Artificial Intelligence and Network Medicine: Path to Precision Medicine.

Over the past two decades, network medicine (NM) has evolved to help define disease mechanisms, identify drug targets, and guide increasingly precise therapies. In recent years, the integration of NM with artificial intelligence (AI), particularly deep learning techniques, has evolved with increasing applications. AI techniques help elucidate complex disease mechanisms and define precise therapies.

Target RNA recognition drives PIWI complex assembly for transposon silencing.

PIWI-clade Argonaute proteins and their associated PIWI-interacting RNAs (piRNAs) are essential guardians of genome integrity, silencing transposable elements through distinct nuclear and cytoplasmic pathways. Nuclear PIWI proteins direct heterochromatin formation at transposon loci, while cytoplasmic PIWIs cleave transposon transcripts to initiate piRNA amplification. Both processes rely on target RNA recognition by PIWI-piRNA complexes, yet how this leads to effector recruitment is unclear.

An ancient and essential miRNA family controls cellular interaction pathways in .

The transition from unicellular to multicellular life required the acquisition of coordinated and regulated cellular behaviors, including adhesion and migration. In metazoans, this involves adhesion proteins, signaling systems, and an elaborate extracellular matrix (ECM) that contributes to adhesion and signaling interactions. Innovations that enabled complex multicellularity occurred through new genes in these pathways, novel functions for existing genes, and regulatory changes.

Mitochondrial ROS drive foam cell formation via STAT5 signaling in atherosclerosis.

Macrophage-to-foam cell transition is an integral part of atherosclerotic plaque progression. Particularly, oxidized low-density lipoprotein (oxLDL) is a driving factor in foam cell formation, altering macrophage function and metabolism. The aim of our research was to understand the impact of oxLDL-induced mitochondrial reactive oxygen species on macrophage-to-foam cell differentiation.

A split-site E3 ligase mechanism enables ZNFX1 to ubiquitinate and cluster single-stranded RNA into ubiquitin-coated nucleoprotein particles.

Eukaryotic cells use a multi-layered immune response to combat intracellular pathogens. The ubiquitin ligase ZNFX1 has emerged as a crucial yet little understood player that regulates the immune response while protecting against RNA viruses. Our study unveils the molecular mechanism of ZNFX1, mediated by the joint activity of a helicase serving as a nucleic acid sensor and a non-conventional E3 module featuring a split active site.

Architecture of the UBR4 complex, a giant E4 ligase central to eukaryotic protein quality control.

Eukaryotic cells have evolved sophisticated quality control mechanisms to eliminate aggregation-prone proteins that compromise cellular health. Central to this defense is the ubiquitin-proteasome system, where UBR4 acts as an essential E4 ubiquitin ligase, amplifying degradation marks on defective proteins. Cryo-electron microscopy analysis of UBR4 in complex with its cofactors KCMF1 and CALM1 reveals a massive 1.

Quantitative profiling of human brain organoid cell diversity across four protocols and multiple cell lines.

Human brain organoids are powerful in vitro models for brain development and disease. However, protocol and pluripotent cell line choices influence organoid variability and cell-type representation, complicating their use in biomedical research. Here, we systematically analyze the cellular and transcriptional landscape of brain organoids across multiple cell lines using four protocols aimed at recapitulating dorsal and ventral forebrain, midbrain, and striatum.

The mitotic STAG3-cohesin complex shapes male germline nucleome.

Germ cells are unique in that they tailor chromatin toward generating totipotency. Accordingly, mammalian spermatogonia, including spermatogonial stem cells that constitute the source for male gametes, acquire distinctive chromatin organization with weak insulation, but the underlying mechanism remains unknown. Here we show that STAG3, so far known to exclusively form meiotic cohesins, generates a mitotic cohesin for male germline nucleome programming in mice.

CLEC18A interacts with sulfated glycosaminoglycans and controls clear cell renal cell carcinoma progression.

C-type lectins are a large protein family with essential functions in both health and disease. In cancer, some C-type lectins have been found to both promote and inhibit tumor growth, but many of the C-type lectins still remain uncharacterized. Here, we report a key role of the C-type lectin domain family 18 members (CLEC18 family) in the progression of clear cell renal cell carcinoma (ccRCC).

The exit from naive pluripotency: a platform for the study of enhancer mechanistics.

Multicellular life depends on the ability to activate and repress genes in a highly context-specific manner. With each cell state transition, a new transcriptional profile is established. As non-coding DNA elements, enhancers mediate their regulatory potential through the effectors they recruit.

An A. thaliana mutant lacking all nine ATG8 isoforms provides genetic evidence for functional specialization of ATG8 in plants.

Autophagy sustains cellular health by recycling damaged or excess components through autophagosomes. Autophagy is mediated by conserved ATG proteins, among which the ubiquitin-like ATG8 proteins play a central role by linking cargo to the growing autophagosomes. Unlike most ATG proteins, the ATG8 gene family is significantly expanded in vascular plants, but its functional specialization remains poorly understood.

In vivo crosslinking and effective 2D enrichment for proteome wide interactome studies.

Cross-linking mass spectrometry has evolved as a powerful technique to study protein-protein interactions and to provide structural information. Low reaction efficiencies, and complex matrices lead to challenging system wide crosslink analysis. We improved and streamlined an Azide-A-DSBSO based in vivo crosslinking workflow employing two orthogonal effective enrichment steps: Affinity enrichment and size exclusion chromatography (SEC).

Protein Storage in Oocytes: Implications for Oocyte Quality, Embryonic Development, and Female Fertility.

Maternal storage is a fundamental feature of female gametes and is essential for maintaining oocyte quality and preserving developmental competence. Embryonic development relies on maternally deposited proteins, transcripts, and nutrients, yet the mechanisms by which oocytes accumulate and store these critical factors-particularly proteins-remain poorly understood. Across eukaryotes, diverse protein storage strategies have evolved, reflecting both conserved and species-specific adaptations.

The evolution of RHO of plant (ROP) proteins and their morphogenetic functions.

The ability of a cell to polarise, and direct cell growth or orient cell division, for example, is fundamental for the morphogenesis of multicellular organisms. A key molecular system for signalling cell polarity in diverse eukaryotes involves the RHO family of small GTPases. Since its origin in early eukaryotes, the RHO family has evolved independently in different lineages, and the plant-specific subfamily of RHO - RHO of plants (ROP) - was established in the streptophyte algal ancestors of land plants.

An unexpected tumor-resistant phenotype from floxing PAK1 in a mouse model of colitis associated cancer.

Inflammatory bowel disease (IBD) and colitis-associated cancer are associated with activation of PAK1 (p-21 activated kinase 1). We previously found that total knockout of PAK1 (PAK1KO) reduced tumorigenesis upon AOM/DSS but enhanced tumorigenesis in another model of IBD with total knockout of IL10 (IL10KO). To better understand the specific role of epithelial PAK1, we crossed Pak1 floxed (PAK1fl) with VillinCre mice for a conditional knockout of PAK1 in intestinal epithelia (PAK1CKO).

Integrated time-series analysis and high-content CRISPR screening delineate the dynamics of macrophage immune regulation.

Macrophages are innate immune cells involved in host defense. Dissecting the regulatory landscape that enables their swift and specific response to pathogens, we performed time-series analysis of gene expression and chromatin accessibility in murine macrophages exposed to various immune stimuli, and we functionally evaluated gene knockouts at scale using a combined CROP-seq and CITE-seq assay. We identified new roles of transcription regulators such as Spi1/PU.

Multi-scale simulations of MUT-16 scaffold protein phase separation and client recognition.

Phase separation of proteins plays a critical role in cellular organization. How phase-separated protein condensates underpin biological function and how condensates achieve specificity remain elusive. We investigated the phase separation of MUT-16, a scaffold protein in Mutator foci, and its role in recruiting the client protein MUT-8, a key component in RNA silencing in Caenorhabditis elegans.

DIY innate immune sensing: Crafting fresh DNA to detect viruses.

The innate immune receptor cGAS is geared toward detecting DNA from pathogens. In a recent Cell publication, Lahaye et al. discovered that viral infection triggers de novo synthesis of self-DNA-activating cGAS.

Functional divergence of conserved developmental plasticity genes between two distantly related nematodes.

Genes diverge in form and function in multiple ways over time; they can be conserved, acquire new roles, or eventually be lost. However, the way genes diverge at the functional level is little understood, particularly in plastic systems. We investigated this process using two distantly related nematode species, Allodiplogaster sudhausi and Pristionchus pacificus.

NIPBL and STAG1 enable loop extrusion by providing differential DNA-cohesin affinity.

DNA loop extrusion by cohesin has emerged as a critical pathway for chromosome organization. In vitro single-molecule experiments indicate that loop extrusion requires the assembly of a heteropentameric complex consisting of the SMC1/SMC3 heterodimer, STAG1, NIPBL, and the kleisin SCC1. The complexity of the complete extrusion machinery, consisting of multiple subunits, DNA binding sites, and ATPases poses substantial challenges for revealing the underlying biomolecular mechanism.

Joint Estimation of Paternity, Sibships and Pollen Dispersal in a Snapdragon Hybrid Zone.

Inferring genealogical relationships of wild populations is useful because it gives direct estimates of mating patterns and variance in reproductive success. Inference can be improved by including information about parentage shared between siblings, or by modelling phenotypes or population data related to mating. However, we currently lack a framework to infer parent-offspring relationships, sibships and population parameters in a single analysis.

Epiplakin expression is lost in psoriatic skin lesions and is downregulated by IFN-γ in skin cultures.

Proteins of the plakin family are predominantly expressed in the epidermis and play a crucial role in cytoskeletal assembly by crosslinking intracellular structural components with cell-cell junctions and the plasma membrane. While most plakins are critical for maintaining epidermal integrity, the role of epiplakin (EPPK1) in inflammatory skin disorders has not been thoroughly investigated. We therefore used single-cell RNA sequencing (scRNAseq) analysis, immunofluorescence, and cytokine treatment of human skin explants to investigate EPPK1 regulation in psoriasis.

The histone core domain evolves at single-residue resolution to directly orchestrate transcription.

Nucleosomes are thought to be structural barriers to transcription, establishing a restrictive ground state that must be destabilized for gene expression. However, structural insights have revealed that transcription can proceed in the presence of nucleosomes, suggesting that this model is incomplete. Here, we reconstituted H2A.

Reconstitution of BNIP3/NIX-mitophagy initiation reveals hierarchical flexibility of the autophagy machinery.

Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. Although the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. Here we demonstrate that the human transmembrane cargo receptors can initiate autophagosome biogenesis not only by recruiting the upstream FIP200/ULK1 complex but also via a WIPI-ATG13 complex.

Octenidine effectively reduces Candida auris colonisation on human skin.

Candidozyma (formerly Candida) auris (C. auris), a WHO critical priority pathogen known for its multi-drug resistance and strong skin tropism, is posing a significant health threat. This study evaluates the efficacy of commercial octenidine-based antiseptics in reducing C.