Ghrelin's Roles in Stress, Mood, and Anxiety Regulation

Several studies suggest that the peptide hormone ghrelin mediates some of the usual behavioral responses to acute and chronic stress. Circulating ghrelin levels have been found to rise following stress. It has been proposed that this elevated ghrelin helps animals cope with stress by generating antidepressant-like behavioral adaptations, although another study suggests that decreasing CNS ghrelin expression has antidepressant-like effects. Ghrelin also seems to have effects on anxiety, although these have been shown to be alternatively anxiogenic or anxiolytic. The current review discusses our current understanding of ghrelin's roles in stress, mood, and anxiety

On the Efficiency of An Election Game of Two or More Parties: How Bad Can It Be?

We extend our previous work on two-party election competition [Lin, Lu & Chen 2021] to the setting of three or more parties. An election campaign among two or more parties is viewed as a game of two or more players. Each of them has its own candidates as the pure strategies to play. People, as voters, comprise supporters for each party, and a candidate brings utility for the the supporters of each party. Each player nominates exactly one of its candidates to compete against the other party's. A candidate is assumed to win the election with higher odds if it brings more utility for all the people. The payoff of each player is the expected utility its supporters get. The game is egoistic if every candidate benefits her party's supporters more than any candidate from the competing party does. In this work, we first argue that the election game always has a pure Nash equilibrium when the winner is chosen by the hardmax function, while there exist game instances in the three-party election game such that no pure Nash equilibrium exists even the game is egoistic. Next, we propose two sufficient conditions for the egoistic election game to have a pure Nash equilibrium. Based on these conditions, we propose a fixed-parameter tractable algorithm to compute a pure Nash equilibrium of the egoistic election game. Finally, perhaps surprisingly, we show that the price of anarchy of the egoistic election game is upper bounded by the number of parties. Our findings suggest that the election becomes unpredictable when more than two parties are involved and, moreover, the social welfare deteriorates with the number of participating parties in terms of possibly increasing price of anarchy. This work alternatively explains why the two-party system is prevalent in democratic countries

Anxiety- and depressive-like responses and c-fos activity in preproenkephalin knockout mice: Oversensitivity hypothesis of enkephalin deficit-induced posttraumatic stress disorder

The present study used the preproenkephalin knockout (ppENK) mice to test whether the endogenous enkephalins deficit could facilitate the anxiety- and depressive-like symptoms of posttraumatic stress disorder (PTSD). On Day 1, sixteen wildtype (WT) and sixteen ppENK male mice were given a 3 mA or no footshock treatment for 10 seconds in the footshock apparatus, respectively. On Days 2, 7, and 13, all mice were given situational reminders for 1 min per trial, and the freezing response was assessed. On Day 14, all mice were tested in the open field test, elevated plus maze, light/dark avoidance test, and forced swim test. Two hours after the last test, brain tissues were stained to examine c-fos expression in specific brain areas. The present results showed that the conditioned freezing response was significant for different genotypes (ppENK vs WT). The conditioned freezing effect of the ppENK mice was stronger than those of the WT mice. On Day 14, the ppENK mice showed more anxiety- and depressive-like responses than WT mice. The magnitude of Fos immunolabeling was also significantly greater in the primary motor cortex, bed nucleus of the stria terminalis-lateral division, bed nucleus of the stria terminalis-supracapsular division, paraventricular hypothalamic nucleus-lateral magnocellular part, central nucleus of the amygdala, and basolateral nucleus of the amygdala in ppENK mice compared with WT mice. In summary, animals with an endogenous deficit in enkephalins might be more sensitive to PTSD-like aversive stimuli and elicit stronger anxiety and depressive PTSD symptoms, suggesting an oversensitivity hypothesis of enkephalin deficit-induced PTSD

Glycogen synthase kinase 3α and 3β have distinct functions during cardiogenesis of zebrafish embryo

<p>Abstract</p> <p>Background</p> <p>Glycogen synthase kinase 3 (GSK3) encodes a serine/threonine protein kinase, is known to play roles in many biological processes. Two closely related GSK3 isoforms encoded by distinct genes: GSK3α (51 kDa) and GSK3β (47 kDa). In previously studies, most GSK3 inhibitors are not only inhibiting GSK3, but are also affecting many other kinases. In addition, because of highly similarity in amino acid sequence between GSK3α and GSK3β, making it difficult to identify an inhibitor that can be selective against GSK3α or GSK3β. Thus, it is relatively difficult to address the functions of GSK3 isoforms during embryogenesis. At this study, we attempt to specifically inhibit either GSK3α or GSK3β and uncover the isoform-specific roles that GSK3 plays during cardiogenesis.</p> <p>Results</p> <p>We blocked <it>gsk3α </it>and <it>gsk3β </it>translations by injection of morpholino antisense oligonucleotides (MO). Both <it>gsk3α</it>- and <it>gsk3β</it>-MO-injected embryos displayed similar morphological defects, with a thin, string-like shaped heart and pericardial edema at 72 hours post-fertilization. However, when detailed analysis of the <it>gsk3α</it>- and <it>gsk3β</it>-MO-induced heart defects, we found that the reduced number of cardiomyocytes in <it>gsk3α </it>morphants during the heart-ring stage was due to apoptosis. On the contrary, <it>gsk3β </it>morphants did not exhibit significant apoptosis in the cardiomyocytes, and the heart developed normally during the heart-ring stage. Later, however, the heart positioning was severely disrupted in <it>gsk3β </it>morphants. <it>bmp4 </it>expression in <it>gsk3β </it>morphants was up-regulated and disrupted the asymmetry pattern in the heart. The cardiac valve defects in <it>gsk3β </it>morphants were similar to those observed in <it>axin1 </it>and <it>apc</it>^{<it>mcr </it>}mutants, suggesting that GSK3β might play a role in cardiac valve development through the Wnt/β-catenin pathway. Finally, the phenotypes of <it>gsk3α </it>mutant embryos cannot be rescued by <it>gsk3β </it>mRNA, and vice versa, demonstrating that GSK3α and GSK3β are not functionally redundant.</p> <p>Conclusion</p> <p>We conclude that (1) GSK3α, but not GSK3β, is necessary in cardiomyocyte survival; (2) the GSK3β plays important roles in modulating the left-right asymmetry and affecting heart positioning; and (3) GSK3α and GSK3β play distinct roles during zebrafish cardiogenesis.</p

Application of Flexible Micro Temperature Sensor in Oxidative Steam Reforming by a Methanol Micro Reformer

Advances in fuel cell applications reflect the ability of reformers to produce hydrogen. This work presents a flexible micro temperature sensor that is fabricated based on micro-electro-mechanical systems (MEMS) technology and integrated into a flat micro methanol reformer to observe the conditions inside that reformer. The micro temperature sensor has higher accuracy and sensitivity than a conventionally adopted thermocouple. Despite various micro temperature sensor applications, integrated micro reformers are still relatively new. This work proposes a novel method for integrating micro methanol reformers and micro temperature sensors, subsequently increasing the methanol conversion rate and the hydrogen production rate by varying the fuel supply rate and the water/methanol ratio. Importantly, the proposed micro temperature sensor adequately controls the interior temperature during oxidative steam reforming of methanol (OSRM), with the relevant parameters optimized as well

Antimicrobial Activity of Lactobacillus Species Against Carbapenem-Resistant Enterobacteriaceae

ObjectiveThis study aims to identify suitable lactobacilli that have anti-carbapenem-resistant Enterobacteriaceae (CRE) activity with in vitro tolerance to pepsin and bile salts.MethodsFifty-seven Lactobacillus spp. strains encompassing nine species were collected for investigation. Their viabilities in the presence of pepsin and bile salts were tested using tolerance tests. Their anti-CRE effects were assessed by agar well diffusion and broth microdilution assay, as well as time-kill test.ResultsOf the 57 Lactobacillus isolates collected, 31 had a less than 2-log reduction in their viability in both pepsin and bile salt tolerance tests. Of these 31 isolates, 5 (LUC0180, LUC0219, LYC0289, LYC0413, and LYC1031) displayed the greatest anti-CRE activity with a CRE zone of inhibition greater than 15 mm in agar well diffusion assays. The minimal inhibitory percentages of supernatants from these five strains against CREs ranged from 10 to 30%. With the exception of LUC0180, which had a minimal bactericidal percentage ≥ 40%, the bactericidal percentage of all the strains ranged from 20 to 40%. The inhibitory effect of the cell-free culture supernatants from these Lactobacillus strains did not change after heating but was abolished as the pH changed to 7.0. After a 24-h incubation, five of the Lactobacillus strains at a concentration of 108 CFU/ml totally inhibited the growth of carbapenem-resistant Escherichia coli (CRE316) and Klebsiella pneumoniae (CRE632). After a 48-h incubation, the growth of CRE316 was completely inhibited under each concentration of lactobacilli based on time-kill test. Furthermore, when the concentration of lactobacilli was at 108 CFU/ml, the decline in pH was faster than at other concentrations.ConclusionSome Lactobacillus strains exhibit anti-CRE activity, which suggests potential applications for controlling or preventing CRE colonization or infection

The Nonsteroidal Farnesoid X Receptor Agonist Cilofexor (GS-9674) Improves Markers of Cholestasis and Liver Injury in Patients With Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC) represents a major unmet medical need. In a phase II double-blind, placebo-controlled study, we tested the safety and efficacy of cilofexor (formerly GS-9674), a nonsteroidal farnesoid X receptor agonist in patients without cirrhosis with large-duct PSC. Patients were randomized to receive cilofexor 100 mg (n = 22), 30 mg (n = 20), or placebo (n = 10) orally once daily for 12 weeks. All patients had serum alkaline phosphatase (ALP) > 1.67 × upper limit of normal and total bilirubin ≤ 2 mg/dL at baseline. Safety, tolerability, pharmacodynamic effects of cilofexor (serum C4 [7α-hydroxy-4-cholesten-3-one] and bile acids), and changes in liver biochemistry and serum fibrosis markers were evaluated. Overall, 52 patients were randomized (median age 43 years, 58% male, 60% with inflammatory bowel disease, 46% on ursodeoxycholic acid). Baseline median serum ALP and bilirubin were 348 U/L (interquartile range 288-439) and 0.7 mg/dL (0.5-1.0), respectively. Dose-dependent reductions in liver biochemistry were observed. At week 12, cilofexor 100 mg led to significant reductions in serum ALP (median reduction -21%; P = 0.029 versus placebo), gamma-glutamyl transferase (-30%; P < 0.001), alanine aminotransferase (ALT) (-49%; P = 0.009), and aspartate aminotransferase (-42%; P = 0.019). Cilofexor reduced serum C4 compared with placebo; reductions in bile acids were greatest with 100 mg. Relative reductions in ALP were similar between ursodeoxycholic acid-treated and untreated patients. At week 12, cilofexor-treated patients with a 25% or more relative reduction in ALP had greater reductions in serum alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, tissue inhibitor of metalloproteinase 1, C-reactive protein, and bile acids than nonresponders. Adverse events were similar between cilofexor and placebo-treated patients. Rates of grade 2 or 3 pruritus were 14% with 100 mg, 20% with 30 mg, and 40% with placebo. Conclusion: In this 12-week, randomized, placebo-controlled study, cilofexor was well tolerated and led to significant improvements in liver biochemistries and markers of cholestasis in patients with PSC

Paternal Tobacco Smoke Correlated to Offspring Asthma and Prenatal Epigenetic Programming

Rationale: Little is known about effects of paternal tobacco smoke (PTS) on the offspring’s asthma and its prenatal epigenetic programming.Objective: To investigate whether PTS exposure was associated with the offspring’s asthma and correlated to epigenetic CG methylation of potential tobacco-related immune genes: LMO2, GSTM1 or/and IL-10 genes.Measurements and Main Results: In a birth cohort of 1,629 newborns, we measured exposure rates of PTS (23%) and maternal tobacco smoke (MTS, 0.2%), cord blood DNA methylation, infant respiratory tract infection, childhood DNA methylation, and childhood allergic diseases. Infants with prenatal PTS exposure had a significantly higher risk of asthma by the age of 6 than those without (p = 0.026). The PTS exposure doses at 0, &lt;20, and ≧20 cigarettes per day were significantly associated with the trend of childhood asthma and the increase of LMO2-E148 (p = 0.006), and IL10_P325 (p = 0.008) CG methylation. The combination of higher CG methylation levels of LMO2_E148, IL10_P325, and GSTM1_P266 corresponded to the highest risk of asthma by 43.48%, compared to other combinations (16.67–23.08%) in the 3-way multi-factor dimensionality reduction (MDR) analysis. The LMO2_P794 and GSTM1_P266 CG methylation levels at age 0 were significantly correlated to those at age of 6.Conclusions: Prenatal PTS exposure increases CG methylation contents of immune genes, such as LMO2 and IL-10, which significantly retained from newborn stage to 6 years of age and correlated to development of childhood asthma. Modulation of the LMO2 and IL-10 CG methylation and/or their gene expression may provide a regimen for early prevention of PTS-associated childhood asthma.Descriptor number: 1.10 Asthma Mediators.Scientific Knowledge on the Subject: It has been better known that maternal tobacco smoke (MTS) has an impact on the offspring’s asthma via epigenetic modification. Little is known about effects of paternal tobacco smoke (PTS) on the offspring’s asthma and its prenatal epigenetic programming.What This Study Adds to the Field: Prenatal tobacco smoke (PTS) can program epigenetic modifications in certain genes, such as LMO2 and IL-10, and that these modifications are correlated to childhood asthma development. The higher the PTS exposure dose the higher the CG methylation levels are found. The combination of higher CG methylation levels of LMO2_E148, IL10_P325 and GSTM1_P266 corresponded to the highest risk of asthma. Measuring the DNA methylation levels of certain genes might help to predict high-risk populations for childhood asthma and provide a potential target to prevent the development of childhood asthma