Lipopolysaccharide Triggers Luminal Acidification to Promote Defense Against Bacterial Infection in Vaginal Epithelium.

The vaginal epithelium plays pivotal roles in host defense against pathogen invasion, contributing to the maintenance of an acidic microenvironment within the vaginal lumen through the activity of acid-base transport proteins. However, the precise defense mechanisms of the vaginal epithelium after a bacterial infection remain incompletely understood. This study showed that bacterial lipopolysaccharide (LPS) potentiated net proton efflux by up-regulating the expression of Na+-H+ exchanger 1 (NHE1) without affecting other acid-base transport proteins in vaginal epithelial cells. Pharmacologic inhibition or genetic knockdown of Toll-like receptor-4 and the extracellular signal-regulated protein kinase signaling pathway effectively counteracted the up-regulation of NHE1 and the enhanced proton efflux triggered by LPS in vaginal epithelial cells. In vivo studies revealed that LPS administration led to luminal acidification through the up-regulation of NHE1 expression in the rat vagina. Moreover, inhibition of NHE exhibited an impaired defense against acute bacterial infection in the rat vagina. These findings collectively indicate the active involvement of vaginal epithelial cells in facilitating luminal acidification during acute bacterial infection, offering potential insights into the treatment of bacterial vaginosis.

Cooperative driver pathway discovery via fusion of multi-relational data of genes, miRNAs and pathways.

Discovering driver pathways is an essential step to uncover the molecular mechanism underlying cancer and to explore precise treatments for cancer patients. However, due to the difficulties of mapping genes to pathways and the limited knowledge about pathway interactions, most previous work focus on identifying individual pathways. In practice, two (or even more) pathways interplay and often cooperatively trigger cancer. In this study, we proposed a new approach called CDPathway to discover cooperative driver pathways. First, CDPathway introduces a driver impact quantification function to quantify the driver weight of each gene. CDPathway assumes that genes with larger weights contribute more to the occurrence of the target disease and identifies them as candidate driver genes. Next, it constructs a heterogeneous network composed of genes, miRNAs and pathways nodes based on the known intra(inter)-relations between them and assigns the quantified driver weights to gene-pathway and gene-miRNA relational edges. To transfer driver impacts of genes to pathway interaction pairs, CDPathway collaboratively factorizes the weighted adjacency matrices of the heterogeneous network to explore the latent relations between genes, miRNAs and pathways. After this, it reconstructs the pathway interaction network and identifies the pathway pairs with maximal interactive and driver weights as cooperative driver pathways. Experimental results on the breast, uterine corpus endometrial carcinoma and ovarian cancer data from The Cancer Genome Atlas show that CDPathway can effectively identify candidate driver genes [area under the receiver operating characteristic curve (AUROC) of $\geq $0.9] and reconstruct the pathway interaction network (AUROC of>0.9), and it uncovers much more known (potential) driver genes than other competitive methods. In addition, CDPathway identifies 150% more driver pathways and 60% more potential cooperative driver pathways than the competing methods. The code of CDPathway is available at http://mlda.swu.edu.cn/codes.php?name=CDPathway.

BEXCIS: Bayesian methods for estimating the degree of the skewness of X chromosome inactivation.

BACKGROUND: X chromosome inactivation (XCI) is an epigenetic phenomenon that one of two X chromosomes in females is transcriptionally silenced during early embryonic development. Skewed XCI has been reported to be associated with some X-linked diseases. There have been several methods measuring the degree of the skewness of XCI. However, these methods may still have several limitations. RESULTS: We propose a Bayesian method to obtain the point estimate and the credible interval of the degree of XCI skewing by incorporating its prior information of being between 0 and 2. We consider a normal prior and a uniform prior for it (respectively denoted by BN and BU). We also propose a penalized point estimate based on the penalized Fieller's method and derive the corresponding confidence interval. Simulation results demonstrate that the BN and BU methods can solve the problems of extreme point estimates, noninformative intervals, empty sets and discontinuous intervals. The BN method generally outperforms other methods with the lowest mean squared error in the point estimation, and well controls the coverage probability with the smallest median and the least variation of the interval width in the interval estimation. We apply all the methods to the Graves' disease data and the Minnesota Center for Twin and Family Research data, and find that SNP rs3827440 in the Graves' disease data may undergo skewed XCI towards the allele C. CONCLUSIONS: We recommend the BN method for measuring the degree of the skewness of XCI in practice. The R package BEXCIS is publicly available at https://github.com/Wen-YiYu/BEXCIS .

Robust association tests for quantitative traits on the X chromosome.

The genome-wide association study is an elementary tool to assess the genetic contribution to complex human traits. However, such association tests are mainly proposed for autosomes, and less attention has been given to methods for identifying loci on the X chromosome due to their distinct biological features. In addition, the existing association tests for quantitative traits on the X chromosome either fail to incorporate the information of males or only detect variance heterogeneity. Therefore, we propose four novel methods, which are denoted as QXcat, QZmax, QMVXcat and QMVZmax. When using these methods, it is assumed that the risk alleles for females and males are the same and that the locus being studied satisfies the generalized genetic model for females. The first two methods are based on comparing the means of the trait value across different genotypes, while the latter two methods test for the difference of both means and variances. All four methods effectively incorporate the information of X chromosome inactivation. Simulation studies demonstrate that the proposed methods control the type I error rates well. Under the simulated scenarios, the proposed methods are generally more powerful than the existing methods. We also apply our proposed methods to data from the Minnesota Center for Twin and Family Research and find 10 single nucleotide polymorphisms that are statistically significantly associated with at least two traits at the significance level of 1 × 10-3.

Simple-to-use nomogram for predicting the risk of syphilis among MSM in Guangdong Province: results from a serial cross-sectional study.

BACKGROUND: The purpose of this study was to develop and validate a simple-to-use nomogram for the prediction of syphilis infection among men who have sex with men (MSM) in Guangdong Province. METHODS: A serial cross-sectional data of 2184 MSM from 2017 to 2019 was used to develop and validate the nomogram risk assessment model. The eligible MSM were randomly assigned to the training and validation dataset. Factors included in the nomogram were determined by multivariate logistic regression analysis based on the training dataset. The receiver operating characteristic (ROC) curves was used to assess its predictive accuracy and discriminative ability. RESULTS: A total of 2184 MSM were recruited in this study. The prevalence of syphilis was 18.1% (396/2184). Multivariate logistic analysis found that age, the main venue used to find sexual partners, condom use in the past 6 months, commercial sex in the past 6 months, infection with sexually transmitted diseases (STD) in the past year were associated with syphilis infection using the training dataset. All these factors were included in the nomogram model that was well calibrated. The C-index was 0.80 (95% CI 0.76-0.84) in the training dataset, and 0.79 (95% CI 0.75-0.84) in the validation dataset. CONCLUSIONS: A simple-to-use nomogram for predicting the risk of syphilis has been developed and validated among MSM in Guangdong Province. The proposed nomogram shows good assessment performance.

["Attenuation-preservation effects" of different processed products of Aconiti Kusnezoffii Radix in industrialized production].

To study the correlation between toxicity and efficacy of different processed Aconiti Kusnezoffii Radix productsin industrial production, in order to define the optimal processing method for "attenuation-preservation effects". The HPLC method was used to determine the content of six aconitine alkaloids in Aconiti Kusnezoffii Radix and its different processed products. The Bliss method was used to determine the half-lethal dose(LD_(50)) or the maximum dose of Aconiti Kusnezoffii Radix and its different processed products in mice. The toluene-induced ear swelling method and the acetic acid twist method were used to investigate the anti-inflammatory and analgesic effects of different processed products. The results showed that: ① the total amount of diester alkaloids incrude Aconiti Kusnezoffii Radix was 0.358 8%; the total amount of diester alkaloids in Aconiti Kusnezoffii Radix prepared by pharmacopoeia-based boiling method was 0.002 2%, and the total amount of monoester alkaloids was 0.036 2%; the total amount of diester alkaloids in Aconiti Kusnezoffii Radix produced by atmospheric steaming method was 0.006 0%, and the total amount of monoester alkaloids was 0.056 7%; ② the LD_(50) of Aconiti Kusnezoffii Radix was 5.4 g·kg~(-1),and the maximum dose of processed products by two methods were 133.34 g·kg~(-1); pathological observation showed that compared with the normal group, the two kinds of processed products of Aconiti Kusnezoffii Radix had certain damage to the heart, liver and kidney; ③products processed by pharmacopoeia-based boiling method and atmospheric steaming method had anti-inflammatory and analgesic effects(P<0.01 or P<0.05). The anti-inflammatory and analgesic effects were as follows: the atmospheric steaming method was superior to the pharmacopoeia-based boiling method. The above results suggest that the crude Aconiti Kusnezoffii Radixis more toxic. The atmospheric steaming method can significantly reduce the toxicity, while retaining its good anti-inflammatory and analgesic effects, which is significantly better than the pharmacopoeia-based boiling method. The atmospheric steaming process is simple and easy to operate, and suitable for industrial production.

A novel functional polymorphism of GSTM3 reduces clear cell renal cell carcinoma risk through enhancing its expression by interfering miR-556 binding.

Dysregulation of glutathione-S-transferase M3 (GSTM3) has been related to clear cell renal cell carcinoma (ccRCC) in our former study. GSTM3 plays a pivotal role of detoxification and clearance of reactive oxygen species (ROS) in tumour tissues. This study aimed to examine: (1) the associations between GSTM3 single nucleotide polymorphisms (SNPs) and risk of ccRCC, and (2) the potential molecular mechanism accounting for its effects. 5 SNPs in 3'UTR of GSTM3 were initially genotyped in 329 cases and 420 healthy controls. A SNP-rs1055259 was found to be significantly associated with the susceptibility of ccRCC (OR = 0.59, 95% CI = 0.41-0.92; P = .019). The minor allele of rs1055259 (G allele) was associated with RCC risk. This SNP was predicted to affect microRNA (miR)-556 binding to 3'UTR of GSTM3 mRNA. To determine the functional impact, plasmid constructs carrying different alleles of rs1055259 were created. Compared to rs1055259 A-allele constructs, cells transfected with rs1055259 G-allele construct had higher transcriptional activity and were less responsive to miR-556 changes and gene expression. Elevated GSTM3 expression in G-allele cells was associated with ROS activity and ccRCC development. Taken together, this study indicated that a functional polymorphism of GSTM3 -rs1055259 reduced susceptibility of RCC in the Chinese population. It influenced GSTM3 protein synthesis by interfering miR-556 binding, subsequently suppressed ROS activity and ccRCC progression.

Critical role for Annexin A7 in secondary brain injury mediated by its phosphorylation after experimental intracerebral hemorrhage in rats.

Glutamate excitotoxicity has been implicated in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI). Synaptosome associated protein 23 (SNAP23) and SNAP25 are respectively participate in presynaptic glutamate release and postsynaptic glutamate receptor (NMDA receptor) trafficking, both of which are essential for glutamate-mediated excitatory toxicity. SNAP23 and SNAP25 exhibit high homology and SNAP23 has been shown to interact with Annexin A7 (ANXA7). This study was to examine the role of ANXA7 in ICH-induced neuronal damage. A collagenase ICH model was performed in adult male Sprague Dawley rats. First, a possible relationship between ANXA7 and ICH pathology was confirmed by an increase in the protein and mRNA level of ANXA7 in the brain tissue around hematoma of ICH rats and the rescue effects of ANXA7 knockdown in vivo on neuronal death, blood-brain barrier damage, brain edema, neurobehavioral deficient, and inflammatory response. In addition, the rescue effect of ANXA7 knockdown on neurobehavioral deficient was also verified in rat autologous blood injection ICH model. Second, we found that ICH significantly increased the phosphorylation ratio of ANXA7 at the threonine residues mainly in neurons. Finally, based on site-specific mutagenesis, we identified that ANXA7 phosphorylation at threonine 286 is required for its interaction with SNAP25 at presynaptic axon terminal and SNAP23 at postsynaptic axon terminal. Collectively, our findings suggest that ANXA7 contributed to SBI at least partially through regulating glutamate toxicity after ICH. Selective inhibition of ANXA7 phosphorylation may be a novel approach to ameliorate ICH-induced SBI.

Protective action of bone marrow mesenchymal stem cells in immune tolerance of allogeneic heart transplantation by regulating CD45RB+ dendritic cells.

BACKGROUND: Bone marrow-derived mesenchymal stem cells (BMSCs) could exert a potent immunosuppressive effect and therefore may have a therapeutic potential in T-cell-dependent pathologies. We aimed to examine the effects of BMSCs on immune tolerance of allogeneic heart transplantation and the involvement of CD45RB+ dendritic cells (DCs). METHODS: Bone marrow-derived DCs and BMSCs were co-cultured, with CD45RB expression on the surface of DCs measured by flow cytometry. qRT-PCR and Western blotting were used to detect mRNA and protein levels. Cytometric bead array was performed to determine the serum level of IL-10. Survival time of transplanted heart and expression of CD4+ , CD8+ , IL-2, IL-4, IL-10, IFN-γ were determined. Immunofluorescence assay was employed to determine intensity of C3d and C4d. RESULTS: DCs co-cultured with BMSCs showed increased CD45RB and Foxp3 levels. CD45RB+ DCs co-cultured with T-cells CD4+ displayed increased T-cell CD4+ Foxp3 ratio and IL-10 than DCs. Both of them extended survival time of transplanted heart, decreased histopathological classification and score, intensity of C3d, C4d, proportion of CD4+ , expression levels of IL-2 and IFN-γ, and increased the CD4+ Foxp3 ratio and levels of IL-4 and IL-10. CD45RB+ DCs achieved better protective effects than DCs. CONCLUSION: BMSCs increased the expression of CD45RB in the bone marrow-derived DCs, thereby strengthening immunosuppression capacity of T cells and immune tolerance of allogeneic heart transplantation.

Novel Mutations in SERPINF1 Result in Rare Osteogenesis Imperfecta Type VI.

Osteogenesis imperfecta (OI) is a group of inherited disorders characterized by recurrent fragile fractures. Serpin peptidase inhibitor, clade F, member 1 (SERPINF1) is known to cause a distinct, extremely rare autosomal recessive form of type VI OI. Here we report, for the first time, the detection of SERPINF1 mutations in Chinese OI patients. We designed a novel targeted next-generation sequencing panel of OI-related genes to identify pathogenic mutations, which were confirmed with Sanger sequencing and by co-segregation analysis. We also investigated the phenotypes of OI patients by evaluating bone mineral density, radiological fractures, serum bone turnover markers, and pigment epithelium-derived factor (PEDF) concentration. Six patients with moderate-to-severe bone fragility, significantly low bone mineral density, and severe deformities of the extremities were recruited from five unrelated families for this study. Six pathogenic mutations in SERPINF1 gene were identified, five of which were novel: (1) a homozygous in-frame insertion in exon 3 (c.271_279dup, p.Ala91_Ser93dup); (2) compound heterozygous mutations in intron 3 (c.283 + 1G > T, splicing site) and exon 5 (c.498_499delCA, p.Arg167SerfsX35, frameshift); (3) a homozygous frameshift mutation in exon 8 (c.1202_1203delCA, p.Thr401ArgfsX); (4) compound heterozygous missense mutation (c.184G > A, p.Gly62Ser) and in-frame insertion (c.271_279dup, p.Ala91_Ser93dup) in exon 3; and (5) a heterozygous nonsense mutation in exon 4 (c.397C>T + ?, p.Gln133X + ?). Serum PEDF levels were barely detectable in almost all subjects. We identified five novel mutations in SERPINF1 and confirmed the diagnostic value of serum PEDF level for the first time in Chinese patients with the extremely rare OI type VI.

Aortic Valve Myxoma in a Young Man: A Case Report and Review of Literature.

Myxoma is the most commonly found cardiac primary tumor. The left atrium is the most common localization of myxoma, followed by the right atrium. However, it is rare in the left and right ventricles. Myxoma originating from cardiac valves is extremely rare. This article presents a case of a 17-year-old male who was admitted due to heart murmur for one year. Transthoracic echocardiography indicated a 1.9 cm round solid mass in the left ventricular outflow tract. Excision surgery and aortic valve replacement were performed in this patient. Histopathology revealed the mass as a myxoma. The aortic valve remains a very rare myxoma localization position. Echocardiography can provide a precise method for myxoma diagnosis. Early excision associated with valve replacement can provide good curative effects.

Targeted next-generation sequencing identification of mutations in patients with disorders of sex development.

BACKGROUND: The identification of causative mutations is important for treatment decisions and genetic counseling of patients with disorders of sex development (DSD). Here, we designed a new assay based on targeted next-generation sequencing (NGS) to diagnose these genetically heterogeneous disorders. METHODS: All coding regions and flanking sequences of 219 genes implicated in DSD were designed to be included on a panel. A total of 45 samples were used for sex chromosome dosage validation by targeted sequencing using the NGS platform. Among these, 21 samples were processed to find the causative mutation. RESULTS: The sex chromosome dosages of all 45 samples in this assay were concordant with their corresponding karyotyping results. Among the 21 DSD patients, a total of 11 mutations in SRY, NR0B1, AR, CYP17A1, GK, CHD7, and SRD5A2 were identified, including five single nucleotide variants, three InDels, one in-frame duplication, one SRY-positive 46,XX, and one gross duplication with an estimated size of more than 427,038 bp containing NR0B1 and GK. We also identified six novel mutations: c.230_231insA in SRY, c.7389delA in CHD7, c.273C>G in NR0B1, and c.2158G>A, c.1825A>G, and c.2057_2065dupTGTGTGCTG in AR. CONCLUSIONS: Our assay was able to make a genetic diagnosis for eight DSD patients (38.1%), and identified variants of uncertain clinical significance in the other three cases (14.3%). Targeted NGS is therefore a comprehensive and efficient method to diagnose DSD. This work also expands the pathogenic mutation spectrum of DSD.

Mesenchymal Stem Cell-Derived Exosomes Improve the Microenvironment of Infarcted Myocardium Contributing to Angiogenesis and Anti-Inflammation.

BACKGROUND/AIMS: Bone marrow mesenchymal stem cells (MSCs) widely applied for treating myocardial infarction face survival challenges in the inflammatory and ischemia microenvironment of acute myocardial infarction. The study hypothesized that MSC-derived exosomes play a significant role in improving microenvironment after acute myocardial infarction and aimed to investigate the paracrine effects of exosomes on angiogenesis and anti-inflammatory activity. METHODS: MSCs were cultured in DMEM/F12 supplemented with 10% exosome-depleted fetal bovine serum and 1% penicillin-streptomycin for 48 h. MSC-derived exosomes were isolated using ExoQuick-TC. Tube formation and T-cell proliferation assays were performed to assess the angiogenic potency of MSC-derived exosomes. Acute myocardial infarction was induced in Sprague-Dawley rats, and myocardium bordering the infarcted zone was injected at four different sites with phosphate-buffered saline (PBS, control), MSC-derived exosomes, and exosome-depleted MSC culture medium. RESULTS: MSC-derived exosomes significantly enhanced the tube formation of human umbilical vein endothelial cells, impaired T-cell function by inhibiting cell proliferation in vitro, reduced infarct size, and preserved cardiac systolic and diastolic performance compared with PBS markedly enhancing the density of new functional capillary and hence blood flow recovery in rat myocardial infarction model. CONCLUSIONS: Exosomes stimulate neovascularization and restrain the inflammation response, thus improving heart function after ischemic injury.

Mental Imagery in the Relationship between Alexithymia and Parental Psychological Control.

This study aims to explore the mediating role of mental imagery in the relationship between alexithymia and parental psychological control among Chinese university students. Conducted between March and April 2023, this descriptive study involved 282 volunteer participants from a university in southern China. Data collection included the Toronto Alexithymia Scale (TAS), the Parental Psychological Control Scale (PPC), and the Vividness of Visual Mental Imagery questionnaire (VVIQ). The results revealed that: (1) based on established cut-off, 81 students were identified as highly alexithymic; (2) the alexithymia group scored higher on both the TAS and PPC and lower on the VVIQ compared to the non-alexithymia and possible-alexithymia groups; and (3) mediating analysis demonstrated a strong and positive correlation between parental psychological control and alexithymia for all participants, with visual mental imagery mediating this relationship. This study underscores the interconnectedness of parental psychological control, visual mental imagery, and alexithymia among college students. The theoretical and clinical implications of these findings are also discussed.

Can Targeted Poverty Alleviation Program Reduce Depression? Evidence From China.

Objectives: This study aimed to examine whether China's Targeted Poverty Alleviation (TPA) program mitigates depression and explores the mechanisms through which the TPA program affects individuals' depression. Methods: Using the data from the China Family Panel Studies (CFPS) survey from 2012 to 2020, we employ a Difference-in-Difference model to analyze the effect of the TPA program on individuals' depression levels. Results: Our findings indicate that the TPA program reduces depression scores by 0.116 points, accounting for 6.82% of the standard deviation of depression scores. Further analyses indicate that these effects are mediated through improvements in local medical conditions, reductions in household healthcare spending, increases in household entertainment expenditures, and greater likelihood of living in family. Conclusion: This study showed that the TPA program significantly mitigates individuals' depression levels. The possible channels include (1) improving local medical conditions, (2) cutting down household healthcare spending, (3) increasing household entertainment expenses, and (4) increasing the likelihood of living in family.

Protective Effects of Isoliquiritigenin and Licochalcone B on the Immunotoxicity of BDE-47: Antioxidant Effects Based on the Activation of the Nrf2 Pathway and Inhibition of the NF-κB Pathway.

2,2',4,4'-Tetrabrominated biphenyl ether (BDE-47) is a polybrominated diphenyl ether (PBDE) homologue that is ubiquitous in biological samples and highly toxic to humans and other organisms. Prior research has confirmed that BDE-47 can induce oxidative damage in RAW264.7 cells, resulting in apoptosis and impaired immune function. The current study mainly focused on how Isoliquiritigenin (ISL) and Licochalcone B (LCB) might protect against BDE-47's immunotoxic effects on RAW264.7 cells. The results show that ISL and LCB could increase phagocytosis, increase the production of MHC-II, and decrease the production of inflammatory factors (TNF-α, IL-6, and IL-1ß) and co-stimulatory factors (CD40, CD80, and CD86), alleviating the immune function impairment caused by BDE-47. Secondly, both ISL and LCB could reduce the expressions of the proteins Bax and Caspase-3, promote the expression of the protein Bcl-2, and reduce the apoptotic rate, alleviating the apoptosis initiated by BDE-47. Additionally, ISL and LCB could increase the levels of antioxidant substances (SOD, CAT, and GSH) and decrease the production of reactive oxygen species (ROS), thereby counteracting the oxidative stress induced by BDE-47. Ultimately, ISL and LCB suppress the NF-κB pathway by down-regulating IKBKB and up-regulating IκB-Alpha in addition to activating the Nrf2 pathway and promoting the production of HO-1 and NQO1. To summarize, BDE-47 causes oxidative damage that can be mitigated by ISL and LCB through the activation of the Nrf2 pathway and inhibition of the NF-κB pathway, which in turn prevents immune function impairment and apoptosis. These findings enrich the current understanding of the toxicological molecular mechanism of BDE-47 and the detoxification mechanism of licorice.

Excess generation and activation of naturally arising memory-phenotype CD4+ T lymphocytes are inhibited by regulatory T cells in steady state.

Conventional CD4+ T lymphocytes consist of naïve, foreign antigen-specific memory, and self-antigen-driven memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells tonically proliferate in response to self-antigens and differentiate into the T-bet+ subset in steady state. How excess proliferation and differentiation of MP cells are inhibited remains unclear. Given immunosuppressive function of regulatory T cells (Tregs), it is possible that they are also involved in inhibition of spontaneous MP cell activation. Here we show using Foxp3-diphtheria toxin receptor-transgenic mice that both MP and naïve CD4+ T cells spontaneously proliferate and differentiate into Th1 cells upon acute Treg depletion. At an early time point post Treg depletion, MP as compared to naïve CD4+ T cells are preferentially activated while at a later stage, the response is dominated by activated cells originated from the naïve pool. Moreover, we argue that MP cell proliferation is driven by TCR and CD28 signaling whereas Th1 differentiation mediated by IL-2. Furthermore, our data indicate that such activation of MP and naïve CD4+ T lymphocytes contribute to development of multi-organ inflammation at early and later time points, respectively, after Treg ablation. Together our findings reveal that Tregs tonically inhibit early, spontaneous proliferation and Th1 differentiation of MP CD4+ T lymphocytes as well as late activation of naïve cells, thereby contributing to maintenance of T cell homeostasis.

Trends in Intention to Take the Second Booster COVID-19 Vaccination and Associated Factors in China: Serial Cross-Sectional Surveys.

BACKGROUND: The escalating complexity of the COVID-19 epidemic underscores the need for heightened attention to booster vaccinations. This study aims to examine the changing trend in the public's intention to receive the second COVID-19 booster vaccination over time and the associated factors following the COVID-19 policy optimization in China. METHOD: Eight cross-sectional surveys utilizing SMS questionnaire links were conducted in Guangzhou, China, from December 2022 to April 2023. The Mann-Kendall test was employed to analyze the trend in intentions to receive the second booster vaccination across the survey time. Adjusted and multivariate logistic analyses were used to analyze the factors associated with vaccination intention. Parallel analyses were performed for two subgroups with different COVID-19 infection statuses. RESULTS: A total of 9860 respondents were surveyed in the eight rounds, of which 8048 completed the first booster vaccination and were included in the analysis. The overall COVID-19 infection rate was 60.0% (4832/8048), while the overall vaccination intention was 72.2% (5810/8048) among respondents. The vaccination intention exhibited a significant declining trend over time, decreasing from 81.5% in December 2022 to 52.2% in April 2023. An adjusted logistic regression analysis revealed that anxiety and depression were negatively associated with an intention to receive the second booster vaccination, while COVID-19-related preventive behaviors and a high engagement in COVID-19-related information were positively associated with an intention to receive the second booster vaccination. A subgroup analysis revealed that the association between psychological and behavioral characteristics and vaccination intention remained relatively stable among individuals with different histories of COVID-19 infections. CONCLUSION: There was a significant decline in the intention to receive the second booster vaccination following the optimization of the COVID policy in China. Our findings emphasize the urgency of the second booster vaccination and provide a foundation for the development of tailored interventions to enhance and sustain vaccination intention among the public.

Precision cardiac targeting: empowering curcumin therapy through smart exosome-mediated drug delivery in myocardial infarction.

Nanoparticle-mediated drug delivery has emerged as a highly promising and effective therapeutic approach for addressing myocardial infarction. However, clinical translation tends to be a failure due to low cardiac retention as well as liver and spleen entrapment in previous therapies. Herein, we report a two-step exosome delivery system, which precludes internalization by the mononuclear phagocyte system before the delivery of therapeutic cardiac targeting exosomes (ExoCTP). Importantly, curcumin released by ExoCTP diminishes reactive oxygen species over-accumulation in ischemic myocardium, as well as serum levels of lactate dehydrogenase, malonyldialdehyde, superoxide dismutase and glutathione, indicating better antioxidant capacity than free curcumin. Finally, our strategy was proven to greatly potentiate the delivery and therapeutic efficacy of curcumin without systemic toxicity. Taken together, our smart exosome-mediated drug delivery strategy can serve either as therapeutics alone or in combination with other drugs for effective heart targeting and subsequent wound healing.

Genetic Screening of Patients with Sporadic Alzheimer's Disease and Frontotemporal Lobar Degeneration in the Chinese Population.

Background: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias. Objective: This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population. Methods: A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results. Results: Four known pathogenic or likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO, and DCTN1, were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort. Conclusions: There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases.