Maternal androgen excess inhibits fetal cardiomyocytes proliferation through RB-mediated cell cycle arrest and induces cardiac hypertrophy in adulthood.

PURPOSE: Maternal hyperandrogenism during pregnancy is associated with adverse gestational outcomes and chronic non-communicable diseases in offspring. However, few studies are reported to demonstrate the association between maternal androgen excess and cardiac health in offspring. This study aimed to explore the relation between androgen exposure in utero and cardiac health of offspring in fetal and adult period. Its underlying mechanism is also illustrated in this research. METHODS: Pregnant mice were injected with dihydrotestosterone (DHT) from gestational day (GD) 16.5 to GD18.5. On GD18.5, fetal heart tissue was collected for metabolite and morphological analysis. The hearts from adult offspring were also collected for morphological and qPCR analysis. H9c2 cells were treated with 75 µM androsterone. Immunofluorescence, flow cytometry, qPCR, and western blot were performed to observe cell proliferation and explore the underlying mechanism. RESULTS: Intrauterine exposure to excessive androgen led to thinner ventricular wall, decreased number of cardiomyocytes in fetal offspring and caused cardiac hypertrophy, compromised cardiac function in adult offspring. The analysis of steroid hormone metabolites in fetal heart tissue by ultra performance liquid chromatography and tandem mass spectrometry showed that the content of androgen metabolite androsterone was significantly increased. Mechanistically, H9c2 cells treated with androsterone led to a significant decrease in phosphorylated retinoblastoma protein (pRB) and cell cycle-related protein including cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin D1 (CCND1) in cardiomyocytes. This resulted in cell cycle arrest at G1-S phase, which in turn inhibited cardiomyocyte proliferation. CONCLUSION: Taken together, our results indicate that in utero exposure to DHT, its metabolite androsterone could directly decrease cardiomyocytes proliferation through cell cycle arrest, which has a life-long-lasting effect on cardiac health. Our study highlights the importance of monitoring sex hormones in women during pregnancy and the follow-up of cardiac function in offspring with high risk of intrauterine androgen exposure.

Coherent Microwave Emission of Gain-Driven Polaritons.

By developing a gain-embedded cavity magnonics platform, we create a gain-driven polariton (GDP) that is activated by an amplified electromagnetic field. Distinct effects of gain-driven light-matter interaction, such as polariton auto-oscillations, polariton phase singularity, self-selection of a polariton bright mode, and gain-induced magnon-photon synchronization, are theoretically studied and experimentally manifested. Utilizing the gain-sustained photon coherence of the GDP, we demonstrate polariton-based coherent microwave amplification (∼40 dB) and achieve high-quality coherent microwave emission (Q>10^{9}).

Two-beam coupling by a hot electron nonlinearity.

Transparent conductive oxides such as indium tin oxide (ITO) bear the potential to deliver efficient all-optical functionality due to their record-breaking optical nonlinearity at epsilon near zero (ENZ) wavelengths. All-optical applications generally involve more than one beam, but, to our knowledge, the coherent interaction between beams has not previously been discussed in these materials, which have a hot electron nonlinearity. Here we study the optical nonlinearity at ENZ in ITO and show that spatial and temporal interference has important consequences in a two-beam geometry. Our pump-probe results reveal a polarization-dependent transient that is explained by diffraction of pump light into the probe direction by a temperature grating produced by pump-probe interference. We further show that this effect allows tailoring the nonlinearity by tuning the frequency or chirp. Having fine control over the strong and ultrafast ENZ nonlinearity may enable applications in all-optical neural networks, nanophotonics, and spectroscopy.

Unconventional Singularity in Anti-Parity-Time Symmetric Cavity Magnonics.

By engineering an anti-parity-time (anti-PT) symmetric cavity magnonics system with precise eigenspace controllability, we observe two different singularities in the same system. One type of singularity, the exceptional point (EP), is produced by tuning the magnon damping. Between two EPs, the maximal coherent superposition of photon and magnon states is robustly sustained by the preserved anti-PT symmetry. The other type of singularity, arising from the dissipative coupling of two antiresonances, is an unconventional bound state in the continuum (BIC). At the settings of BICs, the coupled system exhibits infinite discontinuities in the group delay. We find that both singularities coexist at the equator of the Bloch sphere, which reveals a unique hybrid state that simultaneously exhibits the maximal coherent superposition and slow light capability.

Nonreciprocity and Unidirectional Invisibility in Cavity Magnonics.

We reveal the cooperative effect of coherent and dissipative magnon-photon couplings in an open cavity magnonic system, which leads to nonreciprocity with a considerably large isolation ratio and flexible controllability. Furthermore, we discover unidirectional invisibility for microwave propagation, which appears at the zero-damping condition for hybrid magnon-photon modes. A simple model is developed to capture the generic physics of the interference between coherent and dissipative couplings, which accurately reproduces the observations over a broad range of parameters. This general scheme could inspire methods to achieve nonreciprocity in other systems.

Collective effects of common single nucleotide polymorphisms and genetic risk prediction in type 1 diabetes.

Type 1 diabetes (T1D) is a common autoimmune disease and may be related to multiple genetic and environmental risk factors. Previous genetic studies have focused on looking for individual polymorphic risk variants. Here, we studied the overall levels of genetic diversity in T1D patients by making use of a previously published study including 1865 cases and 2828 reference samples with genotyping data for 500 K common single nucleotide polymorphisms (SNPs). We determined the minor allele (MA) status of each SNP in the reference samples and calculated the total number of MAs or minor allele contents (MAC) of each individual. We found the average MAC of cases to be greater than that of the reference samples. By focusing on MAs with strong linkage to cases, we further identified a set of 112 SNPs that could predict 19.19% of cases. These results suggest that overall genetic variation over a threshold level may be a risk factor in T1D and provide a new genetic method for predicting the disorder.

Level Attraction Due to Dissipative Magnon-Photon Coupling.

We report dissipative magnon-photon coupling caused by the cavity Lenz effect, where the magnons in a magnet induce a rf current in the cavity, leading to a cavity backaction that impedes the magnetization dynamics. This effect is revealed in our experiment as level attraction with a coalescence of hybridized magnon-photon modes, which is distinctly different from level repulsion with mode anticrossing caused by coherent magnon-photon coupling. We develop a method to control the interpolation of coherent and dissipative magnon-photon coupling, and observe a matching condition where the two effects cancel. Our work sheds light on the so-far hidden side of magnon-photon coupling, opening a new avenue for controlling and utilizing light-matter interactions.

Clinical value of combined tests for tumor markers for gastric cancer.

To study the clinical diagnostic value of treating gastric cancer (GC) with combined tests for tumor markers (CEA, CA199, CA242 and CA724), fifty healthy subjects, 50 patients with GC at different stages and 50 patients with benign GC were randomly selected from our hospital. These subjects were divided into a normal group A, an experimental group B and a control group C. Venous blood was drawn and tested for four serum tumor markers. The SPSS 18.0 analytic system was then used to analyze the data. Tumor markers for GC at different stages, different pathological patterns and tumor incidence are discussed. The difference in expression levels of tumor markers between group C and group A was not statistically significant (P>0.05). The differences in expression levels between group B in stage I and stage II and those of groups A and C was statistically significant (P less than 0.05). At the same time, the differences in expression levels of group B in stage III and stage IV and those of groups A and C were also statistically significant (P less than 0.01). For different sizes of tumors, taking 5 cm as a maximum, normal expression and abnormal expression of the four tumor markers was different (P less than 0.05). The tumor incidence of the combined test for the four tumor markers was conspicuously higher than that of single tests. Moreover, the difference between the tumor incidence of the combined test in stages I, II and III and that of single tests in the same stages was of statistical significance (P less than 0.05); however, the difference was not statistically significant in stage IV (P>0.05). The combined testing for tumor markers is useful for clinical diagnosis of GC.

[Expression of Fermintin family homologous protein 2 in non-small cell lung cancer and its clinical significance].

Objective: To investigate the expression of Fermintin family homologous protein 2 (FERMT2) in non-small cell lung cancer and its clinical significance. Methods: Seventy-two patients with non-small cell lung cancer were collected at Xinxiang Central Hospital, Henan Province, from January 2015 to January 2017.There were 48 male and 24 female patients, the age ranged from 37 to 78 years (mean 58 years). The expression of FERMT2 in tumor samples and para-cancerous tissues were detected by immunohistochemistry. Protein and mRNA expression of FERMT2 were detected by Western blot and real-time fluorescence quantitative PCR, respectively. Western blot method was also used to detect integrin-related protein expression, including integrin beta 1 (CD29), vascular cell adhesion molecule (VCAM1), and mobile related protein-1 (MRP1). Results: Immunohistochemistry showed that the positive rates of FERMT2 expression were 81.9%(59/72)in carcinoma tissue and 15.4%(11/72) in para-cancerous tissues, and the difference was statistically significant (P<0.01). Positive FERMT2 expression was different in tumors at different tumor stages: 11/17 at stage Ⅰ, 16/20(80.0%)at stage Ⅱ, 17/20(85.0%)at stage Ⅲ, and 15/15 at stage Ⅳ, and there was a significant difference between each stage (P<0.01). By real-time PCR and Western blot, the expression of FERMT2 in non-small cell lung cancer tissues was significantly higher than that of para-cancerous tissue (P<0.01). The expression levels of integrin related proteins (integrin ß1, VCAM1 and MRP1) in tumor tissues were significantly higher than those in para-cancerous tissues, and positively correlated with the expression of FERMT2 (r=0.531, P<0.01; r=0.483, P<0.01; r=0.612, P<0.01). Conclusions: FERMT2 is highly expressed in non-small cell lung carcinomas. Its expression is closely correlated with the tumor clinical stage. It is hypothesized that FERMT2 may promote tumor metastasis through interactions with integrin-like protein.

Effect of intermittent normobaric hyperoxia for treatment of neuropathic pain in Chinese patients with spinal cord injury.

STUDY DESIGN: Prospective, randomized and controlled study. OBJECTIVES: The aim of the study was to investigate the effect of intermittent normobaric hyperoxia (InHO) for treatment of neuropathic pain in patients with spinal cord injury (SCI). SETTING: The First Affiliated Hospital of Nanhua University, Hengyang, Hunan Province, China. METHODS: Patients with SCI from Hunan Province were recruited from the First Affiliated Hospital of Nanhua University. History, duration, localization and characteristics of pain were recorded. Visual analog scale (VAS), the Patient Global Impression of Change (PGIC) and Short Form-36 walk-wheel (SF-36ww) was used to investigate the effect of InHO. Patients were randomly assigned to study and control groups. In study group, patients were exposed to pure oxygen via non-rebreathing reservoir mask, which increased the provided oxygen at a rate of 7 l min-1 for 1 or 4 h daily in 2 weeks. While in control group, patients breathed air via non-rebreathing reservoir mask at the same rate. RESULTS: A total of 62 SCI patients with neuropathic pain were included in the study. The mean age of the patients was 36.85±10.71 years. Out of 62 patients, 21 were tetraplegic and 41 were paraplegic. Overall, 14 patients had complete SCI while 48 patients had incomplete injuries. Three groups were similar with respect to age, gender, duration, smoker or not, level and severity of injury. In the 4 h per day InHO groups, a statistically significant reduction of the VAS values was observed (P<0.05). Significant difference was also found in SF-36ww pain scores and PGIC (P<0.05). However, such an effect was not evident in the control group. CONCLUSION: This study revealed that in treatment of neuropathic pain of SCI patients, InHO may be effective. PERSPECTIVE: This article presents InHO may effectively complement pharmacological treatment in patients with SCI and neuropathic pain.

CYP4F2 gene single nucleotide polymorphism is associated with ischemic stroke.

The objective of this study was to explore the relationship between CYP4F2 gene polymorphism and ischemic stroke (IS) in the Han Chinese population. We performed a case-control study to genotype four single nucleotide polymorphisms (SNPs) (rs2108622, rs3093100, rs3093105, rs3093135) in the CYF4F2 gene. The genotype and haplotype distributions were compared between the case and control groups. We found that the GG genotype of rs2108622 in the CYP4F2 gene was associated with risk of IS (P = 0.023). Haplotype analysis indicated that the GGGT haplotype comprising rs2108622-rs3093100-rs3093105-rs3093135 was associated with IS, which suggests that the GGGT haplotype may be a risk factor for IS (P = 0.012). CYP4F2 gene polymorphism might increase the risk of IS in the Chinese population.

Association of the ApoE gene polymorphism and dietary factors with cerebral infarction and circulating lipid concentrations.

The aim of this study was to explore the relationship between the ApoE gene polymorphism and dietary factors with stroke and circulating lipid levels in the Chinese population. We selected 580 patients with stroke and 580 age- and gender-matched healthy controls, and examined their ApoE polymorphism genotype using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. We also analyzed the relationship between the ApoE gene polymorphism and dietary factors as well as plasma lipid concentrations in this cohort. We detected six ApoE genotypes in the study populations, and determined that the E4 allele was positively associated with cerebral infarction (CI), whereas allele E2 was negatively associated with total cholesterol (TC) and low-density lipoprotein-cholesterol levels. The dietary habits of the subjects with descending order of average total TC and triglyceride levels were: subjects addicted to oily food > subjects addicted to sweets > subjects addicted to smoking > subjects addicted to alcohol > subjects following a vegetarian diet (P < 0.05). Our results demonstrated that the ApoE gene polymorphism was associated with a risk for CI in a Chinese population.

Effects of MK-801 concentration on cell proliferation in rats with focal cerebral ischemia-reperfusion.

We explored the relationship between MK-801 concentration and neural stem cell proliferation in rats with focal cerebral ischemia-reperfusion (FCIR). A total of 60 male Sprague Dawley rats were randomized into control (six rats), sham-operation (six rats), operation (12 rats), and MK-801 groups. The MK-801 group comprised 36 rats that were subjected to different doses of MK-801 (0.2, 0.4, 0.6, 0.8, 1.0, and 1.2 mg/kg). Suture occlusion was used to establish an ischemia reperfusion model of middle cerebral artery occlusion (MCAO); 30 min before establishing the FCIR model, the MK-801 group rats were intraperitoneally injected with different doses of MK-801, while the sham-operation and control groups were injected with normal saline. Seven days after model establishment, bromodeoxyuridine-positive cerebral cortex cells adjacent to the focus of infarction were labeled for immunohistochemistry. MK-801 at a concentration of 0.4 mg/kg prevented endogenous neural stem cell proliferation, and this inhibitory effect was strengthened with increasing MK-801 concentration, especially at concentrations greater than 0.8 mg/kg. MK-801 inhibits endogenous neural stem cell proliferation in rats with FCIR, and the inhibitory effect is strengthened with increasing MK-801 concentration.

[Clinical significance of high expression with UTX in renal cell carcinoma].

OBJECTIVE: To investigate the expression and significance of ubiquitously transcribed TPR gene on the X chromosome (UTX) in renal cell carcinoma (RCC) tissues, then to explore the relationship between UTX expression and renal cancer pathologic characteristics. METHODS: In the study, 45 patients with dignosed renal cell carcinoma clinical samples were collected in Peking University Shenzhen Hospital. Total RNA and protein were extracted from the cancer tissues and adjacent normal tissues. UTX expression of cancer tissues and adjacent normal tissues was detected on both mRNA and protein levels using real time-PCR and IHC, respectively. And the relationship between UTX expression and the 45 patients' clinical characteristics was analyzed. RESULTS: The mRNA level of UTX in cancer tissues(C) was 4.4 folds, higher than that of the adjacent normal tissues(N) [ 0.883 2±0.703 8 vs. 0.199 7±0.140 0, P<0.05]. The protein expression of UTX in cancer tissues was up-regulated, and the protein score of cancer tissues was 4 folds, change compared with adjacent normal tissues[12±4 vs. 3±3, P<0.05].The expression of UTX was associated with pathological grade(P=0.004)but without gender, age, tumor size and TNM stage. CONCLUSION: UTX is up-regulated in RCC tissues and the expression of UTX is associated with pathological grade, illustrating that UTX may play an important role in renal cancer progression.

Rasch analysis of the perceptions of palliative care instrument (PPCI) in patients with advanced cancer.

RATIONALE, AIMS, AND OBJECTIVES: The Perceptions of Palliative Care Instrument (PPCI) is a tool used to access perceptions towards palliative care in patients with advanced cancer. However, its psychometric properties have not been widely tested using modern psychometric methods. This study aimed to examine the psychometric properties of the PPCI in patients with advanced cancer using Rasch analysis. METHODS: Four hundred and forty four Participants were recruited from the Department of Medical Oncology at a tertiary care hospital in Xinxiang City, Henan Province, China, between October 2020 and February 2021. Participants completed the PPCI. Rasch analysis procedures were conducted, including assessment of unidimensionality, model-date fit, rating scale function, differential item functioning, item-person map, and person and item reliability. RESULTS: The unidimensionality of the PPCI was confirmed, although two items (18 and 21) did not fit the Rasch model. The degree of fit of each item to its respective dimension was excellent, with Infit MNSQ and Outfit MNSQ values ranging from 0.73 to 1.33. The PPCI demonstrated high reliability, with an item reliability of 0.99 and a person reliability of 0.77. CONCLUSION: The PPCI is a valid and reliable instrument for assessing perceptions of palliative care in advanced cancer patients. However, to further improve the quality and applicability of the PPCI, the deletion of items 18 and 21 is recommended, as they did not fit the Rasch model.

A functional variant in IL12B promoter modulates its expression and associates with increased risk of allergic asthma.

The interleukin-12B (IL12B) gene encodes the p40 chain of IL-12, a pro-inflammatory cytokine that antagonizes Th2 phenotype and, hence, may have a critical role in the pathogenesis of allergic asthma. In this report, we describe the identification of a novel IL12B promoter polymorphism (T-to-A exchange) at position -536. The IL12B -536AA genotype was significantly associated with asthma in the Chinese populations (P=0.011, odds ratio=2.227). The risk-associated A allele was linked to reduced expression of IL12B mRNA levels and IL12B production in asthmatic patients. Luciferase reporter assay provided evidence that risk-associated A allele reduced the promoter activity of IL12B gene compared with those of the promoter containing the protective T allele. We further observed that decreasing binding effects between the risk alleles A of IL12B and CCAAT/enhancer binding protein alpha (C/EBPα) through A allele sequence mediated streptavidin-conjugated agarose pulldown and biotin-labelled A allele mediated electrophoretic mobility shift assay. We also observed additive effects of the risk alleles of IL12B and decreased mRNA levels of C/EBPα in asthmatic patients. Therefore, we postulated that the presence of -536A allele in IL12B promoter could predispose to the development of allergic asthma.

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes.

AIMS/HYPOTHESIS: Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes. METHODS: The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m(2) and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case-control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans. RESULTS: Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10(-14)), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10(-11)) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10(-10)). CONCLUSIONS/INTERPRETATION: We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.

Universal method for separating spin pumping from spin rectification voltage of ferromagnetic resonance.

We develop a method for universally resolving the important issue of separating spin pumping from spin rectification signals in bilayer spintronics devices. This method is based on the characteristic distinction of spin pumping and spin rectification, as revealed in their different angular and field symmetries. It applies generally for analyzing charge voltages in bilayers induced by the ferromagnetic resonance (FMR), independent of FMR line shape. Hence, it solves the outstanding problem that device-specific microwave properties restrict the universal quantification of the spin Hall angle in bilayer devices via FMR experiments. Furthermore, it paves the way for directly measuring the nonlinear evolution of spin current generated by spin pumping. The spin Hall angle in a Py/Pt bilayer is thereby directly measured as 0.021±0.015 up to a large precession cone angle of about 20°.

[Influence of sleep fragmentation in infancy and toddler period on emotional and behavioral problem at the age of 6 years: a birth cohort study].

Objective: To investigate the influence of sleep fragmentation in infancy and toddler period on emotional and behavioral problems at the age of 6 years. Methods: Using a prospective cohort design, 262 children were extracted from mother-child birth cohort recruited from May 2012 to July 2013 in Renji Hospital, School of Medicine, Shanghai Jiao Tong University. Children's sleep and physical activities were assessed using actigraphy at 6, 12, 18, 24, and 36 months of age, from which the sleep fragmentation index (FI) at each follow-up point was calculated. Children's emotional and behavioral problems at 6 years of age were assessed using the strengths and difficulties questionnaire. Group-based trajectory model was applied to determine sleep FI in infancy and toddler period trajectory groups with Bayesian information criteria being used to determine the best fitting model. Children's emotional and behavioral problems between groups were examined with independent t test and linear regression models, etc. Results: A total of 177 children, with 91 boys and 86 girls, were included in the final analysis and were divided into 2 groups: high FI group (n=30) and low FI group (n=147). Compared with children in the low FI group, those in the high FI group presents with higher total difficulties score and higher hyperactivity or inattention score ((11.0±4.9) vs. (8.9±4.1), (4.9±2.7) vs. (3.7±2.3) scores, t=2.17, 2.23, both P<0.05, respectively), with the differences remaining significant after adjusting for covariates (t=2.08, 2.09, both P<0.05 respectively). Conclusion: High sleep fragmentation in infancy and toddler period is associated with more emotional and behavioral problems, especially hyperactivity or inattention problems, at 6 years of age.