bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unequal access to diagnosis of myalgic encephalomyelitis in England
Authors: Samms Gemma L. , Ponting Chris P. 
Published: February 2024

AbstractBackgroundPeople with Myalgic Encephalomyelitis (ME/CFS; sometimes referred to as chronic fatigue syndrome) experience very poor health-related quality of life and only rarely recover. ME/CFS has no curative treatment and no single diagnostic test. Public health and policy decisions relevant to ME/CFS require knowledge of its prevalence and barriers to diagnosis. However, people with ME/CFS report lengthy diagnostic delays and widespread misunderstanding of their symptoms. Published prevalence estimates vary greatly by country, gender, age and ethnicity.MethodsHospital Episode Statistics data is routinely collected by the NHS in England together with patient age, gender and ethnicity. This data, downloaded from the Feasibility Self-Service of NHS DigiTrials, was used to stratify individuals with the ICD-10 code that best reflects ME/CFS symptoms (G93.3; “Postviral fatigue syndrome”) according to their age, self-reported gender and ethnicity, General Practice and NHS England Integrated Care Board (ICB).ResultsIn all, 100,055 people in England had been diagnosed with ME/CFS (ICD-10:G93.3) between April 1 1989 and October 7 2023, 0.16% of all registered patients. Of these, 79,445 were females and 20,590 males, a female-to-male ratio of 3.88:1. Female relative to male prevalence peaked at about 6-to-1 in individuals’ fourth and fifth decades of life. Prevalence varied widely across the 42 ICBs: 0.086%-0.82% for females and 0.024%-0.21% for males. White individuals were approximately 5-fold more likely to be diagnosed with ME/CFS than others; black, Asian or Chinese ethnicities are associated with particularly low rates of ME/CFS diagnoses. This ethnicity bias is stronger than for other common diseases. Among active English GP practices, 176 (3%) had no registered ME/CFS patients. Eight ICBs (19%) each contained fewer than 8 other-than-white individuals with a G93.3 code despite their registers containing a total of 293,770 other-than-white patients.ConclusionThose who are disproportionately undiagnosed with ME/CFS are other-than-white ethnic groups, older females (>60y), older males (>80y), and people living in areas of multiple deprivation. The lifetime prevalence of ME/CFS for English females and males may be as high as 0.92% and 0.25%, respectively, or approximately 390,000 UK individuals overall. This improved estimate of ME/CFS prevalence allows more accurate assessment of the socioeconomic and disease burden imposed by ME/CFS.
Political Economy Analysis of Health Taxes (Tobacco, Alcohol Drink, and Sugar Sweteened Beverage): Case Study of Three Provinces in Indonesia
Authors: Ahsan Abdillah , Amalia Nadira , Rahmayanti Krisna Puji , Adani Nadhila , Wiyono Nur Hadi , Endawansa Althof , Utami Maulida Gadis , Yuniar Adela Miranti , Anastasia Erika Valentina , Ayuning Pertiwi Yuyu Buono 
Published: February 2024

AbstractEfforts to implement health tax policies to control the consumption of harmful commodities and enhance public health outcomes have garnered substantial recognition globally. However, their successful adoption remains a complex endeavour. This study takes a problem-driven political economy analysis (PEA) approach to investigate the challenges and opportunities surrounding health tax implementation, with a particular focus on sub-national government in Indonesia, where the decentralization context of health tax remains understudied. Employing a qualitative methodology by collecting data from a total of twelve focus group discussions (FGDs) conducted in three provinces—Lampung, Special Region of/Daerah Istimewa(DI) Yogyakarta, and Bali, each chosen to represent a specific commodity: tobacco, sugar-sweetened beverages (SSBs), and alcoholic beverages—we explore the multifaceted dynamics of health tax policies. These FGDs involved 117 participants, representing governmental institutions, non-governmental organizations (NGOs), and consumers. Our findings reveal that while health tax policies have the potential to contribute significantly to public health, challenges such as a lack of consumer awareness, bureaucratic complexities, and decentralized governance hinder implementation. Furthermore, this study underscores the importance of effective policy communication. It highlights the importance of earmarking health tax revenues for public health initiatives. It also reinforces the need to see health taxes as one intervention as part of a comprehensive public health approach including complementary non-fiscal measures like advertising restrictions and standardized packaging. Addressing these challenges is critical for realizing the full potential of health tax policies.
Wellbeing Impact Study of High-Speed 2 (WISH2): Protocol for a mixed-methods examination of the impact of major transport infrastructure development on mental health and wellbeing
Authors: Morley Katherine I. , Hocking Lucy , Saunders Catherine L. , Bousfield Jennifer W. , Bostock Jennifer , Brimicombe James , Burgoine Thomas , Dawney Jessica , Hofman Joanna , Lee Daniel , Mackett Roger , Phillips William , Sussex Jon , Morris Stephen 
Published: February 2024

AbstractAlthough research has demonstrated that transport infrastructure development can have positive and negative health-related impacts, most of this research has not considered mental health and wellbeing separately from physical health. There is also limited understanding of whether and how any effects might be experienced differently across population groups, whether this differs according to the stage of development (e.g. planning, construction), and how changes to planned infrastructure may affect mental health and wellbeing. This paper presents a protocol for the Wellbeing Impact Study of HS2 (WISH2), which seeks to address these questions using a high-speed rail development in the UK as an applied example. WISH2 is a 10-year, integrated, longitudinal, mixed-methods project using general practices (primary medical care providers in the UK) as an avenue for participant recruitment and for providing a geographically defined population for which aggregated data on mental health indicators are available. The research comprises: (i) a combined longitudinal and repeated cross-sectional cohort study involving multiple waves of survey data collection and data from medical records; (ii) longitudinal, semi-structured interviews and focus groups with residents and community stakeholders from exposed areas; (iii) analysis of administrative data aggregated at the general practice population level; and (iv) health economic analysis of mental health and wellbeing impacts. The study findings will support the development of strategies to reduce negative impacts and/or enhance positive mental health and wellbeing impacts of high-speed rail developments and other large-scale infrastructure projects.
Factors Influencing the Uptake of Public Health Interventions Delivery by Community Pharmacists: A thematic literature review
Authors: Mumbi Audrey , Mugo Peter , Barasa Edwine , Abiiro Gilbert , Nzinga Jacinta 
Published: February 2024

AbstractBackgroundCommunity pharmacies are the first point of contact for most people seeking treatment for minor illnesses in Low– and middle-income countries (LMICs). In recent years, the role of community pharmacists has evolved, and they play a significant role in the delivery of public health interventions (PHIs) aimed at health promotion and prevention such as smoking cessation services, weight management services, HIV prevention, and vaccination. This review aims to explore the evidence on the factors that influence community pharmacists to take up the role of delivery of these interventions.MethodsThree electronic databases namely, Embase, Medline, and Scopus were searched for relevant literature from the inception of the database to December 2023. Reference lists of included articles were also searched for relevant articles. A total of 22 articles were included in the review based on our inclusion and exclusion criteria. The data were analyzed and synthesized using a thematic approach to identify the factors that influence the community pharmacist’s decision to take up the role of PHI delivery. Reporting of the findings was done according to the PRISMA checklist.FindingsThe search identified 10,927 articles of which 22 were included in the review. The main factors that drive the delivery of PHIs by community pharmacists were identified as; training and continuous education, remuneration and collaboration with other healthcare professionals. Other factors included structural and workflow adjustments and support from the government and regulatory bodies.ConclusionsEvidence from this review indicates that the decision to expand the scope of practice of community pharmacists is influenced by various factors. Incorporating these factors into the design of policies and public health programs is critical for the successful integration of community pharmacists in the delivery of broader public health to meet the rising demand for health care across health systems.
Replicating enzymatic activity by positioning active sites with synthetic protein scaffolds
Authors: Ding Yujing , Zhang Shanshan , Hess Henry , Kong Xian , Zhang Yifei 
Published: February 2024

AbstractEvolutionary constraints significantly limit the diversity of naturally occurring enzymes, thereby reducing the sequence repertoire available for enzyme discovery and engineering. Recent breakthroughs in protein structure prediction andde novodesign, powered by artificial intelligence, now enable us to create enzymes with desired functions without relying on traditional genome mining. Here, we demonstrate a computational strategy for creating new-to-nature PET hydrolases by leveraging the known catalytic mechanisms and implementing multiple deep learning algorithms and molecular computations. This strategy includes the extraction of functional motifs from a template enzyme (here we use leaf-branch compost cutinase, LCC), regeneration of new protein scaffolds, computational screening, experimental validation, and sequence refinement. We successfully replicate PET hydrolytic activity with designer enzymes that are at least 30% shorter in sequence length than LCC. Among them,RsPETase 1 stands out due to its robust expressibility. It exhibits comparable activity toIsPETase and considerable thermostability with a melting temperature of 56 °C, despite sharing only 34% sequence similarity with LCC. This work suggests that enzyme diversity can be expanded by recapitulating functional motifs with computationally built protein scaffolds, thus generating opportunities to acquire highly active and robust enzymes that do not exist in nature.
An isothermal calorimetry assay for determining steady state kinetic and enzyme inhibition parameters for SARS-CoV-2 3CL-protease
Authors: Mazzei Luca , Ranieri Sofia , Greene-Cramer Rebecca , Cioffi Christopher , Montelione Gaetano T. , Ciurli Stefano 
Published: February 2024

ABSTRACTThis manuscript describes the application of Isothermal Titration Calorimetry (ITC) to characterize the kinetics of 3CLprofrom the Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) and its inhibition by Ensitrelvir, a known non-covalent inhibitor. 3CLprois the main protease that plays a crucial role of producing the whole array of proteins necessary for the viral infection that caused the spread of COVID-19, responsible for millions of deaths worldwide as well as global economic and healthcare crises in recent years. The proposed calorimetric method proved to have several advantages over the two types of enzymatic assays so far applied to this system, namely Förster Resonance Energy Transfer (FRET) and Liquid Chromatography-Mass Spectrometry (LC-MS). The developed ITC-based assay provided a rapid response to 3CLproactivity, which was used to directly derive the kinetic enzymatic constantsKMandkcatreliably and reproducibly, as well as their temperature dependence, from which the activation energy of the reaction was obtained for the first time. The assay further revealed the existence of two modes of inhibition of 3CLproby Ensitrelvir, namely a competitive mode as previously inferred by crystallography as well as an unprecedented uncompetitive mode, further yielding the respective inhibition constants with high precision. The calorimetric method described in this paper is thus proposed to be generally and widely used in the discovery and development of drugs targeting 3CLpro.
Diversification of molecular pattern recognition in bacterial NLR-like proteins
Authors: Béchon Nathalie , Tal Nitzan , Stokar-Avihail Avigail , Melamed Sarah , Amitai Gil , Sorek Rotem 
Published: February 2024

AbstractAntiviral STANDs (Avs) are bacterial anti-phage proteins that are evolutionarily related to immune pattern recognition receptors of the NLR family. Following recognition of a conserved phage protein, Avs proteins exhibit cellular toxicity and abort phage propagation by killing the infected cell. Type 2 Avs proteins (Avs2) were suggested to recognize the large terminase subunit of the phage as a signature of phage infection. Here, we show that while Avs2 fromKlebsiella pneumoniae(KpAvs2) can be activated when heterologously co-expressed with the terminase of phage SECphi18, during infectionin vivoKpAvs2 recognizes a different phage protein, named KpAvs2-stimulating protein 1 (Ksap1). We show that KpAvs2 directly binds Ksap1 to become activated, and that phages mutated in Ksap1 can escape KpAvs2 defense despite encoding an intact terminase. Our results exemplify the evolutionary diversification of molecular pattern recognition in bacterial Avs2 proteins, and highlight that pattern recognition during infection can differ from results obtained using heterologous co-expression assays.
Evolutionary innovation in conserved regulatory elements across the mammalian tree of life
Authors: Uebbing Severin , Kocher Acadia A. , Baumgartner Marybeth , Ji Yu , Bai Suxia , Xing Xiaojun , Nottoli Timothy , Noonan James P. 
Published: February 2024

AbstractTranscriptional enhancers orchestrate cell type- and time point-specific gene expression programs. Evolution of enhancer sequences can alter target gene expression without causing detrimental misexpression in other contexts. It has long been thought that this modularity allows evolutionary changes in enhancers to escape pleiotropic constraints, which is especially important for evolutionary constrained developmental patterning genes. However, there is still little data supporting this hypothesis. Here we identified signatures of accelerated evolution in conserved enhancer elements across the mammalian phylogeny. We found that pleiotropic genes involved in gene regulatory and developmental processes were enriched for accelerated sequence evolution within their enhancer elements. These genes were associated with an excess number of enhancers compared to other genes, and due to this they exhibit a substantial degree of sequence acceleration over all their enhancers combined. We provide evidence that sequence acceleration is associated with turnover of regulatory function. We studied one acceleration event in depth and found that its sequence evolution led to the emergence of a new enhancer activity domain that may be involved in the evolution of digit reduction in hoofed mammals. Our results provide tangible evidence that enhancer evolution has been a frequent contributor to modifications involving constrained developmental signaling genes in mammals.
Surface versus volume synthesis governs growth-dependent efficacy of aβ-lactam antibiotic
Authors: Brouwers Rebecca , Mancini Leonardo , Tavaddod Sharareh , Biboy Jacob , Mauri Marco , Tatham Elizabeth , Enghardt Marie-Luise , Zander Ariane , Cicuta Pietro , Vollmer Waldemar , Allen Rosalind J. 
Published: February 2024

AbstractThe efficacy ofβ-lactam antibiotics depends strongly on bacterial growth rate. This can lead to poor correlation between in vivo action and in vitro assays, hindering effective prescribing – yet the mechanisms underlying growth-rate dependentβ-lactam action remain unclear. Here, we investigate growth-rate dependent action of mecillinam, aβ-lactam that targets the elongation-mediating PBP2 peptidoglycan transpeptidase enzyme, onEscherichia colicells. We show that mecillinam alters the balance between the rates of cell surface area and volume synthesis in a growth-rate dependent manner. Under mecillinam treatment, cell volume increases exponentially at a rate ﬁxed by the growth medium, but the cell’s ability to produce new surface area is compromised by the antibiotic. On rich medium, this imbalance leads to lysis, but on poor medium, slow-growing cells reach a new balance between surface area and volume synthesis, allowing sustained growth even at concentrations of mecillinam far above the EUCAST MIC value. A mathematical model based on surface area vs volume synthesis can quantitatively explain growth-medium dependent differences in mecillinam killing, as well as rescue from killing when cell morphology is perturbed in a microfluidic device.β-lactam antibiotic action is mechanistically complex, yet our work suggests that simple conceptual principles can help understand the interplay between molecular mechanism and cell physiology, potentially contributing to more effective use of these drugs.
Impacts of Self-Administered 3,4-Methylenedioxypyrovalerone (MDPV) Alone, and in Combination with Caffeine, on Recognition Memory and Striatal Monoamine Neurochemistry in Male Sprague-Dawley Rats: Comparisons with Methamphetamine and Cocaine
Authors: Seaman Robert W. , Lamon Kariann , Whitton Nicholas , Latimer Brian , Sulima Agnieszka , Rice Kenner C. , Murnane Kevin S. , Collins Gregory T. 
Published: February 2024

AbstractRecent data suggest that 3,4-methylenedioxypyrovalerone (MDPV) has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced by the co-use of these two stimulants. The current study investigated the degree to which self-administered MDPV, or a mixture of MDPV+caffeine can produce deficits in recognition memory and alter neurochemistry relative to prototypical stimulants. Male Sprague-Dawley rats were provided 90-min or 12-h access to MDPV, MDPV+caffeine, methamphetamine, cocaine, or saline for 6 weeks. Novel object recognition (NOR) memory was evaluated prior to any drug self-administration history and 3 weeks after the final self-administration session. Rats that had 12-h access to methamphetamine and those that had 90-min or 12-h access to MDPV+caffeine exhibited significant deficits in NOR, whereas no significant deficits were observed in rats that self-administered cocaine or MDPV. Striatal mono-amine levels were not systematically affected. These data demonstrate synergism between MDPV and caffeine with regard to producing recognition memory deficits and lethality, highlighting the importance of recapitulating the manner in which drugs are used (e.g., in mixtures containing multiple stimulants, binge-like patterns of intake).
Building compositional tasks with shared neural subspaces
Authors: Tafazoli Sina , Bouchacourt Flora M. , Ardalan Adel , Markov Nikola T. , Uchimura Motoaki , Mattar Marcelo G. , Daw Nathaniel D. , Buschman Timothy J. 
Published: February 2024

AbstractCognition is remarkably flexible; we are able to rapidly learn and perform many different tasks1. Theoretical modeling has shown artificial neural networks trained to perform multiple tasks will re-use representations2and computational components3across tasks. By composing tasks from these sub-components, an agent can flexibly switch between tasks and rapidly learn new tasks4. Yet, whether such compositionality is found in the brain is unknown. Here, we show the same subspaces of neural activity represent task-relevant information across multiple tasks, with each task compositionally combining these subspaces in a task-specific manner. We trained monkeys to switch between three compositionally related tasks. Neural recordings found task-relevant information about stimulus features and motor actions were represented in subspaces of neural activity that were shared across tasks. When monkeys performed a task, neural representations in the relevant shared sensory subspace were transformed to the relevant shared motor subspace. Subspaces were flexibly engaged as monkeys discovered the task in effect; their internal belief about the current task predicted the strength of representations in task-relevant subspaces. In sum, our findings suggest that the brain can flexibly perform multiple tasks by compositionally combining task-relevant neural representations across tasks.
Sexually Dimorphic Influence of Circadian Pacemaker Neurons on Behavioral Rhythms
Authors: Iyer Aishwarya Ramakrishnan , Scholz-Carlson Eva , Bell Evardra , Biondi Grace , Richhariya Shlesha , Fernandez Maria P. 
Published: February 2024

AbstractThe circadian system regulates the timing of multiple molecular, physiological, metabolic, and behavioral phenomena. InDrosophila,as in other species, most of the research on how the timekeeping system in the brain controls the timing of behavioral outputs has been conducted in males, or sex has not been included as a biological variable. A critical set of circadian pacemaker neurons inDrosophilarelease the neuropeptide pigment-dispersing factor (PDF), which functions as a key output factor in the network with complex effects on other clock neurons. Lack ofPdfor its receptor,PdfR,results in most flies displaying arrhythmicity in activity–rest cycles under constant conditions. However, our results show that female circadian rhythms are less affected by mutations in bothPdfandPdfR. Crispr-Cas9-mediated mutagenesis ofPdf,specifically in ventral lateral neurons (LNvs), also has a greater effect on male rhythms. We tested the influence of M-cells on the circadian network and showed that speeding up the molecular clock specifically in M-cells led to sexually dimorphic phenotypes, with a more pronounced effect on male rhythmic behavior. Our results suggest that the female circadian system is more resilient to manipulations of M-cells and the PDF pathway, suggesting that circadian timekeeping is more distributed across the clock neuron network in females.