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Cell-type-specific functionality encoded within the intrinsically disordered regions of OCT4.
No full textThe cell-type-specific function of transcription factors (TFs) is crucial for determining cellular identity. However, it is unclear how a single TF can function specifically in different cell types. Here, we define the molecular features that enable OCT4 to reprogram somatic cells into pluripotent or trophoblast stem cells, maintain the self-renewal of embryonic stem cells (ESCs), and drive lineage commitment during early embryonic development. Embedded within the intrinsically disordered regions (IDRs) of OCT4, we uncover short linear peptides that are essential for reprogramming (SLiPERs) but dispensable for ESC self-renewal. SLiPERs adopt a quasi-ordered state and, during reprogramming, recruit a unique set of proteins to closed chromatin that are unnecessary for ESC self-renewal. Interestingly, SLiPERs are essential for embryos to develop beyond late gastrulation. Removing SLiPERs leads to aberrant OCT4 binding, derailing the regular transition of ESCs out of pluripotency. Our findings identify modules within IDRs that contribute to the functional versatility and specificity of TFs
The role of general practitioner empathy on patient-reported outcomes in telephone consultations:a cross-sectional study with validation of the Consultation and Relational Empathy (CARE) Measure for measuring empathy in telephone consultations
No full textBackgroundThe Consultation and Relational Empathy (CARE) Measure is a validated measure of GP empathy in face-to-face consultations (FTFC) and higher CARE scores predict better patient outcomes. However, the validity of CARE and its importance in telephone consultations (TC) is unknown.Aims1.To determine the validity and reliability of CARE in TCs2.To determine the associations between CARE and outcomes in TC compared with FTFC.Design and settingCross-sectional survey of 1023 patients who had a TC (n=369) or FTFC (n=654) with a GP in Scotland within the preceding 30 days.MethodsValidity and reliability testing of CARE using standard methods. Associations between low, medium, and high CARE scores and three patient outcomes (enablement, symptom change, and satisfaction) were determined using multilevel binary logistic regression. ResultsCARE was valid and reliable. Compared with the low CARE group, high CARE was positively associated with enablement (adj.OR 6.4; 95%CI 3.48 to 11.84), symptom improvement (adj.OR 5.7; 95%CI 2.70 to 11.93) and satisfaction (adj.OR 20.1; 95%CI 8.93 to 45.35) in TC. Findings were similar in FTFC (enablement adj.OR 6.21; 95%CI 3.90 to 9.89, symptom improvement adj.OR 4.26; 95% CI 2.53 to 7.16, and satisfaction adj.OR 36.29; 96%CI 17.85 to 73.78) , and were not influenced by patient or consultations characteristics.ConclusionThe CARE Measure is valid and reliable in TC and predicts better patient outcomes in TC, similar to FTFC. Given the common use of TC in primary care, strategies to support empathic communication are essential irrespective of consultation modality.<br/
Mechanical stimulation in the residual femur during gait in transfemoral prosthesis users provides a potential reason for bone mineral density loss
No full textIndividuals with transfemoral amputation (TFA) experience bone loss in their residual femur at levels seen in bedridden and post-menopausal individuals. It has been suggested that the time until first prosthesis fitting, gait deviations, and muscle atrophy may be contributing factors, but evidence is inconsistent. Prosthetic sockets are typically designed to off-load the distal end of the residual limb, yet the effect of the load transmission pathways of the prosthetic socket on a residual femur has not been examined. Using existing datasets, we recreated the prosthetic socket environment within finite element (FE) models by extracting the skeletal geometries of 10 able-bodied individuals from computer tomography scans, and anthropometrically pairing them with gait data acquired from individuals with unilateral TFA. Normal skeletal geometries were modified to resemble a TFA and fit with an ischial containment socket (ICS). The modified skeleton was positioned with respect to the socket using motion analysis marker locations and tested using the ground reaction forces corresponding to three gait instances from at least four steps. Additional mirror models without the ICS were created for comparison. We validated our study by comparing hip forces from the original gait data to acetabular contact forces estimated using the FE models. We found that the residual femur wearing an ICS experienced mean compressive strain of -105 ± 42 μE and -722 ± 155 μE without the ICS. Simulations show that this is because the ICS redirects load through the pelvis, diminishing force transmission from the femoral head to the acetabulum.</p
An Expanded Massive Multilingual Dataset for High-Performance Language Technologies (HPLT)
No full textTraining state-of-the-art large language models requires vast amounts of clean and diverse textual data. However, building suitable multilingual datasets remains a challenge. In this work, we present HPLT v2, a collection of high-quality multilingual monolingual and parallel corpora, extending prior work of the HPLT project. The monolingual portion of the data contains 8T tokens covering 193 languages, while the parallel data contains 380M sentence pairs covering 51 languages. We document the entire data pipeline and release the code to reproduce it. We provide extensive analysis of the quality and characteristics of our data. Finally, we evaluate the performance of language models and machine translation systems trained on HPLT v2, demonstrating its value
The Scottish State and the Experience of Government, c. 1560-1707:Essays in Honour of Julian Goodare
No full textThis volume examines the development of Scotland’s institutions of government in the early modern period, and considers how local and central authorities affected the lives of the Scottish people. In the book’s first part, contributors provide up-to-date studies of initiatives to reform, define and reimagine the Scottish state. The essays discuss changes in the privy council, parliament and administration, and assess political and constitutional ideas. The book’s second part explores how Scots experienced government. Contributors consider the material culture of state power and the actions of local courts and officials. Essays reconstruct the perspectives of criminals and religious dissenters, as well as participants in debt litigation and slander suits. Several chapters attend to the role of governing bodies in the Scottish witch-hunts. The essays respond to major themes in the work of Julian Goodare, who retired as Professor of History at the University of Edinburgh in 2021
Introduction: The state, society and witchcraft in early modern Scotland:Current debates and the influence of Julian Goodare
No full textPool formation in oceanic games:Shapley value and proportional sharing
No full textWe study a game-theoretic model for pool formation in Proof of Stake blockchain protocols. In such systems, stakeholders can form pools as a means of obtaining regular rewards from participation in ledger maintenance, with the power of each pool being dependent on its collective stake. The question we are interested in is the design of mechanisms, i.e., “reward sharing schemes,” that suitably split rewards among pool members and achieve favorable properties in the resulting pool configuration. With this in mind, we initiate a non-cooperative game-theoretic analysis of the well known Shapley value scheme from cooperative game theory into the context of blockchains. In particular, we focus on the oceanic model of games, proposed by Milnor and Shapley (1978), which is suitable for populations where a small set of large players coexists with a big mass of rather small, negligible players. This provides an appropriate level of abstraction for pool formation processes that occur among the stakeholders of a blockchain. We provide comparisons between the Shapley mechanism and the more standard proportional scheme, in terms of attained decentralization, via a Price of Stability analysis and in terms of susceptibility to Sybil attacks, i.e., the strategic splitting of a players’ stake with the intention of participating in multiple pools for increased profit. Interestingly, while the widely deployed proportional scheme appears to have certain advantages, the Shapley value scheme, which rewards higher the most pivotal players, emerges as a competitive alternative, by being able to bypass some of the downsides of proportional sharing in terms of Sybil attack susceptibility, while also not being far from optimal guarantees w.r.t. decentralization. Finally, we also complement our study with some variations of proportional sharing, where the profit is split in proportion to a superadditive or a subadditive function of the stake, showing that our results for the Shapley value scheme are maintained in comparison to these functions as well.<br/
Refeeding Syndrome After Metabolic and Bariatric Surgery: A Systematic Review of the Literature
No full textDemographic, occupational factors and pandemic-related stressors associated with heightened mental health difficulties among UK health and social care workers supported by regional Resilience Hubs during the COVID-19 pandemic
No full textBackground During the COVID-19 pandemic, 40 mental health and well-being hubs were funded in England to support health and social care staff affected by the pandemic.Aims To describe the characteristics of staff accessing four hubs for support and identify characteristics associated with clinically significant mental health difficulties and work and social functioning.Method Routinely collected screening data were analysed from 1973 individuals across 4 hubs, including mental health, demographic and occupational data and pandemic-related stressors. Factors associated with clinically significant mental health difficulties were identified via logistic regression.Results Most hub clients identified as white women who worked for the UK National Health Service; other groups were less well represented. Hub clients reported high levels of clinically significant mental health difficulties: 60% had severe and often co-occurring difficulties (ie, depression, anxiety, post-traumatic stress disorder or alcohol use) and 80% reported significantly impaired functioning. Younger age, disability status, identifying as from a minority ethnic group, and sexual orientations excluding heterosexual were associated with higher likelihood of having clinically significant mental health difficulties. Suffering financial loss during the pandemic, and prepandemic emotional well-being concerns were the most consistent factors associated with higher difficulties.Conclusions The hubs supported health and social care staff with significant mental health difficulties. Outreach and engagement with under-represented groups should be undertaken to address potential barriers to service access. The findings add to the knowledge base on the support needs of the health and social care workforce and the planning of support in response to future crises
Experimental analysis of bone marrow adipose tissue and bone marrow adipocytes:An update from the bone marrow adiposity society (BMAS)
Get PDFBone marrow adipose tissue (BMAT) is physiologically linked to bone and energy metabolism, endocrine regulation, hematopoiesis and cancer-related processes. A key challenge in the field is that methods for isolating BMAT or bone marrow adipocytes (BMAds) are variable because there are no widely adopted standardized protocols. To generate awareness of this challenge and to establish uniformity in experimental approaches requiring isolation, storage and characterization of BMAT and BMAds, the Biobanking Working Group of the international Bone Marrow Adiposity Society (BMAS) has previously recommended experimental standards. This paper provides an update on this effort and presents current state-of-the-art methods and technical considerations for isolation and characterization of BMAT and BMAds, including currently available high-throughput omics approaches. This review provides a reference point based on the consensus view of BMAS investigators to support studies on biomedical, biological, biochemical and biophysical questions associated with bone marrow adiposity.</p
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