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Xu-gang Tang,1 Ji-hang Zhang,1 Jun Qin,1 Xu-bin Gao,1 Qian-ning Li,2 Jie Yu,1 Xiao-han Ding,1 Lan Huang1 1Institute of Cardiovascular Diseases, 2Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, People’s Republic of China Background: The aim of this study was to explore the relationship between age and acute mountain sickness (AMS) when subjects are exposed suddenly to high altitude.Methods: A total of 856 young adult men were recruited. Before and after acute altitude exposure, the Athens Insomnia Scale score (AISS) was used to evaluate the subjective sleep quality of subjects. AMS was assessed using the Lake Louise scoring system. Heart rate (HR) and arterial oxygen saturation (SaO2) were measured.Results: Results showed that, at 500 m, AISS and insomnia prevalence were higher in older individuals. After acute exposure to altitude, the HR, AISS, and insomnia prevalence increased sharply, and the increase in older individuals was more marked. The opposite trend was observed for SaO2. At 3,700 m, the prevalence of AMS increased with age, as did severe AMS, and AMS symptoms (except gastrointestinal symptoms). Multivariate logistic regression analysis showed that age was a risk factor for AMS (adjusted odds ratio [OR] 1.07, 95% confidence interval [CI] 1.01–1.13, P

Xu-gang Tang,1 Ji-hang Zhang,1 Xu-bin Gao,1 Qian-ning Li,2 Jia-bei Li,1 Jie Yu1 Jun Qin,1 Lan Huang11Institute of Cardiovascular Diseases, 2Department of Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, People’s Republic of ChinaObjective: We aimed to observe the changes in subjective sleep quality among insomniacs and non-insomniacs after acute ascending to 3,700 m and its possible relationship with acute mountain sickness (AMS). Methods: A total of 600 adult men were recruited. Subjects’ subjective sleep quality was evaluated by the Athens Insomnia Scale. AMS was assessed using the Lake Louise scoring system. Arterial oxygen saturation was measured. Results: Despite insomnia resolution in only a few subjects, the prevalence of insomnia among insomniacs remained stable at 90% after rapid ascent to 3,700 m. However, among non-insomniacs, the prevalence of insomnia sharply increased to 32.13% in the first day of altitude exposure and progressively reduced to 4.26% by the 60th day of altitude stay. Moreover, the prevalences of insomnia symptoms decreased more markedly from day 1 to day 60 at 3,700 m among non-insomniacs than among insomniacs. At 3,700 m, the prevalence of AMS among insomniacs was 79.01%, 60.49%, and 32.10% on the first, third, and seventh days, respectively, which was significantly higher than that among non-insomniacs. Multivariate regression revealed that elevated Athens Insomnia Scale scores are an independent risk factor for AMS (adjusted odds ratio 1.388, 95% confidence interval: 1.314–1.464, P

The e^{+}e^{-}→D_{s}^{+}D_{s1}(2536)^{-} and e^{+}e^{-}→D_{s}^{+}D_{s2}^{*}(2573)^{-} processes are studied using data samples collected with the BESIII detector at center-of-mass energies from 4.530 to 4.946 GeV. The absolute branching fractions of D_{s1}(2536)^{-}→D[over ¯]^{*0}K^{-} and D_{s2}^{*}(2573)^{-}→D[over ¯]^{0}K^{-} are measured for the first time to be (35.9±4.8±3.5)% and (37.4±3.1±4.6)%, respectively. The e^{+}e^{-}→D_{s}^{+}D_{s1}(2536)^{-} and e^{+}e^{-}→D_{s}^{+}D_{s2}^{*}(2573)^{-} cross sections are measured, and a resonant structure at around 4.6 GeV with a width of 50 MeV is observed in both processes with a statistical significance of 7.2σ and 15σ, respectively. The state is observed for the first time in e^{+}e^{-}→D_{s}^{+}D_{s2}^{*}(2573)^{-} and could be the Y(4626) found by the Belle oration in the D_{s}^{+}D_{s1}(2536)^{-} final state, since they have similar masses and widths. There is also evidence for a structure at around 4.75 GeV in both processes.

The J/ψ, ψ(3686)→Σ^{0}Σ[over ¯]^{0} processes and subsequent decays are studied using the world's largest J/ψ and ψ(3686) data samples collected with the BESIII detector. The parity-violating decay parameters of the decays Σ^{0}→Λγ and Σ[over ¯]^{0}→Λ[over ¯]γ, α_{Σ^{0}}=-0.0017±0.0021±0.0018 and α[over ¯]_{Σ^{0}}=0.0021±0.0020±0.0022, are measured for the first time. The strong CP symmetry is tested in the decays of the Σ^{0} hyperons for the first time by measuring the asymmetry A_{CP}^{Σ}=α_{Σ^{0}}+α[over ¯]_{Σ^{0}}=(0.4±2.9±1.3)×10^{-3}. The weak CP test is performed in the subsequent decays of their daughter particles Λ and Λ[over ¯]. Also for the first time, the transverse polarizations of the Σ^{0} hyperons in J/ψ and ψ(3686) decays are observed with opposite directions, and the ratios between the S-wave and D-wave contributions of the J/ψ, ψ(3686)→Σ^{0}Σ[over ¯]^{0} decays are obtained. These results are crucial to understand the decay dynamics of the charmonium states and the production mechanism of the Σ^{0}-Σ[over ¯]^{0} pairs.

Understanding the neural basis of infant social behaviors is crucial for elucidating the mechanisms of early social and emotional development. In this work, we report a specific population of somatostatin-expressing neurons in the zona incerta (ZI SST ) of preweaning mice that responds dynamically to social interactions, particularly those with their mother. Bidirectional neural activity manipulations in pups revealed that widespread connectivity of preweaning ZI SST neurons to sensory, emotional, and cognitive brain centers mediates two key adaptive functions associated with maternal presence: the reduction of behavior distress and the facilitation of learning. These findings reveal a population of neurons in the infant mouse brain that coordinate the positive effects of the relationship with the mother on an infant's behavior and physiology.

Using data samples collected with the BESIII detector operating at the BEPCII storage ring, the cross section of the inclusive process e^{+}e^{-}→η+X, normalized by the total cross section of e^{+}e^{-}→hadrons, is measured at eight center-of-mass energy points from 2.0000 to 3.6710 GeV. These are the first measurements with momentum dependence in this energy region. Our measurement shows a significant discrepancy compared to the existing fragmentation functions. To address this discrepancy, a new QCD analysis is performed at the next-to-next-to-leading order with hadron mass corrections and higher twist effects, which can explain both the established high-energy data and our measurements reasonably well.

Using (10.087±0.044)×10^{9} J/ψ events collected with the BESIII detector at the BEPCII storage ring, the processes Λp→Λp and Λ[over ¯]p→Λ[over ¯]p are studied, where the Λ/Λ[over ¯] baryons are produced in the process J/ψ→ΛΛ[over ¯] and the protons are the hydrogen nuclei in the cooling oil of the beam pipe. Clear signals are observed for the two reactions. The cross sections in -0.9≤cosθ_{Λ/Λ[over ¯]}≤0.9 are measured to be σ(Λp→Λp)=(12.2±1.6_{stat}±1.1_{syst}) and σ(Λ[over ¯]p→Λ[over ¯]p)=(17.5±2.1_{stat}±1.6_{syst})  mb at the Λ/Λ[over ¯] momentum of 1.074  GeV/c within a range of ±0.017  GeV/c, where the θ_{Λ/Λ[over ¯]} are the scattering angles of the Λ/Λ[over ¯] in the Λp/Λ[over ¯]p rest frames. Furthermore, the differential cross sections of the two reactions are also measured, where there is a slight tendency of forward scattering for Λp→Λp, and a strong forward peak for Λ[over ¯]p→Λ[over ¯]p. We present an approach to extract the total elastic cross sections by extrapolation. The study of Λ[over ¯]p→Λ[over ¯]p represents the first study of antihyperon-nucleon scattering, and these new measurements will serve as important inputs for the theoretical understanding of the (anti)hyperon-nucleon interaction.

Objective: To investigate the clinical effects of free superficial circumflex iliac artery (SCIA) superficial branch perforator flap combined with full-thickness skin graft far from the flap donor site in repairing the large wounds in extremities. Methods: The study was a retrospective observational study. From January 2020 to June 2022, 19 patients with large wounds in extremities who met the inclusion criteria were admitted to the First Affiliated Hospital of Bengbu Medical College, including 15 males and 4 females, aged 28-75 years. The debridement, fracture reduction and fixation, tendon, vessel, and nerve repair, and vacuum sealing drainage were performed in the first stage surgery. After debridement in the second stage surgery, the total wound area was 13.0 cm×8.0 cm-34.0 cm×15.0 cm. The tendon and bone exposed wound with area of 9.0 cm×6.0 cm-14.0 cm×7.0 cm was repaired with free SCIA superficial branch perforator flap with area of 10.0 cm×6.5 cm-15.0 cm×8.0 cm. The remaining granulation tissue wound with area of 5.0 cm×3.5 cm-13.0 cm×8.0 cm was repaired with full-thickness skin graft far from the flap donor site with area of 5.0 cm×3.5 cm-13.0 cm×8.0 cm. All the wounds in donor site were sutured. The operation time and amount of bleeding of patients during the surgery were recorded, the survival of flap and skin graft were observed after surgery. During follow-up, the flap and skin graft, scar in the donor site and its effect on donor site function were observed. At the last follow-up, the satisfaction of patients with the efficacy was evaluated by the efficacy satisfaction rating score. Results: The operation time of patients was 2.0-3.5 h. The amount of bleeding of patients during the surgery was 100-320 mL. One patient had ecchymosis and venous crisis in the edge of flap on the second day after surgery, and the flap survived after exploration. The flaps of the other patients survived smoothly. The skin grafts of patients all survived smoothly. Two patients had bloated flaps due to obesity in the later stage, and the expected results were achieved after flap thinning surgery 6 months after operation. During the follow-up of 6 to 24 months, the flaps had good elasticity and soft texture, and the skin grafts had no wear or ulceration; linear scars were left in all the donor sites but their functions were not affected. The patients were all satisfied with the efficacy. Conclusions: Free SCIA superficial perforator flap combined with full-thickness skin graft far from the donor site was used to repair the large wounds in extremities, which was safe, reliable, and less traumatic and short in operation time, and resulted in good postoperative appearance and function in the donor sites and recipient sites.

Objective: To investigate the clinical presentation pattern of acute primary angle-closure glaucoma (PACG) during the 2019 novel coronavirus (2019-nCoV) pandemic over the past three years, and its relationship with 2019-nCoV infections of Omicron variants in Guangdong province. Methods: Ecological study.Patients who were newly diagnosed with acute PACG from February 2020 to January 2023 at the Zhongshan Ophthalmic Center of Sun Yat-sen University were included in the study, and their basic information was collected. Patients were divided into the 2020 group (diagnosed between February 1st, 2020 and January 31st 2021), the 2021 group (diagnosed between February 1st, 2021 and January 31st 2022), and the 2022 group (diagnosed between February 1st, 2022 and January 31st 2023). The clinical presentation pattern of newly diagnosed acute PACG was observed and compared between groups. The daily number of newly diagnosed 2019-nCoV infections in Guangdong province was obtained from the Chinese Center for Disease Control and Prevention. The correlation between the daily number of newly diagnosed acute PACG and that of newly diagnosed 2019-nCoV infections during the epidemic period of Omicron variants between December 2022 and January 2023 was assessed. Results: The study included 1 048 patients with newly diagnosed acute PACG, with 235 for the 2020 group, 274 for the 2021 group, and 539 for the 2022 group. Our results showed that the average weekly number of newly diagnosed acute PACG patients in 2022 [8 (5, 11)] was significantly larger than that in 2020 (4.52±1.95, P <0.05) and 2021 (5.27±2.76, P <0.05). The average weekly number increased to 22.11±20.84 between December 2022 and January 2023. The total number of newly diagnosed acute PACG patients during this period was 199, which was 36.9% (199/539) of the total number of the same year and was 6.63 and 6.42 times as many as that in the same period (December and January) of 2020 and 2021. The proportion of patients with bilateral eye involvement during this period in 2022 was significantly higher than that in 2020 and 2021 ( P <0.05). Further analysis found that 88.6% (109/123) of cases had a history of 2019-nCoV infection 2 (0, 3) days before the onset of acute PACG symptoms in average. The estimated daily number of acute PACG onset increased rapidly, peaked on December 23th, 2022, and then dropped gradually. This trend was similar to that of the daily number of new 2019-nCoV infections in Guangdong province. Changes of the daily number of new 2019-nCoV infections in Guangdong province had a positive correlation with the estimated daily number of acute PACG onset ( r =0.84, P <0.001). Conclusion: A dramatic increase in the clinical presentation of acute PACG was observed at Zhongshan Ophthalmic Center between December 2022 and January 2023, which was the epidemic period of Omicron variants. There is a correlation between the trend of the estimated daily number of acute PACG onset and that of new 2019-nCoV infections of Omicron variants in Guangdong province, but the exact reason remains to be further studied. (This article was published ahead of print on the official website of Chinese Journal of Ophthalmology on August 31, 2023).

As a functional fatty acid, α-linolenic acid (ALA) is essential in promoting animal testosterone biosynthesis. This study investigated the effects of ALA on testosterone biosynthesis and the possible mechanism underlying the signaling pathway in primary Leydig cells of the rooster., Methods: Primary rooster Leydig cells were treated with ALA (0, 20, 40, or 80 μmol/L) or pretreated with a p38 inhibitor (50 μmol/L), a c-Jun NH2-terminal kinase (JNK) inhibitor (20 μmol/L), or an extracellular signal-regulated kinase (ERK) inhibitor (20 μmol/L) before ALA treatment. Testosterone content in the conditioned culture medium was detected using an enzyme-linked immunosorbent assay (ELISA). The expression of steroidogenic enzymes and JNK-SF-1 signaling pathway factors was detected using real-time fluorescence quantitative PCR (qRT-PCR)., Results: Supplementation with ALA significantly increased testosterone secretion within culture media (P < 0.05), and the optimized dose was 40 μmol/L. Compared with the control group, steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (P450scc), and 3β-hydroxysteroid dehydrogenase (3β-HSD) mRNA expression significantly increased (P < 0.05) in the 40 μmol/L ALA group; 17-hydroxylase/c17-20 lyase (P450c17) and p38 mRNA expressions were not significantly different in the 40 μmol/L ALA group; ERK and JNK mRNA expressions were significantly upregulated (P < 0.05) in 40 μmol/L ALA group. In the inhibitor group, testosterone levels were significantly downregulated (P < 0.05). Compared with the 40 μmol/L ALA group, StAR, P450scc, and P450c17 mRNA expressions were significantly decreased (P < 0.05), and 3β-HSD mRNA expression in the p38 inhibitor group did not change; StAR, P450scc, and 3β-HSD mRNA expressions were significantly decreased (P < 0.05), and P450c17 mRNA expression in ERK inhibitor group did not change; StAR, P450scc, 3β-HSD, and P450c17 mRNA expressions were significantly decreased (P < 0.05) in JNK inhibitor group. Additionally, the increased steroidogenic factor 1 (SF-1) gene expression levels induced by ALA were reversed when the cells were pre-incubated with JNK and ERK inhibitors. The levels in the JNK inhibitor group were significantly lower than those in the control group (P < 0.05)., Conclusion: ALA may promote testosterone biosynthesis by activating the JNK-SF-1 signaling pathway to upregulate StAR, P450scc, 3β-HSD, and P450c17 expression in primary rooster Leydig cells., (Copyright © 2023. Published by Elsevier Inc.)

Demetalation, caused by the electrochemical dissolution of metal atoms, poses a significant challenge to the practical application of single-atom catalytic sites (SACSs) in proton exchange membrane-based energy technologies. One promising approach to inhibit SACS demetalation is the use of metallic particles to interact with SACSs. However, the mechanism underlying this stabilization remains unclear. In this study, we propose and validate a unified mechanism by which metal particles can inhibit the demetalation of Fe SACSs. Metal particles act as electron donors, decreasing the Fe oxidation state by increasing the electron density at the FeN 4 position, thereby strengthening the Fe-N bond, and inhibiting electrochemical Fe dissolution. Different types, forms, and contents of metal particles increase the Fe-N bond strength to varying extents. A linear correlation between the Fe oxidation state, Fe-N bond strength, and electrochemical Fe dissolution amount supports this mechanism. Our screening of a particle-assisted Fe SACS led to a 78% reduction in Fe dissolution, enabling continuous operation for up to 430 h in a fuel cell. These findings contribute to the development of stable SACSs for energy applications.

Anorexia nervosa (AN) is a psychiatric illness with the highest mortality. Current treatment options have been limited to psychotherapy and nutritional support, with low efficacy and high relapse rates. Hypothalamic AgRP (agouti-related peptide) neurons that coexpress AGRP and neuropeptide Y (NPY) play a critical role in driving feeding while also modulating other complex behaviors. We have previously reported that genetic ablation of Tet3 , which encodes a member of the TET family dioxygenases, specifically in AgRP neurons in mice, activates these neurons and increases the expression of AGRP, NPY, and the vesicular GABA transporter (VGAT), leading to hyperphagia and anxiolytic effects. Bobcat339 is a synthetic small molecule predicted to bind to the catalytic pockets of TET proteins. Here, we report that Bobcat339 is effective in mitigating AN and anxiety/depressive-like behaviors using a well-established mouse model of activity-based anorexia (ABA). We show that treating mice with Bobcat339 decreases TET3 expression in AgRP neurons and activates these neurons leading to increased feeding, decreased compulsive running, and diminished lethality in the ABA model. Mechanistically, Bobcat339 induces TET3 protein degradation while simultaneously stimulating the expression of AGRP, NPY, and VGAT in a TET3-dependent manner both in mouse and human neuronal cells, demonstrating a conserved, previously unsuspected mode of action of Bobcat339. Our findings suggest that Bobcat339 may potentially be a therapeutic for anorexia nervosa and stress-related disorders.

Aim: To explore the learning curve for ophthalmologists at the start of laser peripheral iridectomy (LPI) training., Methods: The learning curve of 4 doctor groups without previous LPI experience was studied. Three main parameters of LPI were reviewed: total energy, argon energy and neodymium-doped yttrium aluminum garnet (Nd:YAG) energy. Procedures were evaluated in cohorts of 20 cases to identify the turning points of the three variables., Results: There was no significant difference in terms of age or eye among the 4 doctor groups. There were stable trends on the learning curve for the Doctor A and C groups regarding total energy and argon energy. In addition, the turning points on the learning curve were determined after the 20 th procedure for the Doctor B and D groups regarding total energy and argon energy. Moreover, the Nd:YAG energy was relatively stable since the first procedure., Conclusion: It requires approximately 20 procedures for a beginner to reach a turning point on the learning curve regarding LPI. It can serve as a point of reference or guideline for training beginners to perform LPI., (International Journal of Ophthalmology Press.)

Objective: To investigate the prevalence and risk factors of medication non-adherence in children with inflammatory bowel disease (IBD). Methods: A cross-sectional study was conducted in Children's Hospital, Zhejiang University School of Medicine from September 2020 to March 2022 and 112 children with IBD were enrolled. Their general information, medication adherence, and parental disease-related knowledge were collected by questionnaires. According to the medication adherence score, the children were divided into the adherence group (score of 6 to 8) and the non-adherence group (score of <6), then the demographic and clinical characteristics of the two groups were compared. Subsequently, a multivariate binary Logistic regression analysis was performed to determine the risk factors of medication non-adherence. Results: Of the 112 children, 76 were males and 36 females, with the age of 12.9 (9.5, 14.0) years. There were 50 (44.6%) in the non-adherence group and 62 (55.4%) in the adherence group. Regarding the demographic and clinical characteristics, the results showed that the dosage frequency and the parental disease related knowledge were associated with medication non-adherence (both P< 0.05). Multivariate binary Logistic regression analysis showed that compared with 0-6 years old children, the risk of medication non-adherence was significantly increased in children aged 7-12 years ( OR= 9.30, 95% CI 1.58-54.87, P= 0.014) and 13-18 years ( OR= 8.26, 95% CI 1.49-45.85, P= 0.016); and the risk was also significantly increased in children who took medication twice or more per day ( OR= 12.88, 95% CI 2.77-59.80, P= 0.001) compared with children who took medication once per day. Meanwhile, the parental score of the questionnaire on Crohn's disease and ulcerative colitis related knowledge ( OR= 0.76, 95% CI 0.66-0.89, P= 0.001) was also a significant risk factor. Conclusions: Medication non-adherence is common in children with IBD. Children older than 7 years, a dosage frequency of twice or more per day, and parental poor disease-related knowledge are the independent risk factors for medication non-adherence in children with IBD. Clinicians should pay attention to promoting patients' adherence to improve clinical outcomes.

Dysregulation of long interspersed nuclear element 1 (LINE-1, L1), a dominant class of transposable elements in the human genome, has been linked to neurodegenerative diseases, but whether elevated L1 expression is sufficient to cause neurodegeneration has not been directly tested. Here, we show that the cerebellar expression of L1 is significantly elevated in ataxia telangiectasia patients and strongly anti-correlated with the expression of epigenetic silencers. To examine the role of L1 in the disease etiology, we developed an approach for direct targeting of the L1 promoter for overexpression in mice. We demonstrated that L1 activation in the cerebellum led to Purkinje cell dysfunctions and degeneration and was sufficient to cause ataxia. Treatment with a nucleoside reverse transcriptase inhibitor blunted ataxia progression by reducing DNA damage, attenuating gliosis, and reversing deficits of molecular regulators for calcium homeostasis in Purkinje cells. Our study provides the first direct evidence that L1 activation can drive neurodegeneration., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The TET family of dioxygenases promote DNA demethylation by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Hypothalamic agouti-related peptide-expressing (AGRP-expressing) neurons play an essential role in driving feeding, while also modulating nonfeeding behaviors. Besides AGRP, these neurons produce neuropeptide Y (NPY) and the neurotransmitter GABA, which act in concert to stimulate food intake and decrease energy expenditure. Notably, AGRP, NPY, and GABA can also elicit anxiolytic effects. Here, we report that in adult mouse AGRP neurons, CRISPR-mediated genetic ablation of Tet3, not previously known to be involved in central control of appetite and metabolism, induced hyperphagia, obesity, and diabetes, in addition to a reduction of stress-like behaviors. TET3 deficiency activated AGRP neurons, simultaneously upregulated the expression of Agrp, Npy, and the vesicular GABA transporter Slc32a1, and impeded leptin signaling. In particular, we uncovered a dynamic association of TET3 with the Agrp promoter in response to leptin signaling, which induced 5hmC modification that was associated with a chromatin-modifying complex leading to transcription inhibition, and this regulation occurred in both the mouse models and human cells. Our results unmasked TET3 as a critical central regulator of appetite and energy metabolism and revealed its unexpected dual role in the control of feeding and other complex behaviors through AGRP neurons.

Hypothalamic agouti-related peptide and neuropeptide Y-expressing (AgRP) neurons have a critical role in both feeding and non-feeding behaviors of newborn, adolescent, and adult mice, suggesting their broad modulatory impact on brain functions. Here we show that constitutive impairment of AgRP neurons or their peripubertal chemogenetic inhibition resulted in both a numerical and functional reduction of neurons in the medial prefrontal cortex (mPFC) of mice. These changes were accompanied by alteration of oscillatory network activity in mPFC, impaired sensorimotor gating, and altered ambulatory behavior that could be reversed by the administration of clozapine, a non-selective dopamine receptor antagonist. The observed AgRP effects are transduced to mPFC in part via dopaminergic neurons in the ventral tegmental area and may also be conveyed by medial thalamic neurons. Our results unmasked a previously unsuspected role for hypothalamic AgRP neurons in control of neuronal pathways that regulate higher-order brain functions during development and in adulthood., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The hypocretin/orexin (Hcrt/Orx) system in the perifornical lateral hypothalamus has been recognized as a critical node in a complex network of neuronal systems controlling both physiology and behavior in vertebrates. Our understanding of the Hcrt/Orx system and its array of functions and actions has grown exponentially in merely 2 decades. This review will examine the latest progress in discerning the roles played by the Hcrt/Orx system in regulating homeostatic functions and in executing instinctive and learned behaviors. Furthermore, the gaps that currently exist in our knowledge of sex-related differences in this field of study are discussed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Estriol (E 3 ) is a steroid hormone formed only during pregnancy in primates including humans. Although E 3 is synthesized at large amounts through a complex pathway involving the fetus and placenta, it is not required for the maintenance of pregnancy and has classically been considered virtually inactive due to associated very weak canonical estrogen signaling. However, estrogen exposure during pregnancy may have an effect on organs both within and outside the reproductive system, and compounds with binding affinity for estrogen receptors weaker than E 3 have been found to impact reproductive organs and the brain. Here, we explore potential effects of E 3 on fetal development using mouse as a model system., Results: We administered E 3 to pregnant mice, exposing the fetus to E 3 . Adult females exposed to E 3 in utero (E 3 -mice) had increased fertility and superior pregnancy outcomes. Female and male E 3 -mice showed decreased anxiety and increased exploratory behavior. The expression levels and DNA methylation patterns of multiple genes in the uteri and brains of E 3 -mice were distinct from controls. E 3 promoted complexing of estrogen receptors with several DNA/histone modifiers and their binding to target genes. E 3 functions by driving epigenetic change, mediated through epigenetic modifier interactions with estrogen receptors rather than through canonical nuclear transcriptional activation., Conclusions: We identify an unexpected functional role for E 3 in fetal reproductive system and brain. We further identify a novel mechanism of estrogen action, through recruitment of epigenetic modifiers to estrogen receptors and their target genes, which is not correlated with the traditional view of estrogen potency., (© 2022. The Author(s).)

Glaucoma is the leading irreversible blinding eye disease worldwide, and China has the largest amount of primary angle-closure glaucoma (PACG). To reduce blindness, the therapeutic evolution can play a role. With the technical development of minimally invasive glaucoma surgery (MIGS), the treatment of angle-closure glaucoma has been in a transformation. This article reviews the literatures related to the advances of MIGS in the combined treatment of PACG. The research findings show that MIGS may become one of the preferred surgical treatments for PACG in the future clinical management of glaucoma.

Endometriosis is a gynecological disease affecting 6-10% of women of reproductive age. In addition to gynecologic symptoms, endometriosis is associated with various systemic effects, including inflammation, altered body weight, and behavioral changes. Previous murine studies demonstrate that endometriosis is causally inked to increased pain sensitization, behavioral changes, and low body mass index (BMI). One possible cellular target that may mediate some of these findings is the hypocretin/orexin neurons. This neuronal system plays a role in regulating wakefulness/sleep cycles, pain perception, and appetite. We hypothesize that endometriosis alters activity level of the hypocretin/orexin (Hcrt) neuronal system. Mice underwent endometriosis induction surgeries (endo) or sham surgeries (sham) for the development of the experimental model. Immunocytochemistry was performed on harvested samples from the lateral hypothalamus, and activation levels of Hcrt cells were examined by quantifying the expression of phosphorylation of cAMP-responsive element binding protein (CREB) in these cells after an acute stress in sham and endo mice. Mice with endometriosis had greater Hcrt neurons activation than sham mice. Mice with endometriosis fed with high fat diet showed a lower fat/body weight and fat/lean tissue ratio compared to mice without endometriosis. There was no significant difference in food intake between sham and endometriosis mice. These results demonstrate that endometriosis is associated with low body mass and increased hypocretin/orexin activity, which could be implicated in the behavioral changes and to differences in body composition., (© 2021. Society for Reproductive Investigation.)

Microglia have been implicated in synapse remodeling by phagocytosis of synaptic elements in the adult brain, but the mechanisms involved in the regulation of this process are ill-defined. By examining microglia-neuronal interaction in the ventral hippocampus, we found a significant reduction in spine synapse number during the light phase of the light/dark cycle accompanied by increased microglia-synapse contacts and an elevated amount of microglial phagocytic inclusions. This was followed by a transient rise in microglial production of reactive oxygen species (ROS) and a concurrent increase in expression of uncoupling protein 2 (Ucp2), a regulator of mitochondrial ROS generation. Conditional ablation of Ucp2 from microglia hindered phasic elimination of spine synapses with consequent accumulations of ROS and lysosome-lipid droplet complexes, which resulted in hippocampal neuronal circuit dysfunctions assessed by electrophysiology, and altered anxiety-like behavior. These observations unmasked a novel and chronotypical interaction between microglia and neurons involved in the control of brain functions., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Hypothalamic feeding circuits have been identified as having innate synaptic plasticity, mediating adaption to the changing metabolic milieu by controlling responses to feeding and obesity. However, less is known about the regulatory principles underlying the dynamic changes in agouti-related protein (AgRP) perikarya, a region crucial for gating of neural excitation and, hence, feeding. Here we show that AgRP neurons activated by food deprivation, ghrelin administration, or chemogenetics decreased their own inhibitory tone while triggering mitochondrial adaptations in neighboring astrocytes. We found that it was the inhibitory neurotransmitter GABA released by AgRP neurons that evoked this astrocytic response; this in turn resulted in increased glial ensheetment of AgRP perikarya by glial processes and increased excitability of AgRP neurons. We also identified astrocyte-derived prostaglandin E2, which directly activated - via EP2 receptors - AgRP neurons. Taken together, these observations unmasked a feed-forward, self-exciting loop in AgRP neuronal control mediated by astrocytes, a mechanism directly relevant for hunger, feeding, and overfeeding.

Aims: The aim of the study was to evaluate the suitability of the current caffeine dosing regimen for the Chinese population using modelling and simulation approach., Methods: Pharmacokinetic samples were collected from 99 Chinese newborns with premature apnoea. The median (range) of gestational age and postmenstrual age were 28.3 (25.0-33.4) weeks and 31.1 (26.4-38.0) weeks, respectively. Newborns were receiving caffeine citrate at a loading dose of 20 mg/kg/d and a maintenance dose of 5-10 mg/kg/d. Caffeine concentrations and CYP1A2 polymorphisms were investigated. Population pharmacokinetic modelling of caffeine in Chinese preterm newborn on a population-wide scale was conducted using NONMEM., Results: A 1-compartment model with first-order elimination was used to describe population pharmacokinetic. With current weight implemented using 0.75 allometric scaling, clearance (CL) was positively related to current weight and postmenstrual age, but a negative relationship was observed with serum creatinine concentration. Eight genotypes of CYP1A2 were tested and none of them had a significant impact on caffeine pharmacokinetic parameters. Interindividual variability of CL and volume of distribution was 7.70 and 65.9%. The median (range) of 95% confidence intervals of CL were 0.0128 (0.0128-0.0131) L/h/kg. Monte Carlo simulation demonstrated that 80% (loading dose) and 98% (maintenance dose) of premature infants treated with a labelled dosing regimen attained the concentration target range of 5-20 mg/L., Conclusion: A population PK model of caffeine was developed in Chinese newborns. Body weight-implemented allometric scaling, postmenstrual age and serum creatinine concentration markedly affected caffeine clearance. The labelled dosing regimen is suitable for Chinese premature infants., (© 2020 The British Pharmacological Society.)

The basolateral amygdala (BLA) is critical for associating initially neutral cues with appetitive and aversive stimuli and receives dense neuromodulatory acetylcholine (ACh) projections. We measured BLA ACh signaling and activity of neurons expressing CaMKIIα (a marker for glutamatergic principal cells) in mice during cue-reward learning using a fluorescent ACh sensor and calcium indicators. We found that ACh levels and nucleus basalis of Meynert (NBM) cholinergic terminal activity in the BLA (NBM-BLA) increased sharply in response to reward-related events and shifted as mice learned the cue-reward contingency. BLA CaMKIIα neuron activity followed reward retrieval and moved to the reward-predictive cue after task acquisition. Optical stimulation of cholinergic NBM-BLA terminal fibers led to a quicker acquisition of the cue-reward contingency. These results indicate BLA ACh signaling carries important information about salient events in cue-reward learning and provides a framework for understanding how ACh signaling contributes to shaping BLA responses to emotional stimuli., Competing Interests: RC, KK, HB, EG, RK, JC, PR, SP, LR, DT, MJ, YL, XG, YM, MP No competing interests declared

The brain has evolved in an environment where food sources are scarce, and foraging for food is one of the major challenges for survival of the individual and species. Basic and clinical studies show that obesity or overnutrition leads to overwhelming changes in the brain in animals and humans. However, the exact mechanisms underlying the consequences of excessive energy intake are not well understood. Neurons expressing the neuropeptide hypocretin/orexin (Hcrt) in the lateral/perifonical hypothalamus (LH) are critical for homeostatic regulation, reward seeking, stress response, and cognitive functions. In this study, we examined adaptations in Hcrt cells regulating behavioral responses to salient stimuli in diet-induced obese mice. Our results demonstrated changes in primary cilia, synaptic transmission and plasticity, cellular responses to neurotransmitters necessary for reward seeking, and stress responses in Hcrt neurons from obese mice. Activities of neuronal networks in the LH and hippocampus were impaired as a result of decreased hypocretinergic function. The weakened Hcrt system decreased reward seeking while altering responses to acute stress (stress-coping strategy), which were reversed by selectively activating Hcrt cells with chemogenetics. Taken together, our data suggest that a deficiency in Hcrt signaling may be a common cause of behavioral changes (such as lowered arousal, weakened reward seeking, and altered stress response) in obese animals.

Background: More people ascend to high altitude (HA) for various activities, and some individuals are susceptible to HA illness after rapidly ascending from plains. Acute mountain sickness (AMS) is a general complaint that affects activities of daily living at HA. Although genomic association analyses suggest that single nucleotide polymorphisms (SNPs) are involved in the genesis of AMS, no major gene variants associated with AMS-related symptoms have been identified., Methods: In this cross-sectional study, 604 young, healthy Chinese Han men were recruited in June and July of 2012 in Chengdu, and rapidly taken to above 3700 m by plane. Basic demographic parameters were collected at sea level, and heart rate, pulse oxygen saturation (SpO 2 ), systolic and diastolic blood pressure and AMS-related symptoms were determined within 18-24 h after arriving in Lhasa. AMS patients were identified according to the latest Lake Louise scoring system (LLSS). Potential associations between variant genotypes and AMS/AMS-related symptoms were identified by logistic regression after adjusting for potential confounders (age, body mass index and smoking status)., Results: In total, 320 subjects (53.0%) were diagnosed with AMS, with no cases of high-altitude pulmonary edema or high-altitude cerebral edema. SpO 2 was significantly lower in the AMS group than that in the non-AMS group (P = 0.003). Four SNPs in hypoxia-inducible factor-related genes were found to be associated with AMS before multiple hypothesis testing correction. The rs6756667 (EPAS1) was associated with mild gastrointestinal symptoms (P = 0.013), while rs3025039 (VEGFA) was related to mild headache (P = 0.0007). The combination of rs6756667 GG and rs3025039 CT/TT further increased the risk of developing AMS (OR = 2.70, P < 0.001)., Conclusions: Under the latest LLSS, we find that EPAS1 and VEGFA gene variants are related to AMS susceptibility through different AMS-related symptoms in the Chinese Han population; this tool might be useful for screening susceptible populations and predicting clinical symptoms leading to AMS before an individual reaches HA., Trial Registration: Chinese Clinical Trial Registration, ChiCTR-RCS-12002232 . Registered 31 May 2012.

Objective: To explore the association between serum levels of osteopontin (OPN) and systolic pulmonary artery pressure (sPAP) in healthy men following acute high altitude exposure. Methods: According to the inclusion and exclusion criteria, this observational study included 94 male subjects (aged from 18 to 30 years, dwelling in lowland<500 m) who ascended to Litang (4 100 m) from Chongqing (400 m) by bus with a stair-like journey within 7 days in June 2013. Data including basic information, OPN, superoxide dismutase (SOD), and malondialdehyde (MDA) and echocardiographic derived sPAP were collected within 48 hours before ascent and within 2-7 hours after arrival. Accordingly, subjects were divided into 3 groups based on the tertiles of sPAP after acute high altitude exposure: low sPAP group (26.8-32.3 mmHg (1 mmHg=0.133 kPa)) ( n =31), middle sPAP group (32.4-37.4 mmHg) ( n =32) and high sPAP group (37.5-55.6 mmHg) ( n =31). Associations of serum OPN and SOD levels with sPAP were analysed by univariate and multivariate linear regression analysis. Results: After acute high altitude exposure, the levels of sPAP were significantly increased ( P <0.001). There were no differences in age, height, weight, body mass index, percent of Han nationality and smoking among 3 subgroups. However, following acute high altitude exposure, the levels of heart rate, systolic and diastolic blood pressure elevated (all P <0.05), whereas the levels of oxygen saturation were reduced in the total subjects and all subgroups (all P <0.05). Moreover, systolic blood pressure of subjects in the high sPAP group was higher than that in low and middle sPAP groups (both P <0.05), and diastolic blood pressure of subjects in high sPAP group was higher than that in low sPAP group ( P <0.05). The serum levels of OPN were increased in total cohort(27.9 (22.5,34.0) μg/L vs. 25.6 (18.4, 33.1) μg/L, P <0.05)， and high sPAP group ( P <0.05), whereas no differences were found in serum SOD and MDA levels among groups. Furthermore, the serum level of OPN in high sPAP group was higher than that in low sPAP group at high altitude ( P <0.05), and there was a trend for decline in SOD level with increasing sPAP ( P> 0.05). Results from univariable linear regression analysis showed that the serum levels of OPN ( r =0.32, P =0.002) and SOD ( r =-0.22， P =0.032) were linearly correlated with sPAP in total cohort after high altitude exposure. Multivariate regression analysis showed that the serum levels of OPN(β=0.310， P =0.002) and SOD (β=-0.199， P =0.043) were independently associated with the levels of sPAP at high altitude. Conclusion: After acute high altitude exposure, the serum level of OPN is positively associated with sPAP, suggesting that OPN may be a novel bio-marker for predicting the increase of pulmonary pressure in response to acute high altitude exposure.

Objective: To investigate the application of mind mapping-based health education in extended care for children with caries., Methods: This was a prospective study of 159 eligible children with caries. Participants were randomly assigned to an observation group and a control group, and received extended health education and guidance. Patients in the observation group received health education with mind mapping. In the third month after the first visit, a questionnaire survey was conducted to assess knowledge of extended caries diagnosis and treatment in children and their parents. Children also underwent a bacterial plaque test., Results: Caries knowledge was significantly greater in the observation group than in the control group. There was no significant between-group difference in debris index on the bacterial plaque test. The observation group had a significantly greater number of follow-up visits in 12 months than the control group., Conclusions: Mind mapping was effective in the implementation of extended care. Mind mapping information was more accessible to children and their parents, increasing their compliance with health education. Thus, mind mapping is an appropriate health education tool for use in extended care for children with caries.

Objective: To evaluate if oocyte penetration and viability can be confirmed by an electrical resistance increase. Automated (robotic) intracytoplasmic sperm injection (ICSI) requires confirmation of oolemma penetration before sperm injection. Visual assessment using image processing algorithms have been developed but remain unreliable. We hypothesized that an increase in electrical resistance upon oolemma piercing during ICSI can serve as an objective tool to confirm oocyte penetration and viability., Design: Experimental study., Setting: Research laboratory in an academic center., Patients/animals: Oocytes from female mice and women undergoing oocyte retrieval procedure., Intervention: Oolemma piercing attempts with the ICSI pipette were performed by advancing the pipette towards mature (metaphase II) oocytes collected from 6 to 12-week-old mice and immature (germinal vesicle stage and metaphase I) oocytes donated by women who underwent oocyte retrieval. Electrical resistance was measured using a conventional electrophysiological setup that includes an electrical resistance meter and two electrical wires located in the lumina of the holding and ICSI pipettes., Main Outcome Measure(s): The measure of interest was the change in electrical resistance (ΔR) before and after advancing the ICSI pipette in an attempt to penetrate an oocyte. The experiments of resistance measurements were done in 3 steps: Step 1 (proof of concept), penetrated vs. non-penetrated mouse oocytes. Step 2, mouse oocytes with visually intact oolemma vs. fragmented mouse oocytes. Step 3, human oocytes with visually intact oolemma vs. fragmented human oocytes. For each group, median and range (in parenthesis) of ΔR were determined in MΩ. Mann-Whitney test was performed to compare the two groups in each step., Results: In Step 1, the penetrated mouse oocytes showed a statistically significant resistance increase compared to the non-penetrated ones (n = 20, median ΔR = 7.79 [2.57 - 106.00] vs. n = 15, median ΔR = 0.10 [-0.06 - 0.69], respectively. In Step 2, the mouse oocytes with visually intact oolemma showed a statistically significant resistance increase compared to the fragmented ones (n = 45, median ΔR = 6.5 [0.1 - 191.7] vs. n = 13, median ΔR = 0.1 [-0.3 - 2.2], respectively. In Step 3, the human oocytes with visually intact oolemma showed a statistically significant resistance increase compared to the fragmented ones (n = 96, median ΔR = 1.92 [-0.05 - 6.70] vs. n = 17, median ΔR = 0.11 [0.00 - 0.30], respectively., Conclusions: An electrical resistance increase can serve as a reliable tool to confirm oocyte penetration and viability, independent of optical visualization. Following further validation and safety assessment, this technology can potentially be integrated into manual and robotic ICSI systems., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

We hypothesized that bone evolved, in part, to enhance the ability of bony vertebrates to escape danger in the wild. In support of this notion, we show here that a bone-derived signal is necessary to develop an acute stress response (ASR). Indeed, exposure to various types of stressors in mice, rats (rodents), and humans leads to a rapid and selective surge of circulating bioactive osteocalcin because stressors favor the uptake by osteoblasts of glutamate, which prevents inactivation of osteocalcin prior to its secretion. Osteocalcin permits manifestations of the ASR to unfold by signaling in post-synaptic parasympathetic neurons to inhibit their activity, thereby leaving the sympathetic tone unopposed. Like wild-type animals, adrenalectomized rodents and adrenal-insufficient patients can develop an ASR, and genetic studies suggest that this is due to their high circulating osteocalcin levels. We propose that osteocalcin defines a bony-vertebrate-specific endocrine mediation of the ASR., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The identification of animal species in feed and feedstuffs is important for detecting contamination and fraudulent replacement of animal components that might cause health and economic problems. A novel multiplex assay, based on xMAP technology and the generic detection of closely related species, was developed for the simultaneous differential detection of avian, fish, and ruminant DNA in products. Universal primers and probes specific to avian, fish, or ruminant species were designed to target a conserved mitochondrial DNA sequence in the 12S ribosomal RNA gene (rRNA). The assay specificity was validated using samples of 27 target and 10 nontarget animal species. The limits of detection of the purified DNA were determined to be 0.2 pg/μL-0.1 ng/μL by testing the meat samples of six species and four feedstuffs. The detection sensitivity of the experimental mixtures was demonstrated to be 0.01% (weight percentage). The assay's suitability for practical application was evaluated by testing feed samples; unlabeled animal ingredients were detected in 32% of the 56 samples. The assay differentially detected the three targeted categories of animal species in less than 2 h, reflecting improvements in speed and efficiency. Based on these results, this novel multiplex xMAP assay provides a reliable and highly efficient technology for the routine detection of animal species in feed and other products for which this information is needed.

Objective: Dopamine neurons in the Substantia nigra (SN) play crucial roles in control of voluntary movement. Extensive degeneration of this neuronal population is the cause of Parkinson's disease (PD). Many factors have been linked to SN DA neuronal survival, including neuronal pacemaker activity (responsible for maintaining basal firing and DA tone) and mitochondrial function. Dln-101, a naturally occurring splice variant of the human ghrelin gene, targets the ghrelin receptor (GHSR) present in the SN DA cells. Ghrelin activation of GHSR has been shown to protect SN DA neurons against 1-methyl-4-phenyl-1,2,5,6 tetrahydropyridine (MPTP) treatment. We decided to compare the actions of Dln-101 with ghrelin and identify the mechanisms associated with neuronal survival., Methods: Histologial, biochemical, and behavioral parameters were used to evaluate neuroprotection. Inflammation and redox balance of SN DA cells were evaluated using histologial and real-time PCR analysis. Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology was used to modulate SN DA neuron electrical activity and associated survival. Mitochondrial dynamics in SN DA cells was evaluated using electron microscopy data., Results: Here, we report that the human isoform displays an equivalent neuroprotective factor. However, while exogenous administration of mouse ghrelin electrically activates SN DA neurons increasing dopamine output, as well as locomotion, the human isoform significantly suppressed dopamine output, with an associated decrease in animal motor behavior. Investigating the mechanisms by which GHSR mediates neuroprotection, we found that dopamine cell-selective control of electrical activity is neither sufficient nor necessary to promote SN DA neuron survival, including that associated with GHSR activation. We found that Dln101 pre-treatment diminished MPTP-induced mitochondrial aberrations in SN DA neurons and that the effect of Dln101 to protect dopamine cells was dependent on mitofusin 2, a protein involved in the process of mitochondrial fusion and tethering of the mitochondria to the endoplasmic reticulum., Conclusions: Taken together, these observations unmasked a complex role of GHSR in dopamine neuronal protection independent on electric activity of these cells and revealed a crucial role for mitochondrial dynamics in some aspects of this process., (Copyright © 2019. Published by Elsevier GmbH.)

Tumour necrotic factor receptor-2 (TNFR2) has been to be cardiac-protective and is expressed in cardiac progenitor cells. Our goal is to define the mechanism for TNFR2-mediated cardiac stem cell activation and differentiation. By employing a protocol of in vitro cardiac stem cell (CSC) differentiation from human inducible pluripotent stem cell (hiPSC), we show that expression of TNFR2 precedes expression of CSC markers followed by expression of mature cardiomyocyte proteins. Activation of TNFR2 by a specific agonist promotes whereas inhibition of TNFR2 by neutralizing antibody diminishes hiPSC-based CSC differentiation. Interestingly, pluripotent cell factor RNA-binding protein Lin28 enhances TNFR2 protein expression in early CSC activation by directly binding to a conserved Lin28-motif within the 3'UTR of Tnfr2 mRNA. Furthermore, inhibition of Lin28 blunts TNFR2 expression and TNFR2-dependent CSC activation and differentiation. Our study demonstrates a critical role of Lin28-TNFR2 axis in CSC activation and survival, providing a novel strategy to enhance stem cell-based therapy for the ischaemic heart diseases., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Lipid metabolism disorders lead to vascular endothelial injury. Matrine is an alkaloid that has been used to improve obesity and diabetes and for the treatment of hepatitis B. However, its effect on lipid metabolism disorders and vascular injury is unclear. Here, we investigated the effect of matrine on high-fat diet fed mice and oxidized low-density lipoprotein (ox-LDL)-induced human umbilical vein endothelial cells (HUVECs). Computational virtual docking analyses, phosphoinositide 3-kinase (PI3K) and protein kinase C-α (PKCα) inhibitors were used to localize matrine in vascular injuries. The results showed that matrine-treated mice were more resistant to abnormal lipid metabolism and inflammation than vehicle-treated mice and exhibited significantly alleviated ox-LDL-stimulated dysfunction of HUVECs, restored diminished nitric oxide release, decreased reactive oxygen species generation and increased expression phosphorylation of AKT-Ser473 and endothelial nitric oxide synthase (eNOS)-Ser1177. Matrine not only up-regulates eNOS-Ser1177 but also down-regulates eNOS-Thr495, a PKCα-controlled negative regulator of eNOS. Using computational virtual docking analyses and biochemical assays, matrine was also shown to influence eNOS/NO via PKCα inhibition. Moreover, the protective effects of matrine were significantly abolished by the simultaneous application of PKCα and the PI3K inhibitor. Matrine may thus be potentially employed as a novel therapeutic strategy against high-fat diet-induced vascular injury., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

The gut is now recognized as a major regulator of motivational and emotional states. However, the relevant gut-brain neuronal circuitry remains unknown. We show that optical activation of gut-innervating vagal sensory neurons recapitulates the hallmark effects of stimulating brain reward neurons. Specifically, right, but not left, vagal sensory ganglion activation sustained self-stimulation behavior, conditioned both flavor and place preferences, and induced dopamine release from Substantia nigra. Cell-specific transneuronal tracing revealed asymmetric ascending pathways of vagal origin throughout the CNS. In particular, transneuronal labeling identified the glutamatergic neurons of the dorsolateral parabrachial region as the obligatory relay linking the right vagal sensory ganglion to dopamine cells in Substantia nigra. Consistently, optical activation of parabrachio-nigral projections replicated the rewarding effects of right vagus excitation. Our findings establish the vagal gut-to-brain axis as an integral component of the neuronal reward pathway. They also suggest novel vagal stimulation approaches to affective disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To investigate the significance and possible mechanism of miR-791 in the pathogenesis of papillary thyroid carcinoma (PTC)., Patients and Methods: The expression of miR-791 in 80 cases of thyroid carcinoma tissues and 80 cases of paracancerous tissues was detected by quantitative Real-time-polymerase chain reaction (qRT-PCR). After miR-791 mimics were transfected into thyroid cancer cells by liposome method, the cell proliferation was detected by Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EDU), respectively. Cell cycle was detected by flow cytometry., Results: The expression of miR-791 in thyroid cancer tissue was significantly lower than that of normal thyroid. The mir-719 expression is positively correlated with the prognosis of thyroid carcinoma. After transfection of miR-791 mimics, the proliferation ability of TPC-1 and HTH83 cells was weakened, and the cell cycle was blocked in the G0/G1 phase. Further study on the underlying mechanism found that after overexpression of miR-791, the expressions of Cyclin D1, CKD6 and CDK4 decreased significantly, while the expression of cyclin inhibitor P21 increased significantly., Conclusions: MiR-791 is lowly expressed in thyroid cancer. MiR-791 may inhibit thyroid cancer cell proliferation by blocking thyroid cancer cells in G0/G1 phase, thus participating in the impediment of thyroid cancer development.

Endometriosis is an estrogen-dependent inflammatory disorder among reproductive-aged women associated with pelvic pain, anxiety, and depression. Pain is characterized by central sensitization; however, it is not clear if endometriosis leads to increased pain perception or if women with the disease are more sensitive to pain, increasing the detection of endometriosis. Endometriosis was induced in mice and changes in behavior including pain perception, brain electrophysiology, and gene expression were characterized. Behavioral tests revealed that mice with endometriosis were more depressed, anxious and sensitive to pain compared to sham controls. Microarray analyses confirmed by qPCR identified differential gene expression in several regions of brain in mice with endometriosis. In these mice, genes such as Gpr88, Glra3 in insula, Chrnb4, Npas4 in the hippocampus, and Lcn2 in the amygdala were upregulated while Lct, Serpina3n (insula), and Nptx2 (amygdala) were downregulated. These genes are involved in anxiety, locomotion, and pain. Patch clamp recordings in the amygdala were altered in endometriosis mice demonstrating an effect of endometriosis on brain electrophysiology. Endometriosis induced pain sensitization, anxiety, and depression by modulating brain gene expression and electrophysiology; the effect of endometriosis on the brain may underlie pain sensitization and mood disorders reported in women with the disease.

Background: Selenium is a crucial mineral with antioxidant and immune functions, and selenium deficiency may increase the risk of coronary heart disease (CHD). However, the effect of selenium supplementation on CHD is still controversial according to numerous randomized controlled trials (RCTs). The aim of our meta-analysis study was to investigate the impact of selenium on CHD., Methods: PUBMED, EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials databases were systematically searched to identify RCTs evaluating the effect of selenium supplementation on CHD mortality, blood lipid profile (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol), serum C-reactive protein (CRP), and the level of glutathione peroxidase (GSH-PX) from inception until September 20, 2016. Odds ratio of CHD mortality and the associated 95% confidence intervals (CIs) were calculated using the fixed effect model. Weighted mean difference or standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated to determine the lipid profile, serum CRP, and GSH-PX using fixed effect or random effect models depending on the observed heterogeneity., Results: A total of 16 eligible RCTs with 43998 participants were included. Significant effects were observed for serum CRP (SMD=-0.48; 95% CI, -0.96 to 0; p=0.049) and GSH-PX (SMD=0.5; 95% CI, 0.36-0.64; p<0.001) after selenium supplementation. However, selenium supplementation was not statistically associated with CHD mortality and an aberrant lipid profile., Conclusion: Selenium supplementation decreased serum CRP and increased the GSH-PX level, suggesting a positive effect on reducing oxidative stress and inflammation in CHD. However, selenium supplementation is not sufficient to reduce mortality and to improve the lipid status., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16-mo-old mice. A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify Gpr158 , an orphan G protein-coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN's regulation of hippocampal-dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes., (© 2017 Khrimian et al.)

Tralopyril was the active agent of a pro-insecticide chlorfenapyr. To simultaneously solve the problems of the phytotoxicity and non-systemic insecticidal activity of tralopyril, four new tralopyril conjugates containing theanine or glutamic acid moieties were designed and synthesized. Their phytotoxicity to tea shoot, phloem systemicity, and insecticidal activity were evaluated. Phytotoxic symptoms were not observed after the tea shoots were exposed to the four conjugates at concentrations of 2mM. The phloem mobility test on Ricinus communis L. seedlings confirmed that all four conjugates were mobile in the sieve tubes. Results of insecticidal activity against the third-instar larvae of Plutella xylostella showed that only conjugate 20 exhibited activity with an LC 50 value of 0.5882±0.0504mM. After root application to tea seedlings, conjugate 20 showed obviously systemic insecticidal activity against Dendrothrips minowai Priesner, while chlorfenapyr showed no attribute of that. A new conjugate as potential phloem mobile pro-insecticide candidate was provided and so a novel strategy of pro-insecticide for improved phloem systemicity was proposed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

POMC neurons integrate metabolic signals from the periphery. Here, we show in mice that food deprivation induces a linear current-voltage relationship of AMPAR-mediated excitatory postsynaptic currents (EPSCs) in POMC neurons. Inhibition of EPSCs by IEM-1460, an antagonist of calcium-permeable (Cp) AMPARs, diminished EPSC amplitude in the fed but not in the fasted state, suggesting entry of GluR2 subunits into the AMPA receptor complex during food deprivation. Accordingly, removal of extracellular calcium from ACSF decreased the amplitude of mEPSCs in the fed but not the fasted state. Ten days of high-fat diet exposure, which was accompanied by elevated leptin levels and increased POMC neuronal activity, resulted in increased expression of Cp-AMPARs on POMC neurons. Altogether, our results show that entry of calcium via Cp-AMPARs is inherent to activation of POMC neurons, which may underlie a vulnerability of these neurons to calcium overload while activated in a sustained manner during over-nutrition.

Glucose is the primary driver of hypothalamic proopiomelanocortin (POMC) neurons. We show that endothelial hypoxia-inducible factor 1α (HIF-1α) controls glucose uptake in the hypothalamus and that it is upregulated in conditions of undernourishment, during which POMC neuronal activity is decreased. Endothelium-specific knockdown of HIF-1α impairs the ability of POMC neurons to adapt to the changing metabolic environment in vivo, resulting in overeating after food deprivation in mice. The impaired functioning of POMC neurons was reversed ex vivo or by parenchymal glucose administration. These observations indicate an active role for endothelial cells in the central control of metabolism and suggest that central vascular impairments may cause metabolic disorders., (© 2017 by the American Diabetes Association.)

Objective: To explore the clinical application and therapeutic effect of percutaneous vertebroplasty(PVP) and open vertebroplasty for metastatic spinal tumor., Methods: The clinical data of 126 patients with metastatic spinal tumor underwent surgery and obtained follow-up from January 2012 to March 2016 were retrospectively analyzed. These 126 cases were divided into two groups according to different operative methods. The metastatic tumor of 43 cases encroached vertebral canal oppressing spinal cord and nerve root, they were treated with open operation(open vertebroplasty group);and other 83 cases without obviously spinal cord or nerve root compression, or unfit for open operation, were treated with PVP (percutaneous vertebroplasty group) . VAS score, ECOG and Frankel grade were used to evaluate the pain and neurofunction in two groups.All out-hospital patients were followed up every 3 months for 1 time. X-ray, CT, MRI were examined in follow-up., Results: A total of 112 vertebrae underwent PVP with the median surgical time of 50 min;VAS scores decreased significantly at 2 days after operation, which maintained till 1 month later; ECOG grade at 1 month decreased significantly;44 of 112 vertebrae suffered from asymptomatic bone cement leakage, no complications such as nerve injury or pulmonary embolism was found; the median survival time was 16 months. While for open vertebroplasty group, the median surgical time was 160 min and blood loss was 1 000 ml; postoperative VAS scores and ECOG grade at 1 month decreased significantly. Postoperative Frankel grade of 36 patients got improvement in 41 patients with spinal cord functional disturbance(87.8%); and 29 of 40 patients with incompleteness out of motor function were full recovery(76.3%); 12 cases (27.9%) occurred complications and the median survival time was 11 months., Conclusions: The different vertebroplasty treatments can be selected for patients with metastatic spinal tumor, which can relieve the pain, improve the nerve function, reconstruct the spinal stabilization, maintain the local control and raise the life quality., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.