Single-Cell RNA-Seq Identifies Pathways and Genes Contributing to the Hyperandrogenemia Associated with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by hyperandrogenemia of ovarian thecal cell origin, resulting in anovulation/oligo-ovulation and infertility. Our previous studies established that ovarian theca cells isolated and propagated from ovaries of normal ovulatory women and women with PCOS have distinctive molecular and cellular signatures that underlie the increased androgen biosynthesis in PCOS. To evaluate differences between gene expression in single-cells from passaged cultures of theca cells from ovaries of normal ovulatory women and women with PCOS, we performed single-cell RNA sequencing (scRNA-seq).

The Association Between Atypical Speech Development and Adolescent Self-Harm.

Background: Adolescent self-harm is a major public health issue internationally. Various factors associated with adolescent self-harm have been identified, including being bullied and experiencing mental health problems. Stuttering and speech sound disorder are associated with both of these factors.

Loci on chromosome 12q13.2 encompassing ERBB3, PA2G4 and RAB5B are associated with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia of ovarian theca cell origin. We report significant association of androgen production with 15 single nucleotide variants (SNVs) identified by exome sequencing of theca cells from women with PCOS and normal ovulatory women. Ten SNVs are located within a 150 kbp region on 12q13.

The PCOS GWAS Candidate Gene Influences Theca Cell Expression of , , and Androgen Production.

Polycystic ovary syndrome (PCOS), a common endocrine disorder of women, is characterized by increased ovarian androgen production and anovulatory infertility. Genome-wide association studies (GWAS) have identified more than 20 PCOS candidate loci. One GWAS candidate locus encompasses , a zinc finger transcription factor.

Mesenchymal stem cell therapy ameliorates metabolic dysfunction and restores fertility in a PCOS mouse model through interleukin-10.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in reproductive-age women. Excessive inflammation and elevated androgen production from ovarian theca cells are key features of PCOS. Human bone marrow mesenchymal stem cells (BM-hMSC) and their secreted factors (secretome) exhibit robust anti-inflammatory capabilities in various biological systems.

Human DENND1A.V2 Drives Expression and Androgen Production in Mouse Ovaries and Adrenals.

The locus is associated with polycystic ovary syndrome (PCOS), a disorder characterized by androgen excess. Theca cells from ovaries of PCOS women have elevated levels of a splice variant (DENND1A.V2).

Colocalization of Polycystic Ovary Syndrome Candidate Gene Products in Theca Cells Suggests Novel Signaling Pathways.

Genome-wide association studies identified loci associated with polycystic ovary syndrome (PCOS), including those near the LH receptor gene (), a clathrin-binding protein () that functions as a guanine nucleotide exchange factor, and the gene encoding RAB5B, a GTPase involved in vesicular trafficking. We proposed that these three PCOS loci could be assembled into a functional network that contributes to altered gene expression in theca cells, resulting in increased androgen synthesis. The functional significance of this network was supported by our discovery that a truncated protein splice variant of the gene, termed DENND1A.

miRNA Profiling Reveals miRNA-130b-3p Mediates DENND1A Variant 2 Expression and Androgen Biosynthesis.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder of reproductive-age women involving overproduction of ovarian androgens and, in some cases, from the adrenal cortex. Family studies have established that PCOS is a complex heritable disorder with genetic and epigenetic components. Several small, noncoding RNAs (miRNAs) have been shown to be differentially expressed in ovarian cells and follicular fluid and in the circulation of women with PCOS.

VCAM1 Is Induced in Ovarian Theca and Stromal Cells in a Mouse Model of Androgen Excess.

Ovarian theca androgen production is regulated by the pituitary LH and intrafollicular factors. Enhanced androgen biosynthesis by theca cells contributes to polycystic ovary syndrome (PCOS) in women, but the ovarian consequences of elevated androgens are not completely understood. Our study documents the molecular events that are altered in the theca and stromal cells of mice exposed to high androgen levels, using the nonaromatizable androgen DHT.

Cognitive bias modification for social anxiety in adults who stutter: a feasibility study of a randomised controlled trial.

Objective: To determine the feasibility and acceptability of a computerised treatment for social anxiety disorder for adults who stutter including identification of recruitment, retention and completion rates, large cost drivers and selection of most appropriate outcome measure(s) to inform the design of a future definitive trial.

Design: Two-group parallel design (treatment vs placebo), double-blinded feasibility study.

Participants: 31 adults who stutter.

Behavioural, emotional and social development of children who stutter.

Purpose: Developmental stuttering may be associated with diminished psychological well-being which has been documented from late childhood onwards. It is important to establish the point at which behavioural, emotional and social problems emerge in children who stutter.

Methods: The study used data from the Millennium Cohort Study, whose initial cohort comprised 18,818 children.

Stuttering, alcohol consumption and smoking.

Purpose: Limited research has been published regarding the association between stuttering and substance use. An earlier study provided no evidence for such an association, but the authors called for further research to be conducted using a community sample. The present study used data from a community sample to investigate whether an association between stuttering and alcohol consumption or regular smoking exists in late adolescence and adulthood.

Functional genomics of PCOS: from GWAS to molecular mechanisms.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy characterized by increased ovarian androgen biosynthesis, anovulation, and infertility. PCOS has a strong heritable component based on familial clustering and twin studies. Genome-wide association studies (GWAS) identified several PCOS candidate loci including LHCGR, FSHR, ZNF217, YAP1, INSR, RAB5B, and C9orf3.

Birth weight and stuttering: Evidence from three birth cohorts.

Purpose: Previous studies have produced conflicting results with regard to the association between birth weight and developmental stuttering. This study sought to determine whether birth weight was associated with childhood and/or adolescent stuttering in three British birth cohort samples.

Methods: Logistic regression analyses were carried out on data from the Millenium Cohort Study (MCS), British Cohort Study (BCS70) and National Child Development Study (NCDS), whose initial cohorts comprised over 56,000 individuals.

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype.

Polycystic ovary syndrome (PCOS), characterized by increased ovarian androgen biosynthesis, anovulation, and infertility, affects 5-7% of reproductive-age women. Genome-wide association studies identified PCOS candidate loci that were replicated in subsequent reports, including DENND1A, which encodes a protein associated with clathrin-coated pits where cell-surface receptors reside. However, these studies provided no information about functional roles for DENND1A in the pathogenesis of PCOS.

Decreased myo-inositol to chiro-inositol (M/C) ratios and increased M/C epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls.

Previous studies from our and other labs have shown that insulin resistance is associated with an inositol imbalance of excess myo-inositol and deficient chiro-inositol together with a deficiency of myo-inositol to chiro-inositol epimerase in vivo and in vitro. In this report, we utilized well characterized theca cells from normal cycling women, with normal insulin sensitivity, and theca cells from women with polycystic ovary syndrome (PCOS), with increased insulin sensitivity to examine the myo-inositol to chiro-inisitol (M/C) ratio and the myo-inositol to chiro-inositol epimerase activity. PCOS theca cells with increased insulin sensitivity were specifically used to investigate whether the inositol imbalance and myo-inositol to chiro-inositol epimerase are regulated in a similar or the opposite direction than that observed in insulin resistant cells.

The impact of adolescent stuttering and other speech problems on psychological well-being in adulthood: evidence from a birth cohort study.

Background: Developmental stuttering is associated with increased risk of psychological distress and mental health difficulties. Less is known about the impact of other developmental speech problems on psychological outcomes, or the impact of stuttering and speech problems once other predictors have been adjusted for.

Aims: To determine the impact of parent-reported adolescent stuttering and other speech difficulties on psychological distress and associated symptoms as measured by the Rutter Malaise Inventory.

Cholesterol side-chain cleavage gene expression in theca cells: augmented transcriptional regulation and mRNA stability in polycystic ovary syndrome.

Hyperandrogenism is characteristic of women with polycystic ovary syndrome (PCOS). Ovarian theca cells isolated from PCOS follicles and maintained in long-term culture produce elevated levels of progestins and androgens compared to normal theca cells. Augmented steroid production in PCOS theca cells is associated with changes in the expression of genes for several steroidogenic enzymes, including CYP11A1, which encodes cytochrome P450 cholesterol side-chain cleavage.

The impact of adolescent stuttering on educational and employment outcomes: evidence from a birth cohort study.

Purpose: In interview and survey studies, people who stutter report the belief that stuttering has had a negative impact on their own education and employment. This population study sought objective evidence of such disadvantage for people who stutter as a group, compared with people who do not stutter.

Method: A secondary analysis of a British birth cohort dataset was used in the study.

Family-based analysis of candidate genes for polycystic ovary syndrome.

Context: Polycystic ovary syndrome (PCOS) is a complex disorder having both genetic and environmental components. A number of association studies based on candidate genes have reported significant association, but few have been replicated. D19S884, a polymorphic marker in fibrillin 3 (FBN3), is one of the few association findings that has been replicated in independent sets of families.

PDE8A genetic variation, polycystic ovary syndrome and androgen levels in women.

Polycystic ovary syndrome (PCOS) is characterized by excessive theca cell androgen secretion, dependent upon LH, which acts through the intermediacy of 3',5'-cyclic adenosine monophosphate (cAMP). cAMP signaling pathways are controlled through regulation of its synthesis by adenylyl cyclases, and cAMP degradation by phosphodiesterases (PDEs). PDE8A, a high-affinity cAMP-specific PDE is expressed in the ovary and testis.

The Cebpd (C/EBPdelta) gene is induced by luteinizing hormones in ovarian theca and interstitial cells but is not essential for mouse ovary function.

The CCAAT/enhancer binding protein (CEBP) family of transcription factors includes five genes. In the ovary, both Cebpa and Cebpb are essential for granulosa cell function. In this study we have explored the role of the Cebpd gene in ovarian physiology by expression and functional studies.

Human ovarian theca cells in culture.

Elucidating the regulation of androgen biosynthesis in ovarian theca cells is not only important for determining the mechanisms of regulation of estrogen biosynthesis throughout the menstrual cycle, but is also essential for understanding the pathogenesis of excess androgen biosynthesis and polycystic ovary syndrome (PCOS). Human theca cells in primary and long-term culture have provided model systems for examining theca cell differentiation as well as the mechanisms underlying basal and cAMP-regulated steroid biosynthesis at both the transcriptional and post-transcriptional level in normal and PCOS ovaries. Results of these studies are expected to lead to the identification of novel targets for clinical treatment of infertility and PCOS.