Time Scale for Rapid Draining of a Surficial Lake Into the Greenland Ice Sheet

A 2008 report by Das et al. documented the rapid drainage during summer 2006 of a supraglacial lake, of approximately 44×10^6 m^3, into the Greenland ice sheet over a time scale moderately longer than 1 hr. The lake had been instrumented to record the time-dependent fall of water level and the uplift of the ice nearby. Liquid water, denser than ice, was presumed to have descended through the sheet along a crevasse system and spread along the bed as a hydraulic facture. The event led two of the present authors to initiate modeling studies on such natural hydraulic fractures. Building on results of those studies, we attempt to better explain the time evolution of such a drainage event. We find that the estimated time has a strong dependence on how much a pre-existing crack/crevasse system, acting as a feeder channel to the bed, has opened by slow creep prior to the time at which a basal hydraulic fracture nucleates. We quantify the process and identify appropriate parameter ranges, particularly of the average temperature of the ice beneath the lake (important for the slow creep opening of the crevasse). We show that average ice temperatures 5–7  °C below melting allow such rapid drainage on a time scale which agrees well with the 2006 observations

Pleiotropy of FRIGIDA enhances the potential for multivariate adaptation.

An evolutionary response to selection requires genetic variation; however, even if it exists, then the genetic details of the variation can constrain adaptation. In the simplest case, unlinked loci and uncorrelated phenotypes respond directly to multivariate selection and permit unrestricted paths to adaptive peaks. By contrast, 'antagonistic' pleiotropic loci may constrain adaptation by affecting variation of many traits and limiting the direction of trait correlations to vectors that are not favoured by selection. However, certain pleiotropic configurations may improve the conditions for adaptive evolution. Here, we present evidence that the Arabidopsis thaliana gene FRI (FRIGIDA) exhibits 'adaptive' pleiotropy, producing trait correlations along an axis that results in two adaptive strategies. Derived, low expression FRI alleles confer a 'drought escape' strategy owing to fast growth, low water use efficiency and early flowering. By contrast, a dehydration avoidance strategy is conferred by the ancestral phenotype of late flowering, slow growth and efficient water use during photosynthesis. The dehydration avoidant phenotype was recovered when genotypes with null FRI alleles were transformed with functional alleles. Our findings indicate that the well-documented effects of FRI on phenology result from differences in physiology, not only a simple developmental switch

Personalizing neoadjuvant chemotherapy for locally advanced colon cancer:protocols for the international phase III FOxTROT2 and FOxTROT3 randomized controlled trials

AIM: FOxTROT1 established a new standard of care for managing locally advanced colon cancer (CC) with neoadjuvant chemotherapy (NAC). Six weeks of neoadjuvant oxaliplatin and fluoropyrimidine (OxFp) chemotherapy was associated with greater 2-year disease-free survival (DFS) when compared with proceeding straight to surgery (STS). There is now a need to refine the use of NAC and identify those most likely to benefit. FOxTROT2 will aim to investigate NAC in older adults and those with frailty. FOxTROT3 will aim to assess whether intensified triplet NAC provides additional benefits over OxFp.METHOD: FOxTROT2 and FOxTROT3 are international, open-label, phase III randomized controlled trials. Eligible patients will be identified by the multidisciplinary team. Patient age, frailty and comorbidities will be considered to guide trial entry. Participants will be randomized 2:1 to the intervention or control arm: 6 weeks of dose-adapted neoadjuvant OxFp versus STS in FOxTROT2 and 6 weeks of neoadjuvant modified oxaliplatin, 5-fluorouracil and irinotecan versus OxFp in FOxTROT3. The primary endpoint in FOxTROT2 is 3-year DFS. In FOxTROT3, tumour regression grade and 3-year DFS are co-primary endpoints.DISCUSSION: FOxTROT2 and FOxTROT3 will establish the FOxTROT platform, a key part of our long-term strategy to develop neoadjuvant treatments for CC. FOxTROT2 will investigate NAC in a population under-represented in FOxTROT1 and wider research. FOxTROT3 will assess whether it is possible to induce greater early tumour responses and whether this translates to superior long-term outcomes. Looking ahead, the FOxTROT platform will facilitate further trial comparisons and extensive translational research to optimize the use of NAC in CC.</p

Religious education in the experience of young people from mixed-faith families

On the basis of recent ethnographic study at the University of Warwick of the religious identity formation of young people in ‘mixed-faith’ families, this article focuses on their (and their parents’) experiences and perceptions of religious education (RE) and of religious nurture in the community. The young people’s experience of RE differed between primary and secondary school and only a few were engaged in supplementary classes. We highlight the complementarity between school and home in young people’s religious learning and draw out implications for RE

Porcine iGb3s gene silencing provides minimal benefit for clinical xenotransplantation

Background The Galα(1,3)Gal epitope (α-GAL), created by α-1,3-glycosyltransferase-1 (GGTA1), is a major xenoantigen causing hyperacute rejection in pig-to-primate and pig-to-human xenotransplantation. In response, GGTA1 gene-deleted pigs have been generated. However, it is unclear whether there is a residual small amount of α-Gal epitope expressed in GGTA1−/− pigs. Isoglobotrihexosylceramide synthase (iGb3s), another member of the glycosyltransferase family, catalyzes the synthesis of isoglobo-series glycosphingolipids with an α-GAL-terminal disaccharide (iGb3), creating the possibility that iGb3s may be a source of α-GAL epitopes in GGTA1−/− animals. The objective of this study was to examine the impact of silencing the iGb3s gene (A3GalT2) on pig-to-primate and pig-to-human immune cross-reactivity by creating and comparing GGTA1−/− pigs to GGTA1−/−- and A3GalT2−/−-double-knockout pigs. Methods We used the CRISPR/Cas 9 system to target the GGTA1 and A3GalT2 genes in pigs. Both GGTA1 and A3GalT2 genes are functionally inactive in humans and baboons. CRISPR-treated cells used directly for somatic cell nuclear transfer produced single- and double-gene-knockout piglets in a single pregnancy. Once grown to maturity, the glycosphingolipid profile (including iGb3) was assayed in renal tissue by normal-phase liquid chromatography. In addition, peripheral blood mononuclear cells (PBMCs) were subjected to (i) comparative cross-match cytotoxicity analysis against human and baboon serum and (ii) IB4 staining for α-GAL/iGb3. Results Silencing of the iGb3s gene significantly modulated the renal glycosphingolipid profile and iGb3 was not detected. Moreover, the human and baboon serum PBMC cytotoxicity and α-GAL/iGb3 staining were unchanged by iGb3s silencing. Conclusions Our data suggest that iGb3s is not a contributor to antibody-mediated rejection in pig-to-primate or pig-to-human xenotransplantation. Although iGb3s gene silencing significantly changed the renal glycosphingolipid profile, the effect on Galα3Gal levels, antibody binding, and cytotoxic profiles of baboon and human sera on porcine PBMCs was neutral

Regulation of nucleosome positioning by a CHD Type III chromatin remodeler and its relationship to developmental gene expression in Dictyostelium

Nucleosome placement and repositioning can direct transcription of individual genes; however, the precise interactions of these events are complex and largely unresolved at the whole-genome level. The Chromodomain-Helicase-DNA binding (CHD) Type III proteins are a subfamily of SWI2/SNF2 proteins that control nucleosome positioning and are associated with several complex human disorders, including CHARGE syndrome and autism. Type III CHDs are required for multicellular development of animals and Dictyostelium but are absent in plants and yeast. These CHDs can mediate nucleosome translocation in vitro, but their in vivo mechanism is unknown. Here, we use genome-wide analysis of nucleosome positioning and transcription profiling to investigate the in vivo relationship between nucleosome positioning and gene expression during development of wild-type (WT) Dictyostelium and mutant cells lacking ChdC, a Type III CHD protein ortholog. We demonstrate major nucleosome positional changes associated with developmental gene regulation in WT. Loss of chdC caused an increase of intragenic nucleosome spacing and misregulation of gene expression, affecting ∼50% of the genes that are repositioned during WT development. These analyses demonstrate active nucleosome repositioning during Dictyostelium multicellular development, establish an in vivo function of CHD Type III chromatin remodeling proteins in this process, and reveal the detailed relationship between nucleosome positioning and gene regulation, as cells transition between developmental states

Different CHD chromatin remodelers are required for expression of distinct gene sets and specific stages during development of Dictyostelium discoideum

Control of chromatin structure is crucial for multicellular development and regulation of cell differentiation. The CHD (chromodomain-helicase-DNA binding) protein family is one of the major ATP-dependent, chromatin remodeling factors that regulate nucleosome positioning and access of transcription factors and RNA polymerase to the eukaryotic genome. There are three mammalian CHD subfamilies and their impaired functions are associated with several human diseases. Here, we identify three CHD orthologs (ChdA, ChdB and ChdC) in Dictyostelium discoideum. These CHDs are expressed throughout development, but with unique patterns. Null mutants lacking each CHD have distinct phenotypes that reflect their expression patterns and suggest functional specificity. Accordingly, using genome-wide (RNA-seq) transcriptome profiling for each null strain, we show that the different CHDs regulate distinct gene sets during both growth and development. ChdC is an apparent ortholog of the mammalian Class III CHD group that is associated with the human CHARGE syndrome, and GO analyses of aberrant gene expression in chdC nulls suggest defects in both cell-autonomous and non-autonomous signaling, which have been confirmed through analyses of chdC nulls developed in pure populations or with low levels of wild-type cells. This study provides novel insight into the broad function of CHDs in the regulation development and disease, through chromatin-mediated changes in directed gene expression

The prediction of radiationâ induced liver dysfunction using a local dose and regional venous perfusion model

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134805/1/mp1081.pd

Temporal trends in, and risk factors for, HIV seroconversion among female sex workers accessing Zimbabwe's national sex worker programme, 2009–19:a retrospective cohort analysis of routinely collected HIV testing data

Background: The frequency of new HIV infections among female sex workers in sub-Saharan Africa is poorly understood. We used routinely collected data that enable unique identification of repeat HIV testers to assess temporal trends in seroconversion and identify associated risk factors for female sex workers accessing Sisters with a Voice, Zimbabwe's national sex worker programme. Methods: We pooled HIV testing data gathered between Sept 15, 2009, and Dec 31, 2019, from 36 Sisters programme sites in Zimbabwe. We included female sex workers aged 16 years or older with an HIV-negative test and at least one subsequent programme test. We calculated HIV seroconversion rates (using the midpoint between the HIV-positive test and the last negative test as the seroconversion date) and estimated rate ratios to compare 2-year periods by using Poisson regression, with robust SEs to account for clustering by site and adjusting for age and testing frequency to assess temporal trends. We did sensitivity analyses to explore assumptions about seroconversion dates and the effects of variation in follow-up time on our conclusions. Findings: Our analysis included data for 6665 female sex workers, 441 (7%) of whom seroconverted. The overall seroconversion rate was 3·8 (95% CI 3·4–4·2) per 100 person-years at risk. Seroconversion rates fell with time since first negative HIV test. After adjustment, there was evidence of a decrease in seroconversion rates from 2009 to 2019 (p=0·0053). In adjusted analyses, being younger than 25 years, and having a sexually transmitted infection diagnosis at a previous visit, were significantly associated with increased seroconversion rates. Our findings were mostly robust to sensitivity analyses, but when 1 month before an HIV-positive test was used as the seroconversion date, seroconversion rates no longer fell with time. Interpretation: We identified high rates of seroconversion shortly after linkage to programme services, which emphasises the need to strengthen HIV prevention programmes from first contact with female sex workers in Zimbabwe. New infections among female sex workers remain challenging to measure, but longitudinal analysis of routine testing data can provide valuable insights into seroconversion rates and associated risk factors. Funding: UN Population Fund, Deutsche Gesellschaft für Internationale Zusammenarbeit, the Bill &amp; Melinda Gates Foundation, The Global Fund to Fight AIDS, Tuberculosis and Malaria, US President's Emergency Plan for AIDS Relief, US Agency for International Development, and the Elton John AIDS Foundation.</p