Targeted expression profiling reveals distinct stages of early canine fibroblast reprogramming are regulated by 2-oxoglutarate hydroxylases

Background: Ectopic expression of a defined set of transcription factors allows the reprogramming of mammalian somatic cells to pluripotency. Despite continuous progress in primate and rodent reprogramming, limited attention has been paid to cell reprogramming in domestic and companion species. Previous studies attempting to reprogram canine cells have mostly assessed a small number of presumptive canine induced pluripotent stem cell (iPSC) lines for generic pluripotency attributes. However, why canine cell reprogramming remains extremely inefficient is poorly understood. Methods: To better characterize the initial steps of pluripotency induction in canine somatic cells, we optimized an experimental system where canine fetal fibroblasts (cFFs) are transduced with the Yamanaka reprogramming factors by Sendai virus vectors. We use quantitative PCR arrays to measure the expression of 80 target genes at various stages of canine cell reprogramming. We ask how cFF reprogramming is influenced by small molecules affecting the epigenomic modification 5-hydroxymethylcytosine, specifically L-ascorbic acid and retinoic acid (AA/RA). Results: We found that the expression and catalytic output of a class of 2-oxoglutarate-dependent (2-OG) hydroxylases, known as ten-eleven translocation (TET) enzymes, can be modulated in canine cells treated with AA/RA. We further show that AA/RA treatment induces TET1 expression and facilitates early canine reprogramming, evidenced by upregulation of epithelial and pluripotency markers. Using a chemical inhibitor of 2-OG hydroxylases, we demonstrate that 2-OG hydroxylase activity regulates the expression of a subset of genes involved in mesenchymal-to-epithelial transition (MET) and pluripotency in early canine reprogramming. We identify a set of transcription factors depleted in maturing reprogramming intermediates compared to pluripotent canine embryonic stem cells. Conclusions: Our findings highlight 2-OG hydroxylases have evolutionarily conserved and divergent functions regulating the early reprogramming of canine somatic cells and show reprogramming conditions can be rationally optimized for the generation of maturing canine iPSC

A Census of the High-Density Molecular Gas in M82

We present a three-pointing study of the molecular gas in the starburst nucleus of M82 based on 190 - 307 GHz spectra obtained with Z-Spec at the Caltech Submillimeter Observatory. We present intensity measurements, detections and upper limits, for 20 transitions, including several new detections of CS, HNC, C2H, H2CO, and CH3CCH lines. We combine our measurements with previously-published measurements at other frequencies for HCN, HNC, CS, C34S, and HCO+ in a multi-species likelihood analysis constraining gas mass, density and temperature, and the species' relative abundances. We find some 1.7 - 2.7 x 10^8 M_sun of gas with n_H2 between 1 - 6 x 10^4 cm^-3 and T > 50 K. While the mass and temperature are comparable to values inferred from mid-J CO transitions, the thermal pressure is a factor of 10 - 20 greater. The molecular interstellar medium is largely fragmented and is subject to ultraviolet irradiation from the star clusters. It is also likely subject to cosmic rays and mechanical energy input from the supernovae, and is warmer on average than the molecular gas in the massive star formation regions in the Milky Way. The typical conditions in the dense gas in M82's central kpc appear unfavorable for further star formation; if any appreciable stellar populations are currently forming, they are likely biased against low mass stars, producing a top-heavy initial mass function.Comment: 15 pages (using emulateapj.cls), 6 figures, Astrophysical Journal, in pres

Evaluating Four Inosine-Uridine Preferring Nucleoside Hydrolases in Bacillus Anthracis for Decontamination Strategies

Andrew Roser­ is a doctoral student in the School of Biological Sciences at Louisiana Tech University. Abigail Bass, Sophie Bott, Madison Brewton, Adam Broussard, Taylor Clement, Makenzie Cude, Hunter Currie, Claire Herke, Mary Hickman, Lauren James, Hailey Johnson, Madeline Lechtenberg, Sarah Murchison, Alex Plaisance, Wil Plants, Alex Sullivan, Sara Vandenberg, and Kaitlynn Willis are undergraduate students in the School of Biological Sciences at Louisiana Tech University. Rebecca Giorno is an Associate Professor in the School of Biological Sciences at Louisiana Tech University

Development and implementation of a structured intervention for alcohol use disorders for telephone helpline services

A six-session intervention for harmful alcohol use was piloted via a 24-hour alcohol and other drug (AOD) helpline, assessing feasibility of telephone-delivered treatment. The intervention, involving practice elements from Motivational Interviewing, Cognitive-Behavioral Therapy, and node-link mapping, was evaluated using a case file audit (n D 30) and a structured telephone interview one month after the last session (n D 22). Average scores on the Alcohol Use Disorder Identification Test (AUDIT) dropped by more than 50%, and there were significant reductions in psychological distress. Results suggest that, even among dependent drinkers, a telephone intervention offers effective and efficient treatment for those unable or unwilling to access face-to-face treatment

Etiology of hospital mortality in children living in low- and middle-income countries:a systematic review and meta-analysis

In 2019, 80% of the 7.4 million global child deaths occurred in low- and middle-income countries (LMICs). Global and regional estimates of cause of hospital death and admission in LMIC children are needed to guide global and local priority setting and resource allocation but are currently lacking. The study objective was to estimate global and regional prevalence for common causes of pediatric hospital mortality and admission in LMICs. We performed a systematic review and meta-analysis to identify LMIC observational studies published January 1, 2005-February 26, 2021. Eligible studies included: a general pediatric admission population, a cause of admission or death, and total admissions. We excluded studies with data before 2,000 or without a full text. Two authors independently screened and extracted data. We performed methodological assessment using domains adapted from the Quality in Prognosis Studies tool. Data were pooled using random-effects models where possible. We reported prevalence as a proportion of cause of death or admission per 1,000 admissions with 95% confidence intervals (95% CI). Our search identified 29,637 texts. After duplicate removal and screening, we analyzed 253 studies representing 21.8 million pediatric hospitalizations in 59 LMICs. All-cause pediatric hospital mortality was 4.1% [95% CI 3.4%–4.7%]. The most common causes of mortality (deaths/1,000 admissions) were infectious [12 (95% CI 9–14)]; respiratory [9 (95% CI 5–13)]; and gastrointestinal [9 (95% CI 6–11)]. Common causes of admission (cases/1,000 admissions) were respiratory [255 (95% CI 231–280)]; infectious [214 (95% CI 193–234)]; and gastrointestinal [166 (95% CI 143–190)]. We observed regional variation in estimates. Pediatric hospital mortality remains high in LMICs. Global child health efforts must include measures to reduce hospital mortality including basic emergency and critical care services tailored to the local disease burden. Resources are urgently needed to promote equity in child health research, support researchers, and collect high-quality data in LMICs to further guide priority setting and resource allocation

Toxoplasma Effector MAF1 Mediates Recruitment of Host Mitochondria and Impacts the Host Response

Recent information has revealed the functional diversity and importance of mitochondria in many cellular processes including orchestrating the innate immune response. Intriguingly, several infectious agents, such as Toxoplasma, Legionella, and Chlamydia, have been reported to grow within vacuoles surrounded by host mitochondria. Although many hypotheses have been proposed for the existence of host mitochondrial association (HMA), the causes and biological consequences of HMA have remained unanswered. Here we show that HMA is present in type I and III strains of Toxoplasma but missing in type II strains, both in vitro and in vivo. Analysis of F1 progeny from a type II×III cross revealed that HMA is a Mendelian trait that we could map. We use bioinformatics to select potential candidates and experimentally identify the polymorphic parasite protein involved, mitochondrial association factor 1 (MAF1). We show that introducing the type I (HMA+) MAF1 allele into type II (HMA-) parasites results in conversion to HMA+ and deletion of MAF1 in type I parasites results in a loss of HMA. We observe that the loss and gain of HMA are associated with alterations in the transcription of host cell immune genes and the in vivo cytokine response during murine infection. Lastly, we use exogenous expression of MAF1 to show that it binds host mitochondria and thus MAF1 is the parasite protein directly responsible for HMA. Our findings suggest that association with host mitochondria may represent a novel means by which Toxoplasma tachyzoites manipulate the host. The existence of naturally occurring HMA+ and HMA- strains of Toxoplasma, Legionella, and Chlamydia indicates the existence of evolutionary niches where HMA is either advantageous or disadvantageous, likely reflecting tradeoffs in metabolism, immune regulation, and other functions of mitochondria. © 2014 Pernas et al

A General Model for the CO-H2 Conversion Factor in Galaxies with Applications to the Star Formation Law

The most common means of converting an observed CO line intensity into a molecular gas mass requires the use of a conversion factor (Xco). While in the Milky Way this quantity does not appear to vary significantly, there is good reason to believe that Xco will depend on the larger-scale galactic environment. Utilising numerical models, we investigate how varying metallicities, gas temperatures and velocity dispersions in galaxies impact the way CO line emission traces the underlying H2 gas mass, and under what circumstances Xco may differ from the Galactic mean value. We find that, due to the combined effects of increased gas temperature and velocity dispersion, Xco is depressed below the Galactic mean in high surface density environments such as ULIRGs. In contrast, in low metallicity environments, Xco tends to be higher than in the Milky Way, due to photodissociation of CO in metal-poor clouds. At higher redshifts, gas-rich discs may have gravitationally unstable clumps which are warm (due to increased star formation) and have elevated velocity dispersions. These discs tend to have Xco values ranging between present-epoch gas-rich mergers and quiescent discs at low-z. This model shows that on average, mergers do have lower Xco values than disc galaxies, though there is significant overlap. Xco varies smoothly with the local conditions within a galaxy, and is not a function of global galaxy morphology. We combine our results to provide a general fitting formula for Xco as a function of CO line intensity and metallicity. We show that replacing the traditional approach of using one constant Xco for starbursts and another for discs with our best-fit function produces star formation laws that are continuous rather than bimodal, and that have significantly reduced scatter.Comment: Accepted by MNRAS; major revision includes moving the bulk of the equations to an appendi

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

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