The rockefeller university

Despite waning of virus-neutralizing antibodies, protection against severe SARS-CoV-2 in the majority of immune individuals remains high, but the underlying immune mechanisms are incompletely understood. Here, rhesus macaques with pre-existing immunity from Novavax WA-1 and/or P.1 vaccines and WA-1 or P.1 infection are immunized with a bivalent WA-1/Omicron BA.5 Novavax vaccine ten months after the last exposure. The boost vaccination primarily increases the frequency of cross-reactive spike (S)-specific antibodies and B cells instead of inducing de novo BA.5-specific responses. Reinfection with heterologous Omicron XBB.1.5 six months after the boost vaccination results in low levels of virus replication in the respiratory tract compared with virus-na & iuml;ve results from other studies. Whereas systemic S-specific immunity remains largely unchanged in all animals, the animals with complete protection from infection exhibit a stronger influx of S-specific IgG, monocytes, B cells and T cells into the bronchioalveolar space combined with expansion of CD69+CD103+ lung tissue-resident, S-specific CD8 T cells compared to actively infected animals. Our results underscore the importance of localized respiratory immune responses in mediating protection from Omicron reinfection and provide guidance for future vaccine development.

Defining viral proteomes is crucial to understanding viral life cycles and immune recognition but the landscape of translated regions remains unknown for most viruses. We have developed massively parallel ribosome profiling (MPRP) to determine open reading frames (ORFs) across tens of thousands of designed oligonucleotides. MPRP identified 4208 unannotated ORFs in 679 human-associated viral genomes. We found viral peptides originating from detected noncanonical ORFs presented on class-I human leukocyte antigen in infected cells and hundreds of upstream ORFs that likely modulate translation initiation of viral proteins. The discovery of viral ORFs across a wide range of viral families-including highly pathogenic viruses-expands the repertoire of vaccine targets and reveals potential cis-regulatory sequences.

Tauopathies are characterized by the aggregation and accumulation of hyperphosphorylated tau proteins that correlates with cognitive impairment in affected individuals. The presence of tauopathy follows a temporospatial spreading pattern in which certain neuronal cell types in specific brain regions are more vulnerable to tau accumulation and atrophy. However, the mechanisms underlying the selective vulnerability of these neurons and regions to pathological tau accumulation are not fully understood. Here, we characterized the presence of phosphorylated tau in excitatory and inhibitory neurons in post-mortem prefrontal cortex of tauopathy patients, including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal lobar dementia due to a MAPT mutation. We observed that neuronal tau accumulation across these tauopathies occurs predominantly in excitatory neurons compared to inhibitory neurons. Next, we performed viral translating ribosome affinity purification (vTRAP) from vulnerable and resistant brain regions on vGLUT1CRE+ and GAD2CRE+ PS19 mice to understand molecular signatures of tau vulnerability. We observed that both vulnerable regions and vulnerable neurons are characterized by alterations in synaptic transmission and neuronal excitability. Transcription factor Mef2c (myocyte enhancer factor 2c) was identified as an upstream regulator affecting myelination and synaptic organization in vulnerable brain regions in PS19 mice. The relevance of these findings was validated in human tauopathies via coexpression network analysis. Concordantly, we observed tau-induced changes in spontaneous postsynaptic currents of excitatory neurons in mice especially in the prefrontal cortex. Taken together, we conclude that selective vulnerability to tau could arise from changes in neurotransmission and synaptic compositions, potentially due to an altered Mef2c transcriptional network.

The mammalian cochlea benefits from an active process characterized by amplification of mechanical inputs, sharp frequency selectivity, compressive nonlinearity, and spontaneous otoacoustic emission. Similar traits are observed in individual hair cells of nonmammalian tetrapods, in which they emerge from the critical dynamical regime of hair cells operating near a Hopf bifurcation. It remains unclear whether a similar critical regime also underpins the active process of the mammalian cochlea. Efforts to address this question have been limited in part by the absence of an ex vivo preparation that both preserves the physiological integrity of the sensory epithelium and grants direct experimental access to it. To overcome these problems, we improved a two-compartment cochlear preparation (Chan and Hudspeth, 2005a, 2005b) to more closely simulate in vivo conditions and used it to conduct electrophysiological recordings of microphonic signals in isolated cochlear segments of the Mongolian gerbil. Our methodological advances included refining the dissection protocol to reduce the size of the exposed cochlear segment and altering the ionic compositions of the solutions to better control the Ca2+ concentration. We also maintained a constant temperature in order to stabilize the experimental conditions. Most critically, by introducing a mechanism to adjust the pressure in the endolymphatic compartment, we were able to explore how variations in transepithelial pressure influence the electrical response. These changes enabled us to reliably measure compressive nonlinearities with a one-third power law similar to that observed from cochleas in vivo and consistent with the behavior of a dynamical system operating near a Hopf bifurcation.

Bacteria have evolved a wide range of defence strategies to protect themselves against bacterial viruses (phages). Most known bacterial antiphage defence systems target phages with DNA genomes, which raises the question of how bacteria defend against phages with RNA genomes. Bacterial toxin-antitoxin systems that cleave intracellular RNA could potentially protect bacteria against RNA phages, but this has not been explored experimentally. In this study, we investigated the role of a model toxin-antitoxin system, MazEF, in protecting Escherichia coli against two RNA phage species. When challenged with these phages, the native presence of mazEF moderately reduced population susceptibility and increased the survival of individual E. coli cells. Genomic analysis further revealed an underrepresentation of the MazF cleavage site in genomes of RNA phages infecting E. coli, indicating selection against cleavage. These results show that, in addition to other physiological roles, RNA-degrading toxin-antitoxin systems may also help defend against RNA phages.

Background Suppressor of cytokine signalling 1 (SOCS1) insufficiency is an inborn error of immunity affecting the negative regulation of cytokine and growth factor signalling. We aimed to enhance the understanding of clinical manifestations, disease trajectories, disease penetrance, and the effect of Janus kinase (JAK) inhibition in individuals with SOCS1 insufficiency. Methods This study used data from two independent cohorts: the European Society for Immunodeficiencies (ESID) registry and the UK Biobank. Participants from the ESID registry were from nine European countries (Austria, Belgium, France, Germany, Ireland, Italy, Portugal, Sweden, and Ukraine), China, Taiwan, and the USA. Participants from the ESID registry were eligible if they had heterozygous, functionally validated SOCS1 variants; participants from the UK Biobank were included if they had any SOCS1 variant detected in the ESID registry cohort or any other SOCS1 variant that was classed as high-impact. Clinical manifestations of the underlying SOCS1 insufficiency were documented and summarised into nine subgroups, with ICD-10 diagnosis codes collected for participants from the UK Biobank. Participants from the ESID registry were tested for relevant autoantibodies in their local laboratory. Responses to JAK inhibitor treatment in participants from the ESID registry were assessed by the treating physician using a visual analogue scale. Descriptive statistics were used for analysis. People with lived experience were not involved in the study design. Findings We included 119 participants with SOCS1 insufficiency: 67 from the ESID registry, enrolled between Feb 15, 2021, and Dec 31, 2023, and 52 from the UK Biobank. Of the 67 participants from the ESID registry, 39 (58%) were female, 28 (42%) were male, and the median age was 28 years (IQR 15-44, range 2-85). 27 different monoallelic SOCS1 variants were identified in these participants. 62 (93%) of the 67 participants in the ESID registry cohort were symptomatic and five (7%) were asymptomatic family members; of the 62 participants with symptoms, allergy (33 [50%]), inflammatory gastrointestinal (22 [36%]) and skin (18 [29%]) manifestations, autoimmune cytopenia (24 [39%]), and lymphoproliferation (23 [37%]) were most frequent. Rheumatological manifestations (23 [37%]) included systemic lupus erythematosus, Sj & ouml;gren's disease, and rheumatoid arthritis, with typical autoantibody profiles. 42 (68%) of the 62 symptomatic participants had at least three different manifestations. In the UK Biobank we found 52 participants carrying high-impact SOCS1 variants; 29 (56%) were female, 23 (44%) were male, and the median age was 72 years (65-78, 57-86). Only 30 (58%) of these participants had developed manifestations that were potentially related to SOCS1 insufficiency. Allergy and rheumatological manifestations were more common in participants from the UK Biobank than the ESID registry. Female predominance (21 [70%] of 30 participants were female and nine [30%] were male) was also found among symptomatic participants from the UK Biobank. Treatment with JAK inhibitors showed promising results in 12 (92%) of 13 participants in the ESID registry. Interpretation SOCS1 insufficiency differs from other genetic autoimmune lymphoproliferative disorders by the presence of frequent atopic and rheumatological manifestations. Penetrance is incomplete and is higher in females than in males. JAK inhibition is a promising targeted therapy for patients with SOCS1 insufficiency. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

The eukaryotic leading-strand DNA polymerase epsilon(Pol epsilon) is a dual-function enzyme with a proofreading 3 '-5 ' exonuclease (exo) site located 40 & Aring; from the DNA synthesizing pol site. Errors in Pol epsilon proofreading can cause various mutations, including C-to-G trans-versions, the most prevalent mutation in cancers and genetic diseases. Pol epsilon interacts with all three subunits of the PCNA ring to assemble a functional holoenzyme. Despite previous studies on proofreading of several Pol's, how Pol epsilon-or any Pol complexed with its sliding clamp-proofreads a mismatch generated in situ has been unknown. We show here by cryo-EM that a template/primer DNA substrate with a preexisting mismatch cannot enter the exo site of Pol epsilon-PCNA holoenzyme, but a mismatch generated in situ in the pol site yields three bona fide proofreading intermediates of Pol epsilon-PCNA holoenzyme. These intermediates reveal how the mismatch is dislodged from the pol site, how the DNA unwinds six base pairs, and how the unpaired primer 3 '-end is inserted into the exo site for cleavage. These results unexpectedly demonstrate that PCNA imposes strong steric constraints that extend unwinding and direct the trajectory of mismatched DNA and that this trajectory is dramatically different than for Pol epsilon in the absence of PCNA. These findings suggest a physiologically relevant proofreading mechanism for the human Pol epsilon holoenzyme.

Patients with systemic lupus erythematosus (SLE) are photosensitive, developing skin inflammation with even ambient ultraviolet radiation (UVR), and this cutaneous photosensitivity can be associated with UVR-induced flares of systemic disease, which can involve increased autoantibodies and further end-organ injury. Mechanistic insight into the link between the skin responses and autoimmunity is limited. Signals from skin are transmitted directly to the immune system via lymphatic vessels, and here we show evidence for potentiation of UVR-induced lymphatic flow dysfunction in SLE patients and murine models. Improving lymphatic flow by manual lymphatic drainage (MLD) or with a transgenic model with increased lymphatic vessels reduces both cutaneous inflammation and lymph node B and T cell responses, and long-term MLD reduces splenomegaly and titers of a number of autoantibodies. Mechanistically, improved flow restrains B cell responses in part by stimulating a lymph node fibroblastic reticular cell-monocyte axis. Our results point to lymphatic modulation of lymph node stromal function as a link between photosensitive skin responses and autoimmunity and as a therapeutic target in lupus, provide insight into mechanisms by which the skin state regulates draining lymph node function, and suggest the possibility of MLD as an accessible and cost-effective adjunct to add to ongoing medical therapies for lupus and related diseases.

Female sociosexual behaviors, essential for survival and reproduction, are modulated by ovarian hormones and triggered in the context of appropriate social cues. Here, we identify primary estrous-sensitive Cacna1h-expressing medial prefrontal cortex (mPFCCacna1h+) neurons that integrate hormonal states with recognition of potential mates to orchestrate these complex cognitive behaviors. Bidirectional manipulation of mPFCCacna1h+ neurons shifts opposite-sex-directed social behaviors between estrus and diestrus females via anterior hypothalamic outputs. In males, these neurons serve opposite functions compared with estrus females. Miniscope imaging reveals mixed representation of self-estrous states and social target sex in distinct mPFCCacna1h+ subpopulations, with biased encoding of opposite-sex cues in estrus females and males. Mechanistically, ovarian-hormone-induced Cacna1h upregulation enhances T-type rebound excitation after oxytocin inhibition, driving estrus-specific activity changes and the sexually dimorphic function of mPFCCacna1h+ neurons. These findings uncover a prefrontal circuit that integrates internal hormonal states and target-sex information to exert sexually bivalent top-down control over adaptive social behaviors.