Human Pleural Fluid Elicits Pyruvate and Phenylalanine Metabolism in Acinetobacter baumannii to Enhance Cytotoxicity and Immune Evasion

The CCAAT box-harboring proteins represent a family of heterotrimeric transcription factors which is highly conserved in eukaryotes. In fungi, one of the particularly important homologs of this family is the Hap complex that separates the DNA-binding domain from the activation domain and imposes essential impacts on regulation of a wide range of cellular functions. So far, a comprehensive summary of this complex has been described in filamentous fungi but not in the yeast. In this review, we summarize a number of studies related to the structure and assembly mode of the Hap complex in a list of representative yeasts. Furthermore, we emphasize recent advances in understanding the regulatory functions of this complex, with a special focus on its role in regulating respiration, production of reactive oxygen species (ROS) and iron homeostasis.Fil: Nyah, Rodman. California State University; Estados UnidosFil: Martinez, Jasmine. California State University; Estados UnidosFil: Fung, Sammie. California State University; Estados UnidosFil: Nakanouchi, Jun. California State University; Estados UnidosFil: Myers, Amber L.. California State University; Estados UnidosFil: Harris, Caitlin M.. California State University; Estados UnidosFil: Dang, Emily. California State University; Estados UnidosFil: Fernandez, Jennifer. California State University; Estados UnidosFil: Liu, Christine. California State University; Estados UnidosFil: Mendoza, Anthony M.. California State University; Estados UnidosFil: Jimenez, Verónica. California State University; Estados UnidosFil: Nikolaidis, Nikolas. California State University; Estados UnidosFil: Brennan, Catherine A.. California State University; Estados UnidosFil: Bonomo, Robert A.. Louis Stokes Cleveland Department of Veterans Affairs Medical Cente; Estados Unidos. Center for Antimicrobial Resistance and Epidemiology; Estados Unidos. Case Western Reserve University School of Medicine; Estados UnidosFil: Sieira, Rodrigo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ramirez, Maria Soledad. California State University; Estados Unido

Harnessing person-generated health data to accelerate patient-centered outcomes research: the Crohn’s and Colitis Foundation of America PCORnet Patient Powered Research Network (CCFA Partners)

The Crohn’s and Colitis Foundation of America Partners Patient-Powered Research Network (PPRN) seeks to advance and accelerate comparative effectiveness and translational research in inflammatory bowel diseases (IBDs). Our IBD-focused PCORnet PPRN has been designed to overcome the major obstacles that have limited patient-centered outcomes research in IBD by providing the technical infrastructure, patient governance, and patient-driven functionality needed to: 1) identify, prioritize, and undertake a patient-centered research agenda through sharing person-generated health data; 2) develop and test patient and provider-focused tools that utilize individual patient data to improve health behaviors and inform health care decisions and, ultimately, outcomes; and 3) rapidly disseminate new knowledge to patients, enabling them to improve their health. The Crohn’s and Colitis Foundation of America Partners PPRN has fostered the development of a community of citizen scientists in IBD; created a portal that will recruit, retain, and engage members and encourage partnerships with external scientists; and produced an efficient infrastructure for identifying, screening, and contacting network members for participation in research

The biogeochemical impact of glacial meltwater from Southwest Greenland

Biogeochemical cycling in high-latitude regions has a disproportionate impact on global nutrient budgets. Here, we introduce a holistic, multi-disciplinary framework for elucidating the influence of glacial meltwaters, shelf currents, and biological production on biogeochemical cycling in high-latitude continental margins, with a focus on the silica cycle. Our findings highlight the impact of significant glacial discharge on nutrient supply to shelf and slope waters, as well as surface and benthic production in these regions, over a range of timescales from days to thousands of years. Whilst biological uptake in fjords and strong diatom activity in coastal waters maintains low dissolved silicon concentrations in surface waters, we find important but spatially heterogeneous additions of particulates into the system, which are transported rapidly away from the shore. We expect the glacially-derived particles – together with biogenic silica tests – to be cycled rapidly through shallow sediments, resulting in a strong benthic flux of dissolved silicon. Entrainment of this benthic silicon into boundary currents may supply an important source of this key nutrient into the Labrador Sea, and is also likely to recirculate back into the deep fjords inshore. This study illustrates how geochemical and oceanographic analyses can be used together to probe further into modern nutrient cycling in this region, as well as the palaeoclimatological approaches to investigating changes in glacial meltwater discharge through time, especially during periods of rapid climatic change in the Late Quaternary

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

AgRP neuron activity promotes associations between sensory and nutritive signals to guide flavor preference

Objective: The learned associations between sensory cues (e.g., taste, smell) and nutritive value (e.g., calories, post-ingestive signaling) of foods powerfully influences our eating behavior [1], but the neural circuits that mediate these associations are not well understood. Here, we examined the role of agouti-related protein (AgRP)-expressing neurons – neurons which are critical drivers of feeding behavior [2; 3] – in mediating flavor-nutrient learning (FNL). Methods: Because mice prefer flavors associated with AgRP neuron activity suppression [4], we examined how optogenetic stimulation of AgRP neurons during intake influences FNL, and used fiber photometry to determine how endogenous AgRP neuron activity tracks associations between flavors and nutrients. Results: We unexpectedly found that tonic activity in AgRP neurons during FNL potentiated, rather than prevented, the development of flavor preferences. There were notable sex differences in the mechanisms for this potentiation. Specifically, in male mice, AgRP neuron activity increased flavor consumption during FNL training, thereby strengthening the association between flavors and nutrients. In female mice, AgRP neuron activity enhanced flavor-nutrient preferences independently of consumption during training, suggesting that AgRP neuron activity enhances the reward value of the nutrient-paired flavor. Finally, in vivo neural activity analyses demonstrated that acute AgRP neuron dynamics track the association between flavors and nutrients in both sexes. Conclusions: Overall, these data (1) demonstrate that AgRP neuron activity enhances associations between flavors and nutrients in a sex-dependent manner and (2) reveal that AgRP neurons track and rapidly update these associations. Taken together, our findings provide new insight into the role of AgRP neurons in assimilating sensory and nutritive signals for food reinforcement