The rockefeller university

Oral cavity squamous cell carcinoma (OSCC), a leading subtype of head and neck cancer, exhibits high global incidence and mortality rates. Despite advancements in surgery and radiochemotherapy, approximately one third of patients experience relapse. To improve current targeted and immunotherapy strategies for recurrent OSCC, we conducted multi-omics analyses on pretreatment OSCC samples (cohorts 1 and 2, n = 137) and identified A3A and EGFR, both at the RNA and protein levels, as inversely expressed markers for patient stratification and response prediction. Survival analysis demonstrated that elevated A3A or PD-L1 expression levels correlated to improved responses to anti-PD-1 therapy in patients (cohort 3a, n = 50, IHC). In contrast, high RRAS expression (cohort 4, n = 252, qRT-PCR) was significantly associated with OSCC recurrence. Cell-based experiments revealed that RRAS was involved in radiotherapy and cisplatin resistance through the EGFR/ RRAS/AKT/ERK signaling pathway. In OSCC patient-derived xenograft (PDX) mouse models, treatments with cisplatin and cetuximab (anti-EGFR) effectively reduced tumor size in EGFR-high-derived (#34) but not A3Ahigh-derived (#22) PDX tumors. Our study demonstrated that A3A-high tumors were immune-hot and responsive to anti-PD-1 therapy, whereas EGFR-high tumors exhibited chr.7p11.2 gains and DNA repair alterations. Additionally, RRAS-high tumors were associated with OSCC recurrence via AKT and ERK phosphorylation and demonstrate improved clinical outcomes with cetuximab therapy (cohort 3b, n = 49, IHC). This study emphasizes the significance of A3A and EGFR expression levels in OSCC patient stratification and precision therapy, suggesting the use of anti-PD-1 or anti-EGFR treatments, respectively based on these biomarkers. Furthermore, RRAS emerges as a novel prognostic marker for local recurrence.

Neuronal maturation is guided by changes in the chromatin landscape that control developmental gene expression programs. Histone bivalency, the co-occurrence of activating and repressive histone modifications, has emerged as an epigenetic feature of developmentally regulated genes during neuronal maturation. Although initially associated with early embryonic development, recent studies have shown that histone bivalency also exists in differentiated and mature neurons. In this review, we discuss methods to study bivalency in specific populations of neurons and summarize emerging studies on the function of bivalency in central nervous system neuronal maturation and in adult neurons.

Outbreaks of chilblains were reported during the COVID-19 pandemic. Given the essential role of type I interferon (I-IFN) in protective immunity against SARS-CoV-2 and the association of chilblains with inherited type I interferonopathies, we hypothesized that excessive I-IFN responses to SARS-CoV-2 might underlie the occurrence of chilblains in this context. We identified a transient I-IFN signature in chilblain lesions, accompanied by an acral infiltration of activated plasmacytoid dendritic cells (pDCs). Patients with chilblains were otherwise asymptomatic or had mild disease without seroconversion. Their leukocytes produced abnormally high levels of I-IFN upon TLR7 stimulation with agonists or ssRNA viruses-particularly SARS-CoV-2-but not with DNA agonists of TLR9 or the dsDNA virus HSV-1. Moreover, the patients' pDCs displayed cell-intrinsic hyperresponsiveness to TLR7 stimulation regardless of TLR7 levels. Inherited TLR7 or I-IFN deficiency confers a predisposition to life-threatening COVID-19. Conversely, our findings suggest that enhanced TLR7 activity in predisposed individuals could confer innate, pDC-mediated, sterilizing immunity to SARS-CoV-2 infection, with I-IFN-driven chilblains as a trade-off.

Measurements of fiducial and total inclusive cross sections for W and Z boson production are presented in proton-proton collisions at root s = 5.02 and 13TeV. Electron and muon decay modes (l = e or mu) are studied in the data collected with the CMS detector in 2017, in dedicated runs with reduced instantaneous luminosity. The data sets correspond to integrated luminosities of 298 +/- 6 pb(-1) at 5.02TeV and 206 +/- 5 pb(-1) at 13TeV. Measured values of the products of the total inclusive cross sections and the branching fractions at 5.02TeV are sigma(pp -> W+ X)B(W -> l nu) = 7300 +/- 10 (stat) +/- 60 (syst) +/- 140 (lumi) pb, and sigma(pp -> Z+ X)B(Z -> l(+) l(-)) = 669 +/- 2 (stat)+/- 6 (syst)+/- 13 (lumi) pb for the dilepton invariant mass in the range of 60-120 GeV. The corresponding results at 13TeV are 20480 +/- 10 (stat)+/- 170 (syst)+/- 470 (lumi) pb and 1952 +/- 4 (stat)+/- 18 (syst)+/- 45 (lumi) pb. The measured values agree with cross section calculations at next-to-next-to-leading-order in perturbative quantum chromodynamics. Fiducial and total inclusive cross sections, ratios of cross sections of W+ and W- production as well as inclusive W and Z boson production, and ratios of these measurements at 5.02 and 13TeV are reported.

The hierarchical view of the ventral object recognition pathway is primarily based on feedforward mechanisms, starting from a fixed basis set of object primitives and ending on a representation of whole objects in the inferotemporal cortex. Here, we provide a different view. Rather than being a fixed "labeled line" for a specific feature, neurons are continually changing their stimulus selectivities on a moment-to-moment basis, as dictated by top-down influences of object expectation and perceptual task. Here, we also derive the selectivity for stimulus features from an ethologically curated stimulus set, based on a delayed match-to-sample task, that finds components that are informative for object recognition in addition to full objects, though the top-down effects were seen for both informative and uninformative components. Cortical areas responding to these stimuli were identified with functional MRI in order to guide placement of chronically implanted electrode arrays.

Clostridioides difficile causes debilitating colitis via secreted toxins that disrupt the intestinal barrier, and toxemia is associated with severe disease. Thus, therapies that fortify the intestinal barrier will reduce the severity of infection. Innate lymphoid cells (ILCs) are critical in the defense against acute C. difficile infection and represent a promising therapeutic target to limit disease. Here, we report that oral administration of the Toll-like receptor (TLR) 7 agonist R848 limits intestinal damage and protects mice from lethal C. difficile infection without impacting pathogen burden or altering the intestinal microbiome. R848 induced interleukin (IL)- 22 secretion by ILCs, leading to STAT3 phosphorylation in the intestinal epithelium and increased stem cell proliferation. Genetic ablation of ILCs, IL-22, or epithelial-specific STAT3 abrogated R848-mediated protection. R848 reduced intestinal permeability following infection and limited systemic toxin dissemination. Combined, these data identify an immunostimulatory molecule that activates IL-22 production in ILCs to enhance host tissue defenses following C. difficile infection.

A search is presented for fractionally charged particles with charges below 1e, using their small energy loss in the tracking detector as a key variable to observe a signal. The analyzed dataset corresponds to an integrated luminosity of 138 fb(-1) of proton-proton collisions collected at root s = 13 TeV in 2016-2018 at the CERN LHC. This is the first search at the LHC for new particles with a charge between e/3 and 0.9e, including an extension of previous results at a charge of 2e/3. Masses up to 640 GeV and charges as low as e/3 are excluded at 95% confidence level. These are the most stringent limits to date for the considered Drell-Yan-like production mode.

Invariant object recognition-the ability to recognize objects across size, rotation, or context-is fundamental for making sense of a dynamic visual world. Though traditionally studied in primates, emerging evidence suggests rodents recognize objects across a range of identity-preserving transformations. We demonstrate that rats robustly perform visual object recognition and explore a neural pathway that may underlie this capacity by developing a pipeline from high-throughput behavior training to cellular resolution imaging in awake, head-fixed animals. Leveraging our optical approach, we systematically profile neurons in primary and higher-order visual areas and their spatial organization. We find that rat visual cortex exhibits several features similar to those observed in the primate ventral stream but also marked deviations, suggesting species-specific differences in how brains solve visual object recognition. This work reinforces the sophisticated visual abilities of rats and offers the technical foundation to use them as a powerful model for mechanistic perception.

Nanobodies are single domain antibody variants proving themselves to be compelling tools for research, disease diagnostics, and as therapeutics targeting a myriad of disease agents. However, despite this potential, their mechanisms of paratope presentation and structural stabilization have not been fully explored. Here, we show that unlike monoclonal antibodies, a nanobody repertoire maximizes sampling of an antigen surface by binding a single antigen in at least three different orientations, which are correlated with their paratope composition. Structure-guided reengineering of several nanobodies reveals that a single point mutation within the paratope or a highly conserved region of a nanobody's framework 3 (FR3) can markedly improve antigen affinity, nanobody stability, or both. Conversely, we show the negative impact on antigen affinity when "over-stabilizing"nanobodies. Collectively our results provide a universal strategy to tune a nanobody's affinity by modifying specific residues that can readily be applied to guide nanobody optimization and functionalization.

Chronic hepatitis B virus (HBV) infection is an incurable pathogen 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, the Smc5/6 complex. However, the relationship between cccDNA chromatinization and X gene transcription remains poorly understood. By establishing a reconstituted viral minichromosome platform, we found that nucleosome occupancy in cccDNA regulates X transcription. We corroborated these findings in situ and further showed that the chromatin-destabilizing molecule CBL137 inhibits full-length X transcription and HBV infection in primary human hepatocytes. Our results shed light on a long-standing paradox and represent a potential therapeutic approach for the treatment of chronic HBV infection.