Resistance to antibiotics of clinical relevance in the fecal microbiota of Mexican wildlife.

There are a growing number of reports of antibiotic resistance (ATBR) in bacteria living in wildlife. This is a cause for concern as ATBR in wildlife represents a potential public health threat. However, little is known about the factors that might determine the presence, abundance and dispersion of ATBR bacteria in wildlife. Here, we used culture and molecular methods to assess ATBR in bacteria in fecal samples from howler monkeys (Alouatta palliata), spider monkeys (Ateles geoffroyi), tapirs (Tapirus bairdii) and felids (jaguars, Panthera onca; pumas, Puma concolor; jaguarundis, Puma yagouaroundi; and ocelots, Leopardus pardalis) living freely in two regions of the Mexican state of Veracruz under different degrees of human influence. Overall, our study shows that ATBR is commonplace in bacteria isolated from wildlife in southeast Mexico. Most of the resistances were towards old and naturally occurring antibiotics, but we also observed resistances of potential clinical significance. We found that proximity to humans positively affected the presence of ATBR and that ATBR was higher in terrestrial than arboreal species. We also found evidence suggesting different terrestrial and aerial routes for the transmission of ATBR between humans and wildlife. The prevalence and potential ATBR transfer mechanisms between humans and wildlife observed in this study highlight the need for further studies to identify the factors that might determine ATBR presence, abundance and distribution.The authors acknowledge the National Council of Science of Technology (CONACYT) in Mexico and the Veracruz State Government for providing partial financial support to JCA (Grant Number 108990). JCD was supported by grants from the Isaac Newton Trust and The Cambridge Humanities Research Grant Scheme. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final published version. It originally appeared in PLOS One at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0107719

Serum Ferritin Levels Lack Diagnostic Accuracy for Liver Fibrosis in Patients With Nonalcoholic Fatty Liver Disease

BACKGROUND & AIM: Series studies have associated increased serum levels of ferritin with liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to determine the accuracy with which measurements of serum ferritin determine the presence and severity of liver fibrosis, and whether combining noninvasive scoring systems with serum ferritin analysis increases the accuracy of diagnosis of advanced liver fibrosis. METHODS: We performed a retrospective analysis of data from 1014 patients with liver biopsy-confirmed NAFLD. Three cut-points of serum ferritin level, adjusted for sex, were established based on receiver operating characteristics curve analysis: 1.0 (the upper limit of normal [ULN]), 1.5-fold ULN, and 2.0-fold ULN. Three multiple logistic regression models were created to determine the association of these cutoff values with liver fibrosis, adjusting for age, sex, race, diabetes, body mass index, and level of alanine aminotransferase. RESULTS: A greater proportion of patients with increased serum levels of ferritin had definitive NASH and more-advanced fibrosis than patients without increased levels. In all models, serum level of ferritin was significantly associated with the presence and severity of liver fibrosis. However, for all 3 cutoff values, area under the receiver operating characteristic curve values were low (less than 0.60) for the presence of fibrosis or any stage of liver fibrosis; ferritin level identified patients with fibrosis with 16%–41% sensitivity and 70%–92% specificity. The accuracy with which noninvasive scoring systems identified patients with advanced fibrosis did not change with inclusion of serum ferritin values. CONCLUSIONS: Although serum levels of ferritin correlate with more-severe liver fibrosis, based on adjusted multiple logistic regression analysis, serum ferritin levels alone have a low level of diagnostic accuracy for the presence or severity of liver fibrosis in patients with NAFLD

Population genomics reveals that an anthropophilic population of Aedes aegypti mosquitoes in West Africa recently gave rise to American and Asian populations of this major disease vector

Abstract Background The mosquito Aedes aegypti is the main vector of dengue, Zika, chikungunya and yellow fever viruses. This major disease vector is thought to have arisen when the African subspecies Ae. aegypti formosus evolved from being zoophilic and living in forest habitats into a form that specialises on humans and resides near human population centres. The resulting domestic subspecies, Ae. aegypti aegypti, is found throughout the tropics and largely blood-feeds on humans. Results To understand this transition, we have sequenced the exomes of mosquitoes collected from five populations from around the world. We found that Ae. aegypti specimens from an urban population in Senegal in West Africa were more closely related to populations in Mexico and Sri Lanka than they were to a nearby forest population. We estimate that the populations in Senegal and Mexico split just a few hundred years ago, and we found no evidence of Ae. aegypti aegypti mosquitoes migrating back to Africa from elsewhere in the tropics. The out-of-Africa migration was accompanied by a dramatic reduction in effective population size, resulting in a loss of genetic diversity and rare genetic variants. Conclusions We conclude that a domestic population of Ae. aegypti in Senegal and domestic populations on other continents are more closely related to each other than to other African populations. This suggests that an ancestral population of Ae. aegypti evolved to become a human specialist in Africa, giving rise to the subspecies Ae. aegypti aegypti. The descendants of this population are still found in West Africa today, and the rest of the world was colonised when mosquitoes from this population migrated out of Africa. This is the first report of an African population of Ae. aegypti aegypti mosquitoes that is closely related to Asian and American populations. As the two subspecies differ in their ability to vector disease, their existence side by side in West Africa may have important implications for disease transmission

Aqueous-phase mechanism for secondary organic aerosol formation from isoprene: application to the southeast United States and co-benefit of SO2 emission controls

Isoprene emitted by vegetation is an important precursor of secondary organic aerosol (SOA), but the mechanism and yields are uncertain. Aerosol is prevailingly aqueous under the humid conditions typical of isoprene-emitting regions. Here we develop an aqueous-phase mechanism for isoprene SOA formation coupled to a detailed gas-phase isoprene oxidation scheme. The mechanism is based on aerosol reactive uptake coefficients (γ) for water-soluble isoprene oxidation products, including sensitivity to aerosol acidity and nucleophile concentrations. We apply this mechanism to simulation of aircraft (SEAC4RS) and ground-based (SOAS) observations over the southeast US in summer 2013 using the GEOS-Chem chemical transport model. Emissions of nitrogen oxides (NOx ≡ NO + NO2) over the southeast US are such that the peroxy radicals produced from isoprene oxidation (ISOPO2) react significantly with both NO (high-NOx pathway) and HO2 (low-NOx pathway), leading to different suites of isoprene SOA precursors. We find a mean SOA mass yield of 3.3 % from isoprene oxidation, consistent with the observed relationship of total fine organic aerosol (OA) and formaldehyde (a product of isoprene oxidation). Isoprene SOA production is mainly contributed by two immediate gas-phase precursors, isoprene epoxydiols (IEPOX, 58 % of isoprene SOA) from the low-NOx pathway and glyoxal (28 %) from both low- and high-NOx pathways. This speciation is consistent with observations of IEPOX SOA from SOAS and SEAC4RS. Observations show a strong relationship between IEPOX SOA and sulfate aerosol that we explain as due to the effect of sulfate on aerosol acidity and volume. Isoprene SOA concentrations increase as NOx emissions decrease (favoring the low-NOx pathway for isoprene oxidation), but decrease more strongly as SO2 emissions decrease (due to the effect of sulfate on aerosol acidity and volume). The US Environmental Protection Agency (EPA) projects 2013-2025 decreases in anthropogenic emissions of 34 % for NOx (leading to a 7 % increase in isoprene SOA) and 48 % for SO2 (35 % decrease in isoprene SOA). Reducing SO2 emissions decreases sulfate and isoprene SOA by a similar magnitude, representing a factor of 2 co-benefit for PM2.5 from SO2 emission controls

Characterization of organic aerosol across the global remote troposphere: A comparison of ATom measurements and global chemistry models

The spatial distribution and properties of submicron organic aerosol (OA) are among the key sources of uncertainty in our understanding of aerosol effects on climate. Uncertainties are particularly large over remote regions of the free troposphere and Southern Ocean, where very few data have been available and where OA predictions from AeroCom Phase II global models span 2 to 3 orders of magnitude, greatly exceeding the model spread over source regions. The (nearly) pole-to-pole vertical distribution of nonrefractory aerosols was measured with an aerosol mass spectrometer onboard the NASA DC-8 aircraft as part of the Atmospheric Tomography (ATom) mission during the Northern Hemisphere summer (August 2016) and winter (February 2017). This study presents the first extensive characterization of OA mass concentrations and their level of oxidation in the remote atmosphere. OA and sulfate are the major contributors by mass to submicron aerosols in the remote troposphere, together with sea salt in the marine boundary layer. Sulfate was dominant in the lower stratosphere. OA concentrations have a strong seasonal and zonal variability, with the highest levels measured in the lower troposphere in the summer and over the regions influenced by biomass burning from Africa (up to 10 μgsm-3). Lower concentrations (~ 0:1 0.3 μgsm-3) are observed in the northern middle and high latitudes and very low concentrations (< 0:1 μgsm-3) in the southern middle and high latitudes. The ATom dataset is used to evaluate predictions of eight current global chemistry models that implement a variety of commonly used representations of OA sources and chemistry, as well as of the AeroCom-II ensemble. The current model ensemble captures the average vertical and spatial distribution of measured OA concentrations, and the spread of the individual models remains within a factor of 5. These results are significantly improved over the AeroCom-II model ensemble, which shows large overestimations over these regions. However, some of the improved agreement with observations occurs for the wrong reasons, as models have the tendency to greatly overestimate the primary OA fraction and underestimate the sec-ondary fraction. Measured OA in the remote free troposphere is highly oxygenated, with organic aerosol to organic carbon (OA= OC) ratios of ~ 2.2 2.8, and is 30 % 60% more oxygenated than in current models, which can lead to significant errors in OA concentrations. The model measurement comparisons presented here support the concept of a more dynamic OA system as proposed by Hodzic et al. (2016), with enhanced removal of primary OA and a stronger production of secondary OA in global models needed to provide better agreement with observations. © 2020 IEEE Computer Society. All rights reserved

Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 lysine 27 trimethylation

Down syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL)1 and polysomy 21 is the most frequent somatic aneuploidy amongst all B-ALLs2. Yet, the mechanistic links between chr.21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 confers murine progenitor B cell self-renewal in vitro, maturation defects in vivo, and B-ALL with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses H3K27me3 in progenitor B cells and B-ALLs, and “bivalent” genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q223–5, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo

Flow cytometry as a rapid analytical tool to determine physiological responses to changing O2 and iron concentration by Magnetospirillum gryphiswaldense strain MSR-1

Magnetotactic bacteria (MTB) are a diverse group of bacteria that synthesise magnetosomes, magnetic membrane-bound nanoparticles that have a variety of diagnostic, clinical and biotechnological applications. We present the development of rapid methods using flow cytometry to characterize several aspects of the physiology of the commonly-used MTB Magnetospirillum gryphiswaldense MSR-1. Flow cytometry is an optical technique that rapidly measures characteristics of individual bacteria within a culture, thereby allowing determination of population heterogeneity and also permitting direct analysis of bacteria. Scatter measurements were used to measure and compare bacterial size, shape and morphology. Membrane permeability and polarization were measured using the dyes propidium iodide and bis-(1,3-dibutylbarbituric acid) trimethine oxonol to determine the viability and ‘health’ of bacteria. Dyes were also used to determine changes in concentration of intracellular free iron and polyhydroxylakanoate (PHA), a bacterial energy storage polymer. These tools were then used to characterize the responses of MTB to different O2 concentrations and iron-sufficient or iron-limited growth. Rapid analysis of MTB physiology will allow development of bioprocesses for the production of magnetosomes, and will increase understanding of this fascinating and useful group of bacteria

CCAAT/Enhancer Binding Protein alpha uses distinct domains to prolong pituitary cells in the Growth 1 and DNA Synthesis phases of the cell cycle

BACKGROUND: A number of transcription factors coordinate differentiation by simultaneously regulating gene expression and cell proliferation. CCAAT/enhancer binding protein alpha (C/EBPα) is a basic/leucine zipper transcription factor that integrates transcription with proliferation to regulate the differentiation of tissues involved in energy balance. In the pituitary, C/EBPα regulates the transcription of a key metabolic regulator, growth hormone. RESULTS: We examined the consequences of C/EBPα expression on proliferation of the transformed, mouse GHFT1-5 pituitary progenitor cell line. In contrast to mature pituitary cells, GHFT1-5 cells do not contain C/EBPα. Ectopic expression of C/EBPα in the progenitor cells resulted in prolongation of both growth 1 (G1) and the DNA synthesis (S) phases of the cell cycle. Transcription activation domain 1 and 2 of C/EBPα were required for prolongation of G1, but not of S. Some transcriptionally inactive derivatives of C/EBPα remained competent for G1 and S phase prolongation. C/EBPα deleted of its leucine zipper dimerization functions was as effective as full-length C/EBPα in prolonging G1 and S. CONCLUSION: We found that C/EBPα utilizes mechanistically distinct activities to prolong the cell cycle in G1 and S in pituitary progenitor cells. G1 and S phase prolongation did not require that C/EBPα remained transcriptionally active or retained the ability to dimerize via the leucine zipper. G1, but not S, arrest required a domain overlapping with C/EBPα transcription activation functions 1 and 2. Separation of mechanisms governing proliferation and transcription permits C/EBPα to regulate gene expression independently of its effects on proliferation

Organic nitrate chemistry and its implications for nitrogen budgets in an isoprene- and monoterpene-rich atmosphere: constraints from aircraft (SEAC4RS) and ground-based (SOAS) observations in the Southeast US

Formation of organic nitrates (RONO2) during oxidation of biogenic volatile organic compounds (BVOCs: isoprene, monoterpenes) is a significant loss pathway for atmospheric nitrogen oxide radicals (NOx), but the chemistry of RONO2 formation and degradation remains uncertain. Here we implement a new BVOC oxidation mechanism (including updated isoprene chemistry, new monoterpene chemistry, and particle uptake of RONO2) in the GEOS-Chem global chemical transport model with  ∼  25  x  25 km2 resolution over North America. We evaluate the model using aircraft (SEAC4RS) and ground-based (SOAS) observations of NOx, BVOCs, and RONO2 from the Southeast US in summer 2013. The updated simulation successfully reproduces the concentrations of individual gas- and particle-phase RONO2 species measured during the campaigns. Gas-phase isoprene nitrates account for 25-50 % of observed RONO2 in surface air, and we find that another 10 % is contributed by gas-phase monoterpene nitrates. Observations in the free troposphere show an important contribution from long-lived nitrates derived from anthropogenic VOCs. During both campaigns, at least 10 % of observed boundary layer RONO2 were in the particle phase. We find that aerosol uptake followed by hydrolysis to HNO3 accounts for 60 % of simulated gas-phase RONO2 loss in the boundary layer. Other losses are 20 % by photolysis to recycle NOx and 15 % by dry deposition. RONO2 production accounts for 20 % of the net regional NOx sink in the Southeast US in summer, limited by the spatial segregation between BVOC and NOx emissions. This segregation implies that RONO2 production will remain a minor sink for NOx in the Southeast US in the future even as NOx emissions continue to decline

The dopamine D2/D3 receptor agonist quinpirole increases checking-like behaviour in an operant observing response task with uncertain reinforcement: a novel possible model of OCD.

Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an 'observing' lever for information about the location of an 'active' lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial