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It is unknown whether pangolins, the most trafficked mammals, play a role in the zoonotic transmission of bat coronaviruses. We report the circulation of a novel MERS-like coronavirus in Malayan pangolins, named Manis javanica HKU4-related coronavirus (MjHKU4r-CoV). Among 86 animals, four tested positive by pan-CoV PCR, and seven tested seropositive (11 and 12.8%). Four nearly identical (99.9%) genome sequences were obtained, and one virus was isolated (MjHKU4r-CoV-1). This virus utilizes human dipeptidyl peptidase-4 (hDPP4) as a receptor and host proteases for cell infection, which is enhanced by a furin cleavage site that is absent in all known bat HKU4r-CoVs. The MjHKU4r-CoV-1 spike shows higher binding affinity for hDPP4, and MjHKU4r-CoV-1 has a wider host range than bat HKU4-CoV. MjHKU4r-CoV-1 is infectious and pathogenic in human airways and intestinal organs and in hDPP4-transgenic mice. Our study highlights the importance of pangolins as reservoir hosts of coronaviruses poised for human disease emergence.
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Infecciones por Coronavirus , Coronavirus , Dipeptidil Peptidasa 4 , Pangolines , Animales , Humanos , Ratones , Quirópteros , Infecciones por Coronavirus/veterinaria , Infecciones por Coronavirus/virología , Dipeptidil Peptidasa 4/genética , Dipeptidil Peptidasa 4/metabolismo , Endopeptidasas/metabolismo , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/metabolismo , Péptido Hidrolasas/metabolismo , Receptores Virales/metabolismo , Internalización del Virus , Coronavirus/fisiologíaRESUMEN
BACKGROUND: With the increasing incidence of obesity and the childbearing-age delay among women, a debate over obesity's impacts on pregnancy and neonatal outcomes becomes hot. The potential negative effects of obesity and aging on fertility lead to an idea, whether an obese female pursuing IVF treatment can benefit from an ideal BMI achieved over a long-time weight loss process at the cost of aging? We aimed to assess the association between body mass index (BMI) and clinical or neonatal outcomes in patients undergoing in vitro fertilization (IVF) treatment, for answering whether it is necessary to lose weight first for obese patients, particularly those at advanced age. METHODS: A retrospective cohort study was performed using multicentered data from China. The women were stratified into 5 groups in terms of pre-gravid BMI (kg/m2) with the WHO obesity standard (group 1: BMI < 18.5; group 2: 18.5 ≤ BMI < 23.0; group 3: 23.0 ≤ BMI < 25.0; group 4: 25.0 ≤ BMI < 30.0; group 5: BMI ≥ 30.0). The primary outcome was cumulative live birth rate (CLBR), and other clinical and neonatal outcomes were weighed as secondary outcomes. Multivariate logistic regression analyses were carried to evaluate the association between BMI and the CLBR, or between BMI and some neonatal outcomes. Furthermore, we implemented a machine-learning algorithm to predict the CLBR based on age and BMI. RESULTS: A total of 115,287 women who underwent first IVF cycles with autologous oocytes from January 2013 to December 2017 were included in our study. The difference in the CLBR among the five groups was statistically significant (P < 0.001). The multivariate logistic regression analysis showed that BMI had no significant impact on the CLBR, while women's age associated with the CLBR negatively. Further, the calculation of the CLBR in different age stratifications among the five groups revealed that the CLBR lowered with age increasing, quantitatively, it decreased by approximately 2% for each one-year increment after 35 years old, while little difference observed in the CLBR corresponding to the five groups at the same age stratification. The machine-learning algorithm derived model showed that BMI's effect on the CLBR in each age stratification was negligible, but age's impact on the CLBR was overwhelming. The multivariate logistic regression analysis showed that BMI did not affect preterm birth, low birth weight infant, small for gestational age (SGA) and large for gestational age (LGA), while BMI was an independent risk factor for fetal macrosomia, which was positively associated with BMI. CONCLUSIONS: Maternal pre-gravid BMI had no association with the CLBR and neonatal outcomes, except for fetal macrosomia. While the CLBR was lowered with age increasing. For the IVF-pursuing women with obesity plus advanced age, rather than losing weight first, the sooner the treatment starts, the better. A multicentered prospective study with a large size of samples is needed to confirm this conclusion in the future.
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Índice de Masa Corporal , Fertilización In Vitro , Obesidad , Humanos , Femenino , Estudios Retrospectivos , Fertilización In Vitro/métodos , Embarazo , Adulto , China/epidemiología , Obesidad/terapia , Obesidad/epidemiología , Nacimiento Vivo/epidemiología , Resultado del Embarazo/epidemiología , Tasa de Natalidad , Recién Nacido , Índice de EmbarazoRESUMEN
RESEARCH QUESTION: Do fertilization rates differ between intracytoplasmic sperm injection (ICSI) cycles treated with artificial oocyte activation (AOA) using 10 µmol/l ionomycin or commercial A23187 in women at risk of failed or impaired fertilization? DESIGN: This single-centre, 7-year retrospective cohort study included 157 couples with a history of total fertilization failure (TFF, 0%) or low fertilization (<30%) after ICSI, or with severe oligo-astheno-teratozoospermia (OAT) in the male partner. Couples and underwent 171 ICSI-AOA cycles using either 10 µmol/l ionomycin or commercial A23187. The embryological and clinical outcomes were compared. RESULTS: Fertilization rates in the ionomycin group were significantly higher than those in the A23187 group for all three subgroups (TFF, 46.9% versus 28.4%, Pâ¯=â¯0.002; low fertilization, 67.7% versus 49.2%, P < 0.001; severe OAT, 66.4% versus 31.6%, P < 0.001). AOA with ionomycin significantly increased the day 3 cleavage rate (Pâ¯=â¯0.009) when compared with A23187 in the low fertilization group, but not in the TFF or severe OAT group (both P > 0.05). The rates of day 3 good-quality embryos, clinical pregnancy, implantation and live birth, and the cumulative live birth, did not differ between the two groups (all P > 0.05). A total of 64 live births resulted in 72 healthy babies born. CONCLUSIONS: AOA with 10 µmol/l ionomycin may be more effective than commercial A23187 in improving oocyte activation in patients at risk of failed or impaired fertilization, especially in cases of sperm-related defects.
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Oocitos , Semen , Embarazo , Humanos , Masculino , Femenino , Ionomicina/farmacología , Calcimicina , Estudios Retrospectivos , Fertilización , Índice de EmbarazoRESUMEN
BACKGROUND: To compare the aneuploidy rate in spontaneous abortion chorionic villus (SA-CV) after D5 and D6 thawed-frozen blastocyst transfer(TBT). METHODS: This retrospective cohort study recruited 522 patients with early spontaneous abortion from March 2012 to January 2020 in the our center. The aneuploidy rate of SA-CV was compared according to the blastocyst development stage: D5 group (n = 398) and D6 group (n = 124). RESULTS: Patients' characteristics, including age, body mass index, follicle-stimulating hormone, fertilization methods, type of infertility, infertility duration, and gestational age when abortion, did not differ between the two groups (all P > 0.05). Although the mean number of embryos was significantly higher in D6 than in the D5 group (P < 0.001), the mean number of high-quality embryos was similar (P = 0.773). In the D5 group, 46.5% of SA-CV showed aneuploidy, which was comparable to 41.1% in the D6 group (P = 0.296). After further grouping according to age (> 35 years or ≤ 35 years), the difference between the D5 and D6 groups remained not statistically significant (P = 0.247 and P = 0.690). Multivariate logistic analysis showed that women's age was independently associated with the aneuploidy rate (OR = 0.891; 95% CI: [0.854-0.930]; P < 0.001). The rate of chromosomal aneuploidy was significantly higher in the age > 35 years group than in the age ≤ 35 years group (61.0% vs. 39.4%, P < 0.001). Other factors, including blastocyst formation speed, were not significant predictors of aneuploidy rate. CONCLUSIONS: The rate of chromosomal aneuploidy in SB-CV after D6 TBT was comparable to that after D5 TBT. Chromosomal aneuploidy may not be a main factor contributing to the high prevalence early pregnancy loss at D6 group.
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Aborto Espontáneo , Infertilidad , Embarazo , Humanos , Femenino , Adulto , Aborto Espontáneo/epidemiología , Vellosidades Coriónicas , Estudios Retrospectivos , Aneuploidia , Transferencia de EmbriónRESUMEN
Identifying phosphorus (P) sources and contributions from terrestrial sources is important for clean water and eutrophication management in lake watersheds. However, this remains challenging owing to the high complexity of P transport processes. The concentrations of different P fractions in the soils and sediments from Taihu Lake, a representative freshwater lake watershed, were obtained using sequential extraction procedure. The dissolved phosphate (PO4-P) and alkaline phosphatase activity (APA) in the lake's water were also surveyed. The results showed that different P pools in the soil and sediments displayed different ranges. Higher concentrations of P fractions were measured in the solid soils and sediments from the northern and western regions of the lake watershed, indicating a larger input of P from exogenous sources, including agriculture runoff and industrial effluent from the river. Generally, higher Fe-P and Ca-P concentrations of up to 399.5 and 481.4 mg/kg were detected in soils and lake sediments, respectively. Similarly, the lake's water had higher concentrations of PO4-P and APA in the northern region. A significant positive correlation was found between Fe-P in the soil and PO4-P concentrations in the water. Statistical analysis indicated that appropriately 68.75% P was retained in the sediment from terrigenous sources, and 31.25% P experienced dissolution and shifted to the solution phase in the water-sediment ecosystems. The dissolution and release in Fe-P in the soils were responsible for the increase of Ca-P in the sediment after the afflux of soils into the lake. These findings suggest that soil runoff predominantly controls P occurrence in lake sediments as an exogenous source. Generally, the strategy of reducing terrestrial inputs from agricultural soil discharge is still an important step in P management at the catchment scale of lakes.
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Lagos , Contaminantes Químicos del Agua , Fósforo/análisis , Ecosistema , Sedimentos Geológicos , Monitoreo del Ambiente/métodos , Suelo , Agua/análisis , China , Contaminantes Químicos del Agua/análisis , EutrofizaciónRESUMEN
BACKGROUND: Both mild and conventional controlled ovarian stimulation are the frequently used protocols for poor ovarian responders. However, there are some debates about which treatment is better. Moreover, little is known about the follicular physiology after the two ovarian stimulation protocols. This study was intended to investigate the features in granulosa cells and follicular fluid micro-environment after the two different ovarian stimulation protocols in poor responders. METHODS: Granulosa cells RNA were sequenced using Illumina Hiseq technology. Specific differently expressed genes and proteins were verified by real-time quantitative PCR and Western blot analysis. Moreover, hormone and cytokine concentrations in the follicular fluid were measured by electrochemiluminescence immunoassay and enzyme-linked immunoabsorbent assay. The correlation between the results of molecular experiments and the laboratory outcomes were analyzed by Spearman correlation analysis. RESULTS: The differentially expressed genes between the two groups were involved in 4 signaling pathways related to the follicular development; three proteins pertinent to the TGF-ß signaling pathway were expressed differently in granulosa cells between the two, and the constituents in the follicular fluid were also different. Further, a correlation between the TGF-ß signaling pathway and the good-quality embryo was observed. CONCLUSIONS: The present study made a comparison for the first time in the transcriptome of human granulosa cells and the follicular fluid micro-environment between poor responders with the conventional controlled ovarian stimulation or the mild ovarian stimulation, showing that the TGF-ß signaling pathway may correlate with the good-quality of embryos in the mild group, which may be instrumental to the choice of optimal management for IVF patients.
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Líquido Folicular/metabolismo , Células de la Granulosa/metabolismo , Infertilidad Femenina/genética , Inducción de la Ovulación/métodos , Transcriptoma , Adulto , Estudios de Casos y Controles , Microambiente Celular/genética , Femenino , Líquido Folicular/química , Perfilación de la Expresión Génica , Células de la Granulosa/química , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Infertilidad Femenina/metabolismo , Infertilidad Femenina/fisiopatología , Recuperación del Oocito , Reserva Ovárica/genética , Ovulación/genética , Análisis de Secuencia de ADN , Insuficiencia del TratamientoRESUMEN
BACKGROUND: Trachypithecus leucocephalus, the white-headed langur, is a critically endangered primate that is endemic to the karst mountains in the southern Guangxi province of China. Studying the genomic and transcriptomic mechanisms underlying its local adaptation could help explain its persistence within a highly specialized ecological niche. RESULTS: In this study, we used PacBio sequencing and optical assembly and Hi-C analysis to create a high-quality de novo assembly of the T. leucocephalus genome. Annotation and functional enrichment revealed many genes involved in metabolism, transport, and homeostasis, and almost all of the positively selected genes were related to mineral ion binding. The transcriptomes of 12 tissues from three T. leucocephalus individuals showed that the great majority of genes involved in mineral absorption and calcium signaling were expressed, and their gene families were significantly expanded. For example, FTH1 primarily functions in iron storage and had 20 expanded copies. CONCLUSIONS: These results increase our understanding of the evolution of alkali tolerance and other traits necessary for the persistence of T. leucocephalus within an ecologically unique limestone karst environment.
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Colobinae , Álcalis , Animales , China , Genoma , Presbytini , TranscriptomaRESUMEN
Human spermatozoa can fertilize an oocyte only after post-testicular maturation and capacitation. These processes involve dynamic modification and reorganization of the sperm plasma membrane, which allow them to bind to the zona pellucida (ZP) of the oocyte. Defective sperm-ZP binding is one of the major causes of male subfertility. Galectin-3 is a secretory lectin in human seminal plasma well known for its action on cell adhesion. The aim of this study was to determine the role of galectin-3 in spermatozoa-ZP interaction and its association with fertilization rate in clinical assisted reproduction. Our studies revealed that the acrosomal region of ejaculated and capacitated spermatozoa possess strong galectin-3 immunoreactivity, which is much stronger than that of epididymal spermatozoa. Expression of galectin-3 can also be detected on seminal plasma-derived extracellular vesicles (EVs) and can be transferred to the sperm surface. Blocking of sperm surface galectin-3 function by antibody or carbohydrate substrate reduced the ZP-binding capacity of spermatozoa. Purified galectin-3 is capable of binding to ZP, indicating that galectin-3 may serve as a cross-linking bridge between ZP glycans and sperm surface glycoproteins. Galectin-3 levels in seminal plasma-derived EVs were positively associated with fertilization rates. These results suggest that galectin-3 in EVs is transferred to the sperm surface during post-testicular maturation and plays a crucial role in spermatozoa-ZP binding after capacitation. Reduced galectin-3 expression in seminal plasma-derived EVs may be a cause behind a low fertilization rate. Further studies with more clinical samples are required to confirm the relationship between galectin-3 levels and IVF outcomes.
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Fertilización/fisiología , Galectina 3/metabolismo , Zona Pelúcida/metabolismo , Reacción Acrosómica/genética , Reacción Acrosómica/fisiología , Adhesión Celular/fisiología , Fertilización/genética , Galectina 3/genética , Humanos , Masculino , Oocitos/metabolismo , Semen/metabolismo , Capacitación Espermática/fisiología , Interacciones Espermatozoide-Óvulo/genética , Interacciones Espermatozoide-Óvulo/fisiología , Espermatozoides/metabolismoRESUMEN
PURPOSE: To evaluate the efficacy in suppressing the premature LH surge, embryo quality and pregnancy outcomes of progestin-primed ovarian stimulation (PPOS) protocols using medroxyprogesterone acetate versus utrogestan in women of all ages undergoing in vitro fertilization or intracytoplasmic sperm injection. METHODS: 1188 patients were enrolled in the retrospective study, of which 1002 patients were treated with medroxyprogesterone acetate (M group) and recombinant follicle-stimulating hormone (r-FSH)simultaneously from day 3 of the cycle until trigger day, while 186 patients were treated with utrogestan (U group) and r-FSH instead. Viable embryos were cryopreserved for later transfer in both groups. Differences in baseline characteristics, ovarian stimulation characteristics, endocrinological characteristics, embryo development and clinical outcome between two groups were assessed. Statistical analyses were performed stratified by age and number of oocytes retrieved. RESULTS: No significant differences were observed in the baseline characteristics, ovarian stimulation characteristics and clinical outcome of patients between groups. However, blastulation rate in the U group was significantly higher than that in the M group (49.4% vs. 32.9%, P < 0.001). During ovarian stimulation, LH levels remained steady in both groups. Higher percentage of premature LH surge was found in the U group (2.4% vs. 10.2%, P < 0.001), especially for patients aged more than 35 years or who had three oocytes or less retrieved. CONCLUSIONS: Both the administration of medroxyprogesterone acetate and utrogestan in PPOS were sufficient to prevent an untimely LH rise, while for patients with poor ovarian response or aged above 35 years, MPA may result in a more satisfactory LH level. PPOS protocol using medroxyprogesterone acetate or utrogestan was comparable in terms of oocytes and pregnancy outcome, whereas the administration of utrogestan may result in an improved blastulation than medroxyprogesterone acetate, which needs further exploration.
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Fertilización In Vitro/métodos , Inducción de la Ovulación/métodos , Progestinas/farmacología , Inyecciones de Esperma Intracitoplasmáticas/métodos , Adulto , Femenino , Humanos , Acetato de Medroxiprogesterona/farmacología , Embarazo , Progesterona/análogos & derivados , Progesterona/farmacología , Estudios RetrospectivosRESUMEN
The purpose of this study is to determine whether all-blastocyst-culture can benefit advanced maternal age (AMA) patients with low ovarian reserve. We retrospectively analyze AMA patients with low ovarian reserve undergoing IVF/ICSI in Reproductive Medicine Research Center of the Sixth Affiliated Hospital of Sun Yat-sen University from May 2016 to August 2017. We divide them into group A (all-blastocyst-culture) and group B (none-blastocystculture) based on different culture approach of D3 transferrable embryo. We compared the cumulative biochemical pregnancy rate and cumulative clinical pregnancy rate between them. A total of 261 eligible patients are included, with 151 in group A and 110 in group B. The basic conditions of the two groups show no difference. Cumulative biochemical pregnancy rate/clinical pregnancy rate in group A is higher than that of group B, though not statistically significant (p > .05). After removing patients canceling embryo transfer due to failure in blastocyst culture, the cumulative biochemical pregnancy rate/clinical pregnancy rate in group A is significantly higher than group B (p < .05). Multivariate analysis showed that female age and the number of D3 transferrable embryo are risk factors for the failure of blastocyst culture (OR = 0.672 and 2.270, 95%CI 0.511-0.883 and 1.203-4.284, p = .004 and p = .011, respectively). Hence, we drew to conclusion that all-blastocyst-culture will not adversely affect the pregnancy outcome of AMA patients with low ovarian reserve.
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Técnicas de Cultivo de Embriones/métodos , Fertilización In Vitro/métodos , Edad Materna , Reserva Ovárica , Adulto , Toma de Decisiones , Transferencia de Embrión , Femenino , Humanos , Persona de Mediana Edad , Inducción de la Ovulación , Embarazo , Resultado del Embarazo , Índice de Embarazo , Estudios RetrospectivosRESUMEN
TGF-beta induces phosphorylation of the transcription factors Smad2 and Smad3 at the C terminus as well as at an interdomain linker region. TGF-beta-induced linker phosphorylation marks the activated Smad proteins for proteasome-mediated destruction. Here, we identify Nedd4L as the ubiquitin ligase responsible for this step. Through its WW domain, Nedd4L specifically recognizes a TGF-beta-induced phosphoThr-ProTyr motif in the linker region, resulting in Smad2/3 polyubiquitination and degradation. Nedd4L is not interchangeable with Smurf1, a ubiquitin ligase that targets BMP-activated, linker-phosphorylated Smad1. Nedd4L limits the half-life of TGF-beta-activated Smads and restricts the amplitude and duration of TGF-beta gene responses, and in mouse embryonic stem cells, it limits the induction of mesoendodermal fates by Smad2/3-activating factors. Hierarchical regulation is provided by SGK1, which phosphorylates Nedd4L to prevent binding of Smad2/3. Previously identified as a regulator of renal sodium channels, Nedd4L is shown here to play a broader role as a general modulator of Smad turnover during TGF-beta signal transduction.
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Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Proteína Smad2/metabolismo , Proteína smad3/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Ubiquitina-Proteína Ligasas/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Células Cultivadas , Células Madre Embrionarias/citología , Células Madre Embrionarias/efectos de los fármacos , Células Madre Embrionarias/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/genética , Células HeLa , Humanos , Proteínas Inmediatas-Precoces/genética , Proteínas Inmediatas-Precoces/metabolismo , Immunoblotting , Ratones , Datos de Secuencia Molecular , Ubiquitina-Proteína Ligasas Nedd4 , Fosforilación/efectos de los fármacos , Poliubiquitina/metabolismo , Unión Proteica , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Interferencia de ARN , Homología de Secuencia de Aminoácido , Transducción de Señal , Proteína Smad2/genética , Proteína smad3/genética , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
BACKGROUND: Many studies have found an association between mood-disorder-related traits and endometriosis and adenomyosis. However, the cause-effect relationship remains unclear. AIMS: We conducted Mendelian randomisation analyses to evaluate any causal relationship between mood disorders and endometriosis as well as different sites of endometriosis. METHOD: Summary-level statistics for mood-disorder-related traits and endometriosis (8288 cases, 68 969 controls) in European populations were derived from large-scale data-sets of genome-wide association studies. A two-sample Mendelian randomisation was performed using the inverse-variance weighted and weight median methods. Further sensitivity analyses, including heterogeneity, pleiotropy and leave-one-out analyses, were conducted to test the consistency of the results. RESULTS: Genetically determined mood swings (odds ratio = 2.557, 95% CI: 1.192-5.483, P = 0.016) and major depression (odds ratio = 1.233, 95% CI: 1.019-1.493, P = 0.031) were causally associated with an increased risk of endometriosis. Mood swings (odds ratio = 4.238, 95% CI: 1.194-15.048, P = 0.025) and major depression (odds ratio = 1.512, 95% CI: 1.052-2.173, P = 0.025) were also causally associated with the risk of adenomyosis. Sensitivity analyses confirmed the reliability of the results. CONCLUSIONS: Our results suggest that mood-disorder-related traits increase the risk of endometriosis and adenomyosis. This study provides new insights into the potential pathogenesis of endometriosis and adenomyosis, and highlights the importance of preventing endometriosis and adenomyosis in patients with mood-disorder-related traits.
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OBJECTIVE: The probability of embryo implantation in an abnormal location is significantly higher in assisted reproductive technology (ART) than in natural pregnancies. Angular pregnancy is an eccentric intrauterine pregnancy with embryo implantation in the lateral superior angle of the uterine cavity. Cycle-level factors associated with angular pregnancy in patients conceived with ART needed to be explored. METHODS: A total of 11 336 clinical pregnancies cycles were included. Angular pregnancy rate was compared among groups according to the type of embryos transferred. Among them, 53 cases of angular pregnancy and 159 cases of normal intrauterine pregnancy were screened out using propensity score matching. Risk factors of angular pregnancy were explored. RESULTS: The angular pregnancy rate was 0.31% (14/4572) in the day 5 blastocyst transfer group, 0.58% (39/6764) in non-day 5 embryo transfer group, with 0.55% (29/5280) in day 3 embryo transfer and 0.67% (10/1484) in the day 6 blastocyst group, respectively. A multifactor regression analysis was performed and indicated that the number of embryos transferred was significantly associated with angular pregnancy (P = 0.031, OR, 2.23, 95% CI: 1.09-4.68). CONCLUSION: Multiple embryo transfer could possibly be associated with an increased incidence of angular pregnancy in patients conceived with ART.
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Embarazo Angular , Embarazo Múltiple , Embarazo , Femenino , Humanos , Fertilización In Vitro , Transferencia de Embrión/efectos adversos , Índice de Embarazo , Blastocisto , Estudios RetrospectivosRESUMEN
Background: Malignant tumors, mainly solid tumors, are a significant obstacle to the improvement of life expectancy at present. Epithelial cell adhesion molecule (EpCAM), a cancer stem cell biomarker, showed widespread expression in most normal epithelial cells and most cancers. Although the clinical significance of EpCAM in various malignant solid tumors has been studied extensively, the latent relationships between EpCAM and pathological and clinical characteristics in solid tumors and differences in the roles of EpCAM among tumors have not been clearly determined. The destination point of this study was to analyze the value of EpCAM in solid tumors in clinicopathological and prognostic dimension using a meta-analysis approach. Method and materials: A comprehensive and systematic search of the researches published up to March 7th, 2022, in PubMed, EMBASE, Web of Science, Cochrane library and PMC databases was performed. The relationships between EpCAM overexpression, clinicopathological characteristics, and survival outcomes were analyzed. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) and odds ratios (ORs) were estimated as indicators of the degree of correlation. This research was registered on PROSPERO (International prospective register of systematic reviews), ID: CRD42022315070. Results: In total, 57 articles and 14184 cases were included in this study. High EpCAM expression had a significant coherence with a poorer overall survival (OS) (HR: 1.30, 95% CI: 1.08-1.58, P < 0.01) and a worse disease-free survival (DFS) (HR: 1.58, 95% CI: 1.28-1.95, P < 0.01), especially of gastrointestinal tumors' OS (HR: 1.50, 95% CI: 1.15-1.95, P < 0.01), and DFS (HR: 1.84, 95% CI: 1.52-2.33, P < 0.01). The DFS of head and neck tumors (HR: 2.33, 95% CI: 1.51-3.61, P < 0.01) was also associated with the overexpression of EpCAM. There were no positive relationships between the overexpression of EpCAM and sex (RR: 1.03, 95% CI: 0.99-1.07, P = 0.141), T classification (RR: 0.93, 95% CI: 0.82-1.06, P = 0.293), lymph node metastasis (RR: 0.85, 95% CI: 0.54-1.32, P = 0.461), distant metastasis (RR: 0.97, 95% CI: 0.84-1.10, P = 0.606), vascular infiltration (RR: 1.05, 95% CI: 0.85-1.29, P = 0.611), and TNM stage (RR: 0.93, 95% CI: 0.83-1.04, P = 0.187). However, the overexpression of EpCAM exhibited a significant association with the histological grades (RR: 0.88, 95% CI: 0.80-0.97, P < 0.01). Conclusion: Based on pooled HRs, the positive expression of EpCAM was totally correlated to a worse OS and DFS in solid tumors. The expression of EpCAM was related to a worse OS in gastrointestinal tumors and a worse DFS in gastrointestinal tumors and head and neck tumors. Moreover, EpCAM expression was correlated with the histological grade. The results presented pointed out that EpCAM could serve as a prognostic biomarker for gastrointestinal and head and neck tumors. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42022315070.
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Embryo implantation is a key step in human reproduction, and the endometrium plays a key role in this process. Changes in the receptive state of the endometrium are one of the main reasons for embryo implantation failure. However, the mechanism underlying the altered endometrial receptivity remains unclear. In this study, we recruited 140 women undergoing assisted reproductive technology and divided them into a shifting group and a normal group based on their embryo implantation window results. Endometrial transcriptome data suggested that changes in the remodeling process of decidual spiral arterioles and changes in the immune environment might be important mechanisms of implantation window shift. The functional enrichment analysis results also suggested that the changes in microbiota had an important role in the changes in endometrial status. The endometrial functionally active microbial profiles were obtained based on previously validated metatranscriptomic analysis pipelines. Combining host gene expression information, immune cell abundance information and functionally active microbial abundance and activity information, we found that Treponema succinifaciens, Fusobacterium sp. oral taxon 203 and other potentially harmful species may over-activate Eicosapentaenoic acid (EPA) biosynthesis Thus, the balance of the immune environment of the endometrium is disrupted, resulting in the shift of the implantation window and the failure of embryo implantation.
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Ácido Eicosapentaenoico , Endometrio , Femenino , Humanos , Ácido Eicosapentaenoico/metabolismo , Implantación del Embrión , Homeostasis , TranscriptomaRESUMEN
Acute liver injury (ALI) is characteristic of abrupt hepatic dysfunction and inflammatory response, and currently the main treatment for ALI is merely supportive rather than curative. Therefore, the development of novel and effective therapeutic strategies for ALI therapy is highly desirable. The emerging biological understanding of the role of BET Bromodomains has opened up an exciting opportunity to develop potent BET Bromodomain inhibitors as an effective therapeutic strategy for the treatment of acute liver injury. Herein, we synthesized a series of potent BET Bromodomain inhibitors with a tetracyclic scaffold, exemplified by compound 28 which showed good in vitro anti-inflammatory activity and good therapeutic effects in the LPS-induced acute liver injury model without obvious cytotoxicity, suggesting that compound 28 is a highly promising candidate worthy for further development.
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Antiinflamatorios , Factores de Transcripción , Factores de Transcripción/metabolismo , Ciclización , Dominios Proteicos , Hígado/metabolismoRESUMEN
Introduction: Understanding the gut microbiota and antibiotic resistance gene (ARG) profiles in non-human primates (NHPs) is crucial for evaluating their potential impact on human health and the environment. Methods: In this study, we performed metagenomic analysis of 203 primate fecal samples, including nine NHP species and humans, to comprehensively characterize their gut microbiota and ARGs. Results: Our study reveals the prevailing phyla in primates as Firmicutes, Bacteroidetes, Euryarchaeota, and Proteobacteria. The captive NHPs exhibited higher ARG abundance compared to their wild counterparts, with tetracycline and beta-lactam resistance genes prevailing. Notably, ARG subtypes in Trachypithecus leucocephalus (T. leucocephalus) residing in karst limestone habitats displayed a more dispersed distribution compared to other species. Interestingly, ARG profiles of NHPs clustered based on geographic location and captivity status. Co-occurrence network analysis revealed intricate correlations between ARG subtypes and bacterial taxa. Procrustes analysis unveiled a significant correlation between ARGs and microbial phylogenetic community structure. Taxonomic composition analysis further highlighted differences in microbial abundance among NHPs and humans. Discussion: Our study underscores the impact of lifestyle and geographical location on NHP gut microbiota and ARGs, providing essential insights into the potential risks posed by NHPs to antibiotic resistance dissemination. This comprehensive analysis enhances our understanding of the interplay between NHPs and the gut resistome, offering a critical reference for future research on antibiotic resistance and host-microbe interactions.
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A T50I substitution in the K-Ras interswitch domain causes Noonan syndrome and emerged as a third-site mutation that restored the in vivo transforming activity and constitutive MAPK pathway activation by an attenuated KrasG12D,E37G oncogene in a mouse leukemia model. Biochemical and crystallographic data suggested that K-RasT50I increases MAPK signal output through a non-GTPase mechanism, potentially by promoting asymmetric Ras:Ras interactions between T50 and E162. We generated a "switchable" system in which K-Ras mutant proteins expressed at physiologic levels supplant the fms like tyrosine kinase 3 (FLT3) dependency of MOLM-13 leukemia cells lacking endogenous KRAS and used this system to interrogate single or compound G12D, T50I, D154Q, and E162L mutations. These studies support a key role for the asymmetric lateral assembly of K-Ras in a plasma membrane-distal orientation that promotes the formation of active Ras:Raf complexes in a membrane-proximal conformation. Disease-causing mutations such as T50I are a valuable starting point for illuminating normal Ras function, elucidating mechanisms of disease, and identifying potential therapeutic opportunities for Rasopathy disorders and cancer.
Asunto(s)
Leucemia , Proteínas Proto-Oncogénicas p21(ras) , Animales , Ratones , Modelos Animales de Enfermedad , Células Germinativas , Mutación de Línea Germinal , Mutación , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas rasRESUMEN
The purpose of this study was to compare two embryo culture strategies in older women with four or fewer D3 embryos. A total of 556 eligible patients aged >38 years in a single reproductive centre underwent IVF/ICSI leading to the generation of four or fewer D3 embryos from April 2016 to October 2018. Patients whose D3 embryos were all cultured to blastocyst were classified as group A; those in which none of their embryos was cultured to blastocysts were classified as group B. Cumulative biochemical pregnancy rate, clinical pregnancy rate and live birth rate were similar between the two groups (p = 0.582, 0.426 and 0.546, respectively). Though more embryo transfer cycles were achieved in group B, significantly higher biochemical and clinical pregnancy rate per embryo transfer cycle were found in group A (p = 0.001 and 0.003). In patients with blastocyst culture, the clinical conditions of those who had a successful outcome were better than those who failed. Blastocyst culture and transfer can significantly increase pregnancy rate per embryo transfer cycle and may be appropriate in some older patients with a good clinical prognosis.
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Blastocisto , Transferencia de Embrión , Anciano , Técnicas de Cultivo de Embriones , Femenino , Fertilización In Vitro , Humanos , Embarazo , Índice de Embarazo , Estudios RetrospectivosRESUMEN
Cesarean section scar diverticulum (CSD) has become a formidable obstacle preventing women receiving CS from reproducing. However, the pathogenesis of CSD remains unexplored. In this study, we characterized the cervical microbiota, metabolome, and endometrial transcriptome of women with CSD. Based on the 16s rRNA results of cervical microbes, the microbial diversity in the CSD group was higher than that in the control group. Lactobacillus were significantly decreased in the CSD group and were mutually exclusive with potentially harmful species (Sphingomonas, Sediminbacterium, and Ralstonia) abnormally elevated in CSD. The microbiota in the CSD group exhibited low activity in carbohydrate metabolism and high activity in fatty acid metabolism, as confirmed by the metabolomic data. The metabolomic characterization identified 6,130 metabolites, of which 34 were significantly different between the two groups. In the CSD group, N-(3-hydroxy-eicosanoid)-homoserine lactone and Ternatin were significantly increased, in addition to the marked decrease in fatty acids due to high consumption. N-(3-hydroxy-eicosanoyl)-homoserine lactone is a regulator that promotes abnormal apoptosis in a variety of cells, including epithelial cells and vascular endothelial cells. This abnormal apoptosis of endometrial epithelial cells and neovascularization was also reflected in the transcriptome of the endometrium surrounding the CSD. In the endometrial transcriptome data, the upregulated genes in the CSD group were active in negatively regulating the proliferation of blood vessel endothelial cells, endothelial cells, and epithelial cells. This alteration in the host's endometrium is most likely influenced by the abnormal microbiota, which appears to be confirmed in the results by integrating host transcriptome and microbiome data. For the first time, this study described the abnormal activity characteristics of microbiota and the mechanism of host-microbiota interaction in CSD. IMPORTANCE Cesarean section scar diverticulum (CSD) has become a formidable obstacle preventing women receiving CS from reproducing. In this study, we revealed that potentially harmful microbes do have adverse effects on the host endometrium. The mechanism of these adverse effects includes the inhibition of the activity of beneficial bacteria such as lactobacilli, consumption of protective metabolites of the endometrium, and also the production of harmful metabolites. In the present study, we elucidated the mechanism from the perspectives of microbial, metabolic, and host responses, providing an important rationale to design preventive and therapeutic strategies for CSD.