Lysosomal membrane homeostasis and its importance in physiology and disease.

Lysosomes are membranous organelles that are crucial for cell function and organ physiology. Serving as the terminal stations of the endocytic pathway, lysosomes have fundamental roles in the degradation of endogenous and exogenous macromolecules and particles as well as damaged or superfluous organelles. Moreover, the lysosomal membrane is a docking and activation platform for several signalling components, including mTOR complex 1 (mTORC1), which orchestrates metabolic signalling in the cell.

Novel therapies in Sjögren's disease: A systematic review of the literature.

Sjögren's disease (SjD) is a chronic systemic autoimmune disorder that primarily involves lymphocytic infiltration of exocrine glands, with frequent extra-glandular manifestations. Historically, treatment options for SjD have been limited to alleviating symptoms, rather than treating the underlying cause or preventing disease progression. Furthermore, past clinical trials of therapies such as rituximab failed to demonstrate improvement in symptoms or disease activity.

Spatially coordinated predation with division of labor increases feeding success in killer whales.

Group hunting is widespread among large vertebrates and is known to confer considerable advantages compared with foraging alone. Yet, the mechanisms underlying group hunting, including how social predators are organized during a hunt, are largely unknown for marine predators. Using drone videos, we tracked the predatory behavior of killer whales along the Norwegian coast to test the hypothesis that group hunting is organized in space, both in terms of individual roles and interactions with conspecifics.

MED13L pathogenic missense variants impair protein stability and interaction, underlying diverse clinical outcomes.

Heterozygous pathogenic variants in the Mediator complex subunit 13-like gene located in the locus 12q21.21 (MED13L) are associated with intellectual disability, developmental delay, and distinctive facial features. While nonsense and frameshift variants typically cause haploinsufficiency, resulting in a well-characterized clinical presentation, missense variants have been associated with a broader range of phenotypes, including epilepsy and severe motor delay.

Off-pore Nup98 condensates mobilize heterochromatic breaks and exclude Rad51.

Phase separation forms membraneless compartments, including heterochromatin "domains" and repair foci. Pericentromeric heterochromatin mostly comprises repeated sequences prone to aberrant recombination. In Drosophila cells, "safe" homologous recombination (HR) repair of these sequences requires their relocalization to the nuclear periphery before Rad51 recruitment and strand invasion.

Dark-based optical sectioning assists background removal in fluorescence microscopy.

In fluorescence microscopy, a persistent challenge is the defocused background that obscures cellular details and introduces artifacts. Here, we introduce Dark sectioning, a method inspired by natural image dehazing for removing backgrounds that leverages dark channel prior and dual frequency separation to provide single-frame optical sectioning. Unlike denoising or deconvolution, Dark sectioning specifically targets and removes out-of-focus backgrounds, stably improving the signal-to-background ratio by nearly 10 dB and structural similarity index measure of images by approximately tenfold.

Mechanisms of endurance and resistance exercise in type 2 diabetes mellitus: A Narrative review.

In the treatment and management of type 2 diabetes mellitus (T2DM), exercise therapy has received increasing attention due to its accessibility and cost-effectiveness. Regular physical exercise improves glycemic control by ameliorating insulin resistance (IR) and reducing the risk of complications. However, the distinct mechanisms underlying the efficacy of endurance training (ET) and resistance training (RT) in T2DM remain incompletely understood.

Anaerobic digestion of cyanobacterial biomass for plant fertilizer production on Mars.

Background: A sustained presence on Mars requires the production of food on site, but farming is limited by the local availability of suitable nutrients. Cyanobacteria can feed on Martian resources, and we hypothesized that the nutrients they mobilize could be extracted through anaerobic digestion and used as crop fertilizer.

Methods: We therefore tested the abilities of three microbial communities to digest the biomass of Anabaena sp.

Human BioMolecular Atlas Program (HuBMAP): 3D Human Reference Atlas construction and usage.

The Human BioMolecular Atlas Program (HuBMAP) aims to construct a 3D Human Reference Atlas (HRA) of the healthy adult body. Experts from 20+ consortia collaborate to develop a Common Coordinate Framework (CCF), knowledge graphs and tools that describe the multiscale structure of the human body (from organs and tissues down to cells, genes and biomarkers) and to use the HRA to characterize changes that occur with aging, disease and other perturbations. HRA v.

Pre-existing stem cell heterogeneity dictates clonal responses to the acquisition of leukemic driver mutations.

Cancer cells display wide phenotypic variation even across patients with the same mutations. Differences in the cell of origin provide a potential explanation, but traditional assays lack the resolution to distinguish clonally heterogeneous subsets of stem and progenitor cells. To address this challenge, we developed simultaneous tracking of recombinase activation and clonal kinetics (STRACK), a method to trace clonal dynamics and gene expression before and after the acquisition of cancer mutations.

Immune Cell Engagers: Advancing Precision Immunotherapy for Cancer Treatment.

Immune cell engagers (ICEs) are an emerging class of immunotherapies designed to harness the immune system's anti-tumor potential through precise targeting and activation of immune effector cells. By engaging T cells, natural killer (NK) cells, and phagocytes, ICEs overcome challenges such as immune evasion and MHC downregulation, addressing critical barriers in cancer treatment. T-cell engagers (TCEs), led by bispecific T-cell engagers (BiTEs), dominate the field, with innovations such as half-life-extended BiTEs, trispecific antibodies, and checkpoint inhibitory T-cell engagers driving their application in hematologic and solid malignancies.

Reconstitution of SPO11-dependent double-strand break formation.

Meiotic recombination starts with SPO11 generation of DNA double-strand breaks (DSBs). SPO11 is critical for meiosis in most species, but it generates dangerous DSBs with mutagenic and gametocidal potential. Cells must therefore utilize the beneficial functions of SPO11 while minimizing its risks-how they do so remains poorly understood.

AcrVIB1 inhibits CRISPR-Cas13b immunity by promoting unproductive crRNA binding accessible to RNase attack.

Anti-CRISPR proteins (Acrs) inhibit CRISPR-Cas immune defenses, with almost all known Acrs acting on the Cas nuclease-CRISPR (cr)RNA ribonucleoprotein (RNP) complex. Here, we show that AcrVIB1 from Riemerella anatipestifer, the only known Acr against Cas13b, principally acts upstream of RNP complex formation by promoting unproductive crRNA binding followed by crRNA degradation. AcrVIB1 tightly binds to Cas13b but not to the Cas13b-crRNA complex, resulting in enhanced rather than blocked crRNA binding.

DeepPrep: an accelerated, scalable and robust pipeline for neuroimaging preprocessing empowered by deep learning.

Neuroimaging has entered the era of big data. However, the advancement of preprocessing pipelines falls behind the rapid expansion of data volume, causing substantial computational challenges. Here we present DeepPrep, a pipeline empowered by deep learning and a workflow manager.

Adult bi-paternal offspring generated through direct modification of imprinted genes in mammals.

Imprinting abnormalities pose a significant challenge in applications involving embryonic stem cells, induced pluripotent stem cells, and animal cloning, with no universal correction method owing to their complexity and stochastic nature. In this study, we targeted these defects at their source-embryos from same-sex parents-aiming to establish a stable, maintainable imprinting pattern de novo in mammalian cells. Using bi-paternal mouse embryos, which exhibit severe imprinting defects and are typically non-viable, we introduced frameshift mutations, gene deletions, and regulatory edits at 20 key imprinted loci, ultimately achieving the development of fully adult animals, albeit with a relatively low survival rate.

Combining systemic and local osteoporosis treatments: A longitudinal in vivo microCT study in ovariectomized rats.

Introduction: Managing osteoporotic patients at immediate fracture risk is challenging, in part due to the slow and localized effects of anti-osteoporotic drugs. Combining systemic anti-osteoporotic therapies with local bone augmentation techniques offers a promising strategy, but little is known about potential interactions. We hypothesized that integrating systemic treatments with local bone-strengthening biomaterials would have an additive effect on bone density and structure.

Boltz-1 Democratizing Biomolecular Interaction Modeling.

Understanding biomolecular interactions is fundamental to advancing fields like drug discovery and protein design. In this paper, we introduce Boltz-1, an open-source deep learning model incorporating innovations in model architecture, speed optimization, and data processing achieving Alphafold3-level accuracy in predicting the 3D structures of biomolecular complexes. Boltz-1 demonstrates a performance on-par with state-of-the-art commercial models on a range of diverse benchmarks, setting a new benchmark for commercially accessible tools in structural biology.

The ribotoxic stress response drives acute inflammation, cell death, and epidermal thickening in UV-irradiated skin in vivo.

Solar UVB light causes damage to the outermost layer of skin. This insult induces rapid local responses, such as dermal inflammation, keratinocyte cell death, and epidermal thickening, all of which have traditionally been associated with DNA damage response signaling. Another stress response that is activated by UVB light is the ribotoxic stress response (RSR), which depends on the ribosome-associated mitogen-activated protein 3 kinases (MAP3K) ZAKα and culminates in p38 and JNK activation.

Appendicular myology of Skorpiovenator bustingorryi: A first attempt to reconstruct pelvic and hindlimb musculature in an abelisaurid theropod.

We present the pelvic and hindlimb musculature of the abelisaurid Skorpiovenator bustingorryi, constituting the most comprehensive muscle reconstruction to date in ceratosaur theropods. Using extant phylogenetic bracket method, we reconstructed 39 muscles that can commonly found in extant archosaurs. Through the identification of bone correlates, we recognized thigh and hindlimb muscles including knee extensors, m.

Quantitative evidence for dimorphism suggests sexual selection in the maxillary caniniform process of Placerias hesternus.

Placerias hesternus, a Late Triassic dicynodont, is one of the last megafaunal synapsids of the Mesozoic. The species has a tusk-like projection on its maxillary bone, known as the caniniform process. This process has been hypothesized to be sexually dimorphic since the 1950s, however this claim has not been thoroughly investigated quantitatively.