Identification of SNPs Associated with Variola Virus Virulence

Background: Decades after the eradication of smallpox, its etiological agent, variola virus (VARV), remains a threat as a potential bioweapon. Outbreaks of smallpox around the time of the global eradication effort exhibited variable case fatality rates (CFRs), likely attributable in part to complex viral genetic determinants of smallpox virulence. We aimed to identify genome-wide single nucleotide polymorphisms associated with CFR. We evaluated unadjusted and outbreak geographic location-adjusted models of single SNPs and two- and three-way interactions between SNPs. Findings: Using the data mining approach multifactor dimensionality reduction (MDR), we identified five VARV SNPs in models significantly associated with CFR. The topper forming unadjusted model and adjusted models both revealed the same two-way gene-gene interaction. We discuss the biological plausibility of the influence of the SNPs identified these and other significant models on the strain-specific virulence of VARV. Conclusions: We have identified genetic loci in the VARV genome that are statistically associated with VARV virulence as measured by CFR. While our ability to infer a causal relationship between the specific SNPs identified in our analysis and VARV virulence is limited, our results suggest that smallpox severity is in part associated with VARV strain variation and that VARV virulence may be determined by multiple genetic loci. This study represents the first application of MDR to the identification of pathogen gene-gene interactions for predicting infectious disease outbreak severity

PERFORMANCE ASSESSMENT OF GAS TURBINE DRIVEN CENTRIFUGAL COMPRESSOR TRAINS DERIVED FROM FIELD TESTING

LectureField testing of gas turbine driven centrifugal compressor units at operational production facilities can provide valuable information about the condition of the equipment. In this paper, a case study is presented based on field testing performed on the compressors and gas turbine drivers of six units at a gas compression station. Since the compression units at this station are two sets of three identical machines, this case provides a unique opportunity to study both the advantages and some of the challenges inherent in this type of testing. For the compressors, comparisons are presented of the measured values of head rise, required power, and thermodynamic efficiency. For the gas turbines, performance comparisons are presented in terms of delivered power and heat rate. Calculations of the effects of ambient temperature on power and heat rate of the gas turbines are also presented. Some of the challenges of field testing are addressed, with the effects of fluctuations in gas composition on the experimental uncertainty in the measured performance treated in some detail. The topic of how field testing can help to identify degradation of the capability of compressors and gas turbines is also addressed. It is also shown how models derived from the performance tests can be used to forecast when factors such as high ambient temperatures and changes in the composition of the process gas can create situations where the compression units may not be able to deliver the gas flow rates and pressure levels required by the process

PERFORMANCE ASSESSMENT OF GAS TURBINE DRIVEN CENTRIFUGAL COMPRESSOR TRAINS DERIVED FROM FIELD TESTING

LectureField testing of gas turbine driven centrifugal compressor units at operational production facilities can provide valuable information about the condition of the equipment. In this paper, a case study is presented based on field testing performed on the compressors and gas turbine drivers of six units at a gas compression station. Since the compression units at this station are two sets of three identical machines, this case provides a unique opportunity to study both the advantages and some of the challenges inherent in this type of testing. For the compressors, comparisons are presented of the measured values of head rise, required power, and thermodynamic efficiency. For the gas turbines, performance comparisons are presented in terms of delivered power and heat rate. Calculations of the effects of ambient temperature on power and heat rate of the gas turbines are also presented. Some of the challenges of field testing are addressed, with the effects of fluctuations in gas composition on the experimental uncertainty in the measured performance treated in some detail. The topic of how field testing can help to identify degradation of the capability of compressors and gas turbines is also addressed. It is also shown how models derived from the performance tests can be used to forecast when factors such as high ambient temperatures and changes in the composition of the process gas can create situations where the compression units may not be able to deliver the gas flow rates and pressure levels required by the process

Intersection of methamphetamine overdoses and violent crime in the United States and Oklahoma

Background: Systemic violence is associated with drug markets and is an outcome of traditionally aggressive patterns of interactions within the system of drug distribution and use. Increasing methamphetamine availability and use is a societal problem due to the association with violence. One longitudinal birth cohort study found that persons using methamphetamine had a 1.6 increased odds of violence perpetration, including intimate partner violence. Current data associating methamphetamine use and violent crimes, independently, with rural communities requires a more indepth analysis. Thus, our primary objective was to quantify and classify the relationship between methamphetamine use and violent crime and map the intersection across the US at the county level.Methods: Using the data extracted from Federal Bureau of Investigation’s National Incident Based Reporting System (NIBRS), CDC’s Wide-ranging Online Data for Epidemiological Research (WONDER), and the Oklahoma State’s Court Network (OSCN) we estimated the ratio among crude rates of methamphetamine related deaths and violent crimes per 1,000 people at the county level. Drug related violent crimes include rape and sexual assault, robbery, physical assault, and murder that occur with drug use. Heat Maps were created in R 3.6.1 to display the data and identify areas of concern. Regression analysis and correlation coefficients were used to determine the relationship between methamphetamine overdoses and violent crimes adjusted for upstream factors of unemployment and urbanicity.Results: Using NIBRS (national) crime statistics and overdose deaths from WONDER in 2019, we found a statistically significant positive relationship between methamphetamine overdoses and violent crimes (Coeff = 4.64, SE: 0.58, P = < 0.001) when controlling for unemployment (-41.68, 5.83, < 0.001) and urbanicity (-105.00, 19.42, < 0.001), which had an inverse relationship. Using OSCN data for the state of Oklahoma, total violent crime was not significantly associated with methamphetamine overdose deaths, however, association was found with criminal filings of methamphetamine possession (0.64, 0.07, < 0.001), unemployment (60.39, 9.51, < 0.001) and urbanicity (70.51, 21.84, 0.001).Conclusion: In this study, our data analysis builds upon the existing literature by revealing a positive relationship between methamphetamine use and violent crime. Furthermore, demographic data including employment status and urbanicity provides a more in-depth understanding of the sociogeographical variation in methamphetamine use and violent crime. Identifying the communities most affected by the adverse associations of methamphetamine has potential for wide-ranging effects, from improving awareness within the medical community and guiding public health initiatives to prioritizing funding. In a largely rural, low-income, and healthcare provider limited state, such as Oklahoma, gaining the combined understanding of critical issues with their geographical impact could empower positive change in the most critically impacted communities

Depression and family support in breast cancer patients

MTS, migration and invasion assays in DCIS.COM cells that were previously transduced with scrambled control (Control) or BCL9 KD shRNA. The control cells and BCL9 KD cells were re-transduced with empty vector (EV), BCL9 overexpression (BCL9-OE) and BCL9 KD. BCL9-OE was achieved by transduction using the PCDH-BCL9 (BCL9-OE) acquired from Dr. Carrasco [11]. A Western blot analysis was performed using anti-BCL9, anti-vimentin, anti-E-cadherin antibodies, and anti-β-actin as a loading control. B MTS assay on control cells transduced with EV (control + EV), or BCL9-OE (control + BCL9-OE), BCL9-KD transduced with EV (BCL9 KD + EV), and BCL9-KD transduced with BCL9-OE (BCL9 KD + BCL9-OE). Bar graphs represent mean absorbance at 490 nm normalized to control ± standard error of the mean (SEM) (n = 6). C, D Representative images of the migration and invasion assays. Bar graph represents percent area of cells migrated (left) and invaded (right) under the membrane after 24 h. Invasion and migration were determined by ImageJ analysis of microscopic images per sample, the data are mean values normalized to control ± SEM (n = 3). E TopFlash and FopFlash reporter activity in DCIS.COM transduced as above that were either treated with Wnt3A or control conditioned medium (CM). Data represent mean ± SEM (n = 3, letters indicate statistically significant difference). (PDF 964 kb

Expression profiling of in vivo ductal carcinoma in situ progression models identified B cell lymphoma-9 as a molecular driver of breast cancer invasion

Abstract Introduction There are an estimated 60,000 new cases of ductal carcinoma in situ (DCIS) each year. A lack of understanding in DCIS pathobiology has led to overtreatment of more than half of patients. We profiled the temporal molecular changes during DCIS transition to invasive ductal carcinoma (IDC) using in vivo DCIS progression models. These studies identified B cell lymphoma-9 (BCL9) as a potential molecular driver of early invasion. BCL9 is a newly found co-activator of Wnt-stimulated β-catenin-mediated transcription. BCL9 has been shown to promote progression of multiple myeloma and colon carcinoma. However BCL9 role in breast cancer had not been previously recognized. Methods Microarray and RNA sequencing were utilized to characterize the sequential changes in mRNA expression during DCIS invasive transition. BCL9-shRNA knockdown was performed to assess the role of BCL9 in in vivo invasion, epithelial-mesenchymal transition (EMT) and canonical Wnt-signaling. Immunofluorescence of 28 patient samples was used to assess a correlation between the expression of BCL9 and biomarkers of high risk DCIS. The cancer genome atlas data were analyzed to assess the status of BCL9 gene alterations in breast cancers. Results Analysis of BCL9, by RNA and protein showed BCL9 up-regulation to be associated with DCIS transition to IDC. Analysis of patient DCIS revealed a significant correlation between high nuclear BCL9 and pathologic characteristics associated with DCIS recurrence: Estrogen receptor (ER) and progesterone receptor (PR) negative, high nuclear grade, and high human epidermal growth factor receptor2 (HER2). In vivo silencing of BCL9 resulted in the inhibition of DCIS invasion and reversal of EMT. Analysis of the TCGA data showed BCL9 to be altered in 26 % of breast cancers. This is a significant alteration when compared to HER2 (ERBB2) gene (19 %) and estrogen receptor (ESR1) gene (8 %). A significantly higher proportion of basal like invasive breast cancers compared to luminal breast cancers showed BCL9 amplification. Conclusion BCL9 is a molecular driver of DCIS invasive progression and may predispose to the development of basal like invasive breast cancers. As such, BCL9 has the potential to serve as a biomarker of high risk DCIS and as a therapeutic target for prevention of IDC

Chromatin Organization in Sperm May Be the Major Functional Consequence of Base Composition Variation in the Human Genome

Chromatin in sperm is different from that in other cells, with most of the genome packaged by protamines not nucleosomes. Nucleosomes are, however, retained at some genomic sites, where they have the potential to transmit paternal epigenetic information. It is not understood how this retention is specified. Here we show that base composition is the major determinant of nucleosome retention in human sperm, predicting retention very well in both genic and non-genic regions of the genome. The retention of nucleosomes at GC-rich sequences with high intrinsic nucleosome affinity accounts for the previously reported retention at transcription start sites and at genes that regulate development. It also means that nucleosomes are retained at the start sites of most housekeeping genes. We also report a striking link between the retention of nucleosomes in sperm and the establishment of DNA methylation-free regions in the early embryo. Taken together, this suggests that paternal nucleosome transmission may facilitate robust gene regulation in the early embryo. We propose that chromatin organization in the male germline, rather than in somatic cells, is the major functional consequence of fine-scale base composition variation in the human genome. The selective pressure driving base composition evolution in mammals could, therefore, be the need to transmit paternal epigenetic information to the zygote

Late Cretaceous UHP metamorphism recorded in kyanite-garnet schists from the Central Rhodope Mountains, Bulgaria.

In this study, we report the first discovery of microdiamond inclusions in kyanite–garnet schists from the Central Rhodope Mountains in Bulgaria. These inclusions occur in garnets from metapelites that are part of a meta-igneous and meta-sedimentary mélange hosted by Variscan (Hercynian) orthogneiss. Ultra-high-pressure (UHP) conditions are further supported by the presence of exsolved needles of quartz and rutile in the garnet and by geothermobarometry estimates that suggest peak metamorphic temperatures of 750–800 °C and pressures in excess of 4 GPa. The discovery of UHP conditions in the Central Rhodopes of Bulgaria compliments the well-documented evidence for such conditions in the southernmost (Greek) part of the Rhodope Massif. Dating of garnets from these UHP metapelites (Chepelare Shear Zone) using Sm–Nd geochronology indicates a Late Cretaceous age (70.5–92.7 Ma) for the UHP metamorphic event. This is significantly younger than previously reported ages and suggests that the UHP conditions are associated with the Late Mesozoic subduction of the Vardar Ocean northward beneath the Moesian platform (Europe). The present-day structure of the RM is the result of a series of subduction–exhumation events that span the Cenozoic, alongside subsequent post-orogenic extension and metamorphic core complex formation

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Bilateral Diffuse Tumorous Pseudoangiomatous Stromal Hyperplasia: A Case of Bilateral Mastectomy in a 29-Year-Old Woman

Pseudoangiomatous stromal hyperplasia (PASH) is a benign breast lesion commonly encountered as an incidental microscopic finding. However, it can also manifest as a mass-forming lesion (tumorous PASH) capable of recurrence after surgical excision. Most of the previously reported cases of tumorous PASH present as a single dominant mass. Here we reported a rare case of diffuse tumorous PASH involving bilateral breasts clinically mimicking malignancy. A 29-year-old African-American female presented with a one-year history of bilateral breast enlargement and asymmetry. Physical examination revealed multiple palpable nodules in bilateral breasts. Imaging studies demonstrated innumerable homogeneously enhancing masses throughout both breasts, greater on the left, with multiple cysts and edema. Biopsy of the breast nodules demonstrated histopathological changes consistent with PASH. Due to the extent of the lesions and progressive clinical symptoms, decision was made to perform bilateral mastectomy. Macroscopic examination of the bilateral mastectomy specimens revealed markedly enlarged breasts with marked edema and numerous well-defined firm nodules. Microscopic evaluation of the nodules confirmed the diagnosis of PASH. No evidence of malignancy was identified. Recognition of this rare form of PASH is essential for the proper clinical management