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. DENND1A protein was located in the cytoplasm as well as nuclei of theca cells, suggesting a possible role in gene regulation. DENND1A immunostaining was more intense in the theca of PCOS ovaries. Using theca cells isolated and propagated from normal cycling and PCOS women, we found that DENND1A variant 2 (DENND1A.V2) protein and mRNA levels are increased in PCOS theca cells. Exosomal DENND1A.V2 RNA was significantly elevated in urine from PCOS women compared with normal cycling women. Forced overexpression of DENND1A.V2 in normal theca cells resulted in a PCOS phenotype of augmented CYP17A1 and CYP11A1 gene transcription, mRNA abundance, and androgen biosynthesis. Knock-down of DENND1A.V2 in PCOS theca cells reduced androgen biosynthesis and CYP17A1 and CYP11A1 gene transcription. An IgG specific to DENND1A.V2 also reduced androgen biosynthesis and CYP17 and CYP11A1 mRNA when added to the medium of cultured PCOS theca cells. We conclude that the PCOS candidate gene, DENND1A, plays a key role in the hyperandrogenemia associated with PCOS. These observations have both diagnostic and therapeutic implications for this common disorder.
Highlights • GWAS have identified FHSR, LHCGR, INSR , and DENND1A as PCOS candidate genes. • Overexpression of DENND1A variant 2 increases androgen biosynthesis in theca cells from normal cycling ...women, converting them to a PCOS phenotype. • DENND1A, LHCGR, INSR , and RAB5B form a hierarchal signaling network that can influence androgen synthesis. • DENND1A variant 2 is a new diagnostic and therapeutic target for PCOS.
How do genes modify cellular growth to create morphological diversity? We study this problem in two related plants with differently shaped leaves: Arabidopsis thaliana (simple leaf shape) and ...Cardamine hirsuta (complex shape with leaflets). We use live imaging, modeling, and genetics to deconstruct these organ-level differences into their cell-level constituents: growth amount, direction, and differentiation. We show that leaf shape depends on the interplay of two growth modes: a conserved organ-wide growth mode that reflects differentiation; and a local, directional mode that involves the patterning of growth foci along the leaf edge. Shape diversity results from the distinct effects of two homeobox genes on these growth modes: SHOOTMERISTEMLESS broadens organ-wide growth relative to edge-patterning, enabling leaflet emergence, while REDUCED COMPLEXITY inhibits growth locally around emerging leaflets, accentuating shape differences created by patterning. We demonstrate the predictivity of our findings by reconstructing key features of C. hirsuta leaf morphology in A. thaliana.
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•Complete growth and fate maps are made for C. hirsuta and A. thaliana leaf surfaces•Patterning of the leaf margin modifies organ-wide growth pattern to produce leaf shape•Altering growth relative to patterning generates leaf shape diversity•Reconstructing dissected leaf shape by combining STM and RCO in A. thaliana leaves
By understanding the impact of growth and patterning on leaf shape diversity, it is possible to convert the leaf morphology of A. thaliana to that of another plant species.
Polycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility in women. It is also associated with metabolic disturbances that place women at increased risk for obesity and type 2 ...diabetes. There is strong evidence for familial clustering of PCOS and a genetic predisposition. However, the gene(s) responsible for the PCOS phenotypes have not been elucidated. This two-phase family-based and case-control genetic study was designed to address the question of whether SNPs identified as susceptibility loci for obesity in genome-wide association studies (GWAS) are also associated with PCOS and elevated BMI. Members of 439 families having at least one offspring with PCOS were genotyped for 15 SNPs previously shown to be associated with obesity. Linkage and association with PCOS was assessed using the transmission/disequilibrium test (TDT). These SNPs were also analyzed in an independent case-control study involving 395 women with PCOS and 176 healthy women with regular menstrual cycles. Only one of these 15 SNPs (rs2815752 in NEGR1) was found to have a nominally significant association with PCOS (χ(2) = 6.11, P = 0.013), but this association failed to replicate in the case-control study. While not associated with PCOS itself, five SNPs in FTO and two in MC4R were associated with BMI as assessed with a quantitative-TDT analysis, several of which replicated association with BMI in the case-control cohort. These findings demonstrate that certain SNPs associated with obesity contribute to elevated BMI in PCOS, but do not appear to play a major role in PCOS per se. These findings support the notion that PCOS phenotypes are a consequence of an oligogenic/polygenic mechanism.
Premitotic control of cell division orientation is critical for plant development, as cell walls prevent extensive cell remodeling or migration. While many divisions are proliferative and add cells ...to existing tissues, some divisions are formative and generate new tissue layers or growth axes. Such formative divisions are often asymmetric in nature, producing daughters with different fates. We have previously shown that, in the Arabidopsis thaliana embryo, developmental asymmetry is correlated with geometric asymmetry, creating daughter cells of unequal volume. Such divisions are generated by division planes that deviate from a default “minimal surface area” rule. Inhibition of auxin response leads to reversal to this default, yet the mechanisms underlying division plane choice in the embryo have been unclear. Here, we show that auxin-dependent division plane control involves alterations in cell geometry, but not in cell polarity axis or nuclear position. Through transcriptome profiling, we find that auxin regulates genes controlling cell wall and cytoskeleton properties. We confirm the involvement of microtubule (MT)-binding proteins in embryo division control. Organization of both MT and actin cytoskeleton depends on auxin response, and genetically controlled MT or actin depolymerization in embryos leads to disruption of asymmetric divisions, including reversion to the default. Our work shows how auxin-dependent control of MT and actin cytoskeleton properties interacts with cell geometry to generate asymmetric divisions during the earliest steps in plant development.
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•Auxin responses regulate directional cell expansion in Arabidopsis embryos•Cell shape and division orientation are tightly coupled•Transcriptome analysis identifies MT-associated IQD proteins in division control•Cytoskeletal dynamics control division orientation
By combining 3D imaging of cell shapes, nuclear and polarity markers, transcriptome profiling, genetic analysis, and targeted perturbation of cytoskeletal structures, Vaddepalli, de Zeeuw et al. reveal that auxin-dependent control of cell division orientation in Arabidopsis embryos involves regulation of cytoskeleton and cell shape.
Although childhood obesity may have detrimental consequences for childhood self-esteem, the prevalence and magnitude of this problem is controversial. In addition, the social and emotional effects of ...decreased self-esteem in obese children are unknown.
A total of 1520 children, 9 to 10 years of age, born to mothers in the National Longitudinal Survey of Youth were studied. Comprehensive demographic data including race and family income were available in 97% of the cohort. Self-esteem was measured using Self-Perception Profile for Children. The 4-year follow-up Self-Perception Profile for Children scores were available in 79% of the children. Obesity was defined as a body mass index greater than the 95th percentile for age and gender. Additional data include a self-administered questionnaire at 13 to 14 years of age concerning emotional well being, smoking, and alcohol consumption. Data were stratified by race and gender. The data were weighted to reflect a nationally representative sample of children born to mothers 17 to 28 years of age.
Scholastic and global self-esteem scores were not significantly different among 9- to 10-year-old obese and nonobese children. However, over the 4-year period, obese Hispanic females and obese white females showed significantly decreased levels of global self-esteem compared with nonobese Hispanic females and nonobese white females, respectively. Mild decreases in self-esteem also were observed in obese boys compared with nonobese boys. As a result, by 13 to 14 years of age, significantly lower levels of self-esteem were observed in obese boys, obese Hispanic girls, and obese white girls compared with their nonobese counterparts. Decreasing levels of self-esteem in obese children were associated with significantly increased rates of sadness, loneliness, and nervousness compared with obese children whose self-esteem increased or remained unchanged. In addition, obese children with decreasing levels of self-esteem over the 4-year period were more likely to smoke and drink alcohol compared with obese children whose self-esteem increased or remained unchanged.
Obese Hispanic and white females demonstrate significantly lower levels of self-esteem by early adolescence. In addition, obese children with decreasing levels of self-esteem demonstrate significantly higher rates of sadness, loneliness, and nervousness and are more likely to engage in high-risk behaviors such as smoking or consuming alcohol.
Dasatinib is a potent, oral SRC-family kinase inhibitor with preclinical antiproliferative, antimetastatic, and antiosteoclastic activity suggesting dasatinib sensitivity in triple-negative, or ...basal-like, breast cancer cell lines. This phase 2 trial assessed efficacy and safety of single-agent dasatinib in patients with advanced triple-negative breast cancer (TNBC).
Female patients with measurable, locally advanced or metastatic TNBC initially received dasatinib 100 mg twice daily (BID); to improve tolerability, the protocol was amended and subsequent patients received 70 mg BID. Primary endpoint was Response Evaluation Criteria in Solid Tumors-defined objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), safety, and limited pharmacokinetics.
Of the 44 treated patients, 43 were response evaluable. ORR was 4.7%: two patients had confirmed partial responses lasting 14 and 58 weeks, respectively. Of 11 patients with stable disease, two continued for more than 16 weeks, thus protocol-defined DCR was 9.3%. Median PFS was 8.3 weeks (95% CI: 7.3-15.3). Five patients discontinued before first tumor assessment. No grade 4 adverse events (AE) were reported; grade 3 AEs occurring in more than 5% of patients were fatigue (9.1%), diarrhea, pleural effusion, and dyspnea (all 6.8%). Laboratory abnormalities were uncommon. Dasatinib at 100 mg BID was not well tolerated; rates of treatment interruption, dose reduction, and serious AEs were lower with dasatinib 70 mg BID.
Single-agent dasatinib has limited activity in unselected patients with TNBC. Dasatinib 70 mg BID was better tolerated than 100 mg BID. Future studies will investigate dasatinib in other breast cancer settings, including chemotherapy combinations.
A fundamental question in biology is how morphogenesis integrates the multitude of processes that act at different scales, ranging from the molecular control of gene expression to cellular ...coordination in a tissue. Using machine-learning-based digital image analysis, we generated a three-dimensional atlas of ovule development in
, enabling the quantitative spatio-temporal analysis of cellular and gene expression patterns with cell and tissue resolution. We discovered novel morphological manifestations of ovule polarity, a new mode of cell layer formation, and previously unrecognized subepidermal cell populations that initiate ovule curvature. The data suggest an irregular cellular build-up of
expression in the primordium and new functions for
in restricting nucellar cell proliferation and the organization of the interior chalaza. Our work demonstrates the analytical power of a three-dimensional digital representation when studying the morphogenesis of an organ of complex architecture that eventually consists of 1900 cells.
Most children with biallelic SMN1 deletions and three SMN2 copies develop spinal muscular atrophy (SMA) type 2. SPR1NT ( NCT03505099 ), a Phase III, multicenter, single-arm trial, investigated the ...efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated within six postnatal weeks. Of 15 children with three SMN2 copies treated before symptom onset, all stood independently before 24 months (P < 0.0001; 14 within normal developmental window), and 14 walked independently (P < 0.0001; 11 within normal developmental window). All survived without permanent ventilation at 14 months; ten (67%) maintained body weight (≥3rd WHO percentile) without feeding support through 24 months; and none required nutritional or respiratory support. No serious adverse events were considered treatment-related by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention.
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