Major chromosome 5H haplotype switch structures the European two-rowed spring barley germplasm of the past 190 years

Selection over 70 years has led to almost complete fixation of a haplotype spanning ~ 250 Mbp of chomosome 5H in European two-rowed spring barleys, possibly originating from North Africa. Plant breeding and selection have shaped the genetic composition of modern crops over the past decades and centuries and have led to great improvements in agronomic and quality traits. Knowledge of the genetic composition of breeding germplasm is essential to make informed decisions in breeding programs. In this study, we characterized the structure and composition of 209 barley cultivars representative of the European two-rowed spring barley germplasm of the past 190 years. Utilizing high-density SNP marker data, we identified a distinct centromeric haplotype spanning a ~ 250 Mbp large region on chromosome 5H which likely was first introduced into the European breeding germplasm in the early to mid-twentieth century and has been non-recombining and under strong positive selection over the past 70 years. Almost all cultivars in our panel that were released after 2000 carry this new haplotype, suggesting that this region carries one or several genes conferring highly beneficial traits. Using the global barley collection of the German Federal ex situ gene bank at IPK Gatersleben, we found the new haplotype at high frequencies in six-rowed spring-type landraces from Northern Africa, from which it may have been introduced into modern European barley germplasm via southern European landraces. The presence of a 250 Mbp genomic region characterized by lack of recombination and high levels of fixation in modern barley germplasm has substantial implications for the genetic diversity of the modern barley germplasm and for barley breeding

The mass, colour, and structural evolution of today's massive galaxies since z~5

In this paper, we use stacking analysis to trace the mass-growth, colour evolution, and structural evolution of present-day massive galaxies ($\log(M_{*}/M_{\odot})=11.5$) out to $z=5$. We utilize the exceptional depth and area of the latest UltraVISTA data release, combined with the depth and unparalleled seeing of CANDELS to gather a large, mass-selected sample of galaxies in the NIR (rest-frame optical to UV). Progenitors of present-day massive galaxies are identified via an evolving cumulative number density selection, which accounts for the effects of merging to correct for the systematic biases introduced using a fixed cumulative number density selection, and find progenitors grow in stellar mass by $\approx1.5~\mathrm{dex}$ since $z=5$. Using stacking, we analyze the structural parameters of the progenitors and find that most of the stellar mass content in the central regions was in place by $z\sim2$, and while galaxies continue to assemble mass at all radii, the outskirts experience the largest fractional increase in stellar mass. However, we find evidence of significant stellar mass build up at $r4$ probing an era of significant mass assembly in the interiors of present day massive galaxies. We also compare mass assembly from progenitors in this study to the EAGLE simulation and find qualitatively similar assembly with $z$ at $r<3~\mathrm{kpc}$. We identify $z\sim1.5$ as a distinct epoch in the evolution of massive galaxies where progenitors transitioned from growing in mass and size primarily through in-situ star formation in disks to a period of efficient growth in $r_{e}$ consistent with the minor merger scenario.Comment: 19 pages, 14 figures, accepted for publicatio

A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone and mycophenolate mofetil in primary adult liver transplantation: A single center report

Background. Tacrolimus (TAC) and mycophenolate mofetil (MMF) are currently approved immunosuppressants for prevention of rejection in liver transplantation (LTx). They have different modes of action and toxicity profiles, but the efficacy and safety of MMF in primary liver transplantation with TAC has not been determined. Methods. An Institutional Review Board-approved, open-label, single-center, prospective randomized trial was initiated to study the efficacy and toxicity of TAC and steroids (double-drug therapy (D)) versus TAC, steroids, and MMF (triple-drug therapy (T)) in primary adult LTx recipients. Both groups of patients were started on the same doses of TAC and steroids. Patients randomized to T also received 1 gm MMF twice a day. Results. Between August 1995 and May 1998, 350 patients were enrolled at a single center-175 in the D and 175 in the T groups. All patients were followed until May 1998, with a mean follow-up of 33.8±9.1 months. Using an intention-to-treat analysis, the 1-, 2-, 3-, and 4-year patient survival was 85.1%, 81.6%, 78.6%, and 75.8%, respectively, for D and 87.4%, 85.4%, 81.3%, and 79.9%, respectively, for T. The 4-year graft survival was 70% for D and 72.1% for T. Although the rate of acute rejection in the first 3 months was significantly lower for T than for D (28% for triple vs. 38.9% for double, P=0.03), the overall rate of rejection for T at the end of 1 year was not significantly lower than for the D (38.9% triple vs. 45.2% double). The median time to the first episode of rejection was 14 days for D versus 24 days for T (P=0.008). During the study period, 38 of 175 patients in D received MMF to control ongoing acute rejection, nephrotoxicity, and/or neurotoxicity. On the other hand, 103 patients in the T discontinued MMF for infection, myelosuppression, and/or gastrointestinal disturbances. The need for corticosteroids was less after 6 months for T and the perioperative need for dialysis was lower with use of MMF. Conclusion. This final report confirms similar patient survival and graft survival up to 4 years with a trend towards fewer episodes of rejection, lower need for steroids, and better perioperative renal function. However, the complex nature of LTx patients and their posttransplantation course prevents the routine application of MMF

A Massive Galaxy in its Core Formation Phase Three Billion Years After the Big Bang

Most massive galaxies are thought to have formed their dense stellar cores at early cosmic epochs. However, cores in their formation phase have not yet been observed. Previous studies have found galaxies with high gas velocity dispersions or small apparent sizes but so far no objects have been identified with both the stellar structure and the gas dynamics of a forming core. Here we present a candidate core in formation 11 billion years ago, at z=2.3. GOODS-N-774 has a stellar mass of 1.0x10^11 Msun, a half-light radius of 1.0 kpc, and a star formation rate of 90[+45-20]Msun/yr. The star forming gas has a velocity dispersion 317+-30 km/s, amongst the highest ever measured. It is similar to the stellar velocity dispersions of the putative descendants of GOODS-N-774, compact quiescent galaxies at z~2 and giant elliptical galaxies in the nearby Universe. Galaxies such as GOODS-N-774 appear to be rare; however, from the star formation rate and size of the galaxy we infer that many star forming cores may be heavily obscured, and could be missed in optical and near-infrared surveys.Comment: To appear in Natur

Genomic resources for a historical collection of cultivated two-row European spring barley genotypes

Barley genomic resources are increasing rapidly, with the publication of a barley pangenome as one of the latest developments. Two-row spring barley cultivars are intensely studied as they are the source of high-quality grain for malting and distilling. Here we provide data from a European two-row spring barley population containing 209 different genotypes registered for the UK market between 1830 to 2014. The dataset encompasses RNA-sequencing data from six different tissues across a range of barley developmental stages, phenotypic datasets from two consecutive years of field-grown trials in the United Kingdom, Germany and the USA; and whole genome shotgun sequencing from all cultivars, which was used to complement the RNA-sequencing data for variant calling. The outcomes are a filtered SNP marker file, a phenotypic database and a large gene expression dataset providing a comprehensive resource which allows for downstream analyses like genome wide association studies or expression associations.</p

Outcomes in patients with gunshot wounds to the brain.

Introduction:Gunshot wounds to the brain (GSWB) confer high lethality and uncertain recovery. It is unclear which patients benefit from aggressive resuscitation, and furthermore whether patients with GSWB undergoing cardiopulmonary resuscitation (CPR) have potential for survival or organ donation. Therefore, we sought to determine the rates of survival and organ donation, as well as identify factors associated with both outcomes in patients with GSWB undergoing CPR. Methods:We performed a retrospective, multicenter study at 25 US trauma centers including dates between June 1, 2011 and December 31, 2017. Patients were included if they suffered isolated GSWB and required CPR at a referring hospital, in the field, or in the trauma resuscitation room. Patients were excluded for significant torso or extremity injuries, or if pregnant. Binomial regression models were used to determine predictors of survival/organ donation. Results:825 patients met study criteria; the majority were male (87.6%) with a mean age of 36.5 years. Most (67%) underwent CPR in the field and 2.1% (n=17) survived to discharge. Of the non-survivors, 17.5% (n=141) were considered eligible donors, with a donation rate of 58.9% (n=83) in this group. Regression models found several predictors of survival. Hormone replacement was predictive of both survival and organ donation. Conclusion:We found that GSWB requiring CPR during trauma resuscitation was associated with a 2.1% survival rate and overall organ donation rate of 10.3%. Several factors appear to be favorably associated with survival, although predictions are uncertain due to the low number of survivors in this patient population. Hormone replacement was predictive of both survival and organ donation. These results are a starting point for determining appropriate treatment algorithms for this devastating clinical condition. Level of evidence:Level II

Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy

© 2015. Oncotarget. Antibodies that target cell-surface molecules on T cells can enhance anti-tumor immune responses, resulting in sustained immune-mediated control of cancer. We set out to find new cancer immunotherapy targets by phenotypic screening on human regulatory T (Treg) cells and report the discovery of novel activators of tumor necrosis factor receptor 2 (TNFR2) and a potential role for this target in immunotherapy. A diverse phage display library was screened to find antibody mimetics with preferential binding to Treg cells, the most Treg-selective of which were all, without exception, found to bind specifically to TNFR2. A subset of these TNFR2 binders were found to agonise the receptor, inducing iκ-B degradation and NF-κB pathway signalling in vitro. TNFR2 was found to be expressed by tumor-infiltrating Treg cells, and to a lesser extent Teffcells, from three lung cancer patients, and a similar pattern was also observed in mice implanted with CT26 syngeneic tumors. In such animals, TNFR2-specific agonists inhibited tumor growth, enhanced tumor infiltration by CD8+ T cells and increased CD8+ T cell IFN-γ synthesis. Together, these data indicate a novel mechanism for TNF-α-independent TNFR2 agonism in cancer immunotherapy, and demonstrate the utility of target-agnostic screening in highlighting important targets during drug discovery

Establishing a core outcome set for peritoneal dialysis : report of the SONG-PD (standardized outcomes in nephrology-peritoneal dialysis) consensus workshop

Outcomes reported in randomized controlled trials in peritoneal dialysis (PD) are diverse, are measured inconsistently, and may not be important to patients, families, and clinicians. The Standardized Outcomes in Nephrology-Peritoneal Dialysis (SONG-PD) initiative aims to establish a core outcome set for trials in PD based on the shared priorities of all stakeholders. We convened an international SONG-PD stakeholder consensus workshop in May 2018 in Vancouver, Canada. Nineteen patients/caregivers and 51 health professionals attended. Participants discussed core outcome domains and implementation in trials in PD. Four themes relating to the formation of core outcome domains were identified: life participation as a main goal of PD, impact of fatigue, empowerment for preparation and planning, and separation of contributing factors from core factors. Considerations for implementation were identified: standardizing patient-reported outcomes, requiring a validated and feasible measure, simplicity of binary outcomes, responsiveness to interventions, and using positive terminology. All stakeholders supported inclusion of PD-related infection, cardiovascular disease, mortality, technique survival, and life participation as the core outcome domains for PD

Cohesin complex-associated holoprosencephaly

Marked by incomplete division of the embryonic forebrain, holoprosencephaly is one of the most common human developmental disorders. Despite decades of phenotype-driven research, 80–90% of aneuploidy-negative holoprosencephaly individuals with a probable genetic aetiology do not have a genetic diagnosis. Here we report holoprosencephaly associated with variants in the two X-linked cohesin complex genes, STAG2 and SMC1A, with loss-of-function variants in 10 individuals and a missense variant in one. Additionally, we report four individuals with variants in the cohesin complex genes that are not X-linked, SMC3 and RAD21. Using whole mount in situ hybridization, we show that STAG2 and SMC1A are expressed in the prosencephalic neural folds during primary neurulation in the mouse, consistent with forebrain morphogenesis and holoprosencephaly pathogenesis. Finally, we found that shRNA knockdown of STAG2 and SMC1A causes aberrant expression of HPE-associated genes ZIC2, GLI2, SMAD3 and FGFR1 in human neural stem cells. These findings show the cohesin complex as an important regulator of median forebrain development and X-linked inheritance patterns in holoprosencephaly

Cognitive Information Processing

Contains research objectives and summary of research on fourteen research projects and reports on four research projects.Joint Services Electronics Program (Contract DAAB07-75-C-1346)National Science Foundation (Grant EPP74-12653)National Science Foundation (Grant ENG74-24344)National Institutes of Health (Grant 2 PO1 GM19428-04)Swiss National Funds for Scientific ResearchM.I.T. Health Sciences Fund (Grant 76-11)National Institutes of Health (Grant F03 GM58698)National Institutes of Health (Biomedical Sciences Support Grant)Associated Press (Grant