Tumor cell proliferation and migration processes are regulated by multiple metabolic pathways including glycolysis and de novo lipogenesis. Since acetyl-CoA carboxylase (ACC) is at the junction of ...lipids synthesis and oxidative metabolic pathways, we investigated whether use of a dual ACC inhibitor would provide a potential therapy against certain lipogenic cancers. The impact of dual ACC1/ACC2 inhibition was investigated using a dual ACC1/ACC2 inhibitor as well as dual siRNA knock down on the cellular viability and metabolism of two glioblastoma multiform cancer cell lines, U87 and a more aggressive form, U87 EGFRvIII. We first demonstrated that while ACCi inhibited DNL in both cell lines, ACCi preferentially blunted the U87 EGFRvIII cellular proliferation capacity. Metabolically, chronic treatment with ACCi significantly upregulated U87 EGFRvIII cellular respiration and extracellular acidification rate, a marker of glycolytic activity, but impaired mitochondrial health by reducing maximal respiration and decreasing mitochondrial ATP production efficiency. Moreover, ACCi treatment altered the cellular lipids content and increased apoptotic caspase activity in U87 EGFRvIII cells. Collectively these data indicate that ACC inhibition, by reducing DNL and increasing cellular metabolic rate, may have therapeutic utility for the suppression of lipogenic tumor growth and warrants further investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Use of temperature to improve West Nile virus forecasts DeFelice, Nicholas B; Schneider, Zachary D; Little, Eliza ...
PLOS computational biology/PLoS computational biology,
03/2018, Letnik:
14, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Ecological and laboratory studies have demonstrated that temperature modulates West Nile virus (WNV) transmission dynamics and spillover infection to humans. Here we explore whether inclusion of ...temperature forcing in a model depicting WNV transmission improves WNV forecast accuracy relative to a baseline model depicting WNV transmission without temperature forcing. Both models are optimized using a data assimilation method and two observed data streams: mosquito infection rates and reported human WNV cases. Each coupled model-inference framework is then used to generate retrospective ensemble forecasts of WNV for 110 outbreak years from among 12 geographically diverse United States counties. The temperature-forced model improves forecast accuracy for much of the outbreak season. From the end of July until the beginning of October, a timespan during which 70% of human cases are reported, the temperature-forced model generated forecasts of the total number of human cases over the next 3 weeks, total number of human cases over the season, the week with the highest percentage of infectious mosquitoes, and the peak percentage of infectious mosquitoes that on average increased absolute forecast accuracy 5%, 10%, 12%, and 6%, respectively, over the non-temperature forced baseline model. These results indicate that use of temperature forcing improves WNV forecast accuracy and provide further evidence that temperature influences rates of WNV transmission. The findings provide a foundation for implementation of a statistically rigorous system for real-time forecast of seasonal WNV outbreaks and their use as a quantitative decision support tool for public health officials and mosquito control programs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Transport of carbonyl sulfide (OCS) from the troposphere to the stratosphere contributes sulfur to the stratospheric aerosol layer, which reflects incoming short‐wave solar radiation, cooling the ...climate system. Previous analyses of OCS observations have shown no significant trend, suggesting that OCS is unlikely to be a major contributor to the reported increases in stratospheric aerosol loading and indicating a balanced OCS budget. Here we present analyses of ground‐based Fourier transform spectrometer measurements of OCS at three Southern Hemisphere sites spanning 34.45°S to 77.80°S. At all three sites statistically significant positive trends are seen from 2001 to 2014 with an observed overall trend in total column OCS at Wollongong of 0.73 ± 0.03%/yr, at Lauder of 0.43 ± 0.02%/yr, and at Arrival Heights of 0.45 ± 0.05%/yr. These observed trends in OCS imply that the OCS budget is not balanced and could contribute to constraints on current estimates of sources and sinks.
Key Points
First observed positive trend in OCS in the Southern Hemisphere
Observed trends indicate imbalanced OCS budget
Temporal structure of trend is similar across middle‐ and high‐latitude sites
Background Serum levels of vascular cell adhesion molecule-1 (VCAM-1) are reflective of endothelial activation. Although VCAM-1 has been implicated in the pathogenesis of heart failure with preserved ...ejection fraction (HFpEF), the prospective association of VCAM-1 with development of clinically overt heart failure (HF) across ejection fraction categories is unclear. Methods and Results In MESA (the Multi-Ethnic Study of Atherosclerosis), we evaluated the association of VCAM-1 at examination 2 (2002-2004) with incident HF (HFpEF and HF with reduced ejection fraction) after adjustment for cardiovascular risk factors. Incident HF was independently adjudicated as first hospitalization for symptomatic HF. Among 2297 participants (mean age, 63 years; women, 53%), those with higher VCAM-1 were more likely to be White race, had higher blood pressure, and had lower kidney function. Over a median of 14.4 years, there were 102 HF events (HFpEF=65; HF with reduced ejection fraction=37). After covariate adjustment, each doubling of VCAM-1 was associated with incident HF (hazard ratio HR, 1.94; 95% CI, 1.17-3.23;
=0.01). This association appeared stronger among current/former smokers compared with never smokers. On evaluation of HF subtypes, VCAM-1 was associated with incident HFpEF (HR, 1.97; 95% CI, 1.04-3.72;
=0.04) but not with incident HF with reduced ejection fraction, although risk estimates were consistent (HR, 1.82; 95% CI, 0.79-4.21;
=0.16). Conclusions In a multiethnic cohort, VCAM-1 was significantly associated with incident HF over long-term follow-up. These findings suggest a potential role for endothelial activation in driving clinical HF, and specifically HFpEF. Therapies that decrease endothelial activation may prevent the progression from cardiovascular risk factors to clinical HF.
The purpose of this study was to compare inter- and intraobserver agreement of a novel intraoperative subluxation classification for patients undergoing ulnar nerve surgery at the elbow. We ...hypothesize there will be strong inter- and intraobserver agreement of the 4-category classification system, and reviewers will have substantial confidence while reviewing the classification system.
Four blinded fellowship-trained orthopedic hand surgeons reviewed 25 videos in total on 2 separate viewings, 21 days apart. Variables collected were ulnar subluxation classification (A, B, C, or D) and a confidence metric. Subsequent to primary data collection, classification grading was stratified into A/B or C/D subgroups for further analysis. Cohen κ scores were used to evaluate all variables collected in this study. The interpretation of κ scores included ≤0.0 as no agreement, 0.01-0.20 as none to slight, 0.21-0.40 as fair, 0.41-0.60 as moderate, 0.61-0.80 as substantial, and 0.81-1.0 as almost perfect agreement.
Interobserver agreement of subluxation classification as a 4-category scale demonstrated a moderate agreement on first viewing, second viewing, and when both viewings were combined (κ = 0.51, 0.51, and 0.51 respectively). Seventy-five percent (3 of 4) of reviewers had moderate intraobserver agreement for ulnar nerve subluxation classification, whereas 1 reviewer had substantial intraobserver classification (κ = 0.72). Overall, there was high confidence in 65% of classification scores in the second round of viewing, which improved from 58% in the first viewing round. When ulnar subluxation classification selections were regrouped into classes A/B or C/D, 100% of reviewers had substantial interobserver (κ = 0.74-0.75) and substantial to almost perfect intraobserver (κ = 0.71-0.91) agreement.
The 4-category classification was reproducible within and between reviewers. Agreement appeared to increase when simplifying the classification to 2 categories, which may provide guidance to surgical decision making. The validation of a reproducible classification scheme for intraoperative ulnar subluxation may aid with decision making and further postoperative outcomes research.
The COVID‐19 pandemic has had an enormous impact on almost all aspects of human society and endeavor; the natural world and its conservation have not been spared. Through a process of expert ...consultation, we identified and categorized, into 19 themes and 70 subthemes, the ways in which biodiversity and its conservation have been or could be affected by the pandemic globally. Nearly 60% of the effects have been broadly negative. Subsequently, we created a compendium of all themes and subthemes, each with explanatory text, and in August 2020 a diverse group of experienced conservationists with expertise from across sectors and geographies assessed each subtheme for its likely impact on biodiversity conservation globally. The 9 subthemes ranked highest all have a negative impact. These were, in rank order, governments sidelining the environment during their economic recovery, reduced wildlife‐based tourism income, increased habitat destruction, reduced government funding, increased plastic and other solid waste pollution, weakening of nature‐friendly regulations and their enforcement, increased illegal harvest of wild animals, reduced philanthropy, and threats to survival of conservation organizations. In combination, these impacts present a worrying future of increased threats to biodiversity conservation but reduced capacity to counter them. The highest ranking positive impact, at 10, was the beneficial impact of wildlife‐trade restrictions. More optimistically, among impacts ranked 11‐20, 6 were positive and 4 were negative. We hope our assessment will draw attention to the impacts of the pandemic and, thus, improve the conservation community's ability to respond to such threats in the future.
Resumen
La pandemia de COVID‐19 ha tenido un impacto enorme sobre casi todos los aspectos de la sociedad humana y sus proyectos; el mundo natural y su conservación no han sido la excepción. Por medio de un proceso de consultas a expertos, identificamos y categorizamos en 19 temas y 70 subtemas las maneras en las que la biodiversidad y su conservación han sido o podrían ser afectadas mundialmente por la pandemia. Casi el 60% de los efectos han sido claramente negativos. Posteriormente, creamos un compendio de todos los temas y subtemas, cada uno con textos explicativos, para que en agosto de 2020 un grupo diverso de conservacionistas experimentados con conocimiento de todos los sectores y geografías evaluara cada subtema de acuerdo con su probabilidad de impactar sobre la conservación de la biodiversidad en todo el mundo. Los nueve subtemas con la clasificación más alta tienen un impacto negativo. Estos temas son, en orden de clasificación: los gobiernos dejando de lado al ambiente durante su recuperación económica, reducción de los ingresos basados en el turismo de fauna, incremento en la destrucción de hábitat, financiamiento reducido del gobierno, aumento de la contaminación por plásticos y otros desechos sólidos, debilitamiento de las regulaciones en pro de la naturaleza y su aplicación, incremento en la captura ilegal de animales, disminución de la filantropía y amenazas para la supervivencia de las organizaciones de conservación. La combinación de estos impactos representa un futuro preocupante lleno de amenazas para la conservación de la biodiversidad y una capacidad reducida para contrarrestarlas. El impacto positivo con la clasificación más alta, el 10, fue el impacto benéfico de las restricciones en el mercado de fauna. De manera más optimista, entre los impactos clasificados de los lugares del 11 al 20, seis fueron positivos y cuatro fueron negativos. Esperamos que nuestra evaluación enfoque la atención hacia los impactos de la pandemia y así mejore la habilidad de la comunidad conservacionista para responder a tales amenazas en el futuro.
Importancia Relativa de los Impactos de la Pandemia de COVID‐19 sobre la Conservación Mundial de la Biodiversidad
Article impact statement: The COVID‐19 pandemic presents increased threats to biodiversity conservation globally yet reduced capacity to counter them.
Compliant surfaces beneath a casualty diminish the quality of cardiopulmonary resuscitation (CPR) in clinical environments. To examine this issue in a sporting environment, we assessed chest ...compression quality and rescuer exertion upon compliant sports safety matting. Twenty-seven advanced life support providers volunteered (13 male/14 female; mass = 79.0 ± 12.5 kg; stature = 1.77 ± 0.09 m). Participants performed 5 x 2 min, randomized bouts of continuous chest compressions on a mannequin, upon five surfaces: solid floor; low-compliance matting; low-compliance matting with a backboard; high-compliance matting; high-compliance matting with a backboard. Measures included chest compression depth and rate, percentage of adequate compressions, and rescuer heart rate and perceived exertion. Chest compression depth and rate were significantly lower upon high-compliance matting relative to other surfaces (p<0.05). The percentage of adequate compressions (depth greater than or equal to50 mm) was lowest upon high-compliance matting (40 ± 39%) versus low-compliance matting (60 ± 36%) and low-compliance matting with a backboard (59 ± 39%). Perceived exertion was significantly greater upon high-compliance matting versus floor, low-compliance matting, and low-compliance matting with a backboard (p<0.05). Providers of CPR should be alerted to the detrimental effects of compliant safety matting in a sporting environment and prepare to alter the targeted compression depth and rescuer rotation intervals accordingly.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Circulating protease inhibitors are important regulators of inflammation that are implicated in the pathophysiology of heart failure (HF). Secretory leukocyte protease inhibitor (SLPI) is a serine ...protease inhibitor which protects pulmonary tissues against inflammatory damage; however, its role in HF is not well understood. We sought to evaluate associations of circulating SLPI and genetically-mediated serum SLPI with incident HF and its subtypes in a multi-ethnic cohort of adults using clinical and genetic epidemiological approaches. Among 2,297 participants in the Multi-Ethnic Study of Atherosclerosis (MESA), each doubling of serum SLPI was independently associated with incident HF (HR 1.77; 95% CI 1.02-3.02; P = 0.04), particularly incident HF with preserved ejection fraction (HFpEF; HR 2.44; 95% CI 1.23-4.84; P = 0.01) but not HF with reduced ejection fraction (HFrEF; HR 0.95; 95% CI 0.36-2.46; P = 0.91). Previously reported circulating SLPI protein quantitative trait loci (pQTLs) were not associated with serum SLPI levels or incident HF among MESA participants. In conclusion, baseline serum SLPI levels, but not genetically-determined serum SLPI, were significantly associated with incident HF and HFpEF over long-term follow-up in a multi-ethnic cohort. Serum circulating SLPI may be a correlate of inflammation that sheds insight on the pathobiology of HFpEF.
Cervical cancer is the most common cancer affecting sub-Saharan African women and is prevalent among HIV-positive (HIV
) individuals. No comprehensive profiling of cancer genomes, transcriptomes or ...epigenomes has been performed in this population thus far. We characterized 118 tumors from Ugandan patients, of whom 72 were HIV
, and performed extended mutation analysis on an additional 89 tumors. We detected human papillomavirus (HPV)-clade-specific differences in tumor DNA methylation, promoter- and enhancer-associated histone marks, gene expression and pathway dysregulation. Changes in histone modification at HPV integration events were correlated with upregulation of nearby genes and endogenous retroviruses.
Background
Despite effective treatments for fecal incontinence (FI), FI remains underdiagnosed and undertreated. This study sought to characterize and compare rates of, delays in, experiences with, ...and barriers to care seeking for FI among men and women.
Methods
This study was a secondary analysis of electronic survey data collected from adults with FI. The survey included the use of a validated instrument to assess FI severity and questions that now comprise a validated instrument for assessing barriers to care seeking for FI in women. Descriptive analyses characterized differences between men and women. χ2 testing for categorical variables and t‐testing for normally distributed continuous variables compared statistical differences.
Results
The sample (N = 548) was predominately female (84%), non‐Hispanic White (90%), and insured (96%), with a mean Vaizey score (13.4 ± 5.3) consistent with moderate or severe FI. Care seeking rates (p = 0.81) and symptom duration before care seeking (p = 0.23) did not differ between women and men, but women were more likely than men to be told that effective treatments exist; most male and female respondents who sought care were offered treatment. Very few respondents had been asked about FI by a healthcare provider. Whereas normative thinking, limited life impact, and believing that a healthcare provider could not help were more common barriers to care seeking among men, avoidance, fear, and discouragement were more common in women.
Conclusions
Men and women with FI seek care at similar rates and after experiencing symptoms for a similar duration of time. Very few patients with FI have been screened for it by a healthcare provider. Barriers to FI care seeking are different for women and men, and men are less likely than women to be informed about effective treatments by a healthcare provider.
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