Structure-based prediction of protein allostery

Allostery is the functional change at one site on a protein caused by a change at a distant site. In order for the benefits of allostery to be taken advantage of, both for basic understanding of proteins and to develop new classes of drugs, the structure-based prediction of allosteric binding sites, modulators and communication pathways is necessary. Here we review the recently emerging field of allosteric prediction, focusing mainly on computational methods. We also describe the search for cryptic binding pockets and attempts to design allostery into proteins. The development and adoption of such methods is essential or the long-preached potential of allostery will remain elusive

Cost of a diagonal sexual and reproductive health package to enhance reproductive health among female sex workers in Durban, South Africa

Background and objectives: In response to HIV epidemic in Sub- Saharan Africa, there has been widespread concern about the structure and delivery of Sexual Reproductive Health (SRH) and HIV services to improve outcomes among high-risk groups, including sex workers. The ‘Diagonal Interventions to Fast-Forward Enhanced Reproductive health’ (DIFFER) project was conceptualised based on the hypothesis that integrating vertical SRH interventions targeted to FSW, with horizontal health systems strengthening, is likely to be more effective and cost-effective than current practice. The aim of the study was to measure the cost of designing and delivering a SRH package for female sex workers in Durban, South Africa, as part of the DIFFER project. / Methods: We measured the total and incremental costs of the DIFFER intervention package in Durban from a provider perspective, using a combination of ingredients and activity based costing approaches. An excel-based data capture tool was developed to collect the intervention package cost data. The intervention costs were collected prospectively from the project accounts of the implementing agencies and costs to the public health providers were collected via key informant interviews using a cost data capture form and subsequently entered into the spreadsheet. The total and average annual costs, as well as total and average annual costs per sex worker covered were estimated. All costs were adjusted for inflation, discounted and converted to 2016 International dollar. / Results: Total and average annual program costs of implementing the DIFFER intervention in Durban were INT$411,239 (INT$ 428,461, including services provided to the general population) and INT$256,594 (INT$ 273,816, including services provided to the general population) respectively. The total cost and average annual cost per sex worker covered were INT$117 and INT$ 73 respectively. Staff costs accounted for the largest proportion of the intervention cost, comprising more than 80% of the total cost, following by material and supplies, accounting for 10% of costs. / Conclusion: The DIFFER intervention package in Durban is a low cost intervention and likely to be cost-effective and sustainable. The intervention can be considered for replication and scale-up in South Africa and similar settings elsewhere

Acute effects of mango leaf extract on cognitive function in healthy adults: a randomised, double-blind, placebo-controlled crossover study

Copyright \ua9 2024 Dodd, Kennedy, Johnson, Haworth, Greener and Jackson.Introduction: Extracts made from the leaves of the edible mango plant (Mangifera indica L., Anacardiaceae) have a long history of medicinal usage, most likely due to the presence of high levels of mangiferin, a polyphenol compound. Previous research has demonstrated that mango leaf extract (MLE) can beneficially modulate cognitive function in both animals and humans. This study aimed to assess the effects of an acute dose of 300 mg MLE (standardised to contain ≥60% mangiferin) on cognitive performance and mood in healthy adults. Methods: In this double-blind, placebo-controlled, crossover study, 114 healthy men and women (18–43 years) received either MLE or a matched placebo at each testing visit (separated by at least 7 days). Cognitive performance (including the cognitive demand battery) and mood were measured at 30, 180, and 300 min post-dose. Results: The results showed that, compared to placebo, the group taking MLE displayed a significant increase in serial 3 s and serial 7 s subtraction errors overall. There were no other significant effects on cognitive performance. Discussion: The results of the current study suggest that the consumption of 300 mg MLE in the absence of an observed multitasking psychological stressor does not improve cognitive performance or mood at up to 300 min post-dose. Due to the very limited nature of the effects and since they were observed among many analyses, these findings should be treated with caution. Clinical trial registration: http://ClinicalTrials.gov, identifier [NCT05182450]

Conflicting theories on addiction aetiology and the strengths and limitations of substance use disorder disease modelling

A lack of cross-disciplinary unanimity prevails within addiction research. Theories conceptualizing addiction through the three-stage brain disease model contest other theories that substance use disorder is of behavioural or genetic origin. The reverberations of this lack of consensus are noticeable throughout addiction research and within the foundations of disease modelling. The availability of methods to investigate substance use disorder are inconsistent and sometimes unrepresentative. This review discusses theories of addiction aetiology, available models for addiction research and the strengths and limitations of current practical experimental methods of study

Decentralisation and performance: Autonomy and incentives in Local Health Economies

This project will examine the inter-relationship between governance mechanisms, autonomy and incentives in local health economies (LHEs). This interaction shapes decentralisation policies in the NHS and is thought to shape LHE performance. Recently, English health policy has been implementing new forms of decentralisation (eg. earned autonomy, Foundation Trusts) by altering the mix of governance mechanisms (command, collaboration and competition) and making explicit use of autonomy and incentives, thereby aiming to improve NHS performance. Local contextual factors might also shape performance outcomes. The project involves a synergy between the multi-disciplinary teams involved in 2 previous NCC-SDO funded studies. The aim is to investigate the inter-relationship between decentralisation and performance in LHEs. The project has 5 objectives: a. To examine the impact of decentralisation upon performance through analysis of selected 'tracers (as examples of current priorities) in 3 case-studies; b. To describe the local interaction of governance mechanisms; c. To evaluate the degree of autonomy available to local health-care organisations; d. To assess the (financial and non-financial) incentives associated with different policy initiatives; e. To provide lessons for policy-makers and managers at all levels in implementing decentralisation, managing the implications of autonomy and incentives, and addressing performance management through incentives. The study will use mixed methods. First, analysis of policy and performance data will generate the broad pattern of decentralisation and performance across England. Analysis of these data will aid selection of case-studies and 'tracers (examples within case-studies). Second, three case-studies will be selected which represent a maximum variety of pre-defined criteria. Longitudinal, comparative case-study methods include (a) 'mapping LHE performance and organisational characteristics (using local performance and activity data, and published reports); (b) a survey of senior staff in 3 LHEs (n=c.180) to provide their perceptions of current LHE issues and constraints (especially relating to tracer examples); (c) interviews with a sample of stakeholders (n=c.120) will identify the strengths and effects of organisational relationships across the LHE (such as the impact of service developments in the tracer examples); (d) observation of local planning meetings. Parts (a) and (b) will be conducted in year 1, parts (c) and (d) in years 2 and 3. Quantitative analysis will provide descriptive statistics of broad patterns and association. Qualitative analysis will provide thematic comparisons by LHE, organisational type and tracer example. Analysis will identify the pathways by which governance, autonomy and incentives can facilitate improved performance and also the conditions under which the optimal balance of these may be achieved in different contexts. The study will also consider conceptual frameworks (including 'decision space , resource dependency and principal-agent) to improve understanding of the inter-relationships within LHE and the intersection of national/vertical and local/horizontal pressures affecting performance. The study will engage decision-makers at all stages (via data collection, formative and summative feedback and as members of an Advisory Group). Formative feedback to LHEs (and NCC-SDO) will help validate emergent findings and sharpen subsequent fieldwork. Final dissemination will include such (oral and written) feedback, NCC-SDO report, presentations and publications to practitioner and research communities

Geiger Mode Ge-on-Si Single-Photon Avalanche Diode Detectors

High efficiency single photon avalanche detectors (SPADs) based on the Ge-on-Si material system are a promising emerging technology for high sensitivity optical detection in the short-wave infrared region. Here we demonstrate record single photon detection efficiencies of 38% at 1310nm with an operating temperature of 125K. This was achieved using a novel planar geometry which allowed us to achieve an NEPs of 3×10 −16 WHz −1/2 and reduced afterpulsing when compared to InGaAs/InP based SPADs operated in nominally identical conditions

Geiger Mode Ge-on-Si Single-Photon Avalanche Diode Detectors

Ge-on-Si single-photon avalanche diode (SPAD) detectors have demonstrated a high single-photon detection efficiency of 38% at a wavelength of 1310 nm when operated at a temperature of 125 K. These devices exhibit reduced afterpulsing compared to InGaAs/InP SPADs under nominally identical operating conditions