The rockefeller university

Oxytocin, an evolutionarily conserved neuropeptide, plays a crucial role in various physiological and behavioural processes, offering potential therapeutic benefits for several psychiatric and neurodevelopmental conditions. Despite its promise, oxytocin research has been marked by inconsistent results concerning its therapeutic applications and underlying mechanisms. Performing a systematic review and meta-analysis is a popular approach to shed light on mixed findings in a body of literature; however, they can become quickly outdated as new evidence becomes available. Given these challenges, research on the links between oxytocin and biobehavioural outcomes is ideally positioned for the adoption of 'living' meta-analyses, which allow for the continuous integration of new data and updated conclusions. Here we introduce the Active Monitoring of Oxytocin Research Evidence (AMORE) platform (https://amore-project.org), which is a hub that aggregates articles and materials associated with living meta-analyses for biobehavioural oxytocin research in humans. Developed through consensus among 24 expert researchers, a standardized framework was established that either requires or recommends practices ensuring transparency and rigor in living meta-analyses featured on the AMORE platform. Overall, AMORE has been designed to advance human oxytocin biobehavioural research by the timely integration of emerging evidence through transparent living meta-analyses. To date, two living meta-analysis projects at different stages of publication are hosted on AMORE, demonstrating the platform's practical application.

The complement system is a central component of innate and shaping adaptive responses. Deficiencies in complement proteins, whether inherited or acquired, predispose to severe infections, particularly with encapsulated bacteria such as Neisseria meningitidis and Streptococcus pneumoniae. Although rare, inherited defects affect different pathways and may also present with autoimmune or renal diseases. Diagnosis relies on functional and quantitative assays, especially in patients with earlyonset or recurrent infections. Complement inhibition, introduced with eculizumab and expanded to agents targeting C3, Factor B, or Factor D, has transformed the management of complement-mediated disorders but unmasked novel infectious risks, including meningococcal disease and invasive fungal infections.

Immunodeficient mice, particularly the NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) strain and other non-obese diabetic (NOD)-derived lines are widely used in biomedical research due to their profound immunosuppression, which enables stable engraftment of human cells and tissues with minimal rejection. Despite their broad utility, these models exhibit unique immunologic and anatomic features and are predisposed to infectious and noninfectious diseases that may confound experimental outcomes and limit translational relevance. This review summarizes current knowledge on spontaneous, infectious, and experimentally induced lesions in NSG and related strains. These mice characteristically display hypoplastic lymphoid organs, including the spleen, thymus, and lymph nodes, due to a near-complete absence of lymphocytes. Spontaneous background lesions include splenic osseous metaplasia, neurodegeneration, pancreatic mastocytosis, cochlear degeneration, intervertebral disk disease, skull hyperostosis, and pancreatic duct cysts, among others. Common spontaneous neoplasms include lymphomas, osteosarcomas, and mammary gland tumors. Due to their immunodeficient status, NSG and NOD-derived mice are also highly susceptible to opportunistic infections, such as Corynebacterium bovis, Chlamydia muridarum, Clostridioides difficile, and mouse kidney parvovirus. In humanized models, engraftment of human immune cells can result in distinctive syndromes, including xenogeneic graft-versus-host disease, post-transplant lymphoproliferative disorders, and chimeric myeloid cell hyperactivation syndrome, which can impact study outcomes and lead to mortality and morbidity. This review is intended as a resource for comparative pathologists to become familiar with these widely used immunodeficient mice, so they can interpret strain-specific lesions and recognize experimental confounders in these mouse models.

Cell movement and division are complex behaviors driven by a dynamic internal cytoskeleton. The molecular components and principles of cytoskeletal assembly are well studied, but less is known about cytoskeletal remodeling events, including how centrioles transition from ciliary base to centrosome. Here, we address this using the chytrid Rhizoclosmatium globosum, a zoosporic fungus that has centrioles and cilia, lost in most fungal lineages. Chytrids undergo reorganization of their microtubule cytoskeleton as they grow from zoospore to multinucleated coenocyte. We use evolutionary comparison, RNA-sequencing, and expansion microscopy to understand this reorganization and further develop this organism as a model for evolutionary cell biology. We find that when motile zoospores transition to sessile sporangia, cilia are retracted into the cytoplasm and degraded, while centrioles detach from the ciliary axoneme yet persist. During the mitotic cycles, short centrioles are associated with a centrosome-like microtubule-organizing center (MTOC) and a dense microtubule array at the spindle pole. After the mitotic cycles, centrioles elongate and form cilia, driven by transcription of genes associated with centriole maturation and ciliogenesis, and microtubule bundles are reorganized. Thus, in chytrids structural remodeling of the centriole is temporally coupled to specific changes in cytoskeletal organization over the coenocytic lifecycle.

Antiretroviral therapy suppresses HIV-1 infection but fails to eliminate a reservoir of intact latent proviruses that reside primarily in CD4+ T cells. The lack of precise understanding of the latent compartment has made it challenging to develop curative strategies for HIV-1 infection. Here we report on the properties of CD4+ T cell clones carrying intact latent proviruses, expanded in vitro from single cells obtained from the reservoir of people living with HIV-1. The latent proviruses in the clones were integrated into ZNF genes, nongenic satellite, and centromeric regions, frequently associated with latency. Despite their descent from single cells, only a fraction of the cells (0.4-14%) expressed relatively low levels of HIV-1 that did not measurably alter host gene transcriptome. Latency-reversing agents (LRAs) variably increased expression, but the effects were modest and clone and LRA specific. The results suggest that pharmacologic and immunologic approaches to clear the reservoir should be optimized to accommodate intra- and inter-clonal diversity.

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas (CRISPR-associated) systems provide adaptive immunity against phage infection in prokaryotes using an RNA-guided complex that recognizes complementary foreign nucleic acids. Different types of CRISPR-Cas systems have been identified that differ in their mechanism of defense. Upon infection, type III CRISPR-Cas systems employ the Cas10 complex to find phage transcripts and synthesize cyclic oligo-adenylate (cOA) messengers. These ligands bind and activate CARF immune effectors that cause cell toxicity to prevent the completion of the viral lytic cycle. Here, we investigated two proteins containing an N-terminal haloacid dehalogenase (HAD) phosphatase domain followed by four predicted transmembrane helices and a C-terminal CARF domain. We named these proteins Chp for CRISPR-associated HAD phosphatase. We show that, in vivo, Chp localizes to the bacterial membrane and that its activation induces a growth arrest, leads to a depletion of ATP and IMP, and prevents phage propagation during the type III CRISPR-Cas response. In vitro, the CARF domain of Chp binds cyclic tetra-adenylates and the HAD phosphatase domain dephosphorylates dATP, ATP, and IMP. Our findings extend the range of molecular mechanisms employed by CARF effectors to defend prokaryotes against phage infection.

The female Aedes aegypti mosquito's remarkable ability to hunt humans and transmit pathogens relies on her unique biology. Here, we present the Aedes aegypti Mosquito Cell Atlas, a comprehensive single-nucleus RNA sequencing dataset of more than 367,000 nuclei from 19 dissected tissues of adult female and male Aedes aegypti, providing cellular-level resolution of mosquito biology. We identify novel cell types and expand our understanding of sensory neuron organization of chemoreceptors across all sensory tissues. Our analysis uncovers male-specific cells and sexually dimorphic gene expression in the antenna and brain. In female mosquitoes, we find that glial cells, rather than neurons, undergo the most extensive transcriptional changes in the brain following blood feeding. Our findings provide insights into the cellular basis of mosquito behavior and sexual dimorphism. The Aedes aegypti Mosquito Cell Atlas resource enables systematic investigation of cell-type-specific expression across all mosquito tissues.

Cancer cells require substantial metabolic adaptations to metastasize to distant organs, but the metabolites essential for successful colonization remain poorly defined. In this study, we used a mitochondrial metabolomics approach to compare primary and metastatic breast cancer cells. This analysis revealed accumulation of mitochondrial glutathione (GSH) during lung metastasis, driven by elevated expression of SLC25A39, a mitochondrial GSH transporter. Loss of SLC25A39 impairs metastatic colonization in genetic screens, cell line models, and patient-derived xenografts, without affecting primary tumor growth. Mitochondrial GSH import is specifically required during early colonization and functions independently of its canonical antioxidant role. CRISPR activation screens identified ATF4, a stress-induced transcription factor, as a bypass mechanism that restores metastatic potential in SLC25A39-deficient cells. Mechanistically, SLC25A39 is required for optimal ATF4 activation during metastasis and under hypoxia, linking mitochondrial GSH availability to integrated stress response signaling. These findings identify mitochondrial GSH as a necessary and limiting metabolite for metastatic progression.Significance: Mitochondrial GSH import via SLC25A39 is essential for early metastatic colonization in breast cancer, linking metabolic adaptation to stress response signaling. Targeting this pathway may uncover a therapeutic vulnerability specific to metastasis without affecting primary tumor growth.

Replicative helicases need loader proteins to assemble at DNA replication origins. Multiple copies of the bacteriophage lambda P (P) loader bind and load the Escherichia coli DnaB (B) replicative helicase onto single-stranded (ss) DNA from the replication origin. We find that the E. coli DnaB center dot lambda P complex exists in two forms: B6P5 and B6P6. In the 2.66 & Aring; cryo-EM structure of B6P5, five lambda P loader copies form a crown-like shape that tightly grips DnaB. In this complex, the closed, planar DnaB is reconfigured into an open spiral with a large enough breach to allow ssDNA to enter an internal chamber. Transition to the open spiral involves lambda P-induced changes to the Docking Helix (DH)-Linker Helix (LH) interface. Unexpectedly, one lambda P chain in B6P5 is positioned across the breach. The disposition of this lambda P chain implies a complex pathway for entry of a replication-origin-derived ssDNA "bubble" ssDNA into the B6P5 complex. We propose that the B6P6 complex is an early intermediate in helicase activation in which neither DnaB nor lambda P has reached its final form. In this complex, DnaB adopts a partially open, ajar planar configuration. lambda P in B6P6 interacts more loosely with DnaB. The ssDNA- and ATP-binding sites in both complexes are not correctly configured for binding or hydrolysis. Our findings detail the distinct conformations of B6P6 and B6P5, allowing us to propose a structural model for the transition from an ajar planar to an open spiral configuration in the helicase loading pathway.

Nucleoside-modified messenger RNA (mRNA) vaccines elicit protective antibodies through their ability to promote T follicular helper (Tfh) cell differentiation. The lipid nanoparticles (LNPs) of mRNA vaccines possess inherent adjuvant activity. However, the extent to which the nucleoside-modified mRNA is sensed and contributes to Tfh cell responses remains undefined. Herein, we deconvolute the signals induced by LNPs and mRNA that instruct dendritic cells (DCs) to promote Tfh cell differentiation. We demonstrate that the mRNA drives the production of type I interferons, which act on DCs to enhance their maturation and Tfh cell differentiation, and favors plasma cells and memory B cell responses. In parallel, LNPs, which allow for mRNA uptake by DCs within the draining lymph node, also modulate Tfh cell responses by shaping the localization of CD25+ DCs. Our work unravels distinct adjuvant features of mRNA and LNPs necessary for the induction of Tfh cells, with implications for rational vaccine design.