Abnormal Dosage of Ultraconserved Elements Is Highly Disfavored in Healthy Cells but Not Cancer Cells

Ultraconserved elements (UCEs) are strongly depleted from segmental duplications and copy number variations (CNVs) in the human genome, suggesting that deletion or duplication of a UCE can be deleterious to the mammalian cell. Here we address the process by which CNVs become depleted of UCEs. We begin by showing that depletion for UCEs characterizes the most recent large-scale human CNV datasets and then find that even newly formed de novo CNVs, which have passed through meiosis at most once, are significantly depleted for UCEs. In striking contrast, CNVs arising specifically in cancer cells are, as a rule, not depleted for UCEs and can even become significantly enriched. This observation raises the possibility that CNVs that arise somatically and are relatively newly formed are less likely to have established a CNV profile that is depleted for UCEs. Alternatively, lack of depletion for UCEs from cancer CNVs may reflect the diseased state. In support of this latter explanation, somatic CNVs that are not associated with disease are depleted for UCEs. Finally, we show that it is possible to observe the CNVs of induced pluripotent stem (iPS) cells become depleted of UCEs over time, suggesting that depletion may be established through selection against UCE-disrupting CNVs without the requirement for meiotic divisions

Dose de-escalation of intrapleural tissue plasminogen activator therapy for pleural infection. The alteplase dose assessment for Pleural infection Therapy project

Rationale: Intrapleural therapy with a combination of tissue plasminogen activator (tPA) 10 mg and DNase 5 mg administered twice daily has been shown in randomized and open-label studies to successfully manage over 90% of patients with pleural infection without surgery. Potential bleeding risks associated with intrapleural tPA and its costs remain important concerns. The aim of the ongoing Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) project is to investigate the efficacy and safety of dose de-escalation for intrapleural tPA. The first of several planned studies is presented here. Objectives: To evaluate the efficacy and safety of a reduced starting dose regimen of 5 mg of tPA with 5 mg of DNase administered intrapleurally for pleural infection. Methods: Consecutive patients with pleural infection at four participating centers in Australia, the United Kingdom, and New Zealand were included in this observational, open-label study. Treatment was initiated with tPA 5 mg and DNase 5 mg twice daily. Subsequent dose escalation was permitted at the discretion of the attending physician. Data relating to treatment success, radiological and systemic inflammatory changes (blood C-reactive protein), volume of fluid drained, length of hospital stay, and treatment complications were extracted retrospectively from the medical records. Results: We evaluated 61 patients (41 males; age, 57 ± 16 yr). Most patients (n = 58 [93.4%]) were successfully treated without requiring surgery for pleural infection. Treatment success was corroborated by clearance of pleural opacities visualized by chest radiography (from 42% [interquartile range, 22–58] to 16% [8–31] of hemithorax; P < 0.001), increase in pleural fluid drainage (from 175 ml in the 24 h preceding treatment to 2,025 ml [interquartile range, 1,247–2,984] over 72 h of therapy; P <  0.05) and a reduction in blood C-reactive protein (P < 0.05). Seven patients (11.5%) had dose escalation of tPA to 10 mg. Three patients underwent surgery. Three patients (4.9%) received blood transfusions for gradual pleural blood loss; none were hemodynamically compromised. Pain requiring escalation of analgesia affected 36% of patients; none required cessation of therapy. Conclusions: These pilot data suggest that a starting dose of 5 mg of tPA administered intrapleurally twice daily in combination with 5 mg of DNase for the treatment of pl

Single-molecule super-resolution imaging of chromosomes and in situ haplotype visualization using Oligopaint FISH probes

Fluorescence in situ hybridization (FISH) is a powerful single-cell technique for studying nuclear structure and organization. Here we report two advances in FISH-based imaging. We first describe the in situ visualization of single-copy regions of the genome using two single-molecule super-resolution methodologies. We then introduce a robust and reliable system that harnesses single-nucleotide polymorphisms (SNPs) to visually distinguish the maternal and paternal homologous chromosomes in mammalian and insect systems. Both of these new technologies are enabled by renewable, bioinformatically designed, oligonucleotide-based Oligopaint probes, which we augment with a strategy that uses secondary oligonucleotides (oligos) to produce and enhance fluorescent signals. These advances should substantially expand the capability to query parent-of-origin-specific chromosome positioning and gene expression on a cell-by-cell basis

Associations between recent intimate partner violence and receipt and quality of perinatal health services in Uttar Pradesh

Background India suffers some of the highest maternal and neonatal mortality rates in the world. Intimate partner violence (IPV) can be a barrier to utilization of perinatal care, and has been associated with poor maternal and neonatal health outcomes. However, studies that assess the relationship between IPV and perinatal health care often focus solely on receipt of services, and not the quality of the services received. Methods and findings Data were collected in 2016–2017 from a representative sample of women (15-49yrs) in Uttar Pradesh, India who had given birth within the previous 12 months (N = 5020), including use of perinatal health services and past 12 months experiences of physical and sexual IPV. Multivariate logistic regression models assessed whether physical or sexual IPV were associated with perinatal health service utilization and quality. Reports of IPV were not associated with odds of receiving antenatal care or a health worker home visit during the third trimester, but physical IPV was associated with fewer diagnostic tests during antenatal visits (beta = -0.30), and fewer health topics covered during home visits (beta = -0.44). Recent physical and recent sexual IPV were both associated with decreased odds of institutional delivery (physical IPV AOR 0.65; sexual IPV AOR 0.61), and recent sexual IPV was associated with leaving a delivery facility earlier than recommended (AOR = 1.87). Neither form of IPV was associated with receipt of a postnatal home visit, but recent physical IPV was associated with fewer health topics discussed during such visits (beta = -0.26). Conclusions In this study, reduced quantity and quality of perinatal health care were associated with recent IPV experiences. In cases where IPV was not related to care receipt, IPV remained associated with diminished care quality. Additional study to understand the mechanisms underlying associations between IPV and care qualities is required to inform health services

SUITABILITY OF ATTANAGALU OYA AS A DRINKING WATER SOURCE

Attanagalu oya basin is situated between the two major river basins Kelani and Maha Oya .It plays amajor role in national water supply since it contains major national water supply and drainage boardintakes. This study intends to study the quality of water of the Attanagalu Oya and its suitability fordrinking purpose. Because of its significance as a drinking water source it is important to maintain thequality of the water. Samples were collected from ten selected sampling locations along the main riverincluding one near the origin of the river, near the sea outfall, NWS&DB intakes from the main river.Other locations were selected so as to have the similar distance between sampling locations Samplingwas taken during both high and low flow rate conditions. Analysis was done on physical, chemicaland biological parameters.Results showed that records of COD, BOD, DO, pH, nutrient are low during the high flow rate whilethe levels of turbidity, metal iron total coliform and faecal coliform are high during the high flow rate

Identification of economic vulnerability of tsunami affected fishing community in Sri Lanka for rehabilitation and reconstruction A Case study of tsunami affected fishing community in Kalutara district

The Indian Ocean Tsunami that hit the country on 26 December 2004 has had severe impact onFisheries Industry. It affected the Fisheries infrastructures and community in 12 out of 14 coastaldistricts. This study examined the impacts on the vulnerability of fishing community of Kalutaradistrict and the impact of the tsunami reliefand rehabilitation activities on the level of vulnerability ofthis community.A Survey was conducted at Three Fisheries Inspector (FI) Divisions in Kalutara District and compositevulnerability indices were computed by using Normalization method. The variables of income permonth, expenditure per month, number of dependents, number offishing days per month, Land size,value of productive assets, savings per month, loans taken and age of household head were taken intoaccount for the computation of Composite Vulnerability Index. Results showed that compositevulnerability index is 0.41 and fishing community ofKalutara District is in average level of vulnerabilityThe short-term rehabilitation and reconstruction strategies and programmes implemented to assisttsunami affected community to rebuilt their livelihood assets, re-establish their fishing activities andstart fish marketing, processing and distribution showed some success in Kalutara District. However,institutional support facilities and services are not fully completed. To smooth implementation, effectivecoordination will be required for channell ing of official and private funds and improved co-ordinationand communication among the various agencies be critical for rehabilitate and reconstruct on fishingcomrn un ity.This composite vulnerability computation, which can be applied to evaluate effectiveness and successof strategies and programmes, implemented at different time and locations.

Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90) + HLA-DRA hi sublining fibroblasts, IL1B + pro-inflammatory monocytes, ITGAX + TBX21 + autoimmune-associated B cells and PDCD1 + peripheral helper T (T PH ) cells and follicular helper T (T FH ) cells. We defined distinct subsets of CD8 + T cells characterized by GZMK + , GZMB + , and GNLY + phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1 + HLA-DRA hi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis

Triploidy leads to a mismatch of smoltification biomarkers in the gill and differences in the optimal salinity for post-smolt growth in Atlantic salmon

Sterile triploid Atlantic salmon (Salmo salar) show inconsistent seawater grow-out, but the reason why remains unclear. The purpose of this study was to determine the salinity optima of triploid post-smolts. Diploids and triploids were assessed for smoltification status during an underyearling smolt regime before being transferred to one of four different salinities, 0, 11, 23 and 35 ppt at 12 °C and under 24 h continuous light for 83 days. During this period, fish growth, plasma biochemistry, and production traits (vertebral deformities, ocular cataracts, sexual maturation) were monitored. Molecular biomarkers in the gill (nkaα1a, nkaα1b, nkcc1a) suggested triploids reached peak smolt earlier than diploids and began the desmoltification process before the start of the salinity treatments, however this was not reflected in gill Na+/K+-ATPase enzyme activity. At the initiation of the salinity treatments triploids were significantly larger than diploids (mean weight g ± SE: 71 ± 0.7 and 87.2 ± 0.8 for diploids and triploids, respectively) and there was a ploidy effect on post-smolt growth, with body weight showing a clearer positive trend with salinity in diploids (0 < 11 = 23 = 35 ppt) than in triploids (0 < 11 < 35 = 23 ppt) (final mean weight g ± SE: 255.2 ± 7.4, 303.9 ± 9, 313.9 ± 9 and 342.4 ± 12 for diploids and 322.9 ± 9.7, 361.7 ± 10.7, 425.9 ± 12.1, 415.2 ± 12.2 for triploids at 0, 11, 23, and 35 ppt, respectively). Plasma Na+ and Cl− increased, but plasma pH decreased, with increasing salinity in both ploidy. However, ploidy only had transient effects on plasma biochemistry depending on the salinity treatment. There was no ploidy effect on vertebral deformities (21% of both ploidy had one or more deformed vertebra). In contrast, triploids had a significantly higher prevalence of ocular cataracts (84 vs 98% in diploids and triploids, respectively) with a higher mean cataract score (mean ± SE: 1.93 ± 0.1 and 2.78 ± 0.1 for diploids and triploids, respectively), but a significantly lower prevalence of pubertal male post-smolts (15 vs 2% in diploids and triploids, respectively). Salinity treatment had no effect on vertebral deformities, cataracts, or post-smolt sexual maturation. In summary, there was a ploidy mismatch for smoltification biomarkers in the gill and salinity had a strong effect on post-smolt growth, but the effects were ploidy dependent.publishedVersio