Search

Social adversity not only causes severe psychological diseases but also may improve people’s ability to learn and grow. However, the beneficial effects of social adversity are often ignored. In this study, we investigated whether and how social adversity affects learning and memory in a mouse social defeat stress (SDS) model. A total of 652 mice were placed in experimental groups of six to 23 mice each. SDS enhanced spatial, novelty, and fear memory with increased synaptosome associated protein 25 ( SNAP-25) level and dendritic spine density in hippocampal neurons among young but not middle-aged mice. Chemogenetic inhibition of hippocampal CaMK2A + neurons blocked SDS-induced enhancement of learning or memory. Knockdown of SNAP-25 or blockade of N-methyl-D-aspartate (NMDA) receptor subunit GluN2B in the hippocampus prevented SDS-induced learning memory enhancement in an emotion-independent manner. These findings suggest that social adversity promotes learning and memory ability in youths and provide a neurobiological foundation for biopsychological antifragility.

Background: Gender and reproductive status differences exist in both non-alcoholic fatty liver disease (NAFLD) and body composition. Our purpose was to investigate the relationship between body composition and the severity of liver steatosis and fibrosis in NAFLD in different gender and reproductive status populations. Methods: This cross-sectional study included 880 participants (355 men, 417 pre-menopausal women, 108 post-menopausal women). Liver steatosis and fibrosis and body composition data were measured using FibroScan and a bioelectrical impedance body composition analyzer (BIA), respectively. Multiple ordinal logistic regression (MOLR) was used to analyze the correlation between body composition indicators and liver steatosis grade and fibrosis stage in different gender and menopausal status populations. Results: Men have higher waist circumference (WC), appendicular skeletal muscle mass (ASM), appendicular skeletal muscle mass index (ASMI), fat free mass (FFM), and fat free mass to fat mass ratio (FFM/FM) than pre- or post-menopausal women, while pre-menopausal women have higher percent body fat (PBF), visceral fat area (VFA), and fat mass (FM) than the other two groups (p < 0.001). Besides, men have greater controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) values (p < 0.001). For MOLR, after adjusting for confounding factors, WC (OR, 1.07; 95% CI, 1.02-1.12; P = 0.011) and FFM/FM (OR, 0.52; 95% CI, 0.31-0.89; P = 0.017) in men and visceral obesity (OR, 4.16; 95% CI, 1.09-15.90; P = 0.037) in post-menopausal women are independently associated with liver steatosis grade. WC, PBF, and visceral obesity are independently associated with liver fibrosis stage in men (OR, 1.05; 95% CI, 1.01-1.09, P = 0.013; OR, 1.08; 95% CI, 1.01-1.15; P = 0.018; OR, 3.92; 95% CI, 1.97-7.81; P < 0.001, respectively). Conclusions: Increased WC and low FFM/FM in men and visceral obesity in post-menopausal women are independent correlates of aggravated liver steatosis. In addition, increased WC, PBF, and visceral obesity are independent correlates of worsening liver fibrosis in men. These data support the gender- and reproductive status-specific management of NAFLD.

Green light exposure has been shown to reduce pain in animal models. Here, we report a vision-associated enkephalinergic neural circuit responsible for green light–mediated analgesia. Full-field green light exposure at an intensity of 10 lux produced analgesic effects in healthy mice and in a model of arthrosis. Ablation of cone photoreceptors completely inhibited the analgesic effect, whereas rod ablation only partially reduced pain relief. The analgesic effect was not modulated by the ablation of intrinsically photosensitive retinal ganglion cells (ipRGCs), which are atypical photoreceptors that control various nonvisual effects of light. Inhibition of the retino–ventrolateral geniculate nucleus (vLGN) pathway completely abolished the analgesic effects. Activation of this pathway reduced nociceptive behavioral responses; such activation was blocked by the inhibition of proenkephalin (Penk)–positive neurons in the vLGN (vLGN Penk ). Moreover, green light analgesia was prevented by knockdown of Penk in the vLGN or by ablation of vLGN Penk neurons. In addition, activation of the projections from vLGN Penk neurons to the dorsal raphe nucleus (DRN) was sufficient to suppress nociceptive behaviors, whereas its inhibition abolished the green light analgesia. Our findings indicate that cone-dominated retinal inputs mediated green light analgesia through the vLGN Penk -DRN pathway and suggest that this signaling pathway could be exploited for reducing pain.

Patients suffering from trigeminal neuralgia are often accompanied by anxiety and depression. Microglia-mediated neuroinflammation is involved in the development of neuropathic pain and anxiodepression pathogenesis. Whether and how microglia are involved in trigeminal neuralgia-induced anxiodepression remains unclear.Unilateral constriction of the infraorbital nerve (CION) was performed to establish trigeminal neuralgia in rat and mouse models. Mechanical allodynia and anxiodepressive-like behaviours were measured. Optogenetic and pharmacological manipulations were employed to investigate the role of hippocampal microglia in anxiety and depression caused by trigeminal neuralgia.Trigeminal neuralgia activated ipsilateral but not contralateral hippocampal microglia, up-regulated ipsilateral hippocampal ATP and interleukin-1β (IL-1β) levels, impaired ipsilateral hippocampal long-term potentiation (LTP) and induced anxiodepressive-like behaviours in a time-dependent manner in rodents. Pharmacological or optogenetic inhibition of ipsilateral hippocampal microglia completely blocked trigeminal neuralgia-induced anxiodepressive-like behaviours. Activation of unilateral hippocampal microglia directly elicited an anxiodepressive state and impaired hippocampal LTP. Knockdown of ipsilateral hippocampal P2X7 receptors prevented trigeminal neuralgia-induced microglial activation and anxiodepressive-like behaviours. Furthermore, we demonstrated that microglia-derived IL-1β mediated microglial activation-induced anxiodepressive-like behaviours and LTP impairment.These findings suggest that priming of microglia with ATP/P2X7 receptors in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviours via IL-1β. An asymmetric role of the bilateral hippocampus in trigeminal neuralgia-induced anxiety and depression was uncovered. The approaches targeting microglia and P2X7 signalling might offer novel therapies for trigeminal neuralgia-related anxiety and depressive disorder.

Background The gonadotropin-releasing hormone (GnRH) antagonist protocol is advantageous given that it can avoid severe ovarian hyperstimulation syndrome (OHSS), especially for patients with polycystic ovary syndrome (PCOS). Basic and clinical evidence has shown that a threshold of luteinizing hormone (LH) stimulation is required for adequate follicular development and oocyte maturation. Ultra-low or high levels of LH are detrimental to pregnancy outcomes. We previously demonstrated that LH could be an indicator for the timing and dosage of antagonist administration in a retrospective study. Methods/design In this randomized, single-center, non-inferiority trial, we aim to test the hypothesis that there is no significant difference in cumulative ongoing pregnancy rates between PCOS patients stimulated with LH-based flexible protocol versus traditional flexible GnRH antagonist protocol. The primary efficacy endpoint will be the cumulative ongoing pregnancy rate per cycle. The secondary outcomes will be clinical pregnancy rate, cancelation rate, serious OHSS rate, and cost-efficiency. The cumulative ongoing pregnancy rate per cycle in PCOS women was 80%. Considering that a non-inferiority threshold should retain 80% of the clinical effect of a control treatment, a minimal clinical difference of 16% (two-sided: α, 2.5%; β, 20%) and a total of 196 patients were needed. Anticipating a 10% dropout rate, the total number of patients required was 216. Discussion The results of this study will provide evidence for the efficacy and safety of the LH-based flexible GnRH antagonist protocol in PCOS patients. Moreover, it evaluates the cost-efficiency of both protocols. Trial registration Chinese Clinical Trial Registry ChiCTR1800018129. Date assigned: 31 August 2018. Protocol version: 1.0 (18 July 2017)

RESEARCH QUESTION: Granulosa cells (GCs) surrounding oocytes are crucial for follicular growth, oocyte development, ovulation, and luteinization under the dynamic co-stimulation of follicle stimulating hormone (FSH) and luteinizing hormone (LH). This study aimed to investigate the effect of LH levels on GCs in preovulatory follicles under gonadotropin releasing hormone antagonist-based ovarian stimulation. In vitro experiments were also conducted to study the direct effect of LH on GCs. METHODS: Twelve infertile women were divided into low (L), medium (M), and high (H) LH groups according to their serum LH levels during ovarian stimulation. RNA-sequencing (RNA-seq) was conducted to examine the transcriptome profiles of GCs obtained from the above patients during the oocyte retrieval. The activity of mitochondrial dehydrogenase was measured under the stimulation of recombinant LH (rLH) concentration gradient combined with recombinant FSH. The ultrastructures of subcellular organelles were observed. RESULTS: Bioinformatic analyses showed that compared with the M group, molecule and pathway changes in the L group and in the H group were similar. In cultured GCs, both insufficient and excessive rLH impaired the activity of mitochondrial dehydrogenase. With the medium rLH concentration, numerous cell connections and abundant mitochondria and liposomes were observed. Compared with the medium concentration, GCs showed smaller and rounder mitochondria, more autophagosomes, and massive organelles damages with excessive rLH, and swollen, circular, or forked mitochondria were observed with inadequate rLH. CONCLUSIONS: RNA-seq provided a novel spectrum of transcriptome characteristics of GCs potentially affected by serum LH levels during ovarian stimulation. In vitro, rLH could directly affect GCs at the subcellular level. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02066-8.

Background Brain-derived estrogen is implicated in pain-related aversion; however, which estrogen receptors mediate this effect remains unclear. This study hypothesized that the different estrogen receptors in the rostral anterior cingulate cortex play distinct roles in pain-related aversion. Methods Formalin-induced conditioned place avoidance and place escape/avoidance paradigms were used to evaluate pain-related aversion in rodents. Immunohistochemistry and Western blotting were used to detect estrogen receptor expression. Patch-clamp recordings were used to examine N-methyl-d-aspartate–mediated excitatory postsynaptic currents in rostral anterior cingulate cortex slices. Results The administration of the estrogen receptor-β antagonist 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP) or the G protein–coupled estrogen receptor-1 antagonist (3aS*,4R*,9bR*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15) but not the estrogen receptor-α antagonist 1,3-bis (4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP) into the rostral anterior cingulate cortex blocked pain-related aversion in rats (avoidance score, mean ± SD: 1,3-bis [4-hydroxyphenyl]-4-methyl-5-(4-[2-piperidinylethoxy] phenol)-1H-pyrazole dihydrochloride (MPP): 47.0 ± 18.9%, 4-(2-phenyl-5,7-bis [trifluoromethyl] pyrazolo [1,5-a] pyrimidin-3-yl) phenol (PHTPP): −7.4 ± 20.6%, and [3aS*,4R*,9bR*]-4-[6-bromo-1,3-benzodioxol-5-yl]-3a,4,5,9b-3H-cyclopenta [c] quinolone (G15): −4.6 ± 17.0% vs. vehicle: 46.5 ± 12.2%; n = 7 to 9; P < 0.0001). Consistently, estrogen receptor-β knockdown but not estrogen receptor-α knockdown by short-hairpin RNA also inhibited pain-related aversion in mice (avoidance score, mean ± SD: estrogen receptor-α–short-hairpin RNA: 26.0 ± 7.1% and estrogen receptor-β–short-hairpin RNA: 6.3 ± 13.4% vs. control short-hairpin RNA: 29.1 ± 9.1%; n = 7 to 10; P < 0.0001). Furthermore, the direct administration of the estrogen receptor-β agonist 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN) or the G protein–coupled estrogen receptor-1 agonist (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1) into the rostral anterior cingulate cortex resulted in conditioned place avoidance (avoidance score, mean ± SD: 2,3-bis (4-hydroxyphenyl)-propionitrile (DPN): 35.3 ± 9.5% and (±)-1-([3aR*,4S*,9bS*]-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta [c]quinolin-8-yl)-ethanone (G1): 43.5 ± 22.8% vs. vehicle: 0.3 ± 14.9%; n = 8; P < 0.0001) but did not affect mechanical or thermal sensitivity. The activation of the estrogen receptor-β/protein kinase A or G protein–coupled estrogen receptor-1/protein kinase B pathway elicited the long-term potentiation of N-methyl-d-aspartate–mediated excitatory postsynaptic currents. Conclusions These findings indicate that estrogen receptor-β and G protein–coupled estrogen receptor-1 but not estrogen receptor-α in the rostral anterior cingulate cortex contribute to pain-related aversion by modulating N-methyl-d-aspartate receptor–mediated excitatory synaptic transmission. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Patients suffering from trigeminal neuralgia (TN) are often accompanied by anxiety and depression. Whether and how microglia are involved in TN-induced anxiodepressive remains unclear. Here, we unconventionally report that TN activates ipsilateral but not contralateral hippocampal microglia, upregulates ipsilateral hippocampal ATP and interleukin1β (IL-1β) levels, impairs ipsilateral hippocampal long-term potentiation (LTP), and induces anxiodepressive-like behaviors in a time-dependent manner in rodents. Specifically, activation of ipsilateral hippocampal microglia is necessary for TN-induced anxiodepressive-like behaviors; and unilateral activating hippocampal microglia is sufficient to elicit an anxiodepressive state and impair LTP. Knockdown of ipsilateral hippocampal P2X7 receptor prevented TN-induced microglial activation and anxiodepressive-like behaviors. Furthermore, we demonstrate that microglia-derived IL-1β mediates microglial activation-induced anxiodepressive-like behaviors and LTP impairment. Together, these findings suggest that priming of microglia with ATP/P2X7R in the ipsilateral hippocampus drives pain-related anxiodepressive-like behaviors via IL-1β. Our results also reveal an asymmetric role of the bilateral hippocampus in TN-induced anxiety and depression.

Bacterial wilt caused by Ralstonia solanacearum is a distributed and worldwide soilborne disease. The application of biocontrol microbes or agricultural chemicals has been widely used to manage tomato bacterial wilt. However, whether and how agricultural chemicals affect the antagonistic ability of biocontrol microbes is still unknown. Here, we combined potassium phosphite (K-Phite), an environmentally friendly agricultural chemical, and the biocontrol agent Bacillus amyloliquefaciens QPF8 (strain F8) to manage tomato bacterial wilt disease. First, K-Phite at a concentration of 0.05% (wt/vol) could significantly inhibit the growth of R. solanacearum. Second, 0.05% K-Phite enhanced the antagonistic capability of B. amyloliquefaciens F8. Third, the greenhouse soil experiments showed that the control efficiency for tomato bacterial wilt in the combined treatment was significantly higher than that of the application of B. amyloliquefaciens F8 or K-Phite alone. Overall, our results highlighted a novel strategy for the control of tomato bacterial wilt disease via application and revealed a new integrated pattern depending on the enhancement of the antagonistic capability of biocontrol microbes by K-Phite.

This study explored the impact of low luteinizing hormone (LH) levels during ovarian stimulation on endometrial function. Based on previous studies by us and others, we divided the patients into low ( 4 IU/L), medium (4-10 IU/L), and high ( 10 IU/L) LH groups. The study utilized a comparison control group design with three groups of 10 patients. Gene set enrichment analysis (GSEA) was applied for functional annotation. By analyzing the exon differentially expressed genes in the endometrium of these three patient groups during the embryo implantation window, we found that when compared to the medium LH group, low LH downregulated endometrial cell metabolism, including mitochondrial-nicotinamide adenine dinucleotide (Normalized Enrichment Scores, NES = - 1.53) and glycolytic metabolism (NES = - 1.22), immune regulation, and autophagy (NES = - 1.58). Transcription factors were the main regulators of cell function. We found that MCM2 was probably involved in regulating the endometrial function induced by low LH. MCM2 target genes were enriched in low LH group, NES = - 1.54. Low LH, but not high LH, altered the endometrial receptivity assay gene expression in comparison to the medium LH. Our results indicated that low LH impacted the endometrial cell function, with a greater effect than high LH. This research provides timely and necessary data on the involvement of LH in important endometrial cellular processes and these data support further clinical development of endometrial receptivity.

IntroductionMany patients demonstrate an insufficient endogenous luteinising hormone (LH) concentration during ovarian stimulation. With traditional fixed or flexible gonadotropin-releasing hormone (GnRH) antagonist protocols, antagonist administration may further reduce LH activity. Previously, we proved that LH can be used as an indicator for the timing and dosage of antagonist. Patients with a persistently low LH concentration during ovarian stimulation may not require antagonists, whereas antagonist administration can affect reproductive outcomes. To further explore this hypothesis, we designed a randomised clinical trial to compare the LH-based flexible GnRH antagonist protocol with traditional flexible GnRH antagonist protocol in women with normal ovarian response.Methods and analysisThis study was a multicentre, parallel, prospective, randomised, non-inferiority study. The primary efficacy endpoint was cumulative ongoing pregnancy rate per cycle. The study aimed to prove the non-inferiority of cumulative ongoing pregnancy rate per cycle with an LH-based flexible GnRH antagonist protocol versus traditional flexible GnRH antagonist protocol. Secondary endpoints were the high-quality embryo rate, clinical pregnancy rate and cancellation rate. Differences in cost-effectiveness and adverse events were evaluated. The cumulative ongoing pregnancy rate per cycle in women with normal ovarian response was 70%. Considering that a non-inferiority threshold should retain 80% of the clinical effect of a control treatment, a minimal clinical difference of 14% (one-sided: α, 2.5%; β, 20%) and a total of 338 patients were needed. Anticipating a 10% drop-out rate, the total number of patients required was 372.Ethics and disseminationThis trial has been approved by the Institutional Ethical Committee of Beijing Chao-Yang hospital. All participants in the trial will provide written informed consent. The study will be conducted according to the principles outlined in the Declaration of Helsinki and its amendments. Results of this study will be disseminated in peer-reviewed scientific journals.Trial registration numberChiCTR1800018077.

BackgroundUse of gonadotropin-releasing hormone (GnRH) antagonists during the late follicular phase can prevent premature luteinizing hormone (LH) surge. Many patients demonstrate an insufficient endogenous LH concentration during ovarian stimulation. Previous studies have demonstrated that ultra-low LH concentration influences pregnancy outcomes. However, affected patients cannot be distinguished prior to ovarian stimulation using baseline characteristics alone. With traditional fixed or flexible GnRH antagonist protocols, antagonist administration may further reduce LH activity. Previously, we proved that LH can be used as an indicator for the timing and dosage of antagonist. Patients with a persistently low LH concentration during ovarian stimulation may not require antagonists, whereas antagonist administration can affect reproductive outcomes. To further explore this hypothesis, we designed a randomized clinical trial to compare the LH-based flexible GnRH antagonist protocol with traditional flexible GnRH antagonist protocol in women with normal ovarian response. MethodsThis study was a multicenter, parallel, prospective, randomized, non-inferiority study. The primary efficacy endpoint was cumulative ongoing pregnancy rate per cycle. The study aimed to prove the non-inferiority of cumulative ongoing pregnancy rate per cycle with a LH-based flexible GnRH antagonist protocol versus traditional flexible GnRH antagonist protocol. Secondary endpoints were the high-quality embryo rate, clinical pregnancy rate, and cancellation rate. Differences in cost-effectiveness and adverse events were evaluated. The cumulative ongoing pregnancy rate per cycle in women with normal ovarian response was 70%. Considering that a non-inferiority threshold should retain 80% of the clinical effect of a control treatment, a minimal clinical difference of 14% (one-sided: α, 2.5%; β, 20%) and a total of 338 patients were needed. Anticipating a 10% dropout rate, the total number of patients required was 372.DiscussionThis is the first randomized controlled trial to compare the efficacy of a LH-based treatment regimen with a traditional flexible GnRH antagonist protocol during ovarian stimulation. We hypothesized no significant difference in cumulative ongoing pregnancy rate per cycle between the two protocols. Moreover, patients with insufficient endogenous LH during ovarian stimulation may benefit from LH-based GnRH antagonist protocols. The results will provide new information on when to introduce antagonists and the appropriate dosage of antagonist.Trial registration: ClinicalTrials.gov, ChiCTR1800018077. Registered on 29 August, 2018.

High-throughput sequencing, culture-dependent workflows, and microbiome transfer experiments reveal whether potassium phosphite (KP), an environmentally acceptable agricultural chemical, could specifically enrich the antagonistic bacterial community that inhibited the growth of the pathogen Ralstonia solanacearum. The application of KP enriched the potential antagonistic bacteria Paenibacillus and Streptomyces in soil, but depleted most dominant genera belonging to gram negative bacteria, such as Pseudomonas, Massilia, and Flavobacterium on day 7. Moreover, the KP-modulated soil microbiome suppressed R. solanacearum growth in soil. The predicted functions related to the synthesis of antagonistic substances, such as streptomycin, and the predicted functions related to tellurite resistance and nickel transport system were significantly enriched, but the synthesis of lipopolysaccharide (distinct component lipopolysaccharide in gram negative bacteria) were significantly depleted in the KP-treated soils. In addition, the copy numbers of specific sequences for Streptomyces coelicoflavus and Paenibacillus favisporus were significantly increased in the soil amended with KP, inhibited the growth of R. solanacearum, and had a higher tolerance of KP than R. solanacearum. Our study linked the application of fertilizers to the enrichment of antagonistic bacteria, which could support future work that aims to precisely regulate the soil microbiome to protect the host from infection by soil-borne pathogens.

Depression and anxiety are frequently observed in patients suffering from neuropathic pain. The underlying mechanisms remained unclear. The ventrolateral orbital cortex (VLO) has attracted considerable interest in its role in antidepressive effect in rodents. In the present study, we further investigated the role of the VLO in the anxiodepressive consequences of neuropathic pain in a chronic constriction injury of infraorbital nerve–induced trigeminal neuralgia (TN) mouse model. Elevated plus maze, open field, forced swimming, tail suspension, and sucrose preference tests were used to evaluate anxiodepressive-like behaviors. The results show that chemogenetic activation of bilateral VLO neurons, especially CaMK2A+ pyramidal neurons, blocked the TN-induced anxiodepressive-like behaviors. Chemogenetic and optogenetic activation of VGLUT2+ or inhibition of VGAT+ VLO neurons was sufficient to produce an antianxiodepressive effect in TN mice. Pharmacological activation of D1-like receptors (D1Rs) but not D2Rs in the VLO significantly alleviated TN-induced depressive-like behaviors. Electrophysiological recordings revealed a decreased excitability of VLO excitatory neurons following neuropathic pain. Furthermore, activation of submedius thalamic nucleus–VLO (Sm-VLO) projection mimicked the antianxiodepressive effect of VLO excitation. Conversely, activation of VLO-periaqueductal gray matter (PAG) projection had no effect on TN-induced anxiodepressive behaviors. This study provides a potentially novel mechanism–based therapeutic strategy for the anxiodepressive consequences of neuropathic pain., Activating excitatory neurons or inhibiting GABAergice neurons of the VLO improved anxiodepressive consequences of neuropathic pain in a trigeminal neuralgia mouse model.

Background: Obesity is associated with reproductive disorders and infertility. Autophagy is upregulated during decidualization, but is diminished in obesity models with impaired decidualization. Defects in autophagy are related to the occurrence of inflammatory diseases, but its role in endometrial decidualization with obese patients is unknown.Methods: The levels of autophagy-related factors (LC3B-II and Beclin 1), and autophagy-related proteins which have a correlation with endometrial decidualization (ATG3, ATG5, ATG7 and foxo1), as well as autophagy-related inflammatory cytokines in endometrium of lean and obese patients was assessed. We then investigated the the role of autophagic flux during decidualization in ‘obese’- vs ‘lean’- treated cells from matched patients.Results: Alteration in autophagic flux and the expression of autophagy-related genes revealed impaired autophagy in obese patients compared with lean. Autophagy-related proinflammatory cytokines were upregulated in the uterine cavity of obese patients, who also showed impaired decidualization.Conclusions: Obesity downregulates the expression of autophagy-related genes and impairs endometrial stromal cell autophagic flux, and induces inflammation. These alterations in autophagy are associated with increased activation of autophagy-related proinflammatory cytokines might decrease basic uterine receptivity.

Deep convolutional neural networks (CNNs) have achieved commendable results on a variety of medical image segmentation tasks. However, CNNs usually require a large amount of training samples with accurate annotations, which are extremely difficult and expensive to obtain in medical image analysis field. In practice, we notice that the junior trainees after training can label medical images in some medical image segmentation applications. These non-expert annotations are more easily accessible and can be regarded as a source of weak annotation to guide network learning. In this paper, we propose a novel Tri-network learning framework to alleviate the problem of insufficient accurate annotations in medical segmentation tasks by utilizing the non-expert annotations. To be specific, we maintain three networks in our framework, and each pair of networks alternatively select informative samples for the third network learning, according to the consensus and difference between their predictions. The three networks are jointly optimized in such a collaborative manner. We evaluated our method on real and simulated non-expert annotated datasets. The experiment results show that our method effectively mines informative information from the non-expert annotations for improved segmentation performance and outperforms other competing methods.

// Rong-Rong Liu 1, * , Ya-Su Lv 1, * , Yue-Xiao Tang 1 , Yan-Fang Wang 1 , Xiao-Ling Chen 2 , Xiao-Xiao Zheng 1 , Shang-Zhi Xie 1 , Ying Cai 1 , Jun Yu 3 , Xian-Ning Zhang 1 1 Department of Cell Biology and Medical Genetics, Research Center for Molecular Medicine, National Education Base for Basic Medical Sciences, Institute of Cell Biology, Zhejiang University School of Medicine, Hangzhou, 310058, China 2 Department of Biological Chemistry, Zhejiang Chinese Medical University, Hangzhou, 310053, China 3 Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Multi-Organ Transplantation of Ministry of Public Health, Hangzhou, 310003, China * These authors contributed equally to this work Correspondence to: Xian-Ning Zhang, e-mail: zhangxianing@zju.edu.cn Jun Yu, e-mail: Dr.yujun@gmail.com Keywords: eukaryotic translation initiation factor 5A2, reactive oxygen species, epithelial-mesenchymal transition, migration, hepatocellular carcinoma Received: September 24, 2015 Accepted: February 28, 2016 Published: March 23, 2016 ABSTRACT Eukaryotic translation initiation factor 5A2 ( eIF5A2 ) has been identified as a critical gene in tumor metastasis. Research has suggested that reactive oxygen species (ROS) serve as signaling molecules in cancer cell proliferation and migration. However, the mechanisms linking eIF5A2 and ROS are not fully understood. Here, we investigated the effects of ROS on the eIF5A2-induced epithelial-mesenchymal transition (EMT) and migration in six hepatocellular carcinoma (HCC) cell lines. Western hybridization, siRNA transfection, transwell migration assays, wound-healing assays, and immunofluorescence analysis were used. The protein levels of eIF5A2 in tumor and adjacent tissue samples from 90 HCC patients with detailed clinical, pathological, and clinical follow-up data were evaluated. Overexpression of eIF5A2 was found in cancerous tissues compared with adjacent tissues. We found that eIF5A2 overexpression in HCC was associated with reduced overall survival. Knockdown of eIF5A2 and intracellular reduction of ROS significantly suppressed the invasion and metastasis of HCC cells. Interestingly, N1-guanyl-1, 7-diaminoheptane (GC7) suppressed the intracellular ROS levels. After blocking the EMT, administration of GC7 or N-acetyl-L-cysteine did not reduce cell migration further. Based on the experimental data, we concluded that inhibition of eIF5A2 alters progression of the EMT to decrease the invasion and metastasis of HCC cells via ROS-related pathways.

Epidermolytic palmoplantar keratoderma (EPPK) is the most frequent form of such keratodermas. It is inherited in an autosomal dominant pattern and is clinically characterized by diffuse yellowish thickening of the skin on the palms and soles with erythematous borders during the first weeks or months after birth. EPPK is generally caused by mutations of the KRT9 gene. More than 26 KRT9 gene mutations responsible for EPPK have been described (Human Intermediate Filament Database, www.interfil.org), and many of these variants are located within the highly-conserved coil 1A region of the α-helical rod domain of keratin 9. Unfortunately, there is no satisfactory treatment for EPPK. Thus, prenatal molecular diagnosis or pre-pregnancy diagnosis is crucial and benefits those affected who seek healthy descendants. In the present study, we performed amniotic fluid-DNA-based prenatal testing for three at-risk pregnant EPPK women from three unrelated southern Chinese families who carried the KRT9 missense mutations p.Arg163Trp and p.Arg163Gln, and successfully helped two families to bear normal daughters. We suggest that before the successful application of preimplantation genetic diagnosis (PGD), and noninvasive prenatal diagnosis of EPPK that analyzes fetal cells or cell-free DNA in maternal blood, prenatal genetic diagnosis by amniocentesis or chorionic villus sampling (CVS) offers a quite acceptable option for EPPK couples-at-risk to avoid the birth of affected offspring, especially in low- and middle-income countries.

Combining the energy limit theory and the ANSYS finite element simulation analysis, this paper has designed the new integrated quartz crystal resonator and has used oscillator circuits to carry on the experimental comparison on its temperature-frequency characteristic in high-low temperature chamber. The experimental results show that the curve of its temperature-frequency characteristic is cubic in the coordinate system, which is basically consistent with that of the single electrode resonator. The frequency change of each resonator on the same substrate is basically the same when they are in the same circumstance and stimulation. According these similarities, this paper can implement differential processing on output frequencies of different resonators on the same substrate, which can effectively restrain the influence that temperature imposes on frequency.

By analysing the wafer, the electrodes, etc. according to the energy limit theory and the ANSYS finite element simulation, in this paper the author has designed the integrated quartz crystal resonator and oscillator circuit, and has carried on the experimental comparison on the stability of the integrated resonators, which have different structure, different electrode material and thickness. The experimental results show that the frequency stability of quartz crystal resonator is not only related with the electrode material and thickness, but also related with the structure. Under the same condition, resonator of asymmetric structure has better frequency stability, and the stability of Au-electrode was better than others, and its magnitude could reach 10 10. With the increase of the electrode thickness, the resonator oscillator stability will be improved.

Analyzing stress distribution of the thin circular quartz wafer subjected the radial force through the ANSYS finite element simulation, as well as the theoretical simulation, this paper designed two integrated quartz resonators with different structures and carried on experiments on force-frequency characteristic of resonators. The experimental results show that the resonators force-frequency characteristic is not only closely related to adding force azimuth, but also the electrode size and position. And when force azimuths are same, integrated resonator with asymmetric structure has better force-frequency characteristic, its force-frequency conversion coefficient could achieve 551.8Hz/N after electrode was evaporated with Au.

To solve the missing data problem that is caused by reasons, such as occlusion, frame reconstruction by a two-level strategy in multiple images was considered. The method first performed a projective reconstruction combining singular value decomposition (SVD) and subspace method with missing data, which estimated projective shape, projection matrices, projective depths and missing data iteratively. Then it converted the projective solution to a Euclidean one with the unknown focal length and the constant principal point by enforcing constraints. Using the constraints and the fact that scale measurement matrix can recover numberless projection matrices and point matrices, the set equations of the transformation matrix from the projective reconstruction to Euclidean reconstruction were obtained. Experimental results using real images are provided to illustrate the performance of the proposed method.

Extrapontine myelinolysis and pure word deafness are very uncommon disorders. Here, we report a case of a 19-year-old woman who suffered from osmotic demyelination syndrome with coincidence of typical pure word deafness. As a consequence of rapid correction of hyponatremia, the patient demonstrated an initial onset of cortical deafness, and then progressed to generalized auditory agnosia, which eventually developed into confined verbal auditory agnosia (pure word deafness). Bilateral extrapontine myelinolysis was confirmed using brain magnetic resonance imaging. This case suggests that verbal and nonverbal stimuli may involve separate thalamocortical pathways.

Based on the mode-coupling method, numerical analysis is presented to demonstrate the influence of ripple taper on coupling modes on the frequency response in a coaxial Bragg structure. Results show that the interval between the band-gaps of the competing mode and the desired working mode is narrowed by use of a positive taper, but is expanded if a negative taper is employed, and the influence of the negative taper is more obviously advantage than the positive taper. The residual side-lobes of the frequency response on coupling modes can be effectively suppressed by employing the windowing-function technique. These characteristics of a tapered coaxial Bragg structure are favorable to improvement of the performance as a reflector or a filter in its application, also favorable to the mode selectivity and further weaken the excitation of unwanted spurious modes.

To observe the efficacy of Xingnaojing Injection (XI) in treatment of sepsis-associated encephalopathy (SAE).Totally 65 SAE patients were retrospectively analyzed at EICU from September 2010 to September 2013. They were assigned to the control group (32 cases) and the treatment group (33 cases) according to whether they received XI. Patients in the control group received anti-infection and symptomatic support, while those in the treatment group were intravenously injected with XI at 20 mL per day for additional 7-10 days. The fever clearance time, Glasgow coma scale (GCS), C-reactive protein (CRP), neuron-specific enolase (NSE), and improvement of electroen-cephalogram (EEG) were observed in the two groups.Compared with the control group, the fever clearance time was shortened, CRP levels decreased, GCS score and efficacy of EEG was alleviated in the treatment group after treatment with statistical difference (P0.05). No adverse reaction occurred during medication.X1 was safe and effective in treatment of SAE.

AIM: To identify the disease-causing gene mutation in a Chinese pedigree with autosomal dominant cone-rod dystrophy (adCORD). METHODS: A southern Chinese adCORD pedigree including 9 affected individuals was studied. Whole-exome sequencing (WES), coupling the Agilent whole-exome capture system to the Illumina HiSeq 2000 DNA sequencing platform was used to search the specific gene mutation in 3 affected family members and 1 unaffected member. After a suggested variant was found through the data analysis, the putative mutation was validated by Sanger DNA sequencing of samples from all available family members. RESULTS: The results of both WES and Sanger sequencing revealed a novel nonsense mutation c.C766T (p.Q256X) within exon 5 of CRX gene which was pathogenic for adCORD in this family. The mutation could affect photoreceptor-specific gene expression with a dominant-negative effect and resulted in loss of the OTX tail, thus the mutant protein occupies the CRX-binding site in target promoters without establishing an interaction and, consequently, may block transactivation. CONCLUSION: All modes of Mendelian inheritance in CORD have been observed, and genetic heterogeneity is a hallmark of CORD. Therefore, conventional genetic diagnosis of CORD would be time-consuming and labor-intensive. Our study indicated the robustness and cost-effectiveness of WES in the genetic diagnosis of CORD.

Since year 2000, our country, to improve students' English abilities, promoted bilingual education in Universities and Colleges. In response, teachers from all over the country have been working in this domain and published tens of thousands of relative research papers and articles. Recently, more researchers are concerned with the appraisal of bilingual education in order to find out its effectiveness. However, most of these researchers stand on the perspective of the course itself, which made their results relatively parochial. In teaching practice, the author found that factors should be evaluated from a higher perspective. This paper attempts to give an evaluation system to assess the bilingual education of a school from much thorough aspects.

Based on the mode-coupling method, numerical analysis is presented to demonstrate the influence of ripple taper on band-gap overlap in a coaxial Bragg structure operating at terahertz frequency. Results show that the interval between the band-gaps of the competing mode and the desired working mode is narrowed by use of positive-taper ripples, but is expanded if negative-taper ripples are employed, and the influence of the negative-taper ripples is obviously more advantageous than the positive-taper ripples; the band-gap overlap of modes can be efficiently separated by use of negative-taper ripples. The residual side-lobes of the frequency response in a coaxial Bragg structure with ripple taper also can be effectively suppressed by employing the windowing-function technique. These peculiarities provide potential advantage in constructing a coaxial Bragg cavity with high quality factor for single higher-order-mode operation of a high-power free-electron maser in the terahertz frequency range.