Non-coding genetic variants that influence gene transcription in pancreatic islets play a major role in the susceptibility to type 2 diabetes (T2D), and likely also contribute to type 1 diabetes ...(T1D) risk. For many loci, however, the mechanisms through which non-coding variants influence diabetes susceptibility are unknown.
We examine splicing QTLs (sQTLs) in pancreatic islets from 399 human donors and observe that common genetic variation has a widespread influence on the splicing of genes with established roles in islet biology and diabetes. In parallel, we profile expression QTLs (eQTLs) and use transcriptome-wide association as well as genetic co-localization studies to assign islet sQTLs or eQTLs to T2D and T1D susceptibility signals, many of which lack candidate effector genes. This analysis reveals biologically plausible mechanisms, including the association of T2D with an sQTL that creates a nonsense isoform in ERO1B, a regulator of ER-stress and proinsulin biosynthesis. The expanded list of T2D risk effector genes reveals overrepresented pathways, including regulators of G-protein-mediated cAMP production. The analysis of sQTLs also reveals candidate effector genes for T1D susceptibility such as DCLRE1B, a senescence regulator, and lncRNA MEG3.
These data expose widespread effects of common genetic variants on RNA splicing in pancreatic islets. The results support a role for splicing variation in diabetes susceptibility, and offer a new set of genetic targets with potential therapeutic benefit.
This research critically explores deficiencies in the palliative care system, focusing on evaluation and treatment aspects for both adult and paediatric patients. Using a qualitative methodology, the ...study engages healthcare professionals and family caregivers to uncover perspectives on the existing state of palliative care. Conducted through three focus groups and a semi-structured in-depth interview with participants recruited from Virgen de la Arrixaca University Clinical Hospital, this research illustrates critical issues, highlighting the insufficient healthcare workforce and resources to meet the comprehensive needs of patients and their families. Recommendations include holistic care addressing social, emotional, psychological, socio-familiar, and economic dimensions, supported by embedded support groups and the enforcement of relationships with palliative associations. This study also advocates for improved health institutional coordination, social worker support, and ongoing health professional satisfaction monitoring. In paediatric care, specific demands involve specialised units, medical team continuity, 24 h paediatrician care, and a more professional paediatric approach. Beyond problem identification, this study offers valuable insights for shaping health policies and tools, incorporating new indicators and introducing grief bereavement support in clinical reports, contributing to the advancement of patient evaluation in palliative care.
Notch signaling through the Notch2 receptor is essential for normal biliary tubulogenesis during liver development. However, the signaling events downstream of Notch2 critical for this process are ...less well defined. Furthermore, whether Notch signaling also underlies adult hepatic cell fate decisions is largely unknown. By implementing different genetic mouse models, we provide a comprehensive analysis that defines the role of Notch in cell fate control in the developing and adult liver. We show that cell‐specific activation of Notch2 signaling by a Notch2IC (N2IC) transgene leads to rapid biliary specification of embryonic hepatoblasts, but also—when expressed in up to 6‐month‐old adult livers—rapidly reprograms adult hepatocytes to biliary cells with formation of tubular‐cystic structures. When directed specifically to the adult biliary and facultative liver progenitor cell compartment, Notch2 is capable of inducing a ductular reaction. Furthermore, we characterized the significance of key effectors of canonical Notch signaling during normal development and in N2IC‐expressing models. We demonstrate that tubule formation of intrahepatic bile ducts during embryonic development as well as N2IC‐induced specification and morphogenesis of embryonic hepatoblasts and biliary conversion of adult hepatocytes all critically rely on canonical Notch signaling via recombination signal binding protein (RBP)‐Jκ but do not require Hes1. Conclusion: Notch2 appears to be the main determinant not only of biliary commitment of embryonic hepatoblasts during development but also of biliary reprogramming of adult hepatocytes. Notch2‐dictated cell fates and morphogenesis in both embryonic hepatoblasts and adult hepatocytes rely on canonical Notch signaling but do not require Hes1. Adult liver cells possess a remarkable plasticity to assume new cell fates when embryonic signaling pathways are active. (HEPATOLOGY 2013)
The urban spatial distribution of public housing is not a widely addressed issue in Spain, from a geographical perspective. This paper analyses the spatial distribution of public housing in the city ...of Valencia (Spain), as well as to identify its relationship with other socio-residential characteristics of the urban environment. Different techniques of spatial point pattern analysis, exploratory spatial data analysis (ESDA) and clustering methods are implemented. We analyse both the univariate spatial patterns of public housing and its relationship with two variables: a low-income population and median monthly rent. Analysis has revealed that public housing follows a pattern of partial agglomeration and mostly peripheral dispersion in its spatial distribution. However, there does not seem to be a univocal and immanent relationship between such distribution patterns and the characteristics of the socio-residential environment. Conversely, it is possible to point to the existence of multiple local forms of association. The lack of a clear pattern may be due to many reasons: the heterogeneity of profiles eligible for public housing, the size of the projects and the spatial dispersion in their location.
This article critically examines Ken Wilber’s (2006) recent work from a participatory perspective of human spirituality. After a brief introduction to the participatory approach, I limit my ...discussion to the following four key issues: a. the participatory critique of Wilber’s work, b. the cultural versus universal nature of Wilber’s Kosmic habits, c. the question of (post-)metaphysics in spiritual discourse, and d. the nature of enlightenment. The article concludes with some concrete directions in which to move the dialogue forward.
Older persons often have interacting physical and social problems and complex care needs. An integrated care approach in the local context with collaborations between community-, social-, and ...health-focused organisations can contribute to the promotion of independent living and quality of life. In the Urban Health Centres Europe (UHCE) project, five European cities (Greater Manchester, United Kingdom; Pallini (in Greater Athens Area), Greece; Rijeka, Croatia; Rotterdam, the Netherlands; and Valencia, Spain) develop and implement a care template that integrates health and social care and includes a preventive approach. The UHCE project includes an effect and process evaluation.
In a one-year pre-post controlled trial, in each city 250 participants aged 75+ years are recruited to receive the UHCE approach and are compared with 250 participants who receive 'care as usual'. Benefits of UHCE approach in terms of healthy life styles, fall risk, appropriate medication use, loneliness level and frailty, and in terms of level of independence and health-related quality of life and health care use are assessed. A multilevel modeling approach is used for the analyses. The process evaluation is used to provide insight into the reach of the target population, the extent to which elements of the UHCE approach are executed as planned and the satisfaction of the participants.
The UHCE project will provide new insight into the feasibility and effectiveness of an integrated care approach for older persons in different European settings.
ISRCTN registry number is ISRCTN52788952 . Date of registration is 13/03/2017.
Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women ...with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4alpha) and HNF1A/TCF1 (encoding HNF-1alpha), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice.
We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth.
HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life.
Gene targeting studies in primary human islets could advance our understanding of mechanisms driving diabetes pathogenesis. Here, we demonstrate successful genome editing in primary human islets ...using clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9). CRISPR-based targeting efficiently mutated protein-coding exons, resulting in acute loss of islet β-cell regulators, like the transcription factor PDX1 and the K
channel subunit KIR6.2, accompanied by impaired β-cell regulation and function. CRISPR targeting of non-coding DNA harboring type 2 diabetes (T2D) risk variants revealed changes in ABCC8, SIX2 and SIX3 expression, and impaired β-cell function, thereby linking regulatory elements in these target genes to T2D genetic susceptibility. Advances here establish a paradigm for genetic studies in human islet cells, and reveal regulatory and genetic mechanisms linking non-coding variants to human diabetes risk.
The epigenome changes that underlie cellular differentiation in developing organisms are poorly understood. To gain insights into how pancreatic beta-cells are programmed, we profiled key histone ...methylations and transcripts in embryonic stem cells, multipotent progenitors of the nascent embryonic pancreas, purified beta-cells, and 10 differentiated tissues. We report that despite their endodermal origin, beta-cells show a transcriptional and active chromatin signature that is most similar to ectoderm-derived neural tissues. In contrast, the beta-cell signature of trimethylated H3K27, a mark of Polycomb-mediated repression, clusters with pancreatic progenitors, acinar cells and liver, consistent with the epigenetic transmission of this mark from endoderm progenitors to their differentiated cellular progeny. We also identified two H3K27 methylation events that arise in the beta-cell lineage after the pancreatic progenitor stage. One is a wave of cell-selective de novo H3K27 trimethylation in non-CpG island genes. Another is the loss of bivalent and H3K27me3-repressed chromatin in a core program of neural developmental regulators that enables a convergence of the gene activity state of beta-cells with that of neural cells. These findings reveal a dynamic regulation of Polycomb repression programs that shape the identity of differentiated beta-cells.
The transcriptional programs of differentiated cells are tightly regulated by interactions between cell type-specific transcription factors and
-regulatory elements. Long non-coding RNAs (lncRNAs) ...have emerged as additional regulators of gene transcription. Current evidence indicates that lncRNAs are a very heterogeneous group of molecules. For example, selected lncRNAs have been shown to regulate gene expression in
or
, although in most cases the precise underlying molecular mechanisms is unknown. Recent studies have uncovered a large number of lncRNAs that are selectively expressed in pancreatic islet cells, some of which were shown to regulate β cell transcriptional programs. A subset of such islet lncRNAs appears to control the expression of β cell-specific transcription factor (TF) genes by local
-regulation. In this review, we discuss current knowledge of molecular mechanisms underlying
-regulatory lncRNAs and discuss challenges involved in using genetic perturbations to define their function. We then discuss known examples of pancreatic islet lncRNAs that appear to exert
-regulation of TF genes. We propose that
-regulatory lncRNAs could represent a molecular target for modulation of diabetes-relevant genes.
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