The rockefeller university

PurposeInborn errors of IFN--mediated immunity underlie Mendelian Susceptibility to Mycobacterial Disease (MSMD), which is characterized by an increased susceptibility to severe and recurrent infections caused by weakly virulent mycobacteria, such as Bacillus Calmette-Guerin (BCG) vaccines and environmental, nontuberculous mycobacteria (NTM).MethodsIn this study, we investigated four patients from four unrelated consanguineous families from Isfahan, Iran, with disseminated BCG disease. We evaluated the patients' whole blood cell response to IL-12 and IFN-, IL-12R1 expression on T cell blasts, and sequenced candidate genes.ResultsWe report four patients from Isfahan, Iran, ranging from 3months to 26years old, with impaired IL-12 signaling. All patients suffered from BCG disease. One of them presented mycobacterial osteomyelitis. By Sanger sequencing, we identified three different types of homozygous mutations in IL12RB1. Expression of IL-12R1 was completely abolished in the four patients with IL12RB1 mutations.ConclusionsIL-12R1 deficiency was found in the four MSMD Iranian families tested. It is the first report of an Iranian case with S321* mutant IL-12R1 protein. Mycobacterial osteomyelitis is another type of location of BCG infection in an IL-12R1-deficient patient, notified for the first time in this study.

Immune stimulation has emerged as a promising approach to the treatment of neoplastic diseases. Currently approved therapeutics, such as anti-CTLA4 and anti-PD1, are primarily aimed at blocking inhibitory signaling by immune cells. An alternative and potentially synergistic approach would involve activation of immune pathways by agonism of stimulatory receptors, such as CD40. Agonistic antibodies, while promising in principle, have encountered significant barriers in clinical trials limited by the systemic toxicity of such approaches. Using a mouse model humanized for both Fc receptors and CD40, we previously demonstrated enhanced antitumor activity with an Fc-modified antibody. We now demonstrate that this model recapitulates the platelet and hepatic toxicities seen with anti-CD40 antibodies in patients, providing a predictive measure of the dose-limiting activity of this approach. We further show that such toxicity can be circumvented and durable systemic antitumor immunity achieved by intratumoral delivery of an Fc-engineered anti-CD40 agonistic antibody.

Background: Microbiota and bile acids in the gastrointestinal tract profoundly alter systemic metabolic processes. In obese subjects, gradual weight loss ameliorates adipose tissue inflammation and related systemic changes. We assessed how rapid weight loss due to a very low calorie diet (VLCD) affects the fecal microbiome and fecal bile acid composition, and their interactions with the plasma metabolome and subcutaneous adipose tissue inflammation in obesity. Methods: We performed a prospective cohort study of VLCD-induced weight loss of 10% in ten grades 2-3 obese postmenopausal women in a metabolic unit. Baseline and post weight loss evaluation included fasting plasma analyzed by mass spectrometry, adipose tissue transcription by RNA sequencing, stool 16S rRNA sequencing for fecal microbiota, fecal bile acids by mass spectrometry, and urinary metabolic phenotyping by H-1-NMR spectroscopy. Outcome measures included mixed model correlations between changes in fecal microbiota and bile acid composition with changes in plasma metabolite and adipose tissue gene expression pathways. Results: Alterations in the urinary metabolic phenotype following VLCD-induced weight loss were consistent with starvation ketosis, protein sparing, and disruptions to the functional status of the gut microbiota. We show that the core microbiome was preserved during VLCD-induced weight loss, but with changes in several groups of bacterial taxa with functional implications. UniFrac analysis showed overall parallel shifts in community structure, corresponding to reduced abundance of the genus Roseburia and increased Christensenellaceae;g_ (unknown genus). Imputed microbial functions showed changes in fat and carbohydrate metabolism. A significant fall in fecal total bile acid concentration and reduced deconjugation and 7-alpha-dihydroxylation were accompanied by significant changes in several bacterial taxa. Individual bile acids in feces correlated with amino acid, purine, and lipid metabolic pathways in plasma. Furthermore, several fecal bile acids and bacterial species correlated with altered gene expression pathways in adipose tissue. Conclusions: VLCD dietary intervention in obese women changed the composition of several fecal microbial populations while preserving the core fecal microbiome. Changes in individual microbial taxa and their functions correlated with variations in the plasma metabolome, fecal bile acid composition, and adipose tissue transcriptome.

A search is presented for resonances decaying to a Z boson and a photon. The analysis is based on data from proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1), and collected with the CMS detector at the LHC in 2016. Two decay modes of the Z boson are investigated. In the leptonic channels, the Z boson candidates are reconstructed using electron or muon pairs. In the hadronic channels, they are identified using a large-radius jet, containing either light-quark or b quark decay products of the Z boson, via jet substructure and advanced b quark tagging techniques. The results from these channels are combined and interpreted in terms of upper limits on the product of the production cross section and the branching fraction to Z gamma for narrow and broad spin-0 resonances with masses between 0.35 and 4.0 TeV, providing thereby the most stringent limits on such resonances.

Viral infection perturbs host cells and can be used to uncover regulatory mechanisms controlling cellular responses and susceptibility to infections. Using cell biological, biochemical, and genetic tools, we reveal that influenza A virus (IAV) infection induces global transcriptional defects at the 3' ends of active host genes and RNA polymerase II (RNAPII) run-through into extragenic regions. Deregulated RNAPII leads to expression of aberrant RNAs (3' extensions and host-gene fusions) that ultimately cause global transcriptional downregulation of physiological transcripts, an effect influencing antiviral response and virulence. This phenomenon occurs with multiple strains of IAV, is dependent on influenza NS1 protein, and can be modulated by SUMOylation of an intrinsically disordered region (IDR) of NS1 expressed by the 1918 pandemic IAV strain. Our data identify a strategy used by IAV to suppress host gene expression and indicate that polymorphisms in IDRs of viral proteins can affect the outcome of an infection.

A search has been performed for heavy resonances decaying to ZZ or ZW in 2l2q final states, with two charged leptons (l = e, mu) produced by the decay of a Z boson, and two quarks produced by the decay of a W or Z boson. The analysis is sensitive to resonances with masses in the range from 400 to 4500 GeV. Two categories are defined based on the merged or resolved reconstruction of the hadronically decaying vector boson, optimized for high- and low-mass resonances, respectively. The search is based on data collected during 2016 by the CMS experiment at the LHC in proton-proton collisions with a center-of-mass energy of root s = 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). No excess is observed in the data above the standard model background expectation. Upper limits on the production cross section of heavy, narrow spin-1 and spin-2 resonances are derived as a function of the resonance mass, and exclusion limits on the production of W' bosons and bulk graviton particles are calculated in the framework of the heavy vector triplet model and warped extra dimensions, respectively.

We investigate a critically-coupled chain of nonlinear oscillators, whose dynamics displays complex spatiotemporal patterns of activity, including regimes in which glider-like coherent excitations move about and interact. The units in the network are identical simple neural circuits whose dynamics is given by the Wilson-Cowan model and are arranged in space along a one-dimensional lattice with nearest neighbor interactions. The interactions follow an alternating sign rule, and hence the "synaptic matrix" M embodying them is tridiagonal antisymmetric and has purely imaginary (critical) eigenvalues. The model illustrates the interplay of two properties: circuits with a complex internal dynamics, such as multiple stable periodic solutions and period doubling bifurcations, and coupling with a "critical" synaptic matrix, i.e., having purely imaginary eigenvalues. In order to identify the dynamical underpinnings of these behaviors, we explored a discrete-time coupled-map lattice inspired by our system: the dynamics of the units is dictated by a chaotic map of the interval, and the interactions are given by allowing the critical coupling to act for a finite period tau, thus given by a unitary matrix U = exp(tau M-2). It is now explicit that such critical couplings are volume-preserving in the sense of Liouville's theorem. We show that this map is also capable of producing a variety of complex spatiotemporal patterns including gliders, like our original chain of neural circuits. Our results suggest that if the units in isolation are capable of featuring multiple dynamical states, then local critical couplings lead to a wide variety of emergent spatiotemporal phenomena. Published by AIP Publishing.

Background Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12% of patients with CAKUT. Methods We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT. Results In 29 families (13%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient's CAKUT phenotype. In three families (1%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8%). Conclusions We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

PREMISE OF THE STUDY: Lichenized fungi are evolutionarily diverse and ecologically important, but little is known about the processes that drive their diversification and genetic differentiation. Distributions are often assumed to be wholly shaped by ecological requirements rather than dispersal limitations. Furthermore, although asexual and sexual reproductive structures are observable, the lack of information about recombination rates makes inferences about reproductive strategies difficult. We investigated the population genomics of Cetradonia linearis, a federally endangered lichen in the southern Appalachians of eastern North America, to test the relative contributions of environmental and geographic distance in shaping genetic structure, and to characterize the mating system and genome-wide recombination. METHODS: Whole-genome shotgun sequencing was conducted to generate data for 32 individuals of C. linearis. A reference genome was assembled, and reads from all samples were aligned to generate a set of single-nucleotide polymorphisms for further analyses. KEY RESULTS: We found evidence for low rates of recombination and for isolation by distance, but not for isolation by environment. The species is putatively unisexual, given that only one mating-type locus was found. Hindcast species distribution models and the distribution of genetic diversity support C. linearis having a larger range during the Last Glacial Maximum in the southern portion of its current extent. CONCLUSIONS: Our findings contribute to the understanding of factors that shape genetic diversity in C. linearis and in fungi more broadly. Because all populations are highly genetically differentiated, the extirpation of any population would mean the loss of unique genetic diversity; therefore, our results support the continued conservation of this species.