Talin1 dysfunction is genetically linked to systemic capillary leak syndrome.

Systemic capillary leak syndrome (SCLS) is a rare life-threatening disorder due to profound vascular leak. The trigger and the cause of the disease are currently unknown and there is no specific treatment. Here, we identified a rare heterozygous splice-site variant in the TLN1 gene in a familial SCLS case, suggestive of autosomal dominant inheritance with incomplete penetrance.

A cellulose synthase-like protein governs the biosynthesis of alkaloids.

Decades of research on the infamous antinutritional steroidal glycoalkaloids (SGAs) in Solanaceae plants have provided deep insights into their metabolism and roles. However, engineering SGAs in heterologous hosts has remained a challenge. We discovered that a protein evolved from the machinery involved in building plant cell walls is the crucial link in the biosynthesis of SGAs.

A proteome-wide yeast degron collection for the dynamic study of protein function.

Genome-wide collections of yeast strains, known as libraries, revolutionized the way systematic studies are carried out. Specifically, libraries that involve a cellular perturbation, such as the deletion collection, have facilitated key biological discoveries. However, short-term rewiring and long-term accumulation of suppressor mutations often obscure the functional consequences of such perturbations.

Covalent Proximity Inducers.

Molecules that are able to induce proximity between two proteins are finding ever increasing applications in chemical biology and drug discovery. The ability to introduce an electrophile and make such proximity inducers covalent can offer improved properties such as selectivity, potency, duration of action, and reduced molecular size. This concept has been heavily explored in the context of targeted degradation in particular for bivalent molecules, but recently, additional applications are reported in other contexts, as well as for monovalent molecular glues.

Conjugates of amiridine and salicylic derivatives as promising multifunctional CNS agents for potential treatment of Alzheimer's disease.

New conjugates of amiridine and salicylic derivatives (salicylamide, salicylimine, and salicylamine) with different lengths of alkylene spacers were designed, synthesized, and evaluated as potential multifunctional central nervous system therapeutic agents for Alzheimer's disease (AD). Conjugates demonstrated high acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition (IC: AChE, 0.265-4.

Homeostatic synaptic normalization optimizes learning in network models of neural population codes.

Studying and understanding the code of large neural populations hinge on accurate statistical models of population activity. A novel class of models, based on learning to weigh sparse nonlinear Random Projections (RP) of the population, has demonstrated high accuracy, efficiency, and scalability. Importantly, these RP models have a clear and biologically plausible implementation as shallow neural networks.

Examining the NEUROG2-lineage and associated-gene expression in human cortical organoids.

Proneural genes are conserved drivers of neurogenesis across the animal kingdom. How their functions have adapted to guide human-specific neurodevelopmental features is poorly understood. Here, we mined transcriptomic data from human fetal cortices and generated from human embryonic stem cell (hESC)-derived cortical organoids (COs) to show that NEUROG1 and NEUROG2 are most highly expressed in basal neural progenitor cells, with pseudotime trajectory analyses indicating that NEUROG1-derived lineages predominate early and NEUROG2 lineages later.

Dust storm-driven dispersal of potential pathogens and antibiotic resistance genes in the Eastern Mediterranean.

The atmosphere hosts a microbiome that connects distant ecosystems yet remains relatively unexplored. In this study, we tested the hypothesis that dust storms enhance the spread of pathogenic microorganisms and whether these microorganisms carry antibiotic resistance and virulence-related genes in the Eastern Mediterranean. We collected air samples during a seasonal transition period, capturing data from 13 dusty days originating from Middle Eastern sources, including the Saharan Desert, Iraq, Iran, and Saudi Arabia, and 32 clear days, with temperatures ranging from 16.

Squamous cell carcinoma arising in chronically damaged skin (Marjolin's Ulcer): still an unmet need in the era of immunotherapy.

Background: Cutaneous squamous cell carcinoma (cSCC) is characterized by a high tumor mutational burden due to solar damage and a favorable response to anti-PD-1 immunotherapy. Yet, we encounter tumors arising in areas with minimal sun exposure, such as cSCC that develops in chronically inflamed skin, also known as Marjolin's Ulcer (MU). The response of MU-SCC to immunotherapy remains unknown.

Topological Defect Formation in Slow Three-Dimensional Fracture.

Cracks develop various surface patterns as they propagate in three-dimensional (3D) materials. Symmetry-breaking topological defects in nominally tensile (mode-I) fracture emerge in the slow (noninertial) regime, taking the form of surface steps. We show that the same phase-field framework that recently shed basic light on dynamic (inertial) tensile fracture in three dimensions, also gives rise to crack surface steps.

Vacancies in Generic Kitaev Spin Liquids.

The Kitaev honeycomb model supports gapless and gapped quantum spin liquid phases. Its exact solvability relies on extensively many locally conserved quantities. Any real-world manifestation of these phases would include imperfections in the form of disorder and interactions that break integrability.

From Chaos to Integrability in Double Scaled Sachdev-Ye-Kitaev Model via a Chord Path Integral.

We study thermodynamic phase transitions between integrable and chaotic dynamics. We do so by analyzing models that interpolate between the chaotic double scaled Sachdev-Ye-Kitaev (SYK) and the integrable p-spin systems, in a limit where they are described by chord diagrams. We develop a path integral formalism by coarse graining over the diagrams, which we use to argue that the system has two distinct phases: one is continuously connected to the chaotic system, and the other to the integrable.

Earliest modern human genomes constrain timing of Neanderthal admixture.

Modern humans arrived in Europe more than 45,000 years ago, overlapping at least 5,000 years with Neanderthals. Limited genomic data from these early modern humans have shown that at least two genetically distinct groups inhabited Europe, represented by Zlatý kůň, Czechia and Bacho Kiro, Bulgaria. Here we deepen our understanding of early modern humans by analyzing one high-coverage genome and five low-coverage genomes from ~45,000 year-old remains from Ilsenhöhle in Ranis, Germany, and a further high-coverage genome from Zlatý kůň.

Chemical waves in reaction-diffusion networks of small organic molecules.

Chemical waves represent one of the fundamental behaviors that emerge in nonlinear, out-of-equilibrium chemical systems. They also play a central role in regulating behaviors and development of biological organisms. Nevertheless, understanding their properties and achieving their rational synthesis remains challenging.

Cellular and metabolic impacts of repeated sub-acute exposures to biomass-burning extracts in vitro.

The increasing exposure to biomass-burning emissions underscores the need to understand their toxicological impacts on human health. In this study, we developed a laboratory model to evaluate the effects of single and repeated sub-acute exposures to water-soluble wood tar (WT) extracts, a product of biomass burning, on human lung, liver, and immune cells. Using representative cell lines for different tissues, we examined the cytotoxic effects under conditions mimicking sub-acute environmental exposure levels relevant to humans.

An anomalous abundance of tryptophan residues in ceramide synthases based on analysis of all membrane proteins in the Swiss-Prot database.

The relationship between membrane proteins and the lipid constituents of the membrane bilayer depends on finely-tuned atomic interactions, which itself depends on the precise distribution of amino acids within the 3D structure of the protein. In this regard, tryptophan (Trp), one of the least abundant amino acids, is found at higher levels in transmembrane proteins where it likely plays a role in helping anchor them to the membrane. We now re-evaluate Trp distribution in membrane proteins using all known proteins in the Swiss-Prot database and confirm that it is somewhat higher (∼1.

A framework for neural organoids, assembloids and transplantation studies.

As the field of neural organoids and assembloids rapidly expands, there is an emergent need for guidance and advice on designing, conducting and reporting experiments to increase the reproducibility and utility of these models. Here, our consortium- representing specialized laboratories from around the world- presents a framework for the experimental process that ranges from ensuring the quality and integrity of human pluripotent stem cells to characterizing and manipulating neural cells in vitro, and from transplantation techniques to considerations for modeling human development, evolution, and disease. As with all scientific endeavors, we advocate for rigorous experimental designs tailored to explicit scientific questions, and transparent methodologies and data sharing, to provide useful knowledge for both current research practices and for developing regulatory standards.

Everyone is using biological structures, but how does one find the structure(s) one wants?

A comment on how easy (or difficult) it is to find a stucture of interest and some suggestions on what could be done to start to address the problem.

International consensus statement on microbiome testing in clinical practice.

There is growing interest in the potential exploitation of the gut microbiome as a diagnostic tool in medicine, but evidence supporting its clinical usefulness is scarce. An increasing number of commercial providers offer direct-to-consumer microbiome diagnostic tests without any consensus on their regulation or any proven value in clinical practice, which could result in considerable waste of individual and health-care resources and potential drawbacks in the clinical management of patients. We convened an international multidisciplinary expert panel to standardise best practices of microbiome testing for clinical implementation, including recommendations on general principles and minimum requirements for their provision, indications, pre-testing protocols, method of analyses, reporting of results, and potential clinical value.

Wavelet-based time-frequency intermuscular beta-band coherence decreases with age but increases after mental fatigue in ankle muscles during gait independent of age.

Mental fatigue can affect cognitive function and interfere with motor performance. We examined if mental fatigue affected gait through age-specific modulation of wavelet-based time-frequency intermuscular beta-band coherence in muscles while walking on a treadmill at 1.2 m·s-1.

Enhanced spectral reconstruction of ultrafast spatiotemporal encoded 2D NMR spectroscopy.

Background: Nuclear Magnetic Resonance (NMR) is extensively utilized in research as a non-invasive technique for investigating molecular structures and composite components. The spatiotemporal encoding (SPEN) technique effectively accelerates multi-dimensional NMR experiments. In ultrafast SPEN NMR, the acquired data are divided into odd and even segments corresponding to the positive and negative gradients during the decoding stage, respectively.

EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function.

T cell-based immunotherapies have demonstrated effectiveness in treating diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) but predicting response and understanding resistance remains a challenge. To address this, we developed syngeneic models reflecting the genetics, epigenetics, and immunology of human FL and DLBCL. We show that EZH2 inhibitors reprogram these models to re-express T cell engagement genes and render them highly immunogenic.

Automated Approach to Accurate, Precise, and Fast Detector Simulation and Reconstruction.

Detector simulation and reconstruction are a significant computational bottleneck in particle physics. We develop particle-flow neural-assisted simulations (parnassus) to address this challenge. Our deep learning model takes as input a point cloud (particles impinging on a detector) and produces a point cloud (reconstructed particles).

Reversing protonation of weakly basic drugs greatly enhances intracellular diffusion and decreases lysosomal sequestration.

For drugs to be active they have to reach their targets. Within cells this requires crossing the cell membrane, and then free diffusion, distribution, and availability. Here, we explored the in-cell diffusion rates and distribution of a series of small molecular fluorescent drugs, in comparison to proteins, by microscopy and fluorescence recovery after photobleaching (FRAP).