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A phosphate binding pocket is a key determinant of exo- versus endo-nucleolytic activity in the SNM1 nuclease family
No full textThe SNM1 nucleases which help maintain genome integrity are members of the metallo-β-lactamase (MBL) structural superfamily. Their conserved MBL-β-CASP-fold SNM1 core provides a molecular scaffold forming an active site which coordinates the metal ions required for catalysis. The features that determine SNM1 endo- versus exonuclease activity, and which control substrate selectivity and binding are poorly understood. We describe a structure of SNM1B/Apollo with two nucleotides bound to its active site, resembling the product state of its exonuclease reaction. The structure enables definition of key SNM1B residues that form contacts with DNA and identifies a 5′ phosphate binding pocket, which we demonstrate is important in catalysis and which has a key role in determining endo- versus exonucleolytic activity across the SNM1 family. We probed the capacity of SNM1B to digest past sites of common endogenous DNA lesions and find that base modifications planar to the nucleobase can be accommodated due to the open architecture of the active site, but lesions axial to the plane of the nucleobase are not well tolerated due to constriction around the altered base. We propose that SNM1B/Apollo might employ its activity to help remove common oxidative lesions from telomeres
Benchmarking data-driven rainfall-runoff models in Great Britain: a comparison of LSTM-based models with four lumped conceptual models
No full textLong short-term memory (LSTM) models are recurrent neural networks from the field of deep learning (DL) which have shown promise for time series modelling, especially in conditions when data are abundant. Previous studies have demonstrated the applicability of LSTM-based models for rainfall–runoff modelling; however, LSTMs have not been tested on catchments in Great Britain (GB). Moreover, opportunities exist to use spatial and seasonal patterns in model performances to improve our understanding of hydrological processes and to examine the advantages and disadvantages of LSTM-based models for hydrological simulation. By training two LSTM architectures across a large sample of 669 catchments in GB, we demonstrate that the LSTM and the Entity Aware LSTM (EA LSTM) models simulate discharge with median Nash–Sutcliffe efficiency (NSE) scores of 0.88 and 0.86 respectively. We find that the LSTM-based models outperform a suite of benchmark conceptual models, suggesting an opportunity to use additional data to refine conceptual models. In summary, the LSTM-based models show the largest performance improvements in the north-east of Scotland and in south-east of England. The south-east of England remained difficult to model, however, in part due to the inability of the LSTMs configured in this study to learn groundwater processes, human abstractions and complex percolation properties from the hydro-meteorological variables typically employed for hydrological modelling
Forecasting trachoma control and identifying transmission-hotspots
No full textBackground: Tremendous progress towards elimination of trachoma as a public health problem has been made. However, there are areas where the clinical indicator of disease, trachomatous inflammation—follicular (TF), remains prevalent. We quantify the progress that has been made, and forecast how TF prevalence will evolve with current interventions. We also determine the probability that a district is a transmission-hotspot based on its TF prevalence (ie, reproduction number greater than one).
Methods: Data on trachoma prevalence come from the GET2020 global repository organized by the World Health Organization and the International Trachoma Initiative. Forecasts of TF prevalence and the percent of districts with local control is achieved by regressing the coefficients of a fitted exponential distribution for the year-by-year distribution of TF prevalence. The probability of a district being a transmission-hotspot is extrapolated from the residuals of the regression.
Results: Forecasts suggest that with current interventions, 96.5% of surveyed districts will have TF prevalence among children aged 1–9 years <5% by 2030 (95% CI: 86.6%–100.0%). Districts with TF prevalence < 20% appear unlikely to be transmission-hotspots. However, a district having TF prevalence of over 28% in 2016–2019 corresponds to at least 50% probability of being a transmission-hotspot.
Conclusions: Sustainable control of trachoma appears achievable. However there are transmission-hotspots that are not responding to annual mass drug administration of azithromycin and require enhanced treatment in order to reach local control
BH4 increases nNOS Activity and preserves left ventricular function in diabetes
No full textRationale:
In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment. Oxidation of the NOS (nitric oxide synthase) cofactor tetrahydrobiopterin (BH4) and dysfunctional NOS activity have been implicated in the pathogenesis of the diabetic vascular and cardiomyopathic phenotype.
Objective:
Using mice models and human myocardial samples, we evaluated whether and by which mechanism increasing myocardial BH4 availability prevented or reversed LV dysfunction induced by diabetes.
Methods and Results:
In contrast to the vascular endothelium, BH4 levels, superoxide production, and NOS activity (by liquid chromatography) did not differ in the LV myocardium of diabetic mice or in atrial tissue from diabetic patients. Nevertheless, the impairment in both cardiomyocyte relaxation and [Ca2+]i (intracellular calcium) decay and in vivo LV function (echocardiography and tissue Doppler) that developed in wild-type mice 12 weeks post–diabetes induction (streptozotocin, 42–45 mg/kg) was prevented in mGCH1-Tg (mice with elevated myocardial BH4 content secondary to trangenic overexpression of GTP-cyclohydrolase 1) and reversed in wild-type mice receiving oral BH4 supplementation from the 12th to the 18th week after diabetes induction. The protective effect of BH4 was abolished by CRISPR/Cas9-mediated knockout of nNOS (the neuronal NOS isoform) in mGCH1-Tg. In HEK (human embryonic kidney) cells, S-nitrosoglutathione led to a PKG (protein kinase G)-dependent increase in plasmalemmal density of the insulin-independent glucose transporter GLUT-1 (glucose transporter-1). In cardiomyocytes, mGCH1 overexpression induced a NO/sGC (soluble guanylate cyclase)/PKG–dependent increase in glucose uptake via GLUT-1, which was instrumental in preserving mitochondrial creatine kinase activity, oxygen consumption rate, LV energetics (by 31phosphorous magnetic resonance spectroscopy), and myocardial function.
Conclusions:
We uncovered a novel mechanism whereby myocardial BH4 prevents and reverses LV diastolic and systolic dysfunction associated with diabetes via an nNOS-mediated increase in insulin-independent myocardial glucose uptake and utilization. These findings highlight the potential of GCH1/BH4–based therapeutics in human diabetic cardiomyopathy
An experimental medicine investigation of the effects of subacute pramipexole treatment on emotional information processing in healthy volunteers
No full textTreatment with the dopamine D2/D3 receptor agonist pramipexole has demonstrated promising clinical effects in patients with depression. However, the mechanisms through which pramipexole might alleviate depressive symptoms are currently not well understood. Conventional antidepressant drugs are thought to work by biasing the processing of emotional information in favour of positive relative to negative appraisal. In this study, we used an established experimental medicine assay to explore whether pramipexole treatment might have a similar effect. Employing a double-blind, parallel-group design, 40 healthy volunteers (aged 18 to 43 years, 50% female) were randomly allocated to 12 to 15 days of treatment with either pramipexole (at a peak daily dose of 1.0 mg pramipexole salt) or placebo. After treatment was established, emotional information processing was assessed on the neural level by measuring amygdala activity in response to positive and negative facial emotional expressions, using functional magnetic resonance imaging (MRI). In addition, behavioural measures of emotional information processing were collected at baseline and on drug, using an established computerized task battery, tapping into different cognitive domains. As predicted, pramipexole-treated participants, compared to those receiving placebo, showed decreased neural activity in response to negative (fearful) vs. positive (happy) facial expressions in bilateral amygdala. Contrary to our predictions, however, pramipexole treatment had no significant antidepressant-like effect on behavioural measures of emotional processing. This study provides the first experimental evidence that subacute pramipexole treatment in healthy volunteers modifies neural responses to emotional information in a manner that resembles the effects of conventional antidepressant drugs
Heterotopic ossification arising from an anterolateral thigh free flap donor site: a previously unreported phenomenon
No full textHeterotopic ossification is defined as abnormal bone deposition within non-skeletal tissues. Although it is rare, it has been associated with a history of trauma and surgical interventions. Herein, we present the case of a 74-year-old male patient, who was referred to our specialist center with a high-grade myxofibrosarcoma affecting his left knee. After a multidisciplinary discussion, wide resection and reconstruction with a contralateral free anterolateral thigh (ALT) free flap were performed. A 25 × 12 cm flap was harvested and its donor site repaired using a split-thickness skin graft, followed by adjuvant radiotherapy.
Over the course of 9 months following radiotherapy, the patient slowly developed a painless swelling on his right thigh. On examination, he presented a hard, raised mass measuring 12 × 5 cm under the healed split-thickness skin graft on the ALT donor site (Fig. 1). The mass did not affect his mobility. Plain X-ray films (Fig. 2A) and a computed tomography scan (Fig. 2B) were obtained and evaluated by senior radiologists with experience in sarcoma surgery, who agreed that the findings were consistent with heterotopic ossification and that histological confirmation was not required. The patient was reassured, and no further surgical intervention was sought
HIV incidence in a multinational cohort of men and transgender women who have sex with men in sub-Saharan Africa: Findings from HPTN 075
No full textFew studies have assessed HIV incidence in men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa (SSA). We assessed HIV incidence and its correlates among MSM and TGW in SSA enrolled in the prospective, multi-country HIV Prevention Trials Network (HPTN) 075 study, conducted from 2015 to 2017. Participants were enrolled at four sites in SSA (Kisumu, Kenya; Blantyre, Malawi; Cape Town and Soweto, South Africa). Eligible participants reported male sex assignment at birth, were 18 to 44 years of age, and had engaged in anal intercourse with a man in the preceding three months. Participation involved five study visits over 12 months. Visits included behavioral assessments and testing for HIV and sexually transmitted infections. Twenty-one of 329 persons acquired HIV during the study [incidence rate: 6.96/100 person-years (PY) (95% CI: 4.3, 10.6)]. Among TGW, HIV incidence was estimated to be 8.4/100 PY (95% CI: 2.3, 21.5). Four participants were found to have acute HIV infection at their first HIV-positive visit. HIV incidence varied among the four study sites, ranging from 1.3/100 PY to 14.4/100 PY. In multivariate longitudinal analysis, factors significantly associated with HIV acquisition were engagement in unprotected receptive anal intercourse [adjusted hazard ratio (AHR) 5.8, 95% confidence interval (CI): 2.4, 14.4] and incident rectal gonorrhea and/or chlamydia (AHR: 2.7, 95% CI: 1.1, 6.8). The higher HIV incidence in Cape Town compared to Blantyre could be explained by the higher prevalence of several risk factors for HIV infection among participants in Cape Town. Annual HIV incidence observed in this study is substantially higher than reported HIV incidence in the general populations in the respective countries and among MSM in the United States. Intensification of HIV prevention efforts for MSM and TGW in SSA is urgently needed
Supporting bereavement and complicated grief in primary care: a realist review
No full textBackground Bereavement can have significant impacts on physical and mental health, and a minority of people experience complicated and prolonged grief responses. Primary care is ideally situated to offer bereavement care, yet UK provision remains variable and practitioners feel uncertain how best to support bereaved patients.
Aim To identify what works, how, and for whom, in the management of complicated grief in primary care.
Design & setting A review of evidence on the management of complicated grief and bereavement in UK primary care settings.
Method A realist approach was taken which aims to provide causal explanations through the generation and articulation of contexts, mechanisms, and outcomes.
Results Forty-two articles were included. Evidence on the primary care management of complicated or prolonged grief was limited. GPs and nurses view bereavement support as part of their role, yet experience uncertainty over the appropriate extent of their involvement. Patients and clinicians often have differing views on the role of primary care in bereavement. Training in bereavement, local systems for reporting deaths, practitioner time and resources can assist or hinder bereavement care provision. Practitioners find bereavement care can be emotionally challenging. Understanding patients’ needs can encourage a proactive response and help identify appropriate support.
Conclusion Bereavement care in primary care remains variable and practitioners feel unprepared to provide appropriate bereavement care. Patients at higher risk of complicated or prolonged grief may fail to receive the support they need from primary care. Further research is required to address the potential unmet needs of bereaved patients
Energy harvesting based on compressive stress-induced ferroelectric/ferroelastic switching in polycrystalline ferroelectric materials
No full textAlthough piezoelectric energy harvesting is well established, ferroelectric/ferroelastic switching has not been widely used for energy harvesting. The main disadvantage of piezoelectric energy harvesters is their limited power density. In this respect, ferroelectric/ferroelastic switching is attractive because of the greater energies and charge flows involved. However, the associated nonlinearities and the difficulty of establishing a stable working cycle have prevented significant progress. In this work, a robust ferroelectric energy harvester based on partial ferroelectric switching is explored. The device is of simple construction and achieves a per-cycle energy density of about 1 mJ cm−3, orders of magnitude greater than that of typical piezoelectrics. It is shown that only periodic compressive stress is needed to induce the energy harvesting cycles, yielding promising mechanical attributes that limit fatigue or fracture during cyclic loading. The results show this prototype device operating stably over 0.5 × 106 cycles at 20-Hz frequency, demonstrating promise for practical applications
Methodological challenges for living systematic reviews conducted during the COVID-19 pandemic: A concept paper
No full textBackground
A living systematic review (LSR) is an emerging review type that makes use of continual updating. In the COVID-19 pandemic, we were confronted with a shifting epidemiological landscape, clinical uncertainties and evolving evidence. These unexpected challenges compelled us to amend standard LSR methodology.
Objective and outline
Our primary objective is to discuss some challenges faced when conducting LSRs in the context of the COVID-19 pandemic, and to provide methodological guidance for others doing similar work. Based on our experience and lessons learned from two Cochrane LSRs and challenges identified in several non-Cochrane LSRs, we highlight methodological considerations, particularly with regards to the study design, interventions and comparators, changes in outcome measure, and the search strategy. We discuss when to update, or rather when not to update the review, and the importance of transparency when reporting changes.
Lessons learned and conclusion
We learned that a LSR is a very suitable review type for the pandemic context, even in the face of new methodological and clinical challenges. Our experience showed that the decision for updating a LSR depends not only on the evolving disease or emerging evidence, but also on the individual review question and the review teams’ resources