Showing papers by "University of Michigan published in 2014"

Heart Disease and Stroke Statistics—2014 Update A Report From the American Heart Association

Abstract: Author(s): Go, Alan S; Mozaffarian, Dariush; Roger, Veronique L; Benjamin, Emelia J; Berry, Jarett D; Blaha, Michael J; Dai, Shifan; Ford, Earl S; Fox, Caroline S; Franco, Sheila; Fullerton, Heather J; Gillespie, Cathleen; Hailpern, Susan M; Heit, John A; Howard, Virginia J; Huffman, Mark D; Judd, Suzanne E; Kissela, Brett M; Kittner, Steven J; Lackland, Daniel T; Lichtman, Judith H; Lisabeth, Lynda D; Mackey, Rachel H; Magid, David J; Marcus, Gregory M; Marelli, Ariane; Matchar, David B; McGuire, Darren K; Mohler, Emile R; Moy, Claudia S; Mussolino, Michael E; Neumar, Robert W; Nichol, Graham; Pandey, Dilip K; Paynter, Nina P; Reeves, Matthew J; Sorlie, Paul D; Stein, Joel; Towfighi, Amytis; Turan, Tanya N; Virani, Salim S; Wong, Nathan D; Woo, Daniel; Turner, Melanie B; American Heart Association Statistics Committee and Stroke Statistics Subcommittee

Comprehensive molecular characterization of gastric adenocarcinoma

Abstract: Gastric cancer was the world’s third leading cause of cancer mortality in 2012, responsible for 723,000 deaths1. The vast majority of gastric cancers are adenocarcinomas, which can be further subdivided into intestinal and diffuse types according to the Lauren classification2. An alternative system, proposed by the World Health Organization, divides gastric cancer into papillary, tubular, mucinous (colloid) and poorly cohesive carcinomas3. These classification systems have little clinical utility, making the development of robust classifiers that can guide patient therapy an urgent priority. The majority of gastric cancers are associated with infectious agents, including the bacterium Helicobacter pylori4 and Epstein–Barr virus (EBV). The distribution of histological subtypes of gastric cancer and the frequencies of H. pylori and EBV associated gastric cancer vary across the globe5. A small minority of gastric cancer cases are associated with germline mutation in E-cadherin (CDH1)6 or mismatch repair genes7 (Lynch syndrome), whereas sporadic mismatch repair-deficient gastric cancers have epigenetic silencing of MLH1 in the context of a CpG island methylator phenotype (CIMP)8. Molecular profiling of gastric cancer has been performed using gene expression or DNA sequencing9–12, but has not led to a clear biologic classification scheme. The goals of this study by The Cancer Genome Atlas (TCGA) were to develop a robust molecular classification of gastric cancer and to identify dysregulated pathways and candidate drivers of distinct classes of gastric cancer.

Comprehensive molecular profiling of lung adenocarcinoma: The cancer genome atlas research network

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.

Ultralow thermal conductivity and high thermoelectric figure of merit in SnSe crystals

Abstract: The thermoelectric effect enables direct and reversible conversion between thermal and electrical energy, and provides a viable route for power generation from waste heat The efficiency of thermoelectric materials is dictated by the dimensionless figure of merit, ZT (where Z is the figure of merit and T is absolute temperature), which governs the Carnot efficiency for heat conversion Enhancements above the generally high threshold value of 25 have important implications for commercial deployment, especially for compounds free of Pb and Te Here we report an unprecedented ZT of 26 ± 03 at 923 K, realized in SnSe single crystals measured along the b axis of the room-temperature orthorhombic unit cell This material also shows a high ZT of 23 ± 03 along the c axis but a significantly reduced ZT of 08 ± 02 along the a axis We attribute the remarkably high ZT along the b axis to the intrinsically ultralow lattice thermal conductivity in SnSe The layered structure of SnSe derives from a distorted rock-salt structure, and features anomalously high Gruneisen parameters, which reflect the anharmonic and anisotropic bonding We attribute the exceptionally low lattice thermal conductivity (023 ± 003 W m(-1) K(-1) at 973 K) in SnSe to the anharmonicity These findings highlight alternative strategies to nanostructuring for achieving high thermoelectric performance

Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes

Abstract: Background The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. Methods We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Results Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Conclusions Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.)

Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.

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.

Going Deeper with Convolutions

Abstract: We propose a deep convolutional neural network architecture codenamed "Inception", which was responsible for setting the new state of the art for classification and detection in the ImageNet Large-Scale Visual Recognition Challenge 2014 (ILSVRC 2014). The main hallmark of this architecture is the improved utilization of the computing resources inside the network. This was achieved by a carefully crafted design that allows for increasing the depth and width of the network while keeping the computational budget constant. To optimize quality, the architectural decisions were based on the Hebbian principle and the intuition of multi-scale processing. One particular incarnation used in our submission for ILSVRC 2014 is called GoogLeNet, a 22 layers deep network, the quality of which is assessed in the context of classification and detection.

Transcatheter Aortic Valve Replacement with a Self-Expanding Prosthesis

Abstract: BACKGROUND We compared transcatheter aortic-valve replacement (TAVR), using a self-expanding transcatheter aortic-valve bioprosthesis, with surgical aortic-valve replacement in patients with severe aortic stenosis and an increased risk of death during surgery. METHODS We recruited patients with severe aortic stenosis who were at increased surgical risk as determined by the heart team at each study center. Risk assessment included the Society of Thoracic Surgeons Predictor Risk of Mortality estimate and consideration of other key risk factors. Eligible patients were randomly assigned in a 1:1 ratio to TAVR with the self-expanding transcatheter valve (TAVR group) or to surgical aortic-valve replacement (surgical group). The primary end point was the rate of death from any cause at 1 year, evaluated with the use of both noninferiority and superiority testing. RESULTS A total of 795 patients underwent randomization at 45 centers in the United States. In the as-treated analysis, the rate of death from any cause at 1 year was significantly lower in the TAVR group than in the surgical group (14.2% vs. 19.1%), with an absolute reduction in risk of 4.9 percentage points (upper boundary of the 95% confidence interval, −0.4; P<0.001 for noninferiority; P = 0.04 for superiority). The results were similar in the intention-to-treat analysis. In a hierarchical testing procedure, TAVR was noninferior with respect to echocardiographic indexes of valve stenosis, functional status, and quality of life. Exploratory analyses suggested a reduction in the rate of major adverse cardiovascular and cerebrovascular events and no increase in the risk of stroke. CONCLUSIONS In patients with severe aortic stenosis who are at increased surgical risk, TAVR with a self-expanding transcatheter aortic-valve bioprosthesis was associated with a significantly higher rate of survival at 1 year than surgical aortic-valve replacement. (Funded by Medtronic; U.S. CoreValve High Risk Study ClinicalTrials.gov number, NCT01240902.)

Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications: recommendations of the International RDC/TMD Consortium Network* and Orofacial Pain Special Interest Group†

Abstract: Temporomandibular disorders (TMD) are a significant public health problem affecting approximately 5% to 12% of the population.1 TMD is the second most common musculoskeletal condition (after chronic low back pain) resulting in pain and disability.1 Pain-related TMD can impact the individual's daily activities, psychosocial functioning, and quality of life. Overall, the annual TMD management cost in the USA, not including imaging, has doubled in the last decade to $4 billion.1 Patients often seek consultation with dentists for their TMD, especially for pain-related TMD. Diagnostic criteria for TMD with simple, clear, reliable, and valid operational definitions for the history, examination, and imaging procedures are needed to render physical diagnoses in both clinical and research settings. In addition, biobehavioral assessment of pain-related behavior and psychosocial functioning—an essential part of the diagnostic process—is required and provides the minimal information whereby one can determine whether the patient's pain disorder, especially when chronic, warrants further multidisciplinary assessment. Taken together, a new dual-axis Diagnostic Criteria for TMD (DC/TMD) will provide evidence-based criteria for the clinician to use when assessing patients, and will facilitate communication regarding consultations, referrals, and prognosis.2 The research community benefits from the ability to use well-defined and clinically relevant characteristics associated with the phenotype in order to facilitate more generalizable research. When clinicians and researchers use the same criteria, taxonomy, and nomenclature, then clinical questions and experience can be more easily transferred into relevant research questions, and research findings are more accessible to clinicians to better diagnose and manage their patients. The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) have been the most widely employed diagnostic protocol for TMD research since its publication in 1992.3 This classification system was based on the biopsychosocial model of pain4 that included an Axis I physical assessment, using reliable and well-operationalized diagnostic criteria, and an Axis II assessment of psychosocial status and pain-related disability. The intent was to simultaneously provide a physical diagnosis and identify other relevant characteristics of the patient that could influence the expression and thus management of their TMD. Indeed, the longer the pain persists, the greater the potential for emergence and amplification of cognitive, psychosocial, and behavioral risk factors, with resultant enhanced pain sensitivity, greater likelihood of additional pain persistence, and reduced probability of success from standard treatments.5 The RDC/TMD (1992) was intended to be only a first step toward improved TMD classification, and the authors stated the need for future investigation of the accuracy of the Axis I diagnostic algorithms in terms of reliability and criterion validity—the latter involving the use of credible reference standard diagnoses. Also recommended was further assessment of the clinical utility of the Axis II instruments. The original RDC/TMD Axis I physical diagnoses have content validity based on the critical review by experts of the published diagnostic approach in use at that time and were tested using population-based epidemiologic data.6 Subsequently, a multicenter study showed that, for the most common TMD, the original RDC/TMD diagnoses exhibited sufficient reliability for clinical use.7 While the validity of the individual RDC/TMD diagnoses has been extensively investigated, assessment of the criterion validity for the complete spectrum of RDC/TMD diagnoses had been absent until recently.8 For the original RDC/TMD Axis II instruments, good evidence for their reliability and validity for measuring psychosocial status and pain-related disability already existed when the classification system was published.9–13 Subsequently, a variety of studies have demonstrated the significance and utility of the original RDC/TMD biobehavioral measures in such areas as predicting outcomes of clinical trials, escalation from acute to chronic pain, and experimental laboratory settings.14–20 Other studies have shown that the original RDC/TMD biobehavioral measures are incomplete in terms of prediction of disease course.21–23 The overall utility of the biobehavioral measures in routine clinical settings has, however, yet to be demonstrated, in part because most studies have to date focused on Axis I diagnoses rather than Axis II biobehavioral factors.24 The aims of this article are to present the evidence-based new Axis I and Axis II DC/TMD to be used in both clinical and research settings, as well as present the processes related to their development.

Parity–time-symmetric whispering-gallery microcavities

Abstract: It is now shown that coupled optical microcavities bear all the hallmarks of parity–time symmetry; that is, the system’s dynamics are unchanged by both time-reversal and mirror transformations. The resonant nature of microcavities results in unusual effects not seen in previous photonic analogues of parity–time-symmetric systems: for example, light travelling in one direction is resonantly enhanced but there are no resonance peaks going the other way.

Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab

Abstract: Purpose Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. Patients and Methods Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. Results Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Sev...

Robust Nonparametric Confidence Intervals for Regression‐Discontinuity Designs

Abstract: In the regression-discontinuity (RD) design, units are assigned to treatment based on whether their value of an observed covariate exceeds a known cutoff. In this design, local polynomial estimators are now routinely employed to construct confidence intervals for treatment effects. The performance of these confidence intervals in applications, however, may be seriously hampered by their sensitivity to the specific bandwidth employed. Available bandwidth selectors typically yield a “large” bandwidth, leading to data-driven confidence intervals that may be biased, with empirical coverage well below their nominal target. We propose new theory-based, more robust confidence interval estimators for average treatment effects at the cutoff in sharp RD, sharp kink RD, fuzzy RD, and fuzzy kink RD designs. Our proposed confidence intervals are constructed using a bias-corrected RD estimator together with a novel standard error estimator. For practical implementation, we discuss mean squared error optimal bandwidths, which are by construction not valid for conventional confidence intervals but are valid with our robust approach, and consistent standard error estimators based on our new variance formulas. In a special case of practical interest, our procedure amounts to running a quadratic instead of a linear local regression. More generally, our results give a formal justification to simple inference procedures based on increasing the order of the local polynomial estimator employed. We find in a simulation study that our confidence intervals exhibit close-to-correct empirical coverage and good empirical interval length on average, remarkably improving upon the alternatives available in the literature. All results are readily available in R and STATA using our companion software packages described in Calonico, Cattaneo, and Titiunik (2014d, 2014b).

The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism

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.

Spironolactone for Heart Failure with Preserved Ejection Fraction

Abstract: Background Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. Methods In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. Results With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P = 0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P = 0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spiron olactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis. Conclusions In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood Institute; TOPCAT ClinicalTrials.gov number, NCT00094302.)

Inside the Turk Understanding Mechanical Turk as a Participant Pool

Abstract: Mechanical Turk (MTurk), an online labor market created by Amazon, has recently become popular among social scientists as a source of survey and experimental data. The workers who populate this market have been assessed on dimensions that are universally relevant to understanding whether, why, and when they should be recruited as research participants. We discuss the characteristics of MTurk as a participant pool for psychology and other social sciences, highlighting the traits of the MTurk samples, why people become MTurk workers and research participants, and how data quality on MTurk compares to that from other pools and depends on controllable and uncontrollable factors.

Defining the role of common variation in the genomic and biological architecture of adult human height

Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Executive summary: Heart Disease and Stroke Statistics - 2014 Update: A report from the American Heart Association

Abstract: Author(s): Go, Alan S; Mozaffarian, Dariush; Roger, Veronique L; Benjamin, Emelia J; Berry, Jarett D; Blaha, Michael J; Dai, Shifan; Ford, Earl S; Fox, Caroline S; Franco, Sheila; Fullerton, Heather J; Gillespie, Cathleen; Hailpern, Susan M; Heit, John A; Howard, Virginia J; Huffman, Mark D; Judd, Suzanne E; Kissela, Brett M; Kittner, Steven J; Lackland, Daniel T; Lichtman, Judith H; Lisabeth, Lynda D; Mackey, Rachel H; Magid, David J; Marcus, Gregory M; Marelli, Ariane; Matchar, David B; McGuire, Darren K; Mohler, Emile R; Moy, Claudia S; Mussolino, Michael E; Neumar, Robert W; Nichol, Graham; Pandey, Dilip K; Paynter, Nina P; Reeves, Matthew J; Sorlie, Paul D; Stein, Joel; Towfighi, Amytis; Turan, Tanya N; Virani, Salim S; Wong, Nathan D; Woo, Daniel; Turner, Melanie B; American Heart Association Statistics Committee and Stroke Statistics Subcommittee

The machinery of macroautophagy

Abstract: Autophagy is a primarily degradative pathway that takes place in all eukaryotic cells. It is used for recycling cytoplasm to generate macromolecular building blocks and energy under stress conditions, to remove superfluous and damaged organelles to adapt to changing nutrient conditions and to maintain cellular homeostasis. In addition, autophagy plays a critical role in cytoprotection by preventing the accumulation of toxic proteins and through its action in various aspects of immunity including the elimination of invasive microbes and its participation in antigen presentation. The most prevalent form of autophagy is macroautophagy, and during this process, the cell forms a double-membrane sequestering compartment termed the phagophore, which matures into an autophagosome. Following delivery to the vacuole or lysosome, the cargo is degraded and the resulting macromolecules are released back into the cytosol for reuse. The past two decades have resulted in a tremendous increase with regard to the molecular studies of autophagy being carried out in yeast and other eukaryotes. Part of the surge in interest in this topic is due to the connection of autophagy with a wide range of human pathophysiologies including cancer, myopathies, diabetes and neurodegenerative disease. However, there are still many aspects of autophagy that remain unclear, including the process of phagophore formation, the regulatory mechanisms that control its induction and the function of most of the autophagy-related proteins. In this review, we focus on macroautophagy, briefly describing the discovery of this process in mammalian cells, discussing the current views concerning the donor membrane that forms the phagophore, and characterizing the autophagy machinery including the available structural information.

Energy metabolism in the liver

Abstract: The liver is an essential metabolic organ, and its metabolic function is controlled by insulin and other metabolic hormones. Glucose is converted into pyruvate through glycolysis in the cytoplasm, and pyruvate is subsequently oxidized in the mitochondria to generate ATP through the TCA cycle and oxidative phosphorylation. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and/or cholesterol esters in hepatocytes. These complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as very low-density lipoprotein particles. In the fasted state, the liver secretes glucose through both glycogenolysis and gluconeogenesis. During pronged fasting, hepatic gluconeogenesis is the primary source for endogenous glucose production. Fasting also promotes lipolysis in adipose tissue, resulting in release of nonesterified fatty acids which are converted into ketone bodies in hepatic mitochondria though β-oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver energy metabolism is tightly regulated by neuronal and hormonal signals. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis but suppresses gluconeogenesis, and glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze key steps of metabolic pathways, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases.

An Overview of Autophagy: Morphology, Mechanism, and Regulation

Abstract: Significance: Autophagy is a highly conserved eukaryotic cellular recycling process. Through the degradation of cytoplasmic organelles, proteins, and macromolecules, and the recycling of the breakdown products, autophagy plays important roles in cell survival and maintenance. Accordingly, dysfunction of this process contributes to the pathologies of many human diseases. Recent Advances: Extensive research is currently being done to better understand the process of autophagy. In this review, we describe current knowledge of the morphology, molecular mechanism, and regulation of mammalian autophagy. Critical Issues: At the mechanistic and regulatory levels, there are still many unanswered questions and points of confusion that have yet to be resolved. Future Directions: Through further research, a more complete and accurate picture of the molecular mechanism and regulation of autophagy will not only strengthen our understanding of this significant cellular process, but will aid in the development o...

Preterm labor: One syndrome, many causes

Abstract: Preterm birth is associated with 5 to 18% of pregnancies and is a leading cause of infant morbidity and mortality. Spontaneous preterm labor, a syndrome caused by multiple pathologic processes, leads to 70% of preterm births. The prevention and the treatment of preterm labor have been long-standing challenges. We summarize the current understanding of the mechanisms of disease implicated in this condition and review advances relevant to intra-amniotic infection, decidual senescence, and breakdown of maternal-fetal tolerance. The success of progestogen treatment to prevent preterm birth in a subset of patients at risk is a cause for optimism. Solving the mystery of preterm labor, which compromises the health of future generations, is a formidable scientific challenge worthy of investment.

A comparative encyclopedia of DNA elements in the mouse genome

Abstract: The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases

Three keys to the radiation of angiosperms into freezing environments

Abstract: Early flowering plants are thought to have been woody species restricted to warm habitats 1–3 . This lineage has since radiated into almost every climate, with manifold growth forms 4 . As angiosperms spread and climate changed, they evolved mechanisms to cope with episodic freezing. To explore the evolution of traits underpinning the ability to persist in freezing conditions, we assembled a large species-level database of growth habit (woody or herbaceous; 49,064 species), as well as leaf phenology (evergreen or deciduous), diameter of hydraulic conduits (that is, xylem vessels and tracheids) and climate occupancies (exposure to freezing). To model the evolution of species’ traits and climate occupancies, we combined these data with an unparalleled dated molecular phylogeny (32,223 species) for land plants. Here we show that woody clades successfully move di nto freezingprone environments by either possessing transport networks of small

The tenth data release of the Sloan digital sky survey: First spectroscopic data from the SDSS-iii apache point observatory galactic evolution experiment

Abstract: The Sloan Digital Sky Survey (SDSS) has been in operation since 2000 April. This paper presents the Tenth Public Data Release (DR10) from its current incarnation, SDSS-III. This data release includes the first spectroscopic data from the Apache Point Observatory Galaxy Evolution Experiment (APOGEE), along with spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS) taken through 2012 July. The APOGEE instrument is a near-infrared R ~ 22,500 300 fiber spectrograph covering 1.514-1.696 μm. The APOGEE survey is studying the chemical abundances and radial velocities of roughly 100,000 red giant star candidates in the bulge, bar, disk, and halo of the Milky Way. DR10 includes 178,397 spectra of 57,454 stars, each typically observed three or more times, from APOGEE. Derived quantities from these spectra (radial velocities, effective temperatures, surface gravities, and metallicities) are also included. DR10 also roughly doubles the number of BOSS spectra over those included in the Ninth Data Release. DR10 includes a total of 1,507,954 BOSS spectra comprising 927,844 galaxy spectra, 182,009 quasar spectra, and 159,327 stellar spectra selected over 6373.2 deg2.

Guidelines for investigating causality of sequence variants in human disease

Abstract: The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

The role of inventories and speculative trading in the global market for crude oil

Abstract: SUMMARY We develop a structural model of the global market for crude oil that for the first time explicitly allows for shocks to the speculative demand for oil as well as shocks to flow demand and flow supply. The speculative component of the real price of oil is identified with the help of data on oil inventories. Our estimates rule out explanations of the 2003–2008 oil price surge based on unexpectedly diminishing oil supplies and based on speculative trading. Instead, this surge was caused by unexpected increases in world oil consumption driven by the global business cycle. There is evidence, however, that speculative demand shifts played an important role during earlier oil price shock episodes including 1979, 1986 and 1990. Our analysis implies that additional regulation of oil markets would not have prevented the 2003–2008 oil price surge. We also show that, even after accounting for the role of inventories in smoothing oil consumption, our estimate of the short-run price elasticity of oil demand is much higher than traditional estimates from dynamic models that do not account for for the endogeneity of the price of oil. Copyright © 2013 John Wiley & Sons, Ltd.

Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection

Abstract: Background All-oral combination therapy is desirable for patients with chronic hepatitis C virus (HCV) infection. We evaluated daclatasvir (an HCV NS5A replication complex inhibitor) plus sofosbuvir (a nucleotide analogue HCV NS5B polymerase inhibitor) in patients infected with HCV genotype 1, 2, or 3. Methods In this open-label study, we initially randomly assigned 44 previously untreated patients with HCV genotype 1 infection and 44 patients infected with HCV genotype 2 or 3 to daclatasvir at a dose of 60 mg orally once daily plus sofosbuvir at a dose of 400 mg orally once daily, with or without ribavirin, for 24 weeks. The study was expanded to include 123 additional patients with genotype 1 infection who were randomly assigned to daclatasvir plus sofosbuvir, with or without ribavirin, for 12 weeks (82 previously untreated patients) or 24 weeks (41 patients who had previous virologic failure with telaprevir or boceprevir plus peginterferon alfa–ribavirin). The primary end point was a sustained virologi...

Cohort Profile: the Health and Retirement Study (HRS).

Abstract: The Health and Retirement Study (HRS) is a nationally representative longitudinal survey of more than 37 000 individuals over age 50 in 23 000 households in the USA. The survey, which has been fielded every 2 years since 1992, was established to provide a national resource for data on the changing health and economic circumstances associated with ageing at both individual and population levels. Its multidisciplinary approach is focused on four broad topics—income and wealth; health, cognition and use of healthcare services; work and retirement; and family connections. HRS data are also linked at the individual level to administrative records from Social Security and Medicare, Veteran’s Administration, the National Death Index and employer-provided pension plan information. Since 2006, data collection has expanded to include biomarkers and genetics as well as much greater depth in psychology and social context. This blend of economic, health and psychosocial information provides unprecedented potential to study increasingly complex questions about ageing and retirement. The HRS has been a leading force for rapid release of data while simultaneously protecting the confidentiality of respondents. Three categories of data—public, sensitive and restricted—can be accessed through procedures described on the HRS website (hrsonline.isr.umich.edu).