Preliminary Investigation of Tracer Gas Reaeration Method for Shallow Bays

Accurate estimates of surface exchange rates for volatile pollutants in bays are needed to allow predictions of pollutant movement and retention time. The same types of estimates can be used to calculate reaeration rates. The tracer gas technique has been used to measure surface gas transfer rates in rivers, and to a lesser extent, in estuaries. Application of the technique to bays would be extremely useful, but it is complicated by differences in the hydrodynamics and the density stratification that can exist due to fresh river water overriding heavier saline ocean water. The objective of this research has been to investigate field procedures for application of the tracer gas technique to shallow bays. The modified tracer technique was used with propane for the tracer gas and Rhodamine-WT, a fluorescent dye, for the "conservative" tracer. The propane was injected through porous tile diffusers, and the dye was released simultaneously. The propane acts as a model for the surface exchange of other gases and volatile compounds. Three four-day field trips to Lavaca Bay on the Texas coast of the Gulf of Mexico were made during the course of the study. A variety of experimental techniques was investigated. One was to make a short-duration injection (10-30 minutes) and sample the dye cloud as it moved through the bay. Another was to use a long-duration injection (3 to 4 hours) to obtain quasi-steady conditions. The long injections were discontinued because there appeared to be no practical method of determining the travel time for the samples taken from the tracer plume. Drogues (floats) which are normally used for this purpose consistently drifted downwind from the tracer plumes. Pulses of a second fluorescent dye for determining time of travel became too diffuse to be used for this purpose. The most promising method appears to be the short-duration injection method with a large pulse of the second dye released during the injection to mark the middle of the tracer cloud. A special injection device was designed to prevent mixing of the tracers with heavier saline water near the bed of the bay during injection. A field fluorometer was used both in the field to track the tracer cloud and in the laboratory to measure dye concentrations in the field samples. Propane concentrations were determined with gas chromatography. The same equipment was used to perform laboratory studies to test performance of the equipment in the field and to aid in understanding field test results. These were apparently the first tests to be performed using the tracer gas technique in bays. As a result, the emphasis was on the development of techniques rather than on obtaining data. It appears that workable techniques have been developed, but they now need to be tested under a variety of conditions. Also, the preliminary results which were obtained for gas transfer coefficients indicate some anomalous results. After the completion of the project, it was learned that the addition of formalin to the field tracer gas samples may be affecting the samples adversely. Thus, some laboratory tests are now needed to investigate the behavior of tracer gases in bay water. In summary, the method appears to be very promising, but some additional developmental work is required before it can be used on a routine basi

Energy Balance Modulation Impacts Epigenetic Reprogramming, ERα and ERβ Expression, and Mammary Tumor Development in MMTV-neu Transgenic Mice

The association between obesity and breast cancer risk and prognosis is well established in ER-positive disease but less clear in HER2-positive disease. Here, we report preclinical evidence suggesting weight maintenance through calorie restriction may limit risk of HER2-positive breast cancer. In female MMTV-HER2/neu transgenic mice, we found that ERα and ERβ expression, mammary tumorigenesis and survival are energy balance-dependent in association with epigenetic reprogramming. Mice were randomized to receive a calorie restriction (CR), overweight (OW)-inducing, or diet-induced obesity (DIO) regimen (n = 27/group). Subsets of mice (n = 4/group/time point) were euthanized after 1, 3 and 5 months to characterize diet-dependent metabolic, transcriptional, and epigenetic perturbations. Remaining mice were followed up to 22 months. Relative to the OW and DIO regimens, CR decreased body weight, adiposity, and serum metabolic hormones as expected, and also elicited an increase in mammary ERα and ERβ expression. Increased DNA methylation accompanied this pattern, particularly at CpG dinucleotides located within binding or flanking regions for the transcriptional regulator CCCTC-binding factor (CTCF) of ESR1 and ESR2, consistent with sustained transcriptional activation of ERα and ERβ. Mammary expression of the DNA methylation enzyme DNMT1 was stable in CR mice but increased over time in OW and DIO mice, suggesting CR obviates epigenetic alterations concurrent with chronic excess energy intake. In the survival study, CR elicited a significant suppression in spontaneous mammary tumorigenesis. Overall, our findings suggest a mechanistic rationale to prevent or reverse excess body weight as a strategy to reduce HER2-positive breast cancer risk

Viral Mimicry of Cdc2/Cyclin-Dependent Kinase 1 Mediates Disruption of Nuclear Lamina during Human Cytomegalovirus Nuclear Egress

The nuclear lamina is a major obstacle encountered by herpesvirus nucleocapsids in their passage from the nucleus to the cytoplasm (nuclear egress). We found that the human cytomegalovirus (HCMV)-encoded protein kinase UL97, which is required for efficient nuclear egress, phosphorylates the nuclear lamina component lamin A/C in vitro on sites targeted by Cdc2/cyclin-dependent kinase 1, the enzyme that is responsible for breaking down the nuclear lamina during mitosis. Quantitative mass spectrometry analyses, comparing lamin A/C isolated from cells infected with viruses either expressing or lacking UL97 activity, revealed UL97-dependent phosphorylation of lamin A/C on the serine at residue 22 (Ser22). Transient treatment of HCMV-infected cells with maribavir, an inhibitor of UL97 kinase activity, reduced lamin A/C phosphorylation by approximately 50%, consistent with UL97 directly phosphorylating lamin A/C during HCMV replication. Phosphorylation of lamin A/C during viral replication was accompanied by changes in the shape of the nucleus, as well as thinning, invaginations, and discrete breaks in the nuclear lamina, all of which required UL97 activity. As Ser22 is a phosphorylation site of particularly strong relevance for lamin A/C disassembly, our data support a model wherein viral mimicry of a mitotic host cell kinase activity promotes nuclear egress while accommodating viral arrest of the cell cycle

Building blocks for social accountability: a conceptual framework to guide medical schools

Background: This paper presents a conceptual framework developed from empirical evidence, to guide medical schools aspiring towards greater social accountability. Methods: Using a multiple case study approach, seventy-five staff, students, health sector representatives and community members, associated with four medical schools, participated in semi-structured interviews. Two schools were in Australia and two were in the Philippines. These schools were selected because they were aspiring to be socially accountable. Data was collected through on-site visits, field notes and a documentary review. Abductive analysis involved both deductive and inductive iterative theming of the data both within and across cases. Results: The conceptual framework for socially accountable medical education was built from analyzing the internal and external factors influencing the selected medical schools. These factors became the building blocks that might be necessary to assist movement to social accountability. The strongest factor was the demands of the local workforce situation leading to innovative educational programs established with or without government support. The values and professional experiences of leaders, staff and health sector representatives, influenced whether the organizational culture of a school was conducive to social accountability. The wider institutional environment and policies of their universities affected this culture and the resourcing of programs. Membership of a coalition of socially accountable medical schools created a community of learning and legitimized local practice. Communities may not have recognized their own importance but they were fundamental for socially accountable practices. The bedrock of social accountability, that is, the foundation for all building blocks, is shared values and aspirations congruent with social accountability. These values and aspirations are both a philosophical understanding for innovation and a practical application at the health systems and education levels. Conclusions: While many of these building blocks are similar to those conceptualized in social accountability theory, this conceptual framework is informed by what happens in practice - empirical evidence rather than prescriptions. Consequently it is valuable in that it puts some theoretical thinking around everyday practice in specific contexts; addressing a gap in the medical education literature. The building blocks framework includes guidelines for social accountable practice that can be applied at policy, school and individual levels

A Gnotobiotic Mouse Model Demonstrates That Dietary Fiber Protects against Colorectal Tumorigenesis in a Microbiota- and Butyrate-Dependent Manner

It is controversial whether dietary fiber protects against colorectal cancer because of conflicting results from human epidemiologic studies. However, these studies and mouse models of colorectal cancer have not controlled the composition of gut microbiota, which ferment fiber into short-chain fatty acids such as butyrate. Butyrate is noteworthy because it has energetic and epigenetic functions in colonocytes and tumorsuppressive properties in colorectal-cancer cell lines. We utilized gnotobiotic mouse models colonized with wild-type or mutant strains of a butyrate-producing bacterium to demonstrate that fiber does have a potent tumor-suppressive effect but in a microbiota- and butyrate-dependent manner. Furthermore, due to the Warburg effect, butyrate was metabolized less in tumors where it accumulated and functioned as an HDAC inhibitor to stimulate histone acetylation and affect apoptosis and cell proliferation. To support the relevance of this mechanism in human cancer, we demonstrate that butyrate and histone-acetylation levels are elevated in colorectal adenocarcinomas compared to normal colonic tissues

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

BACKGROUND: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). INTERPRETATION: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING: US National Institutes of Health

The Eleventh and Twelfth Data Releases of the Sloan Digital Sky Survey: Final Data from SDSS-III

The third generation of the Sloan Digital Sky Survey (SDSS-III) took data from 2008 to 2014 using the original SDSS wide-field imager, the original and an upgraded multi-object fiber-fed optical spectrograph, a new near-infrared high-resolution spectrograph, and a novel optical interferometer. All of the data from SDSS-III are now made public. In particular, this paper describes Data Release 11 (DR11) including all data acquired through 2013 July, and Data Release 12 (DR12) adding data acquired through 2014 July (including all data included in previous data releases), marking the end of SDSS-III observing. Relative to our previous public release (DR10), DR12 adds one million new spectra of galaxies and quasars from the Baryon Oscillation Spectroscopic Survey (BOSS) over an additional 3000 deg2 of sky, more than triples the number of H-band spectra of stars as part of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE), and includes repeated accurate radial velocity measurements of 5500 stars from the Multi-object APO Radial Velocity Exoplanet Large-area Survey (MARVELS). The APOGEE outputs now include the measured abundances of 15 different elements for each star. In total, SDSS-III added 5200 deg2 of ugriz imaging; 155,520 spectra of 138,099 stars as part of the Sloan Exploration of Galactic Understanding and Evolution 2 (SEGUE-2) survey; 2,497,484 BOSS spectra of 1,372,737 galaxies, 294,512 quasars, and 247,216 stars over 9376 deg2; 618,080 APOGEE spectra of 156,593 stars; and 197,040 MARVELS spectra of 5513 stars. Since its first light in 1998, SDSS has imaged over 1/3 of the Celestial sphere in five bands and obtained over five million astronomical spectra. \ua9 2015. The American Astronomical Society