogenetic relationships studies

Mapping naturally presented T cell antigens in medulloblastoma based on integrative multi-omics

Cultural diversity shaped neolithic subsistence in the Carpathian Basin

Abstract Stable carbon and nitrogen isotope analysis from archaeological human and animal bone collagen is a powerful tool to enlighten past socio-agricultural systems and their close links to environmental conditions. To assess whether isotopic patterns are a function of cultural behavior or rather determined by environmental diversity, we test the spatio-temporal effects of conditional and multivariate exploratory and environmental models on stable isotope variability in the Neolithic and Chalcolithic Carpathian Basin (6000–2800 BCE). Our results stress that variation in environmental settings influence both the isotope baselines and the subsistence strategies of early agricultural societies. Major shifts in isotopic patterns are, however, culturally-driven, which is particularly visible with the development and intensification of adapted agropastoral practices from 5500 − 5350 BCE and among the diet between different cultural groups. We conclude that socio-cultural diversity was the main driver of dietary habits and isotopic variability in early agropastoral societies of Neolithic Hungary.