Identification of two distinct structural regions in a human porcine endogenous retrovirus receptor, HuPAR2, contributing to function for viral entry

<p>Abstract</p> <p>Background</p> <p>Of the three subclasses of Porcine Endogenous Retrovirus (PERV), PERV-A is able to infect human cells via one of two receptors, HuPAR1 or HuPAR2. Characterizing the structure-function relationships of the two HuPAR receptors in PERV-A binding and entry is important in understanding receptor-mediated gammaretroviral entry and contributes to evaluating the risk of zoonosis in xenotransplantation.</p> <p>Results</p> <p>Chimeras of the non-permissive murine PAR and the permissive HuPAR2, which scanned the entire molecule, revealed that the first 135 amino acids of HuPAR2 are critical for PERV-A entry. Within this critical region, eighteen single residue differences exist. Site-directed mutagenesis used to map single residues confirmed the previously identified L109 as a binding and infectivity determinant. In addition, we identified seven residues contributing to the efficiency of PERV-A entry without affecting envelope binding, located in multiple predicted structural motifs (intracellular, extracellular and transmembrane). We also show that expression of HuPAR2 in a non-permissive cell line results in an average 11-fold higher infectivity titer for PERV-A compared to equal expression of HuPAR1, although PERV-A envelope binding is similar. Chimeras between HuPAR-1 and -2 revealed that the region spanning amino acids 152–285 is responsible for the increase of HuPAR2. Fine mapping of this region revealed that the increased receptor function required the full sequence rather than one or more specific residues.</p> <p>Conclusion</p> <p>HuPAR2 has two distinct structural regions. In one region, a single residue determines binding; however, in both regions, multiple residues influence receptor function for PERV-A entry.</p

Cigarette smoking prevalence and associated factors among college students, Amhara, Ethiopia

Introduction:&nbsp;tobacco is the only legal drug that kills many of its users when used exactly as intended by the manufacturers. It is estimated that of the 1.1 billion smokers worldwide, nearly 80% of them live in low and middle-income countries. This trend increases in college and university students with most smokers starting to smoke during adolescent. The aim of this study is to assess cigarette smoking prevalence and associated factors among a select group of college of teachers´ education students. Methods:&nbsp;a cross-sectional study was conducted. Multistage sampling was used to select 605 study participants from across the eight departments of the Injibara College of Teachers´ Education. Each subject was selected by simple random sampling technique after proportional allocation to each class. EpiData version 4.2 was used for data entry and Stata version 14 was used for data cleaning and analysis. Variables with p-value &lt; 0.2 in bi-variable analysis were selected for multi-variable analysis. Adjusted odds ratio (AOR) with 95% confidence interval (CI) was reported to show the strength of association. Results:&nbsp;the current prevalence of cigarette smoking is 6.8% amongst the Injibara College of Teachers´ Education students. Males [AOR: 2.84 (95% CI: 1.13, 7.14)], divorced marital status [AOR: 7.27 (95% CI: 1.23, 42.85)], food source in hostel [AOR: 11.62 (95% CI 3.23, 41.71)] and exposure to family/other smokers [AOR: 6.17 (95% CI: 2.17, 16.06)] were statistically significant factors for cigarette smoking. Conclusion:&nbsp;the prevalence of cigarette smoking was relatively low. Male, marital status, source of food, and exposure to family/other smokers were identified associated factors. Policy makers and health regulatory body are strongly encouraged to consider this evidence and the associated factors for smoking in their efforts to develop and implement tobacco control laws

Burden of podoconiosis in poor rural communities in Guliso woreda, western Ethiopia

Background. Podoconiosis is an environmental lymphoedema affecting people living and working barefoot on irritant red clay soil. Podoconiosis is relatively well described in southern Ethiopia, but remains neglected in other parts of the Ethiopian highlands. This study aimed to assess the burden of podoconiosis in rural communities in western Ethiopia. Methodology/Principal Findings. A cross-sectional study was conducted in Gulliso woreda (district), west Ethiopia. A household survey in the 26 rural kebeles (villages) of this district was conducted to identify podoconiosis patients and to measure disease prevalence. A more detailed study was done in six randomly selected kebeles to describe clinical features of the disease, patients’ experiences of foot hygiene, and shoe wearing practice. 1,935 cases of podoconiosis were registered, giving a prevalence of 2.8%. The prevalence was higher in those aged 15 – 64 years (5.2%) and in females than males (prevalence ratio 2.6:1). 90.3% of patients were in the 15 – 64 year age group. In the detailed study, 335 cases were interviewed and their feet assessed. The majority of patients were farmers, uneducated, and poor. Two-third of patients developed the disease before the age of thirty. Almost all patients (97.0%) had experienced adenolymphangitis (ALA - red, hot legs, swollen and painful groin) at least once during the previous year. Patients experienced an average of 5.5 ALA episodes annually, each of average 4.4 days, thus 24 working days were lost annually. The incidence of ALA in podoconiosis patients was higher than that reported for filariasis in other countries. Shoe wearing was limited mainly due to financial problems. Conclusions. We have documented high podoconiosis prevalence, frequent adenolymphangitis and high disease-related morbidity in west Ethiopia. Interventions must be developed to prevent, treat and control podoconiosis, one of the core neglected tropical diseases in Ethiopia

A panel of recombinant Leishmania donovani cell surface and secreted proteins identifies LdBPK_323600.1 as a serological marker of symptomatic infection

Visceral leishmaniasis is a deadly infectious disease and is one of the world’s major neglected health problems. Because the symptoms of infection are similar to other endemic diseases, accurate diagnosis is crucial for appropriate treatment. Definitive diagnosis using splenic or bone marrow aspirates is highly invasive, and so, serological assays are preferred, including the direct agglutination test (DAT) or rK39 strip test. These tests, however, are either difficult to perform in the field (DAT) or lack specificity in some endemic regions (rK39), making the development of new tests a research priority. The availability of Leishmania spp. genomes presents an opportunity to identify new diagnostic targets. Here, we use genome data and a mammalian protein expression system to create a panel of 93 proteins consisting of the extracellular ectodomains of the Leishmania donovani cell surface and secreted proteins. We use these panel and sera from murine experimental infection models and natural human and canine infections to identify new candidates for serological diagnosis. We observed a concordance between the most immunoreactive antigens in different host species and transmission settings. The antigen encoded by the LdBPK_323600.1 gene can diagnose Leishmania infections with high sensitivity and specificity in patient cohorts from different endemic regions including Bangladesh and Ethiopia. In longitudinal sampling of treated patients, we observed reductions in immunoreactivity to LdBPK_323600.1 suggesting it could be used to diagnose treatment success. In summary, we have identified new antigens that could contribute to improved serological diagnostic tests to help control the impact of this deadly tropical infectious disease. IMPORTANCE Visceral leishmaniasis is fatal if left untreated with patients often displaying mild and non-specific symptoms during the early stages of infection making accurate diagnosis important. Current methods for diagnosis require highly trained medical staff to perform highly invasive biopsies of the liver or bone marrow which pose risks to the patient. Less invasive molecular tests are available but can suffer from regional variations in their ability to accurately diagnose an infection. To identify new diagnostic markers of visceral leishmaniasis, we produced and tested a panel of 93 proteins identified from the genome of the parasite responsible for this disease. We found that the pattern of host antibody reactivity to these proteins was broadly consistent across naturally acquired infections in both human patients and dogs, as well as experimental rodent infections. We identified a new protein called LdBPK_323600.1 that could accurately diagnose visceral leishmaniasis infections in humans

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Petrological and geochemical characteristics of flood and shield basalts from Kesem-Megezez section, northwestern Ethiopian Plateau: Implication for their mantle source variations

The Kesem-Megezez Section is located on the western escarpment of the main Ethiopian rift, central Ethiopia, part of the northwestern Ethiopia plateau, and hosts both flood basalts (Kesem Oligocene basalts) and shield volcano basalts (Megezez Miocene basalts) separated by an Oligo-Miocene silicic pyroclastic formation. Petrography, whole-rock trace, and major element data are presented for the Kesem Oligocene and Megezez Miocene basalts to assess their petrogenetic characteristics and the processes involved in their evolution. The Kesem Oligocene basalts are dominated by aphanitic textures, whereas the Megezez Miocene basalts are dominated by porphyritic textures. The Kesem Oligocene basalts are alkaline, whereas the Megezez Miocene basalts have transitional composition. The Kesem Oligocene basalts and Megezez Miocene basalts show distinct compositional differences. MREE/HREE and LREE/HREE show different depths of melt segregation and degrees of partial melting for the Kesem Oligocene basalts and the Megezez Miocene basalts. The geochemical differences (Zr/Nb, Rb/Zr, K/Nb, Ba/Zr and Nb/Zr) between Kesem alkaline basalts and the Megezez transitional basalts reflect the involvement of EMORB-like and OIB-like mantle sources in different proportion in their petrogenesis. Using primitive mantle, garnet- and spinel-bearing lherzolitic sources, a non-modal equilibrium melting model shows that the Kesem alkali basalt can be produced by equilibrium melting of ∼3–4% residual garnet and about 3% degree of partial melting. Whereas, the Megezez transitional basalts were formed by melting of ∼2–3% residual garnet and >3% degree of partial melting. Geochemical evidences envisioned a scenario in which magmatism started with the arrival of a mantle plume (OIB-like; aka Afar Plume), which comes across a sub-lithospheric geochemically enriched and fertile asthenospheric mantle component (EMORB-like). The upwelling of the hot mantle plume that impinging beneath the lithiosphere at ∼30 Ma generates OIB-type melts due to decompression. The thermal effect of the hot plume also triggered melting of the fertile E-MORB component in the asthenosphere at the garnet stability depth. Then, the interaction between more melts from the plume (OIB) and lesser melts from the E-MORB created flood basalts (Kesem basalts) in the Oligocene. During the Miocene, the progressive melting of OIB and E-MORB generates the plateau shield basalts (Megezez basalts)