Enzymatic logic of ubiquitin chain assembly

Protein ubiquitination impacts virtually every biochemical pathway in eukaryotic cells. The fate of a ubiquitinated protein is largely dictated by the type of ubiquitin modification with which it is decorated, including a large variety of polymeric chains. As a result, there have been intense efforts over the last two decades to dissect the molecular details underlying the synthesis of ubiquitin chains by ubiquitin-conjugating (E2) enzymes and ubiquitin ligases (E3s). In this review, we highlight these advances. We discuss the evidence in support of the alternative models of transferring one ubiquitin at a time to a growing substrate-linked chain (sequential addition model) versus transferring a pre-assembled ubiquitin chain (en bloc model) to a substrate. Against this backdrop, we outline emerging principles of chain assembly: multisite interactions, distinct mechanisms of chain initiation and elongation, optimal positioning of ubiquitin molecules that are ultimately conjugated to each other, and substrate-assisted catalysis. Understanding the enzymatic logic of ubiquitin chain assembly has important biomedical implications, as the misregulation of many E2s and E3s and associated perturbations in ubiquitin chain formation contribute to human disease. The resurgent interest in bifunctional small molecules targeting pathogenic proteins to specific E3s for polyubiquitination and subsequent degradation provides an additional incentive to define the mechanisms responsible for efficient and specific chain synthesis and harness them for therapeutic benefit

Acid/base-triggered switching of circularly polarized luminescence and electronic circular dichroism in organic and organometallic helicenes.

Electronic circular dichroism and circularly polarized luminescence acid/base switching activity has been demonstrated in helicene-bipyridine proligand 1 a and in its “rollover” cycloplatinated derivative 2 a. Whereas proligand 1 a displays a strong bathochromic shift (>160 nm) of the nonpolarized and circularly polarized luminescence upon protonation, complex 2 a displays slightly stronger emission. This strikingly different behavior between singlet emission in the organic helicene and triplet emission in the organometallic derivative has been rationalized by using quantum-chemical calculations. The very large bathochromic shift of the emission observed upon protonation of azahelicene-bipyridine 1 a has been attributed to the decrease in aromaticity (promoting a charge-transfer-type transition rather than a π–π* transition) as well as an increase in the HOMO–LUMO character of the transition and stabilization of the LUMO level upon protonation

Interleukin-17 Expression in the Barrett’s Metaplasia-Dysplasia-Adenocarcinoma Sequence

Original Research ArticleIntroduction. This pilot study evaluated the expression of the proinflammatory cytokine IL-17 along the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence by establishing the expression levels of IL-17 in columnar epithelium, intestinal metaplastic cells, and dysplastic/glandular neoplastic cells. Immunohistochemical techniques were used to examine the accumulation of the proinflammatory cytokine IL-17 in forty () formalin-fixed, paraffin-embedded oesophageal archived specimens across a range of endoscopic diagnostic categories, and a highly significant difference was found, where , in IL-17 expression (Kruskall Wallis and Mann-Whitney ) between all the cell types examined. There was also a strong positive correlation (Spearman's rank correlation) between disease progression and IL-17 expression (, , ), IL-17 expression was absent or absent/weak in columnar epithelium, weak to moderate in columnar metaplastic cells, and moderate to strong in dysplastic/neoplastic cells, which demonstrated that the elevation of IL-17 expression occurs in the progression of the disease. Understanding the differential expression of IL-17 between benign and malignant tissue potentially has a significant diagnostic, prognostic, and therapeutic value. Ultimately, this selective biomarker may be employed in routine clinical practice for the screening of oesophageal adenocarcinoma.The authors thankfully acknowledge the University of Chester for their financial support

Integrative Biological Chemistry Program Includes The Use Of Informatics Tools, GIS And SAS Software Applications

Wesley College is a private, primarily undergraduate minority-serving institution located in the historic district of Dover, Delaware (DE). The College recently revised its baccalaureate biological chemistry program requirements to include a one-semester Physical Chemistry for the Life Sciences course and project-based experiential learning courses using instrumentation, data-collection, data-storage, statistical-modeling analysis, visualization, and computational techniques. In this revised curriculum, students begin with a traditional set of biology, chemistry, physics, and mathematics major core-requirements, a geographic information systems (GIS) course, a choice of an instrumental analysis course or a statistical analysis systems (SAS) programming course, and then, students can add major-electives that further add depth and value to their future post-graduate specialty areas. Open-sourced georeferenced census, health and health disparity data were coupled with GIS and SAS tools, in a public health surveillance system project, based on US county zip-codes, to develop use-cases for chronic adult obesity where income, poverty status, health insurance coverage, education, and age were categorical variables. Across the 48 contiguous states, obesity rates are found to be directly proportional to high poverty and inversely proportional to median income and educational achievement. For the State of Delaware, age and educational attainment were found to be limiting obesity risk-factors in its adult population. Furthermore, the 2004-2010 obesity trends showed that for two of the less densely populated Delaware counties; Sussex and Kent, the rates of adult obesity were found to be progressing at much higher proportions when compared to the national average

Importance of ventilation and occupancy to Mycobacterium tuberculosis transmission rates in congregate settings

BACKGROUND: Ventilation rates are a key determinant of the transmission rate of Mycobacterium tuberculosis and other airborne infections. Targeting infection prevention and control (IPC) interventions at locations where ventilation rates are low and occupancy high could be a highly effective intervention strategy. Despite this, few data are available on ventilation rates and occupancy in congregate locations in high tuberculosis burden settings. METHODS: We collected carbon dioxide concentration and occupancy data in congregate locations and public transport on 88 occasions, in Cape Town, South Africa. For each location, we estimated ventilation rates and the relative rate of infection, accounting for ventilation rates and occupancy. RESULTS: We show that the estimated potential transmission rate in congregate settings and public transport varies greatly between different settings. Overall, in the community we studied, estimated infection risk was higher in minibus taxis and trains than in salons, bars, and shops. Despite good levels of ventilation, infection risk could be high in the clinic due to high occupancy levels. CONCLUSION: Public transport in particular may be promising targets for infection prevention and control interventions in this setting, both to reduce Mtb transmission, but also to reduce the transmission of other airborne pathogens such as measles and SARS-CoV-2

Associations between infection intensity categories and morbidity prevalence in school-age children are much stronger for Schistosoma haematobium than for S. mansoni

BACKGROUND: World Health Organization (WHO) guidelines for measuring global progress in schistosomiasis control classify individuals with Schistosoma spp. infections based on the concentration of excreted eggs. We assessed the associations between WHO infection intensity categories and morbidity prevalence for selected S. haematobium and S. mansoni morbidities in school-age children. METHODOLOGY: A total of 22,488 children aged 6-15 years from monitoring and evaluation cohorts in Burkina Faso, Mali, Niger, Uganda, Tanzania, and Zambia from 2003-2008 were analyzed using Bayesian logistic regression. Models were utilized to evaluate associations between intensity categories and the prevalence of any urinary bladder lesion, any upper urinary tract lesion, microhematuria, and pain while urinating (for S. haematobium) and irregular hepatic ultrasound image pattern (C-F), enlarged portal vein, laboratory-confirmed diarrhea, and self-reported diarrhea (for S. mansoni) across participants with infection and morbidity data. PRINCIPAL FINDINGS: S. haematobium infection intensity categories possessed consistent morbidity prevalence across surveys for multiple morbidities and participants with light infections had elevated morbidity levels, compared to negative participants. Conversely, S. mansoni infection intensity categories lacked association with prevalence of the morbidity measures assessed. CONCLUSIONS/SIGNIFICANCE: Current status infection intensity categories for S. haematobium were associated with morbidity levels in school-age children, suggesting urogenital schistosomiasis morbidity can be predicted by an individual's intensity category. Conversely, S. mansoni infection intensity categories were not consistently indicative of childhood morbidity at baseline or during the first two years of a preventive chemotherapy control program

Schistosomiasis — Assessing Progress toward the 2020 and 2025 Global Goals

BACKGROUND: With the vision of "a world free of schistosomiasis," the World Health Organization (WHO) set ambitious goals of control of this debilitating disease and its elimination as a public health problem by 2020 and 2025, respectively. As these milestones become imminent, and if programs are to succeed, it is important to evaluate the WHO programmatic guidelines empirically. METHODS: We collated and analyzed multiyear cross-sectional data from nine national schistosomiasis control programs (in eight countries in sub-Saharan Africa and in Yemen). Data were analyzed according to schistosome species (Schistosoma mansoni or S. haematobium), number of treatment rounds, overall prevalence, and prevalence of heavy-intensity infection. Disease control was defined as a prevalence of heavy-intensity infection of less than 5% aggregated across sentinel sites, and the elimination target was defined as a prevalence of heavy-intensity infection of less than 1% in all sentinel sites. Heavy-intensity infection was defined as at least 400 eggs per gram of feces for S. mansoni infection or as more than 50 eggs per 10 ml of urine for S. haematobium infection. RESULTS: All but one country program (Niger) reached the disease-control target by two treatment rounds or less, which is earlier than projected by current WHO guidelines (5 to 10 years). Programs in areas with low endemicity levels at baseline were more likely to reach both the control and elimination targets than were programs in areas with moderate and high endemicity levels at baseline, although the elimination target was reached only for S. mansoni infection (in Burkina Faso, Burundi, and Rwanda within three treatment rounds). Intracountry variation was evident in the relationships between overall prevalence and heavy-intensity infection (stratified according to treatment rounds), a finding that highlights the challenges of using one metric to define control or elimination across all epidemiologic settings. CONCLUSIONS: These data suggest the need to reevaluate progress and treatment strategies in national schistosomiasis control programs more frequently, with local epidemiologic data taken into consideration, in order to determine the treatment effect and appropriate resource allocations and move closer to achieving the global goals. (Funded by the Children's Investment Fund Foundation and others.)

Direct estimates of absolute ventilation and estimated Mycobacterium tuberculosis transmission risk in clinics in South Africa

From PLOS via Jisc Publications RouterHistory: collection 2022, received 2022-01-26, accepted 2022-10-03, epub 2022-11-02Acknowledgements: We are grateful to the clinical and management staff at 10 clinics where we obtained ventilation measurements. We thank Thomas Murray, Harriet Gliddon, and Sinethemba Mabuyakhulu who assisted us with ventilation measurements in KZN. We are grateful to Rod Escombe, Ed Nardell, Jon Taylor, Don Milton, and Toby van Reenen for useful discussions about various aspects of ventilation science–they take no responsibility for the content of this manuscript.Publication status: PublishedFunder: Economic and Social Research Council; funder-id: http://dx.doi.org/10.13039/501100000269; Grant(s): ES/P008011/1Funder: Wellcome Trust; funder-id: http://dx.doi.org/10.13039/100004440; Grant(s): 218261/Z/19/ZFunder: National Institute for Health Research; funder-id: http://dx.doi.org/10.13039/501100000272Healthcare facilities are important sites for the transmission of pathogens spread via bioaerosols, such as Mycobacterium tuberculosis. Natural ventilation can play an important role in reducing this transmission. We aimed to measure rates of natural ventilation in clinics in KwaZulu-Natal and Western Cape provinces, South Africa, then use these measurements to estimate Mycobacterium tuberculosis transmission risk. We measured ventilation in clinic spaces using a tracer-gas release method. In spaces where this was not possible, we estimated ventilation using data on indoor and outdoor carbon dioxide levels. Ventilation was measured i) under usual conditions and ii) with all windows and doors fully open. Under various assumptions about infectiousness and duration of exposure, measured absolute ventilation rates were related to risk of Mycobacterium tuberculosis transmission using the Wells-Riley Equation. In 2019, we obtained ventilation measurements in 33 clinical spaces in 10 clinics: 13 consultation rooms, 16 waiting areas and 4 other clinical spaces. Under usual conditions, the absolute ventilation rate was much higher in waiting rooms (median 1769 m3/hr, range 338–4815 m3/hr) than in consultation rooms (median 197 m3/hr, range 0–1451 m3/hr). When compared with usual conditions, fully opening existing doors and windows resulted in a median two-fold increase in ventilation. Using standard assumptions about infectiousness, we estimated that a health worker would have a 24.8% annual risk of becoming infected with Mycobacterium tuberculosis, and that a patient would have an 0.1% risk of becoming infected per visit. Opening existing doors and windows and rearranging patient pathways to preferentially use better ventilated clinic spaces result in important reductions in Mycobacterium tuberculosis transmission risk. However, unless combined with other tuberculosis infection prevention and control interventions, these changes are insufficient to reduce risk to health workers, and other highly exposed individuals, to acceptable levels

The impact of alternative delivery strategies for novel tuberculosis vaccines in low-income and middle-income countries: a modelling study

BackgroundTuberculosis is a leading infectious cause of death worldwide. Novel vaccines will be required to reach global targets and reverse setbacks resulting from the COVID-19 pandemic. We estimated the impact of novel tuberculosis vaccines in low-income and middle-income countries (LMICs) in several delivery scenarios.MethodsWe calibrated a tuberculosis model to 105 LMICs (accounting for 93% of global incidence). Vaccine scenarios were implemented as the base-case (routine vaccination of those aged 9 years and one-off vaccination for those aged 10 years and older, with country-specific introduction between 2028 and 2047, and 5-year scale-up to target coverage); accelerated scale-up similar to the base-case, but with all countries introducing vaccines in 2025, with instant scale-up; and routine-only (similar to the base-case, but including routine vaccination only). Vaccines were assumed to protect against disease for 10 years, with 50% efficacy.FindingsThe base-case scenario would prevent 44·0 million (95% uncertainty range 37·2–51·6) tuberculosis cases and 5·0 million (4·6–5·4) tuberculosis deaths before 2050, compared with equivalent estimates of cases and deaths that would be predicted to occur before 2050 with no new vaccine introduction (the baseline scenario). The accelerated scale-up scenario would prevent 65·5 million (55·6–76·0) cases and 7·9 million (7·3–8·5) deaths before 2050, relative to baseline. The routine-only scenario would prevent 8·8 million (95% uncertainty range 7·6–10·1) cases and 1·1 million (0·9–1·2) deaths before 2050, relative to baseline.InterpretationOur results suggest novel tuberculosis vaccines could have substantial impact, which will vary depending on delivery strategy. Including a one-off vaccination campaign will be crucial for rapid impact. Accelerated introduction—at a pace similar to that seen for COVID-19 vaccines—would increase the number of lives saved before 2050 by around 60%. Investment is required to support vaccine development, manufacturing, prompt introduction, and scale-up