Complex patterns of local adaptation in teosinte

Populations of widely distributed species often encounter and adapt to specific environmental conditions. However, comprehensive characterization of the genetic basis of adaptation is demanding, requiring genome-wide genotype data, multiple sampled populations, and a good understanding of population structure. We have used environmental and high-density genotype data to describe the genetic basis of local adaptation in 21 populations of teosinte, the wild ancestor of maize. We found that altitude, dispersal events and admixture among subspecies formed a complex hierarchical genetic structure within teosinte. Patterns of linkage disequilibrium revealed four mega-base scale inversions that segregated among populations and had altitudinal clines. Based on patterns of differentiation and correlation with environmental variation, inversions and nongenic regions play an important role in local adaptation of teosinte. Further, we note that strongly differentiated individual populations can bias the identification of adaptive loci. The role of inversions in local adaptation has been predicted by theory and requires attention as genome-wide data become available for additional plant species. These results also suggest a potentially important role for noncoding variation, especially in large plant genomes in which the gene space represents a fraction of the entire genome

A randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of neramexane in patients with moderate to severe subjective tinnitus

<p>Abstract</p> <p>Background</p> <p>Neramexane is a new substance that exhibits antagonistic properties at α₉α₁₀cholinergic nicotinic receptors and <it>N</it>-methyl-D-aspartate receptors, suggesting potential efficacy in the treatment of tinnitus.</p> <p>Methods</p> <p>A total of 431 outpatients with moderate to severe subjective tinnitus (onset 3-18 months before screening) were assigned randomly to receive either placebo or neramexane mesylate (25 mg/day, 50 mg/day and 75 mg/day) for 16 weeks, with assessment at 4-week intervals. The primary (intention-to-treat) efficacy analysis was based on the change from baseline in Week 16 in the total score of the adapted German short version of the validated Tinnitus Handicap Inventory questionnaire (THI-12).</p> <p>Results</p> <p>Compared with placebo, the largest improvement was achieved in the 50 mg/d neramexane group, followed by the 75 mg/d neramexane group. This treatment difference did not reach statistical significance at the pre-defined endpoint in Week 16 (<it>p </it>= 0.098 for 50 mg/d; <it>p </it>= 0.289 for 75 mg/d neramexane), but consistent numerical superiority of both neramexane groups compared with placebo was observed. Four weeks after the end of treatment, THI-12 scores in the 50 mg/d group were significantly better than those of the controls. Secondary efficacy variables supported this trend, with <it>p </it>values of < 0.05 for the 50 mg/d neramexane group associated with the functional-communicational subscores of the THI-12 and the assessments of tinnitus annoyance and tinnitus impact on life as measured on an 11-point Likert-like scale. No relevant changes were observed for puretone threshold, for tinnitus pitch and loudness match, or for minimum masking levels. The 25 mg/d neramexane group did not differ from placebo. Neramexane was generally well tolerated and had no relevant influence on laboratory values, electrocardiography and vital signs. Dizziness was the most common adverse event and showed a clear dose-dependence.</p> <p>Conclusions</p> <p>This study demonstrated the safety and tolerability of neramexane treatment in patients with moderate to severe tinnitus. The primary efficacy variable showed a trend towards improvement of tinnitus suffering in the medium- and high-dose neramexane groups. This finding is in line with consistent beneficial effects observed in secondary assessment variables. These results allow appropriate dose selection for further studies.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00405886</p

The Lantern, 2009-2010

• I\u27m Pregnant. It\u27s Yours • The Nightmare • What Death Became After Cyparissus • Substances • Ain\u27t That a Man? • Portrait • The 100th Chemo • Looking into Her Toy Box with a Lover • They Used to Talk About Burning Cities • MESSAGE: Absence for Allen Ginsberg • Lunch with Candide • Behold! Man of Unbelief! Behold! • Dream #1 Final Strophe • Patience (Things You Will Discover) • Four Years • He Falls Like Leaves • The Quilt • Ariel (Turning Tricks at Fisherman\u27s Wharf, Monterey, California) • Extranjera • The Taste of Morning • Fear of Glory • The Rum Bottle\u27s Fortune • While Thinking of What to Write • Dying in Spring • Tutte le Eta di Firenze • Token • A House Grows Into Itself • Gravity • Father with the Skyy • He Says He Dreams of Me • Myth • Sun-Veins and Wishbones • Attempts at Bravery • One Boy in Four Parts • Blacktop Rollin\u27 • Getting My Feet Wet • The Long Ride After Ending • Wet Tongues and Sweaty Cotton • Norman Bates is My Mother • Sims Trek • Tomorrow Comes Today • The Writer\u27s Process • This Too Was Real • Venus from the Waves • Shark • Monday\u27s Expectations • Recognition • The Black Shoes • Climax • Andrew • Bottles • Calle de Cusco • God in the Machine • The 26th of December • Lollipop Lollipop • When Dinosaurs Roamed the Earth • Meaning • Jeffrey • Looking • Jagged Edges • Fading Storm • Shoes • Cover Image: Death by Chocolatehttps://digitalcommons.ursinus.edu/lantern/1175/thumbnail.jp

Targeting Toll-like receptor 7/8 enhances uptake of apoptotic leukemic cells by monocyte-derived dendritic cells but interferes with subsequent cytokine-induced maturation

Therapeutic vaccination with dendritic cells (DC) is an emerging investigational therapy for eradication of minimal residual disease in acute myeloid leukemia. Various strategies are being explored in manufacturing DC vaccines ex vivo, e.g., monocyte-derived DC (MoDC) loaded with leukemia-associated antigens (LAA). However, the optimal source of LAA and the choice of DC-activating stimuli are still not well defined. Here, loading with leukemic cell preparations (harboring both unknown and known LAA) was explored in combination with a DC maturation-inducing cytokine cocktail (CC; IL-1β, IL-6, TNF-α, and PGE2) and Toll-like receptor ligands (TLR-L) to optimize uptake. Since heat shock induced apoptotic blasts were more efficiently taken up than lysates, we focused on uptake of apoptotic leukemic cells. Uptake of apoptotic blast was further enhanced by the TLR7/8-L R848 (20–30%); in contrast, CC-induced maturation inhibited uptake. CC, and to a lesser extent R848, enhanced the ability of MoDC to migrate and stimulate T cells. Furthermore, class II-associated invariant chain peptide expression was down-modulated after R848- or CC-induced maturation, indicating enhanced processing and presentation of antigenic peptides. To improve both uptake and maturation, leukemic cells and MoDC were co-incubated with R848 for 24 h followed by addition of CC. However, this approach interfered with CC-mediated MoDC maturation as indicated by diminished migratory and T cell stimulatory capacity, and the absence of IL-12 production. Taken together, our data demonstrate that even though R848 improved uptake of apoptotic leukemic cells, the sequential use of R848 and CC is counter-indicated due to its adverse effects on MoDC maturation

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

Multi-ethnic genome-wide association study for atrial fibrillation

Atrial fibrillation (AF) affects more than 33 million individuals worldwide and has a complex heritability. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF

Comprehensive molecular characterization of gastric adenocarcinoma

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies