The rockefeller university

CRISPR-Cas systems offer an immune mechanism through which prokaryotic hosts can acquire heritable resistance to genetic parasites, including temperate phages. Co-transcriptional DNA and RNA targeting by type III-A CRISPR-Cas systems restricts temperate phage lytic infections while allowing lysogenic infections to be tolerated under conditions where the prophage targets are transcriptionally repressed. However, long-term consequences of this phenomenon have not been explored. Here we show that maintenance of conditionally tolerant type III-A systems can produce fitness costs within populations of Staphylococcus aureus lysogens. The fitness costs depend on the activity of prophage-internal promoters and type III-A Cas nucleases implicated in targeting, can be more severe in double lysogens, and are alleviated by spacer-target mismatches which do not abrogate immunity during the lytic cycle. These findings suggest that persistence of type III-A systems that target endogenous prophages could be enhanced by spacer-target mismatches, particularly among populations that are prone to polylysogenization.

Vaccination with radiation-attenuated sporozoites has been shown to induce CD8+ T cell-mediated protection against pre-erythrocytic stages of malaria. Empirical evidence suggests that successive inoculations often improve the efficacy of this type of vaccines. An initial dose (prime) triggers a specific cellular response, and subsequent inoculations (boost) amplify this response to create a robust CD8+ T cell memory. In this work we propose a model to analyze the effect of T cell dynamics on the performance of prime-boost vaccines. This model suggests that boost doses and timings should be selected according to the T cell response elicited by priming. Specifically, boosting during late stages of clonal contraction would maximize T cell memory production for vaccines using lower doses of irradiated sporozoites. In contrast, single-dose inoculations would be indicated for higher vaccine doses. Experimental data have been obtained that support theoretical predictions of the model.

A search for narrow vector resonances decaying into quark-antiquark pairs is presented. The analysis is based on data collected in proton-proton collisions at root s = 13 TeV with the CMS detector at the LHC, corresponding to an integrated luminosity of 35.9 fb(-1). The hypothetical resonance is produced with sufficiently high transverse momentum that its decay products are merged into a single jet with two-prong substructure. A signal would be identified as a peak over a smoothly falling background in the distribution of the invariant mass of the jet, using novel jet substructure techniques. No evidence for such a resonance is observed within the mass range of 50-300 GeV. Upper limits at 95% confidence level are set on the production cross section, and presented in a mass-coupling parameter space. The limits further constrain simplified models of dark matter production involving a mediator interacting between quarks and dark matter particles through a vector or axial-vector current. In the framework of these models, the results are the most sensitive to date, extending for the first time the search region to masses below 100 GeV.

Cell division involves mechanical processes, such as chromosome

The antibiotic paenimucillin A was originally identified using a culture-independent synthetic-bioinformatic natural product (syn-BNP) discovery approach. Here we report on a bioinformatics-guided survey of paenimucillin A analogs that led to the discovery of paenimucillin C. Paenimucillin C inhibits the growth of multidrug-resistant (MDR) Acinetobacter baumannii clinical isolates, as well as other Gram-negative bacterial pathogens. In a rat cutaneous wound model, it completely sterilized MDR A. baumannii wound infections with no sign of rebound. Mechanistic studies point to a membrane-associated mode of action that results in leakage of intracellular contents.& para;& para;IMPORTANCE Natural product-inspired antibiotics have saved millions of lives and played a critical role in modern medicine. However, the emergence of drug-resistant pathogens is outpacing the rate at which new clinically useful antibiotics are being discovered. The lack of a means to combat infections caused by multidrug-resistant ( MDR) Acinetobacter baumannii is of particular concern. The sharp increase in cases of MDR A. baumannii infections in recent years prompted the CDC (https://urldefense.proofpoint.com/v2/url?u=https-3A__www.cdc.gov_drugresistance_biggest-5Fthreats.html&d=DwIDaQ&c=JeTkUgVztGMmhKYjxsy2rfoWYibK1YmxXez1G3oNStg&r=bWJiylK2oqB9vBxAFHE1PJcvSYL9TVkBaaVMsMDsLbs&m=2yuUL-2W7Hn85BsfNdK7hhyh8bnrdh_fMoQqJ9Htz3A&s=bDZnP6LOg-9-zPxCn3yWB-BTWAqDNVhYprYUDiz_xg0&e=) and WHO (https://urldefense.proofpoint.com/v2/url?u=http-3A__www.who.int_medicines_publications_global-2Dpriority-2Dlist-2Dantibiot&d=DwIDaQ&c=JeTkUgVztGMmhKYjxsy2rfoWYibK1YmxXez1G3oNStg&r=bWJiylK2oqB9vBxAFHE1PJcvSYL9TVkBaaVMsMDsLbs&m=2yuUL-2W7Hn85BsfNdK7hhyh8bnrdh_fMoQqJ9Htz3A&s=mLdKhjQZCnXH_xMNCKtB0EJAsaf-aR0e8Zxzzn4pctE&e= ic-resistant-bacteria/en/) to list this pathogen as a "serious threat" and "critical pathogen,"respectively. Here we report a new antibiotic, paenimucillin C, active against Gram-negative bacterial pathogens, including many clinical isolates of MDR A. baumannii strains. Mechanistic studies point to membrane disruption leading to leakage of intracellular contents as its antibacterial mode of action. Paenimucillin C sterilizes MDR A. baumannii infections in a rat cutaneous wound model with no sign of rebound infection, providing a potential new therapeutic regimen.

Retroviruses incorporate specific host cell RNAs into virions. In particular, the host noncoding 7SL RNA is highly abundant in all examined retroviruses compared with its cellular levels or relative to common mRNAs such as actin. Using live cell imaging techniques, we have determined that the 7SL RNA does not arrive with the HIV-1 RNA genome. Instead, it is recruited contemporaneously with assembly of the protein HIV-1 Gag at the plasma membrane. Further, we demonstrate that complexes of 7SL RNA and Gag can be immunoprecipitated from both cytosolic and plasma membrane fractions. This indicates that 7SL RNAs likely interact with Gag prior to high-order Gag multimerization at the plasma membrane. Thus, the interactions between Gag and the host RNA 7SL occur independent of the interactions between Gag and the host endosomal sorting complex required for transport (ESCRT) proteins, which are recruited temporarily at late stages of assembly. The interactions of 7SL and Gag are also independent of interactions of Gag and the HIV-1 genome which are seen on the plasma membrane prior to assembly of Gag.

An estimated 50% of depressed patients are inadequately treated by available interventions. Even with an eventual recovery, many patients require a trial and error approach, as there are no reliable guidelines to match patients to optimal treatments and many patients develop treatment resistance over time. This situation derives from the heterogeneity of depression and the lack of biomarkers for stratification by distinct depression sub-types. There is thus a dire need for novel therapies. To address these known challenges, we propose a multi-scale framework for fundamental research on depression, aimed at identifying the brain circuits that are dysfunctional in several animal models of depression as well the changes in gene expression that are associated with these models. When combined with human genetic and imaging studies, our preclinical studies are starting to identify candidate circuits and molecules that are altered both in models of disease and in patient populations. Targeting these circuits and mechanisms can lead to novel generations of antidepressants tailored to specific patient populations with distinctive types of molecular and circuit dysfunction.

A fundamental question in human susceptibility to bacterial infections is to what extent variability is a function of differences in the pathogen species or in individual humans. To focus on the pathogen species, we compared in the same individual the human adaptive T and B cell immune response to multiple strains of two major human pathogens, Staphylococcus aureus and Streptococcus pyogenes. We found wide variability in the acute adaptive immune response induced by various strains of a species, with a unique combination of activation within the two arms of the adaptive response. Further, this was also accompanied by a dramatic difference in the intensity of the specific protective T helper (Th) response. Importantly, the same immune response differences induced by the individual strains were maintained across multiple healthy human donors. A comparison of isogenic phage KO strains, demonstrated that of the pangenome, prophages were the major contributor to inter-strain immune heterogeneity, as the T cell response to the remaining "core genome" was noticeably blunted. Therefore, these findings extend and modify the notion of an adaptive response to a pathogenic bacterium, by implying that the adaptive immune response signature of a bacterial species should be defined either per strain or alternatively to the species' 'core genome', common to all of its strains. Further, our results demonstrate that the acquired immune response variation is as wide among different strains within a single pathogenic species as it is among different humans, and therefore may explain in part the clinical heterogeneity observed in patients infected with the same species.

Our sense of hearing boasts exquisite sensitivity to periodic signals. Experiments and modeling imply, however, that the auditory system achieves this performance for only a narrow range of parameter values. As a result, small changes in these values could compromise the ability of the mechanosensory hair cells to detect stimuli. We propose that, rather than exerting tight control over parameters, the auditory system employs a homeostatic mechanism that ensures the robustness of its operation to variation in parameter values. Through analytical techniques and computer simulations we investigate whether a homeostatic mechanism renders the hair bundle's signal-detection ability more robust to alterations in experimentally accessible parameters. When homeostasis is enforced, the range of values for which the bundle's sensitivity exceeds a threshold can increase by more than an order of magnitude. The robustness of cochlear function based on somatic motility or hair bundle motility may be achieved by employing the approach we describe here.