The rockefeller university

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.

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.

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.

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.

The yellow fever virus 17D (YFV-17D) live attenuated vaccine is considered one of the most successful vaccines ever generated associated with high antiviral immunity, yet the signaling mechanisms that drive the response in infected cells are not understood. Here, we provide a molecular understanding of how metabolic stress and innate immune responses are linked to drive type I IFN expression in response to YFV-17D infection. Comparison of YFV-17D replication with its parental virus, YFV-Asibi, and a related dengue virus revealed that IFN expression requires RIG-I-like Receptor signaling through MAVS, as expected. However, YFV-17D uniquely induces mitochondrial respiration and major metabolic perturbations, including hyperactivation of electron transport to fuel ATP synthase. Mitochondrial hyperactivity generates reactive oxygen species (ROS) including peroxynitrite, blocking of which abrogated MAVS oligomerization and IFN expression in non-immune cells without reducing YFV-17D replication. Scavenging ROS in YFV-17D-infected human dendritic cells increased cell viability yet globally prevented expression of IFN signaling pathways. Thus, adaptation of YFV-17D for high growth imparts mitochondrial hyperactivity to meet energy demands, resulting in generation of ROS as the critical messengers that convert a blunted IFN response into maximal activation of innate immunity essential for vaccine effectiveness.

The last decades have brought a rapid expansion of the number of primary disorders related to the polyubiquitination pathways in humans. Most of these disorders manifest with two seemingly contradictory clinical phenotypes: autoinflammation, immunodeficiency, or both. We provide an overview of the molecular pathogenesis of these disorders, and their role in inflammation and infection. By focusing on data from human genetic diseases, we explore the complexities of the polyubiquitination pathways and the corresponding clinical phenotypes of their deficiencies. We offer a road map for the discovery of new genetic etiologies. By considering the triggers that induce inflammation, we propose autoinflammation and immunodeficiency as continuous clinical phenotypes.