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Pre-eclampsia (PE) is a prevalent pregnancy disease characterized by insufficient trophoblast cell migration (HTR8/SVneo). Consequently, accelerating trophoblast cell proliferation might ameliorate PE. This study assessed the effects and molecular mechanisms of Sufentanil (SUF) on HTR8/SVneo cells proliferation. HTR8/SVneo cells and PE clinical samples were used. Peripheral blood was collected from PE patients' samples, and microRNA (miR)-24-3p and 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) was analyzed in the blood and cells. HTR8/SVneo cells were treated with varying SUF concentrations or transfected with miR-24-3p mimics/inhibitors, or HSD11B2 elevation vector. CCK-8, colony formation, transwell, and flow cytometry assays were then carried out. Association of miR-24 - 3p with HSD11B2 was investigated. PE animal model was constructed using Wistar rats to verify SUF's role on PE

This study aimed to compare the value of a modified chest tube drainage strategy to a traditional drainage strategy in single-port thoracoscopic pulmonary wedge resection.From January 2019 to July 2021, we collected clinical data on 405 patients who underwent single-port thoracoscopic pulmonary wedge resection in the No.1 Department of Thoracic Surgery at Fujian Medical University Union Hospital, with 121 (29.9%) cases in the modified drainage strategy group and 284 (70.1%) cases in the traditional drainage strategy group. The propensity score matching method (Match Ratio = 1:1) was used to reduce differences in clinical characteristics between the two groups.Following 1:1 propensity score matching, 120 matched pairs (240 patients) were included in the study. There was no significant difference in general clinical characteristics between the two groups. There was no statistical difference in intraoperative factors except for operative times (71.42 ± 22.98 min vs. 86.80 ± 36.75 min, p 0.001). In terms of postoperative factors, there were significant differences in postoperative chest tube duration (0.00 ± 0.00 h vs. 32.68 ± 18.51 h, p 0.001), total drainage volume (143.03 ± 118.33 ml vs. 187.73 ± 140.82 ml, p = 0.008), postoperative hospital stay (2.61 ± 0.70 days vs. 3.27 ± 1.88 days, p 0.001), number of additional pain relief (0.14 ± 0.40 vs. 0.42 ± 0.74, p 0.001), facial pain score (2.7 ± 1.8 vs. 3.6 ± 2.7, p = 0.005) and adverse events (p = 0.046). Furthermore, there was a statistical difference between the two groups regarding CTCAE grade-1 complication, but no statistical difference in CTCAE grade-2 complication.A modified drainage strategy in single-port thoracoscopic pulmonary wedge resection is safe and feasible, allowing for less postoperative rehabilitation time, pain relief, reduced postoperative pleural effusion, and reduced clinical workload.

Background Abnormal maternal lipid concentrations are associated with increased risk of preeclampsia. However, previous studies mainly focused on fasting lipid concentrations, scarce data have been published on the relationship between postprandial triglyceride (TG) concentrations in the second trimester and the risk of preeclampsia. Our aim is to evaluate the potential of triglyceride (TG) concentrations at the time of oral lipid tolerance test (OLTT) measurement in the second trimester to predict preeclampsia and to elucidate the lipid metabolic changes related to these diseases. Methods This is a prospective cohort study of Pregnant women at 12–24 weeks of gestation undergone an OLTT in a university affiliated hospital between May 2019 and January 2020. Data were stratified into binaries according to the OLTT results. The receiver operating characteristic (ROC) curve analysis was conducted to determine the optimal cut-off points of TG, HDL-C, LDL-C, sd-LDL, FFA, and BG for predicting preeclampsia. Results 438 pregnant women were recruited to undergo an OLTT at 12–24 weeks of gestation. Among these, 24 women developed preeclampsia and 414 women remained normotensive. Women who subsequently developed preeclampsia had higher concentrations of 4-h postprandial TG than those who remained normotensive. In the linear logistic regression analyses of potential confounding factors, mid-trimester 4-h postprandial TG concentrations at the time of OLTT measurement were significantly higher in preeclamptic cases than in controls. Conclusions Dyslipidemia in the second trimester of pregnancy, particularly postprandial hypertriglyceridemia, appears to be associated with an increased risk of preeclampsia. Mid-trimester 4-h postprandial TG concentration at the time of OLTT measurement may be a potential predictive marker of preeclampsia. Trial registration Data of registration: 2018/10/15. Date of initial participant enrollment: 2019/05/01. Clinical trial identification number: chiCTR1800018884. URL of the registration site: http://www.chictr.org.cn/showproj.aspx?proj=25526. Data sharing information: The data including individual participant data, detailed study protocols, statistical analysis plans will be shared upon request to the corresponding author.

Objective To evaluate serum protein calponin 2 (CNN2) as a candidate biomarker for tubal ectopic pregnancy (EP). Design Retrospective study. Setting Single University affiliated tertiary hospital. Patient(s) Serum samples were obtained from 84 patients with EP, 39 with viable intrauterine pregnancy (vIUP), and 42 with miscarriage. Moreover, 10 fallopian tube and corresponding villous tissue samples from patients with EP, 6 villous tissue samples from patients with vIUP, and 10 villous tissue samples from patients with miscarriage were collected. Intervention(s) Serum CNN2 concentrations were measured using enzyme-linked immunosorbent assay; CNN2 expression in tissues was evaluated via immunohistochemistry and quantitative real-time polymerase chain reaction analysis. Main Outcome Measure(s) The diagnostic performance of serum CNN2 to discriminate an EP from vIUP and miscarriage. Result(s) CNN2 was highly expressed in villous stromal cells isolated from patients with EP, and CNN2 messenger ribonucleic acid expression was upregulated in villous tissues from women with EP compared with that in women with vIUPs and miscarriages. Serum CNN2 concentration was higher in women with EP than that in women with vIUP and miscarriage. The serum CNN2 predicted EP from vIUP and miscarriage with areas under the curve (AUCs) of 0.931 (95% confidence interval: 0.889–0.975). For discriminating EP from miscarriage only, the AUC was 0.906 (95% confidence interval: 0.835–0.977). In contrast, the AUCs for serum human chorionic gonadotropin were 0.809 and 0.637, respectively. Conclusion(s) Our data highlight the possibility of serum CNN2 as a single biomarker for the diagnosis of EP. Clinical Trial Registration Number ChiCTR 1900020483

Skeletal remains encountered frequently in forensic applications are a challenging specimen, since their DNA is usually degraded due to harsh conditions, limiting the utilization of skeletal DNA. Forensic scientists have tried various methods to extract DNA from skeletal remains of low quantity and poor quality or improve detecting technology for more information from compromised DNA. Compared with traditional capillary electrophoresis (CE), massively parallel sequencing (MPS) is more sensitive to shorter fragments, able to detect allele sequences for variations from core motif or flanking regions, and able to detect more markers with a higher discrimination power. In this study, short tandem repeats (STR) and single nucleotide polymorphisms (SNP) from 35 human skeletons were genotyped by MPS platform, and CE method was also used to perform STR genotyping. The results indicated that the detection rates reached 100.00% in 16 of 35 samples with MPS method, while the same 100.00% was reached in only 9 samples with CE. The success rates of MPS were also higher than that of CE method in shared 21 loci (excluding Y-indel, DYS391, and SE33), especially in loci detected by MPS method only. Besides, all SNPs (124 and 90 SNPs in males and females) were detected in 18 samples of 35 samples by MPS method. Some intra-allelic sequence variants were observed in eight loci (D21S11, D8S1179, D5S2800, D3S1358, vWA, D2S1338, D1S1656, D12S391) using MPS technology. Interestingly, there is a sample showing genotyping disagreement in FGA locus. The clone sequencing verified that a "T" deletion discovered in flanking sequence of FGA led to wrong genotyping on Ampliseq Converge. Our results indicated that MPS could be adopted in qualified labs as a supplementary when the DNA of skeletal remains are hard to identify.

Aim To evaluate the value and feasibility of capillary glucose assessment, combined with other non-laboratory measures, in screening for diabetes and prediabetes in the community. Methods In this cross-sectional study, we assessed fasting capillary glucose, fasting plasma glucose, and both capillary glucose and plasma glucose values after 2-h oral glucose tolerance tests in a total of 3736 samples. We determined the optimal threshold of capillary glucose using receiver-operating characteristic curve analysis. The effect of screening methods using capillary glucose combined with other variables, such as age, BMI and waist circumference, was assessed according to area under the receiver-operating characteristic curve. Results There was a strong positive correlation between capillary glucose and venous plasma glucose. The area under the curve for the model using fasting capillary glucose to screen for impaired fasting glucose was 0.722, while that for the model using capillary glucose after a 2-h oral glucose tolerance test to screen for impaired glucose tolerance was 0.916. The area under the curve for the model using fasting capillary glucose to screen for diabetes was 0.835, while that for the model using 2-h oral glucose tolerance test capillary glucose was 0.912. The area under the curve for the model using fasting capillary glucose + 2-h oral glucose tolerance test capillary glucose to screen for diabetes was 0.945. The discriminatory capability of models using capillary glucose was somewhat improved by adding non-laboratory variables. Conclusions Capillary glucose could be an alternative for screening for diabetes and prediabetes, especially in low-resource areas.

Backgroud: The present study aimed to investigate the association between immune cells and gestational diabetes mellitus (GDM) and identify a reasonable predictor of insulin resistance in women with GDM. Objective: The clinical and biochemical characteristics of 124 women with GDM and 168 healthy pregnant women were compared. Methods: The percentage of immune cells in the blood of the subjects was analyzed by flow cytometry. Pearson’s correlation analysis revealed the correlation between the percentage of B lymphocytes and insulin resistance. A cutoff point was determined for the percentage of B lymphocytes, based on insulin resistance, using receiver operating characteristic (ROC) curves. Results: Compared to the healthy pregnant women, the percentages of B lymphocytes and IgA produced by B-cells were significantly different in women with GDM. The percentage of B lymphocytes was positively related to insulin resistance.The number of 14.05% of B lymphocytes was an optimal cutoff point that predicted the insulin resistance in women with GDM. Conclusion: The percentage of B lymphocytes was positively associated with insulin resistance, and hence, might serve as an appropriate predictor of insulin resistance in women with GDM.

Background Human Ectopic Pregnancy (hEP) is the second most common cause of pregnancy-related deaths in the first trimester. Without timely detection, EPs can lead to an increased rate of infertility and an elevated risk for future tubal EPs. In addition, most studies in the field focus on the effect of the fallopian tube (maternal factors) and ignore epigenetic changes in genes and proteins of the embryo, which may also cause EPs. Therefore, the present study hypothesized that embryos also play an important role in the development of EP. The study also speculated that DNA methylation is associated with ectopic pregnancy. Consequently, the effects of DNA methylation on the occurrence and development of ectopic pregnancy were investigated. Moreover, genome-wide DNA methylation of chorionic tissue from ectopic and intrauterine pregnancies was detected using Illumina HumanMethylation450 arrays. Results Forty-three hypermethylated genes involved in the regulation of adhesion as well as gene transcription and translation were identified. Furthermore, the PPI network showed that AMOTL1, SDR42E1, CAMTA1, PIP5K1C, KIAA1614, TSTD1 and DNER may play important roles in the occurrence and development of ectopic pregnancy. In addition, SDR42E1, CAMTA1 and TSTD1 displayed higher levels of methylation in ectopic pregnancy while PIP5K1C and DNER showed low degrees of methylation. Conclusions The study reveals that abnormal increase in methylation may be an early indicator or an inducer of ectopic pregnancy. In addition, AMOTL1, SDR42E1, CAMTA1, PIP5K1C, KIAA1614, TSTD1 and DNER might play important roles in the occurrence and development of ectopic pregnancy. However, the specific molecular mechanisms are still unclear and require further studies.

X-chromosome short tandem repeat (X-STR) markers are a powerful complementary system used for paternity and forensic casework. This study presents the development and validation of a new highly efficient multiplex-fluorescent-labeled 19 X-STR typing system, including DXS10079, DXS101, DXS10135, DXS10162, DXS6795, DXS6800, DXS6803, DXS6807, DXS6809, DXS6810, DXS7133, DXS7423, DXS981, DXS9902, DXS9907, GATA165B12, GATA172D05, GATA31E08 and HPRTB along with sex-typing locus, amelogenin. The system was validated according to guidelines issued by the Scientific Working Group on DNA Analysis Methods. Allele frequency and forensic parameters were investigated from 1085 (494 males and 591 females) unrelated Beijing Han individuals, the combined power of discrimination by the 19 X-STR loci in females and males, as well as the combined mean exclusion chance in trios and duos, were 0.999999999999999995, 0.99999999995, 0.9999999995, and 0.9999996, respectively. The results demonstrate that this multiplex system is robust and reliable, and considered to be a powerful tool for forensic application.

Background. Whether elevated triglyceride (TG) levels during pregnancy were a biomarker for postpartum abnormal glucose metabolism (AGM) in women with previous gestational diabetes mellitus (GDM) remained unknown. The aim of this study was to investigate the association between TG levels during the second trimester and postpartum AGM in GDM women. Methods. This was a retrospective cohort study including 513 GDM women. A 75 g oral glucose tolerance test (OGTT) was performed, and lipid levels were determined during pregnancy and the postpartum period. GDM patients were categorized into tertiles according to their TG levels at 24–28 weeks of gestation (TG<2.14 mmol/L, TG: 2.14–2.89 mmol/L, and TG>2.89 mmol/L). A logistic regression model was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). Results. During pregnancy, women in the high TG tertile showed higher HbA1c levels (5.47±0.58% versus 5.28±0.49%, p=0.006), higher total cholesterol (TC) levels (5.85±1.23 mmol/L versus 5.15±0.97 mmol/L, p=0.026), and higher HOMA-IR (2.36 (1.62-3.45) versus 1.49 (0.97-2.33), p<0.001) than the participants in the low TG tertile. After delivery, the prevalence rates of AGM based on above tertiles of TG levels during pregnancy were 26.90%, 33.33%, and 43.27%, respectively (p=0.006). High TG tertile during the second trimester was associated with the presence of postpartum AGM (adjusted OR: 2.001, 95% CI: 1.054-3.800, p=0.034). Conclusions. The elevated midtrimester TG levels were not only accompanied by higher glucose and lipid levels and more severe insulin resistance at the time of the measurement but were a biomarker for postpartum AGM as well.

Background and purpose Patients with Parkinson's disease (PD) have difficulty performing self-initiated movements. The neural mechanism of this deficiency remains unclear. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the functional connectivity of the subthalamic nucleus (STN) during self-initiated movement in patients with PD. Materials and methods fMRI were acquired from patients with PD and age- and sex-matched healthy control subjects during a self-initiated right hand tapping task. We selected the bilateral sensorimotor subregions of the STN as regions of interest for our connectivity analysis. Results and conclusions We found that the STN contralateral to voluntary hand movement exhibited enhanced connectivity with the midbrain, thalamus, putamen, and so on in patients with PD compared to control subjects. In contrast, the STN ipsilateral to the hand movement exhibited enhanced connectivity with the midbrain and insula in PD patients compared to control subjects. Connectivity between the STN contralateral to the hand movement and the primary motor cortex and supplementary motor area was positively correlated with the severity of bradykinesia. Our findings suggest that STN-related connectivity in the hyperdirect and indirect basal ganglia pathways is strengthened during self-initiated movement in patients with PD. These disrupted network connections may contribute to bradykinesia.

Bone pain is the primary problem for patients with osteoporosis. Ketoprofen is clinically used to treat osteoporotic pain, while long-term oral administration of ketoprofen can cause some side effects. In addition, osteoporosis is also accompanied by bone mass loss and inflammation. In this study, we designed a multifunctional drug (Ket@Mg-MOF-74) adopted Mg-MOF-74 to load ketoprofen to treat osteoporotic pain, bone loss and inflammation comprehensively. Mg-MOF-74 was prepared, and the physicochemical characterization proved that it had excellent physical and chemical stability. Ket@Mg-MOF-74 was synthesized by post-synthetic modification method and a high loading rate of ketoprofen was confirmed. Drug release and ion release experiments indicated Ket@Mg-MOF-74 had a good controlled release of ketoprofen and Mg in solution. Cell experiments in vitro proved the compound drug could significantly reduce the expression of pain-related genes of cyclooxygenase 2 (COX2), obviously up-regulated the expression of osteogenic cytokines and remarkably down-regulated the secretion of pro-inflammatory factors. Therefore, Ket@Mg-MOF-74 is believed a promising painkiller for osteoporotic bone pain, with the function of anti-inflammatory and promoting bone formation.

Objective To study the risk factors for recurrent ectopic pregnancy (REP). Design A retrospective case–control study. Setting A university medical centre. Population 554 women with a history of ectopic pregnancy (EP) were included. Among them were 181 women with current EP, 184 women with current intrauterine pregnancy (IUP) and 189 nonpregnant women (NonP). Methods The three groups were matched at a ratio of 1:1 with respect to current age, age of initial EP and gestational week of initial EP. Socio-demographic characteristics, reproductive history, gynaecological and surgical history, and experience of contraception were compared among the three groups. A multivariable logistic regression analysis was used to adjust for confounders and calculate adjusted odds ratios (AORs). Results The risk of REP increased with history of infertility (AOR = 3.84, 95%CI 2.16–6.86) in REP women compared with IUP controls. Compared with NonP controls, salpingotomy (AOR = 3.04, 95%CI 1.21–36.51) for previous EP was a risk factor for REP. Multiparous women were less likely to suffer REP when compared with NonP women (AOR = 0.36, 95%CI 0.18–0.62) or IUP controls (AOR = 0.35, 95%CI 0.20–0.62). Current use of an intrauterine device (IUD) (REP versus NonP, AOR = 0.02, 95%CI 0.00–0.08) or condoms (REP versus NonP, AOR = 0.16, 95%CI 0.07–0.38) significantly reduced the risk of REP compared with those not using any contraception. Similarly, previous use of condoms also prevented REP compared with those with no previous condom use (REP versus NonP, AOR = 0.20, 95%CI 0.08–0.49; REP versus IUP, AOR = 0.40, 95%CI 0.22–0.71). Conclusions Women with history of infertility or salpingotomy should be alert for the recurrence of EP. Multiparous women are less likely to suffer REP. We propose the use of condoms for effective prevention of REP. Tweetable abstract History of infertility and salpingotomy for last EP are risk factors for recurrent EP.

FKBP14 belongs to the family of FK506-binding proteins (FKBPs). Altered expression of FKBPs has been reported in several malignancies. This study aimed to reveal the expression profile of FKBP14 in ovarian cancer and evaluate whether FKBP14 is a molecular target for cancer therapy. We found that the FKBP14 mRNA level was significantly higher in ovarian cancer tissues than in normal tissues. FKBP14 expression was then knocked down in two ovarian cancer cell lines, SKOV3 and HO8910 cells, by a lentiviral short hairpin RNA (shRNA) delivery system. Reduced expression of FKBP14 markedly impaired the proliferative ability of ovarian cancer cells. Additionally, ovarian cancer cells infected with FKBP14 shRNA lentivirus tended to arrest in the G0/G1 phase and undergo apoptosis. Moreover, knockdown of FKBP14 induced cell apoptosis via increasing the ratio of Bax to Bcl-2. These results indicated that FKBP14 might be a diagnostic marker for ovarian cancer and could be a potential molecular target for the therapy of ovarian cancer.

Transforming growth factor-β1 (TGFβ1) has been identified as a major pathogenic factor underlying the development of diabetic nephropathy (DN). However, the current strategy of antagonizing TGFβ1 has failed to demonstrate favorable outcomes in clinical trials. To identify a different therapeutic approach, we designed a mass spectrometry-based DNA-protein interaction screen to find transcriptional repressors that bind to the TGFB1 promoter and identified Yin Yang 1 (YY1) as a potent repressor of TGFB1. YY1 bound directly to TGFB1 promoter regions and repressed TGFB1 transcription in human renal mesangial cells. In mouse models, YY1 was elevated in mesangial cells during early diabetic renal lesions and decreased in later stages, and knockdown of renal YY1 aggravated, whereas overexpression of YY1 attenuated glomerulosclerosis. In addition, although their duration of diabetic course was comparable, patients with higher YY1 expression developed diabetic nephropathy more slowly compared to those who presented with lower YY1 expression. We found that a small molecule, eudesmin, suppressed TGFβ1 and other profibrotic factors by increasing YY1 expression in human renal mesangial cells and attenuated diabetic renal lesions in DN mouse models by increasing YY1 expression. These results suggest that YY1 is a potent transcriptional repressor of TGFB1 during the development of DN in diabetic mice and that small molecules targeting YY1 may serve as promising therapies for treating DN.

Gestational diabetes mellitus (GDM) imparts a high risk of developing postpartum diabetes and is considered to be an early stage of type 2 diabetes mellitus (T2DM). In this study, a 75-g oral glucose tolerance test was performed on 472 women with GDM at 6-8 weeks after delivery. The clinical and metabolic characteristics were compared between the patients with normal glucose tolerance (NGT) and abnormal glucose metabolism (AGM). These data were then compared between pre-diabetic and diabetic patients. A total of 37.7% of the women with GDM continued to have abnormal glucose levels after delivery. Compared with the women who reverted to normal, HOMA-IR was significantly higher in AGM. A multiple stepwise regression analysis revealed that age, the postpartum body mass index (BMI), low density lipoprotein-cholesterol (LDL-C), 2 h glucose load plasma glucose (2 h PG), triglycerides (TG), hemoglobin A1c (HbA1c), 1 h glucose load plasma insulin (INS) level, and 2 h INS level were independent risk factors for the development of insulin resistance after delivery. This study has identified a high prevalence of AGM after GDM. Insulin resistance appears to be the major contributor. Any treatment to reduce the postpartum BMI and lipids level may be beneficial to decrease insulin resistance.

Background Resting-state functional magnetic resonance imaging (RS-fMRI) has frequently been used to investigate local spontaneous brain activity in Parkinson's disease (PD) in a whole-brain, voxel-wise manner. To quantitatively integrate these studies, we conducted a coordinate-based (CB) meta-analysis using the signed differential mapping method on 15 studies that used amplitude of low-frequency fluctuation (ALFF) and 11 studies that used regional homogeneity (ReHo). All ALFF and ReHo studies compared PD patients with healthy controls. We also performed a validation RS-fMRI study of ALFF and ReHo in a frequency-dependent manner for a novel dataset consisting of 49 PD and 49 healthy controls. Findings Decreased ALFF was found in the left putamen in PD by meta-analysis. This finding was replicated in our independent validation dataset in the 0.027–0.073 Hz band but not in the conventional frequency band of 0.01–0.08 Hz. Conclusions Findings from the current study suggested that decreased ALFF in the putamen of PD patients is the most consistent finding. RS-fMRI is a promising technique for the precise localization of abnormal spontaneous activity in PD. However, more frequency-dependent studies using the same analytical methods are needed to replicate these results. Trial registration: NCT NCT03439163. Registered 20 February 2018, retrospectively registered.

Cerebello-thalamo-cortical circuit has been indicated important for tremor in Parkinson's disease (PD), but the role of dentate nucleus (DN) in parkinsonian tremor remains unclear. To investigate whether DN plays a role in PD tremor, we recruited 50 PD and 29 age-matched health controls (HC). The patients were divided into tremor-dominant (TD) and non-tremor-dominant (NTD) groups. We collected resting-state fMRIs data for each subject. The bilateral DN was then chosen as the region of interest to examine PD tremor-related network changes, as well as its correlation with tremor severity. Voxel-wise functional connectivity analysis revealed that the bilateral DN had higher connectivity with the bilateral cerebellar anterior lobe, and had lower connectivity with the bilateral prefrontal cortex in TD compared to the HC and NTD groups. Functional connectivity of the bilateral DN with the bilateral cerebellar posterior lobe was also higher in TD than NTD group. Functional connectivity between the bilateral DN and the bilateral cerebellar posterior lobe showed positive correlation with tremor severity, while that between the bilateral DN and the bilateral prefrontal cortex displayed negative correlation. Our study demonstrates higher dentato-cerebellar connectivity and lower dentato-prefrontal connectivity in TD patients, which might be involved in the pathogenesis of PD tremor. And we conclude that DN might be associated with the pathogenesis of PD tremor.

Parkinson’s disease (PD) patients have difficulty in performing a dual-task. It has been suggested that the cerebellum is important in dual-tasking. We used functional MRI to investigate the role of the cerebellum in performing a dual motor and cognitive task in PD patients. We have examined whether there are any areas additionally activated for dual-task performance, and compared the neural activity and functional connectivity pattern in the cerebellum between PD patients and healthy controls. We found that the right cerebellar vermis and left lobule V of cerebellar anterior lobe were additionally activated for dual-task performance in healthy controls and for motor task in PD patients. We didn’t find any cerebellar regions additionally activated while performing dual-task in PD patients. In addition, the right cerebellar vermis had enhanced connectivity with motor and cognitive associated networks in PD patients. PD patients have limited cerebellar resources that are already utilized for single tasks and, for dual tasks, cannot augment as necessary in order to integrate motor and cognitive networks.

Embryonic stem cells (ESCs) are pluripotent stem cells from early embryos. It has been well recognized that ESC genomes are maintained in a globally transcriptional hyperactive state, which genetically poised ESCs to the high differentiation potential. However, the transcription factors regulating the global transcription activities in ESCs are not well defined. We show here that mouse and human ESCs express two transcription factors, Aire and Deaf1. Previously known to function in the thymus stromal cells and peripheral lymphoid organs respectively, Aire and Deaf1 help regulate the ectopic expression of diverse tissue-specific antigens to establish self-immune tolerance. Differentiation of ESCs greatly reduced Aire and Deaf1 expression, in a pattern similar to the pluripotent factors, Oct4 and Nanog. Knockdown of Aire in mouse ESCs resulted in significantly decreased clone-forming efficiency as well as attenuated cell cycle, suggesting Aire plays a role in ESC self-renewal. In addition, some differentiation-associated genes that are sporadically expressed in ESCs were reduced in expression upon Aire knockdown. These results suggest that transcription factors such as Aire and Deaf1, which exert global transcriptional regulatory functions, may play important roles in self-renewal of ESCs and maintaining ESC in a transcriptionally hyperactive state.

Methylation is an important silencing mechanism of breast and ovarian cancer susceptibility gene 1 (BRCA1) expression in sporadic ovarian cancer. However, the role of BRCA1 methylation in chemotherapy in sporadic ovarian cancer and the related pathways have not been understood completely. This study has determined the roles of BRCA1 hypermethylation in chemotherapy of sporadic ovarian cancer and its related signaling pathways. We used bisulfite sequencing, real-time polymerase chain reaction, and western blotting to check the methylation state and expression levels of BRCA1 of the following cell lines: platinum-sensitive human ovarian cancer cell line COC1, platinum-resistant cell line COC1/DDP, SKOV-3, and 5-Aza-dC treated COC1. The cisplatin sensitivity of ovarian cancer cells was examined by MTS (methyl-thiazol tetrazolium) assay. Tumorigenicity in vivo and DDP-based chemosensitivity were compared among the above cells. Phosphatidylinositol 3'-kinase (PI3K)-Akt pathway activation in ovarian cancer cells was studied by western blotting. The frequency of BRCA1 methylation in the COC1 cell line was higher than in COC1/DDP and SKOV-3 cell lines, whereas the mRNA and protein expression of BRCA1 were lower than in the COC1/DDP and SKOV-3 cell lines. DNA demethylation decreased the chemosensitivity of COC1 cells and partially increased the expression levels of BRCA1. The activation of the PI3K-Akt pathway was low in ovarian cancer cells. Our results indicate that hypermethylation of BRCA1 might play an important role in the chemosensitivity of ovarian cancer, and that the PI3K-Akt pathway is not involved in this response.

We report here the development of a group of rabbit monoclonal antibodies against Smad1, Smad2, Smad3, and Smad5, and the immunocytochemistry (ICC) staining of human embryonic stem cells (hESC) and mouse embryonic stem cells (mESC). Eight New Zealand rabbits were immunized with synthesized peptides linked to KLH, and splenocytes from these rabbits were fused with rabbit immortal B cell 240E-W2. Resulting hybridomas producing anti-Smad monoclonal antibodies were screened by enzyme-linked immunosorbent assay (ELISA) with BSA-linked peptides. Clones were chosen for antibody production based on their activities in Western blotting and on paraffin-embedded human tissues, and the capacity of the antibodies in immunocytochemistry was demonstrated. Using these antibodies, we performed ICC staining on routinely cultured human and mouse embryonic stem cells, and showed that both cell types strongly express these genes. We propose that both hESCs and mESCs have the ability to transduce signals from both BMPs and TGF-b/Activin.

Objectives To evaluate the technical feasibility and anatomical and functional outcomes of laparoscopically assisted sigmoid colon vaginoplasty (LASV) in women with Mayer–Rokitansky–Kuster–Hauser (MRKH) syndrome. Design A retrospective review of prospectively collected data. Setting Shanghai First People’s Hospital, Shanghai Jiao Tong University. Population Twenty-six women with MRKH syndrome. Methods A record was made of mean operating time, length of hospital stay, perioperative complications and the anatomical and functional outcomes of surgery. Main outcome measures The perioperative results, complications and anatomical and functional outcomes of LASV (with median 20 months follow up, range 5–48 months). Results The mean operating time and hospital stay were 238 minutes and 9.8 days, respectively. The mean fall in haemoglobin was 2.0 g/dl. The only significant perioperative complications were one case with blood transfusion and three cases with infection (one with urinary tract and two with adjunctive incision). A functioning vagina 10 to 15 cm in length and 4 cm in width was created in all women. Introital stenosis occurred in only two women (2 months later). Twenty-two women subsequently had intercourse and 20 women (91%) were satisfied with the surgery and subsequent sexual activity. Conclusions LASV is an effective approach for women with MRKH syndrome. Both the anatomical and functional outcomes are satisfactory.

S100A11 is a calcium-binding protein implicated in a variety of biological functions and is overexpressed in many human cancers. However, S100A11 expression level in ovarian cancer has not been well characterized. High-grade serous ovarian cancer (HGSC) is the most common and lethal type of ovarian cancer. The aim of the present study was to investigate S100A11 expression and its clinical significance in HGSC. S100A11 expression was evaluated by Western blot in 45 snap-frozen specimens (15 normal ovarian epithelia, 15 normal fallopian tube epithelia, and 15 HGSCs) and by immunohistochemistry in 211 paraffin-embedded specimens (40 normal fallopian tube epithelia, 54 normal ovarian epithelia, and 117 HGSCs). S100A11 expression was extremely elevated in HGSC compared with normal epithelial tissues and was positively correlated with FIGO stage (P=0.014), ascitic fluid volume (P=0.009), and residual disease (P=0.004) of HGSC patients. Higher S100A11 expression was associated with poorer disease-free (P=0.004) and overall (P=0.006) survival, whereas multivariate analysis revealed S100A11 to be an independent prognostic factor for disease-free (P=0.019) and overall (P=0.027) survival in patients with HGSC. In conclusion, S100A11 overexpression correlates with an aggressive malignant phenotype and may constitute a novel prognostic factor for HGSC.

Summary Aims The aim of this study was to investigate the involvement of the ventral intermediate nucleus of thalamus (Vim) in the tremor- and akinetic-/rigid-related networks in Parkinson's disease (PD). Methods Tremor-dominant (TD) and akinetic-/rigid-dominant (ARD) PD patients were recruited and scanned by resting-state functional MRI. Functional connectivity from the Vim nucleus was analyzed. Results In the TD patients, the Vim nucleus exhibited increased connectivity with the cerebellum/dentate nucleus, primary motor cortex (M1), supplementary motor area (SMA), premotor cortex, thalamus, globus pallidus, putamen, and parietal cortex compared with the controls, while the connections between the Vim nucleus and M1 and cerebellum/dentate nucleus had positive correlations with the tremor scores. In the ARD patients, the Vim nucleus only showed enhanced connectivity with the globus pallidus and limbic lobe compared with the controls, and no connectivity showed correlation against the akinetic–rigidity scores. TD patients had increased connectivity with the Vim nucleus in the cerebellum, M1, SMA, thalamus, globus pallidus, putamen, and parietal cortex compared with ARD patients. Conclusions This study demonstrates that the Vim nucleus has an important role in the tremor-related network, but not in the akinetic-/rigid-related network. Our finding is helpful to explain the selective effect of Vim deep brain stimulation in PD.

Summary Aims Postural instability/gait difficulty (PIGD) and tremor-dominant (TD) subtypes of Parkinson's disease (PD) show different clinical manifestations; however, their underlying neural substrates remain incompletely understood. This study aimed at investigating the subtype-specific patterns of spontaneous brain activity in PD. Methods Thirty-one patients with PD (12 TD/19 PIGD) and 22 healthy gender- and age-matched controls were recruited. Resting-state functional magnetic resonance imaging data were collected, and amplitude of low-frequency fluctuations (ALFF) was measured. Voxelwise one-way analysis of covariance and post hoc analyses of ALFF were performed among the three groups, with age and gender as covariates (levodopa daily dosage and gray matter volume as additional covariates for validation analysis). Correlations of clinical variables (e.g., disease duration and PIGD/tremor subscale score) with ALFF values were examined. Results Compared with controls, patients with TD exhibited higher ALFF in the right cerebellar posterior lobe and patients with PIGD exhibited lower ALFF in the bilateral putamen and cerebellar posterior lobe, and higher values primarily in several cortical areas including the inferior and superior temporal gyrus, superior frontal, and parietal gyrus. Compared with patients with PIGD, patients with TD had higher ALFF in the bilateral putamen and the cerebellar posterior lobe, as well as lower ALFF in the bilateral temporal gyrus and the left superior parietal lobule. In all patients, ALFF in the bilateral cerebellar posterior lobe positively correlated with tremor score and ALFF in the bilateral putamen negatively correlated with PIGD score. Conclusion Different patterns of spontaneous neural activity in the cerebellum and putamen may underlie the neural substrate of PD motor subtypes.

Micrographia is a common symptom in Parkinson's disease, which manifests as either a consistent or progressive reduction in the size of handwriting or both. Neural correlates underlying micrographia remain unclear. We used functional magnetic resonance imaging to investigate micrographia-related neural activity and connectivity modulations. In addition, the effect of attention and dopaminergic administration on micrographia was examined. We found that consistent micrographia was associated with decreased activity and connectivity in the basal ganglia motor circuit; while progressive micrographia was related to the dysfunction of basal ganglia motor circuit together with disconnections between the rostral supplementary motor area, rostral cingulate motor area and cerebellum. Attention significantly improved both consistent and progressive micrographia, accompanied by recruitment of anterior putamen and dorsolateral prefrontal cortex. Levodopa improved consistent micrographia accompanied by increased activity and connectivity in the basal ganglia motor circuit, but had no effect on progressive micrographia. Our findings suggest that consistent micrographia is related to dysfunction of the basal ganglia motor circuit; while dysfunction of the basal ganglia motor circuit and disconnection between the rostral supplementary motor area, rostral cingulate motor area and cerebellum likely contributes to progressive micrographia. Attention improves both types of micrographia by recruiting additional brain networks. Levodopa improves consistent micrographia by restoring the function of the basal ganglia motor circuit, but does not improve progressive micrographia, probably because of failure to repair the disconnected networks.

To explore the changes of local brain activity in motor subtypes of Parkinson's disease (PD) with functional magnetic resonance imaging (fMRI).A total of 60 idiopathic PD and 30 age- and gender-matched normal controls were examined with resting-state fMRI from January 2013 to March 2014. All subjects gave their written informed consent for the study. The amplitude of low-frequency fluctuation (ALFF) was calculated to measure local brain activity. The PD patients were divided into two groups of tremor dominant (TD) and postural instability/gait difficulty (PIGD) (n = 30 each). All subjects gave their written in formed consent for the study.One-way ANOVA and post-hoc t-test were performed to detect the differences of local brain activity between PD and normal subjects. And the correlations were examined between ALFF, scores and levodopa dose.Compared with normal subjects, the TD group showed increased activity in bilateral cerebellums (-37, -47, -38), thalamus (-18, -17,0), pons (-3, -23, -37) and left precentral gyrus (-41, -30, 46) versus decreased activity in bilateral frontal lobes (-13, 69, 6), temporal lobes (-42, 18, -21), left insula (-32, 22, 2) and left anterior cingulated (-7, 32, -5). The PIGD group showed increased activity in right postcentral gyrus (63, -18, 39) and decreased activity in bilateral putamens (-24, 12, 3), pre-supplementary motor area (10, 10, 58), frontal lobes (15, -15, 57), temporal lobes (-39, 18, -3) and left insula (-29, 20, 11). Compared with PIGD, the TD group showed increased activity in temporal lobes, but decreased activity in frontal lobes. Additionally, ALFF in bilateral cerebellums and frontal lobes was positively correlated with TD scores while ALFF in left precentral gyrus, bilateral putamens and temporal lobes negatively correlated with TD scores. ALFF in bilateral frontal lobes and left temporal lobe was positively correlated with PIGD scores.However, in right postcentral gyrus and bilateral putamens, ALFF was negatively correlated with PIGD scores. The levodopa dose was positively correlated with frontal lobes and temporal lobe in TD and cerebellums and inferior parietal lobule in PIGD.A specific pattern of intrinsic activity in TD and PIGD may provide insights into neurophysiological mechanisms of PD motor subtypes. The changes of brain activity in TD are caused by the interaction between cerebello-thalamo-cortical circuit and basal ganglia loop while the changes in PIGD result largely from damaged basal ganglia loop.

Endometrial cancer (EC) is the most common gynecologic malignancy. MicroRNAs (miRNAs) were recently associated with carcinogenesis and progression of EC. In this review, we discuss recent advances and the emerging role of miRNAs in EC and their clinical implications, with special emphasis on the differences between deregulated miRNAs in type I and type II EC, as well as the impact of this dysregulation on EC initiation and progression.

We investigated the lateralization of brain activity pattern during performance of unilateral movement in drug‐naïve Parkinson's disease (PD) patients with only right hemiparkinsonian symptoms. Functional MRI was obtained when the subjects performed strictly unilateral right hand movement. A laterality index was calculated to examine the lateralization. Patients had decreased activity in the left putamen and left supplementary motor area, but had increased activity in the right primary motor cortex, right premotor cortex, left postcentral gyrus, and bilateral cerebellum. The laterality index was significantly decreased in PD patients compared with controls (0.41 ± 0.14 vs. 0.84 ± 0.09). The connectivity from the left putamen to cortical motor regions and cerebellum was decreased, while the interactions between the cortical motor regions, cerebellum, and right putamen were increased. Our study demonstrates that in early PD, the lateralization of brain activity during unilateral movement is significantly reduced. The dysfunction of the striatum–cortical circuit, decreased transcallosal inhibition, and compensatory efforts from cortical motor regions, cerebellum, and the less affected striatum are likely reasons contributing to the reduced motor lateralization. The disruption of the lateralized brain activity pattern might be a reason underlying some motor deficits in PD, like mirror movements or impaired bilateral motor coordination. Hum Brain Mapp 36:1878–1891, 2015. © 2015 Wiley Periodicals, Inc.

The regulation of gene expression by microRNAs (miRNAs) is complex due to a number of variables involved. The potential for one miRNA to target many genes, the presence of multiple miRNA response elements (MREs) in one mRNA molecule and the interplay between RNAs that share common MREs each add a layer of complexity to the process; making it difficult to determine how regulation of gene expression by miRNAs works within the context of the system as a whole. In this study, we used luciferase report vectors inserted with different 3′UTR fragments as probes to detect the repressive effect of the miRNA pool on gene expression and uncovered some essential characteristics of gene regulation mediated by the miRNA pool, such as the nonlinear correlative relationship between the regulatory potential of a miRNA pool and the number of potential MREs, the buffering effect and the saturating effect of the miRNA pool, and the restrictive effect caused by the density of MREs. Through expressing gradient concentration of 3′UTR fragments, we indirectly detected the regulatory potential of the competing endogenous RNA (ceRNA) pool and analysed its effect on the regulatory potential of the miRNA pool. Our results provide some new insights into miRNA pool mediated gene regulation.

The objective of the study was to evaluate the expression of L-selectin ligands in tubal epithelia during tubal ectopic pregnancy. Sixteen fallopian tube samples from ectopic pregnancies and four normal control fallopian tubes from women undergoing sterilization were obtained for the study. Oviduct tissues from ectopic pregnancies were separated into implantation sites and matched nonimplantation sites. Expression of L-selectin ligands was evaluated by immunohistochemistry with antibodies against HECA-452 and MECA-79 and by real-time PCR. Immunoreactivity levels against HECA-452 and MECA-79 were significantly higher at the implantation site than at the paired nonimplantation site or at the normal oviducts. Moreover, compared with MECA-79 staining, stronger HECA-452 staining was observed in the implantation and nonimplantation groups. HECA-452 histologic scores at implantation sites correlated with serum human chorionic gonadotropin levels. Increased expression of L-selectin ligands may be involved in the implantation process in tubal pregnancy.

Mesenchymal stromal cells (MSCs) are one of the most intensively studied stem cell types with application aims. However, the molecular characterisation and the relationship between the molecular characterisation and functional properties of MSCs are largely unknown. In this study, we purified the surface proteins from rat bone marrow MSCs (rBMMSCs) and characterised their surface proteome by LC-MS/MS. Moreover, we comparatively analysed the data from this study with the surface proteomics data of mouse and human embryonic stem (ES) cells and human mesenchymal stromal cells (hMSCs). The data showed that, in contrast to ES cells and human mesenchymal stromal cells, rBMMSCs possessed a surface proteomics pattern biased to neural and neural-endocrine lineages, indicating a neural/neural crest bias, and suggested a neural differentiation tendency of these cells. The different surface proteomics pattern between rBMMSCs and hMSCs also suggested that MSCs of different origin might possess a different lineage bias.

Objective To determine whether the recently published A global reference for fetal-weight and birthweight percentiles (Global Reference) improves small- (SGA), appropriate- (AGA), and large-for-gestational-age (LGA) definitions in predicting infant mortality. Design Population-based cohort study. Setting The US Linked Livebirth and Infant Death records between 1995 and 2004. Population Singleton births with birthweight >500 g born at 24–41 weeks of gestation. Methods We compared infant mortality rates of SGA, AGA, and LGA infants classified by three different references: the Global Reference; a commonly used birthweight reference; and Hadlock's ultrasound reference. Main outcome measures Infant mortality rates. Results Among 33 997 719 eligible liveborn singleton births, 25% of preterm and 9% of term infants were classified differently for SGA, AGA, and LGA by the Global Reference and the birthweight reference. The Global Reference indicated higher mortality rates in preterm SGA and preterm LGA infants than the birthweight reference. The mortality rate was considerably higher in infants classified as preterm SGA by the Global Reference but not by the birthweight reference, compared with the corresponding infants classified by the birthweight reference but not by the Global Reference (105.7 versus 12.9 per 1000, RR 8.17, 95% CI 7.38–9.06). Yet, the differences in mortality rates were much smaller in term infants than in preterm infants. Black infants had a particularly higher mortality rate than other races in AGA and LGA preterm and term infants. Conclusions In respect to the commonly used birthweight reference, the Global Reference increases the identification of infant deaths by improved classification of abnormal newborn size at birth, and these advantages were more obvious in preterm than in term infants.

Infection by human papillomavirus (HPV) can cause cervical intraepithelial neoplasia (CIN) and cancer. Down-regulation of E6 and E7 expression may be responsible for the positive clinical outcomes observed with IFN treatment, but the molecular basis has not been well determined. As miRNAs play an important role in HPV induced cervical carcinogenesis, we hypothesize that IFN-β can regulate the expressions of specific miRNAs in cervical cancer cells, and that these miRNAs can mediate E6 and E7 expression, thus modulate their oncogenic potential. In this study, we found that miR-129-5p to be a candidate IFN-β inducible miRNA. MiR-129-5p levels gradually decrease with the development of cervical intraepithelial lesions. Manipulation of miR-129-5p expression in Hela cells modulates HPV-18 E6 and E7 viral gene expression. Exogenous miR-129-5p inhibits cell proliferation in Hela cells, promotes apoptosis and blocks cell cycle progression in Hela cells. SP1 is a direct target of miR-129-5p in Hela cells. This study is the first report of a cellular miRNA with anti-HPV activity and provides new insights into regulatory mechanisms between the HPV and the IFN system in host cells at the miRNA level.

BACKGROUND: It has long been proposed that early embryos and reproductive organs exhibit similar gene expression profiles. However, whether this similarity is propagated to the protein level remains largely unknown. We have previously characterised the promiscuous expression pattern of cell surface proteins on mouse embryonic stem (mES) cells. As cell surface proteins also play critical functions in human embryonic stem (hES) cells and germ cells, it is important to reveal whether a promiscuous pattern of cell surface proteins also exists for these cells. METHODS AND PRINCIPAL FINDINGS: Surface proteins of hES cells and human mature sperms (hSperms) were purified by biotin labelling and subjected to proteomic analyses. More than 1000 transmembrane or secreted cell surface proteins were identified on the two cell types, respectively. Proteins from both cell types covered a large variety of functional categories including signal transduction, adhesion and transporting. Moreover, both cell types promiscuously expressed a wide variety of tissue specific surface proteins, and some surface proteins were heterogeneously expressed. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that the promiscuous expression of functional and tissue specific cell surface proteins may be a common pattern in embryonic stem cells and germ cells. The conservation of gene expression patterns between early embryonic cells and reproductive cells is propagated to the protein level. These results have deep implications for the cell surface signature characterisation of pluripotent stem cells and germ cells and may lead the way to a new area of study, i.e., the functional significance of promiscuous gene expression in pluripotent and germ cells.

BACKGROUND: Recent studies have shown that embryonic stem (ES) cells globally express most genes in the genome at the mRNA level; however, it is unclear whether this global expression is propagated to the protein level. Cell surface proteins could perform critical functions in ES cells, so determining whether ES cells globally express cell surface proteins would have significant implications for ES cell biology. METHODS AND PRINCIPAL FINDINGS: The surface proteins of mouse ES cells were purified by biotin labeling and subjected to proteomics analysis. About 1000 transmembrane or secreted cell surface proteins were identified. These proteins covered a large variety if functional categories including signal transduction, adhesion and transporting. More over, mES cells promiscuously expressed a wide variety of tissue specific surface proteins. And many surface proteins were expressed heterogeneously on mES cells. We also find that human ES cells express a wide variety of tissue specific surface proteins. CONCLUSIONS/SIGNIFICANCE: Our results indicate that global gene expression is not simply a result of leaky gene expression, which could be attributed to the loose chromatin structure of ES cells; it is also propagated to the functional level. ES cells may use diverse surface proteins to receive signals from the diverse extracellular stimuli that initiate differentiation. Moreover, the promiscuous expression of tissue specific surface proteins illuminate new insights into the strategies of cell surface marker screening.