Syntectonic deposition and paleohydrology of the spring-fed Hualapai Limestone and implications for 5-6 MA integration of the Colorado River system through Grand Canyon : evidence from sedimentology, geochemistry and detrital zircon analysis

The Hualapai Limestone, at the western edge of the Colorado Plateau, provides the best sedimentary record available for 12 to 6 Ma at the mouth of the Grand Canyon. Because it directly underlies the first Colorado River gravels, this unit is a key element for understanding the integration of the Colorado River from the Colorado Plateau to the Basin and Range province, and the early paleogeography of the Grand Canyon region. This study combines a tectonic investigation with a stratigraphic and sedimentologic analysis that includes new geochemistry, tephrochronology, and detrital zircon analysis to examine variations of the sedimentary and tectonic records from the Hualapai Limestone basins. Thickness variations, with progressively thicker deposits towards the east in two of the four basins, indicate syntectonic deposition of the unit in half grabens formed above listric faults with 5-11 km depth to detachments. A sedimentary facies analysis highlights that the Hualapai Limestone was deposited in spring-fed lake and marsh systems fed by groundwater similar in composition to modern Havasu Creek and western Colorado Plateau groundwater. Stable isotope analysis of carbon and oxygen suggests gradual increase in meteoric water input through time. Sr isotopes, though variable, show an up-section decrease in 87Sr/86Sr and confirm a freshwater origin for the Hualapai Limestone. These data, plus facies analysis, suggest that waters that fed the Hualapai Limestone contained a significant component of endogenic spring inputs. Detrital zircon data for the Grand Wash trough indicate that red siltstones that underlie and interfinger with the Hualapai Limestone, from 13 to 6 Ma, were not derived from the Colorado Plateau, but likely from the Kingman Arch to the south. Western basins contain a more diverse suite of detrital zircons, suggesting possible connections to a northern Paleo Virgin River source. Tephrochronologic analyses show a 12 Ma ash near the base of the unit, extending the basal Hualapai date. We propose that the Hualapai Limestone was a long-lived (12-6 Ma) groundwater-fed series of lake and marsh systems that were deposited in syntectonic half grabens via spring vents along faults and discharge along the dissected aquifer of the Grand Wash Cliffs

Biodiversity and distribution of polar freshwater DNA viruses

Viruses constitute the most abundant biological entities and a large reservoir of genetic diversity on Earth. Despite the recent surge in their study, our knowledge on their actual biodiversity and distribution remains sparse. We report the first metagenomic analysis of Arctic freshwater viral DNA communities and a comparative analysis with other freshwater environments. Arctic viromes are dominated by unknown and single-stranded DNA viruses with no close relatives in the database. These unique viral DNA communities mostly relate to each other and present some minor genetic overlap with other environments studied, including an Arctic Ocean virome. Despite common environmental conditions in polar ecosystems, the Arctic and Antarctic DNA viromes differ at the fine-grain genetic level while sharing a similar taxonomic composition. The study uncovers some viral lineages with a bipolar distribution, suggesting a global dispersal capacity for viruses, and seemingly indicates that viruses do not follow the latitudinal diversity gradient known for macroorganisms. Our study sheds light into the global biogeography and connectivity of viral communities

LGBTQ-Related Material in Undergraduate Medical Education in the Mid-Atlantic Region of the United States

Purpose This study describes the current state of formal lesbian, gay, bisexual, transgender and queer (LGBTQ)-related education at undergraduate medical schools in the Mid-Atlantic region of the United States. A review of literature shows the last time a similar study was conducted was in 2011 by Obedin-Maliver et al and was a survey that included all medical schools of the United States and Canada. Given the changes over time for both the LGBTQ and medical community , it is likely that the state of LGBTQ-related education in undergraduate medical education has changed greatly. Methods This was a cross-sectional Internet-based survey, utilizing Qualtrics to deliver the questionnaire. An email with a unique link to the survey was sent to the designated Dean of Diversity and Inclusion or Dean of Medical Education of all Doctor of Medicine (MD)-granting medical schools and Doctor of Osteopathic Medicine (DO)-granting medical schools in the Mid-Atlantic (Delaware, Maryland, New Jersey, New York, Pennsylvania) region. This questionnaire is derived from the 2011 Obedin-Malliver study and includes 13 questions that evaluate LGBTQ-related undergraduate medical school materials. Results and Conclusions Of the 35 schools, 15 (42.9%) responded and 13 (37.1%) completed the survey. The median time dedicated to teaching LGBTQ-related content in the entire curriculum was 8 hours (interquartile range [IQR], 6-13 hours). None of the schools reported zero hours during pre-clinical years, but 6 (46.1%) schools reported 0 hours during the clinical years. Work should be done to improve both pre-clinical and clinical LGBTQ-related content

Cooperative ordering of treadmilling filaments in cytoskeletal networks of FtsZ and its crosslinker ZapA

During bacterial cell division, the tubulin-homolog FtsZ forms a ring-like structure at the center of the cell. This Z-ring not only organizes the division machinery, but treadmilling of FtsZ filaments was also found to play a key role in distributing proteins at the division site. What regulates the architecture, dynamics and stability of the Z-ring is currently unknown, but FtsZ-associated proteins are known to play an important role. Here, using an in vitro reconstitution approach, we studied how the well-conserved protein ZapA affects FtsZ treadmilling and filament organization into large-scale patterns. Using high-resolution fluorescence microscopy and quantitative image analysis, we found that ZapA cooperatively increases the spatial order of the filament network, but binds only transiently to FtsZ filaments and has no effect on filament length and treadmilling velocity. Together, our data provides a model for how FtsZ-associated proteins can increase the precision and stability of the bacterial cell division machinery in a switch-like manner

Pneumococcal Gene Complex Involved in Resistance to Extracellular Oxidative Stress

Streptococcus pneumoniae is a Gram-positive bacterium which is a member of the normal human nasopharyngeal flora but can also cause serious disease such as pneumonia, bacteremia, and meningitis. Throughout its life cycle, S. pneumoniae is exposed to significant oxidative stress derived from endogenously produced hydrogen peroxide (H2O2) and from the host through the oxidative burst. How S. pneumoniae, an aerotolerant anaerobic bacterium that lacks catalase, protects itself against hydrogen peroxide stress is still unclear. Bioinformatic analysis of its genome identified a hypothetical open reading frame belonging to the thiol-specific antioxidant (TlpA/TSA) family, located in an operon consisting of three open reading frames. For all four strains tested, deletion of the gene resulted in an approximately 10-fold reduction in survival when strains were exposed to external peroxide stress. However, no role for this gene in survival of internal superoxide stress was observed. Mutagenesis and complementation analysis demonstrated that all three genes are necessary and sufficient for protection against oxidative stress. Interestingly, in a competitive index mouse pneumonia model, deletion of the operon had no impact shortly after infection but was detrimental during the later stages of disease. Thus, we have identified a gene complex involved in the protection of S. pneumoniae against external oxidative stress, which plays an important role during invasive disease.

Polo-like kinase 3 regulates CtIP during DNA double-strand break repair in G1

DNA double-strand breaks (DSBs) are repaired by nonhomologous end joining (NHEJ) or homologous recombination (HR). The C terminal binding protein–interacting protein (CtIP) is phosphorylated in G2 by cyclin-dependent kinases to initiate resection and promote HR. CtIP also exerts functions during NHEJ, although the mechanism phosphorylating CtIP in G1 is unknown. In this paper, we identify Plk3 (Polo-like kinase 3) as a novel DSB response factor that phosphorylates CtIP in G1 in a damage-inducible manner and impacts on various cellular processes in G1. First, Plk3 and CtIP enhance the formation of ionizing radiation-induced translocations; second, they promote large-scale genomic deletions from restriction enzyme-induced DSBs; third, they are required for resection and repair of complex DSBs; and finally, they regulate alternative NHEJ processes in Ku−/− mutants. We show that mutating CtIP at S327 or T847 to nonphosphorylatable alanine phenocopies Plk3 or CtIP loss. Plk3 binds to CtIP phosphorylated at S327 via its Polo box domains, which is necessary for robust damage-induced CtIP phosphorylation at S327 and subsequent CtIP phosphorylation at T847

Oncogenic PIK3CA promotes cellular stemness in an allele dose-dependent manner

The PIK3CA gene, which encodes the p110α catalytic subunit of PI3 kinase (PI3K), is mutationally activated in cancer and in overgrowth disorders known as PIK3CA-related overgrowth spectrum (PROS). To determine the consequences of genetic PIK3CA activation in a developmental context of relevance to both PROS and cancer, we engineered isogenic human induced pluripotent stem cells (iPSCs) with heterozygous or homozygous knockin of PIK3CA H1047R While heterozygous iPSCs remained largely similar to wild-type cells, homozygosity for PIK3CA H1047R caused widespread, cancer-like transcriptional remodeling, partial loss of epithelial morphology, up-regulation of stemness markers, and impaired differentiation to all three germ layers in vitro and in vivo. Genetic analysis of PIK3CA-associated cancers revealed that 64% had multiple oncogenic PIK3CA copies (39%) or additional PI3K signaling pathway-activating "hits" (25%). This contrasts with the prevailing view that PIK3CA mutations occur heterozygously in cancer. Our findings suggest that a PI3K activity threshold determines pathological consequences of oncogenic PIK3CA activation and provide insight into the specific role of this pathway in human pluripotent stem cells

The spectrum of rare central nervous system (CNS) tumors with EWSR1-non-ETS fusions: experience from three pediatric institutions with review of the literature

The group of CNS mesenchymal (non-meningothelial) and primary glial/neuronal tumors in association with EWSR1-non-ETS rearrangements comprises a growing spectrum of entities, mostly reported in isolation with incomplete molecular profiling. Archival files from three pediatric institutions were queried for unusual cases of pediatric (≤21 years) CNS EWSR1-rearranged tumors confirmed by at least one molecular technique. Extra-axial tumors and cases with a diagnosis of Ewing sarcoma (EWSR1-ETS family fusions) were excluded. Additional studies, including anchored multiplex-PCR with next-generation sequencing and DNA methylation profiling, were performed as needed to determine fusion partner status and brain tumor methylation class, respectively. Five cases (median 17 years) were identified (M:F of 3:2). Location was parenchymal (n = 3) and undetermined (n = 2) with topographic distributions including posterior fossa (n = 1), frontal (n = 1), temporal (n = 1), parietal (n = 1) and occipital (n = 1) lobes. Final designation with fusion findings included desmoplastic small round cell tumor (EWSR1-WT1; n = 1) and tumors of uncertain histogenesis (EWSR1-CREM, n = 1; EWSR1-CREB1, n = 1; EWSR1-PLAGL1, n = 1; and EWSR1-PATZ1, n = 1). Tumors showed a wide spectrum of morphology and biologic behavior. For EWSR1-CREM, EWSR1-PLAGL1 and EWSR1-PATZ1 tumors, no significant methylation scores were reached in the known brain tumor classes. Available outcome (4/5) was reported as favorable (n = 2) and unfavorable (n = 2) with a median follow-up of 30 months. In conclusion, we describe five primary EWSR1-non-ETS fused CNS tumors exhibiting morphologic and biologic heterogeneity and we highlight the clinical importance of determining specific fusion partners to improve diagnostic accuracy, treatment and monitoring. Larger prospective clinicopathological and molecular studies are needed to determine the prognostic implications of histotypes, anatomical location, fusion partners, breakpoints and methylation profiles in patients with these rare tumors

The T2K ND280 Off-Axis Pi-Zero Detector

The Pi-Zero detector (P{\O}D) is one of the subdetectors that makes up the off-axis near detector for the Tokai-to-Kamioka (T2K) long baseline neutrino experiment. The primary goal for the P{\O}D is to measure the relevant cross sections for neutrino interactions that generate pi-zero's, especially the cross section for neutral current pi-zero interactions, which are one of the dominant sources of background to the electron neutrino appearance signal in T2K. The P{\O}D is composed of layers of plastic scintillator alternating with water bags and brass sheets or lead sheets and is one of the first detectors to use Multi-Pixel Photon Counters (MPPCs) on a large scale.Comment: 17 pages, submitted to NIM