Summertime aerosol chemical components in the marine boundary layer of the Arctic Ocean

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95013/1/jgrd12367.pd

Identifying subtypes of chronic kidney disease with machine learning: development, internal validation and prognostic validation using linked electronic health records in 350,067 individuals

BACKGROUND: Although chronic kidney disease (CKD) is associated with high multimorbidity, polypharmacy, morbidity and mortality, existing classification systems (mild to severe, usually based on estimated glomerular filtration rate, proteinuria or urine albumin-creatinine ratio) and risk prediction models largely ignore the complexity of CKD, its risk factors and its outcomes. Improved subtype definition could improve prediction of outcomes and inform effective interventions. METHODS: We analysed individuals ≥18 years with incident and prevalent CKD (n = 350,067 and 195,422 respectively) from a population-based electronic health record resource (2006-2020; Clinical Practice Research Datalink, CPRD). We included factors (n = 264 with 2670 derived variables), e.g. demography, history, examination, blood laboratory values and medications. Using a published framework, we identified subtypes through seven unsupervised machine learning (ML) methods (K-means, Diana, HC, Fanny, PAM, Clara, Model-based) with 66 (of 2670) variables in each dataset. We evaluated subtypes for: (i) internal validity (within dataset, across methods); (ii) prognostic validity (predictive accuracy for 5-year all-cause mortality and admissions); and (iii) medications (new and existing by British National Formulary chapter). FINDINGS: After identifying five clusters across seven approaches, we labelled CKD subtypes: 1. Early-onset, 2. Late-onset, 3. Cancer, 4. Metabolic, and 5. Cardiometabolic. Internal validity: We trained a high performing model (using XGBoost) that could predict disease subtypes with 95% accuracy for incident and prevalent CKD (Sensitivity: 0.81-0.98, F1 score:0.84-0.97). Prognostic validity: 5-year all-cause mortality, hospital admissions, and incidence of new chronic diseases differed across CKD subtypes. The 5-year risk of mortality and admissions in the overall incident CKD population were highest in cardiometabolic subtype: 43.3% (42.3-42.8%) and 29.5% (29.1-30.0%), respectively, and lowest in the early-onset subtype: 5.7% (5.5-5.9%) and 18.7% (18.4-19.1%). MEDICATIONS: Across CKD subtypes, the distribution of prescription medication classes at baseline varied, with highest medication burden in cardiometabolic and metabolic subtypes, and higher burden in prevalent than incident CKD. INTERPRETATION: In the largest CKD study using ML, to-date, we identified five distinct subtypes in individuals with incident and prevalent CKD. These subtypes have relevance to study of aetiology, therapeutics and risk prediction. FUNDING: AstraZeneca UK Ltd, Health Data Research UK

Genomic analysis of the domestication and post-Spanish conquest evolution of the llama and alpaca

Background Despite their regional economic importance and being increasingly reared globally, the origins and evolution of the llama and alpaca remain poorly understood. Here we report reference genomes for the llama, and for the guanaco and vicuña (their putative wild progenitors), compare these with the published alpaca genome, and resequence seven individuals of all four species to better understand domestication and introgression between the llama and alpaca. Results Phylogenomic analysis confirms that the llama was domesticated from the guanaco and the alpaca from the vicuña. Introgression was much higher in the alpaca genome (36%) than the llama (5%) and could be dated close to the time of the Spanish conquest, approximately 500 years ago. Introgression patterns are at their most variable on the X-chromosome of the alpaca, featuring 53 genes known to have deleterious X-linked phenotypes in humans. Strong genome-wide introgression signatures include olfactory receptor complexes into both species, hypertension resistance into alpaca, and fleece/fiber traits into llama. Genomic signatures of domestication in the llama include male reproductive traits, while in alpaca feature fleece characteristics, olfaction-related and hypoxia adaptation traits. Expression analysis of the introgressed region that is syntenic to human HSA4q21, a gene cluster previously associated with hypertension in humans under hypoxic conditions, shows a previously undocumented role for PRDM8 downregulation as a potential transcriptional regulation mechanism, analogous to that previously reported at high altitude for hypoxia-inducible factor 1α. Conclusions The unprecedented introgression signatures within both domestic camelid genomes may reflect post-conquest changes in agriculture and the breakdown of traditional management practices

Light-stable silver N-Heterocyclic carbene catalysts for the alkynylation of ketones in air

The authors gratefully acknowledge the Royal Society (University Research Fellowship to C.S.J.C) for funding.N-Heterocyclic carbene (NHC) silver(I) complexes were efficiently employed in the alkynylation of ketones. These cationic complexes were found highly active and efficient under mild conditions without the need of additive, and in air. The mechanism of this transformation was investigated. Experiments suggest the formation of a silver-acetylide key intermediate and the release of one ligand from the silver centre enabling the transformation.PostprintPeer reviewe

Phytoplankton Response to Intrusions of Slope Water on the West Florida Shelf: Models and Observations

Previous hypotheses had suggested that upwelled intrusions of nutrient-rich Gulf of Mexico slope water onto the West Florida Shelf (WFS) led to formation of red tides of Karenia brevis. However, coupled biophysical models of (1) wind- and buoyancy-driven circulation, (2) three phytoplankton groups (diatoms, K. brevis, and microflagellates), (3) these slope water supplies of nitrate and silicate, and (4) selective grazing stress by copepods and protozoans found that diatoms won in one 1998 case of no light limitation by colored dissolved organic matter (CDOM). The diatoms lost to K. brevis during another CDOM case of the models. In the real world, field data confirmed that diatoms were indeed the dominant phytoplankton after massive upwelling in 1998, when only a small red tide of K. brevis was observed. Over a 7-month period of the CDOM-free scenario the simulated total primary production of the phytoplankton community was ∼1.8 g C m−2 d−1 along the 40-m isobath of the northern WFS, with the largest accumulation of biomass on the Florida Middle Ground (FMG). Despite such photosynthesis, these models of the WFS yielded a net source of CO2 to the atmosphere during spring and summer and suggested a small sink in the fall. With diatom losses of 90% of their daily carbon fixation to herbivores the simulation supported earlier impressions of a short, diatom-based food web on the FMG, where organic carbon content of the surficial sediments is tenfold those of the surrounding seabeds. Farther south, the simulated near-bottom pools of ammonium were highest in summer, when silicon regeneration was minimal, leading to temporary Si limitation of the diatoms. Termination of these upwelled pulses of production by diatoms and nonsiliceous microflagellates mainly resulted from nitrate exhaustion in the model, however, mimicking most del15PON observations in the field. Yet, the CDOM-free case of the models failed to replicate the observed small red tide in December 1998, tagged with the del15N signature of nitrogen fixation. A large red tide of K. brevis did form in the CDOM-rich case, when estuarine supplies of CDOM favored the growth of the shade-adapted, ungrazed dinoflagellates. The usual formation of large harmful algal blooms of \u3e1 ug chl L−1 (105 cells L−1) in the southern part of the WFS, between Tampa Bay and Charlotte Harbor, must instead depend upon local aeolian and estuarine supplies of nutrients and CDOM sun screen, not those from the shelf break. In the absence of slope water supplies, local upwelling instead focuses nitrate-poor innocula of co-occurring K. brevis and nitrogen fixers at coastal fronts for both aggregation and transfer of nutrients between these phytoplankton groups

Stereoselective Ag-Catalyzed 1,3-Dipolar Cycloaddition of Activated Trifluoromethyl-Substituted Azomethine Ylides

This is the peer reviewed version of the following article: Chemistry – A European Journal 22.14 (2016): 4952 - 4959, which has been published in final form at http://doi.org/10.1002/chem.201504869. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsA silver-catalyzed 1,3-dipolar cycloaddition of fluorinated azomethine ylides and activated olefins is reported. The reaction offers a straightforward and atom-economical procedure for the preparation of fluorinated pyrrolidines. Broad scope and high levels of diastereoselectivity have been achieved simply by using AgOAc/PPh3as the catalyst system. The high efficiency of the cycloaddition relies on the presence of a metal-coordinating group on the imine moiety, such as an ester or heteroaryl group. The asymmetric version of the cycloaddition has been developed by using Taniaphos as a chiral ligandFinancial support of this work by the Ministerio de Economía y Competitividad (MINECO, CTQ2012-35790) is gratefully acknowledge

In Vivo Conditional Pax4 Overexpression in Mature Islet β-Cells Prevents Stress-Induced Hyperglycemia in Mice

OBJECTIVE To establish the role of the transcription factor Pax4 in pancreatic islet expansion and survival in response to physiological stress and its impact on glucose metabolism, we generated transgenic mice conditionally and selectively overexpressing Pax4 or a diabetes-linked mutant variant (Pax4R129 W) in β-cells. RESEARCH DESIGN AND METHODS Glucose homeostasis and β-cell death and proliferation were assessed in Pax4- or Pax4R129 W-overexpressing transgenic animals challenged with or without streptozotocin. Isolated transgenic islets were also exposed to cytokines, and apoptosis was evaluated by DNA fragmentation or cytochrome C release. The expression profiles of proliferation and apoptotic genes and β-cell markers were studied by immunohistochemistry and quantitative RT-PCR. RESULTS Pax4 but not Pax4R129 W protected animals against streptozotocin-induced hyperglycemia and isolated islets from cytokine-mediated β-cell apoptosis. Cytochrome C release was abrogated in Pax4 islets treated with cytokines. Interleukin-1β transcript levels were suppressed in Pax4 islets, whereas they were increased along with NOS2 in Pax4R129 W islets. Bcl-2, Cdk4, and c-myc expression levels were increased in Pax4 islets while MafA, insulin, and GLUT2 transcript levels were suppressed in both animal models. Long-term Pax4 expression promoted proliferation of a Pdx1-positive cell subpopulation while impeding insulin secretion. Suppression of Pax4 rescued this defect with a concomitant increase in pancreatic insulin content. CONCLUSIONS Pax4 protects adult islets from stress-induced apoptosis by suppressing selective nuclear factor-κB target genes while increasing Bcl-2 levels. Furthermore, it promotes dedifferentiation and proliferation of β-cells through MafA repression, with a concomitant increase in Cdk4 and c-myc expression