Re-establishing immune tolerance in multiple sclerosis: focusing on novel mechanisms of mesenchymal stem cell regulation of Th17/Treg balance.

The T-helper 17 (Th17) cell and regulatory T cell (Treg) axis plays a crucial role in the development of multiple sclerosis (MS), which is regarded as an immune imbalance between pro-inflammatory cytokines and the maintenance of immune tolerance. Mesenchymal stem cell (MSC)-mediated therapies have received increasing attention in MS research. In MS and its animal model experimental autoimmune encephalomyelitis, MSC injection was shown to alter the differentiation of CD4+T cells. This alteration occurred by inducing anergy and reduction in the number of Th17 cells, stimulating the polarization of antigen-specific Treg to reverse the imbalance of the Th17/Treg axis, reducing the inflammatory cascade response and demyelination, and restoring an overall state of immune tolerance. In this review, we summarize the mechanisms by which MSCs regulate the balance between Th17 cells and Tregs, including extracellular vesicles, mitochondrial transfer, metabolic reprogramming, and autophagy. We aimed to identify new targets for MS treatment using cellular therapy by analyzing MSC-mediated Th17-to-Treg polarization.

Clinical Features of Paediatric Inflammatory Epidermolysis Bullosa Acquisita: A Case Series Study.

Epidermolysis bullosa acquisita (EBA) rarely develops in childhood. This study retrospectively recruited paediatric patients with EBA (age ≤ 16 years), diagnosed by clinical and histopathological features and results of immunofluorescence, immunoblotting and enzyme-linked immunosorbent assay (ELISA), and reviews their clinical manifestations, histopathology, immunological features, and responses to various treatments. All 7 included patients presented with inflammatory EBA. Among them, 3 had a bullous pemphigoid-like phenotype. Pathologically, in addition to dermal-epidermal blistering, in all patients, the distribution of neutrophils was superficial perivascular or interstitial, or in the dermal papilla. Mixed neutrophils and eosinophils were detected in 2 of the 3 patients with bullous pemphigoid-like phenotypes. In addition to treatment with glucocorticoids, dapsone was administered in 4 patients, while thalidomide and sulfasalazine were administered in 1 patient. All patients responded to the these therapies. Relapse was mainly due to reduction and cessation of glucocorticoids. In conclusion, EBA in childhood may be unique, and thus distinct from its adult counterpart. Specific treatment and follow-up protocols are required for therapy of this rare autoimmune skin disease in children.

Comparison of dermoscopic characteristics on toenail onychomycosis in psoriatic and non-psoriatic patients: A prospective study.

BACKGROUND: Psoriatic patients may experience the coexistence of onychomycosis (OM). However, the evaluation of OM in psoriatics has been hindered by potential clinical differences from OM in non-psoriatics. OBJECTIVE: To assess and compare dermoscopic features between toenail OM in psoriatic and in non-psoriatic patients. PATIENTS AND METHODS: Between September 2020 and September 2023, dermoscopy was conducted on 183 affected toenails by OM in psoriatics and 232 affected toenails by OM in non-psoriatics in two centres. The dermoscopic characteristics were compared using the Chi-squared test. RESULTS: Among toenail OM cases in psoriatic subjects, the most prevalent dermoscopic features included pitting (147/183, 80.33%) and subungual hyperkeratosis (118/183, 64.48%). Conversely, toenail OM in non-psoriatics was characterized by subungual hyperkeratosis (175/232, 75.43%) and nail spikes (139/232, 59.91%). Comparative analysis revealed a significantly higher occurrence of pitting (80.33% vs. 15.96%, p < .001), periungual telangiectasis (22.40% vs. 4.74%, p < .001), oil patches (12.57% vs. 0.43%,p < .001) and transverse grooves (43.72% vs. 28.45%,p < .01) in toenail OM in psoriatics. Furthermore, toenail OM in psoriatics exhibited a significantly lower frequency of yellow structureless area (13.11% vs. 42.67%, p < .001), nail spikes (43.17% vs. 59.91%, p < .01), ruin appearance of sulphur nugget (8.20% vs. 31.03%, p < .001), dotted/blocky haemorrhage (6.01% vs. 20.69%,p < .001) and partial onycholysis (32.79% vs. 46.98%, p < .01). CONCLUSIONS: Dermoscopic features of toenail OM in psoriatic and non-psoriatic patients exhibit notable differences. OM in psoriatics shows a higher frequency of pitting and periungual telangiectasis, while a lower frequency of yellow structureless areas and nail spikes under dermoscopy.

Chinese expert consensus on management of antifungal-resistant dermatophytoses (2024 edition).

Antifungal-resistant dermatophytes (ARD) infection is a hotspot issue in clinical microbiology and the dermatology field. Trichophyton indotineae as the dominant species of dermatophyte with terbinafine-resistance or multidrug resistance, is easy to be missed detection clinically, which brings severe challenges to diagnosis and treatment. ARD infection cases have emerged in China, and it predicts a risk of transmission among human. Based on the existing medical evidence and research data, the Mycology Group of Combination of Traditional and Western Medicine Dermatology and Chinese Antifungal⁃Resistant Dermatophytoses Expert Consensus Group organized experts to make consensus on the management of the infection. Here, the consensus formulated diagnosis and treatment recommendations, to raise attention to dermatophytes drug resistance problem, and expect to provide reference information for the clinical diagnosis, treatment, prevention and control.

Epidemiologic features and therapeutic strategies of kerion: A nationwide multicentre study.

BACKGROUND: Kerion is a severe type of tinea capitis that is difficult to treat and remains a public health problem. OBJECTIVES: To evaluate the epidemiologic features and efficacy of different treatment schemes from real-world experience. METHODS: From 2019 to 2021, 316 patients diagnosed with kerion at 32 tertiary Chinese hospitals were enrolled. We analysed the data of each patient, including clinical characteristics, causative pathogens, treatments and outcomes. RESULTS: Preschool children were predominantly affected and were more likely to have zoophilic infection. The most common pathogen in China was Microsporum canis. Atopic dermatitis (AD), animal contact, endothrix infection and geophilic pathogens were linked with kerion occurrence. In terms of treatment, itraconazole was the most applied antifungal agent and reduced the time to mycological cure. A total of 22.5% of patients received systemic glucocorticoids simultaneously, which reduced the time to complete symptom relief. Furthermore, glucocorticoids combined with itraconazole had better treatment efficacy, with a higher rate and shorter time to achieving mycological cure. CONCLUSIONS: Kerion often affects preschoolers and leads to serious sequelae, with AD, animal contact, and endothrix infection as potential risk factors. Glucocorticoids, especially those combined with itraconazole, had better treatment efficacy.

Nail psoriasis in China: A prospective multicentre study.

BACKGROUND: Data on nail psoriasis (PsO) in China are scarce. OBJECTIVES: To provide nail PsO-related data regarding epidemiologic characteristics, manifestations, fungal infections, arthritic complaints and treatments that may facilitate improved patient management globally. METHODS: From August 2021 to August 2022, patients with nail PsO were enrolled in a prospective multicentre observational study at 25 hospitals in China. We collected and analysed data concerning nail PsO demography, clinical signs, fungal detection, arthritic symptoms and treatment. RESULTS: A total of 817 patients with nail PsO were involved, with a mean body mass index of 24.13 ± 2.93. In addition, 71.41% of the patients were male. The Nail PsO Severity Index score was weakly positively correlated with body surface area. The percentage of nail involvement was 95.29% for fingernails and 57.18% for toenails, with pitting (67.11%) and subungual hyperkeratosis (60.40%) being the most prevalent manifestations, respectively. Toenails showed a significantly higher frequency of nailfold scales, subungual hyperkeratosis and nail plate crumbling and a lower frequency of splinter haemorrhages, pitting and erythema of the lunula. A total of 13.26% of the PsO patients had onychomycosis, and 77.08% were observed in the toenails. Articular symptoms were reported by 12.17% of the patients, with the peripheral type being predominant. Significant associations between articular symptoms and nailfold swelling, subungual hyperkeratosis, nailfold scales, onycholysis and longitudinal ridges were found. Only 2.30% (20 out of 871) of patients with nail PsO received treatment. The most frequently employed therapy for cutaneous PsO with nail involvement was biologic therapy (n = 366). CONCLUSIONS: PsO showed distinct manifestations in the toenails and fingernails. Additionally, toenail PsO combined with onychomycosis requires special attention. Articular symptoms in psoriatic patients are associated with specific nail changes. It is important to research and advocate for more potent treatments for nail PsO.

Systematic evaluation of vertebral bone quality score as an opportunistic screening method for BMD in spine surgery patients.

PURPOSE: This study aimed to evaluate and compare the predictive value of vertebral bone quality (VBQ) score for low BMD and osteoporosis. Furthermore, we sought to enhance diagnostic effectiveness by integrating VBQ with easily accessible patient-specific factors. METHODS: We retrospectively analyzed data from 180 patients. VBQ was obtained by preoperative MRI. Low BMD was classified as meeting the standards for either osteopenia or osteoporosis. The receiver operating characteristic curve analysis and multivariate logistic regression were used to detect the ability of variables to assess BMD. The z-test was used to compare the area under the curves of different variables. RESULTS: VBQ was more effective in identifying low BMD than osteoporosis (AUC, 0.768 vs. 0.613, p = 0.02). Elevated VBQ (OR 6.912, 95% CI 2.72-17.6) and low BMI (0.858, 0.76-0.97) were risk factors for low BMD, while the risk factor for osteoporosis was age (1.067, 1.02-1.12), not VBQ. ROC analysis showed that AUCs were 0.613 for VBQ and 0.665 for age when screening for osteoporosis. The combined variable of VBQ, sex, age, and BMI obtained by logistic regression significantly improved the efficacy of BMD screening, with an AUC of 0.824 for low BMD and 0.733 for osteoporosis. CONCLUSION: VBQ is better at detecting low BMD than identifying osteoporosis. The ability of VBQ to predict osteoporosis is limited, and a similar diagnostic efficacy can be achieved with age. Incorporating VBQ alongside demographic data enhances the efficiency of BMD assessment. With the development of artificial intelligence in medicine, this simple method is promising.

Association of maternal and paternal adverse childhood experiences with emotional and behavioral problems among preschool children.

Although maternal adverse childhood experiences (ACEs) are known to be related to the emotional and behavioral problems (EBPs) of offspring, few studies have surveyed the intergenerational effects of paternal ACEs. In addition, no study has yet explored the combination and interaction effects of maternal and paternal ACEs on preschool children's EBPs in China, and the gender differences in these relationships also remain to be explored. A total of 3,575 preschool children from 12 preschools from Hefei city of Anhui province were included in this study. We used a binomial logistic regression to examine the relationship between maternal ACEs, paternal ACEs and children's EBPs. Logistic regression analysis indicated that maternal and paternal ACEs were significantly related to EBPs in children, respectively. The high maternal ACEs + high paternal ACEs group had the greatest association with children's EBPs. Interaction analysis results showed that, compared with the reference group (low maternal ACEs×low paternal ACEs), the other group (high maternal ACEs×high paternal ACEs ) were significantly related to children's EBPs (OR = 1.84, 95%CI: 1.55-2.19). We found that there were no gender differences in the combination and interaction effects (P>0.05). When fathers and mothers were jointly exposed to high levels of ACEs, children had a higher risk of developing EBPs than when they were exposed independently. Future studies should fully explore the intergenerational health effects of parental ACEs so that references for promoting the physical and mental health of preschool children can be developed.

MFCF-Gait: Small Silhouette-Sensitive Gait Recognition Algorithm Based on Multi-Scale Feature Cross-Fusion.

Gait recognition based on gait silhouette profiles is currently a major approach in the field of gait recognition. In previous studies, models typically used gait silhouette images sized at 64 × 64 pixels as input data. However, in practical applications, cases may arise where silhouette images are smaller than 64 × 64, leading to a loss in detail information and significantly affecting model accuracy. To address these challenges, we propose a gait recognition system named Multi-scale Feature Cross-Fusion Gait (MFCF-Gait). At the input stage of the model, we employ super-resolution algorithms to preprocess the data. During this process, we observed that different super-resolution algorithms applied to larger silhouette images also affect training outcomes. Improved super-resolution algorithms contribute to enhancing model performance. In terms of model architecture, we introduce a multi-scale feature cross-fusion network model. By integrating low-level feature information from higher-resolution images with high-level feature information from lower-resolution images, the model emphasizes smaller-scale details, thereby improving recognition accuracy for smaller silhouette images. The experimental results on the CASIA-B dataset demonstrate significant improvements. On 64 × 64 silhouette images, the accuracies for NM, BG, and CL states reached 96.49%, 91.42%, and 78.24%, respectively. On 32 × 32 silhouette images, the accuracies were 94.23%, 87.68%, and 71.57%, respectively, showing notable enhancements.

[Effects of childhood abuse experience, recent life events and coping styles on depressive symptoms of medical students].

OBJECTIVE: To analyze the influence of childhood abuse experience, recent life events and coping styles on depression symptoms of medical students based on the model of "vulnerability-stress-coping". METHODS: A longitudinal study design was adopted to select freshmen from Hefei City and Anqing City in Anhui province by cluster sampling. A total of 4211 questionnaires were collected at baseline from November to December 2019. Follow-up surveys were conducted in November to December 2020, and a total of 3662 medical students were finally included in this study. The childhood trauma questionnaire, adolescent self-rating life events checklist, coping style questionnaire and self-rating depression scale were used to evaluate childhood abuse experience, recent life events, coping styles and depression symptoms of medical students. The PROCESS software model 1(double interaction analysis) and model 3(triple interaction analysis) were used to investigate the independent and interactive effects of childhood abuse experience, recent life events, and different coping styles on depressive symptoms of medical students during follow-up. RESULTS: Among the 3662 medical students, 976 were male and 2686 were female, with an average age of(19.2±1.0) years. Spearman correlation analysis showed that childhood abuse experience, recent life events, self-blame, fantasy, problem avoidance, and rationalization coping style were positively related to depressive symptoms(P<0.05). The coping style of problem solving and seeking help was negatively related to depressive symptoms(P<0.05). In model 1, both childhood abuse experience(ß=0.097, 95%CI 0.065-0.129) and recent life events(ß=0.102, 95%CI 0.073-0.132) had a positive predictive effect on depressive symptoms, and they also had positive interaction on depressive symptoms(ß=0.030, 95%CI 0.025-0.004). In model 3, there was a negative interaction between childhood abuse, recent life events and seeking help(ß=-0.034, 95%CI-0.061--0.007) or fantasy(ß=-0.039, 95%CI-0.065--0.013) coping styles on depressive symptoms. CONCLUSION: Childhood abuse experience and recent life events are the predisposition factors for depressive symptoms of medical students, and they can mutually promote depression, while seeking help and fantasy coping styles could weaken the promoting effects of both.

[－75 G/A Polymorphism of Apolipoprotein A1 Gene Promoter Region in Normal Pregnant Women and Patients With Gestational Diabetes Mellitus]. / æ­£å¸¸å­•å¦‡åŠå¦Šå¨ ç³–å°¿ç— æ‚£è€ apoA1åŸºå› å¯åŠ¨å­åŒºï¼75 G/Aå¤šæ€æ€§çš„ç ”ç©¶.

Objective: To investigate the －75 G/A single-nucleotide polymorphism in the promoter region of apolipoprotein A1 gene (apoA1) and its association with gestational diabetes mellitus (GDM) in pregnant women and to provide references for the exploration in the molecular genetic basis of GDM. Methods: A total of 626 GDM patients and 1022 normal pregnant women, ie, the controls, were included in the study. The genotyping of apoA1 －75 G/A polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis. Total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose (Glu) were measured by enzymatic methods. Plasma insulin (INS) was measured by chemiluminescence immunoassay. The protein levels of apoA1 and apoB were measured by the turbidimetric immunoassay. Results: Allele frequencies of G and A were 0.718 and 0.282 in the GDM group and 0.713 and 0.287 in the control group, respectively. Distribution of the genotype frequencies was found to be in Hardy-Weinberg equilibrium in both the GDM and control groups. There was no significant difference in the frequencies of alleles G and A and the genotypes of apoA1 －75 G/A polymorphism between the GDM and the control group (P>0.05). In the GDM group, the carriers with the genotype AA were associated with significantly higher levels of TC, HDL-C, and apoA1 than those with genotypes GG and GA did (all P<0.05). After the GDM patients were divided into obese and non-obese subgroups, the genotype-related apoA1 variation was observed only in obese patients, while the genotype-related TC and HDL-C variations were evident in non-obese patients (P<0.05). In the control group, carriers of genotypes AA and GA had higher systolic blood pressure (SBP) and HDL-C than the carriers of genotype GG did (all P<0.05). Carriers of genotypes AA had significantly lower Glu levels than carriers of genotypes GG and GA did (P<0.05). The control subjects were further divided into subgroups according to their body mass index (BMI). Analysis of the subgroups showed that AA carriers were associated with higher SBP levels in the obese control women only, while lower Glu levels were evident in both obese and non-obese control women. Conclusion: These results suggest that －75 G/A polymorphism in the apoA1 gene is not associated with GDM. However, the genetic variation is closed associated with the plasma apoA1, HDL-C, and TC levels in GDM patients and plasma HDL-C, Glu, and SBP levels in the control subjects. The apoA1 variant-associated lipids and SBP variation is BMI dependent in both groups.

Degradable Block Copolymer Nanoparticles Synthesized by Polymerization-Induced Self-Assembly.

Polymerization-induced self-assembly (PISA) combines polymerization and in situ self-assembly of block copolymers in one system and has become a widely used method to prepare block copolymer nanoparticles at high concentrations. The persistence of polymers in the environment poses a huge threat to the ecosystem and represents a significant waste of resources. There is an urgent need to develop novel chemical approaches to synthesize degradable polymers. To meet with this demand, it is crucial to install degradability into PISA nanoparticles. Most recently, degradable PISA nanoparticles have been synthesized by introducing degradation mechanisms into either shell-forming or core-forming blocks. This Minireview summarizes the development in degradable block copolymer nanoparticles synthesized by PISA, including shell-degradable, core-degradable, and all-degradable nanoparticles. Future development will benefit from expansion of polymerization techniques with new degradation mechanisms and adaptation of high-throughput approaches for both PISA syntheses and degradation studies.

A conceptual framework for nomenclatural stability and validity of medically important fungi: a proposed global consensus guideline for fungal name changes supported by ABP, ASM, CLSI, ECMM, ESCMID-EFISG, EUCAST-AFST, FDLC, IDSA, ISHAM, MMSA, and MSGERC.

The rapid pace of name changes of medically important fungi is creating challenges for clinical laboratories and clinicians involved in patient care. We describe two sources of name change which have different drivers, at the species versus the genus level. Some suggestions are made here to reduce the number of name changes. We urge taxonomists to provide diagnostic markers of taxonomic novelties. Given the instability of phylogenetic trees due to variable taxon sampling, we advocate to maintain genera at the largest possible size. Reporting of identified species in complexes or series should where possible comprise both the name of the overarching species and that of the molecular sibling, often cryptic species. Because the use of different names for the same species will be unavoidable for many years to come, an open access online database of the names of all medically important fungi, with proper nomenclatural designation and synonymy, is essential. We further recommend that while taxonomic discovery continues, the adaptation of new name changes by clinical laboratories and clinicians be reviewed routinely by a standing committee for validation and stability over time, with reference to an open access database, wherein reasons for changes are listed in a transparent way.

Characterization of a Filamentous Phage, Vaf1, from Vibrio alginolyticus AP-1.

Filamentous phages are ubiquitously distributed in the global oceans. However, little is known about their biological contribution to their host's genetic and phenotypic diversity. In this study, a filamentous phage, Vaf1, was isolated and characterized from the emerging marine pathogen strain Vibrio alginolyticus AP-1. We explored the effects of the resident phage Vaf1 on the host physiology under diverse conditions by precisely deleting the entire phage Vaf1. Our results demonstrate that the presence of phage Vaf1 significantly increased biofilm formation, swarming motility, and contact-dependent competition. Furthermore, the gene expression profile suggests that several phage genes were upregulated in response to low-nutrient conditions. Unexpectedly, an in vivo study of zebrafish shows that fish infected with strain ΔVaf1 survived longer than those infected with wild-type strain AP-1, indicating that Vaf1 contributes to the virulence of V. alginolyticus. Together, our results provide direct evidence for the effect of Vaf1 phage-mediated phenotypic changes in marine bacteria V. alginolyticus. This further emphasizes the impressive complexity and diversity that filamentous phage-host interactions pose and the challenges associated with bacterial disease control in marine aquaculture. IMPORTANCE Non-lytic filamentous phages can replicate without killing their host, establishing long-term persistence within the bacterial host. In contrast to the well-studied CTXφ phage of the human-pathogenic Vibrio cholerae, little is known about the filamentous phage Vaf1 and its biological role in host fitness. In this study, we constructed a filamentous phage-deleted strain, ΔVaf1, and provided direct evidence on how an intact phage, φVaf1, belonging to the family Inoviridae, helps the bacterial host AP-1 to overcome adverse environmental conditions. Our results likely open new avenues for fundamental studies on how filamentous phage-host interactions regulate different aspects of Vibrio cell behaviors.

Whole genome analysis of echinocandin non-susceptible Candida Glabrata clinical isolates: a multi-center study in China.

BACKGROUND: Candida glabrata is an important cause of invasive candidiasis. Echinocandins are the first-line treatment of invasive candidiasis caused by C. glabrata. The epidemiological echinocandin sensitivity requires long-term surveillance and the understanding about whole genome characteristics of echinocandin non-susceptible isolates was limited. RESULTS: The present study investigated the echinocandin susceptibility of 1650 C. glabrata clinical isolates in China from August 2014 to July 2019. The in vitro activity of micafungin was significantly better than those of caspofungin and anidulafungin (P < 0.001), assessed by MIC50/90 values. Whole genome sequencing was conducted on non-susceptible isolates and geography-matched susceptible isolates. Thirteen isolates (0.79%) were resistant to at least one echinocandin. Six isolates (0.36%) were solely intermediate to caspofungin. Common evolutionary analysis of echinocandin-resistant and echinocandin-intermediate isolates revealed genes related with reduced caspofungin sensitivity, including previously identified sphinganine hydroxylase encoding gene SUR2. Genome-wide association study identified SNPs at subtelometric regions that were associated with echinocandin non-susceptibility. In-host evolution of echinocandin resistance of serial isolates revealed an enrichment for non-synonymous mutations in adhesins genes and loss of subtelometric regions containing adhesin genes. CONCLUSIONS: The echinocandins are highly active against C. glabrata in China with a resistant rate of 0.79%. Echinocandin non-susceptible isolates carried common evolved genes which are related with reduced caspofungin sensitivity. In-host evolution of C. glabrata accompanied intensive changing of adhesins profile.

Gender-based differences in interaction effects between childhood maltreatment and problematic mobile phone use on college students' depression and anxiety symptoms.

BACKGROUND: Childhood maltreatment and problematic mobile phone use are risk factors for depression and anxiety symptoms among college students. However, how the interaction between the two factors affects depression and anxiety has yet to be validated. This study aimed to investigate the independent and interaction effects of childhood maltreatment and problematic mobile phone use on depression and anxiety among college students and explored gender-based differences in these associations. METHOD: A cross-sectional study was conducted from October to December 2019. We collected data from 7623 students at two colleges in Hefei and Anqing cities in Anhui Province, China. Multinomial logistic regression models were performed to explore the associations of childhood maltreatment and problematic mobile phone use with depression and anxiety symptoms and their interaction effects on depression and anxiety symptoms. RESULTS: Childhood maltreatment and problematic mobile phone use were significantly associated with increased risk of depression and anxiety symptoms (P < 0.001). Moreover, following adjustments for covariates, there was a multiplicative interaction between childhood maltreatment and problematic mobile phone use on depression and anxiety symptoms (P < 0.001). Gender-based differences were also observed in the associations. For instance, depression was more common in males and male students with childhood maltreatment were at higher risk of depression-only symptoms. CONCLUSION: Focusing on childhood maltreatment and problematic mobile phone use could facilitate a reduction in the occurrence of depression and anxiety symptoms in college students. Furthermore, it is necessary to develop gender-targeted intervention strategies.

Role of polygenic risk scores in the association between chronotype and health risk behaviors.

BACKGROUND: This study explores the association between chronotypes and adolescent health risk behaviors (HRBs) by testing how genetic background moderates these associations and clarifies the influence of chronotypes and polygenic risk score (PRS) on adolescent HRBs. METHODS: Using VOS-viewer software to select the corresponding data, this study used knowledge domain mapping to identify and develop the research direction with respect to adolescent risk factor type. Next, DNA samples from 264 students were collected for low-depth whole-genome sequencing. The sequencing detected HRB risk loci, 49 single nucleotide polymorphisms based to significant SNP. Subsequently, PRSs were assessed and divided into low, moderate, and high genetic risk according to the tertiles and chronotypes and interaction models were constructed to evaluate the association of interaction effect and clustering of adolescent HRBs. The chronotypes and the association between CLOCK-PRS and HRBs were examined to explore the association between chronotypes and mental health and circadian CLOCK-PRS and HRBs. RESULTS: Four prominent areas were displayed by clustering information fields in network and density visualization modes in VOS-viewer. The total score of evening chronotypes correlated with high-level clustering of HRBs in adolescents, co-occurrence, and mental health, and the difference was statistically significant. After controlling covariates, the results remained consistent. Three-way interactions between chronotype, age, and mental health were observed, and the differences were statistically significant. CLOCK-PRS was constructed to identify genetic susceptibility to the clustering of HRBs. The interaction of evening chronotypes and high genetic risk CLOCK-PRS was positively correlated with high-level clustering of HRBs and HRB co-occurrence in adolescents, and the difference was statistically significant. The interaction between the sub-dimensions of evening chronotypes and the high genetic CLOCK-PRS risk correlated with the outcome of the clustering of HRBs and HRB co-occurrence. CONCLUSIONS: The interaction of PRS and chronotype and the HRBs in adolescents appear to have an association, and the three-way interaction between the CLOCK-PRS, chronotype, and mental health plays important roles for HRBs in adolescents.

Virtual screening for potential discoidin domain receptor 1 (DDR1) inhibitors based on structural assessment.

Discoidin domain receptor 1 (DDR1) (EC Number 2.7.10.1) has recently been considered as a promising therapeutic target for idiopathic pulmonary fibrosis (IPF). However, none of the currently discovered DDR1 inhibitors have been included in clinical studies due to low target specificity or druggability limitations, necessitating various approaches to develop novel DDR1 inhibitors. In this study, to assure target specificity, a docking assessment of the DDR1 crystal structures was undertaken to find the well-differentiated crystal structure, and 4CKR was identified among many crystal structures. Then, using the best pharmacophore model and molecular docking, virtual screening of the ChEMBL database was done, and five potential molecules were identified as promising inhibitors of DDR1. Subsequently, all hit compound complex systems were validated using molecular dynamics simulations and MM/PBSA methods to assess the stability of the system after ligand binding to DDR1. Based on molecular dynamics simulations and hydrogen-bonding occupancy analysis, the DDR1-Cpd2, DDR1-Cpd17, and DDR1-Cpd18 complex systems exhibited superior stability compared to the DDR1-Cpd1 and DDR-Cpd33 complex systems. Meanwhile, when targeting DDR1, the descending order of the five hit molecules' binding free energies was Cpd17 (- 145.820 kJ/mol) > Cpd2 (- 131.818 kJ/mol) > Cpd18 (- 130.692 kJ/mol) > Cpd33 (- 129.175 kJ/mol) > Cpd1 (- 126.103 kJ/mol). Among them, Cpd2, Cpd17, and Cpd18 showed improved binding characteristics, indicating that they may be potential DDR1 inhibitors. In this research, we developed a high-hit rate, effective screening method that serves as a theoretical guide for finding DDR1 inhibitors for the development of IPF therapeutics.

Genetically engineered CXCR4-modified exosomes for delivery of miR-126 mimics to macrophages alleviate periodontitis.

Biofilm-related diseases are a group of diseases that tolerate antimicrobial chemotherapies and therefore are refractory to treatment. Periodontitis, a non-device chronic biofilm disease induced by dental plaque, can serve as an excellent in vivo model to study the important effects of host factors on the biofilm microenvironment. Macrophage activity is one of the key factors that modulate the progression of inflammation-driven destruction in periodontitis; therefore it is an important host immunomodulatory factor. In this study, the reduction of microRNA-126 (miR-126) with the recruitment of macrophages in periodontitis was confirmed in clinical samples, and a strategy for targeted delivery of miR-126 to macrophages was explored. Exosomes overexpressing the C-X-C motif chemokine receptor 4 (CXCR4) loaded with miR-126 (CXCR4-miR126-Exo) was successfully constructed, which reduced off-target delivery to macrophages and regulated macrophages toward the anti-inflammatory phenotype. In vivo local injection of CXCR4-miR126-Exo into sites of periodontitis in rats effectively reduced bone resorption and osteoclastogenesis and inhibited the progression of periodontitis. These results provide new insights for designing novel immunomodulatory factor targeted delivery systems to treat periodontitis and other biofilm-related diseases.