Selective Estrogen Receptor Modulators: A Potential Option For Non-Binary Gender-Affirming Hormonal Care?

Gender dysphoria describes the distress associated with having a gender identity that differs from one’s birth-assigned sex. To relieve this distress, transgender, and gender diverse (henceforth, trans) individuals commonly undergo medical transition involving hormonal treatments. Current hormonal treatment guidelines cater almost exclusively for those who wish to transition from male to female or vice versa. In contrast, there is a dearth of hormonal options for those trans individuals who identify as non-binary and seek an androgynous appearance that is neither overtly male nor female. Though prolonged puberty suppression with gonadotrophin releasing hormone agonists (GnRHa) could in theory be gender-affirming by preventing the development of unwanted secondary sex characteristics, this treatment option would be limited to pre- or peri-pubertal adolescents and likely have harmful effects. Here, we discuss the theoretical use of Selective Estrogen Receptor Modulators (SERMs) for non-binary people assigned male at birth (AMAB) who are seeking an androgynous appearance through partial feminization without breast growth. Given their unique range of pharmacodynamic effects, SERMs may represent a potential gender-affirming treatment for this population, but there is a lack of knowledge regarding their use and potentially adverse effects in this context

Escherichia coli O157:H7 in Feral Swine near Spinach Fields and Cattle, Central California Coast1

We investigated involvement of feral swine in contamination of agricultural fields and surface waterways with Escherichia coli O157:H7 after a nationwide outbreak traced to bagged spinach from California. Isolates from feral swine, cattle, surface water, sediment, and soil at 1 ranch were matched to the outbreak strain

The Ca2+-activated Cl- channel TMEM16B regulates action potential firing and axonal targeting in olfactory sensory neurons

The Ca(2+)-activated Cl(-) channel TMEM16B is highly expressed in the cilia of olfactory sensory neurons (OSNs). Although a large portion of the odor-evoked transduction current is carried by Ca(2+)-activated Cl(-) channels, their role in olfaction is still controversial. A previous report (Billig et al. 2011. Nat. Neurosci. http://dx.doi.org/10.1038/nn.2821) showed that disruption of the TMEM16b/Ano2 gene in mice abolished Ca(2+)-activated Cl(-) currents in OSNs but did not produce any major change in olfactory behavior. Here we readdress the role of TMEM16B in olfaction and show that TMEM16B knockout (KO) mice have behavioral deficits in odor-guided food-finding ability. Moreover, as the role of TMEM16B in action potential (AP) firing has not yet been studied, we use electrophysiological recording methods to measure the firing activity of OSNs. Suction electrode recordings from isolated olfactory neurons and on-cell loose-patch recordings from dendritic knobs of neurons in the olfactory epithelium show that randomly selected neurons from TMEM16B KO mice respond to stimulation with increased firing activity than those from wild-type (WT) mice. Because OSNs express different odorant receptors (ORs), we restrict variability by using a mouse line that expresses a GFP-tagged I7 OR, which is known to be activated by heptanal. In response to heptanal, we measure dramatic changes in the firing pattern of I7-expressing neurons from TMEM16B KO mice compared with WT: responses are prolonged and display a higher number of APs. Moreover, lack of TMEM16B causes a markedly reduced basal spiking activity in I7-expressing neurons, together with an alteration of axonal targeting to the olfactory bulb, leading to the appearance of supernumerary I7 glomeruli. Thus, TMEM16B controls AP firing and ensures correct glomerular targeting of OSNs expressing I7. Altogether, these results show that TMEM16B does have a relevant role in normal olfaction

Disorders of sex development : insights from targeted gene sequencing of a large international patient cohort

Background: Disorders of sex development (DSD) are congenital conditions in which chromosomal, gonadal, or phenotypic sex is atypical. Clinical management of DSD is often difficult and currently only 13% of patients receive an accurate clinical genetic diagnosis. To address this we have developed a massively parallel sequencing targeted DSD gene panel which allows us to sequence all 64 known diagnostic DSD genes and candidate genes simultaneously. Results: We analyzed DNA from the largest reported international cohort of patients with DSD (278 patients with 46, XY DSD and 48 with 46, XX DSD). Our targeted gene panel compares favorably with other sequencing platforms. We found a total of 28 diagnostic genes that are implicated in DSD, highlighting the genetic spectrum of this disorder. Sequencing revealed 93 previously unreported DSD gene variants. Overall, we identified a likely genetic diagnosis in 43% of patients with 46, XY DSD. In patients with 46, XY disorders of androgen synthesis and action the genetic diagnosis rate reached 60%. Surprisingly, little difference in diagnostic rate was observed between singletons and trios. In many cases our findings are informative as to the likely cause of the DSD, which will facilitate clinical management. Conclusions: Our massively parallel sequencing targeted DSD gene panel represents an economical means of improving the genetic diagnostic capability for patients affected by DSD. Implementation of this panel in a large cohort of patients has expanded our understanding of the underlying genetic etiology of DSD. The inclusion of research candidate genes also provides an invaluable resource for future identification of novel genes

Multi-ancestry genome-wide association study accounting for gene-psychosocial factor interactions identifies novel loci for blood pressure traits

Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP, taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from five ancestry groups. In the combined meta-analyses of stages 1 and 2, we identified 59 loci (p value < 5e−8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A and PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5 and CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (>250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: “Some College” (yes/no, for any education beyond high school) and “Graduated College” (yes/no, for completing a 4-year college degree). Genome-wide significant (p &lt; 5 × 10−8) and suggestive (p &lt; 1 × 10−6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.</p

Sloan Digital Sky Survey IV: mapping the Milky Way, nearby galaxies, and the distant universe

We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median ). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July

Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity.

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels