592 research outputs found
Boltzmann energy-based image analysis demonstrates that extracellular domain size differences explain protein segregation at immune synapses
No full textImmune synapses formed by T and NK cells both show segregation of the integrin ICAM1 from other proteins such as CD2 (T cell) or KIR (NK cell). However, the mechanism by which these proteins segregate remains unclear; one key hypothesis is a redistribution based on protein size. Simulations of this mechanism qualitatively reproduce observed segregation patterns, but only in certain parameter regimes. Verifying that these parameter constraints in fact hold has not been possible to date, this requiring a quantitative coupling of theory to experimental data. Here, we address this challenge, developing a new methodology for analysing and quantifying image data and its integration with biophysical models. Specifically we fit a binding kinetics model to 2 colour fluorescence data for cytoskeleton independent synapses (2 and 3D) and test whether the observed inverse correlation between fluorophores conforms to size dependent exclusion, and further, whether patterned states are predicted when model parameters are estimated on individual synapses. All synapses analysed satisfy these conditions demonstrating that the mechanisms of protein redistribution have identifiable signatures in their spatial patterns. We conclude that energy processes implicit in protein size based segregation can drive the patternation observed in individual synapses, at least for the specific examples tested, such that no additional processes need to be invoked. This implies that biophysical processes within the membrane interface have a crucial impact on cell:cell communication and cell signalling, governing protein interactions and protein aggregation
The relationship between depression and chronotype: A longitudinal assessment during childhood and adolescence
No full textBackground/Objective
During adolescence, chronotype shifts towards “eveningness.” “Eveningness” is related to negative physical and mental health outcomes. Little is known about what influences the shift in chronotype beyond pubertal status. The current study examined the influence of earlier depression predicting later individual differences in adolescent chronotype, accounting for pubertal status, and the prospective prediction of later increases in depression from earlier chronotype.
Methods
Youth (age M=12.06, SD=2.35; 56.5% girls) from the community completed repeated assessments of depression, including both self-reports (14 assessments) and diagnostic interviews (8 assessments), over a 48-month period. At the 36-month time-point, participants completed chronotype and pubertal development measures. Regression and ANOVA analyses examined: (1) the influence of earlier depression levels (baseline to 36-months) upon chronotype, and (2) chronotype (at 36 months) upon later depression (48 months).
Results
Youth with higher earlier depression symptoms (β=-.347, p<.001) and history of depression diagnosis (β=-.13, p=.045) showed a greater eveningness preference controlling for pubertal status, age and gender. Further, depression diagnosis history interacted with pubertal status to predict chronotype: (F(1,243)=4.171, p=.045) such that the influence of depression on chronotype was greatest among postpubertal youth (t=3.271, p=.002). Chronotype (greater eveningness preference) predicted prospective increases in depression symptoms (β=-.16, p=.03) and onset of depressive episode (b=-.085, OR=.92, p=.03) one year later.
Conclusion
Depression, experienced earlier in life, predicts greater preference for eveningness, especially among postpubertal youth. In turn, later depression is predicted by evening preference. These findings suggest the reciprocal interplay between mood and biological rhythms, especially depression and chronotype, during adolescence.Submission published under a 24 month embargo labeled 'Closed Access', the embargo will last until 2019-12-01The student, Dustin Haraden, accepted the attached license on 2017-12-12 at 16:34.The student, Dustin Haraden, submitted this Thesis for approval on 2017-12-12 at 16:40.This Thesis was approved for publication on 2017-12-13 at 08:22.DSpace SAF Submission Ingestion Package generated from Vireo submission #11961 on 2018-03-13 at 10:38:25Made available in DSpace on 2018-03-13T17:35:57Z (GMT). No. of bitstreams: 2
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Influences of host community characteristics on Borrelia burgdorferi infection prevalence in Blacklegged ticks
No full textLyme disease is a major vector-borne bacterial disease in the USA. The disease is caused by Borrelia burgdorferi, and transmitted among hosts and humans, primarily by blacklegged ticks (Ixodes scapularis). The ~25 B. burgdorferi genotypes, based on genotypic variation of their outer surface protein C (ospC), can be phenotypically separated as strains that primarily cause human diseases – human invasive strains (HIS) – or those that rarely do – and are non-randomly associated with host species. The goal of this study was to examine the extent to which phenotypic outcomes of B. burgdorferi could be explained by the host communities fed upon by blacklegged ticks. In 2006 and 2009, we determined the host community composition based on abundance estimates of the vertebrate hosts, and collected host-seeking nymphal ticks in 2007 and 2010 to determine the ospC genotypes within infected ticks. We regressed instances of B. burgdorferi phenotypes on site-specific characteristics of host communities by constructing Bayesian hierarchical models that properly handled missing data. The models provided quantitative support for the relevance of host composition on Lyme disease risk pertaining to B. burgdorferi prevalence (i.e., overall nymphal infection prevalence, or NIPAll) and HIS prevalence among the infected ticks (NIPHIS). In 2006, we found positive associations of the relative abundances of mice, of chipmunks, and of shrews with NIPAll. We also found positive associations of NIPHIS with shrews, and with host community diversity (H’), but negative associations with mice, and with chipmunks. In 2009, the relative abundance of mice showed a positive association with NIPAll, whereas the relative abundance of shrews and of H’ showed a negative association. With NIPHIS, only H’ showed a positive association, whereas the relative abundances of mice, of chipmunks, and of shrews, had negative associations. Our study highlights the variability between two years in the effects of host composition on B. burgdorferi genotypes. More importantly, our results highlight how disease risk inference, based on the role of host community, changes when we examine risk overall or at the phenotypic level. Long-term studies will be necessary to detect any consistent effects of host community composition on genotypic variation in the Lyme disease spirochetes
Toward a Methodology for Evaluating DNA Variants in Nuclear Families
No full textThe genetic underpinnings of most pediatric-cancer cases are unknown. Population-based studies use large sample sizes but have accounted for only a small proportion of the estimated heritability of pediatric cancers. Pedigree-based studies are infeasible for most human populations. One alternative is to collect genetic data from a single nuclear family and use inheritance patterns within the family to filter candidate variants. This approach can be applied to common and rare variants, including those that are private to a given family or to an affected individual. We evaluated this approach using genetic data from three nuclear families with 5, 4, and 7 children, respectively. Only one child in each nuclear family had been diagnosed with cancer, and neither parent had been affected. Diagnoses for the affected children were benign low-grade astrocytoma, Wilms tumor (stage 2), and Burkitt’s lymphoma, respectively. We used whole-genome sequencing to profile normal cells from each family member and a linked-read technology for genomic phasing. For initial variant filtering, we used global minor allele frequencies, deleteriousness scores, and functional-impact annotations. Next, we used genetic variation in the unaffected siblings as a guide to filter the remaining variants. As a way to evaluate our ability to detect variant(s) that may be relevant to disease status, the corresponding author blinded the primary author to affected status; the primary author then assigned a risk score to each child. Based on this evidence, the primary author predicted which child had been affected in each family. The primary author’s prediction was correct for the child who had been diagnosed with a Wilms tumor; the child with Burkitt’s lymphoma had the second-highest risk score among the seven children in that family. This study demonstrates a methodology for filtering and evaluating candidate genomic variants and genes within nuclear families that may merit further exploration
Untersuchung von Finanzierungs- und Nachfolgeentscheidungen in kleinen und mittelständischen Unternehmen
No full textSmall and medium sized Enterprises (SMEs) possess central significance for the economic and the social unfolding of societies (Acs, Desai, & Hessels, 2008; Garrigós Simón, González-Cruz, & Contreras-Pacheco, 2017). These organizations are not just miniature versions of larger companies, but occupy a special and unique nature (Cressy & Olofsson, 1997; Loecher, 2000). Young and established SMEs are facing vulnerable moments within their life cycle stages, which potentially may end the organization’s existence (e.g., Block, Colombo, Cumming, & Vismara, 2018; Le Breton-Miller, Miller, & Steier, 2004). Given the importance of SMEs, research regards the continous progression of novel solutions as vital (e.g., Block, Groh, Hornuf, Vanacker, & Vismara, 2021; Daspit, Holt, Chrisman, & Long, 2016). This thesis therefore provides an overview and new impulses for vulnerable life cycle stages of young and established SMEsKleine und mittlere Unternehmen (KMUs) besitzen eine zentrale Bedeutung für die wirtschaftliche und soziale Entfaltungskraft von Gesellschaften (Acs et al., 2008; Garrigós Simón et al., 2017). Diese Organisationen sind nicht nur Miniaturversionen größerer Unternehmen, sondern weisen einen besonderen und einzigartigen Charakter auf (Cressy & Olofsson, 1997; Loecher, 2000). Junge und etablierte KMUs sind in ihren Lebenszyklusphasen mit Schwachstellen kon-frontiert, die möglicherweise das Ende der Organisation bedeuten können (z. B. Block, Colombo, et al., 2018; Le Breton-Miller et al., 2004). Angesichts der Bedeutung von KMUs erachtet die Forschung die kontinuierliche Weiterentwicklung neuer Lösungen als essentiell (z. B. Block et al., 2021; Daspit et al., 2016). Die vorliegende Arbeit bietet daher einen Überblick und neue Impulse für anfällige Lebenszyklusphasen von jungen und etablierten KMU
Porosity block mapping of the Lower Permian San Andres Formation, Cochran and Yoakum counties, TX
No full textThe San Andres Formation is one of the most prolific hydrocarbon producers in the Permian Basin. In 2009, horizontal development of the San Andres in Yoakum County, Texas began with the idea that there is a large amount residual oil (ROZ) that is still producible. While some operators in Yoakum County had mixed success with reservoir development strategies others seemingly drill at random wherever their acreage will allow. Since 2017, a team of researchers at Texas Tech Department of Petroleum Engineering has overseen an industry consortium tasked with developing a deeper understanding of San Andres reservoir characterization primarily in two areas of the county. These two areas include the County Line area and the Bronco area. The objective of this study will be to determine and understand where better potential reservoirs are located within these two areas for future drilling.
Research centered on porosity block mapping techniques in four sequential phases. The initial phase was to obtain the availability of resistivity and porosity digital logs to determine availability and coverage in Yoakum County. Attribute mapping of this data allowed an area of investigation to be defined as well as identify the need for any additional log data. Once established, the regionally correlatable Manzano marker was correlated across all study wells and defined as the upper boundary for block mapping. A deeper correlatable marker was identified and defined as the lower boundary. Initial focus will be to use 10-ft subintervals of equal thickness “top-down” blocking method. Average porosity was calculated for each subinterval, or “block,” and mapped using Petra Software. The final phase of this study entails comparing the results of porosity block mapping against other techniques utilized by the industry consortium to note any visible similarities and anomalies.
This study will assist in future streamlined development in the San Andres Formation. Ideally, the techniques developed with this research will help operators identify where better wells might be drilled. It is also worth noting that the methodology can be applied to any formation property aside from porosity. Because the San Andres is such a complex reservoir, there is a possibility that this method may not prove useful to this particular reservoir, but can still be applicable to other formations in other basins
A Survey of Compound Heterozygous Variants in Pediatric Cancers and Structural Birth Defects
No full textCompound heterozygous (CH) variants occur when two recessive alleles are inherited and the variants are located at different loci within the same gene in a given individual. CH variants are important contributors to many different types of recessively inherited diseases. However, many studies overlook CH variants because identification of this type of variant requires knowing the parent of origin for each nucleotide. Using computational methods, haplotypes can be inferred using a process called “phasing,” which estimates the chromosomal origin of most nucleotides. In this paper, we used germline, phased, whole-genome sequencing (WGS) data to identify CH variants across seven pediatric diseases (adolescent idiopathic scoliosis: n = 16, congenital heart defects: n = 709, disorders of sex development: n = 79, ewing sarcoma: n = 287, neuroblastoma: n = 259, orofacial cleft: n = 107, and syndromic cranial dysinnervation: n = 172), available as parent-child trios in the Gabriella Miller Kids First Data Resource Center. Relatively little is understood about the genetic underpinnings of these diseases. We classified CH variants as “potentially damaging” based on minor allele frequencies (MAF), Combined Annotation Dependent Depletion scores, variant impact on transcription or translation, and gene-level frequencies in the disease group compared to a healthy population. For comparison, we also identified homozygous alternate (HA) variants, which affect both gene copies at a single locus; HA variants represent an alternative mechanism of recessive disease development and do not require phasing. Across all diseases, 2.6% of the samples had a potentially damaging CH variant and 16.2% had a potentially damaging HA variant. Of these samples with potentially damaging variants, the average number of genes per sample was 1 with a CH variant and 1.25 with a HA variant. Across all samples, 5.1 genes per disease had a CH variant, while 35.6 genes per disease had a HA variant; on average, only 4.3% of these variants affected common genes. Therefore, when seeking to identify potentially damaging variants of a putatively recessive disease, CH variants should be considered as potential contributors to disease development. If CH variants are excluded from analysis, important candidate genes may be overlooked
Using Phased Whole Genome Sequence Data to Better Understand the Role of Compound-Heterozygous Variants in Pediatric Diseases
No full textA compound-heterozygous variant occurs when a child inherits a variant from each parent, with these variants occurring at a different position within the same gene and on opposite homologous chromosomes. These inherited variants may result in two nonfunctional versions of the same gene. Compound-heterozygous variants cannot be identified unless a patients\u27 DNA sequence data is phased. Phasing is a computationally demanding process that requires the use of multiple software tools in order to determine which nucleotide was inherited from which parent. First, in Chapter 1, we review the literature to better understand what research has been conducted on the role of compound-heterozygous variants in pediatric cancers and what methods are being used to identify them. In Chapter 2, we develop a pipeline to make it easier for us and other researchers to phase and identify compound-heterozygous variants using VCF files from trios or individuals. We then use this pipeline in Chapter 3 to survey the prevalence of compound-heterozygous variants across 7 pediatric disease types. We show the importance of identifying compound heterozygous and what information would be missed if this variant type was not included in study design. In Chapter 4, we develop a software tool to phase trio data using a combination of Mendelian inheritance logic and an existing phasing software program. We show that our software tool increases the total number of variants that can be phased. Finally, in Chapter 5, we use phased data of three nuclear families, each family having one child with pediatric cancer, to evaluate the potential to use inherited genomic variants to inform diagnostic decisions. The work contained within this dissertation shows the importance of not overlooking compound-heterozygous variants when trying to identify potentially causal genes in pediatric disease. In addition, this work provides software tools that are openly available for other researchers to use; these tools make it easier to phase patient DNA sequence data and to identify compound-heterozygous variants
Morphology of mitochondria and cell respiration,pt.1.
No full textTo reveal the mechanism of liver damage by taking CCl4 the author observed the liver tissues from rats at 1.5, 5, 6, 10, 17, 20, and 22 hours after the CCl4 administration, both by light microscope and electron-microscope. 1. Light microscope observation revealed the swelling of liver cells in the carly stage, the appearance of centrolobular fatty degeneration, focal degeneration area and the appearance of balloon cells, with the circulatory disturbances in accompanying stages and hemorrhage in the later stage. 2. Electron-microscope observation revealed the swelling of mitochondria, appearance of the files of thin ER's in the early stage and the regeneration and degeneration of mitochondria with an increase of microbodies in number. Fat droplets are developed from small ones probably from some microbodies without correlation with mitochondria. 3. From these observations the author is of the opinion that CCl4 arrests the cells at first inducing the swelling of cells and their mitochondria, but later the degenerative changes will become severe being complicated by the anoxia which is induced by the circulatory disturbances caused by the compression of vessels with the swollen cells.</p
Search for new resonances decaying to a or boson and a Higgs boson in the , , and channels with collisions at TeV with the ATLAS detector
No full textSee paper for full list of authors, 18 pages (plus author list + cover pages: 36 pages total), 13 figures, 1 table. Submitted to PLB. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/EXOT-2015-18/International audienceA search is presented for new resonances decaying to a or boson and a Higgs boson in the , , and channels in collisions at TeV with the ATLAS detector at the Large Hadron Collider using a total integrated luminosity of 3.2 fb. The search is conducted by looking for a localized excess in the / invariant or transverse mass distribution. No significant excess is observed, and the results are interpreted in terms of constraints on a simplified model based on a phenomenological Lagrangian of heavy vector triplets
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