Populations of human cytomegalovirus (HCMV), a large DNA virus, are highly polymorphic in patient samples, which may allow for rapid evolution within human hosts. To understand HCMV evolution, ...longitudinally sampled genomic populations from the urine and plasma of 5 infants with symptomatic congenital HCMV infection were analyzed. Temporal and compartmental variability of viral populations were quantified using high throughput sequencing and population genetics approaches. HCMV populations were generally stable over time, with ~88% of SNPs displaying similar frequencies. However, samples collected from plasma and urine of the same patient at the same time were highly differentiated with approximately 1700 consensus sequence SNPs (1.2% of the genome) identified between compartments. This inter-compartment differentiation was comparable to the differentiation observed in unrelated hosts. Models of demography (i.e., changes in population size and structure) and positive selection were evaluated to explain the observed patterns of variation. Evidence for strong bottlenecks (>90% reduction in viral population size) was consistent among all patients. From the timing of the bottlenecks, we conclude that fetal infection occurred between 13-18 weeks gestational age in patients analyzed, while colonization of the urine compartment followed roughly 2 months later. The timing of these bottlenecks is consistent with the clinical histories of congenital HCMV infections. We next inferred that positive selection plays a small but measurable role in viral evolution within a single compartment. However, positive selection appears to be a strong and pervasive driver of evolution associated with compartmentalization, affecting ≥ 34 of the 167 open reading frames (~20%) of the genome. This work offers the most detailed map of HCMV in vivo evolution to date and provides evidence that viral populations can be stable or rapidly differentiate, depending on host environment. The application of population genetic methods to these data provides clinically useful information, such as the timing of infection and compartment colonization.
Anaerobic digestion of waste activated sludge (WAS) is currently enjoying renewed interest due to the potential for methane production. However, methane production is often limited by the slow ...hydrolysis rate and/or poor methane potential of WAS. This study presents a novel pretreatment strategy based on free nitrous acid (FNA or HNO2) to enhance methane production from WAS. Pretreatment of WAS for 24 h at FNA concentrations up to 2.13 mg N/L substantially enhanced WAS solubilization, with the highest solubilization (0.16 mg chemical oxygen demand (COD)/mg volatile solids (VS), at 2.13 mg HNO2–N/L) being six times that without FNA pretreatment (0.025 mg COD/mg VS, at 0 mg HNO2–N/L). Biochemical methane potential tests demonstrated methane production increased with increased FNA concentration used in the pretreatment step. Model-based analysis indicated FNA pretreatment improved both hydrolysis rate and methane potential, with the highest improvement being approximately 50% (from 0.16 to 0.25 d–1) and 27% (from 201 to 255 L CH4/kg VS added), respectively, achieved at 1.78–2.13 mg HNO2–N/L. Further analysis indicated that increased hydrolysis rate and methane potential were related to an increase in rapidly biodegradable substrates, which increased with increased FNA dose, while the slowly biodegradable substrates remained relatively static.
With novel developments in sequencing technologies, time‐sampled data are becoming more available and accessible. Naturally, there have been efforts in parallel to infer population genetic parameters ...from these data sets. Here, we compare and analyse four recent approaches based on the Wright–Fisher model for inferring selection coefficients (s) given effective population size (Ne), with simulated temporal data sets. Furthermore, we demonstrate the advantage of a recently proposed approximate Bayesian computation (ABC)‐based method that is able to correctly infer genomewide average Ne from time‐serial data, which is then set as a prior for inferring per‐site selection coefficients accurately and precisely. We implement this ABC method in a new software and apply it to a classical time‐serial data set of the medionigra genotype in the moth Panaxia dominula. We show that a recessive lethal model is the best explanation for the observed variation in allele frequency by implementing an estimator of the dominance ratio (h).
Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and ...extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.
Transcriptional reprogramming is a fundamental process of living cells in order to adapt to environmental and endogenous cues. In order to allow flexible and timely control over gene expression ...without the interference of native gene expression machinery, a large number of studies have focused on developing synthetic biology tools for orthogonal control of transcription. Most recently, the nuclease-deficient Cas9 (dCas9) has emerged as a flexible tool for controlling activation and repression of target genes, by the simple RNA-guided positioning of dCas9 in the vicinity of the target gene transcription start site.
In this study we compared two different systems of dCas9-mediated transcriptional reprogramming, and applied them to genes controlling two biosynthetic pathways for biobased production of isoprenoids and triacylglycerols (TAGs) in baker's yeast Saccharomyces cerevisiae. By testing 101 guide-RNA (gRNA) structures on a total of 14 different yeast promoters, we identified the best-performing combinations based on reporter assays. Though a larger number of gRNA-promoter combinations do not perturb gene expression, some gRNAs support expression perturbations up to ~threefold. The best-performing gRNAs were used for single and multiplex reprogramming strategies for redirecting flux related to isoprenoid production and optimization of TAG profiles. From these studies, we identified both constitutive and inducible multiplex reprogramming strategies enabling significant changes in isoprenoid production and increases in TAG.
Taken together, we show similar performance for a constitutive and an inducible dCas9 approach, and identify multiplex gRNA designs that can significantly perturb isoprenoid production and TAG profiles in yeast without editing the genomic context of the target genes. We also identify a large number of gRNA positions in 14 native yeast target pomoters that do not affect expression, suggesting the need for further optimization of gRNA design tools and dCas9 engineering.
We draw from the literature on economic geography and from the thematic offshoring literature, and propose three hypotheses that rest on the assumption that the choice of offshoring location is based ...on the fit between the attributes of different destinations and the attributes of the offshored business activities. The study reveals a multi‐faceted location pattern in which firms' location strategies, to some degree, follow a logic whereby manufacturing is relocated to low‐cost destinations, and research and development is relocated to high‐cost destinations. However, the picture is more nuanced when distinguishing between standardized and advanced activities. Asia attracts as many advanced activities as Western Europe while North America attracts more advanced activities even in manufacturing. Central and Eastern Europe attract offshoring in manufacturing and IT, but the activities that are offshored to these regions are typically not advanced. One important theoretical implication of this study is that a more detailed understanding of the nature of offshored activities is needed, since such attributes appear to be an important determinant of location choice.
News reports of scientific research are rarely hedged; in other words, the reports do not contain caveats, limitations, or other indicators of scientific uncertainty. Some have suggested that hedging ...may influence news consumers’ perceptions of scientists’ and journalists’ credibility (perceptions that may be related to support for scientific research and/or adoption of scientific recommendations). But whether hedging does affect audience perceptions is unknown. A multiple‐message experiment (N= 601) found that across five messages, both scientists and journalists were viewed as more trustworthy (a) when news coverage of cancer research was hedged (e.g., study limitations were reported) and (b) when the hedging was attributed to the scientists responsible for the research (as opposed to scientists unaffiliated with the research).
Résumé
Incertitude scientifique dans la couverture de presse de la recherche sur le cancer : Les effets de la nuance sur la crédibilité des scientifiques et des journalistes
Les comptes rendus de presse de la recherche scientifique sont rarement nuancés; en d‘autres termes, ces comptes rendus ne mentionnent ni mises en garde, ni limites, ni aucun autre indicateur d’incertitude scientifique. Certains ont suggéré que la nuance pourrait influencer les perceptions qu‘ont les consommateurs de la crédibilité des scientifiques et des journalistes (des perception qui pourraient être liées au soutien à la recherche scientifique ou à l’adoption de recommandations scientifiques). Mais la question à savoir si la nuance a réellement un impact sur les perceptions des auditoires demeure sans réponse. Une expérience à multiples messages (N = 601) a révélé que pour cinq messages, tant les scientifiques que les journalistes étaient vus comme plus fiables a) lorsque la couverture de la recherche sur le cancer dans les actualités était nuancée (par exemple, les limites de l'étude étaient signalées) et b) lorsque la nuance était attribuée aux scientifiques responsables de la recherche en question (plutôt qu'à des scientifiques non affiliés à la recherche).
Resumen
La Inseguridad Científica en la Cobertura de las Noticias de la Investigación de Cáncer: Los Efectos de la Cobertura sobre la Credibilidad de los Científicos y los Periodistas
Los reportes de noticias de investigaciones científicas son raramente cubiertos; en otras palabras, los reportes no contienen advertencias, limitaciones, u otros indicadores de la inseguridad científica. Algunos han sugerido que la cobertura puede influenciar las percepciones de los consumidores de noticias sobre la credibilidad de los científicos y los periodistas (las percepciones pueden ser relacionadas con el apoyo a la investigación científica y/ó la adopción de recomendaciones científicas). Aún no se sabe si la cobertura afecta las percepciones de la audiencia. Un experimento de mensaje múltiple (N = 601) encontró que, a través de 5 mensajes, los científicos y periodistas fuero vistos como más fidedignos (a) cuando la cobertura de noticias sobre la investigación del cáncer fue cubierta (a saber, las limitaciones del estudio fueron reportados) y (b) cuando la cobertura fue atribuida a los científicos responsables de la investigación (en oposición a científicos no afiliados con la investigación).
ZhaiYao
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Pancreatic ductal adenocarcinoma (PDAC) patients have a 5-year survival rate of only 8% largely due to late diagnosis and insufficient therapeutic options. Neutrophils are among the most abundant ...immune cell type within the PDAC tumor microenvironment (TME), and are associated with a poor clinical prognosis. However, despite recent advances in understanding neutrophil biology in cancer, therapies targeting tumor-associated neutrophils are lacking. Here, we demonstrate, using pre-clinical mouse models of PDAC, that lorlatinib attenuates PDAC progression by suppressing neutrophil development and mobilization, and by modulating tumor-promoting neutrophil functions within the TME. When combined, lorlatinib also improves the response to anti-PD-1 blockade resulting in more activated CD8 + T cells in PDAC tumors. In summary, this study identifies an effect of lorlatinib in modulating tumor-associated neutrophils, and demonstrates the potential of lorlatinib to treat PDAC.
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•Impurities as Cl, S, and K found in bio-oil will deactivate or inhibit MoS2-type catalyst by competing for the active sites.•MoS2-based catalysts will produce sulfur containing ...hydrocarbons during HDO, but these can be removed again if a sufficiently high residence time is used enabling desulfurization of the product.•Chlorine binds more strongly to the active sites of MoS2 based catalysts compared to H2O and H2S, while K irreversibly deactivates the catalyst.
The stability of Ni-MoS2/ZrO2 toward water, potassium, and chlorine containing compounds during hydrodeoxygenation (HDO) of a mixture of phenol and 1-octanol was investigated in a high pressure gas and liquid continuous flow fixed bed setup at 280°C and 100bar. To maintain the stability of the catalyst, sufficient co-feeding of a sulfur source was necessary to avoid oxidation of the sulfide phase by oxygen replacement of the edge sulfur atoms in the MoS2 structure. However, the addition of sulfur to the feed gas resulted in the formation of sulfur containing compounds, mainly thiols, in the oil product if the residence time was too low. At a weight hourly space velocity (WHSV) of 4.9h−1 the sulfur content in the liquid product was 980ppm by weight, but this could be decreased to 5ppm at a WHSV of 1.4h−1. A high co-feed of sulfur was needed when water was present in the feed and the H2O/H2S molar ratio should be below ca. 10 to maintain a decent stability of the catalyst. Chlorine containing compounds caused a reversible deactivation of the catalyst when co-fed to the reactor, where the catalytic activity could be completely regained when removing it from the feed. Commonly, chlorine, H2O, and H2S all inhibited the activity of the catalyst by competing for the active sites, with chlorine being by far the strongest inhibitor and H2S and H2O of roughly the same strength. Dissimilar, potassium was a severe poison and irreversibly deactivated the catalyst to <5% degree of deoxygenation when impregnated on the catalyst in a stoichiometric ratio relative to the active metal. This deactivation was a result of adsorption of potassium on the edge vacancy sites of the MoS2 slabs.
Most research into red blood cell (RBC) lipids focuses on membrane phospholipids and their relationships to metabolic conditions and diet. Triglycerides (TGs) exist in most cells; the TG-fatty acids ...serve as readily available fuel for oxidative phosphorylation. Because RBCs lack mitochondria, they would not be expected to store fatty acids in TG. We followed up on a previous in vitro study that found FFA can be incorporated into RBC-TG by testing whether intravenously infused U-13Cpalmitate could be detected in RBC-TG. We also quantified RBC-TG fatty acid concentrations and profiles as they relate to plasma FFA and lipid concentrations. We found that 1) RBC-TG concentrations measured by glycerol and LC/MS were correlated (r = 0.77; P < 0.001) and averaged <50 nmol/ml RBC; 2) RBC-TG concentrations were stable over 18 h; 3) U-13Cpalmitate was detectable in RBC-TG from half the participants; 4) RBC-TGs were enriched in saturated fatty acids and depleted in unsaturated fatty acid compared with plasma FFA and previously reported RBC membrane phospholipids; 5) RBC-TG fatty acid profiles differed significantly between obese and nonobese adults; 6) weight loss altered the RBC-TG fatty acid profile in the obese group; and 7) the RBC-TG fatty acid composition correlated with plasma lipid concentrations. This is the first report showing that plasma FFA contributes to RBC-TG in vivo, in humans, and that the RBC-TG fatty acid profile is related to metabolic health. The storage of saturated fatty acids in RBC-TG stands in stark contrast to the highly unsaturated profile reported in RBC membrane phospholipids.
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