Endonuclease G promotes hepatic mitochondrial respiration by selectively increasing mitochondrial tRNA production.

Mitochondrial endonuclease G (EndoG) contributes to chromosomal degradation when it is released from mitochondria during apoptosis. It is presumed to also have a mitochondrial function because EndoG deficiency causes mitochondrial dysfunction. However, the mechanism by which EndoG regulates mitochondrial function is not known.

Treating myocardial infarction via a nano-ultrasonic contrast agent-mediated high-efficiency drug delivery system targeting macrophages.

Following myocardial infarction (MI), the accumulation of CD86-positive macrophages in the ischemic injury zone leads to secondary myocardial damage. Precise pharmacological intervention targeting this process remains challenging. This study engineered a nanotherapeutic delivery system with CD86-positive macrophage-specific targeting and ultrasound-responsive release capabilities.

GPSD: a hybrid learning framework for the prediction of phosphatase-specific dephosphorylation sites.

Protein phosphorylation is dynamically and reversibly regulated by protein kinases and protein phosphatases, and plays an essential role in orchestrating a wide range of biological processes. Although a number of tools have been developed for predicting kinase-specific phosphorylation sites (p-sites), computational prediction of phosphatase-specific dephosphorylation sites remains to be a great challenge. In this study, we manually curated 4393 experimentally identified site-specific phosphatase-substrate relationships for 3463 dephosphorylation sites occurring on phosphoserine, phosphothreonine, and/or phosphotyrosine residues, from the literature and public databases.

Biochemical and biophysical mechanisms macrophages use to tune phagocytic appetite.

Macrophages phagocytose, or eat, pathogens, dead cells and cancer cells. To activate phagocytosis, macrophages recognize 'eat me' signals like IgG and phosphatidylserine on the target cell surface. Macrophages must carefully adjust their phagocytic appetite to ignore non-specific or transient eat me signal exposure on healthy cells while still rapidly recognizing pathogens and debris.

ABC transporter activity is affected by the size of lipid nanodiscs.

Lipid nanodiscs have become a widely used approach for studying membrane proteins thanks to several advantages they offer. They have been especially useful for studying ABC transporters, despite the growing concern about the possible restriction of the conformational changes of the transporters due to the small size of the discs. Here, we performed a systematic study to determine the effect of the nanodisc size on the ATPase activity of model ABC transporters from human, plant, and bacteria.

Programming scheduled self-assembly of circadian materials.

Active biological molecules present a powerful, yet largely untapped, opportunity to impart autonomous regulation of materials. Because these systems can function robustly to regulate when and where chemical reactions occur, they have the ability to bring complex, life-like behavior to synthetic materials. Here, we achieve this design feat by using functionalized circadian clock proteins, KaiB and KaiC, to engineer time-dependent crosslinking of colloids.

Evolutionary origins of archaeal and eukaryotic RNA-guided RNA modification in bacterial IS110 transposons.

Transposase genes are ubiquitous in all domains of life and provide a rich reservoir for the evolution of novel protein functions. Here we report deep evolutionary links between bacterial IS110-family transposases, which catalyse RNA-guided DNA recombination using bridge RNAs, and archaeal/eukaryotic Nop5-family proteins, which promote RNA-guided RNA 2'-O-methylation using C/D-box snoRNAs. On the basis of conservation of protein sequence, domain architecture, three-dimensional structure and non-coding RNA features, alongside phylogenetic analyses, we propose that programmable RNA modification emerged through the exaptation of components derived from IS110-like transposons.

NLS-binding deficient Kapβ2 reduces neurotoxicity via selective interaction with C9orf72-ALS/FTD dipeptide repeats.

Arginine-rich dipeptide repeat proteins (R-DPRs) are highly toxic proteins found in patients with C9orf72-linked amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). R-DPRs can cause toxicity by disrupting the natural phase behavior of RNA-binding proteins (RBPs). Mitigating this abnormal phase behavior is, therefore, crucial to reduce R-DPR-induced toxicity.

Emergence of structures in neuronal network activities.

Nonlinear responses of individual neurons are both experimentally established and considered fundamental for the functioning of neuronal circuitry. Consequently, one may envisage the collective dynamics of large networks of neurons exhibiting a large repertoire of nonlinear behaviors. However, an ongoing and central challenge in the modeling of neural dynamics involves the trade-off between tractability and biological realism.

Synthesis and characterization of allomelanin model from 1,8-dihydroxynaphthalene autooxidation.

In this work a novel method for synthesis of 1,8-dihydroxynaphthalene melanin was presented, as well as the physicochemical properties, molecular structure, and characteristics of the pigment. The proposed synthesis protocol is simple and cost-effective with no enzymes or catalysts needed. The final product is not adsorbed on any surface, since the pigment is the result of autooxidation of 1,8-dihydroxynaphthalene.

Conformational landscape of soluble α-klotho revealed by cryogenic electron microscopy.

α-Klotho (KLA) is a type-1 membranous protein that can associate with fibroblast growth factor receptor (FGFR) to form co-receptor for FGF23. The ectodomain of unassociated KLA is shed as soluble KLA (sKLA) to exert FGFR/FGF23-independent pleiotropic functions. The previously determined X-ray crystal structure of the extracellular region of sKLA in complex with FGF23 and FGFR1c suggests that sKLA functions solely as an on-demand coreceptor for FGF23.

Functional protein mining with conformal guarantees.

Molecular structure prediction and homology detection offer promising paths to discovering protein function and evolutionary relationships. However, current approaches lack statistical reliability assurances, limiting their practical utility for selecting proteins for further experimental and in-silico characterization. To address this challenge, we introduce a statistically principled approach to protein search leveraging principles from conformal prediction, offering a framework that ensures statistical guarantees with user-specified risk and provides calibrated probabilities (rather than raw ML scores) for any protein search model.

Surface remodeling and inversion of cell-matrix interactions underlie community recognition and dispersal in Vibrio cholerae biofilms.

Biofilms are ubiquitous surface-associated bacterial communities embedded in an extracellular matrix. It is commonly assumed that biofilm cells are glued together by the matrix; however, how the specific biochemistry of matrix components affects the cell-matrix interactions and how these interactions vary during biofilm growth remain unclear. Here, we investigate cell-matrix interactions in Vibrio cholerae, the causative agent of cholera.

Integrating electronic health records and GWAS summary statistics to predict the progression of autoimmune diseases from preclinical stages.

Autoimmune diseases often exhibit a preclinical stage before diagnosis. Electronic health record (EHR) based-biobanks contain genetic data and diagnostic information, which can identify preclinical individuals at risk for progression. Biobanks typically have small numbers of cases, which are not sufficient to construct accurate polygenic risk scores (PRS).

Long non-coding RNAs direct the SWI/SNF complex to cell type-specific enhancers.

The coordination of chromatin remodeling is essential for DNA accessibility and gene expression control. The highly conserved and ubiquitously expressed SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex plays a central role in cell type- and context-dependent gene expression. Despite the absence of a defined DNA recognition motif, SWI/SNF binds lineage specific enhancers genome-wide where it actively maintains open chromatin state.

MCM2-7 ring closure involves the Mcm5 C-terminus and triggers Mcm4 ATP hydrolysis.

The eukaryotic helicase MCM2-7, is loaded by ORC, Cdc6 and Cdt1 as a double-hexamer onto replication origins. The insertion of DNA into the helicase leads to partial MCM2-7 ring closure, while ATP hydrolysis is essential for consecutive steps in pre-replicative complex (pre-RC) assembly. Currently it is unknown how MCM2-7 ring closure and ATP-hydrolysis are controlled.

A higher order PUF complex is central to regulation of C. elegans germline stem cells.

PUF RNA-binding proteins are broadly conserved stem cell regulators. Nematode PUF proteins maintain germline stem cells (GSCs) and, with key partner proteins, repress differentiation mRNAs, including gld-1. Here we report that PUF protein FBF-2 and its partner LST-1 form a ternary complex that represses gld-1 via a pair of adjacent FBF binding elements (FBEs) in its 3'UTR.

Generic residue numbering of the GAIN domain of adhesion GPCRs.

The GPCR autoproteolysis inducing (GAIN) domain is an ancient protein fold ubiquitous in adhesion G protein-coupled receptors (aGPCR). It contains a tethered agonist necessary and sufficient for receptor activation. The GAIN domain is a hotspot for pathological mutations.

Targeting chromosomally unstable tumors with a selective KIF18A inhibitor.

Chromosome instability is a prevalent vulnerability of cancer cells that has yet to be fully exploited therapeutically. To identify genes uniquely essential to chromosomally unstable cells, we mined the Cancer Dependency Map for genes essential in tumor cells with high levels of copy number aberrations. We identify and validate KIF18A, a mitotic kinesin, as a vulnerability of chromosomally unstable cancer cells.

Invasion of glioma cells through confined space requires membrane tension regulation and mechano-electrical coupling via Plexin-B2.

Glioblastoma (GBM) is a malignant brain tumor with diffuse infiltration. Here, we demonstrate how GBM cells usurp guidance receptor Plexin-B2 for confined migration through restricted space. Using live-cell imaging to track GBM cells negotiating microchannels, we reveal endocytic vesicle accumulation at cell front and filamentous actin assembly at cell rear in a polarized manner.

Endogenous and fluorescent sterols reveal the molecular basis for ligand selectivity of human sterol transporters.

Sterol transport proteins (STPs) play a pivotal role in cholesterol homeostasis and therefore are essential for healthy human physiology. Despite recent advances in dissecting functions of STPs in the human cell, there is still a significant knowledge gap regarding their specific biological functions and a lack of suitable selective probes for their study. Here, we profile fluorescent steroid-based probes across ten STPs, uncovering substantial differences in their selectivity, aiding the retrospective and prospective interpretation of biological results generated with those probes.

Biophysical and Structural Features of αβT-Cell Receptor Mechanosensing: A Paradigmatic Shift in Understanding T-Cell Activation.

αβT cells protect vertebrates against many diseases, optimizing surveillance using mechanical force to distinguish between pathophysiologic cellular alterations and normal self-constituents. The multi-subunit αβT-cell receptor (TCR) operates outside of thermal equilibrium, harvesting energy via physical forces generated by T-cell motility and actin-myosin machinery. When a peptide-bound major histocompatibility complex molecule (pMHC) on an antigen presenting cell is ligated, the αβTCR on the T cell leverages force to form a catch bond, prolonging bond lifetime, and enhancing antigen discrimination.