The rockefeller university

Despite the wide availability of antibiotics, infectious diseases remain a leading cause of death worldwide(1). In the absence of new therapies, mortality rates due to untreatable infections are predicted to rise more than tenfold by 2050. Natural products (NPs) made by cultured bacteria have been a major source of clinically useful antibiotics. In spite of decades of productivity, the use of bacteria in the search for new antibiotics was largely abandoned due to high rediscovery rates(2,3). As only a fraction of bacterial diversity is regularly cultivated in the laboratory and just a fraction of the chemistries encoded by cultured bacteria are detected in fermentation experiments, most bacterial NPs remain hidden in the global microbiome. In an effort to access these hidden NPs, we have developed a culture-independent NP discovery platform that involves sequencing, bioinformatic analysis and heterologous expression of biosynthetic gene clusters captured on DNA extracted from environmental samples. Here, we describe the application of this platform to the discovery of the malacidins, a distinctive class of antibiotics that are commonly encoded in soil microbiomes but have never been reported in culture-based NP discovery efforts. The malacidins are active against multidrug-resistant pathogens, sterilize methicillin-resistant Staphylococcus aureus skin infections in an animal wound model and did not select for resistance under our laboratory conditions.

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency predisposing congenitally affected individuals to diseases caused by weakly virulent mycobacteria, such as Bacillus Calmette-Gu,rin (BCG) vaccine strains and environmental mycobacteria. IL-12p40 deficiency is a genetic etiology of MSMD resulting in impaired IL-12- and IL-23-dependent IFN-gamma immunity. Most of the reported patients with IL-12p40 deficiency originate from Saudi Arabia (30 of 52) and carry the recurrent IL12B mutation c.315insA (27 of 30). Whole-exome sequencing was performed on three patients from two unrelated kindreds from Saudi Arabia with disseminated disease caused by a BCG vaccine substrain. Genetic analysis revealed a homozygous mutation, p.W60X, in exon 3 of the IL12B gene, resulting in complete IL12p40 deficiency. This mutation is recurrent due to a new founder effect. This report provides evidence for a second founder effect for recurrent mutations of IL12B in Saudi Arabia.

Aducanumab, a human-derived antibody targeting amyloid-beta (A beta), is in Phase 3 clinical trials for the treatment of Alzheimer's disease. Biochemical and structural analyses show that aducanumab binds a linear epitope formed by amino acids 3-7 of the A beta peptide. Aducanumab discriminates between monomers and oligomeric or fibrillar aggregates based on weak monovalent affinity, fast binding kinetics and strong avidity for epitope-rich aggregates. Direct comparative studies with analogs of gantenerumab, bapineuzumab and solanezumab demonstrate clear differentiation in the binding properties of these antibodies. The crystal structure of the Fab fragment of aducanumab bound to its epitope peptide reveals that aducanumab binds to the N terminus of A beta in an extended conformation, distinct from those seen in structures with other antibodies that target this immunodominant epitope. Aducanumab recognizes a compact epitope that sits in a shallow pocket on the antibody surface. In silico analyses suggest that aducanumab interacts weakly with the A beta monomer and may accommodate a variety of peptide conformations, further supporting its selectivity for A beta aggregates. Our studies provide a structural rationale for the low affinity of aducanumab for non-pathogenic monomers and its greater selectivity for aggregated forms than is seen for other A beta-targeting antibodies.

The brain is responsible for both recognition and adaptation to stressful stimuli. Many molecular mechanisms have been implicated in this response including those governing neuronal plasticity, neurogenesis and, changes gene expression. Far less is known regarding effects of stress on the deep genome. In the hippocampus, stress appears to regulate expression of non-coding elements of the genome as well as the chromatin permissive for their transcription. Specifically, hippocampal retrotransposon (RT) elements are regulated by acute stress via the accumulation of the repressive H3K9me3 mark at RT loci. Further, corticosteroids appear to induce changes in heterochromatin status as well as RT expression in both adrenalectomized animal and rat cell culture models. Dysregulation of RT expression is predicted to result in functional deficits in affected brain areas. More broadly, however, transposons may have a variety of adaptive functions. As techniques improve to probe the deep genome, this approach to understanding stress neurobiology has the potential to yield insights into environment and genome interactions that may contribute to the physiology underlying a number of stress-related mental health disorders.

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy in adolescents and young adults. Surgery is the mainstay of therapy for primary and metastatic disease. Most patients relapse, with development of both local and distant metastases. Brain metastases from solid tumors are rare in the pediatric and young adult population. Here, we document three patients with brain metastases from FLHCC, confirmed by histology and molecular characterization of the chimeric fusion DNAJB1-PRKACA, each necessitating neurosurgical intervention. These observations highlight the ability of FLHCC to metastasize to the brain and suggest the need for surveillance neuroimaging for patients with advanced-stage disease.

The scientific community is increasingly concerned with the proportion of published "discoveries" that are not replicated in subsequent studies. The field of rodent behavioral phenotyping was one of the first to raise this concern, and to relate it to other methodological issues: the complex interaction between genotype and environment; the definitions of behavioral constructs; and the use of laboratory mice and rats as model species for investigating human health and disease mechanisms. In January 2015, researchers from various disciplines gathered at Tel Aviv University to discuss these issues. The general consensus was that the issue is prevalent and of concern, and should be addressed at the statistical, methodological and policy levels, but is not so severe as to call into question the validity and the usefulness of model organisms as a whole. Well-organized community efforts, coupled with improved data and metadata sharing, have a key role in identifying specific problems and promoting effective solutions. Replicability is closely related to validity, may affect generalizability and translation of findings, and has important ethical implications.

Clinical diagnosis and treatment for chronic granulomatous disease (CGD) have advanced greatly in recent years. However, CGD patients in China have unique clinical features and infection spectrums, which are challenging to their caretakers. Here, we summarized the clinical characteristics, genetic features, treatment, and prognosis of CGD in a single center in Shanghai. One hundred sixty-nine CGD patients were recruited between January 2004 and May 2017 based on clinical diagnosis. Electronic medical charts were reviewed to collect clinical data. Among the 169 patients recruited, CYBB mutations were identified in 150 cases, whereas CYBA mutations were identified in 7 cases, NCF1 in 5, and NCF2 in 7. The medium age at onset was 1 month (interquartile range 1-3). The medium age at diagnosis was 8 months (interquartile range 3-19). The most common infection sites were the lung (95.9%), lymph node (58.5%), skin (45.4%), intestinal (43.1%), and perianal (38.5%). Bacillus Calmette-Gu,rin (BCG) infections were common (59.2%). In addition, other non-infectious complications were also common, including anemia (55.4%) and impaired liver functions (34.6%). Thirty-one patients received stem cell transplantation. By the end of this study, 83/131 patients survived. Similar to other non-consanguineous populations, X-linked CGD accounted for the majority of the cases in China. However, BCG infections were a clinical challenge unique to China. In addition, severe infections were the major cause of death and the overall mortality was still high in China.

Results are presented from a search in the dijet final state for new massive narrow resonances decaying to pairs of W and Z bosons or to a W/Z boson and a quark. Results are based on data recorded in proton-proton collisions at root s = 13 TeV with the CMS detector at the CERN LHC. The data correspond to an integrated luminosity of 35.9 fb(-1). The mass range investigated extends upwards from 1.2 TeV. No excess is observed above the estimated standard model background and limits are set at 95% confidence level on cross sections, which are interpreted in terms of various models that predict gravitons, heavy spin-1 bosons, and excited quarks. In a heavy vector triplet model, W' and Z' resonances, with masses below 3.2 and 2.7 TeV, respectively, and spin-1 resonances with degenerate masses below 3.8 TeV are excluded at 95% confidence level. In the case of a singlet W' resonance masses between 3.3 and 3.6 TeV can be excluded additionally. Similarly, excited quark resonances, q*, decaying to qW and qZ with masses less than 5.0 and 4.7 TeV, respectively, are excluded. In a narrow-width bulk graviton model, upper limits are set on cross sections ranging from 0.6 fb for high resonance masses above 3.6 TeV, to 36.0 fb for low resonance masses of 1.3 TeV.

Alcohol relapse plays a major role in alcohol dependence and is an important focus for the treatment of alcoholism. The alcohol deprivation effect (ADE) is a widely used paradigm in rodents to model the relapse episodes that occur in human alcoholics. Mesyl Salvinorin B (MSB) is a potent and selective kappa opioid receptor (KOP-r) full agonist, with fewer side effects (e.g., sedation or anhedonia) than classic KOP-r full agonists and a longer duration of action in mice than the structurally similar salvinorin A. We have recently found that MSB prevents cocaine seeking in a rat self-administration model and reduces excessive alcohol drinking in a mouse escalation model via a KOP-r-mediated mechanism. Here, we further investigated whether MSB alone (0.3-3 mg/kg) or in combination with naltrexone (mu-opioid receptor antagonist at 1 mg/kg) altered alcohol "relapse" drinking using a mouse ADE paradigm. Both male and female mice, exposed to 3-week intermittent access alcohol drinking in a two-bottle choice paradigm with 24-h access every other day, developed excessive alcohol intake and then displayed pronounced ADE after 1-week abstinence. Acute administration of MSB prevented the ADE at 3 mg/kg in both male and female mice. Upon investigation of potential synergistic effects between naltrexone and MSB, we found that acute administration of a combination of MSB (0.3 mg/kg) and naltrexone (1 mg/kg) reduced the ADE at doses lower than those individual effective doses, with no sex difference. Our study suggests that the KOP-r full agonist MSB both alone and in combination with naltrexone shows potential in alcohol "relapse" treatment models.

Energy is required to sustain life and enable stress adaptation. At the cellular level, energy is largely derived from mitochondria unique multifunctional organelles with their own genome. Four main elements connect mitochondria to stress: (1) Energy is required at the molecular, (epi)genetic, cellular, organellar, and systemic levels to sustain components of stress responses; (2) Glucocorticoids and other steroid hormones are produced and metabolized by mitochondria; (3) Reciprocally, mitochondria respond to neuroendocrine and metabolic stress mediators; and (4) Experimentally manipulating mitochondrial functions alters physiological and behavioral responses to psychological stress. Thus, mitochondria are endocrine organelles that provide both the energy and signals that enable and direct stress adaptation. Neural circuits regulating social behavior as well as psychopathological processes are also influenced by mitochondrial energetics. An integrative view of stress as an energy-driven process opens new opportunities to study mechanisms of adaptation and regulation across the lifespan.