Showing papers by "Indiana University published in 2014"
Eric A. Collisson1, Joshua D. Campbell2, Angela N. Brooks3, Angela N. Brooks2 +315 more•Institutions (41)
TL;DR: In this paper, the authors report molecular profiling of 230 resected lung adnocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses.
Abstract: Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.
4,104 citations
Johns Hopkins University1, Howard Hughes Medical Institute2, Swim Across America3, Boston University4, University of Turin5, Life Technologies6, Indiana University7, Indiana University Health8, Ludwig Institute for Cancer Research9, University of Pennsylvania10, University of Ulsan11, University of São Paulo12, Amgen13, Karolinska Institutet14, University of Colorado Boulder15, Memorial Sloan Kettering Cancer Center16, Indiana University – Purdue University Indianapolis17
TL;DR: The ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types was evaluated and suggested that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes.
Abstract: The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
3,533 citations
Johns Hopkins University1, University of Utah2, University of Rochester3, The Royal Marsden NHS Foundation Trust4, National Institutes of Health5, Stanford University6, Washington University in St. Louis7, Ontario Institute for Cancer Research8, University of Sydney9, St. Jude Medical Center10, University of Toronto11, Mayo Clinic12, American Society of Clinical Oncology13, University of Southern California14, North Carolina State University15, Indiana University16, University of Milan17, University of Michigan18
TL;DR: The Update Committee recommends that HER2 status (HER2 negative or positive) be determined in all patients with invasive breast cancer on the basis of one or more HER2 test results (negative, equivocal, or positive).
Abstract: Purpose
To update the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer to improve the accuracy of HER2 testing and its utility as a predictive marker in invasive breast cancer.
2,934 citations
TL;DR: Ch Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.
Abstract: Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. To date, no molecularly targeted agents have been approved for the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#termsThis paper is distributed under the terms of the Creative Commons. Attribution-Non-Commercial-Share Alike license, and the online version of the paper is freely available to all readers.
2,257 citations
New York University1, Nathan Kline Institute for Psychiatric Research2, MIND Institute3, Katholieke Universiteit Leuven4, University of Utah5, Yale University6, University of California, Los Angeles7, Massachusetts Institute of Technology8, Trinity College, Dublin9, Carnegie Mellon University10, Ben-Gurion University of the Negev11, Ludwig Maximilian University of Munich12, Oregon Health & Science University13, California Institute of Technology14, Indiana University15, San Diego State University16, University of Groningen17, Netherlands Institute for Neuroscience18, University of Wisconsin-Madison19, Cornell University20, University of Pittsburgh21, Stanford University22, University of Michigan23, Kennedy Krieger Institute24, Johns Hopkins University25
TL;DR: W Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity.
Abstract: Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)-a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7-64 years) (http://fcon_1000.projects.nitrc.org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses of 360 male subjects with ASDs and 403 male age-matched TCs. We focused on whole-brain intrinsic functional connectivity and also survey a range of voxel-wise measures of intrinsic functional brain architecture. Whole-brain analyses reconciled seemingly disparate themes of both hypo- and hyperconnectivity in the ASD literature; both were detected, although hypoconnectivity dominated, particularly for corticocortical and interhemispheric functional connectivity. Exploratory analyses using an array of regional metrics of intrinsic brain function converged on common loci of dysfunction in ASDs (mid- and posterior insula and posterior cingulate cortex), and highlighted less commonly explored regions such as the thalamus. The survey of the ABIDE R-fMRI data sets provides unprecedented demonstrations of both replication and novel discovery. By pooling multiple international data sets, ABIDE is expected to accelerate the pace of discovery setting the stage for the next generation of ASD studies.
1,939 citations
National Institutes of Health1, University of Minnesota2, Max Planck Society3, University College London4, Paul Sabatier University5, French Institute of Health and Medical Research6, University of Washington7, Boston University8, University of Tübingen9, deCODE genetics10, Columbia University Medical Center11, Erasmus University Rotterdam12, Stanford University13, University of Thessaly14, Washington University in St. Louis15, Michael J. Fox Foundation16, German Center for Neurodegenerative Diseases17, New York State Department of Health18, Centre national de la recherche scientifique19, University of Paris20, University of Miami21, Indiana University22
TL;DR: This article conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls.
Abstract: We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10−16). We also show six risk loci associated with proximal gene expression or DNA methylation.
1,636 citations
German Center for Neurodegenerative Diseases1, University of Bonn2, Harvard University3, Maastricht University4, Aix-Marseille University5, Pierre-and-Marie-Curie University6, French Institute of Health and Medical Research7, University of Melbourne8, VU University Amsterdam9, New York University10, Mayo Clinic11, City University of New York12, University of New South Wales13, Indiana University14, King's College London15, University of Toulouse16
TL;DR: Research criteria for SCD in pre‐mild cognitive impairment (MCI) are presented and a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings.
Abstract: There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.
1,626 citations
Harvard University1, Goethe University Frankfurt2, Indiana University3, University of California, San Diego4, Joseph Fourier University5, University of Cambridge6, Queen Mary University of London7, Veterans Health Administration8, Autonomous University of Barcelona9, Cornell University10, Duke University11, Casa Sollievo della Sofferenza12
TL;DR: Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection.
Abstract: Background In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. Methods We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir–sofosbuvir plus ribavirin for 12 weeks, ledipasvir–sofosbuvir for 24 weeks, or ledipasvir–sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confide...
1,602 citations
TL;DR: Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability in patients with mild Alzheimer's disease.
Abstract: BackgroundAlzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain. MethodsIn two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study–Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary...
1,388 citations
TL;DR: In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did FIT but had more false positive results.
Abstract: Background An accurate, noninvasive test could improve the effectiveness of colorectal-cancer screening. Methods We compared a noninvasive, multitarget stool DNA test with a fecal immunochemical test (FIT) in persons at average risk for colorectal cancer. The DNA test includes quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and β-actin, plus a hemoglobin immunoassay. Results were generated with the use of a logistic-regression algorithm, with values of 183 or more considered to be positive. FIT values of more than 100 ng of hemoglobin per milliliter of buffer were considered to be positive. Tests were processed independently of colonoscopic findings. Results Of the 9989 participants who could be evaluated, 65 (0.7%) had colorectal cancer and 757 (7.6%) had advanced precancerous lesions (advanced adenomas or sessile serrated polyps measuring ≥1 cm in the greatest dimension) on colonoscopy. The sensitivity for detecting colorectal cancer was 92.3% with DNA testing and 73.8% with FIT (P = 0.002). The sensitivity for detecting advanced precancerous lesions was 42.4% with DNA testing and 23.8% with FIT (P<0.001). The rate of detection of polyps with high-grade dysplasia was 69.2% with DNA testing and 46.2% with FIT (P = 0.004); the rates of detection of serrated sessile polyps measuring 1 cm or more were 42.4% and 5.1%, respectively (P<0.001). Specificities with DNA testing and FIT were 86.6% and 94.9%, respectively, among participants with nonadvanced or negative findings (P<0.001) and 89.8% and 96.4%, respectively, among those with negative results on colonoscopy (P<0.001). The numbers of persons who would need to be screened to detect one cancer were 154 with colonoscopy, 166 with DNA testing, and 208 with FIT. Conclusions In asymptomatic persons at average risk for colorectal cancer, multitarget stool DNA testing detected significantly more cancers than did FIT but had more false positive results. (Funded by Exact Sciences; ClinicalTrials.gov number, NCT01397747.)
1,332 citations
Harvard University1, University of Pennsylvania2, University of Florida3, University of Texas Health Science Center at San Antonio4, Henry Ford Health System5, University of Miami6, Scripps Health7, Saint Louis University8, University of New Mexico9, Duke University10, Johns Hopkins University11, Indiana University12
TL;DR: Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologyic response to prior interferon-based treatment.
Abstract: Background Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. Methods We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir–sofosbuvir plus ribavirin for 12 weeks, ledipasvir–sofosbuvir for 24 weeks, or ledipasvir–sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of ...
TL;DR: In this paper, the authors discuss the characteristics of modern, sophisticated social bots and how their presence can endanger online ecosystems and our society, and review current efforts to detect social bots on Twitter.
Abstract: The Turing test aimed to recognize the behavior of a human from that of a computer algorithm. Such challenge is more relevant than ever in today's social media context, where limited attention and technology constrain the expressive power of humans, while incentives abound to develop software agents mimicking humans. These social bots interact, often unnoticed, with real people in social media ecosystems, but their abundance is uncertain. While many bots are benign, one can design harmful bots with the goals of persuading, smearing, or deceiving. Here we discuss the characteristics of modern, sophisticated social bots, and how their presence can endanger online ecosystems and our society. We then review current efforts to detect social bots on Twitter. Features related to content, network, sentiment, and temporal patterns of activity are imitated by bots but at the same time can help discriminate synthetic behaviors from human ones, yielding signatures of engineered social tampering.
University College London1, University of Duisburg-Essen2, University of Edinburgh3, University of New South Wales4, Katholieke Universiteit Leuven5, Mount Vernon Hospital6, Royal Melbourne Hospital7, Sheba Medical Center8, Tel Aviv Sourasky Medical Center9, Indiana University10, AstraZeneca11, Harvard University12
TL;DR: The hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment is supported.
Abstract: Summary Background Maintenance monotherapy with the PARP inhibitor olaparib significantly prolonged progression-free survival (PFS) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer. We aimed to explore the hypothesis that olaparib is most likely to benefit patients with a BRCA mutation. Methods We present data from the second interim analysis of overall survival and a retrospective, preplanned analysis of data by BRCA mutation status from our randomised, double-blind, phase 2 study that assessed maintenance treatment with olaparib 400 mg twice daily (capsules) versus placebo in patients with platinum-sensitive recurrent serous ovarian cancer who had received two or more platinum-based regimens and who had a partial or complete response to their most recent platinum-based regimen. Randomisation was by an interactive voice response system, stratified by time to progression on penultimate platinum-based regimen, response to the most recent platinum-based regimen before randomisation, and ethnic descent. The primary endpoint was PFS, analysed for the overall population and by BRCA status. This study is registered with ClinicalTrials.gov, number NCT00753545. Findings Between Aug 28, 2008, and Feb 9, 2010, 136 patients were assigned to olaparib and 129 to placebo. BRCA status was known for 131 (96%) patients in the olaparib group versus 123 (95%) in the placebo group, of whom 74 (56%) versus 62 (50%) had a deleterious or suspected deleterious germline or tumour BRCA mutation. Of patients with a BRCA mutation, median PFS was significantly longer in the olaparib group than in the placebo group (11·2 months [95% CI 8·3–not calculable] vs 4·3 months [3·0–5·4]; HR 0·18 [0·10–0·31]; p BRCA , although the difference between groups was lower (7·4 months [5·5–10·3] vs 5·5 months [3·7–5·6]; HR 0·54 [0·34–0·85]; p=0·0075). At the second interim analysis of overall survival (58% maturity), overall survival did not significantly differ between the groups (HR 0·88 [95% CI 0·64–1·21]; p=0·44); similar findings were noted for patients with mutated BRCA (HR 0·73 [0·45–1·17]; p=0·19) and wild-type BRCA (HR 0·99 [0·63–1·55]; p=0·96). The most common grade 3 or worse adverse events in the olaparib group were fatigue (in ten [7%] patients in the olaparib group vs four [3%] in the placebo group) and anaemia (seven [5%] vs one [ BRCA and the overall population. Interpretation These results support the hypothesis that patients with platinum-sensitive recurrent serous ovarian cancer with a BRCA mutation have the greatest likelihood of benefiting from olaparib treatment. Funding AstraZeneca.
TL;DR: Experimental vignette methodology (EVM) as discussed by the authors is a way to address the dilemma of conducting experimental research that results in high levels of confidence regarding internal validity but is challenged by threats to external validity versus conducting nonexperimental research that usually maximizes external validity but whose conclusions are ambiguous regarding causal relationships.
Abstract: We describe experimental vignette methodology (EVM) as a way to address the dilemma of conducting experimental research that results in high levels of confidence regarding internal validity but is challenged by threats to external validity versus conducting nonexperimental research that usually maximizes external validity but whose conclusions are ambiguous regarding causal relationships. EVM studies consist of presenting participants with carefully constructed and realistic scenarios to assess dependent variables including intentions, attitudes, and behaviors, thereby enhancing experimental realism and also allowing researchers to manipulate and control independent variables. We describe two major types of EVM aimed at assessing explicit (i.e., paper people studies) and implicit (i.e., policy capturing and conjoint analysis) processes and outcomes. We offer best practice recommendations regarding the design and implementation of EVM studies based on a multidisciplinary literature review, discuss substant...
TL;DR: The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival.
Abstract: Background Vascular endothelial growth factor (VEGF) promotes angiogenesis, a mediator of disease progression in cervical cancer. Bevacizumab, a humanized anti-VEGF monoclonal antibody, has single-agent activity in previously treated, recurrent disease. Most patients in whom recurrent cervical cancer develops have previously received cisplatin with radiation therapy, which reduces the effectiveness of cisplatin at the time of recurrence. We evaluated the effectiveness of bevacizumab and nonplatinum combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer. Methods Using a 2-by-2 factorial design, we randomly assigned 452 patients to chemotherapy with or without bevacizumab at a dose of 15 mg per kilogram of body weight. Chemotherapy consisted of cisplatin at a dose of 50 mg per square meter of body-surface area, plus paclitaxel at a dose of 135 or 175 mg per square meter or topote can at a dose of 0.75 mg per square meter on days 1 to 3, plus paclitaxel at a dose of 175 mg per square meter on day 1. Cycles were repeated every 21 days until disease progression, the development of unacceptable toxic effects, or a complete response was documented. The primary end point was overall survival; a reduction of 30% in the hazard ratio for death was considered clinically important. Results Groups were well balanced with respect to age, histologic findings, performance status, previous use or nonuse of a radiosensitizing platinum agent, and disease status. Topotecan–paclitaxel was not superior to cisplatin–paclitaxel (hazard ratio for death, 1.20). With the data for the two chemotherapy regimens combined, the addition of bevaciz umab to chemotherapy was associated with increased overall survival (17.0 months vs. 13.3 months; hazard ratio for death, 0.71; 98% confidence interval, 0.54 to 0.95; P = 0.004 in a one-sided test) and higher response rates (48% vs. 36%, P = 0.008). Bevacizumab, as compared with chemotherapy alone, was associated with an increased incidence of hypertension of grade 2 or higher (25% vs. 2%), thromboembolic events of grade 3 or higher (8% vs. 1%), and gastrointestinal fistulas of grade 3 or higher (3% vs. 0%). Conclusions The addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic cervical cancer was associated with an improvement of 3.7 months in median overall survival. (Funded by the National Cancer Institute; GOG 240 ClinicalTrials.gov number, NCT00803062.)
TL;DR: In this article, the authors employed first principles density functional theory calculations to explore the mechanical properties of phosphorene, including ideal tensile strength and critical strain, and they found that a monolayer polysilicon can sustain tensile strain up to 27% and 30% in the zigzag and armchair directions, respectively.
Abstract: Recently, fabricated two dimensional (2D) phosphorene crystal structures have demonstrated great potential in applications of electronics. Mechanical strain was demonstrated to be able to significantly modify the electronic properties of phosphorene and few-layer black phosphorus. In this work, we employed first principles density functional theory calculations to explore the mechanical properties of phosphorene, including ideal tensile strength and critical strain. It was found that a monolayer phosphorene can sustain tensile strain up to 27% and 30% in the zigzag and armchair directions, respectively. This enormous strain limit of phosphorene results from its unique puckered crystal structure. We found that the tensile strain applied in the armchair direction stretches the pucker of phosphorene, rather than significantly extending the P-P bond lengths. The compromised dihedral angles dramatically reduce the required strain energy. Compared to other 2D materials, such as graphene, phosphorene demonstrates superior flexibility with an order of magnitude smaller Young's modulus. This is especially useful in practical large-magnitude-strain engineering. Furthermore, the anisotropic nature of phosphorene was also explored. We derived a general model to calculate the Young's modulus along different directions for a 2D system.
TL;DR: Testing the model of differential gene flow among loci by asking whether absolute divergence is also higher in the previously identified ‘islands’ finds that absolute measures of divergence are not higher in genomic islands, and simulations using the program IMa2 suggest that inferences of any gene flow may be incorrect in many comparisons.
Abstract: The metaphor of ‘genomic islands of speciation’ was first used to describe heterogeneous differentiation among loci between the genomes of closely related species. The biological model proposed to explain these differences was that the regions showing high levels of differentiation were resistant to gene flow between species, while the remainder of the genome was being homogenized by gene flow and consequently showed lower levels of differentiation. However, the conditions under which such differentiation can occur at multiple unlinked loci are restrictive; additionally, essentially, all previous analyses have been carried out using relative measures of divergence, which can be misleading when regions with different levels of recombination are compared. Here, we test the model of differential gene flow by asking whether absolute divergence is also higher in the previously identified ‘islands’. Using five species pairs for which full sequence data are available, we find that absolute measures of divergence are not higher in genomic islands. Instead, in all cases examined, we find reduced diversity in these regions, a consequence of which is that relative measures of divergence are abnormally high. These data therefore do not support a model of differential gene flow among loci, although islands of relative divergence may represent loci involved in local adaptation. Simulations using the program IMa2 further suggest that inferences of any gene flow may be incorrect in many comparisons. We instead present an alternative explanation for heterogeneous patterns of differentiation, one in which postspeciation selection generates patterns consistent with multiple aspects of the data.
University of Bonn1, German Center for Neurodegenerative Diseases2, Harvard University3, Maastricht University4, Aix-Marseille University5, Pierre-and-Marie-Curie University6, French Institute of Health and Medical Research7, University of Melbourne8, VU University Amsterdam9, New York University10, Mayo Clinic11, City University of New York12, University of New South Wales13, Indiana University14, King's College London15, University of Toulouse16
TL;DR: In this paper, research criteria for subjective cognitive decline in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD) are presented.
Abstract: There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus.
University of California, Berkeley1, University College London2, Fred Hutchinson Cancer Research Center3, University of Texas at Austin4, University of British Columbia5, University of Pittsburgh6, Indiana University7, National Institute of Genetics8, Tel Aviv University9, University of Illinois at Urbana–Champaign10, University of Lausanne11, University of Oxford12, Iowa State University13, University of Calgary14
TL;DR: The current understanding of how and why sex determination evolves in animals and plants is reviewed.
Abstract: Sexual reproduction is an ancient feature of life on earth, and the familiar X and Y chromo- somes in humans and other model species have led to the impression that sex determination mecha- nisms are old and conserved. In fact, males and females are deter- mined by diverse mechanisms that evolve rapidly in many taxa. Yet this diversity in primary sex-deter- mining signals is coupled with conserved molecular pathways that trigger male or female develop- ment. Conflicting selection on dif- ferent parts of the genome and on the two sexes may drive many of these transitions, but few systems with rapid turnover of sex determi- nation mechanisms have been rig- orously studied. Here we survey our current understanding of how and why sex determination evolves in animals and plants and identify important gaps in our knowledge that present exciting research op- portunities to characterize the evo- lutionary forces and molecular pathways underlying the evolution of sex determination.
University of Iowa1, Los Alamos National Laboratory2, University of Utah3, Central China Normal University4, Indiana University5, American Physical Society6, Bielefeld University7, Brookhaven National Laboratory8, Lawrence Livermore National Laboratory9, University of Regensburg10, University of California, Santa Barbara11
TL;DR: In this paper, the authors present results for the equation of state in ($2+1$)-flavor QCD using the highly improved staggered quark action and lattices with temporal extent.
Abstract: We present results for the equation of state in ($2+1$)-flavor QCD using the highly improved staggered quark action and lattices with temporal extent ${N}_{\ensuremath{\tau}}=6$, 8, 10, and 12. We show that these data can be reliably extrapolated to the continuum limit and obtain a number of thermodynamic quantities and the speed of sound in the temperature range 130--400 MeV. We compare our results with previous calculations and provide an analytic parameterization of the pressure, from which other thermodynamic quantities can be calculated, for use in phenomenology. We show that the energy density in the crossover region, $145\text{ }\text{ }\mathrm{MeV}\ensuremath{\le}T\ensuremath{\le}163\text{ }\text{ }\mathrm{MeV}$, defined by the chiral transition, is ${\ensuremath{\epsilon}}_{c}=(0.18--0.5)\text{ }\text{ }\mathrm{GeV}/{\mathrm{fm}}^{3}$, i.e., $(1.2--3.1)\text{ }{\ensuremath{\epsilon}}_{\text{nuclear}}$. At high temperatures, we compare our results with resummed and dimensionally reduced perturbation theory calculations. As a byproduct of our analyses, we obtain the values of the scale parameters ${r}_{0}$ from the static quark potential and ${w}_{0}$ from the gradient flow.
Icahn School of Medicine at Mount Sinai1, Pierre-and-Marie-Curie University2, French Institute of Health and Medical Research3, Centre national de la recherche scientifique4, University of Toronto5, Trinity College, Dublin6, University of Pittsburgh7, Utrecht University8, McMaster University9, University College Dublin10, Our Lady's Children's Hospital11, University of Oxford12, University of Lisbon13, Instituto Nacional de Saúde Dr. Ricardo Jorge14, University of California, Los Angeles15, University of Miami16, Goethe University Frankfurt17, University of Pennsylvania18, Vanderbilt University19, Temple University20, University of Bologna21, Cancer Care Ontario22, University of Southern California23, University of Alberta24, University of Birmingham25, Université de Montréal26, Rush University Medical Center27, University of Coimbra28, Kaiser Permanente29, Cornell University30, Newcastle University31, University of Minnesota32, University of Illinois at Chicago33, University of Gothenburg34, Memorial University of Newfoundland35, Duke University36, University of Paris37, Centre for Mental Health38, King's College London39, University of Washington40, Nationwide Children's Hospital41, Indiana University42, Tufts University43, German Cancer Research Center44, University of Utah45, Stanford University46
TL;DR: For example, the authors analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability.
Abstract: Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.
TL;DR: This work presents several early examples and the mechanisms by which IDPs contribute to function, which it hopes will encourage comprehensive discussion of IDPs and IDP regions in biochemistry textbooks and propose future directions for IDP research.
Abstract: Intrinsically disordered proteins (IDPs) and IDP regions fail to form a stable structure, yet they exhibit biological activities. Their mobile flexibility and structural instability are encoded by their amino acid sequences. They recognize proteins, nucleic acids, and other types of partners; they accelerate interactions and chemical reactions between bound partners; and they help accommodate posttranslational modifications, alternative splicing, protein fusions, and insertions or deletions. Overall, IDP-associated biological activities complement those of structured proteins. Recently, there has been an explosion of studies on IDP regions and their functions, yet the discovery and investigation of these proteins have a long, mostly ignored history. Along with recent discoveries, we present several early examples and the mechanisms by which IDPs contribute to function, which we hope will encourage comprehensive discussion of IDPs and IDP regions in biochemistry textbooks. Finally, we propose future directions for IDP research.
California Institute of Technology1, University of California, Davis2, University of Tennessee3, Imperial College London4, Arizona State University5, United States Geological Survey6, Princeton University7, Indiana University8, University of Nantes9, Brown University10, Goddard Space Flight Center11, Ames Research Center12, State University of New York System13, Jacobs Engineering Group14, Planetary Science Institute15, University of Guelph16, Los Alamos National Laboratory17, University of Toulouse18, Smithsonian Institution19, Washington University in St. Louis20, University of Washington21, University of California, Berkeley22, University of Lyon23, University of Texas at Austin24, Rensselaer Polytechnic Institute25, Canadian Space Agency26, NASA Headquarters27, University of New Mexico28, University of Hawaii at Manoa29, Brock University30, Cornell University31, Carnegie Institution for Science32, Massachusetts Institute of Technology33, Lunar and Planetary Institute34
TL;DR: The Curiosity rover discovered fine-grained sedimentary rocks, which are inferred to represent an ancient lake and preserve evidence of an environment that would have been suited to support a martian biosphere founded on chemolithoautotrophy.
Abstract: The Curiosity rover discovered fine-grained sedimentary rocks, which are inferred to represent an ancient lake and preserve evidence of an environment that would have been suited to support a martian biosphere founded on chemolithoautotrophy. This aqueous environment was characterized by neutral pH, low salinity, and variable redox states of both iron and sulfur species. Carbon, hydrogen, oxygen, sulfur, nitrogen, and phosphorus were measured directly as key biogenic elements; by inference, phosphorus is assumed to have been available. The environment probably had a minimum duration of hundreds to tens of thousands of years. These results highlight the biological viability of fluvial-lacustrine environments in the post-Noachian history of Mars.
TL;DR: Significance This study provides evidence of change in the relative importance of different crop plants in national food supplies worldwide over the past 50 years, which heightens interdependence among countries in their food supplies, plant genetic resources, and nutritional priorities, and gives further urgency to nutrition development priorities aimed at bolstering food security.
Abstract: The narrowing of diversity in crop species contributing to the world’s food supplies has been considered a potential threat to food security. However, changes in this diversity have not been quantified globally. We assess trends over the past 50 y in the richness, abundance, and composition of crop species in national food supplies worldwide. Over this period, national per capita food supplies expanded in total quantities of food calories, protein, fat, and weight, with increased proportions of those quantities sourcing from energy-dense foods. At the same time the number of measured crop commodities contributing to national food supplies increased, the relative contribution of these commodities within these supplies became more even, and the dominance of the most significant commodities decreased. As a consequence, national food supplies worldwide became more similar in composition, correlated particularly with an increased supply of a number of globally important cereal and oil crops, and a decline of other cereal, oil, and starchy root species. The increase in homogeneity worldwide portends the establishment of a global standard food supply, which is relatively species-rich in regard to measured crops at the national level, but species-poor globally. These changes in food supplies heighten interdependence among countries in regard to availability and access to these food sources and the genetic resources supporting their production, and give further urgency to nutrition development priorities aimed at bolstering food security.
TL;DR: In this article, the authors found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation.
Abstract: Alternative (M2) activation of macrophages driven via the α-chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation
TL;DR: This work presents the multiple evidence base (MEB) as an approach that proposes parallels whereby indigenous, local and scientific knowledge systems are viewed to generate different manifestations of knowledge, which can generate new insights and innovations through complementarities.
Abstract: Indigenous and local knowledge systems as well as practitioners’ knowledge can provide valid and useful knowledge to enhance our understanding of governance of biodiversity and ecosystems for human well-being. There is, therefore, a great need within emerging global assessment programs, such as the IPBES and other international efforts, to develop functioning mechanisms for legitimate, transparent, and constructive ways of creating synergies across knowledge systems. We present the multiple evidence base (MEB) as an approach that proposes parallels whereby indigenous, local and scientific knowledge systems are viewed to generate different manifestations of knowledge, which can generate new insights and innovations through complementarities. MEB emphasizes that evaluation of knowledge occurs primarily within rather than across knowledge systems. MEB on a particular issue creates an enriched picture of understanding, for triangulation and joint assessment of knowledge, and a starting point for further knowledge generation.
TL;DR: In this article, the authors examine how financial market development affects technological innovation and identify economic mechanisms through which the development of equity markets and credit markets affect technological innovation using a large data set that includes 32 developed and emerging countries and a fixed effects identification strategy.
TL;DR: A novel algorithm is used to systematically identify BGCs in the extensive extant microbial sequencing data, indicating for the first time the important roles these compounds play in Gram-negative cell biology.
TL;DR: The ENIGMA Consortium has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected.
Abstract: The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA's first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations with subcortical volumes (ENIGMA2) and white matter microstructure (ENIGMA-DTI). Working groups also focus on understanding how schizophrenia, bipolar illness, major depression and attention deficit/hyperactivity disorder (ADHD) affect the brain. We review the current progress of the ENIGMA Consortium, along with challenges and unexpected discoveries made on the way.
University of St Andrews1, University of Oxford2, Stanford University3, Australian National University4, University of Vienna5, Indiana University6, Tel Aviv University7, Duke University8, Harvard University9, Stony Brook University10, Michigan State University11, North Carolina State University12, University of British Columbia13, Washington University in St. Louis14
TL;DR: This synthesis maintains that important drivers of evolution, ones that cannot be reduced to genes, must be woven into the very fabric of evolutionary theory, and believes that the EES will shed new light on how Point Yes, urgently is shed.
Abstract: Nobel physicist talks plants with a waiter, then what? p.168 ENERGY Don't assume that renewable energies are problem-free p.168 AGEING Atul Gawande's call to action on end-of-life medical care p.167 HEALTH Lasting legacy of wartime battle against malaria p.166 Does evolutionary theory need a rethink? Researchers are divided over what processes should be considered fundamental. I n October 1881, just six months before he died, Charles Darwin published his final book. The Formation of Vegetable Mould, Through the Actions of Worms 11 sold briskly: Darwin's earlier publications had secured his reputation. He devoted an entire book to these humble creatures in part because they exemplify an interesting feedback process: earthworms are adapted to thrive in an environment that they modify through their own activities. Darwin learned about earthworms from conversations with gardeners and his own simple experiments. He had a genius for distilling penetrating insights about evolutionary processes — often after amassing years of observational and experimental data — and he drew on such disparate topics as agriculture, geology, embryol-ogy and behaviour. Evolutionary thinking ever since has followed Darwin's lead in its emphasis on evidence and in synthesizing information from other fields. A profound shift in evolutionary thinking began C harles Darwin conceived of evolution by natural selection without knowing that genes exist. Now mainstream evolutionary theory has come to focus almost exclusively on genetic inheritance and processes that change gene frequencies. Yet new data pouring out of adjacent fields are starting to undermine this narrow stance. An alternative vision of evolution is beginning to crystallize, in which the processes by which organisms grow and develop are recognized as causes of evolution. Some of us first met to discuss these advances six years ago. In the time since, as members of an interdisciplinary team, we have worked intensively to develop a broader framework, termed the extended evolutionary synthesis 1 (EES), and to flesh out its structure, assumptions and predictions. In essence, this synthesis maintains that important drivers of evolution, ones that cannot be reduced to genes, must be woven into the very fabric of evolutionary theory. We believe that the EES will shed new light on how POINT Yes, urgently Without an extended evolutionary framework, the theory neglects key processes, say Kevin Laland and colleagues.