Browse Articles

A pilot study on aging-related effects on step performance: The role of muscle quality, size, and strength

All-2D vertical metal-semiconductor field-effect transistor with sub-10 nm channel and contact lengths

Indices of trophic and competitive relationships in a planktonic meta-network of carp ponds

Conformational cycling of the Wntless transporter drives trafficking and secretion of Wnt morphogens

Abstract Wnt proteins are lipid-modified morphogens fundamental in development and disease. During Wnt biogenesis, the G-protein-coupled receptor (GPCR)-like transporter Wntless (WLS) escorts lipidated Wnts from the endoplasmic reticulum to the plasma membrane, then transfers them to extracellular carriers, forming active and soluble morphogen-carrier complexes. To dissect the mechanisms involved, we solve cryo-EM structures of Wnt-bound WLS and unliganded WLS, and perform structure-guided functional experiments. Wnts engage WLS via three conserved hairpins, which are all required for Wnt trafficking to the cell surface and carrier-mediated secretion. Wnt release from cells is driven by dramatic conformational changes in the WLS transmembrane domain, reminiscent of GPCR activation, together with WLS extracellular rearrangements. Unexpectedly, we find that Wnt5a bound to WLS forms dimers, with implications for Wnt signaling. These findings define the mechanism of WLS conformational cycling that governs the intracellular transport and extracellular release of Wnt morphogens, essential steps in the Wnt pathway.

Co-occurrence of uranium, fluoride and nitrate in Sahelian groundwater of Agadez (Niger) drives population health risks

Molecular mechanisms of transhydrogenase activity and allosteric regulation in eukaryotic type II PHGDH Ser33

Abstract L-serine is a critical structural constituent of proteins and membrane phospholipids, playing major roles in cell signaling, metabolism and development. L-Serine is synthesized through a conserved de novo pathway starting from the glycolytic intermediate 3-phosphoglycerate (PGA), being oxidized by 3-phosphoglycerate dehydrogenase (PHGDH) into 3-phosphohydroxypyruvate (PHP). In certain organisms, PHGDH operates as a transhydrogenase using α-ketoglutarate rather than NAD + as the final electron acceptor and producing both PHP and D-2-hydroxyglutarate (2HG). We provide high-resolution X-ray crystal structures of the transhydrogenase Ser33 from Saccharomyces cerevisiae , in complex with the cofactor NADH, and with PGA, PHP, 2HG and the negative allosteric regulator L-serine. Combining extensive alanine scanning mutagenesis, enzyme activity assays and kinetics, molecular dynamics simulations, biophysical methods, and phylogenetic analysis, we establish the molecular basis of substrate recognition, transhydrogenase activity, and allosteric inhibition mechanisms, including the role of an N-terminal extension in the regulation of eukaryotic Type II PHGDHs.

Assessing county-level high-quality development and spatial adaptation paths under the space of flows perspective: a coupling detrended fluctuation analysis approach

A domestication gene links plant architecture and nitrogen metabolism to enhance yield in foxtail millet

Allicin-loaded soluplus polymeric micelles differentially modulate doxorubicin response in adenocarcinoma and myocardial cell models

Scaling covalent ligand discovery through dynamic combinatorial library-versus-proteome screening

The effect of customer incivility on proactive customer service performance mediated by emotional exhaustion and moderated by proactive personality

Multiplexed cytokine and antigen mRNA administration generates durable anti-tumor immunity against pancreatic cancer

Methylprednisolone for heart surgery in pediatric patients: a meta-analysis of randomized trials

Enabling high-voltage aqueous dual-ion batteries capable of working at −40 °C in a low-concentration salt electrolyte

Compound hydrogeomorphic cascades and rapid upstream to downstream hazard coupling in the Eastern Himalaya

Disruption of the brain-spleen axis impairs monocyte-microglia communication and accelerates disease progression in a mouse model of amyloidosis

Correlation between fecal eosinophil cationic protein and cow’s milk protein allergy in extremely preterm infants and its value in auxiliary diagnosis

A cyclin-polarity feedback network ensures healthy cell proliferation

Abstract Healthy proliferation requires the coordination of cell cycle progression with cell polarity. In budding yeast, polarity is established when G1-cyclin-Cdc28 Cdk1 triggers Cdc42 activation to generate a cell pole that is used as an axis for growth and division. While polarity defects delay the cell cycle temporally, permitting error correction, it is unknown if Cdc28 Cdk1 directly rectifies errant polarity. Here, we identify an adaptive response where G1-cyclin-Cdc28 Cdk1 participates in error correction via the augmentation of its kinase activity towards substrates that activate Cdc42. The response involves temporal and spatial cell cycle reconfiguration via extended G1 cyclin expression, nucleocytoplasmic rerouting and signaling. However, this strategy has a cost: if the defect is irreparable, high G1-cyclin levels enforce inexorable cell cycle commitment in the absence of a daughter cell, generating multinucleate cells. G1-cyclins therefore not only trigger G1 events, but also monitor their execution, employing feedback to coordinate polarity with cell cycle progression.

Controllable synthesis of small-sized Pd nanoparticles on acetic acid-modified halloysite for enhanced toluene oxidation

Scalable, fast and accurate differential gene expression testing from millions of cells of multiple patients

Abstract Since the development of DNA microarrays and later RNA bulk sequencing, testing with statistically independent samples has been the standard method for detecting genes with different transcription patterns. Single-cell assays challenge these assumptions because individual cells are statistically dependent, and all proposed methodologies present mathematical limitations or computational bottlenecks that prevent a seamless integration of data from many cells and patients simultaneously. In this work, we solve this crucial limitation by introducing a Bayesian framework that retrieves the independence structure at the level of individual patients, separating differences across individuals from actual transcriptional differences. Leveraging multi-GPU and variational inference, our approach excels across different experimental designs and scales to analyse over 10 million cells. This framework enables single-cell differential expression analysis that can finally integrate datasets from large clinical cohorts, atlas projects, or drug-response screens with thousands of samples and millions of cells.