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DNA methylation is the most stable type of epigenetic modification modulating the transcriptional plasticity of mammalian genomes. Using bisulfite DNA sequencing, we report high-resolution methylation profiles of human chromosomes 6, 20 and 22, providing a resource of about 1.9 million CpG methylation values derived from 12 different tissues. Analysis of six annotation categories showed that evolutionarily conserved regions are the predominant sites for differential DNA methylation and that a core region surrounding the transcriptional start site is an informative surrogate for promoter methylation. We find that 17% of the 873 analyzed genes are differentially methylated in their 5′ UTRs and that about one-third of the differentially methylated 5′ UTRs are inversely correlated with transcription. Despite the fact that our study controlled for factors reported to affect DNA methylation such as sex and age, we did not find any significant attributable effects. Our data suggest DNA methylation to be ontogenetically more stable than previously thought.

In 1953 Medawar pointed out that survival of the genetically disparate (allogeneic) mammalian conceptus contradicts the laws of tissue transplantation. Rapid T cell-induced rejection of all allogeneic concepti occurred when pregnant mice were treated with a pharmacologic inhibitor of indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme expressed by trophoblasts and macrophages. Thus, by catabolizing tryptophan, the mammalian conceptus suppresses T cell activity and defends itself against rejection.

Diabetic eye screening (DES) represents a significant opportunity for the application of machine learning (ML) technologies, which may improve clinical and service outcomes. However, successful integration of ML into DES requires careful product development, evaluation, and implementation. Target product profiles (TPPs) summarize the requirements necessary for successful implementation so these can guide product development and evaluation. This study aims to produce a TPP for an ML-automated retinal imaging analysis software (ML-ARIAS) system for use in DES in England. This work will consist of 3 phases. Phase 1 will establish the characteristics to be addressed in the TPP. A list of candidate characteristics will be generated from the following sources: an overview of systematic reviews of diagnostic test TPPs; a systematic review of digital health TPPs; and the National Institute for Health and Care Excellence's Evidence Standards Framework for Digital Health Technologies. The list of characteristics will be refined and validated by a study advisory group (SAG) made up of representatives from key stakeholders in DES. This includes people with diabetes; health care professionals; health care managers and leaders; and regulators and policy makers. In phase 2, specifications for these characteristics will be drafted following a series of semistructured interviews with participants from these stakeholder groups. Data collected from these interviews will be analyzed using the shortlist of characteristics as a framework, after which specifications will be drafted to create a draft TPP. Following approval by the SAG, in phase 3, the draft will enter an internet-based Delphi consensus study with participants sought from the groups previously identified, as well as ML-ARIAS developers, to ensure feasibility. Participants will be invited to score characteristic and specification pairs on a scale from \"definitely exclude\" to \"definitely include,\" and suggest edits. The document will be iterated between rounds based on participants' feedback. Feedback on the draft document will be sought from a group of ML-ARIAS developers before its final contents are agreed upon in an in-person consensus meeting. At this meeting, representatives from the stakeholder groups previously identified (minus ML-ARIAS developers, to avoid bias) will be presented with the Delphi results and feedback of the user group and asked to agree on the final contents by vote. Phase 1 was completed in November 2023. Phase 2 is underway and expected to finish in March 2024. Phase 3 is expected to be complete in July 2024. The multistakeholder development of a TPP for an ML-ARIAS for use in DES in England will help developers produce tools that serve the needs of patients, health care providers, and their staff. The TPP development process will also provide methods and a template to produce similar documents in other disease areas. DERR1-10.2196/50568.

IntroductionHealth Data Research UK designated seven UK-based Hubs to facilitate health data use for research. PIONEER is the Hub in Acute Care. PIONEER delivered workshops where patients/public citizens agreed key principles to guide access to unconsented, anonymised, routinely collected health data. These were used to inform the protocol.MethodsThis paper describes the PIONEER infrastructure and data access processes. PIONEER is a research database and analytical environment that links routinely collected health data across community, ambulance and hospital healthcare providers. PIONEER aims ultimately to improve patient health and care, by making health data discoverable and accessible for research by National Health Service, academic and commercial organisations. The PIONEER protocol incorporates principles identified in the public/patient workshops. This includes all data access requests being reviewed by the Data Trust Committee, a group of public citizens who advise on whether requests should be supported prior to licensed access.Ethics and disseminationEast Midlands–Derby REC (20/EM/0158): Confidentiality Advisory Group (20/CAG/0084). www.PIONEERdatahub.co.uk

The sequence of the mouse genome is a key informational tool for understanding the contents of the human genome and a key experimental tool for biomedical research. Here, we report the results of an international collaboration to produce a high-quality draft sequence of the mouse genome. We also present an initial comparative analysis of the mouse and human genomes, describing some of the insights that can be gleaned from the two sequences. We discuss topics including the analysis of the evolutionary forces shaping the size, structure and sequence of the genomes; the conservation of large-scale synteny across most of the genomes; the much lower extent of sequence orthology covering less than half of the genomes; the proportions of the genomes under selection; the number of protein-coding genes; the expansion of gene families related to reproduction and immunity; the evolution of proteins; and the identification of intraspecies polymorphism.

The mental processing abilities of 29 adults with Down syndrome (aged between 19 and 42 years) and 90 children without intellectual impairment (aged between 5 and 10 years) are examined on experimental tasks designed to assess flexibility of thinking. The abilities of 27 of the adults and 39 of the children matched for performance on a non-verbal reasoning test (R.C.P.X.) are compared separately. The measures of flexibility of thinking are problem-solving tasks which require mental operations involving reciprocal transformations of the attributes of stimulus figures. Performance on these tasks is compared with simultaneous processing ability (measured by R.C.P.X.) and sequential processing ability (measured by the auditory-vocal sub-test of the I.T.P.A. and a visual-motor test devised for the investigation). The findings show that the experimental tasks prove to be effective in revealing increasing ability to exercise flexibility in thinking in children through the age-range of 5 to 10 years. Visual-motor sequential processing ability is shown to be the discriminating variable most associated with performances on the experimental tasks. It is proposed that this association can be accounted for by the fact that both measures require efficiency in a specific performance component called upon to operationally order thought through multiple inter-related concepts. The adults with Down syndrome are shown to be unable to process the experimental tasks successfully. No difference is shown between the solution strategies they employed and those employed by children who were also unable to carry out the processing requirements. A training study is then reported, undertaken with 6 of the adults aged between 20 and 23 years, which seeks to induce the processing requirements of the tasks or to identify those components of the processing skill which present unsurmountable difficulties. The methodology of the training study employs concrete aids to demonstrate and assist in the processing of separate operations involved in the tasks. Intervention is shown to be completely successful for two of the trainees. Their performance levels on re-test improved from the average of 5 to 6 year old children to the average for 9 year old children. Transfer of learning to parallel tasks is also achieved. The principal reason for failure in the four unsuccessful trainees is shown to be inability to order thought through operations involving different successive transformations. The author proposes that the instructional methods employed in the training study may provide the methodology for enhancement of mental processing skills in other areas of logical reasoning. It is stressed that an essential condition for this enhancement in any individual is the present efficiency of the performance component called upon to order multiple inter-related concepts. The importance of this specific performance component for information-processing theory and concepts of intelligence is discussed. It is reasoned that this specific component will make a significant contribution to the quality of thinking that is demonstrated in problem-solving tasks. It is proposed that this component could constitute 'g', which is thus unitary, and may be defined as 'the general capacity of an individual to perform mental processing that involves operational ordering of multiple inter-related concepts'.