Identification of specific microbiota members that induce beige fat biogenesis in response to dietary cues.

Activation of brown and beige fat biogenesis promotes metabolic health in rodents and humans, but typically requires cold exposure or pharmacological activation of β-adrenergic receptors, which may pose cardiovascular risks. Dietary intervention represents a clinically viable alternative strategy to induce beige cells and thus enhance metabolic health, though the underlying mechanisms remain poorly understood. In this study, we identified specific microbiota members in both mice and humans that promote browning of white adipose tissue (WAT) and ameliorate metabolic disorders in the context of a low-protein diet (LPD).

The sparse driver system for single-cell labeling and manipulation in .

In this protocol, we introduce a sparse driver system for cell-type specific single-cell labeling and manipulation in , enabling complete and simultaneous expression of multiple transgenes in the same cells. The system precisely controls expression probability and sparsity via mutant sites with reduced recombination efficiency and tunable FLP levels adjusted by heat-shock durations. We demonstrate that this generalizable toolkit enables tunable sparsity, multi-color staining, single-cell trans-synaptic tracing, single-cell manipulation, and analysis of cell-autonomous gene function.

Cryo-EM structure of a photosystem I variant containing an unusual plastoquinone derivative in its electron transfer chain.

Photosystem I (PS I) is a light-driven oxidoreductase responsible for converting photons into chemical bond energy. Its application for renewable energy was revolutionized by the creation of the MenB deletion (Δ) variant in the cyanobacterium sp. PCC 6803, in which phylloquinone is replaced by plastoquinone-9 with a low binding affinity.

Analysis of shared variants between cancer biospecimens.

Purpose: Mutational data from multiple solid and liquid biospecimens of a single patient is often integrated to track cancer evolution. However, there is no accepted framework to resolve if individual samples from the same individual share variants due to common identity versus coincidence.

Experimental Design: Utilizing 8,000 patient tumors from The Cancer Genome Atlas (TCGA) across 33 cancer types, we estimated background rates of co-occurrence rates of mutations between discrete pairs of samples across cancers and by cancer type.

Directed evolution of the multicopper oxidase laccase for cell surface proximity labeling and electron microscopy.

Enzymes that oxidize aromatic substrates have shown utility in a range of cell-based technologies including live cell proximity labeling (PL) and electron microscopy (EM), but are associated with drawbacks such as the need for toxic HO. Here, we explore laccases as a novel enzyme class for PL and EM in mammalian cells. LaccID, generated via 11 rounds of directed evolution from an ancestral fungal laccase, catalyzes the one-electron oxidation of diverse aromatic substrates using O instead of toxic HO, and exhibits activity selective to the surface plasma membrane of both living and fixed cells.

Mouse Pachytene piRNAs Cleave Hundreds of Transcripts, But Alter the Steady-State Abundance of Only a Minority of Targets.

In animals, 18-35-nt piRNAs guide PIWI proteins to regulate complementary RNAs. During male meiosis, mammals produce an exceptionally abundant class of piRNAs called pachytene piRNAs. Pachytene piRNAs are required for spermatogenesis and have been proposed to control gene expression by various mechanisms.

A coordinated kinase and phosphatase network regulates Stu2 recruitment to yeast kinetochores.

Cells coordinate diverse events at anaphase onset, including separase activation, cohesin cleavage, chromosome separation, and spindle reorganization. Regulation of the XMAP215 family member and microtubule polymerase, Stu2, at the metaphase-anaphase transition determines a specific redistribution from kinetochores to spindle microtubules. We show that cells modulate Stu2 kinetochore-microtubule localization by Polo-like kinase1/Cdc5-mediated phosphorylation of T866, near the Stu2 C-terminus, thereby promoting dissociation from the kinetochore Ndc80 complex.

AlphaFold2 enables accurate deorphanization of ligands to single-pass receptors.

Secreted proteins play crucial roles in paracrine and endocrine signaling; however, identifying ligand-receptor interactions remains challenging. Here, we benchmarked AlphaFold2 (AF2) as a screening approach to identify extracellular ligands to single-pass transmembrane receptors. Key to the approach is the optimization of AF2 input and output for screening ligands against receptors to predict the most probable ligand-receptor interactions.

Spatiotemporal modeling of molecular holograms.

Quantifying spatiotemporal dynamics during embryogenesis is crucial for understanding congenital diseases. We developed Spateo (https://github.com/aristoteleo/spateo-release), a 3D spatiotemporal modeling framework, and applied it to a 3D mouse embryogenesis atlas at E9.

Intermittent rate coding and cue-specific ensembles support working memory.

Persistent, memorandum-specific neuronal spiking activity has long been hypothesized to underlie working memory. However, emerging evidence suggests a potential role for 'activity-silent' synaptic mechanisms. This issue remains controversial because evidence for either view has largely relied either on datasets that fail to capture single-trial population dynamics or on indirect measures of neuronal spiking.

Ribosomal peptides with polycyclic isoprenoid moieties.

Isoprenoid modifications of proteins and peptides serve fundamental biological functions and are of therapeutic interest. While C (farnesyl) and C (geranylgeranyl) moieties are prevalent among proteins, known ribosomal peptide prenylations involve shorter-chain units not exceeding farnesyl in size. To our knowledge, cyclized terpene moieties have not been reported from either biomolecule class.

Comparison of orientation encoding across layers within single columns of primate V1 revealed by high-density recordings.

Primary visual cortex (V1) has been the focus of extensive neurophysiological investigations, with its laminar organization serving as a crucial model for understanding the functional logic of neocortical microcircuits. Utilizing newly developed high-density, Neuropixels probes, we measured visual responses from large populations of simultaneously recorded neurons distributed across layers of macaque V1. Within single recordings, myriad differences in the functional properties of neuronal subpopulations could be observed.

PRC2-RNA interactions: Viewpoint from Tom Cech, Chen Davidovich, and Richard Jenner.

Diverse biochemical, structural, and in vivo data support models for the regulation of polycomb repressive complex 2 (PRC2) activity by RNAs, which may contribute to the maintenance of epigenetic states. Here, we summarize this research and also suggest why it can be difficult to capture biologically relevant PRC2-RNA interactions in living cells.

Optimized expansion microscopy reveals species-specific spindle microtubule organization in egg extracts.

The spindle is a key structure in cell division as it orchestrates the accurate segregation of genetic material. While its assembly and function are well-studied, the mechanisms regulating spindle architecture remain elusive. In this study, we investigate the differences in spindle organization between and , leveraging expansion microscopy (ExM) to overcome the limitations of conventional imaging techniques.

Glial Malignancies.

Gliomas comprise a diverse spectrum of related tumor subtypes with varying biological and molecular features and clinical outcomes. Advances in detailed genetic and epigenetic characterizations along with an appreciation that subtypes associated with developmental origins, including brain location and patient age, have shifted glioma classification from the historical reliance on histopathological features to updated categories incorporating molecular signatures and spatiotemporal incidence. Within a subtype, individual gliomas show cellular heterogeneity, generally containing subpopulations resembling different types of normal glial and progenitor cells.

Substrate Specificity of a Methyltransferase Involved in the Biosynthesis of the Lantibiotic Cacaoidin.

Modification of the N- and C-termini of peptides enhances their stability against degradation by exopeptidases. The biosynthetic pathways of many peptidic natural products feature enzymatic modification of their termini, and these enzymes may represent a valuable pool of biocatalysts. The lantibiotic cacaoidin carries an ,-dimethylated N-terminal amine group.

Bibacillin 1: a two-component lantibiotic from .

Here we describe bibacillin 1 - a two-component lantibiotic from . The peptides that comprise bibacillin 1 are modified by a class II lanthipeptide synthetase Bib1M producing two peptides with non-overlapping ring patterns that are reminiscent of cerecidin and the short component of the enterococcal cytolysin (CylL''), a virulence factor associated with human disease. Stereochemical analysis demonstrated that each component contains ll-methyllanthionine and dl-lanthionine.

Targeting Ras-, Rho-, and Rab-family GTPases via a conserved cryptic pocket.

The family of Ras-like GTPases consists of over 150 different members, regulated by an even larger number of guanine exchange factors (GEFs) and GTPase-activating proteins (GAPs) that comprise cellular switch networks that govern cell motility, growth, polarity, protein trafficking, and gene expression. Efforts to develop selective small molecule probes and drugs for these proteins have been hampered by the high affinity of guanosine triphosphate (GTP) and lack of allosteric regulatory sites. This paradigm was recently challenged by the discovery of a cryptic allosteric pocket in the switch II region of K-Ras.

Dimensionality reduction simplifies synaptic partner matching in an olfactory circuit.

The distribution of postsynaptic partners in three-dimensional (3D) space presents complex choices for a navigating axon. Here, we discovered a dimensionality reduction principle in establishing the 3D glomerular map in the fly antennal lobe. Olfactory receptor neuron (ORN) axons first contact partner projection neuron (PN) dendrites at the 2D spherical surface of the antennal lobe during development, regardless of whether the adult glomeruli are at the surface or interior of the antennal lobe.

Structures of the human leading strand Polε-PCNA holoenzyme.

In eukaryotes, the leading strand DNA is synthesized by Polε and the lagging strand by Polδ. These replicative polymerases have higher processivity when paired with the DNA clamp PCNA. While the structure of the yeast Polε catalytic domain has been determined, how Polε interacts with PCNA is unknown in any eukaryote, human or yeast.