Abnormal regulation of TSG101 in mice with spongiform neurodegeneration

AbstractSpongiform neurodegeneration is characterized by the appearance of vacuoles throughout the central nervous system. It has many potential causes, but the underlying cellular mechanisms are not well understood. Mice lacking the E3 ubiquitin ligase Mahogunin Ring Finger-1 (MGRN1) develop age-dependent spongiform encephalopathy. We identified an interaction between a “PSAP” motif in MGRN1 and the ubiquitin E2 variant (UEV) domain of TSG101, a component of the endosomal sorting complex required for transport I (ESCRT-I), and demonstrate that MGRN1 multimonoubiquitinates TSG101. We examined the in vivo consequences of loss of MGRN1 on TSG101 expression and function in the mouse brain. The pattern of TSG101 ubiquitination differed in the brains of wild-type mice and Mgrn1 null mutant mice: at 1 month of age, null mutant mice had less ubiquitinated TSG101, while in adults, mutant mice had more ubiquitinated, insoluble TSG101 than wild-type mice. There was an associated increase in epidermal growth factor receptor (EGFR) levels in mutant brains. These results suggest that loss of MGRN1 promotes ubiquitination of TSG101 by other E3s and may prevent its disassociation from endosomal membranes or cause it to form insoluble aggregates. Our data implicate loss of normal TSG101 function in endo-lysosomal trafficking in the pathogenesis of spongiform neurodegeneration in Mgrn1 null mutant mice

Identification and preliminary characterization of mouse Adam33

BACKGROUND: The metalloprotease-disintegrin family, or ADAM, proteins, are implicated in cell-cell interactions, cell fusion, and cell signaling, and are widely distributed among metazoan phyla. Orthologous relationships have been defined for a few ADAM proteins including ADAM10 (Kuzbanian), and ADAM17 (TACE), but evolutionary relationships are not clear for the majority of family members. Human ADAM33 refers to a testis cDNA clone that does not contain a complete open reading frame, but portions of the predicted protein are similar to Xenopus laevis ADAM13. RESULTS: In a 48 kb region of mouse DNA adjacent to the Attractin gene on mouse chromosome 2, we identified sequences very similar to human ADAM33. A full-length mouse cDNA was identified by a combination of gene prediction programs and RT-PCR, and the probable full-length human cDNA was identified by comparison to human genomic sequence in the homologous region on chromosome 20p13. Mouse ADAM33 is 44% identical to Xenopus laevis ADAM13, however a phylogenetic alignment and consideration of functional domains suggests that the two genes are not orthologous. Mouse Adam33 is widely expressed, most highly in the adult brain, heart, kidney, lung and testis. CONCLUSIONS: While mouse ADAM33 is similar to Xenopus ADAM13 in sequence, further examination of its embryonic expression pattern, catalytic activity and protein interactions will be required to assess the functional relationship between these two proteins. Adam33 is expressed in the mouse adult brain and could play a role in complex processes that require cell-cell communication

Distribution of Mahogany/Attractin mRNA in the rat central nervous system

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116967/1/feb2s0014579399014945.pd

Acute bronchiolitis in infancy as risk factor for wheezing and reduced pulmonary function by seven years in Akershus County, Norway

BACKGROUND: Acute viral bronchiolitis is one of the most common causes of hospitalisation during infancy in our region with respiratory syncytial virus (RSV) historically being the major causative agent. Many infants with early-life RSV bronchiolitis have sustained bronchial hyperreactivity for many years after hospitalisation and the reasons for this are probably multifactorial. The principal aim of the present study was to investigate if children hospitalised for any acute viral bronchiolitis during infancy in our region, and not only those due to RSV, had more episodes of subsequent wheezing up to age seven years and reduced lung function at that age compared to children not hospitalised for acute bronchiolitis during infancy. A secondary aim was to compare the hospitalised infants with proven RSV bronchiolitis (RS+) to the hospitalised infants with non-RSV bronchiolitis (RS-) according to the same endpoints. METHODS: 57 infants hospitalised at least once with acute viral bronchiolitis during two consecutive winter seasons in 1993–1994 were examined at age seven years. An age-matched control group of 64 children, who had not been hospitalised for acute viral bronchiolitis during infancy, were recruited from a local primary school. Epidemiological and clinical data were collected retrospectively from hospital discharge records and through structured clinical interviews and physical examinations at the follow-up visit. RESULTS: The children hospitalised for bronchiolitis during infancy had decreased lung function, more often wheezing episodes, current medication and follow-up for asthma at age seven years than did the age matched controls. They also had lower average birth weight and more often first order family members with asthma. We did not find significant differences between the RSV+ and RSV- groups. CONCLUSION: Children hospitalised for early-life bronchiolitis are susceptible to recurrent wheezing and reduced pulmonary function by seven years compared to age-matched children not hospitalised for early-life bronchiolitis. We propose that prolonged bronchial hyperreactivity could follow early-life RSV negative as well as RSV positive bronchiolitis

Male gays in the female gaze: women who watch m/m pornography

This paper draws on a piece of wide-scale mixed-methods research that examines the motivations behind women who watch gay male pornography. To date there has been very little interdisciplinary research investigating this phenomenon, despite a recent survey by PornHub (one of the largest online porn sites in the world) showing that gay male porn is the second most popular choice for women porn users out of 25+ possible genre choices. While both academic literature and popular culture have looked at the interest that (heterosexual) men have in lesbian pornography, considerably less attention has been paid to the consumption of gay male pornography by women. Research looking at women's consumption of pornography from within the Social Sciences is very focused around heterosexual (and, to a lesser extent, lesbian) pornography. Research looking more generally at gay pornography/erotica (and the subversion of the ‘male gaze’/concept of ‘male as erotic object’) often makes mention of female interest in this area, but only briefly, and often relies on anecdotal or observational evidence. Research looking at women's involvement in slashfic (primarily from within media studies), while very thorough and rich, tends to view slash writing as a somewhat isolated phenomenon (indeed, in her influential article on women's involvement in slash, Bacon-Smith talks about how ‘only a small number’ of female slash writers and readers have any interest in gay literature or pornography more generally, and this phenomenon is not often discussed in more recent analyses of slash); so while there has been a great deal of very interesting research done in this field, little attempt has been made to couch it more generally within women's consumption and use of pornography and erotica or to explore what women enjoy about watching gay male pornography. Through a series of focus groups, interviews, and an online questionnaire (n = 275), this exploratory piece of work looks at what women enjoy about gay male pornography, and how it sits within their consumption of erotica/pornography more generally. The article investigates what this has to say about the existence and nature of a ‘female gaze’

"What should be next in lifelong posterior hypospadias: Conclusions from the 2023 ERN eUROGEN and EJP-RD networking meeting"

BACKGROUND: A congenital disease is for life. Posterior hypospadias, the severe form of hypospadias with a penoscrotal, scrotal, or perineal meatus, is a challenging condition with a major impact on lifelong quality of life. AIM: Our network meeting is aimed to identify what is currently missing in the lifelong treatment of posterior hypospadias, to improve care, quality of life, and awareness for these patients. METHODS: The network meeting "Lifelong Posterior Hypospadias" in Utrecht, The Netherlands was granted by the European Joint Programme on Rare Diseases-Networking Support Scheme. There was a combination of interactive sessions (hackathons) and lectures. This paper can be regarded as the last phase of the hackathon. RESULTS: Surgery for hypospadias remains challenging and complications may occur until adulthood. Posterior hypospadias affects sexual function, fertility, and hormonal status. Transitional care from childhood into adulthood is currently insufficiently established. Patients should be more involved in defining desired treatment approach and outcome measures. For optimal outcome evaluation standardization of data collection and registration at European level is necessary. Tissue engineering may provide a solution to the shortage of healthy tissue in posterior hypospadias. For optimal results, cooperation between basic researchers from different centers, as well as involving clinicians and patients is necessary. CONCLUSIONS: To improve outcomes for patients with posterior hypospadias, patient voices should be included and lifelong care by dedicated healthcare professionals guaranteed. Other requirements are joining forces at European level in uniform registration of outcome data and cooperation in basic research

Jak3 Is Involved in Dendritic Cell Maturation and CCR7-Dependent Migration

BACKGROUND: CCR7-mediated signalling is important for dendritic cell maturation and homing to the lymph nodes. We have previously demonstrated that Jak3 participates in the signalling pathway of CCR7 in T lymphocytes. METHODOLOGY AND PRINCIPAL FINDINGS: Here, we used Jak3(-/-) mice to analyze the role of Jak3 in CCR7-mediated dendritic cells migration and function. First, we found no differences in the generation of DCs from Jak3(-/-) bone marrow progenitors, when compared to wild type cells. However, phenotypic analysis of the bone marrow derived DCs obtained from Jak3(-/-) mice showed reduced expression of co-stimulatory molecules compared to wild type (Jak3(+/+)). In addition, when we analyzed the migration of Jak3(-/-) and Jak3(+/+) mature DCs in response to CCL19 and CCL21 chemokines, we found that the absence of Jak3 results in impaired chemotactic responses both in vitro and in vivo. Moreover, lymphocyte proliferation and contact hypersensitivity experiments showed that DC-mediated T lymphocyte activation is reduced in the absence of Jak3. CONCLUSION/SIGNIFICANCE: Altogether, our data provide strong evidence that Jak3 is important for DC maturation, migration and function, through a CCR7-mediated signalling pathway

Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 x 10(-8)) with GDM, mapping to/near MTNR1B (P = 4.3 x 10(-54)), TCF7L2 (P = 4.0 x 10(-16)), CDKAL1 (P = 1.6 x 10(-4)), CDKN2A-CDKN2B (P = 4.1 x 10(-9)) and HKDC1 (P = 2.9 x 10(-8)). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.Peer reviewe

Plants in aquatic ecosystems: current trends and future directions

Aquatic plants fulfil a wide range of ecological roles, and make a substantial contribution to the structure, function and service provision of aquatic ecosystems. Given their well-documented importance in aquatic ecosystems, research into aquatic plants continues to blossom. The 14th International Symposium on Aquatic Plants, held in Edinburgh in September 2015, brought together 120 delegates from 28 countries and six continents. This special issue of Hydrobiologia includes a select number of papers on aspects of aquatic plants, covering a wide range of species, systems and issues. In this paper we present an overview of current trends and future directions in aquatic plant research in the early 21st century. Our understanding of aquatic plant biology, the range of scientific issues being addressed and the range of techniques available to researchers have all arguably never been greater; however, substantial challenges exist to the conservation and management of both aquatic plants and the ecosystems in which they are found. The range of countries and continents represented by conference delegates and authors of papers in the special issue illustrate the global relevance of aquatic plant research in the early 21st century but also the many challenges that this burgeoning scientific discipline must address