150259 research outputs found
Sort by
The role of psychopharmacology and cognitive neuroscience in understanding the brain in the treatment of psychiatric disorders and neurological diseases for the benefit of society.
No full textThis perspectives piece reflects on some of the major scientific contributions in psychopharmacology, cognitive neuroscience, and public policy of Professor Barbara J. Sahakian, Commander of the Most Excellent Order of the British Empire (CBE). Her pioneering research has advanced the understanding of brain mechanisms, including neurotransmitter modulation, and psychological processes involved in cognition, emotion, and motivation, leading to novel treatments for disorders such as Alzheimer's disease, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. She has also contributed to a better understanding of brain mechanisms underlying and psychological processes involved in these disorders. She has championed early detection of Alzheimer's disease through neuropsychological tools, such as the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning (PAL) test and contributed to identifying cognitive and neural changes in Huntington's disease gene carriers. Beyond clinical research, Sahakian has influenced public health policy through initiatives such as the UK Government Foresight Project on Mental Capital and Wellbeing and the National Institute for Health and Care Excellence guidelines on gambling-related harms. She has also led efforts in neuroethics and public engagement, co-authoring accessible science books and participating in global forums. Recent research emphasises preventative psychiatry, including lifestyle interventions, such as diet, sleep, social connection, and lifelong learning as preventive strategies for cognitive decline and mental health problems. Through interdisciplinary collaborations and mentorship, Sahakian continues to inspire the next generation of scientists to pursue innovative research for societal benefit in neuropsychopharmacology and cognitive neuroscience
Early-Life Sugar Restriction and Long-Term Risk of Cancer: A Natural Experiment Study in the UK
No full textObjective: To examine whether early-life exposure to sugar rationing is associated with reduced risk of cancer and cardiometabolic disease in adulthood, leveraging a natural experiment created by the abrupt end of post-war sugar rationing in the United Kingdom on 26 September 1953.
Design: Natural experiment study using an event-study design based on variation in the duration of exposure to sugar rationing during the first 1000 days of life (from conception to age 2 years).
Setting: UK Biobank, a large prospective cohort recruited from across the UK.
Participants: 64,761 UK Biobank participants born between 1951 and 1956, a window spanning the 1953 de-rationing event. Exposure to sugar restriction was determined by birth date relative to the policy change. Individuals with multiple births, adoption, birth outside the UK, or pre-existing disease were excluded.
Main outcome measures: Adult incidence of major cancers, digestive (liver, rectum), respiratory (lung), and hormonesensitive (prostate, breast), estimated using Cox proportional hazards models. We also assessed long-term behavioural outcomes (dietary patterns) and biological markers (leukocyte telomere length; circulating Granzyme B).
Results: Longer exposure to sugar rationing during early life was associated with lower risk of multiple diseases in adulthood. Participants exposed in utero plus one to two years had lower incidence of digestive cancers (liver: hazard ratio 0.31, 95% confidence interval 0.18 to 0.49; rectum: 0.60, 0.51 to 0.69), respiratory cancer (lung: 0.59, 0.50 to 0.68), and hormonesensitive cancers (prostate: 0.48, 0.43 to 0.55; breast: 0.64, 0.58 to 0.70).
Mechanisms: Two complementary mechanisms were identified: (1) a behavioural programming pathway, wherein early-life restriction led to a persistent hedonic shift resulting in lower sugar intake and healthier dietary habits five decades later; and (2) a biological imprinting pathway, evidenced by 0.05 SD longer leukocyte telomere length (≈ 2.2 years less biological ageing) and lower circulating Granzyme B levels.
Conclusion: Exposure to sugar restriction during the first 1,000 days was associated with lower cancer and slower biological ageing, offering rare causal evidence that early-life nutrition can permanently shape disease susceptibility. During rationing, adults consumed about 40 g/day of sugar, well within WHO-recommended levels, whereas intake doubled to roughly 80g/day once controls ended. This natural contrast shows that maintaining WHO-level sugar intake in early life can yield lasting health benefits. With current consumption far above recommended thresholds, the case for early-life sugar reduction is both urgent and highly consequential
Co-creation of community-based innovations to improve access to malaria treatment in conflict-affected regions of Cameroon
No full textBackgroundIn conflict-affected regions of Cameroon, access to malaria care is severely hindered by displacement, insecurity, and disrupted health systems. In response, we conducted an operational research aimed at breaking barriers to malaria services in conflict-affected communities of Cameroon.MethodsIn 2021, a participatory co-creation workshop was held on the 21st and 22nd of October 2021, bringing together stakeholders from government health services, community leaders, internally displaced persons (IDPs), and community health workers (CHWs)to collaboratively design interventions aimed at addressing barriers to accessing malaria treatment. The workshop built on prior formative research conducted in 80 conflict-affected communities across the South West and Littoral regions of Cameroon, which identified context-specific challenges to malaria care. The design process included plenary sessions, group discussions, and facilitated brainstorming, and employed participatory methods to ensure that community voices shaped the development of the interventions.Lessons learnedThree community-based innovations were co-created through this process. Community Health Participatory Approach (CoHPA) was designed to replace the traditional top-down community dialogue structure with a participatory, inclusive model. The Health Voucher System was designed to address financial and geographical barriers, a voucher-based system was introduced to enable access to subsidized malaria services. Vouchers covered malaria testing, treatment, and transport to health facilities. The Supportive Supervision Model was developed to enhance the capacity and motivation of CHWs, who play a crucial role in delivering malaria services in hard-to-reach areas.DiscussionThe co-creation process was key to developing contextually relevant and community-owned malaria interventions. It led to three innovations: the CoHPA model, which introduced internal community-led accountability mechanisms; a Health Voucher System that addressed both financial and transport barriers to care; and a supportive supervision model that aimed to improve CHW performance through bi-directional feedback and recognition. While each intervention introduced novel, context-sensitive elements, concerns remain about their scalability, sustainability, and integration into existing health systems without continued support and investment.ConclusionThe co-creation process produced three community-driven interventions with potential to break key barriers in access to malaria case management in conflict-affected communities of Cameroon. Pilot implementation and community buy-in for integration into national health systems are essential next steps
Unravelling the molecular mechanisms causal to type 2 diabetes across global populations and disease-relevant tissues.
No full textType 2 diabetes (T2D) is a prevalent disease arising from complex molecular mechanisms. Here we leverage T2D genetic associations to identify causal molecular mechanisms in an ancestry-aware and tissue-aware manner. Using two-sample Mendelian randomization corroborated by colocalization across four global ancestries, we analyse 20,307 gene and 1,630 protein expression levels using blood-derived cis-quantitative trait loci (QTLs). We detect causal effects of genetically predicted levels of 335 genes and 46 proteins on T2D risk, with 16.4% and 50% replication in independent cohorts, respectively. Using gene expression cis-QTLs derived from seven T2D-relevant tissues, we identify causal links between the expression of 676 genes and T2D risk, refining known associations such as BAK1 and describing additional ones like CPXM1. Causal effects are mostly shared across ancestries but are highly heterogeneous across tissues. Our findings provide insights into cross-ancestry and tissue-informed multi-omics causal inference approaches and demonstrate their power in uncovering molecular processes driving T2D
Dissolved organic matter specialisation drives temporal dynamics of simplified bacterial communities in a microcosm experiment
No full textMicroorganisms form the base of aquatic food webs and play a key role in the global carbon cycle by decomposing dissolved organic matter (DOM). Climate change is predicted to shift the composition of DOM in northern freshwaters from predominantly small, low molecular weight compounds to aromatic, high molecular weight compounds. However, the consequences of these changes for bacterial communities and their role in wider ecosystem processes is poorly understood. Here, we used a 14-day incubation experiment to test how the same bacterial community responded to diverse DOM sources that varied in their bioavailability and were representative of predicted compositional changes in northern waters. Using full-length 16S amplicon sequencing, we found that bacterial communities differed in their composition across sources within 24 hours of exposure to novel DOM, but changed similarly over time thereafter, primarily driven by consistent increases in the relative abundance of one generalist species. Microbial reworking of DOM, characterised using ultra high resolution mass spectrometry, led to an increase in the relative abundance of less bioavailable compounds on sources with higher initial bioavailability. Our study advances previous work by demonstrating that interactions between bacteria and DOM under novel environmental conditions depend on their level of specialisation and that any losses in resource specialisation may have consequences for the persistence and trophic transfer of carbon in aquatic food webs
Modelling cultural responses to disease spread in Neolithic Trypillia mega-settlements.
No full textAs zoonotic diseases coevolved with early agriculture, social distancing within dense human settlements could have conferred a selective advantage in terms of infection risk. Here, we consider the case of Trypillia mega-settlements after 4000 BC, as virulent diseases began affecting humans in the Black Sea region. Through epidemiological susceptible-infected-recovered-susceptible (SIRS) models situated on clustered networks and on a site plan of a Trypillia mega-settlement, we show the adaptive benefits of decreasing either occupation density or the frequency of interactions with other communities across the settlement. We explore critical thresholds in these parameters that may shed light on the fluctuations of population densities at Trypillia mega-settlements before and after approximately 3600 BCE. Our findings suggest that disease was probably a significant driver of human settlement patterns by late Neolithic times
The Value of Worker Rights in Collective Bargaining
No full textCollective bargaining agreements (CBAs) specify the contractual rights of unionized workers, but their full legal content has not yet been analyzed by economists. This paper develops novel natural language methods to analyze the empirical determinants and economic value of these rights using a new collection of 30,000 CBAs from Canada in the period 1986-2015. We parse legally binding rights (e.g., "workers shall receive. . . ") and obligations (e.g., "the employer shall provide. . . ") from contract text and validate our measures through evaluation of clause pairs and comparison to firm surveys on HR practices. Using timevarying province-level variation in labor income tax rates, we find that higher taxes increase the share of worker-rights clauses while reducing pre-tax wages in unionized firms, consistent with a substitution effect away from taxed wages toward untaxed rights. Further, an exogenous increase in the value of outside options (from a leave-one-out instrument for labor demand) increases the share of worker rights clauses in CBAs. Combining the regression estimates, we infer that a one-standard-deviation increase in worker rights is valued at about 5.7% of wages
Pangenome-guided sequence assembly via binary optimization
No full textAbstract
De novo genome assembly is challenging in highly repetitive regions; however, reference-guided assemblers often suffer from bias. We propose a framework for pangenome-guided sequence assembly that can resolve short-read data in complex regions without bias towards a single reference genome. Our primary contribution is to frame the assembly as a graph traversal optimization problem, which can be implemented classically or on a quantum computer. The workflow involves first annotating pangenome graphs with estimated copy numbers for each node, then finding a path on the graph that best explains those copy numbers. On simulated data, our approach significantly reduces the number of contigs compared with de novo assemblers. While they introduce a small increase in inaccuracies, such as false joins, our optimization-based methods are competitive with current exhaustive search techniques. They are also designed to scale more efficiently as the problem size grows and will run effectively on future quantum computers; a small experiment on a real quantum device showcases this behaviour. Moreover, they are more resilient to noise in copy number estimation inherent in short-read-based assembly. We also develop novel tools for creating realistic synthetic pangenomes, aligning reads to pangenomes and for evaluating assembly quality.</jats:p
Dissecting the Binding Interactions of the Chromatin Remodeler SMARCA4 with G-Quadruplex DNA.
No full textDNA G-quadruplexes (G4s) are key structural features in chromatin that are important to genome function. G4s have an apparent capacity to recruit a wide variety of proteins, including chromatin remodelers, yet the molecular basis and biophysical principles governing these interactions remain poorly understood. Here, we sought to build insights into the interactions of chromatin remodeler SMARCA4 with G4s using a biophysical approach. We found that SMARCA4 selectively recognizes the G4 structure over duplex and single-stranded DNA. SMARCA4 binds a wide range of G4s with different topologies and loop lengths with similar low nanomolar affinities. SMARCA4 was also observed to have a longer residency time on the G4 structure compared to that of other known protein-DNA interactions. We also found that the D1 (DExx-c) helicase domain of SMARCA4, which is important for tethering SMARCA4 to chromatinized DNA, was the predominant binding domain for G4 recognition. Our findings reveal new insights into how G4s interact with proteins, which may have important implications for understanding G4-mediated genome mechanisms
BICEP/Keck. XX. Component-separated Maps of the Polarized Cosmic Microwave Background and Thermal Dust Emission Using Planck and BICEP/Keck Observations through the 2018 Observing Season
No full textWe present component-separated polarization maps of the cosmic microwave background (CMB) and Galactic thermal dust emission, derived using data from the BICEP/Keck experiments through the 2018 observing season and Planck. By employing a maximum-likelihood method that utilizes observing matrices, we produce unbiased maps of the CMB and dust signals. We outline the computational challenges and demonstrate an efficient implementation of the component map estimator. We show methods to compute and characterize power spectra of these maps, opening up an alternative way to infer the tensor-to-scalar ratio from our data. We compare the results of this map-based separation method with the baseline BICEP/Keck analysis. Our analysis demonstrates consistency between the two methods, finding an 84% correlation between the pipelines