The role of sialidase Neu1 in respiratory diseases.

Neu1 is a sialidase enzyme that plays a crucial role in the regulation of glycosylation in a variety of cellular processes, including cellular signaling and inflammation. In recent years, numerous evidence has suggested that human NEU1 is also involved in the pathogenesis of various respiratory diseases, including lung infection, chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis. This review paper aims to provide an overview of the current research on human NEU1 and respiratory diseases.

The impact of renovation on the air quality in the stadium, and prevention of indoor air pollution.

Indoor air quality is a critical factor influencing athletic performance, particularly in professional sports settings, yet its impact remains underexplored. This study utilizes a panel dataset from 2516 Chinese Basketball Association (CBA) matches across 20 cities in China between 2014 and 2019. We integrate daily air pollution metrics with player efficiency ratings (PER) to investigate the effects of air quality on individual performance. We find that a 10% increase in the air quality index (AQI) corresponds to a 1.4223 decrease in PER, indicating a strong negative effect of poor air quality on player productivity. Different pollutants have varying effects, with some exacerbating the decline in both overall performance and precision in tasks. Notably, older players and international players exhibit greater resilience to air pollution. These insights contribute to the development of a comprehensive index for assessing work efficiency under varying air quality conditions and suggest targeted strategies to mitigate the negative impacts of air pollution in competitive athletic settings.

Echinacoside: A promising active natural products and pharmacological agents.

Echinacoside, a natural phenylethanoid glycoside, was discovered and isolated from the garden plant Echinacea angustifolia DC., belonging to the Compositae family, approximately sixty years ago. Extensive investigations have revealed that it possesses a wide array of pharmacologically beneficial activities for human health, particularly notable for its neuroprotective and anticancer activity. Several crucial concerns surfaced, encompassing the recognition of active metabolites that exhibited inadequate bioavailability in their prototype form, the establishment of precise molecular signal pathways or targets associated with the aforementioned effects of echinacoside, and the scarcity of dependable clinical trials. Hence, the question remains unanswered as to whether scientific research can effectively utilize this natural compound. To support future studies on this natural product, it is imperative to provide a systematic overview and insights into potential future prospects. The current review provides a comprehensive analysis of the existing knowledge on echinacoside, encompassing its wide distribution, structural diversity and metabolism, diverse therapeutic applications, and improvement of echinacoside bioavailability for its potential utilization.

Safety and Immunogenicity of SARS-CoV-2 Vaccines in Patients With Chronic Liver Diseases (CHESS-NMCID 2101): A Multicenter Study.

BACKGROUND & AIMS: We aimed to assess the safety and immunogenicity of inactivated whole-virion severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with chronic liver diseases (CLD) in this study. METHODS: This was a prospective, multi-center, open-label study. Participants aged over 18 years with confirmed CLD and healthy volunteers were enrolled. All participants received 2 doses of inactivated whole-virion SARS-CoV-2 vaccines. Adverse reactions were recorded within 14 days after any dose of SARS-CoV-2 vaccine, laboratory testing results were collected after the second dose, and serum samples of enrolled subjects were collected and tested for SARS-CoV-2 neutralizing antibodies at least 14 days after the second dose. RESULTS: A total of 581 participants (437 patients with CLD and 144 healthy volunteers) were enrolled from 15 sites in China. Most adverse reactions were mild and transient, and injection site pain (n = 36; 8.2%) was the most frequently reported adverse event. Three participants had grade 3 aminopherase elevation (defined as alanine aminopherase >5 upper limits of normal) after the second dose of inactivated whole-virion SARS-CoV-2 vaccination, and only 1 of them was judged as severe adverse event potentially related to SARS-CoV-2 vaccination. The positive rates of SARS-CoV-2 neutralizing antibodies were 76.8% in the noncirrhotic CLD group, 78.9% in the compensated cirrhotic group, 76.7% in the decompensated cirrhotic group (P = .894 among CLD subgroups), and 90.3% in healthy controls (P = .008 vs CLD group). CONCLUSION: Inactivated whole-virion SARS-CoV-2 vaccines are safe in patients with CLD. Patients with CLD had lower immunologic response to SARS-CoV-2 vaccines than healthy population. The immunogenicity is similarly low in noncirrhotic CLD, compensated cirrhosis, and decompensated cirrhosis.

Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity.

Previous studies have shown that AgRP neurons in the arcuate nucleus (ARC) respond to energy deficits and play a key role in the control of feeding behavior and metabolism. Here, we demonstrate that chronic unpredictable stress, an animal model of depression, decreases spontaneous firing rates, increases firing irregularity and alters the firing properties of AgRP neurons in both male and female mice. These changes are associated with enhanced inhibitory synaptic transmission and reduced intrinsic neuronal excitability. Chemogenetic inhibition of AgRP neurons increases susceptibility to subthreshold unpredictable stress. Conversely, chemogenetic activation of AgRP neurons completely reverses anhedonic and despair behaviors induced by chronic unpredictable stress. These results indicate that chronic stress induces maladaptive synaptic and intrinsic plasticity, leading to hypoactivity of AgRP neurons and subsequently causing behavioral changes. Our findings suggest that AgRP neurons in the ARC are a key component of neural circuitry involved in mediating depression-related behaviors and that increasing AgRP neuronal activity coule be a novel and effective treatment for depression.

Cloning and sequence analysis of a serine protease gene from Rhizoctonia solani Kühn AG5.

The present study aimed to identify the subtilisin-like proteases (SLPs) of Rhizoctonia solani Kühn potentially involved in the virulence of this phytopathogenic fungus, which has 14 anastomosis groups (AGs) responsible for many crop diseases. Through mycelial microscope observation and strain identification of pathogenic fungus MS-3, it was determined to be R. solani AG-5. Both 5' and 3' rapid amplification of cDNA ends were used to clone the serine protease gene RsSLP from R. solani AG-5. The full-length obtained for RsSLP was 1714 bp with an open reading frame of 1587 bp, encoding a protein of 528 amino acids with a molecular mass of 55.8 kDa. This protein contained a predicted signal peptide for secretion but lacked a transmembrane domain or membrane anchor site. Bioinformatics analysis identified this protein as a serine protease with the Peptidase_S8 and Inhibitor_I9 characteristic domains of SLPs. Phylogenetic analysis suggested that frequent gene duplications of the SLPs occurred in R. solani (RsSLP), and RsSLP shares characteristic sequence features with virulence factors of other phytopathogenic fungi. Because the secretory serine protease RsSLP from R. solani AG5 is similar to the virulence factors of other phytopathogenic fungi, its identification will be helpful in studies considering the roles of these proteases in pathogen virulence.

Neuraminidase 1 is a driver of experimental cardiac hypertrophy.

AIMS: Despite considerable therapeutic advances, there is still a dearth of evidence on the molecular determinants of cardiac hypertrophy that culminate in heart failure. Neuraminidases are a family of enzymes that catalyze the cleavage of terminal sialic acids from glycoproteins or glycolipids. This study sought to characterize the role of neuraminidases in pathological cardiac hypertrophy and identify pharmacological inhibitors targeting mammalian neuraminidases. METHODS AND RESULTS: Neuraminidase 1 (NEU1) was highly expressed in hypertrophic hearts of mice and rats, and this elevation was confirmed in patients with hypertrophic cardiomyopathy (n = 7) compared with healthy controls (n = 7). The increased NEU1 was mainly localized in cardiomyocytes by co-localization with cardiac troponin T. Cardiomyocyte-specific NEU1 deficiency alleviated hypertrophic phenotypes in response to transverse aortic constriction or isoproterenol hydrochloride infusion, while NEU1 overexpression exacerbated the development of cardiac hypertrophy. Mechanistically, co-immunoprecipitation coupled with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated that NEU1 translocated into the nucleus and interacted with GATA4, leading to Foetal gene (Nppa and Nppb) expression. Virtual screening and experimental validation identified a novel compound C-09 from millions of compounds that showed favourable binding affinity to human NEU1 (KD = 0.38 µM) and effectively prevented the development of cardiac remodelling in cellular and animal models. Interestingly, anti-influenza drugs zanamivir and oseltamivir effectively inhibited mammalian NEU1 and showed new indications of cardio-protection. CONCLUSIONS: This work identifies NEU1 as a critical driver of cardiac hypertrophy and inhibition of NEU1 opens up an entirely new field of treatment for cardiovascular diseases.

Comparison between outcomes of IgA nephropathy with nephrotic-range proteinuria and nephrotic syndrome: do podocytes play a role?

BACKGROUND: Nephrotic syndrome (NS) and nephrotic-range proteinuria (NRP) are uncommon in IgA nephropathy (IgAN), and their clinicopathology and prognosis have not been discussed. Podocytes may play an important role in both clinical phenotypes. METHODS: We investigated 119 biopsy-proven IgAN patients with proteinuria over 2 g/d. The patients were divided into three groups according to proteinuria level: the overt proteinuria (OP) group, NS group, and NRP group. In addition, according to the severity of foot process effacement (FPE), the patients were divided into three groups: the segmental FPE (SFPE) group, moderate FPE (MFPE) group, and diffuse FPE (DFPE) group. The outcome was survival from a combined event defined by a doubling of the baseline serum creatinine and a 50% reduction in eGFR or ESRD. RESULTS: Compared with the NRP group, patients in the NS group had more severe microscopic hematuria, presented with more severe endocapillary hypercellularity and had a higher percentage of DFPE. The Kaplan-Meier curve showed that MFPE patients had a better outcome in the NRP group <50% of tubular atrophy/interstitial fibrosis. In the multivariate model, the NRP group (HR = 17.098, 95% CI = 3.835-76.224) was associated with an increased risk of the combined event, while MFPE (HR = 0.260, 95% CI = 0.078-0.864; p = 0.028) was associated with a reduced risk of the combined event. After the addition of renin-angiotensin system inhibitors (RASi), the incidence of the combined event in the MFPE group (HR = 0.179, 95% CI = 0.047-0.689; p = 0.012) was further reduced. CONCLUSIONS: NS presented more active lesions and more severe FPE in IgAN. NRP was an independent risk factor for progression to the renal endpoint, while MFPE indicated a better prognosis in NRP without obvious chronic renal lesions, which may benefit from RASi.

MEX3A promotes triple negative breast cancer proliferation and migration via the PI3K/AKT signaling pathway.

Triple-negative breast cancer (TNBC) has the characteristics of fast growth, easy invasion, metastasis, poor prognosis, low tumor-free survival rate and overall survival rate. In this study, the RNA-binding protein MEX3A was selected by using the methods of TCGA database analysis, mRNA microarrays, and tissue chip immunohistochemistry experiments. The high expression of MEX3A is associated with malignancy and poor prognosis of TNBC. In addition, MEX3A knockdown can inhibit the growth and migration of TNBC cells while MEX3A overexpression shows the opposite effect. In vivo experiments, we also demonstrated that downregulating MEX3A can inhibit the tumorigenicity of TNBC cells. The mRNA microarrays and Ingenuity pathway analysis (IPA) were used to explore the downstream of MEX3A, and verified the relationship between PI3K/AKT signaling pathway and MEX3A. Additionally, we have simultaneously up-regulated MEX3A and treated with pathway inhibitors in vitro experiments and found that it can slow down the growth of TNBC cells. In short, we identified MEX3A as a tumor promoter, potential prognostic indicator and therapeutic target for TNBC, may function through the regulation of the PI3K/AKT signaling pathway.

Pro-inflammatory cytokines in the paraventricular nucleus mediate the adipose afferent reflex in rats.

Our previous study showed that the adipose afferent reflex (AAR) induced by chemical stimulation of white adipose tissue (WAT) increased sympathetic outflow and blood pressure. We also found that pro-inflammatory cytokines (PICs) in the hypothalamic paraventricular nucleus (PVN) potentiate the cardiac sympathetic afferent reflex in rats. However, the role of PICs in the PVN in regulating the AAR is still not clear. This study determined whether PICs in the PVN mediate the AAR in rats. The AAR was evaluated based on renal sympathetic nerve activity and mean arterial blood pressure in response to capsaicin injection into inguinal WAT (iWAT). PIC levels were measured by ELISA. PVN microinjection with the PICs tumor necrosis factor (TNF)-α or interleukin (IL)-1ß enhanced the AAR in a dose-dependent manner. Furthermore, pretreatment via the bilateral microinjection of the TNF-α-blocker etanercept or IL-1ß blocker IL-1ra into the PVN attenuated the AAR. In rats pretreated with TNF-α or IL-1ß, a sub-response dose of angiotensin II (Ang II) significantly enhanced the AAR. Moreover, delivery of the angiotensin II type 1(AT1) receptor antagonist losartan into the PVN attenuated the effects of TNF-α or IL-1ß on the AAR. In addition, stimulating either iWAT or retroperitoneal WAT with capsaicin increased TNF-α or IL-1ß levels in the PVN, but the injection of capsaicin into the jugular vein, skeletal muscle, and skin had no effects on TNF-α or IL-1ß levels in the PVN. These results suggest that TNF-α or IL-1ß and Ang II in the PVN synergistically enhance the AAR in rats.

Inhibitory effects of berberine on proinflammatory M1 macrophage polarization through interfering with the interaction between TLR4 and MyD88.

BACKGROUNDS: Inflammation is recognized as the key pathological mechanism of type 2 diabetes. The hypoglyceamic effects of berberine (BBR) are related to the inhibition of the inflammatory response, but the mechanism is not completely clear. METHODS: The inflammatory polarization of Raw264.7 cells and primary peritoneal macrophages were induced by LPS, and then effects and underlying mechanisms of BBR were explored. An inflammatory model was established by LPS treatment at different concentrations for different treatment time. An ELISA assay was used to detect the secretions of TNF-α. RT-PCR was applied to detect M1 inflammatory factors. The F4/80+ ratio and CD11c+ ratio of primary peritoneal macrophages were determined by flow cytometry. The expressions of p-AMPK and TLR4 were detected by Western blot. The cytoplasmic and nuclear distributions of NFκB p65 were observed by confocal microscopy. The binding of TLR4 to MyD88 was tested by CoIP, and the affinity of BBR for TLR4 was assessed by molecular docking. RESULTS: Upon exposure to LPS, the secretion of TNF-α and transcription of inflammatory factors in macrophages increased, cell morphology changed and protrusions appeared gradually, the proportion of F4/80+CD11c+ M1 macrophages increased, and the nuclear distribution of NFκB p65 increased. BBR pretreatment partially inhibited the changes mentioned above. However, the expression of TLR4 and p-AMPK did not change significantly after LPS intervention for 3 h. Meanwhile, CoIP showed that the interaction between TLR4 and MyD88 increased, and BBR inhibited the binding. Molecular docking suggested that BBR might interact with TLR4. CONCLUSIONS: Inflammatory changes were induced in macrophages after LPS stimulation for 3 h, and BBR pretreatment inhibited inflammatory polarization. BBR might interact with TLR4 and disturb TLR4/MyD88/NFκB signalling pathway, and it might be the mechanism by which BBR attenuated inflammation in the early phase.

Short hairpin RNA interference targeting interleukin 1 receptor type I in the paraventricular nucleus attenuates hypertension in rats.

Blood pressure is controlled by tonic sympathetic activities, excessive activation of which contributes to the pathogenesis and progression of hypertension. Interleukin (IL)-1ß in the paraventricular nucleus (PVN) is involved in sympathetic overdrive and hypertension. Here, we investigated the therapeutic effects of IL-1 receptor type I (IL-1R1) gene silencing in the PVN on hypertension. Recombinant lentivirus vectors expressing a short hairpin RNA (shRNA) targeting IL-1R1 (Lv-shR-IL-1R1) or a control shRNA were microinjected into PVN of spontaneously hypertensive rats (SHRs) and normotensive WKY rats. The fluorescence of green fluorescent protein-labelled vectors appeared at 2 weeks after injection and persisted for at least 8 weeks. IL-1R1 protein expression in the PVN was reduced 4 weeks after Lv-shR-IL-1R1 injection in SHRs. IL-1R1 interference also reduced basal sympathetic activity, cardiac sympathetic afferent reflex in SHRs. Depressor effects were observed from week 2 to 10 after Lv-shR-IL-1R1 treatment in SHRs, with the most prominent effects seen at the end of week 4. Furthermore, Lv-shR-IL-1R1 treatment decreased the ratio of left ventricular weight to body weight and cross-sectional areas of myocardial cells in SHRs. Additionally, Lv-shR-IL-1R1 treatment prevented an increase in superoxide anion and pro-inflammatory cytokines (PICs, TNF-α and IL-1ß) in the PVN of SHR, and upregulated anti-inflammatory cytokine (AIC, IL-10) expression. These results indicate that shRNA interference targeting IL-1R1 in the PVN decreases arterial blood pressure, attenuates excessive sympathetic activity and cardiac sympathetic afferent reflex, and improves myocardial remodelling in SHRs by restoring the balance between PICs and AICs to attenuate oxidative stress.

Gastric Bypass Surgery Reverses Diabetic Phenotypes in Bdnf-Deficient Mice.

Duodenum-jejunum gastric bypass (DJB) has been used to treat morbid diabetic patients. However, neither the suitability among patients nor the mechanisms of this surgical treatment is clear. Previously, we reported a new mouse strain named Timo as type 2 diabetes model caused by brain-derived neurotrophic factor (Bdnf) deficiency. In this study, we found that DJB on Timo mice reversed their metabolic abnormalities without altering the expression of Bdnf. Glucose tolerance and insulin sensitivity were improved greatly, along with reduction of fat accumulation in liver and white adipose tissue. The gut flora population was altered by DJB with increased proportion of Firmicutes and decreased Actinobacteria and Proteobacteria in the ileum after surgery. Systemic inflammation in Timo mice was greatly suppressed with less macrophage infiltration and lower tumor necrosis factor-α levels in liver and white adipose tissue after surgery. Interestingly, the alteration of gut microflora abundance and improved metabolism preceded the inflammation alleviation after DJB surgery. These results suggested that DJB can reverse Bdnf deficiency-associated metabolic abnormality. In addition, the reduced inflammation may not be the initial cause for the DJB-associated metabolic and microbiota alterations. The increased BDNF protein levels in hypothalamus and hippocampus may result from microbiota change after DJB surgery.

[Pharmacokinetic and pharmacodynamic characteristics of berberine and jateorhizine in Coptidis Rhizoma powder and their monomeric compounds in type 2 diabetic rats].

This article focused on a comparative analysis on the pharmacokinetic and pharmacodynamic characteristics of berberine (BER) and jateorhizine(JAT) in Coptidis Rhizoma powder (HL-P) and their monomeric compounds (BER + JAT, BJ) in type 2 diabetic (T2D) rats to explore the beneficial. effect of HL-P in the treatment of T2D. The T2D rats were treated with HL-P, BER, JAT and BJ, respectively for 63 d. The pharmacokinetic parameters, dynamic changes in blood glucose level and blood lipid values were measured. The results showed that, compared with other corresponding group, t(max), T(½ka) of BER and JAT in HL-P group were reduced, while C(max), AUC(inf), AUC(last), V(L)/F were significantly increased; compared with model group, blood glucose levels were decreased significantly in HL-P group since the 18th day, while those in BER or BJ group were reduced since the 36th day, however, blood glucose levels showed no obvious changes in JAT group; compared with model group, FFA values in all treatment group were decreased significantly. Moreover, TG, HDL and LDL value in HL-P group, LDL value in BER group and HDL value in BJ group were improved significantly. The above results showed that Coptidis Rhizoma powder showed excellent pharmacokinetic characteristics and excellent activity of lowering blood glucose and lipid. It provided a scientific basis for oral application of Coptidis Rhizoma powder in the treatment of T2D.

Enhanced endoplasmic reticulum SERCA activity by overexpression of hepatic stimulator substance gene prevents hepatic cells from ER stress-induced apoptosis.

Although the potential pathogenesis of nonalcoholic fatty liver disease (NAFLD) is unclear, increasing evidence indicates that endoplasmic reticulum (ER) stress may link free fatty acids to NAFLD. Since we previously reported that hepatic stimulator substance (HSS) could protect the liver from steatosis, this study is aimed to investigate whether HSS protection could be related with its inhibition on ER stress. The HSS gene was stably transfected into BEL-7402 hepatoma cells and effectively expressed in ER. The palmitic acid (PA)-induced heptocyte lipotoxicity was reproduced in the HSS-transfected cells, and HSS alleviation of the ER stress and apoptosis were subsequently examined. The results showed that PA treatment led to a heavy accumulation of fatty acids within the cells and a remarkable increase in reactive oxygen species (ROS). However, in the HSS-expressing cells, production of ROS was inhibited and ER stress-related marker glucose-regulated protein 78 (GRP-78), sterol regulatory element-binding protein (SREBP), anti-phospho-PRK-1ike ER kinase (p-PERK), anti-phospho-eukaryotic initiation factor 2α (p-eIF2α), and anti-C/EBP homologous protein (CHOP) were downregulated compared with the wild-type or mutant HSS-transfected cells. Furthermore, PA treatment severely impaired the activity of sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), leading to imbalanced calcium homeostasis during ER stress, which could be rescued in the HSS-trasfected cells. The protection provided by HSS to the SERCA is identical to that observed with N-acetyl-l-cysteine (NAC) and sodium dimercaptopropane sulfonate (Na-DMPS), which are two typical free radical scavengers. As a consequence, the rate of ER stress-mediated apoptosis in the HSS-expressing cells was significantly reduced. In conclusion, the protective effect of HSS against ER stress may be associated with the removal of ROS to restore the activity of the SERCA.

Traditional herbal pair Portulacae Herba and Granati Pericarpium alleviates DSS-induced colitis in mice through IL-6/STAT3/SOCS3 pathway.

BACKGROUND: Portulacae Herba and Granati Pericarpium pair (PGP) is a traditional Chinese herbal medicine treatment for colitis, clinically demonstrating a relatively favorable effect on relieving diarrhea and abnormal stools. However, the underlying mechanism remain uncertain. PURPOSE: The present study intends to evaluate the efficacy of PGP in treating colitis in mice and investigate its underlying mechanism. METHODS: The protective effect of PGP against colitis was determined by monitoring body weight, colon length, colon weight, and survival rate in mice. Colonic inflammation was assessed by serum cytokine levels, colonic H&E staining, and local neutrophil infiltration. The reversal of intestinal epithelial barrier damage by PGP was subsequently analyzed with Western blot and histological staining. Furthermore, RNA-seq analysis and molecular docking were performed to identify potential pathways recruited by PGP. Following the hints of the transcriptomic results, the role of PGP through the IL-6/STAT3/SOCS3 pathway in DSS-induced colitis mice was verified by Western blot. RESULTS: DSS-induced colitis in mice was significantly curbed by PGP treatment. PGP treatment significantly mitigated DSS-induced colitis in mice, as evidenced by improvements in body weight, DAI severity, survival rate, and inflammatory cytokines levels in serum and colon. Moreover, PGP treatment up-regulated the level of Slc26a3, thereby increasing the expressions of the tight junction/adherens junction proteins ZO-1, occludin and E-cadherin in the colon. RNA-seq analysis revealed that PGP inhibits the IL-6/STAT3/SOCS3 pathway at the transcriptional level. Molecular docking indicated that the major components of PGP could bind tightly to the proteins of IL-6 and SOCS3. Meanwhile, the result of Western blot revealed that the IL-6/STAT3/SOCS3 pathway was inhibited at the protein level after PGP administration. CONCLUSION: PGP could alleviate colonic inflammation and reverse damage to the intestinal epithelial barrier in DSS-induced colitis mice. The underlying mechanism involves the inhibition of the IL-6/STAT3/SOCS3 pathway.

Longitudinal Analysis of Humoral and Cellular Immune Response up to 6 Months after SARS-CoV-2 BA.5/BF.7/XBB Breakthrough Infection and BA.5/BF.7-XBB Reinfection.

The rapid mutation of SARS-CoV-2 has led to multiple rounds of large-scale breakthrough infection and reinfection worldwide. However, the dynamic changes of humoral and cellular immunity responses to several subvariants after infection remain unclear. In our study, a 6-month longitudinal immune response evaluation was conducted on 118 sera and 50 PBMC samples from 49 healthy individuals who experienced BA.5/BF.7/XBB breakthrough infection or BA.5/BF.7-XBB reinfection. By studying antibody response, memory B cell, and IFN-γ secreting CD4+/CD8+ T cell response to several SARS-CoV-2 variants, we observed that each component of immune response exhibited distinct kinetics. Either BA.5/BF.7/XBB breakthrough infection or BA.5/BF.7-XBB reinfection induces relatively high level of binding and neutralizing antibody titers against Omicron subvariants at an early time point, which rapidly decreases over time. Most of the individuals at 6 months post-breakthrough infection completely lost their neutralizing activities against BQ.1.1, CH.1.1, BA.2.86, JN.1 and XBB subvariants. Individuals with BA.5/BF.7-XBB reinfection exhibit immune imprinting shifting and recall pre-existing BA.5/BF.7 neutralization antibodies. In the BA.5 breakthrough infection group, the frequency of BA.5 and XBB.1.16-RBD specific memory B cells, resting memory B cells, and intermediate memory B cells gradually increased over time. On the other hand, the frequency of IFN-γ secreting CD4+/CD8+ T cells induced by WT/BA.5/XBB.1.16 spike trimer remains stable over time. Overall, our research indicates that individuals with breakthrough infection have rapidly declining antibody levels but have a relatively stable cellular immunity that can provide some degree of protection from future exposure to new antigens.

Effects of Interleukin-19 overexpression in the medial prefrontal cortex on anxiety-related behaviors, BDNF expression and p38/JNK/ERK pathways.

Anxiety is a prevalent mental illness known for its high incidence, comorbidity, and tendency to recur, posing significant societal and individual burdens. Studies have highlighted Interleukin-19 (IL-19) as having potential relevance in neuropsychiatric disorders. Our previous research revealed that IL-19 overexpression in colonies exacerbated anxiety-related behaviors induced by dextran sodium sulfate/stress. However, the precise role and molecular mechanisms of IL-19 in anxiety regulation remain uncertain. In this study, we initiated an acute restraint stress (ARS)-induced anxious mouse model and identified heightened expression of IL-19 and IL-20Rα in the medial prefrontal cortex (mPFC) of ARS mice. Notably, IL-19 and IL-20Rα were predominantly present in the excitatory pyramidal neurons of the mPFC under both basal and ARS conditions. Utilizing the adeno-associated virus (AAV) strategy, we demonstrated that IL-19 overexpression in the mPFC induced anxiety-related behaviors and elevated stress susceptibility. Additionally, we observed decreased protein levels of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95) in the mPFC of IL-19 overexpression mice, accompanied by reduced phosphorylation of in the p38, JNK, and Erk signaling pathways. These findings emphasize the role of IL-19 in modulating anxiety-related behaviors within the mPFC and suggest its potential as a pathological gene and therapeutic target for anxiety.

Enhanced neutralization of SARS-CoV-2 variant BA.2.86 and XBB sub-lineages by a tetravalent COVID-19 vaccine booster.

Emerging SARS-CoV-2 sub-lineages like XBB.1.5, XBB.1.16, EG.5, HK.3 (FLip), and XBB.2.3 and the variant BA.2.86 have recently been identified. Understanding the efficacy of current vaccines on these emerging variants is critical. We evaluate the serum neutralization activities of participants who received COVID-19 inactivated vaccine (CoronaVac), those who received the recently approved tetravalent protein vaccine (SCTV01E), or those who had contracted a breakthrough infection with BA.5/BF.7/XBB virus. Neutralization profiles against a broad panel of 30 sub-lineages reveal that BQ.1.1, CH.1.1, and all the XBB sub-lineages exhibit heightened resistance to neutralization compared to previous variants. However, despite their extra mutations, BA.2.86 and the emerging XBB sub-lineages do not demonstrate significantly increased resistance to neutralization over XBB.1.5. Encouragingly, the SCTV01E booster consistently induces higher neutralizing titers against all these variants than breakthrough infection does. Cellular immunity assays also show that the SCTV01E booster elicits a higher frequency of virus-specific memory B cells. Our findings support the development of multivalent vaccines to combat future variants.