Arsenic contamination in groundwater and residents from Ha Nam and Ha Tay Provinces of Red River Delta, Vietnam

Joint Research on Environmental Science and Technology for the Eart

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

Aims The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. Methods and Results We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analyzed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as “pathogenic” by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that 2 variants in KCNH2 and SCN5A, 4 variants in SCN10A, and 1 variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from “Uncertain significance” to “Likely pathogenic” in 6 probands. Conclusions Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD. Translational Perspective Whole-exome sequencing (WES) may be helpful in determining the causes of cardiac conduction system disease (CCSD), however, the identification of pathogenic variants remains a challenge. We performed WES of 23 probands diagnosed with early-onset CCSD, and identified 12 pathogenic or likely pathogenic variants in 11 of these probands (48%) according to the 2015 ACMG standards and guidelines. In this context, functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants, and SCN10A may be one of the major development factors in CCSD

Cross-National Differences in Victimization : Disentangling the Impact of Composition and Context

Varying rates of criminal victimization across countries are assumed to be the outcome of countrylevel structural constraints that determine the supply ofmotivated o¡enders, as well as the differential composition within countries of suitable targets and capable guardianship. However, previous empirical tests of these ‘compositional’ and ‘contextual’ explanations of cross-national di¡erences have been performed upon macro-level crime data due to the unavailability of comparable individual-level data across countries. This limitation has had two important consequences for cross-national crime research. First, micro-/meso-level mechanisms underlying cross-national differences cannot be truly inferred from macro-level data. Secondly, the e¡ects of contextual measures (e.g. income inequality) on crime are uncontrolled for compositional heterogeneity. In this paper, these limitations are overcome by analysing individual-level victimization data across 18 countries from the International CrimeVictims Survey. Results from multi-level analyses on theft and violent victimization indicate that the national level of income inequality is positively related to risk, independent of compositional (i.e. micro- and meso-level) di¡erences. Furthermore, crossnational variation in victimization rates is not only shaped by di¡erences in national context, but also by varying composition. More speci¢cally, countries had higher crime rates the more they consisted of urban residents and regions with lowaverage social cohesion.

Altered Host Immunity, Human T Lymphotropic Virus Type I Replication, and Risk of Adult T-Cell Leukemia/Lymphoma: A Prospective Analysis from the ATL Cohort Consortium

Background: Adult T-cell leukemia/lymphoma (ATL) is a rare and often fatal outcome of infection with human T-lymphotropic virus type I (HTLV-I). Altered host immunity in HTLV-I carriers has been postulated as a risk factor for ATL, but is not well understood. Methods: We prospectively examined well-validated serologic markers of HTLV-I pathogenesis and host immunity in 53 incident ATL cases and 150 carefully matched asymptomatic HTLV-I carriers from eight population-based studies in Japan, Jamaica, the United States and Brazil. We used multivariable conditional logistic regression, conditioned on the matching factors (cohort/race, age, sex, and sample collection year), to evaluate the biomarkers’ associations with ATL in all subjects and by years (≤5, >5) from blood draw to ATL diagnosis. Results: In the pooled population, above-median soluble interleukin-2-receptor-alpha levels (sIL2R, v. ≤ median; odds ratio (OR), 95% confidence interval (CI)=4.08, 1.47-11.29) and anti-Tax seropositivity (anti-Tax; OR, 95% CI=2.97, 1.15-7.67), which indicate T cell activation and HTLV-I replication, respectively, were independently associated with an increased ATL risk. Above-median total immunoglobulin E levels (v. ≤ median; OR, 95% CI=0.45, 0.19-1.06), which indicate type 2 (B cell) activation, predicted a lower ATL risk. The sIL2R and anti-Tax associations with ATL were stronger in samples collected ≤5 years pre-diagnosis. Conclusions: The biomarker profile predictive of ATL risk suggests a role for heightened T cell activation and HTLV-I replication and diminished type 2 immunity in the etiology of ATL in HTLV-I carriers. Translation of these findings to clinical risk prediction or early ATL detection requires further investigation. Acknowledgements: This abstract is presented on behalf of the ATL Cohort Consortium

Support for UNRWA's survival

The United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) provides life-saving humanitarian aid for 5·4 million Palestine refugees now entering their eighth decade of statelessness and conflict. About a third of Palestine refugees still live in 58 recognised camps. UNRWA operates 702 schools and 144 health centres, some of which are affected by the ongoing humanitarian disasters in Syria and the Gaza Strip. It has dramatically reduced the prevalence of infectious diseases, mortality, and illiteracy. Its social services include rebuilding infrastructure and homes that have been destroyed by conflict and providing cash assistance and micro-finance loans for Palestinians whose rights are curtailed and who are denied the right of return to their homeland

Burden of Total and Cause-Specific Mortality Related to Tobacco Smoking among Adults Aged ≥45 Years in Asia: A Pooled Analysis of 21 Cohorts

Background:Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest.Methods and Findings:We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan-accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37-1.51) and 1.48-fold (1.38-1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%-17.2%) and 3.3% (2.6%-4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000-1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: A 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y.Conclusions:Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented.Please see later in the article for the Editors' Summary. © 2014 Zheng et al

Insights into Land Plant Evolution Garnered from the Marchantia polymorpha Genome.

The evolution of land flora transformed the terrestrial environment. Land plants evolved from an ancestral charophycean alga from which they inherited developmental, biochemical, and cell biological attributes. Additional biochemical and physiological adaptations to land, and a life cycle with an alternation between multicellular haploid and diploid generations that facilitated efficient dispersal of desiccation tolerant spores, evolved in the ancestral land plant. We analyzed the genome of the liverwort Marchantia polymorpha, a member of a basal land plant lineage. Relative to charophycean algae, land plant genomes are characterized by genes encoding novel biochemical pathways, new phytohormone signaling pathways (notably auxin), expanded repertoires of signaling pathways, and increased diversity in some transcription factor families. Compared with other sequenced land plants, M. polymorpha exhibits low genetic redundancy in most regulatory pathways, with this portion of its genome resembling that predicted for the ancestral land plant. PAPERCLIP

Novel Drug Delivery Particles Can Provide Dual Effects on Cancer "Theranostics" in Boron Neutron Capture Therapy

Boron (B) neutron capture therapy (BNCT) is a novel non-invasive targeted cancer therapy based on the nuclear capture reaction 10B (n, alpha) 7Li that enables the death of cancer cells without damaging neighboring normal cells. However, the development of clinically approved boron drugs remains challenging. We have previously reported on self-forming nanoparticles for drug delivery consisting of a biodegradable polymer, namely, “AB-type” Lactosome® nanoparticles (AB-Lac particles)- highly loaded with hydrophobic B compounds, namely o-Carborane (Carb) or 1,2-dihexyl-o-Carborane (diC6-Carb), and the latter (diC6-Carb) especially showed the “molecular glue” effect. Here we present in vivo and ex vivo studies with human pancreatic cancer (AsPC-1) cells to find therapeutically optimal formulas and the appropriate treatment conditions for these particles. The biodistribution of the particles was assessed by the tumor/normal tissue ratio (T/N) in terms of tumor/muscle (T/M) and tumor/blood (T/B) ratios using near-infrared fluorescence (NIRF) imaging with indocyanine green (ICG). The in vivo and ex vivo accumulation of B delivered by the injected AB-Lac particles in tumor lesions reached a maximum by 12 h post-injection. Irradiation studies conducted both in vitro and in vivo showed that AB-Lac particles-loaded with either 10B-Carb or 10B-diC6-Carb significantly inhibited the growth of AsPC-1 cancer cells or strongly inhibited their growth, with the latter method being significantly more effective. Surprisingly, a similar in vitro and in vivo irradiation study showed that ICG-labeled AB-Lac particles alone, i.e., without any 10B compounds, also revealed a significant inhibition. Therefore, we expect that our ICG-labeled AB-Lac particles-loaded with 10B compound(s) may be a novel and promising candidate for providing not only NIRF imaging for a practical diagnosis but also the dual therapeutic effects of induced cancer cell death, i.e., “theranostics”