The histone chaperone SPT2 regulates chromatin structure and function in Metazoa.

Histone chaperones control nucleosome density and chromatin structure. In yeast, the H3-H4 chaperone Spt2 controls histone deposition at active genes but its roles in metazoan chromatin structure and organismal physiology are not known. Here we identify the Caenorhabditis elegans ortholog of SPT2 (CeSPT-2) and show that its ability to bind histones H3-H4 is important for germline development and transgenerational epigenetic gene silencing, and that spt-2 null mutants display signatures of a global stress response. Genome-wide profiling showed that CeSPT-2 binds to a range of highly expressed genes, and we find that spt-2 mutants have increased chromatin accessibility at a subset of these loci. We also show that SPT2 influences chromatin structure and controls the levels of soluble and chromatin-bound H3.3 in human cells. Our work reveals roles for SPT2 in controlling chromatin structure and function in Metazoa.

European standards for undergraduate medical education in general practice; a blueprint - for action.

There is compelling evidence that general practice (GP) is the most effective form of healthcare. However, healthcare policy appears independent of evidence and GP is woefully under-resourced in all countries, and this affects recruitment. Recruitment to GP is proportional to the quantity and quality of undergraduate experience and national and transnational guidelines can improve undergraduate experiences by defining both the desired quantity and quality. There is good evidence that these professionally developed guidelines can be effective in changing Government policy if they are used as a touchstone to collaborate with policymakers.EURACT (European Academy of Teachers in General Practice / Family Medicine) have therefore developed transnational guidelines covering the European region. The guidelines cover the desired quantity, quality and support for undergraduate experience. Three main design principles have been used. Firstly, it is democratic. Secondly it is evidence-based, using extensive literature searching, situational analysis and surveys. Finally, it adopts a 'principles-based approach'. Generalist medicine is articulated as a series of interconnected principles that integrate and then re-focus specialist medicine to achieve the enhanced patient-orientated outcomes of primary-care. This way of articulating generalist practice delivers general principles, which can be used as learning outcomes, that are adaptable to a wide range of learning environments. Most clinical learning documents are irrelevant and are destined for dusty drawers or forgotten digital files. We therefore encourage primary care educators to use these guidelines to work with policy-makers at all levels to advocate for change, strengthening primary care education at local, national and international levels.

Early clinical exposure in undergraduate medical education: A questionnaire survey of 30 European countries.

PURPOSE: Fifteen years ago, a European survey demonstrated widespread adoption of early clinical exposure (ECE) programmes but little emphasis in the curricula of medical schools. We now repeat the survey in light of the ample emerging data suggesting multiple positive outcomes of ECE. METHODS: Online cross-sectional survey in European medical schools conducted by the EURACT Basic Medical Education Committee in 2021. Descriptive quantitative analyses and a thematic analysis approach were used. RESULTS: Eighy-nine (48%) medical schools in 30 European countries responded. ECE was used in 65 (73%) of the medical schools, and 88% of ECE programmes took place in primary care. The median total time spent on the ECE programme was 5 days. Teaching methods covered unstructured learning opportunities such as observation or shadowing doctors, as well as work-based learning whilst seeing real patients or reflecting on own encounters. Learning goals included knowledge, skills, and attitudes. More than half of the respondents expressed barriers to implementing or expanding ECE. CONCLUSIONS: Compared to the previous survey, there was no significant change in the adoption or curricular emphasis of ECE programmes. Institutional attitudes towards certain disciplines and a lack of willingness to experiment with new teaching methods may be partially responsible.

Widespread transposon co-option in the Caenorhabditis germline regulatory network.

The movement of selfish DNA elements can lead to widespread genomic alterations with potential to create novel functions. We show that transposon expansions in Caenorhabditis nematodes led to extensive rewiring of germline transcriptional regulation. We find that about one-third of Caenorhabditis elegans germline-specific promoters have been co-opted from two related miniature inverted repeat transposable elements (TEs), CERP2 and CELE2. These promoters are regulated by HIM-17, a THAP domain-containing transcription factor related to a transposase. Expansion of CERP2 occurred before radiation of the Caenorhabditis genus, as did fixation of mutations in HIM-17 through positive selection, whereas CELE2 expanded only in C. elegans. Through comparative analyses in Caenorhabditis briggsae, we find not only evolutionary conservation of most CERP2 co-opted promoters but also a substantial fraction that are species-specific. Our work reveals the emergence and evolutionary conservation of a novel transcriptional network driven by TE co-option with a major impact on regulatory evolution.

DREAM represses distinct targets by cooperating with different THAP domain proteins.

The DREAM (dimerization partner [DP], retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell-cycle and other genes, but its mechanism of action is unclear. Here, we demonstrate that two C. elegans THAP domain proteins, LIN-15B and LIN-36, co-localize with DREAM and function by different mechanisms for repression of distinct sets of targets. LIN-36 represses classical cell-cycle targets by promoting DREAM binding and gene body enrichment of H2A.Z, and we find that DREAM subunit EFL-1/E2F is specific for LIN-36 targets. In contrast, LIN-15B represses germline-specific targets in the soma by facilitating H3K9me2 promoter marking. We further find that LIN-36 and LIN-15B differently regulate DREAM binding. In humans, THAP proteins have been implicated in cell-cycle regulation by poorly understood mechanisms. We propose that THAP domain proteins are key mediators of Rb/DREAM function.

Allergen immunotherapy in atopic dermatitis: Light and shadow in children.

Atopic dermatitis (AD) is a chronic remitting-relapsing inflammatory skin disorder. Due to the multifactorial pathogenesis, there are numerous therapeutic management approaches, mainly based on symptomatic treatments. In recent years, allergen immunotherapy (AIT) has been progressively advanced as targeted disease-modifying treatment of allergic disease. The most recent guideline from the American Academy of Dermatology concludes that data available do not support its use in AD. The Joint Task Force and The European Academy of Dermatology suggest that clinicians can consider AIT treatment in selected patients characterized by aeroallergen sensitization, prevalently HDM, severe AD, and clinical exacerbation after exposure to the causative allergen. Nevertheless, its role in AD is still under debate, especially in children.

Repurposing of promoters and enhancers during mammalian evolution.

Promoters and enhancers-key controllers of gene expression-have long been distinguished from each other based on their function. However, recent work suggested that common architectural and functional features might have facilitated the conversion of one type of element into the other during evolution. Here, based on cross-mammalian analyses of epigenome and transcriptome data, we provide support for this hypothesis by detecting 445 regulatory elements with signatures of activity turnover (termed P/E elements). Most events represent transformations of putative ancestral enhancers into promoters, leading to the emergence of species-specific transcribed loci or 5' exons. Distinct GC sequence compositions and stabilizing 5' splicing (U1) regulatory motif patterns may have predisposed P/E elements to regulatory repurposing, and changes in the U1 and polyadenylation signal densities and distributions likely drove the evolutionary activity switches. Our work suggests that regulatory repurposing facilitated regulatory innovation and the origination of new genes and exons during evolution.

Evaluating case studies of community-oriented integrated care.

This paper summarises a ten-year conversation within London Journal of Primary Care about the nature of community-oriented integrated care (COIC) and how to develop and evaluate it. COIC means integration of efforts for combined disease-treatment and health-enhancement at local, community level. COIC is similar to the World Health Organisation concept of a Community-Based Coordinating Hub - both require a local geographic area where different organisations align their activities for whole system integration and develop local communities for health. COIC is a necessary part of an integrated system for health and care because it enables multiple insights into 'wicked problems', and multiple services to integrate their activities for people with complex conditions, at the same time helping everyone to collaborate for the health of the local population. The conversation concludes seven aspects of COIC that warrant further attention.

Carelli on art 'The Dali Universe'.

Interactive and multimedia methods are the future, already developing in teaching and learning modules in Medicine. It happens and has to happen because: 1) It improves tools for the teacher in preparing and showing the bulk of materials on which students must study and learn; it enables interactivity with learners both in formative pathway and in final assessment. 2) It improves attention, interest and involvement of students and learners, and acts as a guideline to progressive broadening in researches, studies, considerations, and information exchanges among different learners. 3) The rapid progress in application of technology, WEB area and sources researches allows such a deepening and widening interactivity that before was never possible to imagine. It is the same thing also in CME, sometimes so dry, and dropped from above, while the new methodology may/must get rid of negative and boring features, often not useful in producing particular improvements in knowledge and quality. The Professional Doctor needs to feel a protagonist part in situation to be investigated, where interaction with all what media tools can offer may produce an "educative" improvement, much faster, effective and pleasant/rewarding.

Broad Chromatin Domains: An Important Facet of Genome Regulation.

Chromatin composition differs across the genome, with distinct compositions characterizing regions associated with different properties and functions. Whereas many histone modifications show local enrichment over genes or regulatory elements, marking can also span large genomic intervals defining broad chromatin domains. Here we highlight structural and functional features of chromatin domains marked by histone modifications, with a particular emphasis on the potential roles of H3K27 methylation domains in the organization and regulation of genome activity in metazoans.

Strengthening general practice/family medicine in Europe-advice from professionals from 30 European countries.

BACKGROUND: Substantial variations are still to be found in the strength of general practice/family medicine (GP/FM) across Europe regarding governance, workforce competence and performance, as well as academic development and position. Governments are encouraged by the WHO to secure high quality primary health care to their population, a necessity for reaching the goal "Health for all". The present study aimed at investigating the opinions of council members of the European Academy of Teachers in General Practice (EURACT) on necessary actions to strengthen the position of GP/FM in their country. METHODS: The study used a mixed methods exploratory sequential design. EURACT representatives from 32 European countries first participated in brain-storming on how to strengthen GP/FM in Europe. Later, representatives from 37 countries were asked to individually score the relevance of the proposed actions for their country on a 9-point Likert scale. They were also asked to evaluate the status of GP/FM in their country on four dimensions. RESULTS: Respondents from 30 European countries returned complete questionnaires. To build and secure GP/FM as an academic discipline comprising teaching and research was seen as essential, regardless the present status of GP/FM in the respective country. To build GP/FM as a specialty on the same level as other specialties was seen as important in countries where GP/FM held a strong or medium strong position. The importance of common learning objectives and a defined bibliography were stated by respondents from countries where GP/FM presently has a weak position. CONCLUSIONS: In order to strengthen GP/FM throughout Europe, EURACT and other professional organizations must establish common goals and share expertise between countries. To influence decision makers through information on cost-effectiveness of a GP/FM-based health care system is also important.

The life history of retrocopies illuminates the evolution of new mammalian genes.

New genes contribute substantially to adaptive evolutionary innovation, but the functional evolution of new mammalian genes has been little explored at a broad scale. Previous work established mRNA-derived gene duplicates, known as retrocopies, as models for the study of new gene origination. Here we combine mammalian transcriptomic and epigenomic data to unveil the processes underlying the evolution of stripped-down retrocopies into complex new genes. We show that although some robustly expressed retrocopies are transcribed from preexisting promoters, most evolved new promoters from scratch or recruited proto-promoters in their genomic vicinity. In particular, many retrocopy promoters emerged from ancestral enhancers (or bivalent regulatory elements) or are located in CpG islands not associated with other genes. We detected 88-280 selectively preserved retrocopies per mammalian species, illustrating that these mechanisms facilitated the birth of many functional retrogenes during mammalian evolution. The regulatory evolution of originally monoexonic retrocopies was frequently accompanied by exon gain, which facilitated co-option of distant promoters and allowed expression of alternative isoforms. While young retrogenes are often initially expressed in the testis, increased regulatory and structural complexities allowed retrogenes to functionally diversify and evolve somatic organ functions, sometimes as complex as those of their parents. Thus, some retrogenes evolved the capacity to temporarily substitute for their parents during the process of male meiotic X inactivation, while others rendered parental functions superfluous, allowing for parental gene loss. Overall, our reconstruction of the "life history" of mammalian retrogenes highlights retroposition as a general model for understanding new gene birth and functional evolution.