Structure of the flotillin complex in a native membrane environment.

In this study, we used cryoelectron microscopy to determine the structures of the Flotillin protein complex, part of the Stomatin, Prohibitin, Flotillin, and HflK/C (SPFH) superfamily, from cell-derived vesicles without detergents. It forms a right-handed helical barrel consisting of 22 pairs of Flotillin1 and Flotillin2 subunits, with a diameter of 32 nm at its wider end and 19 nm at its narrower end. Oligomerization is stabilized by the C terminus, which forms two helical layers linked by a β-strand, and coiled-coil domains that enable strong charge-charge intersubunit interactions.

Eosinophils in hidradenitis suppurativa patients exhibit pro-inflammatory traits, implicating a potential pathogenic role in the disease.

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and purulent secretions in intertriginous regions. Intense pruritus frequently accompanies HS lesions, adding further discomfort for patients. While Th17 pathway activation is implicated in HS pathogenesis, disease mechanisms are still not fully understood, and therapeutics are lacking.

Replicative senescence is ATM driven, reversible, and accelerated by hyperactivation of ATM at normoxia.

Programmed telomere shortening limits tumorigenesis through the induction of replicative senescence. Here we address three long-standing questions concerning senescence. First, we show that the ATM kinase is solely responsible for the induction of replicative senescence.

Metabolic gene function discovery platform GeneMAP identifies SLC25A48 as necessary for mitochondrial choline import.

Organisms maintain metabolic homeostasis through the combined functions of small-molecule transporters and enzymes. While many metabolic components have been well established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association studies (GWAS) to develop a multiomic Gene-Metabolite Association Prediction (GeneMAP) discovery platform.

Establishing African genomics and bioinformatics programs through annual regional workshops.

The African BioGenome Project (AfricaBP) Open Institute for Genomics and Bioinformatics aims to overcome barriers to capacity building through its distributed African regional workshops and prioritizes the exchange of grassroots knowledge and innovation in biodiversity genomics and bioinformatics. In 2023, we implemented 28 workshops on biodiversity genomics and bioinformatics, covering 11 African countries across the 5 African geographical regions. These regional workshops trained 408 African scientists in hands-on molecular biology, genomics and bioinformatics techniques as well as the ethical, legal and social issues associated with acquiring genetic resources.

Human life within a narrow range: The lethal ups and downs of type I interferons.

The past 20 years have seen the definition of human monogenic disorders and their autoimmune phenocopies underlying either defective or enhanced type I interferon (IFN) activity. These disorders delineate the impact of type I IFNs in natural conditions and demonstrate that only a narrow window of type I IFN activity is beneficial. Insufficient type I IFN predisposes humans to life-threatening viral diseases (albeit unexpectedly few) with a central role in immunity to respiratory and cerebral viral infection.

IL-12 drives the differentiation of human T follicular regulatory cells.

T follicular regulatory (T) cells can counteract the B cell helper activity of T follicular helper (T) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (T) cells into T cells is still missing. Herein, we report that low doses of the pro-T cytokine interleukin-12 (IL-12) drive the induction of a T cell program on activated human T cells while also preserving their regulatory function.

FLT1 activation in cancer cells promotes PARP-inhibitor resistance in breast cancer.

Acquired resistance to PARP inhibitors (PARPi) remains a treatment challenge for BRCA1/2-mutant breast cancer that drastically shortens patient survival. Although several resistance mechanisms have been identified, none have been successfully targeted in the clinic. Using new PARPi-resistance models of Brca1- and Bard1-mutant breast cancer generated in-vivo, we identified FLT1 (VEGFR1) as a driver of resistance.

Apoptotic and Nonapoptotic Cell Death in Development.

Programmed cell death (PCD) is an essential component of animal development, and aberrant cell death underlies many disorders. Understanding mechanisms that govern PCD during development can provide insight into cell death programs that are disrupted in disease. Key steps mediating apoptosis, a highly conserved cell death program employing caspase proteases, were first uncovered in the nematode , a powerful model system for PCD research.

An IDR-dependent mechanism for nuclear receptor control of Mediator interaction with RNA polymerase II.

The essential Mediator (MED) coactivator complex plays a well-understood role in regulation of basal transcription in all eukaryotes, but the mechanism underlying its role in activator-dependent transcription remains unknown. We investigated modulation of metazoan MED interaction with RNA polymerase II (RNA Pol II) by antagonistic effects of the MED26 subunit and the CDK8 kinase module (CKM). Biochemical analysis of CKM-MED showed that the CKM blocks binding of the RNA Pol II carboxy-terminal domain (CTD), preventing RNA Pol II interaction.

A familiar face and person processing area in the human temporal pole.

How does the brain process the faces of familiar people? Neuropsychological studies have argued for an area of the temporal pole (TP) linking faces with person identities, but magnetic susceptibility artifacts in this region have hampered its study with fMRI. Using data acquisition and analysis methods optimized to overcome this artifact, we identify a familiar face response in TP, reliably observed in individual brains. This area responds strongly to visual images of familiar faces over unfamiliar faces, objects, and scenes.

Early intermediates in bacterial RNA polymerase promoter melting visualized by time-resolved cryo-electron microscopy.

During formation of the transcription-competent open complex (RPo) by bacterial RNA polymerases (RNAPs), transient intermediates pile up before overcoming a rate-limiting step. Structural descriptions of these interconversions in real time are unavailable. To address this gap, here we use time-resolved cryogenic electron microscopy (cryo-EM) to capture four intermediates populated 120 ms or 500 ms after mixing Escherichia coli σ-RNAP and the λP promoter.

Search for Baryon Number Violation in Top Quark Production and Decay Using Proton-Proton Collisions at sqrt[s]=13 TeV.

A search is presented for baryon number violating interactions in top quark production and decay. The analysis uses data from proton-proton collisions at a center-of-mass energy of 13 TeV, collected with the CMS detector at the LHC with an integrated luminosity of 138  fb^{-1}. Candidate events are selected by requiring two oppositely charged leptons (electrons or muons) and exactly one jet identified as originating from a bottom quark.

 sp. nov.: A new Chinese (Hymenoptera, Formicidae, Dorylinae) species with a dealate queen, closely allied to the queenless clonal raider ant .

The clonal raider ant, , is a queenless species that reproduces asexually, and these traits make it an attractive model system for laboratory research. However, it is unclear where on the ant phylogeny these traits evolved, partly because few closely related species have been described and studied. Here, we describe a new raider ant species, , from Zhejiang, China.

Reexamining the use of race in medical algorithms: the maternal health calculator debate.

The concept of race is prevalent in medical, nursing, and public health literature. Clinicians often incorporate race into diagnostics, prognostic tools, and treatment guidelines. An example is the recently heavily debated use of race and ethnicity in the Vaginal Birth After Cesarean (VBAC) calculator.

Subcellular location of L1 retrotransposon-encoded ORF1p, reverse transcription products, and DNA sensors in lupus granulocytes.

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unpredictable course of recurrent exacerbations alternating with more stable disease. SLE is characterized by broad immune activation and autoantibodies against double-stranded DNA and numerous proteins that exist in cells as aggregates with nucleic acids, such as Ro60, MOV10, and the L1 retrotransposon-encoded ORF1p.

Results: Here we report that these 3 proteins are co-expressed and co-localized in a subset of SLE granulocytes and are concentrated in cytosolic dots that also contain DNA: RNA heteroduplexes and the DNA sensor ZBP1, but not cGAS.

Next-generation neuropeptide Y receptor small-molecule agonists inhibit mosquito-biting behavior.

Background: Female Aedes aegypti mosquitoes can spread disease-causing pathogens when they bite humans to obtain blood nutrients required for egg production. Following a complete blood meal, host-seeking is suppressed until eggs are laid. Neuropeptide Y-like receptor 7 (NPYLR7) plays a role in endogenous host-seeking suppression and previous work identified small-molecule NPYLR7 agonists that inhibit host-seeking and blood-feeding when fed to mosquitoes at high micromolar doses.

Simulation of Radiation-Induced DNA Damage and Protection by Histones Using the Code RITRACKS.

(1) Background: DNA damage is of great importance in the understanding of the effects of ionizing radiation. Various types of DNA damage can result from exposure to ionizing radiation, with clustered types considered the most important for radiobiological effects. (2) Methods: The code RITRACKS (Relativistic Ion Tracks), a program that simulates stochastic radiation track structures, was used to simulate DNA damage by photons and ions spanning a broad range of linear energy transfer (LET) values.

Pathogenic variants in autism gene cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics.

Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with autism spectrum disorders (ASD). a member of Katanin family microtubule-severing ATPases, is a known ASD risk gene, but its roles in human brain development remain unclear. Here, we show that nonsense truncation of () in mice results in classic ciliopathy phenotypes, including impaired spermatogenesis and cerebral ventriculomegaly.

A nucleosome switch primes Hepatitis B Virus infection.

Chronic hepatitis B virus (HBV) infection is an incurable global health threat responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, Smc5/6.