Tipping the polaron–bipolaron balance : concentration and spin effects in doped oligo(aniline)s observed by UV-vis-NIR and TD-DFT

The oxidation states and doped forms of oligo(aniline)s are readily interconverted, and each state has characteristic UV-vis-NIR absorptions, making this spectroscopic technique ideal for in situ analysis of oligo(aniline) behaviour. However, experimental isolation of some of these states can be challenging and quantitative agreement between experimental and calculated spectra has been poor, making it difficult to identify the exact structure(s) and properties of each state. Here we report a comprehensive study of the UV-vis-NIR spectra of all oxidation states and doped forms of a series of oligo(aniline)s of varying lengths (dimer, tetramer and octamer), using a computationally inexpensive DFT method that is particularly suited to molecules with charge-transfer character. The computational study suggests that doped oligo(aniline)s form mixtures of spin isomers (polaronic and bipolaronic forms) in solution, and we have been able to evaluate and compare the most likely electronic configurations, as well as supporting our insights experimentally, by ESR spectroscopy. This doping approach enables tuning of the spin isomer equilibrium position by varying the concentration of protonic dopant, offering a new pathway to explore the electronic structure of π-conjugated molecules more generally, and opening up new approaches to the design of spintronic materials

ABCA7 frameshift deletion associated with Alzheimer disease in African Americans

Objective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD. Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. Results: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance (p = 1.414 × 10−5, OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. Conclusions: This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD

Understanding interactions in face-to-face and remote undergraduate science laboratories

This paper reviews the ways in which interactions have been studied, and the findings of such studies, in science education in both face-to-face and remote laboratories. Guided by a systematic selection process, 27 directly relevant articles were analysed based on three categories: the instruments used for measuring interactions, the research findings on student interactions, and the theoretical frameworks used in the studies of student interactions. In face-to-face laboratories, instruments for measuring interactions and the characterisation of the nature of interactions were prominent. For remote laboratories, the analysis of direct interactions was found to be lacking. Instead, studies of remote laboratories were mainly concerned with their practical scope. In addition, it is found that only a limited number of theoretical frameworks have been developed and applied in the research design. Existent theories are summarised and possible theoretical frameworks that may be implemented in studies of interactions in undergraduate laboratories are proposed. Finally, future directions for research on the interrelationship between student interactions and laboratory learning are suggested

Cartography of Methicillin-Resistant S. aureus Transcripts: Detection, Orientation and Temporal Expression during Growth Phase and Stress Conditions

BACKGROUND: Staphylococcus aureus is a versatile bacterial opportunist responsible for a wide spectrum of infections. The severity of these infections is highly variable and depends on multiple parameters including the genome content of the bacterium as well as the condition of the infected host. Clinically and epidemiologically, S. aureus shows a particular capacity to survive and adapt to drastic environmental changes including the presence of numerous antimicrobial agents. Mechanisms triggering this adaptation remain largely unknown despite important research efforts. Most studies evaluating gene content have so far neglected to analyze the so-called intergenic regions as well as potential antisense RNA molecules. PRINCIPAL FINDINGS: Using high-throughput sequencing technology, we performed an inventory of the whole transcriptome of S. aureus strain N315. In addition to the annotated transcription units, we identified more than 195 small transcribed regions, in the chromosome and the plasmid of S. aureus strain N315. The coding strand of each transcript was identified and structural analysis enabled classification of all discovered transcripts. RNA purified at four time-points during the growth phase of the bacterium allowed us to define the temporal expression of such transcripts. A selection of 26 transcripts of interest dispersed along the intergenic regions was assessed for expression changes in the presence of various stress conditions including pH, temperature, oxidative shocks and growth in a stringent medium. Most of these transcripts showed expression patterns specific for the defined stress conditions that we tested. CONCLUSIONS: These RNA molecules potentially represent important effectors of S. aureus adaptation and more generally could support some of the epidemiological characteristics of the bacterium

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18

The effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis

Background A growing body of research identifies the harmful effects that adverse childhood experiences (ACEs; occurring during childhood or adolescence; eg, child maltreatment or exposure to domestic violence) have on health throughout life. Studies have quantified such effects for individual ACEs. However, ACEs frequently co-occur and no synthesis of findings from studies measuring the effect of multiple ACE types has been done. Methods In this systematic review and meta-analysis, we searched five electronic databases for cross-sectional, case-control, or cohort studies published up to May 6, 2016, reporting risks of health outcomes, consisting of substance use, sexual health, mental health, weight and physical exercise, violence, and physical health status and conditions, associated with multiple ACEs. We selected articles that presented risk estimates for individuals with at least four ACEs compared with those with none for outcomes with sufficient data for meta-analysis (at least four populations). Included studies also focused on adults aged at least 18 years with a sample size of at least 100. We excluded studies based on high-risk or clinical populations. We extracted data from published reports. We calculated pooled odds ratios (ORs) using a random-effects model. Findings Of 11 621 references identified by the search, 37 included studies provided risk estimates for 23 outcomes, with a total of 253 719 participants. Individuals with at least four ACEs were at increased risk of all health outcomes compared with individuals with no ACEs. Associations were weak or modest for physical inactivity, overweight or obesity, and diabetes (ORs of less than two); moderate for smoking, heavy alcohol use, poor self-rated health, cancer, heart disease, and respiratory disease (ORs of two to three), strong for sexual risk taking, mental ill health, and problematic alcohol use (ORs of more than three to six), and strongest for problematic drug use and interpersonal and self-directed violence (ORs of more than seven). We identified considerable heterogeneity (I 2 of > 75%) between estimates for almost half of the outcomes. Interpretation To have multiple ACEs is a major risk factor for many health conditions. The outcomes most strongly associated with multiple ACEs represent ACE risks for the next generation (eg, violence, mental illness, and substance use). To sustain improvements in public health requires a shift in focus to include prevention of ACEs, resilience building, and ACE-informed service provision. The Sustainable Development Goals provide a global platform to reduce ACEs and their life-course effect on health. Funding Public Health Wales. © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licens

Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome (“global” ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles (“local” ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry.

OBJECTIVES: To determine factors associated with COVID-19-related death in people with rheumatic diseases. METHODS: Physician-reported registry of adults with rheumatic disease and confirmed or presumptive COVID-19 (from 24 March to 1 July 2020). The primary outcome was COVID-19-related death. Age, sex, smoking status, comorbidities, rheumatic disease diagnosis, disease activity and medications were included as covariates in multivariable logistic regression models. Analyses were further stratified according to rheumatic disease category. RESULTS: Of 3729 patients (mean age 57 years, 68% female), 390 (10.5%) died. Independent factors associated with COVID-19-related death were age (66-75 years: OR 3.00, 95% CI 2.13 to 4.22; >75 years: 6.18, 4.47 to 8.53; both vs ≤65 years), male sex (1.46, 1.11 to 1.91), hypertension combined with cardiovascular disease (1.89, 1.31 to 2.73), chronic lung disease (1.68, 1.26 to 2.25) and prednisolone-equivalent dosage >10 mg/day (1.69, 1.18 to 2.41; vs no glucocorticoid intake). Moderate/high disease activity (vs remission/low disease activity) was associated with higher odds of death (1.87, 1.27 to 2.77). Rituximab (4.04, 2.32 to 7.03), sulfasalazine (3.60, 1.66 to 7.78), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate or tacrolimus: 2.22, 1.43 to 3.46) and not receiving any disease-modifying anti-rheumatic drug (DMARD) (2.11, 1.48 to 3.01) were associated with higher odds of death, compared with methotrexate monotherapy. Other synthetic/biological DMARDs were not associated with COVID-19-related death. CONCLUSION: Among people with rheumatic disease, COVID-19-related death was associated with known general factors (older age, male sex and specific comorbidities) and disease-specific factors (disease activity and specific medications). The association with moderate/high disease activity highlights the importance of adequate disease control with DMARDs, preferably without increasing glucocorticoid dosages. Caution may be required with rituximab, sulfasalazine and some immunosuppressants

Extensive sequencing of seven human genomes to characterize benchmark reference materials

The Genome in a Bottle Consortium, hosted by the National Institute of Standards and Technology (NIST) is creating reference materials and data for human genome sequencing, as well as methods for genome comparison and benchmarking. Here, we describe a large, diverse set of sequencing data for seven human genomes; five are current or candidate NIST Reference Materials. The pilot genome, NA12878, has been released as NIST RM 8398. We also describe data from two Personal Genome Project trios, one of Ashkenazim Jewish ancestry and one of Chinese ancestry. The data come from 12 technologies: BioNano Genomics, Complete Genomics paired-end and LFR, Ion Proton exome, Oxford Nanopore, Pacific Biosciences, SOLiD, 10X Genomics GemCode WGS, and Illumina exome and WGS paired-end, mate-pair, and synthetic long reads. Cell lines, DNA, and data from these individuals are publicly available. Therefore, we expect these data to be useful for revealing novel information about the human genome and improving sequencing technologies, SNP, indel, and structural variant calling, and de novo assembly