Regulation of G protein-coupled receptors by palmitoylation and cholesterol

Due to their membrane location, G protein-coupled receptors (GPCRs) are subject to regulation by soluble and integral membrane proteins as well as membrane components, including lipids and sterols. GPCRs also undergo a variety of post-translational modifications, including palmitoylation. A recent article by Zheng et al. in BMC Cell Biology demonstrates cooperative roles for receptor palmitoylation and cholesterol binding in GPCR dimerization and G protein coupling, underlining the complex regulation of these receptors

Monthly quasi-periodic eruptions from repeated stellar disruption by a massive black hole

In recent years, searches of archival X-ray data have revealed galaxies exhibiting nuclear quasi-periodic eruptions with periods of several hours. These are reminiscent of the tidal disruption of a star by a supermassive black hole. The repeated, partial stripping of a white dwarf in an eccentric orbit around an ~105 M⊙ black hole provides an attractive model. A separate class of periodic nuclear transients, with much longer timescales, have recently been discovered optically and may arise from the partial stripping of a main-sequence star by an ~107 M⊙ black hole. No clear connection between these classes has been made. We present the discovery of an X-ray nuclear transient that shows quasi-periodic outbursts with a period of weeks. We discuss possible origins for the emission and propose that this system bridges the two existing classes outlined above. This discovery was made possible by the rapid identification, dissemination and follow-up of an X-ray transient found by the new live Swift-XRT transient detector, demonstrating the importance of low-latency, sensitive searches for X-ray transients

Stepped Care for Maternal Mental Health: A Case Study of the Perinatal Mental Health Project in South Africa

As one article in a series on Global Mental Health Practice, Simone Honikman and colleagues from South Africa provide a case study of the Perinatal Mental Health Project, which delivered mental health care to pregnant women in a collaborative, step-wise manner, making use of existing resources in primary care

Monthly quasi-periodic eruptions from repeated stellar disruption by a massive black hole

In recent years, searches of archival X-ray data have revealed galaxies exhibiting nuclear quasi-periodic eruptions with periods of several hours. These are reminiscent of the tidal disruption of a star by a supermassive black hole, and the repeated, partial stripping of a white dwarf in an eccentric orbit around a∼105M⊙ black hole provides an attractive model. A separate class of periodic nuclear transients, with significantly longer timescales, have recently been discovered optically, and may arise from the partial stripping of a main-sequence star by a∼107M⊙black hole. No clear connection between these classes has been made. We present the discovery of an X-ray nuclear transient which shows quasi periodic outbursts with a period of weeks. We discuss possible origin for the emission, and propose that this system bridges the two existing classes outlined above. This discovery was made possible by the rapid identification, dissemination and follow up of an Xray transient found by the new live Swift-XRT transient detector, demonstrating the importance of low-latency, sensitive searches for X-ray transients

Between life and death: exploring the sociocultural context of antenatal mental distress in rural Ethiopia

The high prevalence of antenatal common mental disorders in sub-Saharan Africa compared to high-income countries is poorly understood. This qualitative study explored the sociocultural context of antenatal mental distress in a rural Ethiopian community. Five focus group discussions and 25 in-depth interviews were conducted with purposively sampled community stakeholders. Inductive analysis was used to develop final themes. Worry about forthcoming delivery and fears for the woman’s survival were prominent concerns of all participants, but only rarely perceived to be pathological in intensity. Sociocultural practices such as continuing physical labour, dietary restriction, prayer and rituals to protect against supernatural attack were geared towards safe delivery and managing vulnerability. Despite strong cultural norms to celebrate pregnancy, participants emphasised that many pregnancies were unwanted and an additional burden on top of pre-existing economic and marital difficulties. Short birth interval and pregnancy out of wedlock were both seen as shameful and potent sources of mental distress. The notion that pregnancy in traditional societies is uniformly a time of joy and happiness is misplaced. Although antenatal mental distress may be self-limiting for many women, in those with enduring life difficulties, including poverty and abusive relationships, poor maternal mental health may persist

Identification of Dmrt2a downstream genes during zebrafish early development using a timely controlled approach

This research was supported by FCT (Portugal) grant (PTDC/SAU-BID/119627/2010) given to L.S. L.S. was supported by an IF contract from FCT (Portugal). R.A.P. was supported by a PhD fellowship (SFRH/BD/87607/2012) from FCT (Portugal). Publication was sponsored by LISBOA-01-0145-FEDER-007391, project co-funded by FEDER through POR Lisboa 2020 - Programa Operacional Regional de Lisboa, PORTUGAL 2020 and by Fundacao para a Ciencia e a Tecnologia.BACKGROUND: Dmrt2a is a zinc finger like transcription factor with several roles during zebrafish early development: left-right asymmetry, synchronisation of the somite clock genes and fast muscle differentiation. Despite the described functions, Dmrt2a mechanism of action is unknown. Therefore, with this work, we propose to identify Dmrt2a downstream genes during zebrafish early development. RESULTS: We generated and validated a heat-shock inducible transgenic line, to timely control dmrt2a overexpression, and dmrt2a mutant lines. We characterised dmrt2a overexpression phenotype and verified that it was very similar to the one described after knockdown of this gene, with left-right asymmetry defects and desynchronisation of somite clock genes. Additionally, we identified a new phenotype of somite border malformation. We generated several dmrt2a mutant lines, but we only detected a weak to negligible phenotype. As dmrt2a has a paralog gene, dmrt2b, with similar functions and expression pattern, we evaluated the possibility of redundancy. We found that dmrt2b does not seem to compensate the lack of dmrt2a. Furthermore, we took advantage of one of our mutant lines to confirm dmrt2a morpholino specificity, which was previously shown to be a robust knockdown tool in two independent studies. Using the described genetic tools to perform and validate a microarray, we were able to identify six genes downstream of Dmrt2a: foxj1b, pxdc1b, cxcl12b, etv2, foxc1b and cyp1a. CONCLUSIONS: In this work, we generated and validated several genetic tools for dmrt2a and identified six genes downstream of this transcription factor. The identified genes will be crucial to the future understanding of Dmrt2a mechanism of action in zebrafish.publishersversionpublishe

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy.

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases

Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

\ua9 The Author(s) 2024.In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3−/−; ttn.1+/−) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases

The psychometric properties of the subscales of the GHQ-28 in a multi-ethnic maternal sample: results from the Born in Bradford cohort

Background: Poor maternal mental health can impact on children’s development and wellbeing; however, there is concern about the comparability of screening instruments administered to women of diverse ethnic origin. Methods: We used confirmatory factor analysis (CFA) and exploratory factor analysis (EFA) to examine the subscale structure of the GHQ-28 in an ethnically diverse community cohort of pregnant women in the UK (N = 5,089). We defined five groups according to ethnicity and language of administration, and also conducted a CFA between four groups of 1,095 women who completed the GHQ-28 both during and after pregnancy. Results: After item reduction, 17 of the 28 items were considered to relate to the same four underlying concepts in each group; however, there was variation in the response to individual items by women of different ethnic origin and this rendered between group comparisons problematic. The EFA revealed that these measurement difficulties might be related to variation in the underlying concepts being measured by the factors. Conclusions: We found little evidence to recommend the use of the GHQ-28 subscales in routine clinical or epidemiological assessment of maternal women in populations of diverse ethnicity