Positive association between insulin resistance and fatty liver disease in psoriasis: evidence from a cross-sectional study.

Background: Fatty liver disease (FLD) is a common comorbidity of psoriasis and is often referred to as non-alcoholic fatty liver disease (NAFLD). However, the role of inflammation or insulin resistance (IR) in FLD is inconclusive. The study aims to explore whether FLD in psoriasis patients is more related to insulin resistance or systemic inflammation level. Methods: Data for this study were collected from the Shanghai Psoriasis Effectiveness Evaluation Cohort, a prospective cohort that examines psoriasis characteristics in the Chinese population. IR was assessed using the triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) indicators. Systemic non-specific inflammation was assessed using the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), and systemic immune inflammation index (SII). Results: The analysis included a total of 647 patients. Subsequent logistic regression analysis revealed that NLR, dNLR, and SII were not significantly associated with FLD in psoriasis patients, while TyG and TyG-BMI showed significant associations with FLD. Subgroup analysis indicated that in the majority of subgroups, TyG and TyG-BMI were significantly associated with FLD, particularly TyG-BMI. Excluding individuals with methotrexate and acitretin resulted in consistent findings with the main analysis. Further analysis revealed a significantly higher diagnosis rate of metabolic-associated fatty liver disease (MAFLD) compared to NAFLD. Conclusions: Metabolic factors play a crucial role in FLD in patients with psoriasis, and TyG and TyG-BMI are potential predictors of FLD. Therefore, MAFLD can be recommend as a term to describe FLD in psoriasis patients. Trial registration: https://www.chictr.org.cn/showproj.html?proj=58256, identifier ChiCTR2000036186. A multi-center clinical study of systemic treatment strategies for psoriasis in Chinese population. Registered 31 August 2020.

Four-Color ImmunoSpot® Assays Requiring Only 1-3 mL of Blood Permit Precise Frequency Measurements of Antigen-Specific B Cells-Secreting Immunoglobulins of All Four Classes and Subclasses.

The B lymphocyte response can encompass four immunoglobulin (Ig) classes and four IgG subclasses, each contributing fundamentally different effector functions. Production of the appropriate Ig class/subclass is critical for both successful host defense and avoidance of immunopathology. The assessment of an antigen-specific B cell response, including its magnitude and Ig class/subclass composition, is most often confined to the antibodies present in serum and other biological fluids and neglects monitoring of the memory B cell (Bmem) compartment capable of mounting a faster and more efficient antibody response following antigen reencounter. Here, we describe how the frequency and Ig class and IgG subclass use of an antigen-specific Bmem repertoire can be determined with relatively little labor and cost, requiring only 8 × 105 freshly isolated peripheral blood mononuclear cells (PBMC), or if additional cryopreservation and polyclonal stimulation is necessary, 3 × 106 PBMC per antigen. To experimentally validate such cell saving assays, we have documented that frequency measurements of antibody-secreting cells (ASC) yield results indistinguishable from those of enzymatic (ELISPOT) or fluorescent (FluoroSpot) versions of the ImmunoSpot® assay, including when the latter are detected in alternative fluorescent channels. Moreover, we have shown that frequency calculations that are based on linear regression analysis of serial PBMC dilutions using a single well per dilution step are as accurate as those performed using replicate wells. Collectively, our data highlight the capacity of multiplexed B cell FluoroSpot assays in conjunction with serial dilutions to significantly reduce the PBMC requirement for detailed assessment of antigen-specific B cells. The protocols presented here allow GLP-compliant high-throughput measurements which should help to introduce high-dimensional Bmem characterization into the standard immune monitoring repertoire.

A novel online calculator based on clinical features and hematological parameters to predict total skin clearance in patients with moderate to severe psoriasis.

BACKGROUND: Treatment responses to biologic agents vary between patients with moderate to severe psoriasis; while some patients achieve total skin clearance (TSC), a proportion of patients may only experience partial improvement. OBJECTIVE: This study was designed to identify potential predictors for achieving TSC in psoriasis patients treated with IL-17 inhibitors. It also aimed to develop an easy-to-use calculator incorporating these factors by the nomogram to predict TSC response. METHODS: A total of 381 patients with psoriasis receiving ixekizumab were included in the development cohort and 229 psoriasis patients who initiated secukinumab treatment were included in the validation cohort. The study endpoint was achieving TSC after 12 weeks of IL-17 inhibitors treatment, defined as the 100% improvement in Psoriasis Area and Severity Index (PASI 100). Multivariate Cox regression analyses and LASSO analysis were performed to identify clinical predictors and blood predictors respectively. RESULTS: The following parameters were identified as predictive factors associated with TSC: previous biologic treatment, joint involvement, genital area affected, early response (PASI 60 at week 4), neutrophil counts and uric acid levels. The nomogram model incorporating these factors achieved good discrimination in the development cohort (AUC, 0.721; 95% CI 0.670-0.773) and validation cohort (AUC, 0.715; 95% CI 0.665-0.760). The calibration curves exhibited a satisfactory fit, indicating the accuracy of the model. Furthermore, the decision curve analysis confirmed the clinical utility of the nomogram, highlighting its favorable value for practical application. Web-based online calculator has been developed to enhance the efficiency of clinical applications. CONCLUSIONS: This study developed a practical and clinically applicable nomogram model for the prediction of TSC in patients with moderate to severe psoriasis. The nomogram model demonstrated robust predictive performance and exhibited significant clinical utility. Trial registration A multi-center clinical study of systemic treatment strategies for psoriasis in Chinese population;ChiCTR2000036186; Registered 31 August 2020; https://www.chictr.org.cn/showproj.html?proj=58256 .

Preliminary MRS study of critical values of relevant brain metabolites in elderly Chinese patients with post-stroke cognitive impairment.

Objective: Proton magnetic resonance spectroscopy (1H-MRS) was applied in this study to detect metabolite changes in the brain of post-stroke cognitive impairment (PSCI) and normal volunteers. The levels of N-acetylaspartate (NAA) and creatinine (Cr) and in the frontal lobe, hippocampus and cingulate gyrus were measured to distinguish patients with post-stroke cognitive impairment (PSCI) and normal control group (NC). The relationship between them and cognitive function was explored and a critical value of the metabolite ratio was predicted. This study may serve as a reference for the diagnosis of cognitive dysfunction after stroke. Methods: A total of 46 patients with PSCI (PSCI group, all patients are unilateral cerebral infarction or intracerebral haemorrhage) were screened by the Mini-Mental Status Examination (MMSE), and 35 healthy volunteers were selected as normal control group (NC group). The general information of gender, age, and education level was matched between the two groups. Two groups of subjects were examined using MRS and evaluated for cognitive function using the MMSE test and the Montreal Cognitive Assessment Scale (MoCA). The correlation between MRS and neurobehavioral scale (MMSE test and MoCA scale) was analysed, and the possible demarcation points of the brain metabolism of PSCI were evaluated. Result: The MMSE and MoCA scores of patients with PSCI were lower significantly when compared with those of the NC group (P < 0.05). The NAA/Cr values of the bilateral hippocampus, bilateral frontal lobe and bilateral anterior and posterior cingulate gyrus in the PSCI group were lower than those in the NC group (P < 0.05). The NAA/Cr cut-off value for the right frontal lobe was 1.533, and the NAA/Cr sensitivity, specificity and Youden index for the right frontal lobe were 0.943, 0.935, and 0.878. Conclusion: NAA/Cr values in the MRS bilateral frontal, bilateral hippocampus and bilateral anterior and posterior cingulate gyrus were reduced in the cognitively impaired post-stroke patients compared to the normal control group. MRS was also found to be correlated with the score of neurobehavioral scale (MMSE test and MoCA scale) and the combination of the two could evaluate cognitive dysfunction more comprehensively and objectively. NAA/Cr value of the right frontal lobe < 1.533 indicated that PSCI may occur. In accordance with this cut-off point, PSCI could be detected as early as possible and timely intervention could be carried out.

Short-term safety of inactivated SARS-Cov-2 vaccines in Chinese patients with central nervous system inflammatory demyelinating diseases.

Objective: This study aims to evaluate the short-term safety of inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in Chinese patients with central nervous system inflammatory demyelinating diseases (CNS IDDs). Methods: A web-based survey was conducted among patients with CNS IDDs from April 15 to 19, 2022 in China. In total, 645 patients with CNS IDDs were identified, including 425 patients with multiple sclerosis (MS), 194 with neuromyelitis optica spectrum disorder (NMOSD), and 26 with other CNS IDDs. The questionnaire consisted of demographic data, clinical records, history of SARS-CoV-2 vaccination, and vaccination-related symptoms within one month after vaccination. The demographic data, clinical information, and relapse rates between vaccinated and non-vaccinated patients were compared. Results: Among 645 patients with CNS IDDs, 78 were vaccinated and 567 were non-vaccinated with the vaccination rate of 12.1 %. Compared to non-vaccinated group, a lower percentage of patients on DMDs therapy (41.0 % vs. 71.8 %, P < 0.001) and an increased proportion of patients with other vaccination in past 3 years (17.9 % vs. 4.8 %, P < 0.001) were observed in vaccinated group. Six patients experienced a relapse within 30 days of a vaccination. Additionally, vaccine-associated relapse rates in vaccinated patients did not significantly differ from these in non-vaccinated patients among 2020, 2021, and from January 1 to October 1, 2022. Conclusions: No increased risk of vaccination-associated relapses among Chinese patients with CNS IDDs indicated that inactivated SARS-CoV-2 vaccines appear to be safe for this population.

Attenuation of Alzheimer's brain pathology in 5XFAD mice by PTH1-34, a peptide of parathyroid hormone.

BACKGROUND: Alzheimer's disease (AD) and osteoporosis are two distinct diseases but often occur in the same patient. Their relationship remains poorly understood. Studies using Tg2576 AD animal model demonstrate bone deficits, which precede the brain phenotypes by several months, arguing for the independence of bone deficits on brain degeneration and raising a question if the bone deficits contribute to the AD development. To address this question, we investigated the effects of PTH1-34, a peptide of parathyroid hormone analog and a well-recognized effective anabolic therapy drug for patients with osteoporosis, on 5XFAD animal model. METHODS: 5XFAD mice, an early onset ß-amyloid (Aß)-based AD mouse model, were treated with PTH1-34 intermittently [once daily injection of hPTH1-34 (50 µg/Kg), 5 days/week, starting at 2-month old (MO) for 2-3 month]. Wild type mice (C57BL/6) were used as control. The bone phenotypes were examined by microCT and evaluated by measuring serum bone formation and resorption markers. The AD relevant brain pathology (e.g., Aß and glial activation) and behaviors were assessed by a combination of immunohistochemical staining analysis, western blots, and behavior tests. Additionally, systemic and brain inflammation were evaluated by serum cytokine array, real-time PCR (qPCR), and RNAscope. RESULTS: A reduced trabecular, but not cortical, bone mass, accompanied with a decrease in bone formation and an increase in bone resorption, was detected in 5XFAD mice at age of 5/6-month old (MO). Upon PTH1-34 treatments, not only these bone deficits but also Aß-associated brain pathologies, including Aß and Aß deposition levels, dystrophic neurites, glial cell activation, and brain inflammatory cytokines, were all diminished; and the cognitive function was improved. Further studies suggest that PTH1-34 acts on not only osteoblasts in the bone but also astrocytes in the brain, suppressing astrocyte senescence and expression of inflammatory cytokines in 5XFAD mice. CONCLUSIONS: These results suggest that PTH1-34 may act as a senolytic-like drug, reducing systemic and brain inflammation and improving cognitive function, and implicate PTH1-34's therapeutic potential for patients with not only osteoporosis but also AD.

Efficient local delivery of FK506 using blocking patches in psoriasis.

FK506 is a local drug that is commonly used in the treatment of psoriasis. Its clinical application, however, is limited by its transdermal drug delivery rate, the time-consuming, and the greasy therapy. In this study, which was inspired by local block injection used in the clinical treatment for keloid, a hyaluronic acid (HA) based system to transport FK506 into the skin to treat psoriasis, named blocking patch (BP) was developed. BP has a complete appearance, sufficient puncture strength, and is virtually non-irritating in vivo. By confocal fluorescence microscopy, BP loaded with FK506 (FK506-BP) showed satisfactory transdermal release ability in vivo. Further animal studies revealed that FK506-BP showed a good anti-inflammatory ability in the imiquimod (IMQ)-induced mouse psoriasis-like dermatitis and inhibited the activation of associated immune cells. This study indicates that BP as a novel delivery system, realizes an efficient local delivery of FK506 in psoriasis and holds great potential in transdermal delivery.

A new sesquiterpenoid from the aconitum-derived fungus Aspergillus fumigatus M1.

A new bergamotane sesquiterpenoid, fumigatanol (1), along with nine known compounds (2-10) were isolated from the Aconitum-derived fungus Aspergillus fumigatus M1. Their structures were established on the basis of extensive spectroscopic analyses, ECD experiment and NMR computational method. Antibacterial and cytotoxic activities of compound 1 were evaluated and no obvious antibacterial and cytotoxic activities were observed at concentrations of 256 µg/mL and 40.00 µM, respectively.

Potential Zoning of Construction Land Consolidation in the Loess Plateau Based on the Evolution of Human-Land Relationship.

Towns serve as the basic unit of implementation for comprehensive land consolidation and rehabilitation. The utilization of scaling law can provide a new perspective for construction land consolidation. From two perspectives of the town hierarchic system and the growth of a single town, this research applies the Rank-Size Rule and Allometric Scaling Law to analyze the scale structure, hierarchy and allometric scaling evolution relationship of population and construction land in the Loess Plateau at the town scale in 2000, 2010, and 2017. Furthermore, the consolidation potential of construction land is divided into five zones and puts forward recommendations for the comprehensive consolidation of the construction land. The results indicate: (1) The majority of towns have small or medium populations and 62% of the towns in the study show negative population growth. Geographically, the northern part has a smaller population size compared with the southern part. 96% of the towns show an increasing trend in the quantity of construction land, and the south and north parts of the study area have more construction land compared with the center part. The zone of the Valley Plain has the largest population size, and the zone of the Sandy and Desert Area has the largest quantity of construction land. (2) The rank-size distributions of both population and construction land comply with the power-law relation. The population hierarchy has changed from equilibrium to concentration, while the hierarchy of construction land shows an opposite pattern. So, the whole town hierarchic system of the Loess Plateau is gradually tending to the optimal distribution, which is the town hierarchic system gradually forming an ideal sequence structure. (3) The population-construction land relationship obeys the allometric scaling law, and the major allometric type is positive allometry. The human-land relationship tends to be coordinated, and the town system tends to be reasonable. The allometric scaling coefficient is not robust in different geographical areas, especially in Irrigated Agricultural Areas. Furthermore, 90% of the towns have weak coordination of human-land relationships, and 60% of the towns have a relatively faster growth rate of construction land than the relative growth (decline) rate of population. (4) The consolidation potential of construction land is divided into five types. High Consolidation Potential Area concentrates in the Eastern Loess Plateau, while Medium and Low Consolidation Potential Area concentrically distribute in the Western Loess Plateau. The Human-land Coordination Area has a small number and scattered spatial distribution. The land use of towns that are concentrated around prefecture-level cities or with unique resources is not intensive enough. The zoning of construction land consolidation potential based on the results of the allometric scale is in line with reality, and local governments should make use of the characteristics and trends of the town system to formulate planning schemes to promote the integrated development of urban and rural areas.

Correlation between galectin-3, RDW, Hepc, HS and ferritin and prognosis of patients with acute onset of chronic heart failure.

BACKGROUND: Chronic heart failure (CHF) is characterized by a high hospitalization rate and a high mortality rate. It is particularly important to identify biomarkers for predicting the prognosis of patients with acute attack of CHF. PURPOSE: To observe the correlation between galectin-3, RDW, Hepc, HS and ferritin and the prognosis of patients with acute onset of CHF. METHODS: The study included 92 patients with acute onset of CHF who received treatment at our hospital between August 2020 and December 2021. After treatment, the patients were divided into the effective group and the non-effective group based on the effectiveness of treatment. The levels of galectin-3, RDW, Hepc, HS and ferritin before and after treatment were compared between the two groups and the correlation between prognosis of patients with acute attack of CHF and galectin-3, RDW, Hepc, HS and ferritin was observed. RESULTS: The effective rate was 71.74% (66/92) and the ineffective rate was 28.26% (26/92) in the 92 patients with acute attack of CHF in the study. Before and after treatment, the levels of galectin-3, RDW, Hepc, and HS were lower in the effective group than those of the non-effective group while the level of ferritin was higher in the effective group than that of the non-effective group (P < 0.05). Spearman correlation analysis showed that the level of prognosis of patients with acute attack of CHF was positively correlated with galectin-3, RDW, Hepc, and HS (r = 0.217, 0.109, 0.376, 0.765, P = 0.026, 0.032, 0.021, 0.006), and negatively correlated with ferritin (r = - 0.127, P = 0.037). The independent variables were galectin-3, RDW, Hepc, HS and ferritin and the dependent variable was prognosis of patients with acute attack of CHF. Univariate logistic regression analysis showed that alectin-3, RDW, Hepc, HS, and ferritin were protective factors for the prognosis of patients with acute attack of CHF. The independent variables were galectin-3, RDW, Hepc, HS and ferritin, dependent variables and the dependent variable was prognosis of patients with acute attack of CHF. Multivariate logistic regression analysis revealed that galectin-3, RDW, and Hepc were risk factors of the prognosis of patients with acute attack of CHF. CONCLUSION: Galectin-3, RDW, Hepc, HS and ferritin were closely related with the prognosis of patients with acute attack of CHF and galectin-3, RDW, and Hepc were risk factors of the prognosis of patients with acute attack of CHF.

RNA modifications: importance in immune cell biology and related diseases.

RNA modifications have become hot topics recently. By influencing RNA processes, including generation, transportation, function, and metabolization, they act as critical regulators of cell biology. The immune cell abnormality in human diseases is also a research focus and progressing rapidly these years. Studies have demonstrated that RNA modifications participate in the multiple biological processes of immune cells, including development, differentiation, activation, migration, and polarization, thereby modulating the immune responses and are involved in some immune related diseases. In this review, we present existing knowledge of the biological functions and underlying mechanisms of RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), N7-methylguanosine (m7G), N4-acetylcytosine (ac4C), pseudouridine (Ψ), uridylation, and adenosine-to-inosine (A-to-I) RNA editing, and summarize their critical roles in immune cell biology. Via regulating the biological processes of immune cells, RNA modifications can participate in the pathogenesis of immune related diseases, such as cancers, infection, inflammatory and autoimmune diseases. We further highlight the challenges and future directions based on the existing knowledge. All in all, this review will provide helpful knowledge as well as novel ideas for the researchers in this area.

A novel spinal neuron connection for heat sensation.

Heat perception enables acute avoidance responses to prevent tissue damage and maintain body thermal homeostasis. Unlike other modalities, how heat signals are processed in the spinal cord remains unclear. By single-cell gene profiling, we identified ErbB4, a transmembrane tyrosine kinase, as a novel marker of heat-sensitive spinal neurons in mice. Ablating spinal ErbB4+ neurons attenuates heat sensation. These neurons receive monosynaptic inputs from TRPV1+ nociceptors and form excitatory synapses onto target neurons. Activation of ErbB4+ neurons enhances the heat response, while inhibition reduces the heat response. We showed that heat sensation is regulated by NRG1, an activator of ErbB4, and it involves dynamic activity of the tyrosine kinase that promotes glutamatergic transmission. Evidence indicates that the NRG1-ErbB4 signaling is also engaged in hypersensitivity of pathological pain. Together, these results identify a spinal neuron connection consisting of ErbB4+ neurons for heat sensation and reveal a regulatory mechanism by the NRG1-ErbB4 signaling.

Microglial VPS35 deficiency impairs Aß phagocytosis and Aß-induced disease-associated microglia, and enhances Aß associated pathology.

BACKGROUND: Vacuolar sorting protein 35 (VPS35), a key component of the retromer, plays an essential role in selectively retrieval of transmembrane proteins from endosomes to trans-Golgi networks. Dysfunctional retromer is a risk factor for neurodegenerative disorders, including Alzheimer's disease (AD). Microglial VPS35 deficiency is found in AD patients' brain; however, it remains unclear if and how microglial VPS35-loss contributes to AD development. METHODS: We used mice with VPS35 cKO (conditional knockout) in microglial cells in 5XFAD, an AD mouse model. The AD related brain pathology (Aß and glial activation), behavior, and phagocytosis of Aß were accessed by a combination of immunofluorescence staining analyses and neurological behavior tests. RESULTS: A decrease in learning and memory function, but increases in insoluble, fibrillar, and plaques of ß-amyloids (Aß), dystrophic neurites, and reactive astrocytes are observed in microglial VPS35 deficient 5XFAD mice. Further examining microglial phenotype demonstrates necessity of microglial VPS35 in disease-associated microglia (DAM) development and microglial uptake of Aß, revealing a tight association of microglial Aß uptake with DAM development. CONCLUSIONS: Together, these results uncovered a mechanism by which microglial VPS35-deficiency precipitates AD pathology in 5XFAD mice likely by impairing DAM development and DAM mediated Aß uptake and clearance, and thus accelerating the cognition decline.

Corrigendum: Effects of virtual reality-based intervention on cognition, motor function, mood, and activities of daily living in patients with chronic stroke: A systematic review and meta-analysis of randomized controlled trials.

[This corrects the article DOI: 10.3389/fnagi.2021.766525.].

Effects of Virtual Reality-Based Intervention on Cognition, Motor Function, Mood, and Activities of Daily Living in Patients With Chronic Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: The efficacy of virtual reality (VR)-based intervention for improving cognition in patients with the chronic stage of stroke is controversial. The aims of this meta-analysis were to evaluate the effect of VR-based training combined with traditional rehabilitation on cognition, motor function, mood, and activities of daily living (ADL) after chronic stroke. Methods: The search was performed in the Cochrane Library (CENTRAL), EBSCO, EMBASE, Medline (OVID), Web of Science databases, PubMed, CINAHL Ovid, and Scopus from inception to May 31, 2021. All included studies were randomized controlled trials (RCTs) examining VR-based intervention combined with traditional rehabilitation for chronic stroke. The main outcomes of this study were cognition, including overall cognition (combined with all cognitive measurement results), global cognition (measured by the Montreal Cognitive Assessment, MoCA, and/or Mini-Mental State Examination, MMSE), and attention/execution. The additional outcomes were motor function, mood, and ADL. Subgroup analyses were conducted to verify the potential factors for heterogeneity. Results: Six RCTs including 209 participants were included for systematic review, and five studies of 177 participants were included in meta-analyses. Main outcome analyses showed large and significant effect size (ES) of VR-based training on overall cognition (g = 0.642; 95% CI = 0.134-1.149; and P = 0.013) and attention/execution (g = 0.695; 95% CI = 0.052-1.339; and P = 0.034). Non-significant result was found for VR-based intervention on global cognition (g = 0.553; 95% CI = -0.273-1.379; and P = 0.189). Additional outcome analyses showed no superiority of VR-based intervention over traditional rehabilitation on motor function and ADL. The ES of VR-based intervention on mood (g = 1.421; 95% CI = 0.448-2.393; and P = 0.004) was large and significant. In the subgroup analysis, large effects for higher daily intensity, higher weekly frequency, or greater dose of VR intervention were found. Conclusion: Our findings indicate that VR-based intervention combined with traditional rehabilitation showed better outcomes for overall cognition, attention/execution, and depressive mood in individuals with chronic stroke. However, VR-based training combined with traditional rehabilitation showed a non-significant effect for global cognition, motor function, and ADL in individuals with chronic stroke.

Osteoblastic Swedish mutant APP expedites brain deficits by inducing endoplasmic reticulum stress-driven senescence.

Patients with Alzheimer's disease (AD) often have osteoporosis or osteopenia. However, their direct link and relationship remain largely unclear. Previous studies have detected osteoporotic deficits in young adult Tg2576 and TgAPPsweOCN mice, which express APPswe (Swedish mutant) ubiquitously and selectively in osteoblast (OB)-lineage cells. This raises the question, whether osteoblastic APPswe contributes to AD development. Here, we provide evidence that TgAPPsweOCN mice also exhibit AD-relevant brain pathologies and behavior phenotypes. Some brain pathologies include age-dependent and regional-selective increases in glial activation and pro-inflammatory cytokines, which are accompanied by behavioral phenotypes such as anxiety, depression, and altered learning and memory. Further cellular studies suggest that APPswe, but not APPwt or APPlon (London mutant), in OB-lineage cells induces endoplasmic reticulum-stress driven senescence, driving systemic and cortex inflammation as well as behavioral changes in 6-month-old TgAPPsweOCN mice. These results therefore reveal an unrecognized function of osteoblastic APPswe to brain axis in AD development.

Qualitatively and quantitatively investigating the metabolism of 20(S)-protopanaxadiol-type ginsenosides by gut microbiota of different species.

Ginsenosides Rb1, Rb2, Rb3 and Rc, four major protopanaxadiol (PPD)-type ginsenosides, can be metabolized by gut microbiota. The composition of gut microbiota varies in different species. Existing publications have reported the metabolite fates of ginsenosides by gut microbiota from single species. However, their microbiota-related metabolic species differences have not been evaluated yet. In current study, in vitro anaerobic incubations of PPD-type ginsenosides with gut microbiota from humans, rabbits and rats were conducted. The metabolites of each ginsenoside were then identified by LC-MS. A total of 15 metabolites from the four ginsenosides were identified. The major metabolic pathways were stepwise removals of the C-20 and C-3 sugar moieties to obtain aglycone PPD. The results showed that the hydrolysis rate of C-20 terminal ß-D-glucopyranosyl was significantly higher than those of α-L-arabinopyranosyl, ß-D-xylopyranosyl and α-L-arabinofuranosyl in different species. The activity of ß-glucosidase, the metabolic rates of parent compounds and the formation rates of their metabolites were significantly higher in gut microbiota from rabbits than from humans and rats. Our research draws researchers' attention to the species differences of microbiota-related drug metabolism.

Diagnostic performance of miR-214, BNP, NT-proBNP and soluble ST2 in acute heart failure.

PURPOSE: This study aimed to investigate the potential diagnostic value of miR-214, B-type natriuretic peptide (BNP), N terminal-pro BNP (NT-proBNP) and soluble ST2 (sST2) in acute heart failure (AHF). METHOD: This study included 176 patients as the AHF group and 60 healthy subjects as the control group from February 2018 to February 2020. Patients in the AHF group were classified according to the New York Heart Association (NYHA) functional classification, including 60 level II patients, 59 level III patients and 57 level IV patients. The expression level of miR-214, BNP, NT-proBNP and sST2 of both groups were recorded and analysed. RESULTS: The morbidity of cardiovascular diseases was significantly higher in the AHF group than in the control group (P < .05). The expression level of miR-214, BNP, NT-proBNP and sST2 in the AHF group were all significantly higher than in the control group (P < .05). Besides, the expression level of all the molecules in level IV was significantly higher than that of level III and level II, respectively (P < .001, P < .001). In addition, the expression level of all the molecules in level III was significantly higher than that of level II (P < .001). The area under the ROC curve of miR-214, BNP, NT-proBNP and sST2 were 0.913, 0.836, 0.849 and 0.855, respectively, indicating good diagnostic value. CONCLUSION: MiR-214, BNP, NT-proBNP and sST2 can be used as effective biomarkers for AHF, providing a new strategy for diagnosis and for judging the severity of AHF.

A 16S rRNA gene sequencing based study of oral microbiota in migraine patients in China.

Migraine is a primary headache characterized by moderate or severe headache attacks, accompanied with reversible neurological and systemic symptoms. There are rare biomarkers for the disease. While emerging evidence has indicated the connection between gut microbiota and migraine, the relation between oral microbiota and migraine is barely known. Thus, the objective of the current study was to explore a possible correlation between oral microbiota and migraine. We compared the oral microbiota communities of migraine patients (26) with healthy subjects (29) via 16S rRNA gene sequencing. Alpha diversity indices were higher in migraine group compared with control group, whereas beta diversity indices also showed significant difference. A total of 23 genera were found differentially abundant between migraine and control groups. To conclude, there was a significant compositional difference in oral microbiota in migraine patients compared with healthy subjects.

Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response.

Epilepsy, a common neurological disorder, is featured with recurrent seizures. Its underlying pathological mechanisms remain elusive. Here, we provide evidence for loss of neogenin (NEO1), a coreceptor for multiple ligands, including netrins and bone morphological proteins, in the development of epilepsy. NEO1 is reduced in hippocampi from patients with epilepsy based on transcriptome and proteomic analyses. Neo1 knocking out (KO) in mouse brains displays elevated epileptiform spikes and seizure susceptibility. These phenotypes were undetectable in mice, with selectively depleted NEO1 in excitatory (NeuroD6-Cre+) or inhibitory (parvalbumin+) neurons, but present in mice with specific hippocampal astrocytic Neo1 KO. Additionally, neurons in hippocampal dentate gyrus, a vulnerable region in epilepsy, in mice with astrocyte-specific Neo1 KO show reductions in inhibitory synaptic vesicles and the frequency of miniature inhibitory postsynaptic current(mIPSC), but increase of the duration of miniature excitatory postsynaptic current and tonic NMDA receptor currents, suggesting impairments in both GABAergic transmission and extracellular glutamate clearance. Further proteomic and cell biological analyses of cell-surface proteins identified GLAST, a glutamate-aspartate transporter that is marked reduced in Neo1 KO astrocytes and the hippocampus. NEO1 interacts with GLAST and promotes GLAST surface distribution in astrocytes. Expressing NEO1 or GLAST in Neo1 KO astrocytes in the hippocampus abolishes the epileptic phenotype. Taken together, these results uncover an unrecognized pathway of NEO1-GLAST in hippocampal GFAP+ astrocytes, which is critical for GLAST surface distribution and function, and GABAergic transmission, unveiling NEO1 as a valuable therapeutic target to protect the brain from epilepsy.