OSBPL2 compound heterozygous variants cause dyschromatosis, ichthyosis, deafness and atopic disease syndrome.

PURPOSE: In this study, we identified and diagnosed a novel inherited condition called Dyschromatosis, Ichthyosis, Deafness, and Atopic Disease (DIDA) syndrome. We present a series of studies to clarify the pathogenic variants and specific mechanism. METHODS: Exome sequencing and Sanger sequencing was conducted in affected and unaffected family members. A variety of human and cell studies were performed to explore the pathogenic process of keratosis. RESULTS: Our finding indicated that DIDA syndrome was caused by compound heterozygous variants in the oxysterol-binding protein-related protein 2 (OSBPL2) gene. Furthermore, our findings revealed a direct interaction between OSBPL2 and Phosphoinositide phospholipase C-beta-3 (PLCB3), a key player in hyperkeratosis. OSBPL2 effectively inhibits the ubiquitylation of PLCB3, thereby stabilizing PLCB3. Conversely, OSBPL2 variants lead to enhanced ubiquitination and subsequent degradation of PLCB3, leading to epidermal hyperkeratosis, characterized by aberrant proliferation and delayed terminal differentiation of keratinocytes. CONCLUSIONS: Our study not only unveiled the association between OSBPL2 variants and the newly identified DIDA syndrome but also shed light on the underlying mechanism.

Clinical Research Progress of the Post-Stroke Upper Limb Motor Function Improvement via Transcutaneous Auricular Vagus Nerve Stimulation.

Stroke is a disease with high morbidity and disability, and motor impairment is a common sequela of stroke. Transcutaneous auricular vagus nerve stimulation (taVNS) is a type of non-invasive stimulation, which can effectively improve post-stroke motor dysfunction. This review discusses stimulation parameters, intervention timing, and the development of innovative devices for taVNS. We further summarize the application of taVNS in improving post-stroke upper limb motor function to further promote the clinical research and application of taVNS in the rehabilitation of post-stroke upper limb motor dysfunction.

Construction of a novel ESIPT and AIE-based fluorescent sensor for sequentially detecting Cu2+ and H2S in both living cells and zebrafish.

The development of effective methods for tracking Cu2+ and H2S in living organisms is urgently required due to their vital function in a variety of pathophysiological processes. In this work, a new fluorescent sensor BDF with excited-state intramolecular proton transfer (ESIPT) and aggregation-induced emission (AIE) features for the successive detection of Cu2+ and H2S was constructed by introducing 3,5-bis(trifluoromethyl)phenylacetonitrile into the benzothiazole skeleton. BDF showed a fast, selective and sensitive fluorescence "turn off" response to Cu2+ in physiological media, and the situ-formed complex can serve as a fluorescence "turn on" sensor for highly selective detection of H2S through the Cu2+ displacement approach. In addition, the detection limits of BDF for Cu2+ and H2S were determined to be 0.05 and 1.95 µM, respectively. Encouraged by its favourable features, including strong red fluorescence from the AIE effect, large Stokes shift (285 nm), high anti-interference ability and good function at physiological pH as well as a low toxicity, BDF was successfully applied for the consequent imaging of Cu2+ and H2S in both living cells and zebrafish, making it an ideal candidate for detecting and imaging of Cu2+ and H2S in live systems.

Bioinformatics-integrated screening of systemic sclerosis-specific expressed markers to identify therapeutic targets.

Background: Systemic sclerosis (SSc) is a rare autoimmune disease characterized by extensive skin fibrosis. There are no effective treatments due to the severity, multiorgan presentation, and variable outcomes of the disease. Here, integrated bioinformatics was employed to discover tissue-specific expressed hub genes associated with SSc, determine potential competing endogenous RNAs (ceRNA) regulatory networks, and identify potential targeted drugs. Methods: In this study, four datasets of SSc were acquired. To identify the genes specific to tissues or organs, the BioGPS web database was used. For differentially expressed genes (DEGs), functional and enrichment analyses were carried out, and hub genes were screened and shown in a network of protein-protein interactions (PPI). The potential lncRNA-miRNA-mRNA ceRNA network was constructed using the online databases. The specifically expressed hub genes and ceRNA network were validated in the SSc mouse and in normal mice. We also used the receiver operating characteristic (ROC) curve to determine the diagnostic values of effective biomarkers in SSc. Finally, the Drug-Gene Interaction Database (DGIdb) identified specific medicines linked to hub genes. Results: The pooled datasets identified a total of 254 DEGs. The tissue/organ-specifically expressed genes involved in this analysis are commonly found in the hematologic/immune system and bone/muscle tissue. The enrichment analysis of DEGs revealed the significant terms such as regulation of actin cytoskeleton, immune-related processes, the VEGF signaling pathway, and metabolism. Cytoscape identified six gene cluster modules and 23 hub genes. And 4 hub genes were identified, including Serpine1, CCL2, IL6, and ISG15. Consistently, the expression of Serpine1, CCL2, IL6, and ISG15 was significantly higher in the SSc mouse model than in normal mice. Eventually, we found that MALAT1-miR-206-CCL2, let-7a-5p-IL6, and miR-196a-5p-SERPINE1 may be promising RNA regulatory pathways in SSc. Besides, ten potential therapeutic drugs associated with the hub gene were identified. Conclusions: This study revealed tissue-specific expressed genes, SERPINE1, CCL2, IL6, and ISG15, as effective biomarkers and provided new insight into the mechanisms of SSc. Potential RNA regulatory pathways, including MALAT1-miR-206-CCL2, let-7a-5p-IL6, and miR-196a-5p-SERPINE1, contribute to our knowledge of SSc. Furthermore, the analysis of drug-hub gene interactions predicted TIPLASININ, CARLUMAB and BINDARIT as candidate drugs for SSc.

Clinical efficacy and safety of targeted injection of PRP with skin booster in the treatment of aging face.

Platelet-rich plasma (PRP) with skin booster is a popular treatment for improving skin quality and reducing the signs of aging. However, few studies have evaluated its clinical efficacy in patients with aging face. This study aimed to evaluate the clinical efficacy, adverse reactions, and follow-up results of targeted injection of PRP with skin booster in treating patients with aging face. The study included 80 patients treated with targeted injection of PRP with skin booster from July 2022 to February 2023. The doctors compared the changes of the patients' facial skin indicators, quality of life, and satisfaction with their appearance before and after treatment, and analyzed the clinical efficacy, adverse reactions, and follow-up results of the patients after treatment. After one course of treatment, the patients' facial skin indicators, quality of life, and satisfaction with their appearance improved significantly, with P < 0.05. The total clinical effective rate was 88.75%, and the incidence of adverse reactions was 6.25%. After half a year of follow-up, 48.75% of the patients were willing to receive further treatment, and their facial soft feel, natural expression, and self-feeling comfort had significantly improved. Targeted injection of PRP with skin booster is an effective and safe treatment for improving facial skin symptoms such as coarse pores and wrinkles in patients with aging face. The results of this study provide evidence for the clinical use of PRP with skin booster in aesthetic medicine.

Evaluation of Psychiatric Comorbidities and Quality of Life As Well As Brain-Derived Neurotrophic Factor (BDNF) Concentrations Among Patients Suffering From Acne Vulgaris: A Systematic Review and Meta-Analysis.

Acne vulgaris usually affects the dermal layer of the skin and is revealed frequently in young adulthood and adolescence. It has serious psychosocial comorbidities. We conducted the present systematic review and meta-analysis to elucidate the association of acne vulgaris with psychiatric comorbidities and quality of life as well as the brain-derived neurotrophic factor (BDNF) level. A systematic review and meta-analysis of the published articles were carried out following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We investigated diverse databases: Web of Science, PubMed, the Cochrane Library, Embase, PsycINFO, and CINAHL to search for articles reporting the prevalence of psychosocial comorbidities among patients with acne vulgaris from database inception through June 2022. The outcomes were depression, anxiety, symptom checklist-90-R (SCL-90-R), quality of life, self-esteem, stress, loneliness, and BDNF concentrations. Of 3647 articles identified, 23 met the inclusion criteria. Patients with acne vulgaris have a significantly higher level of anxiety, depression, and stress (P<0.05). Yet, the reported findings of the SCL-90-R, self-esteem, loneliness, and BDNF scores among patients suffering from acne vulgaris were variable and did not differ significantly compared to healthy participants (P>0.05), hampering any conclusive findings on absolute prevalence. Subgroup analysis and comparison showed that heterogeneity between studies was likely due to factors, including country, study design, and assessment tools. This comprehensive review and meta-analysis revealed that anxiety, depression, and stress are significantly more frequent among patients suffering from acne vulgaris. These findings confirm that acne vulgaris has both psychiatric and medical characteristics and requires a multidisciplinary approach.

Neural signatures for the n-back task with different loads: An event-related potential study.

The n-back task is widely used in working memory (WM) research. However, it remains unclear how the electrophysiological correlates of WM processes, the P2, N2, P300, and negative slow wave (NSW), are affected by differences in load. Specifically, while previous work has examined the P300, less attention has been paid to the other components assessing the load of the n-back paradigm. The present study aims to investigate whether other sub-processes in WM (such as inhibitory control) are as sensitive to n-back load changes as the update process by observing changes in the above event-related potential (ERP) components. The results showed poorer behavioral performance with increasing WM load. Greater NSW and smaller P300 amplitudes were elicited by n-back task with a higher load compared to that with lower load. In contrast, there was no significant effect of the n-back load on the amplitudes of P2 and N2. These findings suggest that the updating process and the maintenance process are sensitive to the n-back load change. Therefore, changes in the updating and maintenance processes should be considered when using the n-back task to manipulate the WM load in experiments. The present study may contribute to the understanding of the complexity of WM loads. Additionally, a theoretical basis for follow-up research to explore ways of improving WM performance with high load is provided.

Dietary supplementation of n-3 PUFAs ameliorates LL37-induced rosacea-like skin inflammation via inhibition of TLR2/MyD88/NF-κB pathway.

Rosacea is a facial chronic inflammatory skin disease with dysfunction of immune and neurovascular system and treatments for rosacea are challenging. N-3 polyunsaturated fatty acids (PUFAs), one of essential fatty acids, are needed for health maintenance and exert anti-inflammation and immunomodulatory effects in a series of cutaneous diseases such as atopic dermatitis and photoaging through dietary supplementation. However, the role of n-3 PUFAs on rosacea remains to be elucidated. In this study, KEGG enrichment analysis and GO analysis indicated that the biological process and signaling pathways, including chemokine signaling pathway, regulated by n-3 PUFAs highly overlapped with those in the pathogenic biological process of rosacea, especially the erythema telangiectasia type. Next, mice were randomized to fed with a customized n-3 PUFAs diet. We showed that n-3 PUFAs ameliorated skin erythema, inhibited dermal inflammatory cell infiltration (mast cells, neutrophils, and CD4 +T cells) and suppressed elevated pro-inflammatory cytokines in LL37-induced rosacea-like mice. Besides, n-3 PUFAs were also verified to repress angiogenesis in LL37-induced mice skin. Further investigation revealed that n-3 PUFAs attenuated LL37-induced inflammation via TLR2/ MyD88/ NF-κB pathway both in mice and in keratinocytes. In conclusion, our findings underscore that dietary supplementation of n-3 PUFAs have the potential to become an efficient and safe clinical therapeutic candidate for rosacea.

Evolution of Microstructures and Mechanical Properties of Nb-V Alloyed Ultra-High Strength Hot Stamping Steel in Austenitizing Process.

Clarifying the influence of Nb and V microalloying on the ultra-high strength hot stamping steel (UHSHSS) and exploring appropriate process parameters are the basis for effectively regulating properties of the final product. In this study, the effects of different austenitizing temperatures and holding times on the phase transitions, grain sizes and mechanical properties of 22MnB5NbV with Nb and V alloyed are studied by using JMatPro thermodynamic calculations and experiments. By comparing with 22MnB5 without Nb and V alloyed, the effects of Nb and V elements on quenching microstructures, grain sizes and mechanical properties of UHSHSS are analyzed. The suitable austenitizing process parameters of 22MnB5NbV have been obtained. The results show that the grain size of Nb-V-alloyed UHSHSS grows with the increase in the austenitizing temperature and holding time. The 22MnB5NbV steel can be completely austenitized while the austenitizing temperatures ≥870 °C and holding time ≥3 min. Combined with the actual production process, the best austenitizing temperature and holding time are 930 °C and 3 min. Under these conditions, the average grain size is 7.7 µm, the tensile strength, elongation and strength-ductility product are 1570.8 MPa, 6.6% and 10.4 GPa·%, respectively. With the addition of Nb and V elements, the nanoscale precipitates lead to the refinement of the quenched structure and grain size, and the comprehensive properties of UHSHSS have been effectively promoted, in which the elongation and strong-plastic products are increased by ~0.6% and ~1.2 GPa·%, respectively.

Comparison of Sensory Observation and Somatosensory Stimulation in Mirror Neurons and the Sensorimotor Network: A Task-Based fMRI Study.

Objective: This study aimed to investigate brain plasticity by somatosensory stimulation (SS) and sensory observation (SO) based on mirror neuron and embodied cognition theory. Action observation therapy has been widely adopted for motor function improvement in post-stroke patients. However, it is uncertain whether the SO approach can also contribute to the recovery of sensorimotor function after stroke. In this study, we explored the therapeutic potential of SO for sensorimotor dysfunction and provided new evidence for neurorehabilitation. Methods: Twenty-six healthy right-handed adults (12 men and 14 women), aged 18-27 (mean, 22.12; SD, 2.12) years were included. All subjects were evaluated with task-based functional magnetic resonance imaging (fMRI) to discover the characteristics and differences in brain activation between SO and SS. We adopted a block design with two conditions during fMRI scanning: observing a sensory video of brushing (task condition A, defined as SO) and brushing subjects' right forearms while they watched a nonsense string (task condition B, defined as SS). One-sample t-tests were performed to identify brain regions and voxels activated for each task condition. A paired-sample t-test and conjunction analysis were performed to explore the differences and similarities between SO and SS. Results: The task-based fMRI showed that the bilateral postcentral gyrus, left precentral gyrus, bilateral middle temporal gyrus, right supramarginal gyrus, and left supplementary motor area were significantly activated during SO or SS. In addition to these brain regions, SO could also activate areas containing mirror neurons, like the left inferior parietal gyrus. Conclusion: SO could activate mirror neurons and sensorimotor network-related brain regions in healthy subjects like SS. Therefore, SO may be a promising novel therapeutic approach for sensorimotor dysfunction recovery in post-stroke patients.

Innate immune responses against the fungal pathogen Candida auris.

Candida auris is a multidrug-resistant human fungal pathogen responsible for nosocomial outbreaks worldwide. Although considerable progress has increased our understanding of the biological and clinical aspects of C. auris, its interaction with the host immune system is only now beginning to be investigated in-depth. Here, we compare the innate immune responses induced by C. auris BJCA001 and Candida albicans SC5314 in vitro and in vivo. Our results indicate that C. auris BJCA001 appears to be less immunoinflammatory than C. albicans SC5314, and this differential response correlates with structural features of the cell wall.

[Effect of transcutaneous auricular vagus nerve stimulation on the expressions of GFAP and MAP2 in ischemic penumbra of rats with middle cerebral artery ischemia].

OBJECTIVE: To observe the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the motor function and the expression of glial fibrillary acidic protein (GFAP) and microtubule associated protein 2 (MAP2) in cerebral ischemic penumbra of rats with middle cerebral artery occlusion (MCAO) and explore the mechanism of taVNS in the improvement of motor function in MCAO rats. METHODS: A total of 48 male SD rats were randomized into a sham-operation group, a model group, a transcutaneous auricular non-vagus nerve stimulation (tnVNS) group and a taVNS group, with 12 rats in each group. The suture-occluded method was adopted to prepare MCAO rat model. The auricular rim was stimulated in the tnVNS group and the concha stimulated in the taVNS group, 2 mA in intensity, 10 Hz in frequency, 30 min each time, once a day, for 14 days consecutively. The nerve functional assessment was recorded in each group. The expressions of nicotinic acetylcholine receptor (α7nAchR) in the cerebral ischemic penumbra and the spleen were detected by using Western blot. With the immunofluorescence, the expressions of GFAP and MAP2 were detected. RESULTS: After modeling, compared with the sham-operation group, the nerve functional score was increased in the model group, the tnVNS group and the taVNS group (P<0.01), suggesting the success of modeling. After treatment, the score was increased in the model group (P<0.01) as compared with the sham-operation group. Compared with the model group, the neurological deficit score was reduced in the taVNS group (P<0.01). Compared with the sham-operation group, GFAP expression was increased and MAP2 expression was reduced remarkably in the cerebral ischemic penumbra in the model group (P<0.05). In comparison with the model group, GFAP expression was reduced, while MAP2 expression was increased remarkably in the cerebral ischemic penumbra in the taVNS group (P<0.05). There were no significant differences in the abovementioned indexes between the model group and tnVNS group (P>0.05). The differences in the expression of α7nAchR in the cerebral ischemic penumbra and the spleen had no statistical significance among groups (P>0.05). CONCLUSION: TaVNS is effective on neuroprotection in MCAO rats, which may be related to its function of inhibition of GFAP expression and promotion of MAP2 expression in the ischemic penumbra.

High expression of lncRNA HSD11B1-AS1 indicates favorable prognosis and is associated with immune infiltration in cutaneous melanoma.

Cutaneous melanoma is an aggressive malignant cancer associated with poor prognosis. Identification of reliable biomarkers for predicting prognosis of melanoma contributes to improved clinical outcome and disease management. Long non-coding RNAs (lncRNAs) serve a crucial regulatory role of oncogenesis and tumor suppression in melanoma. Using data from The Cancer Genome Atlas database, novel lncRNA 11ß-hydroxysteroid dehydrogenase type 1-antisense RNA 1 (HSD11B1-AS1) was identified, which was significantly downregulated in malignant melanoma and its downregulation was significantly associated with poor clinicopathological characteristics, including advanced T and pathological stage, Clark level, Breslow depth and ulceration and worse prognosis. Multivariate analysis showed that HSD11B1-AS1, as well as N stage and Breslow depth, were independent prognostic factors in cutaneous melanoma, and nomograms suggested a good predictive value of 1-, 3- and 5-year overall survival, progression-free interval and disease-specific survival. In vitro experiments verified the decreased HSD11B1-AS1 expression in melanoma cell lines compared with human epidermal melanocytes. Moreover, cell experiments in vitro, including Cell Counting Kit-8, colony formation, wound healing and Transwell assay, suggested that overexpression of HSD11B1-AS1 significantly inhibited melanoma cell proliferation, migration and invasion. Functional enrichment showed significantly enriched pathways in IFN-γ and -α response, TNF-α signaling via NF-κB and IL-2/STAT-5 and IL-6/JAK/STAT-3 signaling. In addition, immune infiltration analysis demonstrated that HSD11B1-AS1 may function by accelerating immune response regulation and the immune cell infiltration of various immunocytes, especially T, T helper 1, activated dendritic and B cells. The present study revealed HSD11B1-AS1 as a potential therapeutic target and promising biomarker for diagnosis and prognosis of cutaneous melanoma.

The mechanisms through which auricular vagus nerve stimulation protects against cerebral ischemia/reperfusion injury.

Previous studies have shown that vagus nerve stimulation can improve patients' locomotor function. The stimulation of the auricular vagus nerve, which is the only superficial branch of the vagus nerve, may have similar effects to vagus nerve stimulation. However, the precise mechanisms remain poorly understood. In this study, rat models of cerebral ischemia/reperfusion injury were established by modified Longa ligation. Twenty-four hours later, 7-day auricular vagus nerve stimulation was performed. The results showed that auricular vagus nerve stimulation promoted the secretion of acetylcholine, inhibited the secretion of interleukin-1ß, interleukin-6, and tumor necrosis factor-α, and reduced connexin 43 phosphorylation in the ischemic penumbra and motor cortex, promoting locomotor function recovery in rats with cerebral ischemia/reperfusion injury. These findings suggested that auricular vagus nerve stimulation promotes the recovery of locomotor function in rats with cerebral ischemia/reperfusion injury by altering the secretion of acetylcholine and inflammatory factors and the phosphorylation of connexin 43. This study was approved by the Animal Use and Management Committee of Shanghai University of Traditional Chinese Medicine on November 8, 2019 (approval No. PZSHUTCM191108014).

The Epidemiological Analysis of HIV/AIDS Patients: Sexually Transmitted Diseases Department vs. other Departments in A General Hospital of Shanghai, China.

BACKGROUND: Hospital is an important place for HIV/AIDS screening, and a general hospital is composed of multiple departments. Different departments have different levels of understanding of HIV/AIDS, especially the sexually transmitted diseases (STD) department is the main place for HIV/AIDS screening. OBJECTIVE: The study aims to validate the common knowledge that the STD department is an important place for HIV/AIDS screening by comparing the epidemiological characteristics of HIV/AIDS patients in the STD department and other departments in Tongji Hospital, which can provide a theoretical basis for the precise and differentiated control of HIV/AIDS. METHODS: A total of 283,525 HIV screening cases were analyzed from January 1st 2006 to December 31st 2018 in the STD department and other departments. The epidemiological data of 226 HIV/AIDS cases were retrospectively analyzed. RESULTS: Firstly, the incidence of HIV/AIDS in the population served by Tongji Hospital was higher than that in Shanghai and China. Secondly, the positive rate of HIV screening test in the STD department was ten times higher than that of other departments. Thirdly, the social-demographic characteristics of HIV/AIDS patients in the STD department were different from those in other departments. Fourthly, there were differences in age, education, marital status and number of sex partners between men who have sex with men (MSM) and men who have sex with women (MSW). Fifthly, there was no difference except age in social-demographic characteristics of MSM between the STD department and other departments. Sixthly, compared with other departments, the majority of HIV/AIDS patients in the STD department were MSM. Seventhly, syphilis and HIV co-infection were not statistically significant in HIV/AIDS patients between the STD department and other departments. CONCLUSION: Firstly, the significantly higher positive rate of an HIV screening test in the STD department emphasizes its importance as a place for screening HIV/AIDS patients. Secondly, HIV/AIDS patients diagnosed in the general hospital were mainly transmitted by sexual contact, and MSM accounted for the most part of these patients. More attention should be paid to screen outpatients, especially in the STD department and young men.

The Therapeutic Effects of Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells on Scleroderma.

BACKGROUND: Scleroderma is a multisystem disease in which tissue fibrosis is caused by inflammation and vascular damage. The mortality of scleroderma has remained high due to a lack of effective treatments. However, exosomes derived from human umbilical cord mesenchymal stem cells (HUMSCs)-Ex have been regarded as potential treatments for various autoimmune diseases, and may also act as candidates for treating scleroderma. METHODS: Mice with scleroderma received a single 50 µg HUMSCs-Ex. HUMSCs-Ex was characterized using transmission electron microscopy, nanoparticle tracking analysis and nanoflow cytometry. The therapeutic efficacy was assessed using histopathology, immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay and western blot. RESULTS: HUMSCs-Ex ameliorated the deposition of extracellular matrix and suppressed the epithelial-mesenchymal transition process, and the effects lasted at least three weeks. In addition, HUMSCs-Ex promoted M1 macrophage polarization and inhibited M2 macrophage polarization, leading to the restoration of the balance of M1/M2 macrophages. CONCLUSION: We investigated the potential antifibrotic and anti-inflammatory effects of HUMSCs-Ex in a bleomycin-induced mouse model of scleroderma. So HUMSCs-Ex could be considered as a candidate therapy for scleroderma.

Alteration of the m6A methylation landscape in a mouse model of scleroderma.

Aim: To explore the N6-methyladenosine (m6A) methylation of mRNAs and its roles in a mouse model of scleroderma. Materials & methods: To evaluate whether the mouse model of scleroderma could meet the experimental requirements, we examined skin tissue specimens by pathological staining and identified the related indicators by quantitative PCR  (qPCR). m6A-tagged mRNAs were identified via m6A epitranscriptomic microarray, and m6A-RNA-immunoprecipitation qPCR and qPCR were performed to confirm microarray data. Results: There were differences in m6A methylation among 843 mRNAs. Further, there were significant differences among Hras, Saa1, Ccl3, Ccl9 and Il1b in terms of methylation and expression. Conclusion: The m6A methylation spectrum in a mouse model of scleroderma may explain the occurrence of scleroderma.

Lay abstract Scleroderma is an autoimmune disease with an unknown etiology. At present there is no effective treatment, and the prognosis is poor. Although m⁶A methylation is the most common RNA modification and affects cell biological function by influencing mRNA expression levels, the role of m⁶A methylation in scleroderma is unknown. Based on a mouse model of scleroderma, we screened and validated mRNAs related to m⁶A regulation, including Hras, Lama3, Stat3, Tnc, Ccl3, Ccl9, Saa1 and Il1b. While the results are encouraging, they are only preliminary. We plan to explore the altered pattern of m⁶A methylation in skin specimens from patients with scleroderma. This study is important for developing biomarkers for diagnosis and treatment of scleroderma in the future.

The Modulation of Working-Memory Performance Using Gamma-Electroacupuncture and Theta-Electroacupuncture in Healthy Adults.

Working memory (WM), a central component of general cognition, plays an essential role in human beings' daily lives. WM impairments often occur in psychiatric, neurodegenerative, and neurodevelopmental disorders, mainly presenting as loss of high-load WM. In previous research, electroacupuncture (EA) has been shown to be an effective treatment for cognitive impairments. Frequency parameters are an important factor in therapeutic results, but the optimal frequency parameters of EA have not yet been identified. In this study, we chose theta-EA (θ-EA; 6 Hz) and gamma-EA (γ-EA; 40 Hz), corresponding to the transcranial alternating-current stimulation (tACS) frequency parameters at the Baihui (DU20) and Shenting (DU24) acupoints, in order to compare the effects of different EA frequencies on WM. We evaluated WM performance using visual 1-back, 2-back, and 3-back WM tasks involving digits. Each participant (N = 30) attended three different sessions in accordance with a within-subject crossover design. We performed θ-EA, γ-EA, and sham-EA in a counterbalanced order, conducting the WM task both before and after intervention. The results showed that d-prime (d') under all three stimulation conditions had no significance in the 1-back and 2-back tasks. However, in the 3-back task, there was a significant improvement in d' after intervention compared to d' before intervention under θ-EA (F [1, 29] = 22.64; P < 0.001), while we saw no significant difference in the γ-EA and sham-EA groups. Reaction times for hits (RT-hit) under all three stimulation conditions showed decreasing trends in 1-, 2-, and 3-back tasks but without statistically significant differences. These findings suggest that the application of θ-EA might facilitate high-load WM performance.

Investigation of the Emerging Nosocomial Wickerhamomyces anomalus Infections at a Chinese Tertiary Teaching Hospital and a Systemic Review: Clinical Manifestations, Risk Factors, Treatment, Outcomes, and Anti-fungal Susceptibility.

Wickerhamomyces anomalus is an emerging pathogen, which has been associated with clonal outbreaks and poor clinical outcomes. Despite being an important emerging yeasts species, our understanding concerning the microbiological and clinical characteristics of infections due to this species is limited. Herein, we are reporting a retrospective analysis of fungemia patients with W. anomalus from a 2,100-bed hospital in Shanghai during 2014-2016. Moreover, we conducted an extensive literature review to gain a deeper clinical and microbiological insights. Detailed clinical data were recorded. Antifungal susceptibility testing (AFST) followed CLSI M27-A3, and isolates were identified using MALDI-TOF MS. In total, 13 patients were identified with a mortality rate of 38.5% (5/13). Central venous catheter (CVC), broad-spectrum antibiotic therapy, total parenteral nutrition (TPN), surgery, and mechanical ventilation were the most frequently observed risk factors. Eight patients (61.5%) experienced mixed bacterial/Candida bloodstream infections, and four patients developed mixed candidemia (MC). W. anomalus isolates showed high minimum inhibitory concentrations (MICs) against all azoles tested and flucytosine, while AMB showed the highest in vitro activity. Azoles were used for 84.6% (11/13) of the cases, while 36.4% (4/11) of them died. When combining with the AFST data and the literature review, our study highlights the poor efficacy of azoles and optimal efficacy of AMB and LAMB against infections caused by W. anomalus. In conclusion, our study highlights the emerging threat of W. anomalus affecting both neonates and adults. Furthermore, our results advocate the use of AMB formulations rather than azoles among patients infected with W. anomalus. Future studies are warranted to reach a definitive consensus regarding the utility of echinocandins among such patients.

BMSC-derived extracellular vesicles intervened the pathogenic changes of scleroderma in mice through miRNAs.

BACKGROUND: Systemic sclerosis (SSc) is a disease that features severe fibrosis of the skin and lacks effective therapy. Bone marrow mesenchymal stem cell (BMSC)-derived extracellular vesicles (EVs) are potential stem cell-based tools for the treatment of SSc. METHODS: BMSCs were isolated from the bone marrow of mice and identified with surface markers according to multilineage differentiation. EVs were isolated from the BMSC culture medium by ultracentrifugation and identified with a Nanosight NS300 particle size analyzer, transmission electron microscopy (TEM), and western blot. The microRNAs (miRNAs) of BMSC-derived EVs (BMSC-EVs) were studied via miRNA sequencing (miRNA-seq) and bioinformatic analysis. An SSc mouse model was established via subcutaneous bleomycin (BLM) injection, and the mice were treated with BMSCs or BMSC-derived EVs. Skin tissues were dissociated and analyzed with H&E staining, RNA sequencing (RNA-seq), western blot, and immunohistochemical staining. RESULTS: Evident pathological changes, like fibrosis and inflammation, were induced in the skin of BLM-treated mice. BMSCs and BMSC-EVs effectively intervened such pathological manifestations and disease processes in a very similar way. The effects of the BMSC-EVs were found to be caused by the miRNAs they carried, which were proven to be involved in regulating the proliferation and differentiation of multiple cell types and in multiple EV-related biological processes. Furthermore, TGF-ß1-positive cells and α-SMA-positive myofibroblasts were significantly increased in the scleroderma skin of BLM-treated mice but evidently reduced in the scleroderma skin of the EV-treated SSc group. In addition, the numbers of mast cells and infiltrating macrophages and lymphocytes were evidently increased in the skin of BLM-treated mice but significantly reduced by EV treatment. In line with these observations, there were significantly higher mRNA levels of the inflammatory cytokines Il6, Il10, and Tnf-α in SSc mice than in control mice, but the levels decreased following EV treatment. Through bioinformatics analysis, the TGFß and WNT signaling pathways were revealed to be closely involved in the pathogenic changes seen in mouse SSc, and these pathways could be therapeutic targets for treating the disease. CONCLUSIONS: BMSC-derived EVs could be developed as a potential therapy for treating skin dysfunction in SSc, especially considering that they show similar efficacy to BMSCs but have fewer developmental regulatory requirements than cell therapy. The effects of EVs are generated by the miRNAs they carry, which alleviate SSc pathogenic changes by regulating the WNT and TGFß signaling pathways.