Cholesterol-dependent dynamic changes in the conformation of the type 1 cholecystokinin receptor affect ligand binding and G protein coupling.

Development of optimal therapeutics for disease states that can be associated with increased membrane cholesterol requires better molecular understanding of lipid modulation of the drug target. Type 1 cholecystokinin receptor (CCK1R) agonist actions are affected by increased membrane cholesterol, enhancing ligand binding and reducing calcium signaling, while agonist actions of the closely related CCK2R are not. In this work, we identified a set of chimeric human CCK1R/CCK2R mutations that exchange the cholesterol sensitivity of these 2 receptors, providing powerful tools when expressed in CHO and HEK-293 model cell lines to explore mechanisms. Static, low energy, high-resolution structures of the mutant CCK1R constructs, stabilized in complex with G protein, were not substantially different, suggesting that alterations to receptor dynamics were key to altered function. We reveal that cholesterol-dependent dynamic changes in the conformation of the helical bundle of CCK receptors affects both ligand binding at the extracellular surface and G protein coupling at the cytosolic surface, as well as their interrelationships involved in stimulus-response coupling. This provides an ideal setting for potential allosteric modulators to correct the negative impact of membrane cholesterol on CCK1R.

Cortical gray to white matter signal intensity ratio as a sign of neurodegeneration and cognition independent of ß-amyloid in dementia.

Cortical gray to white matter signal intensity ratio (GWR) measured from T1-weighted magnetic resonance (MR) images was associated with neurodegeneration and dementia. We characterized topological patterns of GWR during AD pathogenesis and investigated its association with cognitive decline. The study included a cross-sectional dataset and a longitudinal dataset. The cross-sectional dataset included 60 cognitively healthy controls, 61 mild cognitive impairment (MCI), and 63 patients with dementia. The longitudinal dataset included 26 participants who progressed from cognitively normal to dementia and 26 controls that remained cognitively normal. GWR was compared across the cross-sectional groups, adjusted for amyloid PET. The correlation between GWR and cognition performance was also evaluated. The longitudinal dataset was used to investigate GWR alteration during the AD pathogenesis. Dementia with ß-amyloid deposition group exhibited the largest area of increased GWR, followed by MCI with ß-amyloid deposition, MCI without ß-amyloid deposition, and controls. The spatial pattern of GWR-increased regions was not influenced by ß-amyloid deposits. Correlation between regional GWR alteration and cognitive decline was only detected among individuals with ß-amyloid deposition. GWR showed positive correlation with tau PET in the left supramarginal, lateral occipital gyrus, and right middle frontal cortex. The longitudinal study showed that GWR increased around the fusiform, inferior/superior temporal lobe, and entorhinal cortex in MCI and progressed to larger cortical regions after progression to AD. The spatial pattern of GWR-increased regions was independent of ß-amyloid deposits but overlapped with tauopathy. The GWR can serve as a promising biomarker of neurodegeneration in AD.

Loss of synaptic density in nucleus basalis of meynert indicates distinct neurodegeneration in Alzheimer's disease: the RJNB-D study.

BACKGROUND: The nucleus basalis of Meynert (NBM) is known to play a crucial role in the development and pathogenesis of Alzheimer's Disease (AD), particularly the cholinergic system within the NBM. However, the relationship between synaptic loss in the NBM and the clinical profile of AD remains unclear. METHODS: In our study, we included 44 Aß-negative normal controls (CN) and 76 Aß-positive participants with cognitive impairment (CI). All participants underwent structural and diffusion magnetic resonance imaging (MRI), as well as positron emission tomography (PET) imaging to measure synaptic vesicle glycoprotein 2 A (SV2A) levels (Trial registration: NCT05623124. Registered 21 November 2022). The SV2A standardized uptake value ratios (SUVR) distribution in the NBM of CN participants was used as the reference norm. We investigated the association between NBM synaptic density and clinical performance, traditional AD biomarkers, and white matter tracts that passed the NBM. RESULTS: Participants with cognitive impairment (CI) who had NBM synaptic density below 1.5 standard deviations (SD) or 0.5 SD of the norm exhibited worse cognitive performance compared to cognitively normal (CN) individuals. Crucially, the extent of deviation in synaptic density from the norm was directly proportional to the severity of cognitive impairment and neurodegeneration biomarkers. Furthermore, among patients with cognitive impairment, synaptic loss in the NBM was associated with potential impairment in the density and organization of neurites within the white matter tracts connected to the NBM. Finally, neurite density index in the medial tracts may play a mediating role in the relationship between NBM synaptic density and MMSE scores. CONCLUSION: The extent that synaptic density in NBM deviated from the norm suggested the extent of worse cognitive performance and severe neurodegeneration. Furthermore, cognitive impairment associated with synaptic loss in the NBM may be mediated by its pathological impact on NBM white matter tracts.

Structures of the human cholecystokinin 1 (CCK1) receptor bound to Gs and Gq mimetic proteins provide insight into mechanisms of G protein selectivity.

G protein-coupled receptors (GPCRs) are critical regulators of cellular function acting via heterotrimeric G proteins as their primary transducers with individual GPCRs capable of pleiotropic coupling to multiple G proteins. Structural features governing G protein selectivity and promiscuity are currently unclear. Here, we used cryo-electron microscopy (cryo-EM) to determine structures of the cholecystokinin (CCK) type 1 receptor (CCK1R) bound to the CCK peptide agonist, CCK-8 and 2 distinct transducer proteins, its primary transducer Gq, and the more weakly coupled Gs. As seen with other Gq/11-GPCR complexes, the Gq-α5 helix (αH5) bound to a relatively narrow pocket in the CCK1R core. Surprisingly, the backbone of the CCK1R and volume of the G protein binding pocket were essentially equivalent when Gs was bound, with the Gs αH5 displaying a conformation that arises from "unwinding" of the far carboxyl-terminal residues, compared to canonically Gs coupled receptors. Thus, integrated changes in the conformations of both the receptor and G protein are likely to play critical roles in the promiscuous coupling of individual GPCRs.

Signalling of Adrenoceptors: Canonical Pathways and New Paradigms.

The concept of G protein-coupled receptors initially arose from studies of the ß-adrenoceptor, adenylyl cyclase, and cAMP signalling pathway. Since then both canonical G protein-coupled receptor signalling pathways and emerging paradigms in receptor signalling have been defined by experiments focused on adrenoceptors. Here, we discuss the evidence for G protein coupling specificity of the nine adrenoceptor subtypes. We summarise the ability of each of the adrenoceptors to activate proximal signalling mediators including cAMP, calcium, mitogen-activated protein kinases, and protein kinase C pathways. Finally, we highlight the importance of precise spatial and temporal control of adrenoceptor signalling that is controlled by the localisation of receptors at intracellular membranes and in larger protein complexes.

LncRNA XIST Protects Against Polycystic Ovary Syndrome via the Regulation of miR-212-3p/RASA1 Axis.

The polycystic ovary syndrome (PCOS), a common endocrine disorder, is mainly related to infertility. Moreover, it is characterized by promoted androgen, suppressed ovulation and insulin resistance. Long non-coding RNA X inactive specific transcript (lncRNA XIST), known as an oncogene or a cancer inhabited factor, is involved in several disease. However, the diagnostic mechanisms of lncRNA XIST in PCOS have not been clarified. Our study aimed to explain whether lncRNA XIST regulates KGN cells proliferation and apoptosis via microRNA (miR)-212-3p/RASA1 axis in PCOS. Levels of lncRNA XIST, miR-212-3p and RASA1 in KGN cells were detected through reverse transcription quantitative polymerase chain reaction (RT-qPCR) assay. Fluorescence in situ Hybridization (FISH) was performed to confirm the expression of lncRNA XIST and miR-212-3p in KGN cells. StarBase and dual-luciferase reporter assay were applied for exploring the interaction between miR-212-3p and RASA1. Cell viability, apoptosis, protein expression of Bcl-2 and Bax were assessed by MTT, flow cytometry analysis, RT-qPCR and western blot, respectively. We found that lncRNA XIST was low-expressed, miR-212-3p was over-expressed, and RASA1 was dramatically down-regulated in KGN cells. LncRNA XIST negatively regulated miR-212-3p expression in KGN cells. MiR-212-3p interacted with RASA1 and negatively regulated RASA1 levels in KGN cells. Up-regulation of lncRNA XIST signally decreased cells viability, stimulated more apoptotic cells, enhanced Bax expression, and depressed Bcl-2 level in KGN cells. However, these observations were abolished after miR-212-3p mimic treatment. Furthermore, miR-212-3p inhibitor significantly inhibited cell proliferation, enhanced more apoptotic cells, increased Bax expression, and decreased Bcl-2 level in KGN cells, and these effects were eliminated by RASA1-siRNA transfection. Our observations revealed that lncRNA XIST protects against PCOS through regulating miR-212-3p/RASA1 axis, suggesting that lncRNA XIST may be a promising therapeutic target for PCOS therapy.

Linking white matter hyperintensities to regional cortical thinning, amyloid deposition, and synaptic density loss in Alzheimer's disease.

INTRODUCTION: We investigated the association between white matter hyperintensities (WMH) and regional cortical thickness, amyloid and tau deposition, and synaptic density in the WMH-connected cortex using multimodal images. METHODS: We included 107 participants (59 with Alzheimer's disease [AD]; 27 with mild cognitive impairment; 21 cognitively normal controls) with amyloid beta (Aß) positivity on amyloid positron emission tomography (PET). The cortex connected to WMH was identified using probabilistic tractography. RESULTS: We found that WMH connected to the cortex with more severe regional degeneration as measured by cortical thickness, Aß and tau deposition, and synaptic vesicle glycoprotein 2 A (SV2A) density using 18F-SynVesT-1 PET. In addition, higher ratios of Aß in the deep WMH-connected versus WMH-unconnected cortex were significantly related to lower cognitive scores. Last, the cortical thickness of WMH-connected cortex reduced more than WMH-unconnected cortex over 12 months. DISCUSSION: Our results suggest that WMH may be associated with AD-intrinsic processes of degeneration, in addition to vascular mechanisms. HIGHLIGHTS: We studied white matter hyperintensities (WMHs) and WMH-connected cortical changes. WMHs are associated with more severe regional cortical degeneration. Findings suggest WMHs may be associated with Alzheimer's disease-intrinsic processes of degeneration.

Assessment of beneficial effects and identification of host adaptation-associated genes of Ligilactobacillus salivarius isolated from badgers.

BACKGROUND: Ligilactobacillus salivarius has been frequently isolated from the gut microbiota of humans and domesticated animals and has been studied as a candidate probiotic. Badger (Meles meles) is known as a "generalist" species that consumes complex foods and exhibits tolerance and resistance to certain pathogens, which can be partly attributed to the beneficial microbes such as L. salivarius in the gut microbiota. However, our understanding of the beneficial traits and genomic features of badger-originated L. salivarius remains elusive. RESULTS: In this study, nine L. salivarius strains were isolated from wild badgers' feces, one of which exhibited good probiotic properties. Complete genomes of the nine L. salivarius strains were generated, and comparative genomic analysis was performed with the publicly available complete genomes of L. salivarius obtained from humans and domesticated animals. The strains originating from badgers harbored a larger genome, a higher number of protein-coding sequences, and functionally annotated genes than those originating from humans and chickens. The pan-genome phylogenetic tree demonstrated that the strains originating from badgers formed a separate clade, and totally 412 gene families (12.6% of the total gene families in the pan-genome) were identified as genes gained by the last common ancestor of the badger group. The badger group harbored significantly more gene families responsible for the degradation of complex carbohydrate substrates and production of polysaccharides than strains from other hosts; many of these were acquired by gene gain events. CONCLUSIONS: A candidate probiotic and nine L. salivarius complete genomes were obtained from the badgers' gut microbiome, and several beneficial genes were identified to be specifically present in the badger-originated strains that were gained in the evolution. Our study provides novel insights into the adaptation of L. salivarius to the intestinal habitat of wild badgers and provides valuable strain and genome resources for the development of L. salivarius as a probiotic.

Treatment patterns and cost of exacerbations in patients with chronic obstructive pulmonary disease using multiple inhaler triple therapy in South Korea.

BACKGROUND: Multiple inhaler triple therapy (MITT), comprising inhaled corticosteroids (ICS), long-acting beta-agonists (LABA), and long-acting muscarinic antagonists (LAMA), has been used as an escalation treatment for patients with chronic obstructive pulmonary disease (COPD). However, real-world use of MITT has not been investigated in Asia, including South Korea. This study reports baseline characteristics of patients with COPD initiated on MITT in South Korea, and their treatment patterns. Healthcare resource utilization (HRU) and costs associated with COPD exacerbations following MITT initiation were also assessed. METHODS: This was a retrospective cohort study using the South Korea National Health Insurance database (2014-2018). Included patients were ≥ 40 years, had a COPD diagnosis, were newly initiated on MITT and had ≥ 12 months' data both before (baseline) and after index date (the first day with overlapping supply of all MITT components). Treatment immediately before initiation and immediately following discontinuation of MITT were identified, and proportion of days covered (PDC) by MITT was calculated. HRU and costs (per person per year [PPPY]) associated with exacerbations were identified following MITT initiation; costs were calculated using the average 2020 exchange rate (0.0008 USD/KRW). RESULTS: Among 37,400 patients, the mean age was 69 (SD 10) years and 73% were males; 56% had ≥ 1 COPD exacerbation during the baseline period, with a mean of 2 (SD 5) events/year. ICS/LABA was the most frequent regimen prescribed immediately before initiation (37%) and immediately following discontinuation (41% of 34,264 patients) of MITT. At 3, 6, and 12 months from treatment initiation, mean PDC was 81%, 63% and 49%, respectively; median treatment duration was 102 days. The mean (95% confidence interval [CI]) number of total visits for severe COPD exacerbations was 0.77 PPPY (0.75-0.78); mean PPPY total healthcare costs were 2093 USD. CONCLUSIONS: Patients with COPD in South Korea experienced frequent exacerbations prior to MITT, and PDC by MITT was low. Patients may benefit from early optimization of COPD therapy, and greater emphasis on adherence to inhaled COPD therapy. Severe exacerbations were found to incur substantial costs; treatment alternatives that can reduce the rate of severe exacerbations are likely to minimize healthcare costs.

A balanced gut microbiota is essential to maintain health in captive sika deer.

Certain animals harbor a high proportion of pathogens, particular the zoonotic pathogens, in their gut microbiome but are usually asymptomic; however, their carried pathogens may seriously threaten the public health. By understanding how the microbiome overcomes the negative effects of pathogens to maintain host health, we can develop novel solutions to control animal-mediated pathogen transmission including identification and application of beneficial microbes. Here, we analyzed the gut microbiota of 10 asymptomic captive sika deer individuals by full-length 16S rDNA sequencing. Twenty-nine known pathogens capable of infecting humans were identified, and the accumulated proportions of the identified pathogens were highly variable among individuals (2.33 to 39.94%). The relative abundances of several beneficial bacteria, including Lactobacillus and Bifidobacterium, were found to be positively correlated with the relative abundances of accumulated pathogens. Whole-genome metagenomic analysis revealed that the beneficial- and pathogenic-associated functions, such as genes involved in the synthesis of short chain fatty acids and virulence factors, were also positively correlated in the microbiome, indicating that the beneficial and pathogenic functions were maintained at a relatively balanced ratio. Furthermore, the bacteriophages that target the identified pathogens were found to be positively correlated with the pathogenic content in the microbiome. Several high-quality genomes of beneficial bacteria affiliated with Lactobacillus and Bifidobacterium and bacteriophages were recovered from the metagenomic data. Overall, this study provides novel insights into the interplay between beneficial and pathogenic content to ensure maintenance of a healthy gut microbiome, and also contributes to discovery of novel beneficial microbes and functions that control pathogens. KEY POINTS: • Certain asymptomic captive sika deer individuals harbor relatively high amounts of zoonotic pathogens. • The beneficial microbes and the beneficial functions are balanced with the pathogenic contents in the gut microbiome. • Several high-quality genomes of beneficial bacteria and bacteriophages are recovered by metagenomics.

Exogenous Melatonin Improves Seed Germination of Wheat (Triticum aestivum L.) under Salt Stress.

Melatonin (MT) can effectively reduce oxidative damage induced by abiotic stresses such as salt in plants. However, the effects of MT on physiological responses and molecular regulation during wheat germination remains largely elusive. In this study, the response of wheat seeds to MT under salt stress during germination was investigated at physiological and transcriptome levels. Our results revealed that application of MT significantly reduced the negative influence of salt stress on wheat seed germination. The oxidative load was reduced by inducing high activities of antioxidant enzymes. In parallel, the content of gibberellin A3 (GA3) and jasmonic acid (JA) increased in MT-treated seedling. RNA-seq analysis demonstrated that MT alters oxidoreductase activity and phytohormone-dependent signal transduction pathways under salt stress. Weighted correlation network analysis (WGCNA) revealed that MT participates in enhanced energy metabolism and protected seeds via maintained cell morphology under salt stress during wheat seed germination. Our findings provide a conceptual basis of the MT-mediated regulatory mechanism in plant adaptation to salt stress, and identify the potential candidate genes for salt-tolerant wheat molecular breeding.

A novel acid polysaccharide from Boletus edulis: extraction, characteristics and antitumor activities in vitro.

A novel cold-water-soluble polysaccharide (BEP), with a molecular weight of 6.0 × 106 Da, was isolated from Boletus edulis. BEP consists of galactose, glucose, xylose, mannose, glucuronic, and galacturonic acid in a ratio of 0.34:0.28:0.28:2.57:1.00:0.44. The IR results showed that BEP was an acid polysaccharide, containing α-type and ß-type glucoside bonds. MTT assay showed BEP could inhibit cell proliferation significantly. Morphological observation demonstrated that BEP-treated MDA-MB-231 and Ca761 cells exhibited typical apoptotic morphological features. Flow cytometry analysis revealed that BEP caused mitochondrial membrane potential collapse. Annexin V-FITC/PI staining indicated that BEP induced apoptosis of MDA-MB-231 and Ca761 cells through cell block in S phase and G0/G1 phase, respectively. Western blot results showed that BEP could increase the Bax/Bcl-2 ratios, promote the release of cytochrome C, and activate the expression of caspase-3 and caspase-9 in MDA-MB-231 and Ca761 cells. In conclusion, our results demonstrated that BEP could inhibit the proliferation of breast cancer cells and induce apoptosis through mitochondrial pathways.

Early prediction of cerebral-cardiac syndrome after ischemic stroke: the PANSCAN scale.

BACKGROUND: Cerebral-cardiac syndrome, newly developed cardiac damage manifestations subsequent to cerebral injuries, is a common complication of stroke and leads to increased morbidity and mortality. The current study is aimed to develop a risk prediction scale to stratify high-risk population of CCS among ischemic stroke patients. METHODS: The study included 410 cases from four tertiary medical centers from June 2018 to April 2019. The risk prediction model was established via logistic regression from the derivation cohort including 250 cases admitted between June 2018 and December 2018. Another 160 cases admitted from January 2019 to April 2019 were included as the validation cohort for external validation. The performance of the model was determined by the area under curve of the receiver operating characteristic curve. A rating scale was developed based on the magnitude of the logistic regression coefficient. RESULTS: The prevalence of CCS was 55.2% in our study. The predictive model derived from the derivation cohort showed good calibration by Hosmer-Lemeshow test (P = 0.492), and showed sensitivity of 0.935, specificity of 0.720, and Youden index of 0.655. The C-statistic for derivation and validation cohort were 0.888 and 0.813, respectively. Our PANSCAN score (0 to 10 points) was then established, which consists of the following independent risk factors: PT(12 s-14 s = 0; otherwise = 1), APTT(30s-45s = 0, otherwise = 1), Neutrophils(50-70% = 0; otherwise = 1), Sex(female = 1), Carotid artery stenosis(normal or mild = 0; moderate to severe = 2), Age(≥65 years = 1), NIHSS score(1 to 4 = 2; ≥5 = 3). Patients scored 3 or more points were stratified as high risk. CONCLUSION: The risk prediction model showed satisfactory prediction effects. The PANSCAN scale provides convenient reference for preventative treatment and early management for high-risk patients. TRIAL REGISTRATION: The study was retrospectively registered in Chinese Trial Registry. The date of registration is April 17, 2019. TRIAL REGISTRATION NUMBER: ChiCTR1900022587 .

Concordance Between Physician-rated and Caregiver-perceived Disease Severity in Children with Atopic Dermatitis: A Cross-sectional Study.

This study examined concordance between caregiver-reported and physician-rated estimates of severity of atopic dermatitis (AD) in paediatric patients and explored potential explanatory factors. Physician-reported severity of AD was retrieved from medical records, while caregiver-reported disease severity and sociodemographic data were obtained through a survey that also collected information on out-of-pocket expenses due to AD. There was 38.5% (95% confidence interval (95% CI) 30.1, 43.5) disagreement between physician and caregivers with regards to both underestimating and overestimating the condition. A duration since AD diagnosis shorter than 6 months showed higher concordance (kappa: 44.4%; 95% CI 30.6, 58.2) between caregiver and physician estimates of AD severity compared with a duration of 6 months or longer. Caregivers underestimating their child's AD accounted for 27.7% among all participants, while 10.8% overestimated the severity of AD compared with physicians. Factors significantly associated with caregiver's underestimation of disease severity were age of the child and time since disease diagnosis. Comparison of concordance between caregiver-reported and physician-rated estimates of severity of AD in paediatric patients revealed a tendency amongst caregivers to underestimate severity of AD. This information may have clinical implications for treatment outcomes if caregivers fail to adhere to medical advice.

Stress adaptation disorders play a role in rat gestational diabetes with oxidative stress and glucose transporter-4 expression.

Stress adaptation disorder exists in gestational diabetes mellitus (GDM) women, this study was to investigate the impact of stress adaptation disorder on glucose disposal and skeletal muscle glucose transporter4 (GLUT4) expression in GDM rat model. Rats were assigned randomly to Normal control (NC) group and GDM group. We analyzed the levels of corticosterone, epinephrine (E), norepinephrine (NE), malondialdehyde (MDA) and superoxide dismutase (SOD), interleukin-6 (IL-6) and expression of GLUT4 were also detected. Homeostasis model assessment (HOMA-IR) was used to evaluate insulin resistance. Compared with NC group, E, NE and Corticosterone were increased significantly, SOD and MDA were higher and GLUT4 expression was significantly lower in GDM rats. Corticosterone was positively related to MDA, MDA was positively and SOD was negatively related to HOMA-IR in both groups, IL-6 showed significant positive correlations with HOMA-IR. NE and Corticosterone were negative related to GLUT4 in GDM group. Stress hormones (E, NE and Corticosterone), MDA and IL-6 were the risk factors of GDM, SOD was the protective factor of GDM. Changes of stress hormones indicate that stress adaptation disorder exists in GDM rats. Stress adaptation disorder increase oxidative stress injury and inflammation, decrease GLUT4 and lead to incline of glucose uptake, result in hyperglycemia. Gaining an insight into correlations of these changes may be beneficial to maternal and child health and is important for the prevention of glycemia-related diseases.

Lipocalin-2 may produce damaging effect after cerebral ischemia by inducing astrocytes classical activation.

BACKGROUND: Functions of astrocytes in the rehabilitation after ischemic stroke, especially their impacts on inflammatory processes, remain controversial. This study uncovered two phenotypes of astrocytes, of which one was helpful, and the other harmful to anoxic neurons after brain ischemia. METHODS: We tested the levels of inflammatory factors including TNF-a, IL-6, IL-10, iNOS, IL-1beta, and CXCL10 in primary astrocytes at 0 h, 6 h, 12 h, 24 h, and 48 h after OGD, grouped the hypoxia astrocytes into iNOS-positive (iNOS(+)) and iNOS-negative (iNOS(-)) by magnetic bead sorting, and then co-cultured the two groups of cells with OGD-treated neurons for 24 h. We further verified the polarization of astrocytes in vivo by detecting the co-localization of iNOS, GFAP, and Iba-1 on MCAO brain sections. Lentivirus overexpressing LCN2 and LCN2 knockout mice (#024630. JAX, USA) were used to explore the role of LCN2 in the functional polarization of astrocytes. 7.0-T MRI scanning and the modified Neurological Severity Score (mNSS) were used to evaluate the neurological outcomes of the mice. RESULTS: After oxygen-glucose deprivation (OGD), iNOS mRNA expression increased to the peak at 6 h in primary astrocytes, but keep baseline expression in LCN2-knockout astrocytes. In mice with transient middle cerebral artery occlusion (tMCAO), LCN2 was proved necessary for astrocyte classical activation. In LCN2 knockout mice with MCAO, no classically activated astrocytes were detected, and smaller infarct volumes and better neurological functions were observed. CONCLUSIONS: The results indicated a novel pattern of astrocyte activation after ischemic stroke and lipocalin-2 (LCN2) plays a key role in polarizing and activating astrocytes.

Oxytocin system alleviates intestinal inflammation by regulating macrophages polarization in experimental colitis.

Inflammatory bowel disease (IBD) is a chronic intestinal inflammation, but the accurate etiology remains to be elucidated. Increasing evidence has shown that macrophages polarize to different phenotypes depending on the intestinal microenvironment and are associated with the progression of IBD. In the present study, we investigated the effect of oxytocin, a neuroendocrinal, and pro-health peptide, on the modulation of macrophages polarization and the progression of experimental colitis. Our data demonstrated that oxytocin decreased the sensitivity of macrophages to lipopolysaccharide stimulation with lower expression of inflammatory cytokines, like IL-1ß, IL-6, and TNF-α, but increased the sensitivity to IL-4 stimulation with enhanced expression of M2-type genes, arginase I (Arg1), CD206, and chitinase-like 3 (Chil3). This bidirectional modulation was partly due to the up-regulation of ß-arrestin2 and resulted in the inhibition of NF-κB signaling and reinforcement of Signal transducer and activator of transcription (STAT) 6 phosphorylation. Moreover, oxytocin receptor (OXTR) myeloid deficiency mice were more susceptible to dextran sulfate sodium (DSS) intervention compared with the wild mice. For the first time, we reveal that oxytocin-oxytocin receptor system participates in modulating the polarization of macrophages to an anti-inflammatory phenotype and alleviates experimental colitis. These findings provide new potential insights into the pathogenesis and therapy of IBD.

Digital Education for Health Professions in the Field of Dermatology: A Systematic Review by Digital Health Education Collaboration.

Digital health education is a new approach that is receiving increasing attention with advantages such as scalability and flexibility of education. This study employed a Cochrane review approach to assess the evidence for the effectiveness of health professions' digital education in dermatology to improve knowledge, skills, attitudes and satisfaction. Twelve trials (n = 955 health professionals) met our eligibility criteria. Nine studies evaluated knowledge; of those two reported that digital education improved the outcome. Five studies evaluated skill; of those 3 studies stated that digital education improved this outcome whereas 2 showed no difference when compared with control. Of the 5 studies measuring learners' satisfaction, 3 studies claimed high satisfaction scores. Two studies reported that when compared with traditional education, digital education had little effect on satisfaction. The evidence for the effectiveness of digital health education in dermatology is mixed and the overall findings are inconclusive, mainly because of the predominantly very low quality of the evidence. More methodologically robust research is needed to further inform clinicians and policymakers.

Using structural equation modeling to detect response shift in quality of life in patients with Alzheimer's disease.

ABSTRACTBackground:Our study aims to detect different types of response shifts (RS) and true changes of quality of life (QOL) measurement in patients with Alzheimer's disease (AD) using structural equation modeling (SEM) in domain level. METHODS: Patients with AD aged over 60 years old were collected from the Department of Neurology and Geriatrics in Taiyuan Central Hospital, China. The 12-item Short Form (SF-12) Health Survey was measured in 238 patients with AD prior to hospitalization and one month following discharge. RS was detected by SEM approach. The statistical process consisted of four steps and fitted four models. We interpreted changes of parameters in models to detect RS and to assess true change. RESULTS: The results showed reprioritization of social functioning (SF) (χ2 = 4.13, p < 0.05), reconceptualization of role limitations due to emotional problems (RE) (χ2 = 17.03, p < 0.001), uniform recalibration of bodily pain (BP) (χ2 = 12.24, p < 0.001), and non-uniform recalibration of mental health (MH) (χ2 = 4.41, p < 0.05), respectively. The true changes of common factors were deteriorated in general physical health (PHYS) (-0.10, χ2 = 8.30, p < 0.005) and improved in general mental health (MENT) (+0.29, χ2 = 20.95, p < 0.001). The effect-sizes of RS were only small. CONCLUSION: This study showed that patients with AD occurred three types of RS and true changes one month following discharge. RS had effects on the QOL of patients. Better understanding of potential changes in QOL in patients with AD is crucial.

When variety is not the spice of life: The influence of perceived relational self-threat on variety seeking in snack choices.

People often seek variety in food choices because they believe variety offers them many benefits such as giving them a chance to explore new foods while decreasing the likelihood of boredom from eating the same food repeatedly. While much research has explored situational factors that increase variety seeking behavior, we explore a situational factor that decreases variety seeking. Specifically, this research investigates how perceived relational threat affects variety seeking in snack choices. Across three studies, we experimentally manipulate relational self-threat and find that those who experience high (vs. low) threat seek less variety (Study 1), even when the same choice set is construed as having more (vs. less) variety (Study 2). This effect is attenuated when people have the chance to engage in self-affirmation (Study 3).