Correlation between biomarkers of exposure, effect and potential harm in the urine of electronic cigarette users.

ObjectivesTo determine if urinary biomarkers of effect and potential harm are elevated in electronic cigarette users compared with non-smokers and if elevation correlates with increased concentrations of metals in urine.Study design and settingThis was a cross-sectional study of biomarkers of exposure, effect and potential harm in urine from non-smokers (n=20), electronic cigarette users (n=20) and cigarette smokers (n=13). Participant's screening and urine collection were performed at the Roswell Park Comprehensive Cancer Center, and biomarker analysis and metal analysis were performed at the University of California, Riverside.ResultsMetallothionein was significantly elevated in the electronic cigarette group (3761±3932 pg/mg) compared with the non-smokers (1129±1294 pg/mg, p=0.05). 8-OHdG (8-hydroxy-2'-deoxyguanosine) was significantly elevated in electronic cigarette users (442.8±300.7 ng/mg) versus non-smokers (221.6±157.8 ng/mg, p=0.01). 8-Isoprostane showed a significant increase in electronic cigarette users (750.8±433 pg/mg) versus non-smokers (411.2±287.4 pg/mg, p=0.03). Linear regression analysis in the electronic cigarette group showed a significant correlation between cotinine and total metal concentration; total metal concentration and metallothionein; cotinine and oxidative DNA damage; and total metal concentration and oxidative DNA damage. Zinc was significantly elevated in the electronic cigarette users (584.5±826.6 µg/g) compared with non-smokers (413.6±233.7 µg/g, p=0.03). Linear regression analysis showed a significant correlation between urinary zinc concentration and 8-OHdG in the electronic cigarette users.ConclusionsThis study is the first to investigate biomarkers of potential harm and effect in electronic cigarette users and to show a linkage to metal exposure. The biomarker levels in electronic cigarette users were similar to (and not lower than) cigarette smokers. In electronic cigarette users, there was a link to elevated total metal exposure and oxidative DNA damage. Specifically, our results demonstrate that zinc concentration was correlated to oxidative DNA damage

Examining the Entrepreneurial Intentions of U.S. Ethnic Minorities During the Covid-19 Pandemic

We examine minority entrepreneurial intentions in the U.S. and seek to make business leaders and business educators aware of minority students’ interest in entrepreneurship activity. Utilizing the theory of planned behavior, we investigated if demographic and behavioral factors are related to entrepreneurial intentions. A major contextual factor was that we performed our research during the COVID-19 pandemic. We surveyed the entrepreneurial intentions of 400 U.S. business college students, comparing minority respondents (n=137) with white respondents (n=263). The minority respondents belonged to the three predominant minority entrepreneur groups in the U.S. -- African Americans, Hispanic Americans, and Asian Americans. Minority respondents had significantly greater entrepreneurial intentions than their white counterparts. We investigated contextual factors affecting minority entrepreneurial intentions and found that a significant difference existed regarding the influence of the COVID-19 pandemic in that it counter-intuitively increased minority entrepreneurial intentions. Significant personal factors included having family members who own a business and having a role model

Über Long-Tails, Mikroarrays, und Markersets: Integrative wissenschaftliche Ansätze in funktioneller Genomik, Populationsgenetik und genetischer Epidemiologie

The work in the three presented articles provides several demonstrations of how an integrative approach to scientific research has led to a better understand of biological phenomena. The first article incorporates research from the overlapping fields of biotechnology, functional genomics, and bioinformatics. The study's objective is to describe the nature of the distribution of gene expression levels measured with microarrays with the aim of developing an inter-array normalization method. The normalization method is compared to other existing normalization methods and is found to be especially suited to so-called boutique microarrays. The second article uses genotyping data generated by microarrays with the goal of examining the population genetic structure of the European human population. This study combines aspects of the fields of biotechnology, bioinformatics, and population genetics and sheds light on the genetic differences between Europeans by characterizing a strong correlation between geographic and genetic distance. In the final article, focus switches from genetic differences to genetic similarities in the same European individuals by examining the relationship structure of genetic nearest neighbors. Observations about these relationships lead to the proposal of a genetic matched-pair study design that contributes a methodological improvement to the field of genetic epidemiology. The proposed study design has the potential to increase the power of analysis of genome-wide association studies which are used to discover disease-causing genes. A presentation of previously unpublished research which was generated during the course of the work is also included. Finally, a discussion of long-tail data distributions initially observed in the first article leads to conclusions on the fundamental properties of the informational content of genetic marker sets ascertained in the last two articles.Die Arbeiten, die in den drei vorliegenden Artikeln präsentiert werden, zeigen, wie ein integrativer wissenschaftlicher Ansatz zu einem besseren Verständnis biologischer Phänomene führt. Der erste Artikel verknüpft Forschung aus den sich überlappenden Fachgebieten Biotechnologie, funktionelle Genomik und Bioinformatik. Das Ziel der Studie war es, mittels Mikroarrays die Verteilungsform der Genexpressionsniveaus zu bestimmen, um eine Normalisierungsmethode zu entwickeln. Diese Normalisierungsmethode wurde mit anderen bereits bekannten Normalisierungsmethoden verglichen und sie erwies sich als besonders geeignet für sogenannte Boutique-Mikroarrays. Der zweite Artikel verfolgt das Ziel, mit Hilfe von humanen Genotypisierungsdaten aus Mikroarrays die populationsgenetische Struktur der europäischen Population zu charakterisieren. Diese Studie verbindet Aspekte der Forschungsgebiete Biotechnologie, Bioinformatik und Populationsgenetik und gibt damit Aufschluss über die Muster genetischer Unterschiede zwischen Europäern: Es konnte eine hohe Korrelation zwischen geographischen und genetischen Distanzen gezeigt werden. Der letzte Artikel richtet den Blick auf die genetischen Gemeinsamkeiten der selben europäischen Individuen, indem er die Verwandtschaftsstruktur mittels eines genetischen "nearest neighbors"-Algorithmus untersucht. Die beobachteten Verwandtschaftsstrukturen führen zum Vorschlag eines genetischen Matched-Pair-Studiendesigns, das auf dem Gebiet der genetischen Epidemiologie eine erhebliche methodische Verbesserung darstellt. Das vorgeschlagene Studiendesign kann die Aussagekraft der statistischen Analysen bei Genom-weiten Assoziationsstudien erhöhen, also bei Studien, die durchgeführt werden, um krankheitsverursachende Gene zu identifizieren. Darüber hinaus werden bisher unveröffentlichte Forschungsergebnisse vorgestellt, die im Zusammenhang mit den obigen Studien gewonnen wurden. Eine abschließende Diskussion der Long-Tailed-Verteilung der Daten, die zunächst in der ersten Studie beobachtet wurde, führt zu Schlussfolgerungen über die grundlegenden Eigenschaften des Informationsgehaltes genetischer Markersets, welche nachfolgend in den letzten beiden Studien bestätigt wurden

Spinal Projection Neurons Control Turning Behaviors in Zebrafish

SummaryDiscrete populations of brainstem spinal projection neurons (SPNs) have been shown to exhibit behavior-specific responses during locomotion [1–9], suggesting that separate descending pathways, each dedicated to a specific behavior, control locomotion. In an alternative model, a large variety of motor outputs could be generated from different combinations of a small number of basic motor pathways. We examined this possibility by studying the precise role of ventromedially located hindbrain SPNs (vSPNs) in generating turning behaviors. We found that unilateral laser ablation of vSPNs reduces the tail deflection and cycle period specifically during the first undulation cycle of a swim bout, whereas later tail movements are unaffected. This holds true during phototaxic [10], optomotor [11], dark-flash-induced [12], and spontaneous turns [13], suggesting a universal role of these neurons in controlling turning behaviors. Importantly, we found that the ablation not only abolishes turns but also results in a dramatic increase in the number of forward swims, suggesting that these neurons transform forward swims into turns by introducing turning kinematics into a basic motor pattern of symmetric tail undulations. Finally, we show that vSPN activity is direction specific and graded by turning angle. Together, these results provide a clear example of how a specific motor pattern can be transformed into different behavioral events by the graded activation of a small set of SPNs

Analyzing Learned Molecular Representations for Property Prediction

Advancements in neural machinery have led to a wide range of algorithmic solutions for molecular property prediction. Two classes of models in particular have yielded promising results: neural networks applied to computed molecular fingerprints or expert-crafted descriptors, and graph convolutional neural networks that construct a learned molecular representation by operating on the graph structure of the molecule. However, recent literature has yet to clearly determine which of these two methods is superior when generalizing to new chemical space. Furthermore, prior research has rarely examined these new models in industry research settings in comparison to existing employed models. In this paper, we benchmark models extensively on 19 public and 16 proprietary industrial datasets spanning a wide variety of chemical endpoints. In addition, we introduce a graph convolutional model that consistently matches or outperforms models using fixed molecular descriptors as well as previous graph neural architectures on both public and proprietary datasets. Our empirical findings indicate that while approaches based on these representations have yet to reach the level of experimental reproducibility, our proposed model nevertheless offers significant improvements over models currently used in industrial workflows

Construction of a series of vectors for high throughput cloning and expression screening of membrane proteins from Mycobacterium tuberculosis

<p>Abstract</p> <p>Background</p> <p>One of the major challenges for membrane protein structural genomics is establishing high-throughput cloning and expression screening methods to obtain enough purified protein in a homogeneous preparation for structural and functional studies. Here a series of ligation independent cloning based vectors were constructed to address this challenge.</p> <p>Results</p> <p>The feasibility of these vectors was tested with 41 putative membrane proteins from <it>Mycobacterium tuberculosis</it>. The efficiency for direct cloning of these target genes from PCR products was 95% (39/41). Over 40% of cloned genes were overexpressed in <it>Escherichia coli </it>BL21 (DE3)-RP codon plus strain in the first round of expression screening. For those proteins which showed no expression, three protein fusion partners were prepared and it was found that each of the target proteins could be overexpressed by at least one of these fusions, resulting in the overexpression of two thirds of the cloned genes.</p> <p>Conclusion</p> <p>This expression platform features high throughput cloning, high flexibility for different constructs, and high efficiency for membrane protein overexpression, and is expected to be useful in membrane protein structural and functional studies.</p

Three-dimensional Structure of Victorivirus HvV190S Suggests Coat Proteins in Most Totiviruses Share a Conserved Core

Double-stranded (ds)RNA fungal viruses are currently assigned to six different families. Those from the family Totiviridae are characterized by nonsegmented genomes and single-layer capsids, 300–450 Å in diameter. Helminthosporium victoriae virus 190S (HvV190S), prototype of recently recognized genus Victorivirus, infects the filamentous fungus Helminthosporium victoriae (telomorph: Cochliobolus victoriae), which is the causal agent of Victoria blight of oats. The HvV190S genome is 5179 bp long and encompasses two large, slightly overlapping open reading frames that encode the coat protein (CP, 772 aa) and the RNA-dependent RNA polymerase (RdRp, 835 aa). To our present knowledge, victoriviruses uniquely express their RdRps via a coupled termination–reinitiation mechanism that differs from the well-characterized Saccharomyces cerevisiae virus L-A (ScV-L-A, prototype of genus Totivirus), in which the RdRp is expressed as a CP/RdRp fusion protein due to ribosomal frameshifting. Here, we used transmission electron cryomicroscopy and three-dimensional image reconstruction to determine the structures of HvV190S virions and two types of virus-like particles (capsids lacking dsRNA and capsids lacking both dsRNA and RdRp) at estimated resolutions of 7.1, 7.5, and 7.6 Å, respectively. The HvV190S capsid is thin and smooth, and contains 120 copies of CP arranged in a “T = 2” icosahedral lattice characteristic of ScV-L-A and other dsRNA viruses. For aid in our interpretations, we developed and used an iterative segmentation procedure to define the boundaries of the two, chemically identical CP subunits in each asymmetric unit. Both subunits have a similar fold, but one that differs from ScV-L-A in many details except for a core α-helical region that is further predicted to be conserved among many other totiviruses. In particular, we predict the structures of other victoriviruses to be highly similar to HvV190S and the structures of most if not all totiviruses including, Leishmania RNA virus 1, to be similar as well

Identification of IbeR as a Stationary-Phase Regulator in Meningitic Escherichia coli K1 that Carries a Loss-of-Function Mutation in rpoS

IbeR is a regulator present in meningitic Escherichia coli strain E44 that carries a loss-of-function mutation in the stationary-phase (SP) regulatory gene rpoS. In order to determine whether IbeR is an SP regulator in E44, two-dimensional gel electrophoresis and LC-MS were used to compare the proteomes of a noninvasive ibeR deletion mutant BR2 and its parent strain E44 in the SP. Four up-regulated (TufB, GapA, OmpA, AhpC) and three down-regulated (LpdA, TnaA, OpmC) proteins in BR2 were identified when compared to E44. All these proteins contribute to energy metabolism or stress resistance, which is related to SP regulation. One of the down-regulated proteins, tryptophanase (TnaA), which is regulated by RpoS in other E. coli strains, is associated with SP regulation via production of a signal molecule indole. Our studies demonstrated that TnaA was required for E44 invasion, and that indole was able to restore the noninvasive phenotype of the tnaA mutant. The production of indole was significantly reduced in BR2, indicating that ibeR is required for the indole production via tnaA. Survival studies under different stress conditions indicated that IbeR contributed to bacteria stress resistance in the SP. Taken together, IbeR is a novel regulator contributing to the SP regulation

SHCal13 Southern Hemisphere calibration, 0–50,000 years cal BP

The Southern Hemisphere SHCal04 radiocarbon calibration curve has been updated with the addition of new data sets extending measurements to 2145 cal BP and including the ANSTO Younger Dryas Huon pine data set. Outside the range of measured data, the curve is based upon the Northern Hemisphere data sets as presented in IntCal13, with an interhemispheric offset averaging 43 ± 23 yr modeled by an autoregressive process to represent the short-term correlations in the offset