The rockefeller university

This study uses reporter cells engineered with a minimal expression construct and cells cultured directly from the reservoir of HIV-1 infected individuals to show that proviral transcription in latently infected cells is predominantly dependent on the site of proviral integration. HIV-1 antiretroviral therapy is highly effective but fails to eliminate a reservoir of latent proviruses, leading to a requirement for life-long treatment. How the site of integration of authentic intact latent proviruses might impact their own or neighboring gene expression or reservoir dynamics is poorly understood. Here, we report on proviral and neighboring gene transcription at sites of intact latent HIV-1 integration in cultured T cells obtained directly from people living with HIV, as well as engineered primary T cells and cell lines. Proviral gene expression was correlated to the level of endogenous gene expression under resting but not activated conditions. Notably, latent proviral promoters were 100-10,000x less active than in productively infected cells and had little or no measurable impact on neighboring gene expression under resting or activated conditions. Thus, the site of integration has a dominant effect on the transcriptional activity of intact HIV-1 proviruses in the latent reservoir, thereby influencing cytopathic effects and proviral immune evasion.

Telomere-to-telomere (T2T) assemblies reveal new insights into the structure and function of the previously 'invisible' parts of the genome and allow comparative analyses of complete genomes across entire clades. We present here an open collaborative effort, termed the 'Ruminant T2T Consortium' (RT2T), that aims to generate complete diploid assemblies for numerous species of the Artiodactyla suborder Ruminantia to examine chromosomal evolution in the context of natural selection and domestication of species used as livestock. Here we describe an open collaborative effort termed the 'Ruminant T2T Consortium'. It aims to generate complete diploid assemblies for many species of ruminants to examine chromosomal evolution in the context of natural selection and domestication.

According to Mendel's second law, chromosomes segregate randomly in meiosis. Non-random segregation is primarily known for cases of selfish meiotic drive in females, in which particular alleles bias their own transmission into the oocyte. Here we report a rare example of unselfish meiotic drive for crossover inheritance in the clonal raider ant, Ooceraea biroi, in which both alleles are co-inherited at all loci across the entire genome. This species produces diploid offspring parthenogenetically via fusion of two haploid nuclei from the same meiosis. This process should cause rapid genotypic degeneration due to loss of heterozygosity, which results if crossover recombination is followed by random (Mendelian) segregation of chromosomes. However, by comparing whole genomes of mothers and daughters, we show that loss of heterozygosity is exceedingly rare, raising the possibility that crossovers are infrequent or absent in O. biroi meiosis. Using a combination of cytology and whole-genome sequencing, we show that crossover recombination is, in fact, common but that loss of heterozygosity is avoided because crossover products are faithfully co-inherited. This results from a programmed violation of Mendel's law of segregation, such that crossover products segregate together rather than randomly. This discovery highlights an extreme example of cellular 'memory' of crossovers, which could be a common yet cryptic feature of chromosomal segregation. This study reports non-random segregation of chromosomes during meiosis in the clonal raider ant, Ooceraea biroi, but no loss of heterozygosity because crossover products are faithfully co-inherited.

Telomere-to-telomere (T2T) assemblies reveal new insights into the structure and function of the previously 'invisible' parts of the genome and allow comparative analyses of complete genomes across entire clades. We present here an open collaborative effort, termed the 'Ruminant T2T Consortium' (RT2T), that aims to generate complete diploid assemblies for numerous species of the Artiodactyla suborder Ruminantia to examine chromosomal evolution in the context of natural selection and domestication of species used as livestock. Here we describe an open collaborative effort termed the 'Ruminant T2T Consortium'. It aims to generate complete diploid assemblies for many species of ruminants to examine chromosomal evolution in the context of natural selection and domestication.

The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3-/- (Shn3-/-) mice with augmented osteoblast activity, we show Shn3-/-mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3-/-mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome. The mediators of bone-fat axis remain largely unknown. Here, the authors show SHN3 gene-deficiency in bone can protect mouse models from weight gain driven by diet-induced obesity through secreting a bone-derived cytokine, C-fragment of SLIT2, which could stimulate adipocyte browning.

Neurotransmitters play a crucial role in regulating communication between neurons within the brain and central nervous system. Thus, imaging neurotransmitters has become a high priority in neuroscience. This minireview focuses on recent advancements in the development of fluorescent small-molecule fluorescent probes for neurotransmitter imaging and applications of these probes in neuroscience. Innovative approaches for probe design are highlighted as well as attributes which are necessary for practical utility, with a view to inspiring new probe development capable of visualizing neurotransmitters. This minireview focuses on recent progress in the field of small-molecule fluorescent probes designed for imaging neurotransmitters. We delve into the methodologies employed in creating these probes, specifically targeting a variety of neurotransmitters. Additionally, we emphasize the essential properties necessary for practical applications. image

Elevated pernio incidence was observed during the COVID-19 pandemic. This prospective study enrolled subjects with pandemic-associated pernio in Wisconsin and Switzerland. Because pernio is a cutaneous manifestation of the interferonopathies, and type I interferon (IFN-I) immunity is critical to COVID-19 recovery, we tested the hypothesis that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)mediated IFN-I signaling might underlie some pernio cases. Tissue-level IFN-I activity and plasmacytoid dendritic cell infiltrates were demonstrated in 100% of the Wisconsin cases. Across both cohorts, sparse SARS-CoV-2 RNA was captured in 25% (6/22) of biopsies, all with high inflammation. Affected patients lacked adaptive immunity to SARS-CoV-2. A hamster model of intranasal SARS-CoV-2 infection was used as a proof-of-principle experiment: RNA was detected in lungs and toes with IFN-I activity at both the sites, while replicating virus was found only in the lung. These data support a viral trigger for some pernio cases, where sustained local IFN-I activity can be triggered in the absence of seroconversion.

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. Unlike the known role of VEGF signaling in angiogenesis, we demonstrate a novel, non-canonical role for FLT1 signaling that protects cancer cells from PARPi in-vivo through a combination of cell-intrinsic and cell-extrinsic pathways. We demonstrate that FLT1 blockade suppresses AKT activation, increases tumor infiltration of CD8+ T cells, and causes dramatic regression of PARPi-resistant breast tumors in a T-cell-dependent manner. Moreover, PARPi-resistant tumor cells can be readily re-sensitized to PARPi by targeting Flt1 either genetically (Flt1-suppression) or pharmacologically (axitinib). Importantly, a retrospective series of breast cancer patients treated with PARPi demonstrated shorter progression-free survival in cases with FLT1 activation at pre-treatment. Our study therefore identifies FLT1 as a potential therapeutic target in PARPi-resistant, BRCA1/2-mutant breast cancer. PARP inhibitor (PARPi) resistance is a major treatment challenge that dramatically shortens patient survival. Using new mouse models of PARPi response and recurrence, we identified FLT1 as a potential biomarker and therapeutic target for reversing PARPi resistance in BRCA-mutant breast cancer.New mouse models were developed that recapitulate the PARPi response and recurrence observed in patients.A novel PARPi-adaptive resistance mechanism driven by the PGF-FLT1-AKT pathway was identified.FLT1 signaling protected the cells from PARPi-induced death by activating AKT pro-survival pathways and by dampening the cytotoxic immune response.Blocking FLT1 signaling, either genetically or pharmacologically using axitinib, re-sensitized PARPi-resistant tumors to PARPi treatment in mice.High FLT1 activation in tumor cells at pre-treatment significantly correlated with shorter progression-free survival on PARPi in patients with breast cancer. PARP inhibitor (PARPi) resistance is a major treatment challenge that dramatically shortens patient survival. Using new mouse models of PARPi response and recurrence, we identified FLT1 as a potential biomarker and therapeutic target for reversing PARPi resistance in BRCA-mutant breast cancer.

Monoclonal antibodies (mAbs) have provided valuable information regarding the structure and function of platelet aIIb(33. Protein disulfide isomerase (PDI) has been implicated in aIIb(33 activation and binds to thrombin-activated aIIb(33. Using human platelets as the immunogen, we identified a new mAb (R21D10) that inhibits the binding of PDI to platelets activated with thrombin receptor-activating peptide (T6). R21D10 also partially inhibited T6-induced fibrinogen and PAC-1 binding to platelets, as well as T6- and adenosine 5'-diphosphate-induced platelet aggregation. Mutual competition experiments showed that R21D10 does not inhibit the binding of mAbs 10E5 (anti-aIIb cap domain) or 7E3 (anti-(33 (3-I domain), and immunoblot studies indicated that R21D10 binds to (33. The dissociation of aIIb(33 by EDTA had a minimal effect on R21D10 binding. Cryogenic electron microscopy of the aIIb(33-R21D10 Fab complex revealed that R21D10 binds to the (33 integrin-epidermal growth factor 1 (I-EGF1) domain and traps an intermediate conformation of aIIb(33 with semiextended leg domains. The binding of R21D10 produces a major structural change in the (33 I-EGF2 domain associated with a new interaction between the (33 I-EGF2 and aIIb thigh domains, which may prevent the swing-out motion of the (33 hybrid domain required for high-affinity ligand binding and protect aIIb(33 from EDTA-induced dissociation. R21D10 partially reversed the ligand binding priming effect of eptifibatide, suggesting that it could convert the swung-out conformation into a semiextended conformation. We concluded that R21D10 inhibits ligand binding to aIIb(33 via a unique allosteric mechanism, which may or may not be related to its inhibition of PDI binding.

A search for long-lived particles (LLPs) decaying in the CMS muon detectors is presented. A data sample of proton-proton collisions at root s = 13 TeV corresponding to an integrated luminosity of 138 fb(-1), recorded at the LHC in 2016-2018, is used. The decays of LLPs are reconstructed as high multiplicity clusters of hits in the muon detectors. In the context of twin Higgs models, the search is sensitive to LLP masses from 0.4 to 55 GeV and a broad range of LLP decay modes, including decays to hadrons, tau leptons, electrons, or photons. No excess of events above the standard model background is observed. The most stringent limits to date from LHC data are set on the branching fraction of the Higgs boson decay to a pair of LLPs with masses below 10 GeV. This search also provides the best limits for various intervals of LLP proper decay length and mass. Finally, this search sets the first limits at the LHC on a dark quantum chromodynamic sector whose particles couple to the Higgs boson through gluon, Higgs boson, photon, vector, and dark-photon portals, and is sensitive to branching fractions of the Higgs boson to dark quarks as low as 2 x 10(-3).