Publications search

Cell division involves mechanical processes, such as chromosome

Stem cells are highly resistant to viral infection compared to their differentiated progeny; however, the mechanism is mysterious. Here, we analyzed gene expression in mammalian stem cells and cells at various stages of differentiation. We find that, conserved across species, stem cells express a subset of genes previously classified as interferon (IFN) stimulated genes (ISGs) but that expression is intrinsic, as stem cells are refractory to interferon. This intrinsic ISG expression varies in a cell-type-specific manner, and many ISGs decrease upon differentiation, at which time cells become IFN responsive, allowing induction of a broad spectrum of ISGs by IFN signaling. Importantly, we show that intrinsically expressed ISGs protect stem cells against viral infection. We demonstrate the in vivo importance of intrinsic ISG expression for protecting stem cells and their differentiation potential during viral infection. These findings have intriguing implications for understanding stem cell biology and the evolution of pathogen resistance.

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.

Drawing upon sources in neuroethics, civil rights, and disability rights law, we argue for the reintegration of people with severe brain injury back into the nexus of their families and communities consistent with the Americans with Disabilities Act (ADA) and the UN Convention on the Rights of Persons with Disabilities, both of which call for the maximal integration of people with disability into society. To this end, we offer a rights-based argument to address the care of people with severe brain injury. Instead of viewing the provision of rehabilitation as a reimbursement issue, which it surely is, we argue that it can be productively understood as a question of civil rights for a population generally segregated from the medical mainstream and from society itself. Their segregation in the chronic care sector constitutes disrespect for persons, made all the more consequential because recent advances in brain injury rehabilitation make reintegration into civil society an aspirational, if not achievable goal.

Background: Poor maternal vitamin D status and elevated circulating corticotropin-releasing hormone (CRH) are associated with preterm birth. It is not known if these risk factors are independent or interrelated. Both are associated with inflammation.Methods: We measured maternal circulating 25-hydroxyvitamin D (25-OH-D) and CRH from 97 samples collected from 15 early-preterm, 31 late-preterm, 21 early-term, and 30 term births. The potential involvement of vitamin D in the regulation of inflammation was evaluated by Q-PCR in human uterine smooth muscle (UTSM) cell line.Results: Maternal 25-OH-D was lowest in early-preterm births (22.94.2ng/ml versus 34.4 +/- 1.4ng/ml; p=.029). Circulating CRH was high in early-preterm births (397 +/- 30pg/ml). Late-preterm (304 +/- 13pg/ml) and early-term births (347 +/- 17pg/ml) were not different from term births (367 +/- 19pg/ml), after accounting for gestational age. Maternal circulating 25-OH-D and CRH were not associated in term births. In preterm births, 25-OH-D below 30ng/ml was associated with higher CRH. Vitamin D treatment of UTSM significantly reduced mRNA for leptin and IL-6 receptors. Deletion of vitamin D receptor from UTSM promoted the expression of the cox2 inflammatory marker.Conclusion: Early-preterm birth showed a syndrome of high maternal CRH and low vitamin D status.

Neurons in Caenorhabditis elegans and other nematodes have been thought to lack classical action potentials. Unexpectedly, we observe membrane potential spikes with defining characteristics of action potentials in C. elegans AWA olfactory neurons recorded under current-clamp conditions. Ion substitution experiments, mutant analysis, pharmacology, and modeling indicate thatAWA fires calcium spikes, which are initiated by EGL-19 voltage-gated CaV1 calcium channels and terminated by SHK-1 Shaker-type potassium channels. AWA action potentials result in characteristic signals in calcium imaging experiments. These calcium signals are also observed when intact animals are exposed to odors, suggesting that natural odor stimuli induce AWA spiking. The stimuli that elicit action potentials match AWA's specialized function in climbing odor gradients. Our results provide evidence that C. elegans neurons can encode information through regenerative all-or-none action potentials, expand the computational repertoire of its nervous system, and inform future modeling of its neural coding and network dynamics.

We explore some consequences of a theory of internal symmetries for elementary particles constructed on exceptional quantum mechanical spaces based on Jordan algebra formulation that admit exceptional groups as gauge groups.

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.

Bacterial RNA polymerase (RNAP) is an RNA-synthesizing molecular machine and a target for antibiotics. In transcription, RNAP can interact with DNA sequence-specifically, during promoter recognition by the sigma-containing holoenzyme, or nonspecifically, during productive RNA elongation by the core RNAP. We describe high-affinity single-stranded DNA aptamers that are specifically recognized by the core RNAP from Thermos aquaticus. The aptamers interact with distinct epitopes inside the RNAP main channel, including the rifamycin pocket, and sense the binding of other RNAP ligands such as rifamycin and the sigma(A) subunit. The aptamers inhibit RNAP activity and can thus be used for functional studies of transcription and development of novel RNAP inhibitors. (C) 2017 Elsevier Inc. All rights reserved.

The protection and efficient restart of stalled replication forks is critical for the maintenance of genome integrity. Here, we identify a regulatory pathway that promotes stalled forks recovery from replication stress. We show that the mammalian replisome component C20orf43/ RTF2 (homologous to S. pombe Rtf2) must be removed for fork restart to be optimal. We further show that the proteasomal shuttle proteins DDI1 and DDI2 are required for RTF2 removal from stalled forks. Persistence of RTF2 at stalled forks results in fork restart defects, hyperactivation of the DNA damage signal, accumulation of single-stranded DNA (ssDNA), sensitivity to replication drugs, and chromosome instability. These results establish that RTF2 removal is a key determinant for the ability of cells to manage replication stress and maintain genome integrity.