Biallelic Germline Transcription at the κ Immunoglobulin Locus

Rearrangement of antigen receptor genes generates a vast array of antigen receptors on lymphocytes. The establishment of allelic exclusion in immunoglobulin genes requires differential treatment of the two sequence identical alleles. In the case of the κ immunoglobulin locus, changes in chromatin structure, methylation, and replication timing of the two alleles are all potentially involved in regulating rearrangement. Additionally, germline transcription of the κ locus which precedes rearrangement has been proposed to reflect an opening of the chromatin structure rendering it available for rearrangement. As the initial restriction of rearrangement to one allele is critical to the establishment of allelic exclusion, a key question is whether or not germline transcription at the κ locus is monoallelic or biallelic. We have used a sensitive reverse transcription-polymerase chain reaction (RT-PCR) assay and an RNA–fluorescence in situ hybridization (FISH) to show that germline transcription of the κ locus is biallelic in wild-type immature B cells and in recombination activating gene (RAG)−/−, μ+ B cells. Therefore, germline transcription is unlikely to dictate which allele will be rearranged first and rather reflects a general opening on both alleles that must be accompanied by a mechanism allowing one of the two alleles to be rearranged first

Ten years of integrated care: backwards and forwards. The case of the province of Québec, Canada

<strong>Introduction: </strong>Québec's rapidly growing elderly and chronically ill population represents a major challenge to its healthcare delivery system, attributable in part to the system's focus on acute care and fragmented delivery. <strong></strong><p><strong>Description of policy practice: </strong>Over the past few years, reforms have been implemented at the provincial policy level to integrate hospital-based, nursing home, homecare and social services in 95 catchment areas. Recent organizational changes in primary care have also resulted in the implementation of family medicine groups and network clinics. Several localized initiatives were also developed to improve integration of care for older persons or persons with chronic diseases.<strong></strong></p><p><strong>Conclusion and discussion</strong>: Québec has a history of integration of health and social services at the structural level. Recent evaluations of the current reform show that the care provided by various institutions in the healthcare system is becoming better integrated. The Québec health care system nevertheless continues to face three important challenges in its management of chronic diseases: implementing the reorganization of primary care, successfully integrating primary and secondary care at the clinical level, and developing effective governance and change management.</p><p>Efforts should focus on strengthening primary care by implementing nurse practitioners, developing a shared information system, and achieving better collaboration between primary and secondary care.</p

Hybrid dysgenesis in Drosophila virilis results in clusters of mitotic recombination and loss-of-heterozygosity but leaves meiotic recombination unaltered

This work is licensed under a Creative Commons Attribution 4.0 International License.Background Transposable elements (TEs) are endogenous mutagens and their harmful effects are especially evident in syndromes of hybrid dysgenesis. In Drosophila virilis, hybrid dysgenesis is a syndrome of incomplete gonadal atrophy that occurs when males with multiple active TE families fertilize females that lack active copies of the same families. This has been demonstrated to cause the transposition of paternally inherited TE families, with gonadal atrophy driven by the death of germline stem cells. Because there are abundant, active TEs in the male inducer genome, that are not present in the female reactive genome, the D. virilis syndrome serves as an excellent model for understanding the effects of hybridization between individuals with asymmetric TE profiles. Results Using the D. virilis syndrome of hybrid dysgenesis as a model, we sought to determine how the landscape of germline recombination is affected by parental TE asymmetry. Using a genotyping-by-sequencing approach, we generated a high-resolution genetic map of D. virilis and show that recombination rate and TE density are negatively correlated in this species. We then contrast recombination events in the germline of dysgenic versus non-dysgenic F1 females to show that the landscape of meiotic recombination is hardly perturbed during hybrid dysgenesis. In contrast, hybrid dysgenesis in the female germline increases transmission of chromosomes with mitotic recombination. Using a de novo PacBio assembly of the D. virilis inducer genome we show that clusters of mitotic recombination events in dysgenic females are associated with genomic regions with transposons implicated in hybrid dysgenesis. Conclusions Overall, we conclude that increased mitotic recombination is likely the result of early TE activation in dysgenic progeny, but a stable landscape of meiotic recombination indicates that either transposition is ameliorated in the adult female germline or that regulation of meiotic recombination is robust to ongoing transposition. These results indicate that the effects of parental TE asymmetry on recombination are likely sensitive to the timing of transposition

Diagnostic study, design and implementation of an integrated model of care in France: a bottom-up process with continuous leadership

<strong>Background: </strong>Sustaining integrated care is difficult, in large part because of problems encountered securing the participation of health care and social service professionals and, in particular, general practitioners (GPs). <p><br /><strong>Purpose: </strong>To present an innovative bottom-up and pragmatic strategy used to implement a new integrated care model in France for community-dwelling elderly people with complex needs.</p><p><br /><strong>Results: </strong>In the first step, a diagnostic study was conducted with face-to-face interviews to gather data on current practices from a sample of health and social stakeholders working with elderly people. In the second step, an integrated care model called Coordination Personnes Agées (COPA) was designed by the same major stakeholders in order to define its detailed characteristics based on the local context. In the third step, the model was implemented in two phases: adoption and maintenance. This strategy was carried out by a continuous and flexible leadership throughout the process, initially with a mixed leadership (clinician and researcher) followed by a double one (clinician and managers of services) in the implementation phase.</p><p><br /><strong>Conclusion: </strong>The implementation of this bottom-up and pragmatic strategy relied on establishing a collaborative dynamic among health and social stakeholders. This enhanced their involvement throughout the implementation phase, particularly among the GPs, and allowed them to support the change practices and services arrangements</p

Self-sculpting of a dissolvable body due to gravitational convection

© 2018 American Physical Society. Natural sculpting processes such as erosion or dissolution often yield universal shapes that bear no imprint or memory of the initial conditions. Here we conduct laboratory experiments aimed at assessing the shape dynamics and role of memory for the simple case of a dissolvable boundary immersed in a fluid. Though no external flow is imposed, dissolution and consequent density differences lead to gravitational convective flows that in turn strongly affect local dissolving rates and shape changes, and we identify two distinct behaviors. A flat boundary dissolving from its lower surface tends to retain its overall shape (an example of near perfect memory) while bearing small-scale pits that reflect complex near-body flows. A boundary dissolving from its upper surface tends to erase its initial shape and form an upward spike structure that sharpens indefinitely. We propose an explanation for these different outcomes based on observations of the coupled shape dynamics, concentration fields, and flows

A multidisciplinary systematic literature review on frailty: Overview of the methodology used by the Canadian Initiative on Frailty and Aging

<p>Abstract</p> <p>Background</p> <p>Over the past two decades, there has been a substantial growth in the body of literature on frailty in older persons. However, there is no consensus on its definition or the criteria used to identify frailty. In response to this lack of consensus, the Canadian Initiative on Frailty and Aging carried out a set of systematic reviews of the literature in ten areas of frailty research: biological basis; social basis; prevalence; risk factors; impact; identification; prevention and management; environment and technology; health services; health and social policy. This paper describes the methodology that was developed for the systematic reviews.</p> <p>Methods</p> <p>A Central Coordination Group (CCG) was responsible for developing the methodology. This involved the development of search strategies and keywords, article selection processes, quality assessment tools, and guidelines for the synthesis of results. Each review was conducted by two experts in the content area, with the assistance of methodologists and statisticians from the CCG.</p> <p>Results</p> <p>Conducting a series of systematic literature reviews involving a range of disciplines on a concept that does not have a universally accepted definition posed several conceptual and methodological challenges. The most important conceptual challenge was determining what would qualify as literature on frailty. The methodological challenges arose from our goal of structuring a consistent methodology for reviewing literature from diverse fields of research. At the outset, certain methodological guidelines were deemed essential to ensure the validity of all the reviews. Nevertheless, it was equally important to permit flexibility in the application of the proposed methodology to capture the essence of frailty research within the given fields.</p> <p>Conclusion</p> <p>The results of these reviews allowed us to establish the status of current knowledge on frailty and promote collaboration between disciplines. Conducting systematic literature reviews in health science that involve multiple disciplines is a mechanism to facilitate interdisciplinary collaboration and a more integrated understanding of health. This initiative highlighted the need for further methodological development in the performance of multidisciplinary systematic reviews.</p

pp-wave limits and orientifolds

We study the pp-wave limits of various elliptic models with orientifold planes and D7-branes, as well as the pp-wave limit of an orientifold of adS_5 x T^{11}. Many of the limits contain both open and closed strings. We also present pp-wave limits of theories which give rise to a compact null direction and contain open strings. Maps between the string theory states and gauge theory operators are proposed.Comment: 33 pages, no figures, LaTeX. v2: reference fixe