Chronic Stress-Induced Elevation of Melanin-Concentrating Hormone in the Locus Coeruleus Inhibits Norepinephrine Production and Associated With Depression-Like Behaviors in Rats.

BACKGROUND: Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that projects throughout the central nervous system, including the noradrenergic locus coeruleus (LC). Our previous study suggested that MCH/MCH receptor 1 (MCHR1) in the LC may be involved in the regulation of depression. The present study investigated whether the role of MCH/MCHR1 in the LC in depression-like behaviors is associated with the regulation of norepinephrine. METHOD: Chronic unpredictable stress (CUS) and an acute intra-LC microinjection of MCH induced depression-like behaviors in rats. The MCHR1 antagonist SNAP-94847 was also microinjected in the LC in rats that were suffering CUS or treated with MCH. The sucrose preference, forced swim, and locomotor tests were used for behavioral evaluation. Immunofluorescence staining, enzyme-linked immunosorbent assay, western blot, and high-performance liquid chromatography with electrochemical detection were used to explore the mechanism of MCH/MCHR1 in the regulation of depression-like behaviors. RESULTS: CUS induced an abnormal elevation of MCH levels and downregulated MCHR1 in the LC, which was highly correlated with the formation of depression-like behaviors. SNAP-94847 exerted antidepressant effects in CUS-exposed rats by normalizing tyrosine hydroxylase, dopamine ß hydroxylase, and norepinephrine in the LC. An acute microinjection of MCH induced depression-like behaviors through its action on MCHR1. MCHR1 antagonism in the LC significantly reversed the MCH-induced downregulation of norepinephrine production by normalizing MCHR1-medicated cAMP-PKA signaling. CONCLUSIONS: Our study confirmed that the MCH/MCHR1 system in the LC may be involved in depression-like behaviors by downregulating norepinephrine production. These results improve our understanding of the pathogenesis of depression that is related to the MCH/MCHR1 system in the LC.

A novel pencil graphite electrode modified with an iron-based conductive metal-organic framework exhibited good ability in simultaneous sensing bisphenol A and bisphenol S.

Bisphenol A (BPA) and its substitute bisphenol S (BPS) are desirable materials widely used in manufacturing plastic products but can pose carcinogenic risks to humans. A new conductive iron-based metal-organic framework (Fe-HHTP)-modified pencil graphite electrode (PGE) for electrochemically sensing BPA and BPS was prepared and fully characterized by SEM, TEM, FT-IR, XRD, and XPS. Results showed that the optimal conditions for preparing Fe-HHTP/PGE were a pH of 6.5, a Fe-HHTP concentration of 2 mg·mL-1, a deposition potential of 0 V, and a deposition time of 100 s. The Fe-HHTP/PGE prepared under such conditions harbored a significant electrocatalytic activity with a detection limit of 0.8 nM for BPA and 1.7 nM for BPS (S/N = 3). Correspondingly, the electrochemical response current was linearly correlated to BPA and BPS, ranging from 0.01 to 100 µM. Fe-HHTP/PGE also obtained satisfactory recoveries by 93.8-102.1% and 96.0-101.3% for detecting BPA and BPS in plastic food packaging samples. Our work has provided a novel electrochemical tool to simultaneously detect BPA and BPS in food packaging samples and environmental matrixes.

Inhibition of Indoleamine 2,3-Dioxygenase Exerts Antidepressant-like Effects through Distinct Pathways in Prelimbic and Infralimbic Cortices in Rats under Intracerebroventricular Injection with Streptozotocin.

The application of intracerebroventricular injection of streptozotocin (ICV-STZ) is considered a useful animal model to mimic the onset and progression of sporadic Alzheimer's disease (sAD). In rodents, on day 7 of the experiment, the animals exhibit depression-like behaviors. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn), is closely related to depression and AD. The present study aimed to investigate the pathophysiological mechanisms of preliminary depression-like behaviors in ICV-STZ rats in two distinct cerebral regions of the medial prefrontal cortex, the prelimbic cortex (PrL) and infralimbic cortex (IL), both presumably involved in AD progression in this model, with a focus on IDO-related Kyn pathways. The results showed an increased Kyn/Trp ratio in both the PrL and IL of ICV-STZ rats, but, intriguingly, abnormalities in downstream metabolic pathways were different, being associated with distinct biological effects. In the PrL, the neuroprotective branch of the Kyn pathway was attenuated, as evidenced by a decrease in the kynurenic acid (KA) level and Kyn aminotransferase II (KAT II) expression, accompanied by astrocyte alterations, such as the decrease in glial fibrillary acidic protein (GFAP)-positive cells and increase in morphological damage. In the IL, the neurotoxicogenic branch of the Kyn pathway was enhanced, as evidenced by an increase in the 3-hydroxy-kynurenine (3-HK) level and kynurenine 3-monooxygenase (KMO) expression paralleled by the overactivation of microglia, reflected by an increase in ionized calcium-binding adaptor molecule 1 (Iba1)-positive cells and cytokines with morphological alterations. Synaptic plasticity was attenuated in both subregions. Additionally, microinjection of the selective IDO inhibitor 1-Methyl-DL-tryptophan (1-MT) in the PrL or IL alleviated depression-like behaviors by reversing these different abnormalities in the PrL and IL. These results suggest that the antidepressant-like effects linked to Trp metabolism changes induced by 1-MT in the PrL and IL occur through different pathways, specifically by enhancing the neuroprotective branch in the PrL and attenuating the neurotoxicogenic branch in the IL, involving distinct glial cells.

Spartina alterniflora invasion altered phosphorus retention and microbial phosphate solubilization of the Minjiang estuary wetland in southeastern China.

Spartina alterniflora invasion is considered a critical event affecting sediment phosphorus (P) availability and stock. However, P retention and microbial phosphate solubilization in the sediments invaded with or without S. alterniflora have not been fully investigated. In this study, a sequential fractionation method and high-throughput sequencing were used to analyze P transformation and the underlying microbial mechanisms in the sediments of no plant (NP) zone, transition (T) zone, and plant (P) zone. Results showed that except for organic phosphate (OP), total phosphate (TP), inorganic phosphate (IP), and available phosphate (AP) all followed a significant decrease trend from the NP site to the T site, and to the P site. The vertical decrease of TP, IP, and AP was also observed with an increase in soil depth. Among the six IP fractions, Fe-P, Oc-P, and Ca10-P were the predominant forms, while the presence of S. alterniflora resulted in an obvious P depletion except for Ca8-P and Al-P. Although S. alterniflora invasion did not significantly alter the alpha diversity of phosphate-solubilizing bacteria (PSB) harboring phoD gene, several PSB belonging to p_Proteobacteria, p_Planctomycetes, and p_Cyanobacteriota showed close correlations with P speciation and IP fractions. Further correlation analysis revealed that the reduced soil pH, soil TN and soil EC, and the increased soil TOC mediated by the invasion of S. alterniflora also significantly correlated to these PSB. Overall, this study elucidates the linkage between PSB and P speciation and provides new insights into understanding P retention and microbial P transformation in the coastal sediment invaded by S. alterniflora.

Clinical prospective study of Gallium 68 (68Ga)-labeled fibroblast-activation protein inhibitor PET/CT in the diagnosis of biliary tract carcinoma.

PURPOSE: This study is to investigate the [68Ga]Ga-DOTA-FAPI PET/CT diagnosis performance in biliary tract carcinoma (BTC) and analyze the association between [68Ga]Ga-DOTA-FAPI PET/CT and clinical indexes. METHODS: A prospective study (NCT05264688) was performed between January 2022 and July 2022. Fifty participants were scanned using [68Ga]Ga-DOTA-FAPI and [18F]FDG PET/CT and acquired pathological tissue. We employed the Wilcoxon signed-rank test to compare the uptake of [68Ga]Ga-DOTA-FAPI and [18F]FDG, and the McNemar test was used to compare the diagnostic efficacy between the two tracers. Spearman or Pearson correlation was used to assess the association between [68 Ga]Ga-DOTA-FAPI PET/CT and clinical indexes. RESULTS: In total, 47 participants (mean age 59.09 ± 10.98 [range 33-80 years]) were evaluated. The [68Ga]Ga-DOTA-FAPI detection rate was greater than [18F]FDG in primary tumors (97.62% vs. 85.71%), nodal metastases (90.05% vs. 87.06%), and distant metastases (100% vs. 83.67%). The uptake of [68Ga]Ga-DOTA-FAPI was higher than [18F]FDG in primary lesions (intrahepatic cholangiocarcinoma, 18.95 ± 7.47 vs. 11.86 ± 0.70, p = 0.001; extrahepatic cholangiocarcinoma, 14.57 ± 6.16 vs. 8.80 ± 4.74, p = 0.004), abdomen and pelvic cavity nodal metastases (6.91 ± 6.56 vs. 3.94 ± 2.83, p < 0.001), and distant metastases (pleural, peritoneum, omentum, and mesentery, 6.37 ± 4.21 vs. 4.50 ± 1.96, p = 0.01; bone, 12.15 ± 6.43 vs. 7.51 ± 4.54, p = 0.008). There was a significant correlation between [68Ga]Ga-DOTA-FAPI uptake and fibroblast-activation protein (FAP) expression (Spearman r = 0.432, p = 0.009), carcinoembryonic antigen (CEA) (Pearson r = 0.364, p = 0.012), and platelet (PLT) (Pearson r = 0.35, p = 0.016). Meanwhile, a significant relationship between [68Ga]Ga-DOTA-FAPI metabolic tumor volume and carbohydrate antigen199 (CA199) (Pearson r = 0.436, p = 0.002) was confirmed. CONCLUSION: [68Ga]Ga-DOTA-FAPI had a higher uptake and sensitivity than [18F]FDG in the diagnosis of BTC primary and metastatic lesions. The correlation between [68Ga]Ga-DOTA-FAPI PET/CT indexes and FAP expression, CEA, PLT, and CA199 were confirmed. TRIAL REGISTRATION: clinicaltrials.gov: NCT 05,264,688.

Functional characterization of four antenna-biased chemosensory proteins in Dioryctria abietella reveals a broadly tuned olfactory DabiCSP1 and its key residues in ligand-binding.

The orientation of the oligophagous cone-feeding moth Dioryctria abietella (Lepidoptera: Pyralidae) to host plants primarily relies on olfactory-related proteins, particularly those candidates highly expressed in antennae. Here, through a combination of expression profile, ligand-binding assay, molecular docking and site-directed mutagenesis strategies, we characterized the chemosensory protein (CSP) gene family in D. abietella. Quantitative real-time PCR (qPCR) analyses revealed the detectable expression of all 22 DabiCSPs in the antennae, of which seven genes were significantly enriched in this tissue. In addition, the majority of the genes (19/22 relatives) had the expression in at least one reproductive tissue. In the interactions of four antenna-dominant DabiCSPs and different chemical classes, DabiCSP1 was broadly tuned to 27 plant-derived odors, three man-made insecticides and one herbicide with high affinities (Ki < 6.60 µM). By contrast, three other DabiCSPs (DabiCSP4, CSP6 and CSP17) exhibited a narrow odor binding spectrum, in response to six compounds for each protein. Our mutation analyses combined with molecular docking simulations and binding assays further identified four key residues (Tyr25, Thr26, Ile65 and Val69) in the interactions of DabiCSP1 and ligands, of which binding abilities of this protein to 12, 15, 16 and three compounds were significantly decreased compared to the wildtype protein, respectively. Our study reveals different odor binding spectra of four DabiCSPs enriched in antennae and identifies key residues responsible for the binding of DabiCSP1 and potentially active compounds for the control of this pest.

Research on detection of different metallographic structures of high speed wheel steel based on laser-induced breakdown spectroscopy.

The laser-induced breakdown spectroscopy (LIBS) experimental platform was applied to obtain LIBS spectral the data of 10 CL60 wheel steel samples. The principle component analysis (PCA) was used to preliminarily analyze the macroscopic characteristics of LIBS spectral data. With the spectral intensity and spectral intensity combined with spectral intensity ratio as variables, three spectral correction methods including median filtering, baseline correction and multiple scattering correction (MSC) were used for pretreatment. And the support vector machine (SVM) qualitative model was established to determine the metallographic structure. It was found that the SVM model established by using the pre-processed data of MSC as the input variable has the best effect. The accuracy rate of calibration set is 100%, and the accuracy rate of prediction set is 98.4%. The research has shown that LIBS combined with SVM model can be used for discriminant analysis of different metallographic structures of train wheel steel.

Compliance with Oral Nutritional Supplementation among Gastric Cancer Patients at Nutritional Risk: A Cross-Sectional Study.

AIMS: To explore compliance with oral nutritional supplementation (ONS) and to identify the risk factors for noncompliance among gastric cancer patients based on the health belief model (HBM). METHODS: This prospective, observational study included gastric cancer patients at nutritional risk who were prescribed ONS from July to September 2020. Demographic factors, clinical factors, ONS-related factors, social factors and variables derived from the HBM were collected. The outcome of interest was compliance with ONS, which was measured by self-reported intake of ONS. Uni- and multivariate analyses of potential risk factors for noncompliance were performed. RESULTS: A total of 162 gastric cancer patients in the preoperative and adjuvant chemotherapy periods were analyzed. The compliance rate with ONS was 24.7%. Univariate analysis identified thirteen variables as risk factors for decreased compliance. Multivariate logistic analysis indicated that ONS compliance was independently associated with the treatment period, perceived barriers to ONS, the motivation to take ONS, and the timing of taking ONS. CONCLUSION: This study showed that overall ONS compliance among gastric cancer patients was notably low. Patients in the chemotherapy treatment period who took ONS at random times each day perceived more barriers to taking ONS and had a lower level of motivation were associated with lower compliance with ONS.

Polymelamine Formaldehyde-Coated MIL-101 as an Efficient Dual-Functional Core-Shell Composite to Catalyze the Deacetalization-Knoevenagel Tandem Reaction.

Porous organic polymer (POP) coated on a metal-organic framework (MOF) has the functions and advantages of MOF and POP at the same time and has excellent catalytic ability. In this study, an efficient dual-functional core-shell composite MOF@POP with Lewis acid and Brønsted base sites was synthesized using the impregnation method in which MIL-101(Cr) was the core component and polymelamine formaldehyde (PMF) was the shell component. Most importantly, the obtained MIL-101(Cr)@PMF showed perfect catalytic activity in the deacetalization-Knoevenagel tandem reaction. In addition, it could still maintain ultrahigh physical and chemical stability.

Angelica sinensis Polysaccharide and Astragalus membranaceus Polysaccharide Accelerate Liver Regeneration by Enhanced Glycolysis via Activation of JAK2/STAT3/HK2 Pathway.

The promotion of liver regeneration is crucial to avoid liver failure after hepatectomy. Angelica sinensis polysaccharide (ASP) and Astragalus membranaceus polysaccharide (AMP) have been identified as being associated with hepatoprotective effects. However, their roles and specific mechanisms in liver regeneration remain to be elucidated. In the present study, it suggested that the respective use of ASP or AMP strikingly promoted hepatocyte proliferation in vitro with a wide range of concentrations (from 12.5 µg/mL to 3200 µg/mL), and a stronger promoting effect was observed in combined interventions. A significantly enhanced liver/body weight ratio (4.20%) on day 7 and reduced serum transaminase (ALT 243.53 IU/L and AST 423.74 IU/L) and total bilirubin (52.61 IU/L) levels on day 3 were achieved by means of ASP-AMP administration after partial hepatectomy in mice. Metabonomics showed that differential metabolites were enriched in glycolysis with high expression of beta-d-fructose 6-phosphate and lactate, followed by significantly strengthened lactate secretion in the supernatant (0.54) and serum (0.43) normalized to control. Upon ASP-AMP treatment, the knockdown of hexokinase 2 (HK2) or inhibited glycolysis caused by 2-deoxy-d-glucose decreased hepatocyte proliferation in vitro and in vivo. Furthermore, pathway analysis predicted the role of JAK2/STAT3 pathway in ASP-AMP-regulated liver regeneration, and phosphorylation of JAK2 and STAT3 was proven to be elevated in this promoting process. Finally, downregulated expression of HK2, an attenuated level of lactate secretion, and reduced hepatocyte proliferation were displayed when STAT3 was knocked out in vitro. Therefore, it can be concluded that ASP-AMP accelerated liver regeneration and exerted a hepatoprotective effect after hepatectomy, in which the JAK2/STAT3/HK2 pathway was actively involved in activating glycolysis.

[Exploration of active components and mechanism of Scutellariae Radix-Phellodendri Chinensis Cortex drug pair in treatment of psoriasis based on network pharmacology and molecular docking].

This paper aims to explore active components and mechanism of Scutellariae Radix(SR)-Phellodendri Chinensis Cortex(PCC) drug pair in treatment of psoriasis by network pharmacology and molecular docking. Specifically, the chemical components of SR and PCC were retrieved from literature and TCMSP, as well as targets of these components from PharmMapper and UniProt, and the targets related to psoriasis from OMIM, TTD, PharmGkb, and DrugBank. Then the chemical component-medicinal target, protein-protein interaction(PPI), and chemical component-psoriasis target networks were constructed by Cytoscape. Gene ontology(GO) term enrichment analysis and Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis were performed based on Metascape. Finally, molecular docking of the chemical components(high degree) with core therapeutic targets was carried out by AutoDock vina. The results showed 88 compounds of SR and PCC(including baicalin, wogonoside, berberine and phellodendrine) and 30 targets of the pair in the treatment of psoriasis. The 30 targets mainly involved the biological processes such as neutrophil mediated immunity(GO: 0002446) and T cell activation(GO: 0042110), and the signaling pathways such as metabolism of xenobiotics by cytochrome P450(hsa00980), apoptosis(hsa04210), and PI3 K-Akt signaling pathway(hsa04151). The results of molecular docking demonstrated that the main active components can spontaneously bind to the targets and the binding energy of 46 components with epidermal growth factor receptor(EGFR) was less than-8 kcal·mol~(-1). According to the PPI analysis, EGFR may be a key target for the treatment of psoriasis. Active components such as baicalin and berberine had high binding affinity with EGFR. This study preliminarily revealed the multi-component, multi-target and multi-pathway mechanism of SR-PCC drug pair in the treatment of psoriasis, which provided theoretical basis for the research on the mechanism of the drug pair in the treatment of psoriasis.

Serotonergic system may be involved in alterations of sleep homeostasis in spontaneously hypertensive rats.

Hypertension is associated with sleep disorders. Spontaneously hypertensive rats are derived from Wistar-Kyoto rats and widely used in research on hypertension. The present study investigated the propensity to sleep and electroencephalographic spectrum changes over 24 hr in spontaneously hypertensive rats, and proposed the involvement of the serotonergic system in these alterations. Time-course analysis showed that spontaneously hypertensive rats exhibit hyperarousal during the light phase but hypersomnia during the dark phase. Spontaneously hypertensive rats also exhibited less slight fluctuation in electroencephalographic delta power density over 24 hr as compared with Wistar-Kyoto rats, suggesting that the accumulation or elimination of sleep pressure was disrupted. Sleep deprivation disrupted the regulation of sleep homeostasis in spontaneously hypertensive rats, reflected by less sleep time and poor sleep quality during the recovery period. The density and activity of serotonergic neurons in the dorsal raphe nucleus were higher in spontaneously hypertensive rats compared with Wistar-Kyoto rats. Interestingly, we observed the absence of fluctuations in 5-hydroxytryptamine and 5-hydroxyindoleacetic acid across the sleep, wake, sleep deprivation and sleep recovery stages in spontaneously hypertensive rats, which were dramatically different from Wistar-Kyoto rats. These results indicate that the disruption of sleep-wake pattern and sleep homeostasis in spontaneously hypertensive rats might be related to abnormalities of the serotonergic system.

Protection from Amyloid ß Peptide-Induced Memory, Biochemical, and Morphological Deficits by a Phosphodiesterase-4D Allosteric Inhibitor.

Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer's pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Aß 1-42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Aß impairment. Microinjection of oligomeric Aß 1-42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Aß-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brain-derived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Aß-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer's disease. SIGNIFICANCE STATEMENT: This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Aß 1-42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer's disease in a model of oligomeric Aß 1-42 neurotoxicity.

Copulation Exerts Significant Effects on mRNA Expression of Cryptochrome Genes in a Moth.

It is recognized that the behavioral rhythms of organisms are controlled by the circadian clock, while the reverse direction, i.e., whether changes in physiology and behavior react to the internal rhythms, is unclear. Cryptochromes (CRYs) are photolyase-like flavoproteins with blue-light receptor function and other functions on circadian clock and migration in animals. Here, we cloned the full-length cDNA of CRY1 and CRY2 in Spodoptera litura (Fabricius, 1775) (Lepidoptera: Noctuidae). Sl-CRYs show high similarity to orthologs from other insects, and their conserved regions contain a DNA photolyase domain and a FAD-binding seven domain. The expression levels of both genes were relatively low during the larval stage, which increased during the pupal stage and then peaked at the adult stage. The expression of Sl-CRY1 and Sl-CRY2 showed differences between males and females and between scotophase and photophase. Further, our study demonstrated that copulation has a significant effect on the expression of Sl-CRYs. More interestingly, the changes in the expression of Sl-CRY1 and Sl-CRY2 due to copulation showed the same trend in both sexes, in which the expression levels of both genes in copulated males and females decreased in the subsequent scotophase after copulation and then increased significantly in the following photophase. Considering the nature of the dramatic changes in reproductive behavior and physiology after copulation in S. litura, we propose that the changes in the expression of Sl-CRYs after copulation could have some function in the reproductive process.

Melanin-Concentrating Hormone (MCH) and MCH-R1 in the Locus Coeruleus May Be Involved in the Regulation of Depressive-Like Behavior.

Background: Previous anatomical and behavioral studies have shown that melanin-concentrating hormone is involved in the modulation of emotional states. However, little is known about brain regions other than the dorsal raphe nucleus that relate the melanin-concentrating hormone-ergic system to depressive states. Numerous studies have shown that the locus coeruleus is involved in the regulation of depression and sleep. Although direct physiological evidence is lacking, previous studies suggest that melanin-concentrating hormone release in the locus coeruleus decreases neuronal discharge. However, remaining unclear is whether the melanin-concentrating hormone-ergic system in the locus coeruleus is related to depressive-like behavior. Method: We treated rats with an intra-locus coeruleus injection of melanin-concentrating hormone, intracerebroventricular injection of melanin-concentrating hormone, or chronic subcutaneous injections of corticosterone to induce different depressive-like phenotypes. We then assessed the effects of the melanin-concentrating hormone receptor 1 antagonist SNAP-94847 on depressive-like behavior in the forced swim test and the sucrose preference test. Results: The intra-locus coeruleus and intracerebroventricular injections of melanin-concentrating hormone and chronic injections of corticosterone increased immobility time in the forced swim test and decreased sucrose preference in the sucrose preference test. All these depressive-like behaviors were reversed by an intra-locus coeruleus microinjection of SNAP-94847. Conclusions: These results suggest that the melanin-concentrating hormone-ergic system in the locus coeruleus might play an important role in the regulation of depressive-like behavior.

Dysfunction of GABAergic neurons in the parafacial zone mediates sleep disturbances in a streptozotocin-induced rat model of sporadic Alzheimer's disease.

Sleep disturbances are prevalent among patients with Alzheimer's disease (AD) and often precede the onset and progression of dementia. However, there are no reliable animal models for investigating sleep disturbances in patients with sporadic AD (sAD), which accounts for more than 90% of all AD cases. In the present study, we characterize the sleep/wake cycles and explore a potential mechanism underlying sleep disturbance in a rat model of sAD induced via intracerebroventricular (icv) injection of streptozotocin (STZ). STZ-icv rats exhibited progressive decreases in slow wave sleep (SWS) during the light phase and throughout the light/dark cycle beginning from 7 days after STZ-icv. Additionally, increased wakefulness and decreased rapid-eye-movement (REM) and non-REM (NREM) sleep were observed from 14 days after STZ-icv. Beginning on day 7, STZ-icv rats exhibited significant decreases in delta (0.5-4.0 Hz) power accompanied by increased power in the beta (12-30 Hz) and low gamma bands (30-50 Hz) during NREM sleep, resembling deficits in sleep quality observed in patients with AD. Immunohistochemical staining revealed a significant reduction in the ratio of c-Fos-positive GABAergic neurons in the parafacial zone (PZ) beginning from day 7 after STZ-icv. These results suggest that the STZ-icv rat model is useful for evaluating sleep disturbances associated with AD, and implicate the dysregulation of GABAergic neuronal activity in the PZ is associated with sleep disturbance induced by STZ.

Type 2 Diabetes Genetic Variants and Risk of Diabetic Retinopathy.

PURPOSE: Genetic association studies to date have not identified any robust risk loci for diabetic retinopathy (DR). We hypothesized that individuals with more diabetes genetic risk alleles have a higher risk of developing DR. DESIGN: Case-control genetic association study. PARTICIPANTS: We evaluated the aggregate effects of multiple type 2 diabetes-associated genetic variants on the risk of DR among 1528 participants with diabetes from the Singapore Epidemiology of Eye Diseases Study, of whom 547 (35.8%) had DR. METHODS: Participants underwent a comprehensive ocular examination, including dilated fundus photography. Retinal photographs were graded using the modified Airlie House classification system to assess the presence and severity of DR following a standardized protocol. We identified 76 previously discovered type 2 diabetes-associated single nucleotide polymorphisms (SNPs) and constructed multilocus genetic risk scores (GRSs) for each individual by summing the number of risk alleles for each SNP weighted by the respective effect estimates on DR. Two GRSs were generated: an overall GRS that included all 76 discovered type 2 diabetes-associated SNPs, and an Asian-specific GRS that included a subset of 55 SNPs previously found to be associated with type 2 diabetes in East and/or South Asian ancestry populations. Associations between the GRSs with DR were determined using logistic regression analyses. Discriminating ability of the GRSs was determined by the area under the receiver operating characteristic curve (AUC). MAIN OUTCOME MEASURES: Odds ratios on DR. RESULTS: Participants in the top tertile of the overall GRS were 2.56-fold more likely to have DR compared with participants in the lowest tertile. Participants in the top tertile of the Asian-specific GRS were 2.00-fold more likely to have DR compared with participants in the bottom tertile. Both GRSs were associated with higher DR severity levels. However, addition of the GRSs to traditional risk factors improved the AUC only modestly by 3% to 4%. CONCLUSIONS: Type 2 diabetes-associated genetic loci were significantly associated with higher risks of DR, independent of traditional risk factors. Our findings may provide new insights to further our understanding of the genetic pathogenesis of DR.

Heterologous Expression of Pteris vittata Arsenite Antiporter PvACR3;1 Reduces Arsenic Accumulation in Plant Shoots.

Arsenic (As) is a toxic carcinogen so it is crucial to decrease As accumulation in crops to reduce its risk to human health. Arsenite (AsIII) antiporter ACR3 protein is critical for As metabolism in organisms, but it is lost in flowering plants. Here, a novel ACR3 gene from As-hyperaccumulator Pteris vittata, PvACR3;1, was cloned and expressed in Saccharomyces cerevisiae (yeast), Arabidopsis thaliana (model plant), and Nicotiana tabacum (tobacco). Yeast experiments showed that PvACR3;1 functioned as an AsIII-antiporter to mediate AsIII efflux to an external medium. At 5 µM AsIII, PvACR3;1 transgenic Arabidopsis accumulated 14-29% higher As in the roots and 55-61% lower As in the shoots compared to WT control, showing lower As translocation. Besides, transgenic tobacco under 5 µM AsIII or AsV also showed similar results, indicating that expressing PvACR3;1 gene increased As retention in plant roots. Moreover, observation of PvACR3;1-green fluorescent protein fusions in transgenic Arabidopsis showed that PvACR3;1 protein localized to the vacuolar membrane, indicating that PvACR3;1 mediated AsIII sequestration into vacuoles, consistent with increased root As. In addition, soil experiments showed ∼22% lower As in the shoots of transgenic tobacco than control. Thus, our study provides a potential strategy to limit As accumulation in plant shoots, representing the first report to decrease As translocation by sequestrating AsIII into vacuoles, shedding light on engineering low-As crops to improve food safety.

Emergency preparedness for mass gatherings: Lessons of "12.31" stampede in Shanghai Bund.

According to WHO, one of these mass gatherings with critical risk is stampedes. Shanghai "12.31" stampede was a preventable tragedy that the government and event planner hold responsibility for. At the same time, it can be a legacy for improvement in the future. The government should draw experience on the implementation of an emergency preparedness system, in order to improve the rapid emergency response during mass gatherings in the future.