Molecular tools enabling pennycress (\u3ci\u3eThlaspi arvense\u3c/i\u3e) as a model plant and oilseed cash cover crop

Thlapsi arvense L. (pennycress) is being developed as a profitable oilseed cover crop for the winter fallow period throughout the temperate regions of the world, controlling soil erosion and nutrients run-off on otherwise barren farmland. We demonstrate that pennycress can serve as a user-friendly model system akin to Arabidopsis that is well-suited for both laboratory and field experimentation. We sequenced the diploid genome of the spring-type Spring 32-10 inbred line (1C DNA content of 539 Mb; 2n = 14), identifying variation that may explain phenotypic differences with winter-type pennycress, as well as predominantly a one-to-one correspondence with Arabidopsis genes, which makes translational research straightforward. We developed an Agrobacterium-mediated floral dip transformation method (0.5% transformation efficiency) and introduced CRISPR-Cas9 constructs to produce indel mutations in the putative FATTY ACID ELONGATION1 (FAE1) gene, thereby abolishing erucic acid production and creating an edible seed oil comparable to that of canola. We also stably transformed pennycress with the Euonymus alatus diacylglycerol acetyltransferase (EaDAcT) gene, producing low-viscosity acetyltriacylglycerol- containing seed oil suitable as a diesel-engine drop-in fuel. Adoption of pennycress as a model system will accelerate oilseed-crop translational research and facilitate pennycress’ rapid domestication to meet the growing sustainable food and fuel demands

Thermodynamic Behavior of a Model Covalent Material Described by the Environment-Dependent Interatomic Potential

Using molecular dynamics simulations we study the thermodynamic behavior of a single-component covalent material described by the recently proposed Environment-Dependent Interatomic Potential (EDIP). The parameterization of EDIP for silicon exhibits a range of unusual properties typically found in more complex materials, such as the existence of two structurally distinct disordered phases, a density decrease upon melting of the low-temperature amorphous phase, and negative thermal expansion coefficients for both the crystal (at high temperatures) and the amorphous phase (at all temperatures). Structural differences between the two disordered phases also lead to a first-order transition between them, which suggests the existence of a second critical point, as is believed to exist for amorphous forms of frozen water. For EDIP-Si, however, the unusual behavior is associated not only with the open nature of tetrahedral bonding but also with a competition between four-fold (covalent) and five-fold (metallic) coordination. The unusual behavior of the model and its unique ability to simulation the liquid/amorphous transition on molecular-dynamics time scales make it a suitable prototype for fundamental studies of anomalous thermodynamics in disordeered systems.Comment: 48 pages (double-spaced), 13 figure

Psychosocial Characteristics and Sexual Behaviors of People in Care for HIV Infection: An Examination of Men Who Have Sex with Men, Heterosexual Men and Women

Few studies have examined the psychosocial factors associated with sexual transmission behaviors among HIV-positive men who have sex with men (MSM), heterosexual men (MSW) and women. We enrolled 1,050 sexually active HIV-positive patients at seven HIV clinics in six US cities as part of a clinic-based behavioral intervention. We describe the sexual transmission behaviors and examine demographic, clinical, psychosocial, and clinic prevention variables associated with unprotected anal or vaginal intercourse (UAVI). Twenty-three percent of MSM, 12.3% of MSW and 27.8% of women engaged in UAVI with partners perceived to be HIV-negative or of unknown serostatus. Among MSM and MSW, having multiple partners and lower self-efficacy were associated with increased odds of UAVI. Self-rating one’s health status as excellent/very good was a risk factor for UAVI among MSM. Among women, binge drinking and stressful life events were associated with UAVI. These findings identify variables that warrant attention in targeted interventions

Dietary Oxidative Balance Scores and Biomarkers of Inflammation among Individuals with and without Chronic Kidney Disease

Background: Oxidative stress and inflammation are proposed mechanisms of nonspecific kidney injury and progressive kidney failure. Higher dietary oxidative balance scores (OBS) are associated with lower prevalence of chronic kidney disease (CKD). Methods: We investigated the association between OBS and biomarkers of inflammation using data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Nutrient estimates from the Block Food Frequency Questionnaires were used to define tertiles of 11 pro- and antioxidant factors. Points for each OBS component were summed, with a higher score indicating predominance of antioxidant exposures. Multivariable linear regression models were used to estimate the association between OBS and biomarkers of inflammation (interleukin-6 [IL-6], interleukin-8 [IL-8], interleukin-10 [IL-10], fibrinogen, C-reactive protein [CRP], white blood cell count, and cystatin C). An interaction term was included to determine if associations between OBS and inflammatory markers differed between individuals with and without CKD. Results: Of 682 participants, 22.4% had CKD. In adjusted models, OBS was associated with CRP and IL-6. For every 5-unit increase in OBS, the CRP concentration was –15.3% lower (95% CI: –25.6, –3.6). The association of OBS with IL-6 differed by CKD status; for every 5-unit increase in OBS, IL-6 was –10.7% lower (95% CI: –16.3, –4.7) among those without CKD, but there was no association among those with CKD (p = 0.03). Conclusion: This study suggests that a higher OBS is associated with more favorable levels of IL-6 and CRP, and that the association of OBS and IL-6 may be modified by CKD status

Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial

BACKGROUND: Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia. METHODS: This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m2 on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617. FINDINGS: Between April 19, 2012, and July 10, 2017, 586 patients were randomly assigned to standard of care (n=292) or standard of care plus rituximab (n=294). Nine patients were excluded from the final analysis due to misdiagnosis (standard of care n=4, standard of care plus rituximab n=5). In the standard-of-care group, median age was 45 years (IQR 22-65), 159 (55%) of 292 participants were male, 128 (44%) were female, one (<1%) was intersex, and 143 (59%) of 244 participants had high-risk cytogenetics. In the standard-of-care plus rituximab group, median age was 46 years (IQR 23-65), 159 (55%) of 294 participants were male, 130 (45%) were female, and 140 (60%) of 235 participants had high-risk cytogenetics. After a median follow-up of 53·7 months (IQR 40·3-70·4), 3-year event-free survival was 43·7% (95% CI 37·8-49·5) for standard of care versus 51·4% (45·4-57·1) for standard of care plus rituximab (hazard ratio [HR] 0·85 [95% CI 0·69-1·06]; p=0·14). The most common adverse events were infections and cytopenias, with no difference between the groups in the rates of adverse events. There were 11 (4%) fatal (grade 5) events in induction phases 1 and 2 in the standard-of-care group and 13 (5%) events in the standard-of-care plus rituximab group). 3-year non-relapse mortality was 23·7% (95% CI 19·0-29·4) in the standard-of-care group versus 20·6% (16·2-25·9) in the standard-of-care plus rituximab group (HR 0·88 [95% CI 0·62-1·26]; p=0·49). INTERPRETATION: Standard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient. FUNDING: Cancer Research UK and Blood Cancer UK

‘Not a country at all’: landscape and Wuthering Heights

This article explores the issue of women’s representational genealogies through an analysis of Andrea Arnold’s 2011 Wuthering Heights. Beginning with 1970s feminist arguments for a specifically female literary tradition, it argues that running through both these early attempts to construct an alternative female literary tradition and later work in feminist philosophy, cultural geography and film history is a concern with questions of ‘alternative landscapes’: of how to represent, and how to encounter, space differently. Adopting Mary Jacobus’ notion of intertextual ‘correspondence’ between women’s texts, and taking Arnold’s film as its case study, it seeks to trace some of the intertextual movements – the reframings, deframings and spatial reorderings – that link Andrea Arnold’s film to Emily Brontë’s original novel. Focusing on two elements of her treatment of landscape – her use of ‘unframed’ landscape and her focus on visceral textural detail – it points to correspondences in other women’s writing, photography and film-making. It argues that these intensely tactile close-up sequences which puncture an apparently realist narrative constitute an insistent presence beneath, or within, the ordered framing which is our more usual mode of viewing landscape. As the novel Wuthering Heights is unmade in Arnold’s adaptation and its framings ruptured, it is through this disturbance of hierarchies of time, space and landscape that we can trace the correspondences of an alternative genealogy

Four models of HIV counseling and testing: utilization and test results in South Africa.

BACKGROUND: HIV Counseling and Testing (HCT) is the point-of-entry for pathways of HIV care and prevention. However, HCT is not reaching many who are HIV infected and this may be related to the HCT provision model. We describe HCT utilization and HIV diagnosis using four models of HCT delivery: clinic-based, urban mobile, rural mobile, and stand-alone. METHODS: Using cross-sectional data from routine HCT provided in South Africa, we described client characteristics and HIV test results from information collected during service delivery between January 2009 and June 2012. RESULTS: 118,358 clients received services at clinic-based units, 18,597; stand-alone, 28,937; urban mobile, 38,840; and rural mobile, 31,984. By unit, clients were similar in terms of median age (range 28-31), but differed in sex distribution, employment status, prior testing, and perceived HIV risk. Urban mobile units had the highest proportion of male clients (52%). Rural mobile units reached the highest proportion of clients with no prior HCT (61%) and reporting no perceived HIV risk (64%). Overall, 10,862 clients (9.3%) tested HIV-positive. CONCLUSIONS: Client characteristics varied by HCT model. Importantly, rural and urban mobile units reached more men, first-time testers, and clients who considered themselves to be at low risk for HIV

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts