M2 Macrophage Polarization and Tissue Remodeling in Autologous Fat Grafting for Diabetic Skin Defects.

Autologous adipose tissue was recognized as a promising therapeutic option for soft tissue defects owing to its regenerative potential and ability to facilitate tissue reconstruction. However, the mechanisms by which autologous fat grafting (AFG) promotes healing remain unclear, hindering its potential applications. This study aimed to investigate the distribution and phenotypic transition of infiltrating macrophages in transplanted adipose tissue, as well as their correlation with diabetic skin defect remodeling. Streptozotocin-induced diabetic rats with full-thickness dorsal skin defects were included in this study. The transplanted adipose tissue at the skin defects was collected and analyzed using flow cytometry to determine macrophage proportion and phenotype. The healing of skin defects was evaluated, and treatment was continued until day 14 as the designated endpoint of healing, followed by histopathologic examinations. Immunostaining with CD31 and lymphatic vessel endothelial receptor-1 was performed on wound tissues to analyze angiogenesis and lymphangiogenesis, respectively. Western blot and quantitative polymerase chain reaction analyses were used to assess the expression of the representative genes involved in the healing process. The results showed early polarization of M2 macrophages in the transplanted adipose tissue, concomitant with the upregulation of growth factors and downregulation of inflammatory factors. In vivo experiments revealed that AFG significantly promoted macrophage infiltration and M2 transformation in diabetic skin defects compared to the control groups, thereby promoting tissue extracellular matrix remodeling and lymphatic and vascular regeneration. However, the beneficial effects of AFG were inhibited by macrophage depletion. This study further demonstrated the potential of AFG for treating diabetic skin defects.

Construction of a Lentiviral Vector for Fgfr2 Overexpression and its Impact on the Biological Behavior of Cranial Suture Mesenchymal Stem Cells.

OBJECTIVE: Suture mesenchymal stem cells (SuSCs), possessing self-renewal and multilineage differentiation abilities, play a crucial role in cranial bone growth. However, the impact of the disease-causing fibroblast growth factor receptor 2 (FGFR2) mutation on SuSCs in Crouzon syndrome has not been explored. This study aims to employ a lentivirus to overexpress Fgfr2 and investigate its role in the pathogenesis of Crouzon syndrome. METHODS: Starting with the prevalent FGFR2 mutation site in patients with Crouzon syndrome, a lentiviral vector carrying the Fgfr2.C361Y mutation was developed and transfected into SuSCs, with a determined multiplicity of infection values. The experimental group, SuSCs+Fgfr2.C361Y, was compared with the empty vector and normal SuSC groups. Cell proliferation, cycle, apoptosis, and osteogenic functionality were assessed using CCK-8 assays, flow cytometry, ALP activity assays, and real-time quantitative polymerase chain reaction. RESULTS: The lentiviral vector effectively infected SuSCs, leading to heightened Fgfr2 expression, with optimal multiplicity of infection values of 80. The experimental group demonstrated decreased proliferation activity and a higher apoptosis rate compared with controls (P < 0.05). After osteogenic induction, the experimental group showed significantly higher ALP activity than controls (P < 0.05). Real-time quantitative polymerase chain reaction indicated lower mRNA expression levels of Gli1, Axin2, Pcna, Cdk2, and Bcl-2 in the experimental group than controls, whereas Bax, Runx2, and Bmp-2 showed higher expression (P < 0.05). CONCLUSION: This study constructed a lentivirus vector to upregulate Fgfr2 expression in SuSCs, suppressing stem cell stemness by inhibiting proliferation, promoting apoptosis, and accelerating premature osteogenic differentiation, resulting in premature suture closure. These findings establish the groundwork for further understanding the pathogenesis of Crouzon syndrome.

Network pharmacology and experimental evidence: ERK/CREB/BDNF signaling pathway is involved in the antidepressive roles of Kaiyu Zhishen decoction.

ETHNOPHARMACOLOGICAL RELEVANCE: Major Depressive Disorder (MDD) emerges as a complex psychosomatic condition, notable for its considerable suicidality and mortality rates. Increasing evidence suggests the efficacy of Chinese herbal medicine in mitigating depression symptoms and offsetting the adverse effects associated with conventional Western therapeutics. Notably, clinical trials have revealed the adjunctive antidepressant potential of Kaiyu Zhishen Decoction (KZD) alongside Western medication. However, the standalone antidepressant efficacy of KZD and its underlying mechanisms merit in-depth investigation. AIM OF THE STUDY: This research aims to elucidate the impact of KZD on MDD and delineate its mechanistic pathways through integrated network pharmacological assessments and empirical in vitro and in vivo analyses. MATERIALS AND METHODS: To ascertain the optimal antidepressant dosage and mechanism of KZD, a Chronic Unpredictable Mild Stress (CUMS)-induced depression model in mice was established to evaluate depressive behaviors. High-Performance Liquid Chromatography (HPLC) and network pharmacological approaches were employed to predict KZD's antidepressant mechanisms. Subsequently, hippocampal samples were subjected to 4D-DIA proteomic sequencing and validated through Western blot, immunofluorescence, Nissl staining, and pathway antagonist applications. Additionally, cortisol-stimulated PC12 cells were utilized to simulate neuronal damage, analyzing protein and mRNA levels of MAPK-related signals and cell proliferation markers. RESULTS: The integration of network pharmacology and HPLC identified kaempferol and quercetin as KZD's principal active compounds for MDD treatment. Proteomic and network pharmacological KEGG pathway analyses indicated the MAPK signaling pathway as a critical regulatory mechanism for KZD's therapeutic effect on MDD. KZD was observed to mitigate CUMS-induced upregulation of p-ERK/ERK, CREB, and BDNF protein expressions in hippocampal cells by attenuating oxidative stress, thereby ameliorating neuronal damage and exerting antidepressant effects. The administration of PD98059 counteracted KZD's improvements in depression-like behaviors and downregulated p-ERK/ERK and BDNF protein expressions in the hippocampus. CONCLUSIONS: This investigation corroborates KZD's pivotal, dose-dependent role in antidepressant activity. Both in vivo and in vitro experiments demonstrate KZD's capacity to modulate the ERK-CREB-BDNF signaling pathway by diminishing ROS expression induced by oxidative stress, enhancing neuronal repair, and thus, manifesting antidepressant properties. Accordingly, KZD represents a promising herbal candidate for further antidepressant research.

Salmonella manipulates macrophage migration via SteC-mediated myosin light chain activation to penetrate the gut-vascular barrier.

The intestinal pathogen Salmonella enterica rapidly enters the bloodstream after the invasion of intestinal epithelial cells, but how Salmonella breaks through the gut-vascular barrier is largely unknown. Here, we report that Salmonella enters the bloodstream through intestinal CX3CR1+ macrophages during early infection. Mechanistically, Salmonella induces the migration/invasion properties of macrophages in a manner dependent on host cell actin and on the pathogen effector SteC. SteC recruits host myosin light chain protein Myl12a and phosphorylates its Ser19 and Thr20 residues. Myl12a phosphorylation results in actin rearrangement, and enhanced migration and invasion of macrophages. SteC is able to utilize a wide range of NTPs other than ATP to phosphorylate Myl12a. We further solved the crystal structure of SteC, which suggests an atypical dimerization-mediated catalytic mechanism. Finally, in vivo data show that SteC-mediated cytoskeleton manipulation is crucial for Salmonella breaching the gut vascular barrier and spreading to target organs.

Double Chin Concerns after En Bloc Mandibular U-Shaped Osteotomy: Submental-Cervical Soft Tissue Changes and Anterior Belly of Digastric Muscle Assessment.

OBJECTIVE: To assess submental-cervical soft tissue changes after en bloc mandibular U-shaped osteotomy and examine alterations in the anterior belly of digastric muscle (ABDM). METHODS: A retrospective study analyzed 20 patients who underwent en bloc mandibular U-shaped osteotomy from 2018 to 2023. Preoperative (Tp) and long-term follow-up (Tf) CT data were collected for analysis, measuring mandibular volume, soft tissue thickness at menton (Mes) and cervicale (C), and ABDM parameters (length, cross-sectional area (CSA), volume, distance from centroid point to the mandibular margin). Correlation analyses were performed to investigate the connection between soft tissue thickness changes, ABDM changes, and mandibular osteotomy volume. RESULTS: Long-term follow-up revealed a significant increase in soft tissue thickness at the Mes and C points after U-shaped mandibular osteotomy, especially at the C point. The adaptive length of ABDM decreased, CSA increased, and volume decreased, but the ABDM centroid point shifted downward relative to the mandibular margin, indicating drooping protrusion. The increment of soft tissue thickness was moderately positively correlated with the amount of osteotomy, and the decrement of ABDM length and volume were slightly positively correlated with the amount of osteotomy. CONCLUSION: The degree of soft tissue relaxation after U-shaped osteotomy is related to the extent of osteotomy. Notably, the protrusion of ABDM relative to the mandibular margin affects submental-cervical contour aesthetics. Prior to U-shaped osteotomy, it is crucial to assess the soft tissue condition of the patient's lower face, and the individualized design of the osteotomy volume should be carried out cautiously and safely. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A c-di-GMP binding effector STM0435 modulates flagellar motility and pathogenicity in Salmonella.

Flagella play a crucial role in the invasion process of Salmonella and function as a significant antigen that triggers host pyroptosis. Regulation of flagellar biogenesis is essential for both pathogenicity and immune escape of Salmonella. We identified the conserved and unknown function protein STM0435 as a new flagellar regulator. The ∆stm0435 strain exhibited higher pathogenicity in both cellular and animal infection experiments than the wild-type Salmonella. Proteomic and transcriptomic analyses demonstrated dramatic increases in almost all flagellar genes in the ∆stm0435 strain compared to wild-type Salmonella. In a surface plasmon resonance assay, purified STM0435 protein-bound c-di-GMP had an affinity of ~8.383 µM. The crystal structures of apo-STM0435 and STM0435&c-di-GMP complex were determined. Structural analysis revealed that R33, R137, and D138 of STM0435 were essential for c-di-GMP binding. A Salmonella with STM1987 (GGDEF protein) or STM4264 (EAL protein) overexpression exhibits completely different motility behaviours, indicating that the binding of c-di-GMP to STM0435 promotes its inhibitory effect on Salmonella flagellar biogenesis.

Prediction of Early Antidepressant Efficacy in Patients with Major Depressive Disorder Based on Multidimensional Features of rs-fMRI and P11 Gene DNA Methylation: Prédiction de l'efficacité précoce d'un antidépresseur chez des patients souffrant du trouble dépressif majeur d'après les caractéristiques multidimensionnelles de la méthylation de l'ADN du gène P11 et de la IRMf-rs.

OBJECTIVE: This study established a machine learning model based on the multidimensional data of resting-state functional activity of the brain and P11 gene DNA methylation to predict the early efficacy of antidepressant treatment in patients with major depressive disorder (MDD). METHODS: A total of 98 Han Chinese MDD were analysed in this study. Patients were divided into 51 responders and 47 nonresponders according to whether the Hamilton Depression Rating Scale-17 items (HAMD-17) reduction rate was ≥50% after 2 weeks of antidepressant treatment. At baseline, the Illumina HiSeq Platform was used to detect the methylation of 74 CpG sites of the P11 gene in peripheral blood samples. Resting-state functional magnetic resonance imaging (rs-fMRI) scan detected the amplitude of low-frequency fluctuations (ALFF), regional homogeneity (ReHo), and functional connectivity (FC) in 116 brain regions. The least absolute shrinkage and selection operator analysis method was used to perform feature reduction and feature selection. Four typical machine learning methods were used to establish support vector machine (SVM), random forest (RF), Naïve Bayes (NB), and logistic regression (LR) prediction models based on different combinations of functional activity of the brain, P11 gene DNA methylation and clinical/demographic features after screening. RESULTS: The SVM model based on ALFF, ReHo, FC, P11 methylation, and clinical/demographic features showed the best performance, with 95.92% predictive accuracy and 0.9967 area under the receiver operating characteristic curve, which was better than RF, NB, and LR models. CONCLUSION: The multidimensional data features combining rs-fMRI, DNA methylation, and clinical/demographic features can predict the early antidepressant efficacy in MDD.

The Interaction of LAMA2 and Duration of Illness Affects the Thickness of the Right Transverse Temporal Gyrus in Major Depressive Disorder.

Background: Depression is a heritable brain disorder. Laminin genes were recently identified to affect the brain's overall thickness through neurogenesis, differentiation, and migration in depression. This study aims to explore the effects of the LAMA2's single nucleotide polymorphisms (SNP), a subunit gene of laminin, on the detected brain regions of patients with major depressive disorder (MDD). Methods: The study included 89 patients with MDD and 60 healthy controls with T1-weighted structural magnetic resonance imaging and blood samples for genotyping. The interactions between LAMA2 gene SNPs and diagnosis as well as duration of illness (DOI) were explored on brain measures controlled for age, gender, and site. Results: The right transverse temporal gyrus and right parahippocampal gyrus showed reduced thickness in MDD. Almost all seven LAMA2 SNPs showed significant interactions with diagnosis on both gyrus (corrected p < 0.05 or trending). In MDD, rs6569604, rs2229848, rs2229849, rs2229850, and rs2784895 interacted with DOI on the right transverse temporal gyrus (corrected p < 0.05), but not the right parahippocampal gyrus. Conclusion: The thickness of the right transverse temporal gyrus in patients with MDD may be affected by LAMA2 gene and DOI.

Abnormal spontaneous activity of regions related to mood regulation mediates the effect of childhood emotional neglect on major depressive disorder.

This study investigated the mediating factors between childhood emotional neglect (EN) and major depressive disorder (MDD) and whether combining multi-indicator could help diagnose MDD. Regional homogeneity (ReHo) and clinical features were compared between 33 MDD patients and 36 healthy controls (HC). Mediation analysis was employed to explore whether social support or ReHo mediates the association between EN and MDD. The linear discriminant analysis model was constructed with EN, social support, and ReHo, and applied to distinguish MDD from HC in both primary and replication cohorts. We found that MDD patients experienced severer EN and poorer social support, and exhibited lower ReHo in the left middle occipital gyrus and bilateral postcentral gyrus, and higher ReHo in the right cerebellum crus1. EN could affect MDD directly and indirectly through ReHo in these discrepant brain regions and social support. Combining ReHo values of these four distinct brain regions, EN, and objective support could classify MDD patients from HC, and the 10-fold cross-validation accuracy within-study replication and in the independent cohort was 83.78 % ± 1.49 % and 82.72 % ± 2.22 %, respectively. These findings suggested that childhood EN, social support, and emotional-related regions' ReHo were associated with risks of MDD, providing new insights into the pathological mechanisms underlying MDD.

The trends of psychosomatic symptoms and perceived stress among healthcare workers during the COVID-19 pandemic in China: Four cross-sectional nationwide surveys, 2020-2023.

An unseen wave of vast infection was detected in China in December 2022, and healthcare workers faced inevitable challenges and heavy stress. We aimed to present a dynamic mental health map and, most importantly, provide a timely report of the current situation in healthcare workers. The current study conducted four national cross-sectional online surveys from February and March 2020, Apr 2022, and Jan 2023. The Psychosomatic Symptom Scale (PSSS) and Perceived Stress Scale-10 (PSS-10) were used to assess psychosomatic symptoms and perceived stress. Fourteen thousand nine hundred forty-five participants (8578 healthcare workers and 6367 others) participated in the surveys. The prevalence of psychosomatic syndrome, reflected by PSSS, was 19.3% (Wave1), 22.9% (Wave2), 36.4% (Wave3), and 60.7% (Wave4) among healthcare workers, compared to 24.0% (Wave1), 35.7% (Wave2), 34.2% (Wave3) and 50.5% (Wave4) among the others. In addition, healthcare workers exhibited lower PSSS total scores at the beginning but higher in later waves. Despite their infection status, they now suffer from more severe psychosomatic symptoms than the rest of society. Our findings suggest that healthcare workers in China have now experienced severe psychosomatic symptoms and tremendous stress. Therefore, there is an urgent need to utilize social support for them.

Elevated Expression of ADAM10 Induced by HPV E6 Influences the Prognosis of Cervical Cancer.

Objective: To explore the abnormal expression of ADAM10, its cause, and its clinical value in the prognosis of cervical lesions. Methods: The abnormal expression of ADAM10 was explored using the Gene Expression Profiling Interactive Analysis database, and the abnormal expression in cervical lesions was verified using immunohistochemistry (IHC). The transfection effect of shRNA was evaluated using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The expression of ADAM10 in cells was analyzed using western blotting. Results: ADAM10 was highly expressed in multiple cancers. As the disease progressed, the expression of ADAM10 gradually increased (p < 0.05). Patients with higher expression of ADAM10 had poorer survival outcomes than those with lower expression levels (p < 0.05). The expression levels of ADAM10 decreased after expression levels of E6 was inhibited. Conclusion: ADAM10 is highly expressed in cervical cancer; the higher the expression levels, the worse the survival outcome. HPV E6 is the critical driver of the elevated expression of ADAM10 in cervical cancer.

The dynamic changes of psychosomatic symptoms in three waves of COVID-19 outbreak and fatigue caused by enduring pandemic in China.

BACKGROUND: Two years have passed since the 2019 novel coronavirus disease (COVID-19) was first reported. The persistent pandemic might lead to severe psychosomatic problems and fatigue. In addition, the recent rapid rising COVID-19 cases in China have become a trending issue. Therefore, this study aimed to investigate the dynamic changes in psychosomatic problems at the initial and current stages of the pandemic. METHODS: Three waves of cross-sectional online survey were conducted during the initial COVID outbreak in China. The psychosomatic symptom scale (PSSS), perceived stress scale (PSS), and pandemic fatigue scale (PFS) were used to assess the psychosomatic problems, stress, and fatigue. RESULTS: 4317, 1096, and 2172 participants completed the first, second, and third surveys. The prevalence of psychosomatic disorder was 22 %, 28 %, and 39 %, respectively. The network structure of PSSS symptoms has not significantly changed as the pandemic progresses. However, the global strength of the PSSS networks, indicating the overall connectivity, in the third wave was significantly higher than in the first wave (s = 0.54, P = 0.007). The most central symptoms in the first and third wave networks were depressed mood and tiredness. The PFS score was higher in the people concerned with indirect impact than those concerned with health (P < 0.001). PFS has positive relationships with PSSS and PSS score (R = 0.41, P < 0.001 and R = 0.35, P < 0.001, respectively). CONCLUSIONS: The persistence of the pandemic caused critical psychosomatic issues, stress, and indirect burden over time, leading to inevitable fatigue. People endured needing immediate attention to prevent or reduce psychosomatic disorders.

Astaxanthin Promotes the Survival of Adipose-Derived Stem Cells by Alleviating Oxidative Stress via Activating the Nrf2 Signaling Pathway.

The survival of free fat grafts is dependent primarily on adipose-derived stem cells (ADSCs); however, ADSCs are susceptible to oxidative stress in the recipient area. Astaxanthin (Axt) is a natural xanthophyll carotenoid with potent antioxidant properties and numerous clinical applications. To date, the therapeutic potential of Axt in fat grafting has not been explored. The purpose of this study is to investigate the effects of Axt on oxidatively stressed ADSCs. An oxidative model of ADSCs was developed to simulate the host's microenvironment. Oxidative insult decreased the protein levels of Cyclin D1, type I collagen alpha 1 (COL1A1), and type II collagen alpha 1 (COL2A1), while increasing the expression of cleaved Caspase 3 and secretion of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in ADSCs. Axt pre-treatment significantly reduced oxidative stress, increased the synthesis of an adipose extracellular matrix, alleviated inflammation, and restored the impaired adipogenic potential in the present model. Furthermore, Axt immensely activated the NF-E2-related factor 2 (Nrf2) pathway, and ML385, an inhibitor of Nrf2, could negate Axt's protective effects. Additionally, Axt alleviated apoptosis by inhibiting bcl-2-associated X protein (BAX)/Caspase 3 signaling and improving the mitochondrial membrane potential (MMP), which could also be abolished by ML385. Our results suggest that Axt may exert its cytoprotective effect on ADSCs through the Nrf2 signaling pathway and could be therapeutic in fat grafting.

Cooperative Regulation of Flagellar Synthesis by Two EAL-Like Proteins upon Salmonella Entry into Host Cells.

When Salmonella enters host cells, the synthesis of flagella is quickly turned off to escape the host immune system. In this study, we investigated the cooperative regulatory mechanism of flagellar synthesis by two EAL-like proteins, STM1344 and STM1697, in Salmonella. We found that Salmonella upregulated the expression of both STM1344 and STM1697 to various degrees upon invading host cells. Importantly, deletion of STM1697 or STM1344 led to failure of Salmonella flagellar control within host cells, suggesting that the two factors are not redundant but indispensable. STM1697 was shown to modulate Salmonella flagellar biogenesis by preventing the flagellar master protein FlhDC from recruiting RNA polymerase. However, STM1344 was identified as a bifunctional factor that inhibits RNA polymerase recruitment of FlhDC at low molar concentrations and the DNA binding activity of FlhDC at high molar concentrations. Structural analysis demonstrated that STM1344-FlhD binds more tightly than STM1697-FlhD, and size exclusion chromatography (SEC) experiments showed that STM1344 could replace STM1697 in a STM1697-FlhDC complex. Our data suggest that STM1697 might be a temporary flagellar control factor upon Salmonella entry into the host cell, while STM1344 plays a more critical role in persistent flagellar control when Salmonella organisms survive and colonize host cells for a long period of time. Our study provides a more comprehensive understanding of the complex flagellar regulatory mechanism of Salmonella based on regulation at the protein level of FlhDC. IMPORTANCE Salmonella infection kills more than 300,000 people every year. After infection, Salmonella mainly parasitizes host cells, as it prevents host cell pyroptosis by turning off the synthesis of flagellar antigen. Previous studies have determined that there are two EAL-like proteins, STM1344 and STM1697, encoded in the Salmonella genome, both of which inhibit flagellar synthesis by interacting with the flagellar master protein FlhDC. However, the expression order and simultaneous mechanism of STM1344 and STM1697 are not clear. In this study, we determined the expression profiles of the two proteins after Salmonella infection and demonstrated the cooperative mechanism of STM1344 and STM1697 interaction with FlhDC. We found that STM1344 might play a more lasting regulatory role than STM1697. Our results reveal a comprehensive flagellar control process after Salmonella entry into host cells.

Common susceptibility variants of KDR and IGF-1R are associated with poststroke depression in the Chinese population.

Background: Depression, one of the most frequent complications after stroke, increases the disease's burden and physical disability. Poststroke depression (PSD) is a multifactorial disease with genetic, environmental and biological factors involved in its occurrence. Genetic studies on PSD to date have mainly focused on the monoamine system and brain-derived neurotrophic factors. However, understanding is still limited about the influence of the single nucleotide polymorphism (SNP) of other neurotrophic factors on PSD. Aims: The present study aimed to investigate the relationship between seven vascular endothelial growth factor (VEGF) family gene variants that occur with PSD. Methods: A multicentre candidate gene study from five hospitals in Jiangsu Province from June 2013 to December 2014 involved 121 patients with PSD and 131 patients with non-PSD. Demographic characteristics and neuropsychological assessments were collected. The χ2 test was used to evaluate categorical variables, while the independent t-test was applied to continuous variables. SNPs in seven genes (VEGFA, VEGFB, KDR, FLT-1, IGF-1, IGF-1R and PlGF) were genotyped. Single-marker association for PSD was analysed by χ2 tests and logistic regression using SPSS and PLINK software. Results: Patients with PSD included more women and those with lower education levels, lower body mass indexes, lower Mini-Mental State Examination scores, and higher scores on the 17-item Hamilton Depression Rating Scale than non-PSD patients. Ninety-two SNPs with seven genes were genotyped and passed quality control. The rs7692791 CC genotypes, the C allele of KDR and the rs9282715 T allele of IGF-1R increased the risk for PSD (χ2=7.881, p=0.019; χ2=4.259, p=0.039; χ2=4.222, p=0.040, respectively). In addition, the SNP rs7692791 of KDR was significantly associated with PSD by the logistic regression of an additive model (p=0.015, OR=9.584, 95% CI: 1.549 to 59.31). Conclusions: Patients with rs7692791 C allele carriers or the CC genotype of KDR and the rs9282715 T allele of IGF-1R may have PSD susceptibility. Findings such as these may help clinicians to identify the high-risk population for PSD earlier and, thus, enable them to provide more timely interventions. Trial registration number: ChiCTR-OCH-13003133.

Integrating functional neuroimaging and serum proteins improves the diagnosis of major depressive disorder.

BACKGROUND: The lack of effective objective diagnostic biomarkers for major depressive disorder (MDD) leads to high misdiagnosis. Compared with healthy controls (HC), abnormal brain functions and protein levels are often observed in MDD. However, it is unclear whether combining these changed multidimensional indicators could help improve the diagnosis of MDD. METHODS: Sixty-three MDD and eighty-one HC subjects underwent resting-state fMRI scans, among whom 37 MDD and 45 HC provided blood samples. Amplitudes of low-frequency fluctuation (ALFF), regional homogeneity (ReHo), and serum levels of brain-derived neurotrophic factor (BDNF), cortisol, and multiple cytokines were measured and put into the linear discriminant analysis (LDA) to construct corresponding MDD diagnostic models. The area under the receiver operating characteristic curve (AUC) of 5-fold cross-validation was calculated to evaluate each model's performance. RESULTS: Compared with HC, MDD patients' spontaneous brain activity, serum BDNF, cortisol, interleukin (IL)-4, IL-6, and IL-10 levels changed significantly. The combinations of unidimensional multi-indicator had better diagnostic performance than a single one. The model consisted of multidimensional multi-indicator further exhibited conspicuously superior diagnostic efficiency than those constructed with unidimensional multi-indicator, and its AUC, sensitivity, specificity, and accuracy of 5-fold cross-validation were 0.99, 92.0 %, 100.0 %, and 96.3 %, respectively. LIMITATIONS: This cross-sectional study consists of relatively small samples and should be replicated in larger samples with follow-up data to optimize the diagnostic model. CONCLUSIONS: MDD patients' neuroimaging features and serum protein levels significantly changed. The model revealed by LDA could diagnose MDD with high accuracy, which may serve as an ideal diagnostic biomarker for MDD.

iPSC-based model of Vogt-Koyanagi-Harada disease for phenotype recapitulation and drug screening.

Vogt-Koyanagi-Harada (VKH) disease, a major blinding eye disease, is characterized by an autoimmune response against melanocytes in multiple organs throughout the body. Currently, the aetiology and pathogenesis of VKH disease are unclear, and the treatment strategy needs to be further optimized. The retinal pigment epithelium (RPE), a monolayer of pigmented cells of the fundus, is essential for maintaining normal visual function and is involved in both the acute and chronic stages of VKH disease. Therefore, the functions of the RPE may play a critical role in the aetiology and treatment of VKH disease. Herein, we established a human induced pluripotent stem cell (hiPSC) RPE model of VKH disease by reprogramming peripheral blood mononuclear cells (PBMCs) into iPSCs and then differentiating them into RPE cells. Patient-derived RPE cells exhibited barrier disruption, impaired phagocytosis, and depigmentation compared with those from normal controls, which was consistent with the features of VKH disease. Furthermore, a small molecular compound targeting EGR2 was found to rescue the barrier and phagocytic functions of the hiPSC-RPE cells through high-throughput virtual screening and functional studies, suggesting a promising strategy for the treatment of VKH disease.

Predicting the diagnosis of various mental disorders in a mixed cohort using blood-based multi-protein model: a machine learning approach.

The lack of objective diagnostic methods for mental disorders challenges the reliability of diagnosis. The study aimed to develop an easily accessible and useable objective method for diagnosing major depressive disorder (MDD), schizophrenia (SZ), bipolar disorder (BPD), and panic disorder (PD) using serum multi-protein. Serum levels of brain-derived neurotrophic factor (BDNF), VGF (non-acronymic), bicaudal C homolog 1 (BICC1), C-reactive protein (CRP), and cortisol, which are generally recognized to be involved in different pathogenesis of various mental disorders, were measured in patients with MDD (n = 50), SZ (n = 50), BPD (n = 55), and PD along with 50 healthy controls (HC). Linear discriminant analysis (LDA) was employed to construct a multi-classification model to classify these mental disorders. Both leave-one-out cross-validation (LOOCV) and fivefold cross-validation were applied to validate the accuracy and stability of the LDA model. All five serum proteins were included in the LDA model, and it was found to display a high overall accuracy of 96.9% when classifying MDD, SZ, BPD, PD, and HC groups. Multi-classification accuracy of the LDA model for LOOCV and fivefold cross-validation (within-study replication) reached 96.9 and 96.5%, respectively, demonstrating the feasibility of the blood-based multi-protein LDA model for classifying common mental disorders in a mixed cohort. The results suggest that combining multiple proteins associated with different pathogeneses of mental disorders using LDA may be a novel and relatively objective method for classifying mental disorders. Clinicians should consider combining multiple serum proteins to diagnose mental disorders objectively.

Antibiofilm peptides enhance the corrosion resistance of titanium in the presence of Streptococcus mutans.

Titanium alloys have gained popularity in implant dentistry for the restoration of missing teeth and related hard tissues because of their biocompatibility and enhanced strength. However, titanium corrosion and infection caused by microbial biofilms remains a significant clinical challenge leading to implant failure. This study aimed to evaluate the effectiveness of antibiofilm peptides 1018 and DJK-5 on the corrosion resistance of titanium in the presence of Streptococcus mutans. Commercially pure titanium disks were prepared and used to form biofilms. The disks were randomly assigned to different treatment groups (exposed to S. mutans supplied with sucrose) including a positive control with untreated biofilms, peptides 1018 or DJK-5 at concentrations of 5 µg/mL or 10 µg/mL, and a negative control with no S. mutans. Dynamic biofilm growth and pH variation of all disks were measured after one or two treatment periods of 48 h. After incubation, the dead bacterial proportion, surface morphology, and electrochemical behaviors of the disks were determined. The results showed that peptides 1018 and DJK-5 exhibited significantly higher dead bacterial proportions than the positive control group in a concentration dependent manner (p < 0.01), as well as far less defects in microstructure. DJK-5 at 10 µg/mL killed 84.82% of biofilms and inhibited biofilm growth, preventing acidification due to S. mutans and maintaining a neutral pH. Potential polarization and electrochemical impedance spectroscopy data revealed that both peptides significantly reduced the corrosion and passive currents on titanium compared to titanium surfaces with untreated biofilms, and increased the resistance of the passive film (p < 0.05), with 10 µg/mL of DJK-5 achieving the greatest effect. These findings demonstrated that antibiofilm peptides are effective in promoting corrosion resistance of titanium against S. mutans, suggesting a promising strategy to enhance the stability of dental implants by endowing them with antibiofilm and anticorrosion properties.