Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1

There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for the Wilms' tumour gene, Wt1, lack kidneys, gonads, and spleen and die at mid-gestation due to defective coronary vasculature. Wt1 is vital for maintaining the mesenchymal–epithelial balance in these tissues and is required for the epithelial-to-mesenchyme transition (EMT) that generates coronary vascular progenitors. Although Wt1 is only expressed in rare cell populations in adults including glomerular podocytes, 1% of bone marrow cells, and mesothelium, we hypothesised that this might be important for homeostasis of adult tissues; hence, we deleted the gene ubiquitously in young and adult mice. Within just a few days, the mice suffered glomerulosclerosis, atrophy of the exocrine pancreas and spleen, severe reduction in bone and fat, and failure of erythropoiesis. FACS and culture experiments showed that Wt1 has an intrinsic role in both haematopoietic and mesenchymal stem cell lineages and suggest that defects within these contribute to the phenotypes we observe. We propose that glomerulosclerosis arises in part through down regulation of nephrin, a known Wt1 target gene. Protein profiling in mutant serum showed that there was no systemic inflammatory or nutritional response in the mutant mice. However, there was a dramatic reduction in circulating IGF-1 levels, which is likely to contribute to the bone and fat phenotypes. The reduction of IGF-1 did not result from a decrease in circulating GH, and there is no apparent pathology of the pituitary and adrenal glands. These findings 1) suggest that Wt1 is a major regulator of the homeostasis of some adult tissues, through both local and systemic actions; 2) highlight the differences between foetal and adult tissue regulation; 3) point to the importance of adult mesenchyme in tissue turnover

Problematic online behaviors among adolescents and emerging adults: associations between cyberbullying perpetration, problematic social media use, and psychosocial factors

Over the past two decades, young people's engagement in online activities has grown markedly. The aim of the present study was to examine the relationship between two specific online behaviors (i.e., cyberbullying perpetration, problematic social media use) and their relationships with social connectedness, belongingness, depression, and self-esteem among high school and university students. Data were collected from two different study groups via two questionnaires that included the Cyberbullying Offending Scale, Social Media Use Questionnaire, Social Connectedness Scale, General Belongingness Scale, Short Depression-Happiness Scale, and Single Item Self-Esteem Scale. Study 1 comprised 804 high school students (48% female; mean age 16.20 years). Study 2 comprised 760 university students (60% female; mean age 21.48 years). Results indicated that problematic social media use and cyberbullying perpetration (which was stronger among high school students) were directly associated with each other. Belongingness (directly) and social connectedness (indirectly) were both associated with cyberbullying perpetration and problematic social media use. Path analysis demonstrated that while age was a significant direct predictor of problematic social media use and cyberbullying perpetration among university students, it was not significant among high school students. In both samples, depression was a direct predictor of problematic social media use and an indirect predictor of cyberbullying perpetration. However, majority of these associations were relatively weak. The present study significantly adds to the emerging body of literature concerning the associations between problematic social media use and cyberbullying perpetration

Epicardial cells derived from human embryonic stem cells augment cardiomyocyte-driven heart regeneration.

The epicardium and its derivatives provide trophic and structural support for the developing and adult heart. Here we tested the ability of human embryonic stem cell (hESC)-derived epicardium to augment the structure and function of engineered heart tissue in vitro and to improve efficacy of hESC-cardiomyocyte grafts in infarcted athymic rat hearts. Epicardial cells markedly enhanced the contractility, myofibril structure and calcium handling of human engineered heart tissues, while reducing passive stiffness compared with mesenchymal stromal cells. Transplanted epicardial cells formed persistent fibroblast grafts in infarcted hearts. Cotransplantation of hESC-derived epicardial cells and cardiomyocytes doubled graft cardiomyocyte proliferation rates in vivo, resulting in 2.6-fold greater cardiac graft size and simultaneously augmenting graft and host vascularization. Notably, cotransplantation improved systolic function compared with hearts receiving either cardiomyocytes alone, epicardial cells alone or vehicle. The ability of epicardial cells to enhance cardiac graft size and function makes them a promising adjuvant therapeutic for cardiac repair.: This work was supported by the British Heart Foundation (BHF; Grants NH/11/1/28922, G1000847, FS/13/29/30024 and FS/18/46/33663), Oxford-Cambridge Centre for Regenerative Medicine (RM/13/3/30159), the UK Medical Research Council (MRC) and the Cambridge Hospitals National Institute for Health Research Biomedical Research Centre funding (SS), as well as National Institutes of Health Grants P01HL094374, P01GM081619, R01HL12836 and a grant from the Fondation Leducq Transatlantic Network of Excellence (CEM). J.B. was supported by a Cambridge National Institute for Health Research Biomedical Research Centre Cardiovascular Clinical Research Fellowship and subsequently, by a BHF Studentship (Grant FS/13/65/30441). DI received a University of Cambridge Commonwealth Scholarship. LG is supported by BHF Award RM/l3/3/30159 and LPO is funded by a Wellcome Trust Fellowship (203568/Z/16/Z). NF was supported by BHF grants RG/13/14/30314. NL was supported by the Biotechnology and Biological Sciences Research Council (Institute Strategic Programmes BBS/E/B/000C0419 and BBS/E/B/000C0434). SS and MB were supported by the British Heart Foundation Centre for Cardiovascular Research Excellence. Core support was provided by the Wellcome-MRC Cambridge Stem Cell Institute (203151/Z/16/Z), The authors thank Osiris for provision of the primary mesenchymal stem cells (59

Childhood emotional trauma and cyberbullying perpetration among emerging adults: a multiple mediation model of the role of problematic social media use and psychopathology

Research suggests that a small minority of social media users experience problems as a result of their online use. The purpose of the present study was to examine the association of cyberbullying perpetration and problematic social media use with childhood emotional trauma, Cluster B (narcissistic, histrionic, antisocial, and borderline) personality traits, dissociative experiences (DEs), depression, and self-esteem in a nonclinical undergraduate sample. A total of 344 university students volunteered to complete a questionnaire that included measures on the aforementioned dimensions. Thirty-eight percent of the participants had emotional neglect and 27% had emotional abuse, while 44% of them demonstrated at least one cyberbullying perpetration behavior. Results indicated that cyberbullying perpetrators had higher scores on problematic social media use, dissociative experiences, Cluster B traits, depression and childhood emotional trauma, and lower on self-esteem. Path analysis demonstrated that, while adjusting for gender and age, childhood emotional trauma was directly and indirectly associated with cyberbullying perpetration via Cluster B traits. Moreover, depression and dissociation were directly associated with problematic social media use. The findings of this study emphasize the important direct role of childhood emotional trauma and pathological personality traits on cyberbullying perpetration

Design, synthesis, and biological activity of hybrid compounds between uramustine and DNA minor groove binder distamycin A

The design, synthesis, characterization, DNA binding properties, and cytotoxic activity of a novel series of hybrids, namely, a mol. combination of the natural antibiotic distamycin A and the antineoplastic agent uramustine, are reported, and the structure-​activity relationships are discussed. This homologous series 29-​34 consisted of the minor groove binder distamycin A joined to uramustine (uracil mustard) by suitable aliph. carboxylic acid moieties contg. a flexible polymethylene chain that is variable in length (CH2)​n, where n = 1-​6. All the hybrid compds. in this series exhibit enhanced activity compared to both distamycin A and uramustine derivs. 22-​27 used for conjugation, giving IC50 values in the range 7.26-​0.07 μM following a 1 h exposure of human leukemic K562 cells, with maximal activity shown when n = 6. The distance between the uramustine and distamycin frame is crucial for the cytotoxicity, with compds. having linker lengths of four to six being at least 20-​fold more cytotoxic than liker lengths one to three. Taq polymerase stop expts. demonstrated selective covalent binding of uramustine-​distamycin hybrids to A​/T rich DNA sequences, which was again more efficient with compds. 32-​34 with a longer linker length. Two consequences can be derived from our study: (a) the distamycin moiety directs binding to the minor groove of A​/T rich DNA sequences and, consequently, is responsible for the alkylation regioselectivity found in footprinting studies; (b) the higher flexibility due to a longer linker between the distamycin and uracil moieties allows the formation of complexes with the mustard moiety situated more deeply in the minor groove and, hence, with better alkylating properties

Characterization of epicardial-derived cardiac interstitial cells: differentiation and mobilization of heart fibroblast progenitors

The non-muscular cells that populate the space found between cardiomyocyte fibers are known as 'cardiac interstitial cells' (CICs). CICs are heterogeneous in nature and include different cardiac progenitor/stem cells, cardiac fibroblasts and other cell types. Upon heart damage CICs soon respond by initiating a reparative response that transforms with time into extensive fibrosis and heart failure. Despite the biomedical relevance of CICs, controversy remains on the ontogenetic relationship existing between the different cell kinds homing at the cardiac interstitium, as well as on the molecular signals that regulate their differentiation, maturation, mutual interaction and role in adult cardiac homeostasis and disease. Our work focuses on the analysis of epicardial-derived cells, the first cell type that colonizes the cardiac interstitium. We present here a characterization and an experimental analysis of the differentiation potential and mobilization properties of a new cell line derived from mouse embryonic epicardium (EPIC). Our results indicate that these cells express some markers associated with cardiovascular stemness and retain part of the multipotent properties of embryonic epicardial derivatives, spontaneously differentiating into smooth muscle, and fibroblast/myofibroblast-like cells. Epicardium-derived cells are also shown to initiate a characteristic response to different growth factors, to display a characteristic proteolytic expression profile and to degrade biological matrices in 3D in vitro assays. Taken together, these data indicate that EPICs are relevant to the analysis of epicardial-derived CICs, and are a god model for the research on cardiac fibroblasts and the role these cells play in ventricular remodeling in both ischemic or non/ischemic myocardial disease