A framework for systematic promoter motif discovery and expression profiling from high dimensional brain transcriptome data

Understanding the regulatory logic of genes across discrete brain substructures can elucidate the basis for neural network connectivity and the cause of disease. Promoter motifs, in particular, that govern high or low expression gene networks present an important fulcrum for phenotypic behavior. Using the Allen Institute Brain Atlas we took various clustering approaches to find closely regulated genes, and generated substructure specific expression profiles to run through FIRE, a motif discovery algorithm and iPAGE, a functional ontology algorithm. Notably, we found a single large cluster of genes that had tightly coordinated behavior across hundreds of brain substructures, as well as a unique upstream promoter signature, yet highly diverse ontological characteristics. We also present a BRain EXpression Profile ASSembly script (BEXPASS) whose output is customized for FIRE and iPAGE input. Lastly we look at language processing and speech control areas of the brain and put forward recommendations for promoters that can serve as part of DNA constructs for optogenetic research an emerging neuroscientific research method that uses bacterial light-gated ion channel protein, channelrhodopsin (ChR1 or ChR2), as an activity control tool to activate neural pathway signaling

Reduction of rework at a large aerospace manufacturer

Thesis (M.B.A.)--Massachusetts Institute of Technology, Sloan School of Management; and, (S.M.)--Massachusetts Institute of Technology, Dept. of Materials Science and Engineering; in conjunction with the Leaders for Global Operations Program at MIT, 2012.Cataloged from PDF version of thesis.Includes bibliographical references (p. 88-91).It is an axiom of the manufacturing of any complex product that errors will occur that require repair or discard of said product. In building aircraft, Raptor Aerospace encounters and repairs numerous deviations from the original design drawings. This process is known as rework. Reducing the amount of rework necessary represents a substantial opportunity both for improving quality and for cutting cost. Rework can be further split into several categories, with the simplest repairs referred to as reworkable discrepancies which has been valued at over $50,000,000 per year. This thesis will present a project that began at the start of the internship, when the author was paired with a specialist from Raptor Aerospace to lead a team whose purpose was to develop an approach and implement improvements that would generate a significant reduction in rework. This process would include both physical changes to the manufacturing process and would target specific aspects of the prevailing culture at Raptor. With no existing plan for reducing rework, the two team leaders began the project by conducting a thorough analysis of existing rework data, focusing on the descriptive texts that were provided by inspectors. This analysis generated a pareto of the inspectors' words, enabling the team to identify the most common causes of rework at Raptor. Based on these results, small teams were created to perform root cause and corrective action analyses on the biggest issues. In addition to the small teams, the co-leaders also searched for solutions that would have a systemic impact on the volume of rework. To this end, an automated tool was developed that would report the rework history of every single task completed in final assembly. Within the timeframe of the internship (6.5 months), the various approaches completed by the project team produced verified annualized savings of over$2,000,000, as well as time savings of over 40 manhours per week. In addition, other efforts that were begun but not yet completed have anticipated savings of over $10,000,000. Finally, the project has produced indications of cultural improvements within Raptor Aerospace, as individuals and departments have begun volunteering to contribute and lead improvement efforts. Overall, it appears that the approaches taken by the project team have successfully launched a change initiative which could have substantial and long-lasting value to Raptor Aerospace.by Jeremy A. Lieberman.S.M.M.B.A

Best Practices for Publishing, Retrieving, and Using Spatial Data on the Web

Data owners are creating an ever richer set of information resources online, and these are being used for more and more applications. With the rapid growth of connected embedded devices, GPS-enabled mobile devices, and various organizations that publish their location-based data (i.e., weather and traffic services), maps and geographical and spatial information (i.e., GIS and open maps), spatial data on the Web is becoming ubiquitous and voluminous. However, the heterogeneity of the available spatial data, as well as some challenges related to spatial data in particular make it difficult for data users, web applications and services to discover, interpret and use the information in large and distributed web systems. This paper summarizes some of the efforts that have been undertaken in the joint W3C/OGC Working Group on Spatial Data on the Web, in particular the effort to describe the best practices for publishing spatial data on the Web. This paper presents the set of principles that guide the selection of these best practices, describes best practices that are employed to enable publishing, discovery and retrieving (querying) this type of data on the Web, and identifies some areas where a best practice has not yet emerged

Lucy's Flat Feet: The Relationship between the Ankle and Rearfoot Arching in Early Hominins

BACKGROUND. In the Plio-Pleistocene, the hominin foot evolved from a grasping appendage to a stiff, propulsive lever. Central to this transition was the development of the longitudinal arch, a structure that helps store elastic energy and stiffen the foot during bipedal locomotion. Direct evidence for arch evolution, however, has been somewhat elusive given the failure of soft-tissue to fossilize. Paleoanthropologists have relied on footprints and bony correlates of arch development, though little consensus has emerged as to when the arch evolved. METHODOLOGY/PRINCIPAL FINDINGS. Here, we present evidence from radiographs of modern humans (n=261) that the set of the distal tibia in the sagittal plane, henceforth referred to as the tibial arch angle, is related to rearfoot arching. Non-human primates have a posteriorly directed tibial arch angle, while most humans have an anteriorly directed tibial arch angle. Those humans with a posteriorly directed tibial arch angle (8%) have significantly lower talocalcaneal and talar declination angles, both measures of an asymptomatic flatfoot. Application of these results to the hominin fossil record reveals that a well developed rearfoot arch had evolved in Australopithecus afarensis. However, as in humans today, Australopithecus populations exhibited individual variation in foot morphology and arch development, and "Lucy" (A.L. 288-1), a 3.18 Myr-old female Australopithecus, likely possessed asymptomatic flat feet. Additional distal tibiae from the Plio-Pleistocene show variation in tibial arch angles, including two early Homo tibiae that also have slightly posteriorly directed tibial arch angles. CONCLUSIONS/SIGNIFICANCE. This study finds that the rearfoot arch was present in the genus Australopithecus. However, the female Australopithecus afarensis "Lucy" has an ankle morphology consistent with non-pathological flat-footedness. This study suggests that, as in humans today, there was variation in arch development in Plio-Pleistocene hominins.Leakey Foundatio

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (β = 16.1, CI(β) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (β = 4.86,CI(β) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies

Genetic correlation between amyotrophic lateral sclerosis and schizophrenia

A. Palotie on työryhmän Schizophrenia Working Grp Psychiat jäsen.We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P = 1 x 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P = 8.4 x 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.Peer reviewe