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  1. Article ; Online: What Is the Male Polycystic Ovary Syndrome Phenotype?

    Welt, Corrine K

    The Journal of clinical endocrinology and metabolism

    2021  Volume 107, Issue 5, Page(s) e2188–e2189

    MeSH term(s) Female ; Humans ; Insulin Resistance ; Male ; Phenotype ; Polycystic Ovary Syndrome/genetics ; Sex Hormone-Binding Globulin/genetics
    Chemical Substances Sex Hormone-Binding Globulin
    Language English
    Publishing date 2021-12-14
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/clinem/dgab898
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  2. Article ; Online: Genetics of Polycystic Ovary Syndrome: What is New?

    Welt, Corrine K

    Endocrinology and metabolism clinics of North America

    2021  Volume 50, Issue 1, Page(s) 71–82

    Abstract: Polycystic ovary syndrome (PCOS) is a complex genetic disorder with many genetic loci contributing small risk. Large genome-wide association studies identified 21 genetic risk loci for PCOS in European and Han Chinese women. The genetic architecture is ... ...

    Abstract Polycystic ovary syndrome (PCOS) is a complex genetic disorder with many genetic loci contributing small risk. Large genome-wide association studies identified 21 genetic risk loci for PCOS in European and Han Chinese women. The genetic architecture is similar across PCOS diagnostic categories. The next wave of analysis will incorporate large genotyped datasets linked to medical records, increasing numbers and ethnic subsets. The resulting genetic risk loci can then be used to create robust genetic risk scores enhanced with clinical information, environment and lifestyle data for a precision medicine approach to PCOS diagnosis and treatment.
    MeSH term(s) Female ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Humans ; Polycystic Ovary Syndrome/genetics ; Polycystic Ovary Syndrome/therapy ; Polymorphism, Single Nucleotide
    Language English
    Publishing date 2021-01-11
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 92116-6
    ISSN 1558-4410 ; 0889-8529
    ISSN (online) 1558-4410
    ISSN 0889-8529
    DOI 10.1016/j.ecl.2020.10.006
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  3. Article ; Online: Practical Approach to Hyperandrogenism in Women.

    Sharma, Anu / Welt, Corrine K

    The Medical clinics of North America

    2021  Volume 105, Issue 6, Page(s) 1099–1116

    Abstract: The approach to hyperandrogenism in women varies depending on the woman's age and severity of symptoms. Once tumorous hyperandrogenism is excluded, the most common cause is PCOS. Hirsutism is the most common presenting symptom. The woman's concern about ... ...

    Abstract The approach to hyperandrogenism in women varies depending on the woman's age and severity of symptoms. Once tumorous hyperandrogenism is excluded, the most common cause is PCOS. Hirsutism is the most common presenting symptom. The woman's concern about her symptoms plays an important role in the management of disease. Although measurement of testosterone is useful in identifying an underlying cause, care must be taken when interpreting the less accurate assays that are available commercially. Surgical resection is curative in tumorous etiologies, whereas medical management is the mainstay for non-tumorous causes.
    MeSH term(s) Age Factors ; Androgen Antagonists/therapeutic use ; Female ; Humans ; Hyperandrogenism/diagnosis ; Hyperandrogenism/drug therapy ; Hyperandrogenism/etiology ; Hyperandrogenism/physiopathology ; Polycystic Ovary Syndrome/complications ; Racial Groups ; Testosterone/blood ; Women's Health
    Chemical Substances Androgen Antagonists ; Testosterone (3XMK78S47O)
    Language English
    Publishing date 2021-09-08
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 215710-x
    ISSN 1557-9859 ; 0025-7125
    ISSN (online) 1557-9859
    ISSN 0025-7125
    DOI 10.1016/j.mcna.2021.06.008
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  4. Article ; Online: PRL Mutation Causing Alactogenesis: Insights Into Prolactin Structure and Function Relationships.

    Moriwaki, Mika / Welt, Corrine K

    The Journal of clinical endocrinology and metabolism

    2021  Volume 106, Issue 8, Page(s) e3021–e3026

    Abstract: Context: Isolated prolactin deficiency is a rare disorder manifesting as absence of puerperal lactation. We identified a 2-generation family with 3 women experiencing alactogenesis.: Objective: We hypothesized a heterozygous genetic mutation.: ... ...

    Abstract Context: Isolated prolactin deficiency is a rare disorder manifesting as absence of puerperal lactation. We identified a 2-generation family with 3 women experiencing alactogenesis.
    Objective: We hypothesized a heterozygous genetic mutation.
    Methods: This was a family-based study. Two generations of women (proband, sister, and niece) with puerperal alactogenesis and one control were studied. Prolactin levels in the 3 women ranged from 0.618 to 1.4 ng/mL (range, 2.8-29.2 ng/mL). All the women had regular menstrual cycles during their reproductive years. The niece required fertility treatment to become pregnant and the proband and sister underwent menopause before age 45 years. Prolactin gene (PRL) exons 1 to 5 were sequenced. We sought a heterozygous, deleterious gene variant with functional consequences.
    Results: We identified a heterozygous mutation (c.658C > T) changing CGA to TGA (p.Arg220Ter) in exon 5 of the prolactin gene. Transfection of PRL containing the stop gain mutation resulted in similar intracellular prolactin levels compared to PRL wild type, but little detectable immunoactive or bioactive prolactin in conditioned medium. Prolactin secretion was also impaired by a PRL stop gain mutation deleting both of the terminal cysteine amino acids (c.652A > T; p.Lys218Ter).
    Conclusion: This is the first report of a PRL mutation causing familial prolactin deficiency and alactogenesis. The loss of the terminal cysteine resulted in failure of prolactin secretion. Secretion was not rescued by deleting the penultimate cysteine, with which it forms a disulfide bond. These data suggest that the PRL C terminal is critical for protein secretion.
    MeSH term(s) Adult ; Aged ; Female ; Genetic Diseases, Inborn/genetics ; Humans ; Lactation/genetics ; Lactation Disorders/genetics ; Menarche/genetics ; Pedigree ; Prolactin/deficiency ; Prolactin/genetics
    Chemical Substances Prolactin (9002-62-4)
    Language English
    Publishing date 2021-03-26
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/clinem/dgab201
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  5. Article ; Online: Primary ovarian insufficiency has strong familiality: results of a multigenerational genealogical study.

    Verrilli, Lauren / Johnstone, Erica / Welt, Corrine / Allen-Brady, Kristina

    Fertility and sterility

    2022  Volume 119, Issue 1, Page(s) 128–134

    Abstract: Objective: To determine the familiality of primary ovarian insufficiency (POI) at population level through examination of multigenerational genealogical information linked to electronic medical records.: Design: Case-control study.: Setting: Not ... ...

    Abstract Objective: To determine the familiality of primary ovarian insufficiency (POI) at population level through examination of multigenerational genealogical information linked to electronic medical records.
    Design: Case-control study.
    Setting: Not applicable.
    Patient(s): Women with POI were identified using International Classification of Disease 9 and 10 codes in electronic medical records (1995-2021) from 2 major health care systems in Utah and reviewed for accuracy. Cases were linked to genealogy information in the Utah Population Database (UPDB). All included POI cases (n = 396) were required to have genealogy information available for at least 3 generations of ancestors. The risk of POI in relatives was compared with population rates for POI matched by age, sex, and birthplace.
    Intervention(s): Not applicable.
    Main outcome measure(s): Relative risk of POI in first-, second-, and third-degree relatives.
    Result(s): We identified 396 validated cases of POI with an associated 2,132 first-degree relatives, 5,245 second-degree relatives, and 10,853 third-degree relatives. We found an increased risk of POI among the extended relatives of cases. Specifically, first-degree relatives demonstrated an 18-fold increased risk of POI compared with controls relative risk ([RR],18.52 95% confidence interval [CI], 10.12-31.07), second-degree relatives demonstrated a 4-fold increase (RR, 4.21; CI, 1.15-10.79), and third-degree relatives demonstrated a 2.7-fold increase (RR, 2.65; CI, 1.14-5.21]).
    Conclusion(s): This is the first population-based study to assess the familial clustering of POI. The data demonstrate excess familiality, familial clustering of POI in excess compared with matched population rates of disease, among first-, second-, and third-degree relatives. These findings support a genetic contribution to POI.
    MeSH term(s) Humans ; Female ; Genetic Predisposition to Disease ; Case-Control Studies ; Primary Ovarian Insufficiency/diagnosis ; Primary Ovarian Insufficiency/epidemiology ; Primary Ovarian Insufficiency/genetics ; Risk ; Family ; Utah/epidemiology
    Language English
    Publishing date 2022-10-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 80133-1
    ISSN 1556-5653 ; 0015-0282
    ISSN (online) 1556-5653
    ISSN 0015-0282
    DOI 10.1016/j.fertnstert.2022.09.027
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  6. Article ; Online: Health-related quality of life in women with primary ovarian insufficiency: a scoping review of the literature and implications for targeted interventions.

    McDonald, Isabella R / Welt, Corrine K / Dwyer, Andrew A

    Human reproduction (Oxford, England)

    2022  Volume 37, Issue 12, Page(s) 2817–2830

    Abstract: Study question: What is known about health-related quality of life (HR-QoL) in women with idiopathic primary ovarian insufficiency (POI)?: Summary answer: Women with POI have a range of unmet psychosocial needs relating to three interrelated themes: ' ...

    Abstract Study question: What is known about health-related quality of life (HR-QoL) in women with idiopathic primary ovarian insufficiency (POI)?
    Summary answer: Women with POI have a range of unmet psychosocial needs relating to three interrelated themes: 'diagnostic odyssey', 'isolation and stigma' and impaired 'ego integrity'.
    What is known already: Prior studies have reported increased depressive symptoms, diminished sexual function and altered body image/self-concept in women with POI.
    Study design, size, duration: A systematic scoping review (11 databases) on HR-QoL in POI including published quantitative, qualitative and mixed-methods studies as well as unpublished gray literature (i.e. unpublished dissertations) through June, 2021.
    Participants/materials, setting, methods: After removing duplicates, 1244 articles underwent title and abstract review by independent reviewers. The remaining 72 relevant articles underwent dual full text review to determine inclusion criteria yielding 24 articles (100% concordance) for data extraction. Findings were summarized in tables by methodology and recurrent HR-QoL themes/sub-themes were mapped to define key aspects of HR-QoL in POI. Promoters of active coping were charted at the individual, interpersonal and healthcare system levels. Targets for tailored interventions supporting active coping and improved HR-QoL were mapped to the Theory of Planned Behavior (TPB).
    Main results and the role of chance: Three interrelated themes affecting HR-QoL in POI emerged from the data synthesis. First, the theme 'diagnostic odyssey' comprised sub-themes of uncertainty, lack of control, knowledge gaps, discontinuous care and negative clinical interactions. The second theme 'isolation and stigma' included sub-themes of guilt, shame, concealment, feeling labeled as infertile, lack of social support and unsympathetic clinicians. The third theme, impaired 'ego integrity' captured sub-themes of decreased sexual function, altered body image, psychological vulnerability and catastrophizing. Targets promoting active coping at the individual (n = 2), interpersonal (n = 1) and healthcare system (n = 1) levels were mapped to the TPB to inform development of tailored interventions supporting active coping and improved HR-QoL in POI (i.e. narrative intervention, co-creating patient-facing materials, peer-to-peer support and provider resources).
    Limitations, reasons for caution: No studies using a POI-specific HR-QoL instrument were identified. No interventional studies aimed at improving HR-QoL in POI were identified. Only articles published in English were included in the study.
    Wider implications of the findings: Women with POI frequently have impaired HR-QoL related to the life-altering infertility diagnosis. The range of unmet psychosocial needs may be relevant for informing interventions for other populations with infertility.
    Study funding/competing interest(s): This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development 'Massachusetts General Hospital-Harvard Center for Reproductive Medicine' (1 P50 HD104224-01 NICHD). The authors have no conflicts to declare.
    Registration number: N/A.
    MeSH term(s) Child ; Humans ; Female ; Primary Ovarian Insufficiency/therapy ; Quality of Life ; Adaptation, Psychological ; Mutation ; Infertility
    Language English
    Publishing date 2022-10-05
    Publishing country England
    Document type Systematic Review ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 632776-x
    ISSN 1460-2350 ; 0268-1161 ; 1477-741X
    ISSN (online) 1460-2350
    ISSN 0268-1161 ; 1477-741X
    DOI 10.1093/humrep/deac200
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  7. Article: Heterozygous

    Moriwaki, Mika / Liu, Lihua / James, Emma R / Tolley, Neal / O'Connora, Ashley M / Emery, Benjamin / Aston, Kenneth Ivan / Campbell, Robert A / Welt, Corrine K

    bioRxiv : the preprint server for biology

    2024  

    Abstract: We created the c.1286C>G stop-gain mutation found in a family with primary ovarian insufficiency (POI) at age 30 years. ... ...

    Abstract We created the c.1286C>G stop-gain mutation found in a family with primary ovarian insufficiency (POI) at age 30 years. The
    Language English
    Publishing date 2024-04-11
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.04.09.588694
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  8. Article ; Online: Shared genetics between nonobstructive azoospermia and primary ovarian insufficiency.

    Verrilli, Lauren / Johnstone, Erica / Allen-Brady, Kristina / Welt, Corrine

    F&S reviews

    2021  Volume 2, Issue 3, Page(s) 204–213

    Abstract: Objective: Primary ovarian insufficiency (POI) and Non-obstructive azoospermia (NOA) both represent disease states of early, and often complete, failure of gametogenesis. Because oogenesis and spermatogenesis share the same conserved steps in meiosis I, ...

    Abstract Objective: Primary ovarian insufficiency (POI) and Non-obstructive azoospermia (NOA) both represent disease states of early, and often complete, failure of gametogenesis. Because oogenesis and spermatogenesis share the same conserved steps in meiosis I, it is possible that inherited defects in meiosis I could lead to shared causes of both POI and NOA. Currently, known genes that contribute to both POI and NOA are limited. In this review article, we provide a systematic review of genetic mutations in which both POI and NOA phenotypes exist.
    Evidence review: A PubMed literature review was conducted from January 1, 2000 through October 2020. We included all studies that demonstrated human cases of POI or NOA due to a specific genetic mutation either within the same family or in separate families.
    Results: We identified 33 papers that encompassed 10 genes of interest with mutations implicated in both NOA and POI. The genes were all involved in processes of meiosis I.
    Conclusion: Mutations in genes involved in processes of meiosis I may cause both NOA and POI. Identifying these unique phenotypes among shared genotypes leads to biologic plausibility that the key error occurs early in gametogenesis with an etiology shared among both male and female offspring. From a clinical standpoint, this shared relationship may help us better understand and identify individuals at high risk for gonadal failure within families and suggests that clinicians obtain history for opposite sex family members when approaching a new diagnosis of POI or NOA.
    Language English
    Publishing date 2021-04-14
    Publishing country United States
    Document type Journal Article
    ISSN 2666-5719
    ISSN (online) 2666-5719
    DOI 10.1016/j.xfnr.2021.04.001
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  9. Article ; Online: The Use of Ceramides to Predict Metabolic Response to Metformin in Women With PCOS.

    Sharma, Anu / Krick, Benjamin / Li, Ying / Summers, Scott A / Playdon, Mary C / Welt, Corrine

    Journal of the Endocrine Society

    2022  Volume 6, Issue 11, Page(s) bvac131

    Abstract: Context: Polycystic ovarian syndrome (PCOS) is a complex disorder in which metabolic abnormalities are associated with reproductive dysfunction. Women with PCOS have increased ceramide concentrations. Previous studies demonstrated that treating ... ...

    Abstract Context: Polycystic ovarian syndrome (PCOS) is a complex disorder in which metabolic abnormalities are associated with reproductive dysfunction. Women with PCOS have increased ceramide concentrations. Previous studies demonstrated that treating metabolic abnormalities of PCOS with metformin improved glucose effectiveness after 12 weeks.
    Objective: We evaluated whether, in women with PCOS, lower baseline ceramide, diacylglycerol (DAG), and triacylglycerol (TAG) concentrations were associated with improved metabolic response to metformin.
    Methods: Women (n = 29), aged 29 ± 5 years and diagnosed with PCOS by the NIH criteria underwent an intravenous glucose tolerance test (IVGTT) before and after 12-week treatment with metformin (1500 mg per day). Metabolic responders were defined by improved glucose effectiveness, specifically, the ability of glucose to stimulate uptake and suppress production, after metformin treatment.
    Results: Twelve weeks of metformin resulted in weight loss (-1.7 ± 2.6 kg,
    Conclusion: Lower total Cer(16:0) and DHSM concentrations are associated with a beneficial metabolic response to metformin in women with PCOS. Based on the known association between higher ceramide levels and type 2 diabetes, the data suggest that metformin improves metabolic parameters in women with mild metabolic derangements.
    Language English
    Publishing date 2022-09-02
    Publishing country United States
    Document type Journal Article
    ISSN 2472-1972
    ISSN (online) 2472-1972
    DOI 10.1210/jendso/bvac131
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  10. Article ; Online: DIS3 Variants are Associated With Primary Ovarian Insufficiency: Importance of Transcription/Translation in Oogenesis.

    Johnstone, Erica Boiman / Gorsi, Bushra / Coelho, Emily / Moore, Barry / Farr, Ashley M / Cooper, Amber R / Mardis, Elaine R / Rajkovic, Aleksander / Chow, Clement Y / Yandell, Mark / Welt, Corrine K

    The Journal of clinical endocrinology and metabolism

    2023  Volume 108, Issue 9, Page(s) 2330–2335

    Abstract: Context: A genetic etiology accounts for the majority of unexplained primary ovarian insufficiency (POI).: Objective: We hypothesized a genetic cause of POI for a sister pair with primary amenorrhea.: Design: The study was an observational study. ... ...

    Abstract Context: A genetic etiology accounts for the majority of unexplained primary ovarian insufficiency (POI).
    Objective: We hypothesized a genetic cause of POI for a sister pair with primary amenorrhea.
    Design: The study was an observational study. Subjects were recruited at an academic institution.
    Subjects: Subjects were sisters with primary amenorrhea caused by POI and their parents. Additional subjects included women with POI analyzed previously (n = 291). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233).
    Intervention: We performed whole exome sequencing, and data were analyzed using the Pedigree Variant Annotation, Analysis and Search Tool, which identifies genes harboring pathogenic variants in families. We performed functional studies in a Drosophila melanogaster model.
    Main outcome: Genes with rare pathogenic variants were identified.
    Results: The sisters carried compound heterozygous variants in DIS3. The sisters did not carry additional rare variants that were absent in publicly available datasets. DIS3 knockdown in the ovary of D. melanogaster resulted in lack of oocyte production and severe infertility.
    Conclusions: Compound heterozygous variants in highly conserved amino acids in DIS3 and failure of oocyte production in a functional model suggest that mutations in DIS3 cause POI. DIS3 is a 3' to 5' exoribonuclease that is the catalytic subunit of the exosome involved in RNA degradation and metabolism in the nucleus. The findings provide further evidence that mutations in genes important for transcription and translation are associated with POI.
    MeSH term(s) Animals ; Humans ; Female ; Primary Ovarian Insufficiency/genetics ; Primary Ovarian Insufficiency/pathology ; Drosophila melanogaster/genetics ; Amenorrhea/genetics ; Oogenesis/genetics ; Exosome Multienzyme Ribonuclease Complex
    Chemical Substances DIS3 protein, human (EC 3.1.13.-) ; Exosome Multienzyme Ribonuclease Complex (EC 3.1.-)
    Language English
    Publishing date 2023-03-03
    Publishing country United States
    Document type Observational Study ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/clinem/dgad126
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