Ribosome*RelA structures reveal the mechanism of stringent response activation

Stringent response is a conserved bacterial stress response underlying virulence and antibiotic resistance. RelA/SpoT-homolog proteins synthesize transcriptional modulators (p)ppGpp, allowing bacteria to adapt to stress. RelA is activated during amino-acid starvation, when cognate deacyl-tRNA binds to the ribosomal A (aminoacyl-tRNA) site. We report four cryo-EM structures of E. coli RelA bound to the 70S ribosome, in the absence and presence of deacyl-tRNA accommodating in the 30S A site. The boomerang-shaped RelA with a wingspan of more than 100 A wraps around the A/R (30S A-site/RelA-bound) tRNA. The CCA end of the A/R tRNA pins the central TGS domain against the 30S subunit, presenting the (p)ppGpp-synthetase domain near the 30S spur. The ribosome and A/R tRNA are captured in three conformations, revealing hitherto elusive states of tRNA engagement with the ribosomal decoding center. Decoding-center rearrangements are coupled with the step-wise 30S-subunit \u27closure\u27, providing insights into the dynamics of high-fidelity tRNA decoding

Current tobacco use and susceptibility to using tobacco among non-users of tobacco: A cross-sectional study among school-going adolescents in Sierra Leone.

From PubMed via Jisc Publications RouterHistory: received 2022-03-20, revised 2022-12-02, accepted 2022-12-05Publication status: epublishTobacco use is a global health threat associated with a high disease burden and death. Current tobacco use and susceptibility to using tobacco products among adolescents who are potential adult tobacco users have not been explored in Sierra Leone. Thus, we aimed to estimate the prevalence and correlates of current tobacco use and tobacco non-users susceptibility to using tobacco amongst high school students in Sierra Leone. We used data obtained from the 2017 Sierra Leone Global Youth Tobacco Survey (GYTS), which presented information collected from 6680 students aged 11-17 years nationwide. Gender-based correlates of current use and susceptibility to using tobacco among non-tobacco users were determined by complex sample logistic regression analyses. Adjusted odds ratios (AOR) and respective 95% confidence intervals (CIs) are reported. A p<0.05 was considered significant. The prevalence of current tobacco use among high school adolescents in Sierra Leone was 24.6%, higher in males (27.9%) than in females (18.6%). Male (AOR=1.50; 95% CI: 1.18-1.91), parental smoking (AOR=1.73; 95% CI: 1.32-2.26) exposure to household secondhand smoke (AOR=1.82; 95% CI: 1.27-2.62), having peers who smoke (AOR=2.24; 95% CI: 1.51-3.31) were more likely to be currently using tobacco. The overall tobacco non-users susceptibility to using tobacco among adolescents in Sierra Leone was 18.2% (males 18.0%, females 18.5%). Exposure to tobacco promotion (AOR=1.50; 95% CI: 1.06-2.10) and non-exposure to anti-smoking education (AOR=1.39; 95% CI: 1.05-1.86) were significantly associated with tobacco non-users' susceptibility to using tobacco. Our study suggests that one in four school-going adolescents currently uses tobacco, with nearly one in five non-users susceptible to using tobacco. Given the high prevalence of tobacco product use among adults in Sierra Leone, our findings highlight the need for policies and interventions to prevent tobacco use behavior among adolescents, aimed at averting tobacco use in adulthood. [Abstract copyright: © 2023 James P.B. et al.]pubpu

Health-related quality of life among Ebola survivors in Sierra Leone: The role of socio-demographic, health-related and psycho-social factors

From Springer Nature via Jisc Publications RouterBackground: Evidence of how social factors affect the health-related quality of life (HRQoL) of Ebola virus disease (EVD) survivors is limited. Our study explores the association between socio-demographic, health-related and psycho-social (stigma) factors and EVD survivors' health-related quality of life (HRQoL) in Sierra Leone. Methods: We conducted a nationwide cross-sectional study among 358 EVD survivors between January and August 2018. We used a multistage sampling method to recruit EVD survivors, and the RAND 36-Item Health Survey item was used to assess the HRQoL. Data were analysed using descriptive statistics and multiple linear regression. Results: When comparing by each dimension in relation to their respective summary scores, role limitation physical [0.00 (50.00)] and role limitation emotional [0.00 (33.33)] were the most affected physical health and mental health domains among EVD survivors respectively. EVD survivors who were older (β = − 3.90, 95% CI − 6.47 to − 1.32, p = 0.003), had no formal education (β = − 2.80, 95% CI − 5.16 to − 0.43, p = 0.021), experienced a unit increase in the number of post-Ebola symptoms (β = − 1.08, 95% CI − 1.74 to − 0.43, p < 0.001) and experienced a unit increase in enacted stigma (β = − 2.61, 95% CI − 4.02 to − 1.20, p < 0.001) were more likely to report a decreased level of physical health. EVD survivors who experienced a unit increase in the time spent in the Ebola treatment centre (β = − 0.60, 95% CI − 0.103 to − 0.18, p = 0.006) and those who experienced a unit increase in enacted Stigma were more likely to report decreased levels of mental health (β = − 1.50, 95% CI − 2.67 to − 0.33, p = 0.012). Conclusion: Sociodemographic, health-related, and psycho-social factors were significantly associated with decrease levels of HRQoL. Our findings improve our understanding of the factors that might influence the HRQoL and suggest the need for EVD survivors to be provided with a comprehensive healthcare package that caters for their physical and mental health needs.pubpu

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

MeV-Stealth: A CD46-specific oncolytic measles virus resistant to neutralization by measles-immune human serum.

The frequent overexpression of CD46 in malignant tumors has provided a basis to use vaccine-lineage measles virus (MeV) as an oncolytic virotherapy platform. However, widespread measles seropositivity limits the systemic deployment of oncolytic MeV for the treatment of metastatic neoplasia. Here, we report the development of MeV-Stealth, a modified vaccine MeV strain that exhibits oncolytic properties and escapes antimeasles antibodies in vivo. We engineered this virus using homologous envelope glycoproteins from the closely-related but serologically non-cross reactive canine distemper virus (CDV). By fusing a high-affinity CD46 specific single-chain antibody fragment (scFv) to the CDV-Hemagglutinin (H), ablating its tropism for human nectin-4 and modifying the CDV-Fusion (F) signal peptide we achieved efficient retargeting to CD46. A receptor binding affinity of ~20 nM was required to trigger CD46-dependent intercellular fusion at levels comparable to the original MeV H/F complex and to achieve similar antitumor efficacy in myeloma and ovarian tumor-bearing mice models. In mice passively immunized with measles-immune serum, treatment of ovarian tumors with MeV-Stealth significantly increased overall survival compared with treatment with vaccine-lineage MeV. Our results show that MeV-Stealth effectively targets and lyses CD46-expressing cancer cells in mouse models of ovarian cancer and myeloma, and evades inhibition by human measles-immune serum. MeV-Stealth could therefore represent a strong alternative to current oncolytic MeV strains for treatment of measles-immune cancer patients

Research capacity. Enabling the genomic revolution in Africa.

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