Molecular traces of Drosophila hemocytes reveal transcriptomic conservation with vertebrate myeloid cells.

Drosophila hemocytes serve as the primary defense system against harmful threats, allowing the animals to thrive. Hemocytes are often compared to vertebrate innate immune system cells due to the observed functional similarities between the two. However, the similarities have primarily been established based on a limited number of genes and their functional homologies. Thus, a systematic analysis using transcriptomic data could offer novel insights into Drosophila hemocyte function and provide new perspectives on the evolution of the immune system. Here, we performed cross-species comparative analyses using single-cell RNA sequencing data from Drosophila and vertebrate immune cells. We found several conserved markers for the cluster of differentiation (CD) genes in Drosophila hemocytes and validated the role of CG8501 (CD59) in phagocytosis by plasmatocytes, which function much like macrophages in vertebrates. By comparing whole transcriptome profiles in both supervised and unsupervised analyses, we showed that Drosophila hemocytes are largely homologous to vertebrate myeloid cells, especially plasmatocytes to monocytes/macrophages and prohemocyte 1 (PH1) to hematopoietic stem cells. Furthermore, a small subset of prohemocytes with hematopoietic potential displayed homology with hematopoietic progenitor populations in vertebrates. Overall, our results provide a deeper understanding of molecular conservation in the Drosophila immune system.

Clustering malignant cell states using universally variable genes.

Single-cell RNA sequencing (scRNA-seq) has revealed important insights into the heterogeneity of malignant cells. However, sample-specific genomic alterations often confound such analysis, resulting in patient-specific clusters that are difficult to interpret. Here, we present a novel approach to address the issue. By normalizing gene expression variances to identify universally variable genes (UVGs), we were able to reduce the formation of sample-specific clusters and identify underlying molecular hallmarks in malignant cells. In contrast to highly variable genes vulnerable to a specific sample bias, UVGs led to better detection of clusters corresponding to distinct malignant cell states. Our results demonstrate the utility of this approach for analyzing scRNA-seq data and suggest avenues for further exploration of malignant cell heterogeneity.

Tumor immune microenvironment lncRNAs.

Long non-coding ribonucleic acids (RNAs) (lncRNAs) are key players in tumorigenesis and immune responses. The nature of their cell type-specific gene expression and other functional evidence support the idea that lncRNAs have distinct cellular functions in the tumor immune microenvironment (TIME). To date, the majority of lncRNA studies have heavily relied on bulk RNA-sequencing data in which various cell types contribute to an averaged signal, limiting the discovery of cell type-specific lncRNA functions. Single-cell RNA-sequencing (scRNA-seq) is a potential solution for tackling this limitation despite the lack of annotations for low abundance yet cell type-specific lncRNAs. Hence, updated annotations and further understanding of the cellular expression of lncRNAs will be necessary for characterizing cell type-specific functions of lncRNA genes in the TIME. In this review, we discuss lncRNAs that are specifically expressed in tumor and immune cells, summarize the regulatory functions of the lncRNAs at the cell type level and highlight how a scRNA-seq approach can help to study the cell type-specific functions of TIME lncRNAs.

Dysregulated Liver Metabolism and Polycystic Ovarian Syndrome.

A significant fraction of couples around the world suffer from polycystic ovarian syndrome (PCOS), a disease defined by the characteristics of enhanced androgen synthesis in ovarian theca cells, hyperandrogenemia, and ovarian dysfunction in women. Most of the clinically observable symptoms and altered blood biomarker levels in the patients indicate metabolic dysregulation and adaptive changes as the key underlying mechanisms. Since the liver is the metabolic hub of the body and is involved in steroid-hormonal detoxification, pathological changes in the liver may contribute to female endocrine disruption, potentially through the liver-to-ovary axis. Of particular interest are hyperglycemic challenges and the consequent changes in liver-secretory protein(s) and insulin sensitivity affecting the maturation of ovarian follicles, potentially leading to female infertility. The purpose of this review is to provide insight into emerging metabolic mechanisms underlying PCOS as the primary culprit, which promote its incidence and aggravation. Additionally, this review aims to summarize medications and new potential therapeutic approaches for the disease.

Kv4.1, a Key Ion Channel For Low Frequency Firing of Dentate Granule Cells, Is Crucial for Pattern Separation.

The dentate gyrus (DG) in the hippocampus may play key roles in remembering distinct episodes through pattern separation, which may be subserved by the sparse firing properties of granule cells (GCs) in the DG. Low intrinsic excitability is characteristic of mature GCs, but ion channel mechanisms are not fully understood. Here, we investigated ionic channel mechanisms for firing frequency regulation in hippocampal GCs using male and female mice, and identified Kv4.1 as a key player. Immunofluorescence analysis showed that Kv4.1 was preferentially expressed in the DG, and its expression level determined by Western blot analysis was higher at 8-week than 3-week-old mice, suggesting a developmental regulation of Kv4.1 expression. With respect to firing frequency, GCs are categorized into two distinctive groups: low-frequency (LF) and high-frequency (HF) firing GCs. Input resistance (Rin) of most LF-GCs is lower than 200 MΩ, suggesting that LF-GCs are fully mature GCs. Kv4.1 channel inhibition by intracellular perfusion of Kv4.1 antibody increased firing rates and gain of the input-output relationship selectively in LF-GCs with no significant effect on resting membrane potential and Rin, but had no effect in HF-GCs. Importantly, mature GCs from mice depleted of Kv4.1 transcripts in the DG showed increased firing frequency, and these mice showed an impairment in contextual discrimination task. Our findings suggest that Kv4.1 expression occurring at late stage of GC maturation is essential for low excitability of DG networks and thereby contributes to pattern separation.SIGNIFICANCE STATEMENT The sparse activity of dentate granule cells (GCs), which is essential for pattern separation, is supported by high inhibitory inputs and low intrinsic excitability of GCs. Low excitability of GCs is thought to be attributable to a high K+ conductance at resting membrane potentials, but this study identifies Kv4.1, a depolarization-activated K+ channel, as a key ion channel that regulates firing of GCs without affecting resting membrane potentials. Kv4.1 expression is developmentally regulated and Kv4.1 currents are detected only in mature GCs that show low-frequency firing, but not in less mature high-frequency firing GCs. Furthermore, mice depleted of Kv4.1 transcripts in the dentate gyrus show impaired pattern separation, suggesting that Kv4.1 is crucial for sparse coding and pattern separation.

Progression to prediabetes or diabetes in young Korean women with polycystic ovary syndrome: A longitudinal observational study.

OBJECTIVE: To investigate changes in glycaemic status in women with polycystic ovary syndrome (PCOS). DESIGN: Longitudinal observational study. PATIENTS: Women with PCOS who underwent baseline and follow-up screening tests for diabetes (n = 262). Four patients with type 2 diabetes (T2DM) at baseline and 6 patients who were taking drugs at the final follow-up were excluded. MEASUREMENTS: Changes in glycaemic classification based on fasting glucose, haemoglobin A1c and oral glucose tolerance test. RESULTS: The median length of follow-up was 2.9 years. The mean age and body mass index in the normoglycaemia group (n = 202) were 23.0 years and 21.6 kg/m2 , while it was 23.6 years and 22.9 kg/m2 in the prediabetes group (n = 50). In the normoglycaemia group, 38 (18.8%) and 2 (1.0%) developed prediabetes and T2DM, respectively. In the prediabetes group, 22 (44.0%) remained in the same category, 6 (12.0%) developed T2DM, while 22 (44.0%) achieved normoglycaemia. The incidence rate of T2DM was 9.3 per 1,000 person-years, which was significantly higher than that of the female population of similar age, and the incidence was higher in women with fasting glucose ≥ 5.6 mmol/L at baseline than in women with < 5.6 mmol/L. CONCLUSIONS: About 20% of normoglycaemic women had developed prediabetes or T2DM after a median time of 2.9 years. Meanwhile, nearly half of prediabetes women achieved normoglycaemia. Higher baseline fasting glucose levels were associated with an increased incidence of T2DM. Our results are the first to evaluate glycaemic status changes using all three parameters in patients with PCOS.

Association Between Polycystic Ovary Syndrome and the Polymorphisms of Aryl Hydrocarbon Receptor Repressor, Glutathione-S-transferase T1, and Glutathione-S-transferase M1 Genes.

OBJECTIVE: To investigate the association between the aryl hydrocarbon receptor repressor (AhRR) C/G polymorphisms and glutathione-S-transferase M1 (GSTM1) and GSTT1 null mutation and the risk of polycystic ovary syndrome (PCOS) in Korean women. METHODS: This was a case-control study of 478 women with PCOS and 376 aged-matched healthy controls. Genotyping of the AhRR C/G polymorphism and GSTM1 and GSTT1 were performed using real-time PCR analysis and multiplex PCR, respectively. RESULTS: The genotype distribution of the AhRR C/G polymorphisms and GSTM1/GSTT1 null mutations did not differ between women with PCOS and controls. Using the wild-type combined AhRR CC and GSTT1 present genotype as a reference, the odds that a woman had PCOS were 1.54 (95% CIs 1.04-2.29) times higher if she had a combined AhRR CG or GG and GSTT1 null genotype. The odds that a woman had PCOS was 1.48 (95% CIs 1.08-2.04) times higher if she had a combined GSTM1/GSTT1 null genotype compared with the wild-type combined GSTM1/GSTT1 present genotype. However, there were no significant associations between the risk of PCOS and any combined AhRR and GSTM1. CONCLUSIONS: Our data suggest that a combined AhRR CG or GG and GSTT1 null genotype or a combined GSTT1/GSTM1 null genotype might be associated with an increased risk of PCOS.

High-confidence coding and noncoding transcriptome maps.

The advent of high-throughput RNA sequencing (RNA-seq) has led to the discovery of unprecedentedly immense transcriptomes encoded by eukaryotic genomes. However, the transcriptome maps are still incomplete partly because they were mostly reconstructed based on RNA-seq reads that lack their orientations (known as unstranded reads) and certain boundary information. Methods to expand the usability of unstranded RNA-seq data by predetermining the orientation of the reads and precisely determining the boundaries of assembled transcripts could significantly benefit the quality of the resulting transcriptome maps. Here, we present a high-performing transcriptome assembly pipeline, called CAFE, that significantly improves the original assemblies, respectively assembled with stranded and/or unstranded RNA-seq data, by orienting unstranded reads using the maximum likelihood estimation and by integrating information about transcription start sites and cleavage and polyadenylation sites. Applying large-scale transcriptomic data comprising 230 billion RNA-seq reads from the ENCODE, Human BodyMap 2.0, The Cancer Genome Atlas, and GTEx projects, CAFE enabled us to predict the directions of about 220 billion unstranded reads, which led to the construction of more accurate transcriptome maps, comparable to the manually curated map, and a comprehensive lncRNA catalog that includes thousands of novel lncRNAs. Our pipeline should not only help to build comprehensive, precise transcriptome maps from complex genomes but also to expand the universe of noncoding genomes.

Impact of the newly recommended antral follicle count cutoff for polycystic ovary in adult women with polycystic ovary syndrome.

STUDY QUESTION: What is the impact of the newly recommended antral follicle count (AFC) cutoff for polycystic ovary (PCO) on the diagnostic status of polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Among patients with phenotypes requiring the presence of PCO for diagnosis, approximately half (48.2%) were excluded from having PCOS based on the new AFC cutoff, although these excluded women had worse metabolic and hormonal profiles than the controls and were indistinguishable from the remaining patients with regard to major hormonal and metabolic parameters. WHAT IS KNOWN ALREADY: In the Rotterdam criteria, PCO is defined as either 12 or more follicles measuring 2-9 mm in diameter or an increased ovarian volume >10 cm3. Recently, an international PCOS guideline development group recommended an AFC threshold for PCO of ≥20 in adult women when using transducers with a high-resolution frequency, including 8 MHz. STUDY DESIGN, SIZE, DURATION: The current study used a case control design. PARTICIPANTS/MATERIALS, SETTING, METHODS: PCOS was diagnosed according to the Rotterdam criteria. Ultrasonography examinations were conducted with wide band frequency (5-9 MHz) transvaginal transducers and the centre frequency was 8 MHz. In patients who show both irregular menstruation and hyperandrogenism (HA), a diagnosis of PCOS can be made irrespective of the ovarian criteria change. Patients who were diagnosed according to HA and PCO (n = 86) or irregular menstruation and PCO (n = 443) were initially included among a total of 1390 adult women with PCOS (aged 20-40 years). Regardless of the AFC, if the ovarian volume is ≥10 cm3, a diagnosis of PCO can still be made. Thus, only patients who had an ovarian volume of <10 cm3 were analysed. Subjects who had an AFC of 12-19 and an ovarian volume <10 cm3 were designated as the 'low AFC group' (n = 255) and were the main focus of the study because they were excluded from having PCOS based on the new cutoff. Subjects with an AFC ≥20 and an ovarian volume <10 cm3 were designated as the 'high AFC group' (n = 101). A total of 562 premenopausal women without PCOS were enrolled as controls. MAIN RESULTS AND THE ROLE OF CHANCE: Among patients with irregular menstruation and PCO or HA and PCO phenotypes, approximately half (48.2%, 255/529) were excluded from having PCOS, which corresponded to one-fifth (18.3%, 255/1390) of the total adult patients. However, compared to the control group, these excluded women had worse metabolic profiles and were more androgenised. Notably, they were indistinguishable from the 'high AFC group' with regard to major hormonal and metabolic parameters (BMI and diabetic classification status, and the prevalence of insulin resistance, metabolic syndrome and HA). LIMITATIONS, REASONS FOR CAUTION: We cannot exclude the possibility of inter- and intraobserver variation in the evaluation of AFC. WIDER IMPLICATIONS OF THE FINDINGS: With the newly recommended follicle count cutoff, a substantial proportion of women with PCOS might be classified as not having PCOS despite visiting a hospital due to irregular menstruation or hyperandrogenic symptoms. A practical approach to them would involve controlling the menstrual or hyperandrogenic symptoms in hand and regularly evaluating them regarding newly developed or worsening PCOS-related symptoms or metabolic abnormalities. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by a grant from the Seoul National University Hospital Research Fund (No. 2520140090), Republic of Korea. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: Not applicable.

Transcriptome Analysis Reveals Nonfoamy Rather Than Foamy Plaque Macrophages Are Proinflammatory in Atherosclerotic Murine Models.

RATIONALE: Monocyte infiltration into the subintimal space and its intracellular lipid accumulation are the most prominent features of atherosclerosis. To understand the pathophysiology of atherosclerotic disease, we need to understand the characteristics of lipid-laden foamy macrophages in the subintimal space during atherosclerosis. OBJECTIVE: We sought to examine the transcriptomic profiles of foamy and nonfoamy macrophages isolated from atherosclerotic intima. METHODS AND RESULTS: Single-cell RNA sequencing analysis of CD45+ leukocytes from murine atherosclerotic aorta revealed that there are macrophage subpopulations with distinct differentially expressed genes involved in various functional pathways. To specifically characterize the intimal foamy macrophages of plaque, we developed a lipid staining-based flow cytometric method for analyzing the lipid-laden foam cells of atherosclerotic aortas. We used the fluorescent lipid probe BODIPY493/503 and assessed side-scattered light as an indication of cellular granularity. BODIPYhiSSChi foamy macrophages were found residing in intima and expressing CD11c. Foamy macrophage accumulation determined by flow cytometry was positively correlated with the severity of atherosclerosis. Bulk RNA sequencing analysis showed that compared with nonfoamy macrophages, foamy macrophages expressed few inflammatory genes but many lipid-processing genes. Intimal nonfoamy macrophages formed the major population expressing IL (interleukin)-1ß and many other inflammatory transcripts in atherosclerotic aorta. CONCLUSIONS: RNA sequencing analysis of intimal macrophages from atherosclerotic aorta revealed that lipid-loaded plaque macrophages are not likely the plaque macrophages that drive lesional inflammation.

Laparoscopic management is feasible for nonobstetric surgical disease in all trimesters of pregnancy.

BACKGROUND: Nonobstetric surgical interventions are required in some women during pregnancy. The most common nonobstetric conditions requiring surgery during pregnancy are acute appendicitis and cholecystitis. This study aimed to evaluate pregnancy outcomes and complications following surgical procedures for presumed nonobstetric surgical interventions during pregnancy, and to compare the outcomes between the laparoscopic and open approaches. METHODS: We conducted a retrospective study of patients who underwent laparoscopic or open surgery during pregnancy for nonobstetric surgical indications at our institution between 2008 and 2016. RESULTS: A total of 62 consecutive patients who underwent surgical intervention due to nonobstetric causes during pregnancy were included in our study. Of these, 35 (56.5%) were managed with laparoscopy and 27 (43.5%) with the open approach. Patients who underwent laparoscopy had a significantly shorter hospital stay and lower pain score on postoperative day 2 than those who underwent open surgery (5.5 vs. 7.2 days, p = 0.03 and 1.4 vs. 2.4, p < 0.01, respectively). There were no significant differences in operative complications between both groups. In advanced pregnancy (gestational age ≥ 23 weeks), 7 patients (41.2%) were managed with laparoscopy and 10 (58.8%) with the open approach. No differences in surgical complications were found between both groups in advanced pregnancy as well. CONCLUSIONS: In our study, laparoscopic surgery was found to be feasible and safe in the late second and third trimesters as well as in the first and early second trimesters without adverse effects on pregnancy.

Methylenetetrahydrofolate Reductase Polymorphisms and Risk of Recurrent Pregnancy Loss: a Case-Control Study.

The balance between coagulation and fibrinolysis is an essential part in early pregnancy. Mutations in methylenetetrahydrofolate reductase (MTHFR) gene lead to decreased activity of the enzyme and hyperhomocysteinemia, which then induces platelet aggregation by promoting endothelial oxidative damage, possibly resulting in adverse effect on maintenance of pregnancy. We investigated the role of MTHFR single nucleotide polymorphisms (SNPs), C677T and A1298C, in Korean patients with recurrent pregnancy loss (RPL). We conducted a prospective case-control study in the Korean population. Subjects included 302 women with 2 or more consecutive, unexplained, spontaneous miscarriages before 20 weeks of gestation and 315 control women without a history of recurrent miscarriages. The genotyping for C677T and A1298C polymorphisms was performed using the TaqMan assay. Continuous variables were compared using Student's t-test, and χ² test was used to evaluate differences in the genotype distributions between the RPL and the controls. The genotype distribution of both polymorphisms in the RPL group did not differ from those of the controls. For further analysis, if RPL patients were divided according to the numbers of pregnancy losses (≥ 2 and ≥ 3) neither group was significantly different compared with controls. MTHFR gene C677T and A1298C polymorphisms are not associated with idiopathic RPL in Korean women, suggesting that those may not be susceptible allelic variants or be deficient to cause RPL.

FSH receptor gene p. Thr307Ala and p. Asn680Ser polymorphisms are associated with the risk of polycystic ovary syndrome.

PURPOSE: The purpose of this study was to investigate whether the follicle-stimulating hormone receptor (FSHR) gene p. Thr307Ala (c.919A>G, rs6165) and p. Asn680Ser (c.2039A>G, rs6166) polymorphisms are associated with susceptibility to polycystic ovary syndrome (PCOS). METHODS: Genotyping was performed in 377 women with PCOS and 388 age-matched controls. Difference in the genotype distribution was assessed using a Fisher's exact or chi-square test, and continuous variables were compared using a Student's t test. To evaluate the association between the presence of PCOS status and SNP, logistic regression analyses were performed. RESULTS: Linkage disequilibrium between the two polymorphisms was approximately complete (r 2 = 99%). The genotype distributions of the PCOS group significantly differed from those of the control group (Thr/Thr, Thr/Ala, and Ala/Ala frequencies were 38.5, 46.7, and 14.9% for the PCOS group and 46.6, 45.4, and 8.0% for the controls, respectively, P = .005; Asn/Asn, Asn/Ser, and Ser/Ser frequencies were 39.5, 47.2, and 13.3% for the PCOS group and 46.4, 45.4, and 8.2% for the controls, respectively, P = .035). Using the wild-type genotypes as the references, the odds ratios that a woman has PCOS were 2.23 (95% confidence intervals 1.38-3.68) for the Ala/Ala genotype, 1.87 (95% confidence intervals 1.14-3.06) for the Ser/Ser genotype, and 1.96 (95% confidence intervals 1.19-3.24) for the homozygous variant combination (Ser/Ser-Ala/Ala). However, there were no significant differences in serum hormonal, ovarian, and metabolic markers according to each genotype. CONCLUSIONS: Findings of this study suggest a significant association between FSHR gene p. Thr307Ala or p. Asn680Ser coding sequence change and PCOS. The variant homozygote genotype results in a higher risk of PCOS.

Correlation between the serum luteinizing hormone to folliclestimulating hormone ratio and the anti-Müllerian hormone levels in normo-ovulatory women.

Serum anti-Müllerian hormone (AMH) levels are regarded as an age-specific marker for predicting the ovarian reserve in women of reproductive age. Some studies have shown that the luteinizing hormone (LH)/follicle stimulating hormone (FSH) ratio can be used as a predictor of ovarian reserve. The purpose of this study was to assess the variation of LH/FSH ratio with aging and to evaluate the correlation between serum LH/FSH ratio and AMH levels as a predictor of the ovarian reserve in normo-ovulatory women. We retrospectively analyzed the day 3 serum hormone levels in 1,251 patients (age range: 20-50 yr) between January 2010 and January 2011. We divided the patients into 6 groups according to their age. Relation between serum AMH level and LH/FSH ratio was analyzed statistically. The serum AMH level was inversely correlated with age (r = -0.400, P < 0.001). A significant negative correlation was found between serum LH/FSH ratio and age (r = -0.213, P < 0.001). There was a significant partial correlation between serum LH/FSH ratio and AMH level when adjusted by age (r = 0.348, P < 0.001). The LH/FSH ratio could be considered as a useful marker for the ovarian reserve and could be applied to the clinical evaluation with AMH.

Chronic non-social stress affects depressive behaviors but not anxiety in mice.

The etiology of most psychiatric disorders is still incompletely understood. However, growing evidence suggests that stress is a potent environmental risk factor for depression and anxiety. In rodents, various stress paradigms have been developed, but psychosocial stress paradigms have received more attention than non-social stress paradigms because psychosocial stress is more prevalent in humans. Interestingly, some recent studies suggest that chronic psychosocial stress and social isolation affects mainly anxiety-related behaviors in mice. However, it is unclear whether chronic non-social stress induces both depression- and anxiety-related phenotypes or induces one specific phenotype in mice. In the present study, we examined the behavioral consequences of three chronic non-social stress paradigms: chronic predictable (restraint) stress (CPS), chronic unpredictable stress (CUS), and repeated corticosterone-HBC complex injection (RCI). Each of the three paradigms induced mild to severe depression/despair-like behaviors in mice and resulted in increased immobility in a tail suspension test. However, anxiety-related phenotypes, thigmotaxis and explorative behaviors, were not changed by the three paradigms. These results suggest that depression- and anxiety-related phenotypes can be dissociated in mouse stress models and that social and non-social stressors might affect brain circuits and behaviors differently.

Robust sound-guided image manipulation.

Recent successes suggest that an image can be manipulated by a text prompt, e.g., a landscape scene on a sunny day is manipulated into the same scene on a rainy day driven by a text input "raining". These approaches often utilize a StyleCLIP-based image generator, which leverages multi-modal (text and image) embedding space. However, we observe that such text inputs are often bottlenecked in providing and synthesizing rich semantic cues, e.g., differentiating heavy rain from rain with thunderstorms. To address this issue, we advocate leveraging an additional modality, sound, which has notable advantages in image manipulation as it can convey more diverse semantic cues (vivid emotions or dynamic expressions of the natural world) than texts. In this paper, we propose a novel approach that first extends the image-text joint embedding space with sound and applies a direct latent optimization method to manipulate a given image based on audio input, e.g., the sound of rain. Our extensive experiments show that our sound-guided image manipulation approach produces semantically and visually more plausible manipulation results than the state-of-the-art text and sound-guided image manipulation methods, which are further confirmed by our human evaluations. Our downstream task evaluations also show that our learned image-text-sound joint embedding space effectively encodes sound inputs. Examples are provided in our project page: https://kuai-lab.github.io/robust-demo/.

Clinical efficacy of a novel method of fertility-preserving adenomyomectomy in infertile women with diffuse adenomyosis.

Beneficial and detrimental effect of surgical adenomyomectomy is still controversial in infertile women with severely diffuse adenomyosis. The primary objective of this study was to assess whether a novel method of fertility-preserving adenomyomectomy could improve pregnancy rates. The secondary objective was to evaluate whether it could improve dysmenorrhea and menorrhagia symptoms in infertile patients with severe adenomyosis. A prospective clinical trial was conducted between December 2007 and September 2016. Fifty women with infertility due to adenomyosis were enrolled in this study after clinical assessments by infertility experts. A novel method of fertility-preserving adenomyomectomy was performed on 45 of 50 patients. The procedure included T- or transverse H-incision of the uterine serosa followed by preparation of the serosal flap, excision of the adenomyotic tissue using argon laser under ultrasonographic monitoring, and a novel technique of suturing between the residual myometrium and serosal flap. After the adenomyomectomy, the changes in the amount of menstrual blood, relief of dysmenorrhea, pregnancy outcomes, clinical characteristics, and surgical features were recorded and analyzed. All patients obtained dysmenorrhea relief 6 months postoperatively (numeric rating scale [NRS]; 7.28 ±â€…2.30 vs 1.56 ±â€…1.30, P < .001). The amount of menstrual blood decreased significantly (140.44 ±â€…91.68 vs 66.33 ±â€…65.85 mL, P < .05). Of the 33 patients who attempted pregnancy postoperatively, 18 (54.5%) conceived either by natural means, in vitro fertilization and embryo transfer (IVF-ET), or thawing embryo transfer. Miscarriage occurred in 8 patients, while 10 (30.3%) had viable pregnancies. This novel method of adenomyomectomy resulted in improved pregnancy rates, as well as relief of dysmenorrhea and menorrhagia. This operation is effective in preserving fertility potential in infertile women with diffuse adenomyosis.

Developmental retardation, microcephaly, and peptiduria in mice without aminopeptidase P1.

Cytosolic aminopeptidase P1 (APP1) is one of the three known mammalian aminopeptidase Ps (APPs) that cleave the N-terminal amino acid residue of peptides in which the penultimate amino acid is proline. In mammals, many biologically active peptides have a highly conserved N-terminal penultimate proline. However, little is known about the physiological role of APP1. In addition, there is no direct evidence to associate a deficiency in APP1 with metabolic diseases. Although two human subjects with reduced APP activity exhibited peptiduria, it is unclear which of the three APP isoforms is responsible for this disorder. In this study, we generated APP1-deficient mice by knocking out Xpnpep1. Mouse APP1 deficiency causes severe growth retardation, microcephaly, and modest lethality. In addition, imino-oligopeptide excretion was observed in urine samples from APP1-deficient mice. These results suggest an essential role for APP1-mediated peptide metabolism in body and brain development, and indicate a strong causal link between APP1 deficiency and peptiduria.

Polycystic ovary syndrome is not associated with polymorphisms of the TCF7L2, CDKAL1, HHEX, KCNJ11, FTO and SLC30A8 genes.

OBJECTIVE: Insulin resistance is a core feature of polycystic ovary syndrome (PCOS). Recently, genome-wide association studies have reported a number of single-nucleotide polymorphisms (SNPs) with reproducible associations and susceptibilities to type 2 diabetes. We examined the potential association between the diabetogenic genes uncovered in the genome-wide association studies and PCOS in Korean women. DESIGN: Case-control study. PATIENTS: Women with or without PCOS. MEASUREMENTS: DNA samples from 377 patients with PCOS and 386 age-matched controls were genotyped. RESULTS: None of the 12 SNPs in the six genes (KCNJ11, TCF7L2, SLC30A8, HHEX, FTO and CDKAL1) uncovered in the genome-wide association studies were associated with PCOS. For further analysis, the patients with PCOS were divided into two or three subgroups according to genotype, and the associations between the genotypes and insulin resistance or insulin secretory capacity were assessed. No SNPs were significantly associated with HOMA-IR, HOMA (ßcell) (%), or 2-h 75-g oral glucose tolerance test insulin levels in the patients with PCOS; there were no significant associations with other serum hormonal and metabolic markers, such as androgen or glucose levels. CONCLUSIONS: Our results suggest that the six type 2 diabetes-associated genes identified in genome-wide association studies are not associated with PCOS.

Inhibin α gene promoter polymorphisms in Korean women with idiopathic premature ovarian failure.

BACKGROUND: It has been suggested that variations in the inhibin α gene (INHA) may affect the ovarian function of women. This study was performed to investigate whether the genetic polymorphisms of the INHA gene are associated with idiopathic premature ovarian failure (POF) in a Korean population. METHODS: The subjects consisted of 159 idiopathic POF patients and 233 post-menopausal controls. Genotyping for the -16C>T polymorphism was performed by an minor groove binder (MGB) primer/probe Taqman assay, and the -124A>G polymorphism was identified using PCR restriction fragment length polymorphism analysis. Haplotypes were deduced by using the Haploview version 4.1. RESULTS: There were no significant differences in the genotype distributions or allele frequencies of the INHA gene -16C>T and -124A>G polymorphisms between the POF and the control group. Haplotype analysis also showed no significant difference between groups. CONCLUSIONS: The distribution of the INHA gene promoter polymorphisms in a Korean POF population was not significantly different from controls, implying that the INHA gene polymorphisms may not be associated with the risk of idiopathic POF.