Expanded Somatic Mutation Spectrum of MED12 Gene in Uterine Leiomyomas of Saudi Arabian Women

MED12, a subunit of mediator complex genes is known to harbor genetic mutations, (mostly in exon 2), causal to the genesis of uterine leiomyomas among Caucasian, African American, and Asian women. However, the precise relationship between genetic mutations vs. protein or disease phenotype is not well-explained. Therefore, we sought to replicate the MED12 mutation frequency in leiomyomas of Saudi Arabian women, who represents ethnically and culturally distinct population. We performed molecular screening of MED12 gene (in 308 chromosomes belonging to 154 uterine biopsies), analyzed the genotype-disease phenotype correlations and determined the biophysical characteristics of mutated protein through diverse computational approaches. We discovered that >44% (34/77) leiomyomas of Arab women carry a spectrum of MED12 mutations (30 missense, 1 splice site, and 3 indels). In addition to known codon 44, we observed novel somatic mutations in codons 36, 38, and 55. Most genetically mutated tumors (27/30; 90%) demonstrated only one type of genetic change, highlighting that even single allele change in MED12 can have profound impact in transforming the normal uterine myometrium to leiomyomas. An interesting inverse correlation between tumor size and LH is observed when tumor is positive to MED12 mutation (p < 0.05). Our computational investigations suggest that amino acid substitution mutations in exon-2 region of MED12 might contribute to potential alterations in phenotype as well as the stability of MED12 protein. Our study, being the first one from Arab world, confirms the previous findings that somatic MED12 mutations are critical to development and progression of uterine leiomyomas irrespective of the ethnic background. We recommend that mutation screening, particularly codon 44 of MED12 can assist in molecular diagnostics of uterine leiomyomas in majority of the patients

Effect of spark plasma sintering and high-pressure torsion on the microstructural and mechanical properties of a Cu–SiC composite

This investigation examines the problem of homogenization in metal matrix composites (MMCs) and the methods of increasing their strength using severe plastic deformation (SPD). In this research MMCs of pure copper and silicon carbide were synthesized by spark plasma sintering (SPS) and then further processed via highpressure torsion (HPT). The microstructures in the sintered and in the deformed materials were investigated using Scanning Electron Microscopy (SEM) and Scanning Transmission Electron Microscopy (STEM). The mechanical properties were evaluated in microhardness tests and in tensile testing. The thermal conductivity of the composites was measured with the use of a laser pulse technique. Microstructural analysis revealed that HPT processing leads to an improved densification of the SPS-produced composites with significant grain refinement in the copper matrix and with fragmentation of the SiC particles and their homogeneous distribution in the copper matrix. The HPT processing of Cu and the Cu-SiC samples enhanced their mechanical properties at the expense of limiting their plasticity. Processing by HPT also had a major influence on the thermal conductivity of materials. It is demonstrated that the deformed samples exhibit higher thermal conductivity than the initial coarse-grained samples

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019 : a comprehensive demographic analysis for the Global Burden of Disease Study 2019

Background: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. Methods: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10–14 and 50–54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. Findings: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66–2·79) in 2000 to 2·31 (2·17–2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5–137·8) in 2000 to a peak of 139·6 million (133·0–146·9) in 2016. Global livebirths then declined to 135·3 million (127·2–144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4–27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8–67·6) in 2000 to 73·5 years (72·8–74·3) in 2019. The total number of deaths increased from 50·7 million (49·5–51·9) in 2000 to 56·5 million (53·7–59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1–10·3) in 2000 to 5·0 million (4·3–6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0–6·3) in 2000 to 7·7 billion (7·5–8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1–60·8) in 2000 to 63·5 years (60·8–66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019

Mapping inequalities in exclusive breastfeeding in low- and middle-income countries, 2000–2018

Exclusive breastfeeding (EBF)—giving infants only breast-milk for the first 6 months of life—is a component of optimal breastfeeding practices effective in preventing child morbidity and mortality. EBF practices are known to vary by population and comparable subnational estimates of prevalence and progress across low- and middle-income countries (LMICs) are required for planning policy and interventions. Here we present a geospatial analysis of EBF prevalence estimates from 2000 to 2018 across 94 LMICs mapped to policy-relevant administrative units (for example, districts), quantify subnational inequalities and their changes over time, and estimate probabilities of meeting the World Health Organization’s Global Nutrition Target (WHO GNT) of ≥70% EBF prevalence by 2030. While six LMICs are projected to meet the WHO GNT of ≥70% EBF prevalence at a national scale, only three are predicted to meet the target in all their district-level units by 2030

Identification of Biomarkers for Resistance to Fusarium oxysporum f. sp. cubense Infection and in Silico Studies in Musa paradisiaca Cultivar Puttabale through Proteomic Approach

Panama wilt caused by Fusarium oxysporum f. sp. cubense (Foc) is one of the major disease constraints of banana production. Previously, we reported the disease resistance Musa paradisiaca cv. puttabale clones developed from Ethylmethanesulfonate and Foc culture filtrate against Foc inoculation. Here, the same resistant clones and susceptible clones were used for the study of protein accumulation against Foc inoculation by two-dimensional gel electrophoresis (2-DE), their expression pattern and an in silico approach. The present investigation revealed mass-spectrometry identified 16 proteins that were over accumulated and 5 proteins that were under accumulated as compared to the control. The polyphosphoinositide binding protein ssh2p (PBPssh2p) and Indoleacetic acid-induced-like (IAA) protein showed significant up-regulation and down-regulation. The docking of the pathogenesis-related protein (PR) with the fungal protein endopolygalacturonase (PG) exemplify the three ionic interactions and seven hydrophobic residues that tends to good interaction at the active site of PG with free energy of assembly dissociation (1.5 kcal/mol). The protein-ligand docking of the Peptide methionine sulfoxide reductase chloroplastic-like protein (PMSRc) with the ligand β-1,3 glucan showed minimum binding energy (−6.48 kcal/mol) and docking energy (−8.2 kcal/mol) with an interaction of nine amino-acid residues. These explorations accelerate the research in designing the host pathogen interaction studies for the better management of diseases

Exploring knowledge sharing in the Requirement Engineering phase of globally distributed Information Systems development : Perceived challenges and suggestions for improvement

The Master thesis explores the knowledge sharing that takes place during the requirement engineering phase of globally distributed information systems development. In recent years, due to globalization, information systems development activities have become increasingly distributed across different geographical locations. Requirement engineering is an important and knowledge intensive phase in the development of information systems. Requirement engineering is the process of identifying, analyzing, documenting, validating and managing the requirements of a system. Effective and efficient knowledge sharing during the requirement engineering is vital for the successful development of information systems. However, the global distribution of the stakeholders has affected knowledge sharing during requirement engineering in various ways making it more challenging.   Drawing on the theories of knowledge sharing within the field of information systems, this interpretive research study aims at exploring stakeholders’ perceptions about the challenges met during the knowledge sharing in requirement engineering phase of globally distributed information systems development projects. More specifically, this Master thesis explores the perceived challenges and generates a list of suggestions to overcome the challenges by conducting qualitative semi-structured interviews among the key stakeholders, both customers and business analysts.   The findings indicate that the knowledge sharing is influenced by challenges such as cultural differences, language barriers, communication issues, coordination issues arising from multiple stakeholders, time difference and difficulty in sharing tacit knowledge in the globally distributed settings. Participants’ suggestions for overcoming these challenges include cultural trainings, kick off meetings, language trainings, use of translator, face-to-face communication and interaction, video conferencing, scheduling important meetings in the common suitable timings, identification of the main stakeholders, having a mediator and making close observations with face-to-face interactions.     Keywords:  Information Systems, Information Systems Development, Requirement Engineering, Knowledge Sharing, Global Distribution, Outsourcing  

Characterization and in-vitro cytotoxicity of lupeol isolated from leaf extract of ficus mysorensis

Medicinal plant extracts gain more attention in research of modern medical sciences due to their non-lethal activity. The use of traditional medicine practices from plants has been accepted as a main sources for drug discovery in various health disorder especially cancer. Ficus mysorensis has a long history of usage as traditional medicine. The leaf extract of this plant possess phytochemicals such as alkaloids, flavonoids, terpenoids, steroids, saponins, Phenolics and glycosides. The ethanol leaf extract has been subjected to compound isolation and confirmed by GCMS, HPLC Chromatogram, 13C and 1H nuclear magnetic resonance (NMR), IR spectra. Based on spectral studies the isolated compound confirmed that Lupeol. Lupeol compound was evaluated against MCF-7 cell lines by MTT assay. Lupeol induced an effective change in the cell viability of MCF-7 cells with IC50 concentration (198.75 g/ml). Induction of cell death, change in cell morphology and cancerous cells population was observed in the treated cells, but the normal cells was not affected

Development of a nano-zirconia based <SUP>68</SUP>Ge/<SUP>68</SUP>Ga generator for biomedical applications

Introduction: Most of the commercially available 68Ge/68Ga generator systems are not optimally designed for direct applications in a clinical context. We have developed a nano-zirconia based 68Ge/68Ga generator system for accessing 68Ga amenable for the preparation of radiopharmaceuticals. Methods: Nano-zirconia was synthesized by the in situ reaction of zirconyl chloride with ammonium hydroxide in alkaline medium. The physical characteristics of the material were studied by various analytical techniques. A 740 MBq (20 mCi) 68Ge/68Ga generator was developed using this sorbent and its performance was evaluated for a period of 1 year. The suitability of 68Ga for labeling biomolecules was ascertained by labeling DOTA-TATE with 68Ga. Results: The material synthesized was nanocrystalline with average particle size of ∼7 nm, pore-size of ∼4 Å and a high surface area of 340±10 m2 g-1. 68Ga could be regularly eluted from this generator in 0.01N HCl medium with an overall radiochemical yield >80% and with high radionuclidic (&#60;10-5% of 68Ge impurity) and chemical purity (&#60;0.1 ppm of Zr, Fe and Mn ions). The compatibility of the product for preparation of 68Ga-labeled DOTA-TATE under the optimized reaction conditions was found to be satisfactory in terms of high labeling yields (>99%). The generator gave a consistent performance with respect to the elution yield and purity of 68Ga over a period of 1 year. Conclusions: The feasibility of preparing an efficient 68Ge/68Ga generator which can directly be used for biomedical applications has been demonstrated

Practicality of tetragonal nano-zirconia as a prospective sorbent in the preparation of <SUP>99</SUP>Mo/<SUP>99m</SUP>Tc generator for biomedical applications

The feasibility of using tetragonal nano-zirconia (t-ZrO2) as an effective sorbent for developing a 99Mo/99mTc chromatographic generator was demonstrated. The structural characteristics of the sorbent matrix were investigated by different analytical techniques such as XRD, BET surface area analysis, FT-IR, TEM etc. The material synthesized was nanocrystalline, in tetragonal phase with an average particle size of ~7 nm and a large surface area of 340 m2 g−1. The equilibrium sorption capacity of t-ZrO2 is >250 mg Mo g−1. The present study indicates that 99Mo is both strongly and selectively retained by t-ZrO2 at acidic pH and 99mTc could be readily eluted from it, using 0.9% NaCl solution. A 9.25 GBq (250 mCi) t-ZrO2 based chromatographic 99Mo/99mTc generator was developed and its performance was repeatedly evaluated for 10 days. 99mTc could be eluted with >85% yield having acceptable radionuclidic, radiochemical and chemical purity for clinical applications. The compatibility of the product in the preparation of 99mTc labeled formulations such as 99mTc-EC and 99mTc-DMSA was evaluated and found to be satisfactory