Hua-Feng-Dan alleviates LPS-induced neuroinflammation by inhibiting the TLR4/Myd88/NF-κB pathway: Through Integrating Network Pharmacology and Experimental Validation.

BACKGROUND: Neuroinflammation is the pathological basis of many neurological diseases, including neurodegenerative diseases and stroke. Hua-Feng-Dan (HFD) is a well-established traditional Chinese medicine that has been used for centuries to treat stroke and various other brain-related ailments. OBJECTIVE: Our study aims to elucidate the molecular mechanism by which HFD mitigates neuroinflammation by combining network pharmacology and in vitro experiments. METHODS: TCMSP and SymMap databases were used to extract active compounds and their related targets. The neuroinflammation-related targets were obtained from the GeneCards database. The common targets of HFD and neuroinflammation were used to construct a protein-protein interaction (PPI) network. MCODE plug-in was used to find the hub module genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were used to dissect the hub module genes. The lipopolysaccharide (LPS)-induced BV2 microglial neuroinflammation model was utilized to assess the therapeutic effects of HFD on neuroin- flammation. Western blotting analysis was performed to examine the core target proteins in the TLR4/My- D88/NF-κB signaling pathway, potentially implicated in HFD's therapeutic effects on neuroinflammation. Hoechst 33342 staining and JC-1 staining were employed to evaluate neuronal apoptosis. RESULTS: Through network pharmacology, 73 active compounds were identified, with quercetin, beta-sitos- terol, luteolin, and (-)-Epigallocatechin-3-Gallate recognized as important compounds. Meanwhile, 115 com- mon targets of HFD and neuroinflammation were identified, and 61 targets were selected as the hub targets uti- lizing the MCODE algorithm. The results of in vitro experiments demonstrated that HFD significantly inhibit- ed microglial-mediated neuronal inflammation induced by LPS. Integrating the predictions from network phar- macology with the in vitro experiment results, it was determined that the mechanism of HFD in mitigating neu- roinflammation is closely related to the TLR4/MyD88/NF-κB pathway. Furthermore, HFD demonstrated the capacity to shield neurons from apoptosis by curbing the secretion of pro-inflammatory factors subsequent to microglial activation. CONCLUSION: The findings demonstrated that HFD had an inhibitory effect on LPS-induced neuroinflammation in microglia and elucidated its underlying mechanism. These findings will offer a theoretical foundation for the clinical utilization of HFD in treating neurodegenerative diseases associated with neuroinflammation.

Scorpiones, Scolopendra and Gekko Inhibit Lung Cancer Growth and Metastasis by Ameliorating Hypoxic Tumor Microenvironment via PI3K/AKT/mTOR/HIF-1α Signaling Pathway.

OBJECTIVE: To investigate whether Buthus martensii karsch (Scorpiones), Scolopendra subspinipes mutilans L. Koch (Scolopendra) and Gekko gecko Linnaeus (Gekko) could ameliorate the hypoxic tumor microenvironment and inhibit lung cancer growth and metastasis by regulating phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin/hypoxia-inducible factor-1α (PI3K/AKT/mTOR/HIF-1α) signaling pathway. METHODS: Male C57BL/6J mice were inoculated with luciferase labeled LL/2-luc-M38 cell suspension to develop lung cancer models, with rapamycin and cyclophosphamide as positive controls. Carboxy methyl cellulose solutions of Scorpiones, Scolopendra and Gekko were administered intragastrically as 0.33, 0.33, and 0.83 g/kg, respectively once daily for 21 days. Fluorescent expression were detected every 7 days after inoculation, and tumor growth curves were plotted. Immunohistochemistry was performed to determine CD31 and HIF-1α expressions in tumor tissue and microvessel density (MVD) was analyzed. Western blot was performed to detect the expression of PI3K/AKT/mTOR/HIF-1α signaling pathway-related proteins. Enzyme-linked immunosorbent assay was performed to detect serum basic fibroblast growth factor (bFGF), transforming growth factor-ß1 (TGF-ß1) and vascular endothelial growth factor (VEGF) in mice. RESULTS: Scorpiones, Scolopendra and Gekko prolonged the survival time and inhibited lung cancer metastasis and expression of HIF-1α (all P<0.01). Moreover, Scorpiones, Scolopendra and Gekko inhibited the phosphorylation of AKT and ribosomal protein S6 kinase (p70S6K) (P<0.05 or P<0.01). In addition, they also decreased the expression of CD31, MVD, bFGF, TGF-ß1 and VEGF compared with the model group (P<0.05 or P<0.01). CONCLUSION: Scorpiones, Scolopendra and Gekko all showed beneficial effects on lung cancer by ameliorating the hypoxic tumor microenvironment via PI3K/AKT/mTOR/HIF-1α signaling pathway.

Stable O3 Decomposition by Layered Double Hydroxides: The Pivotal Role of NiOOH Transformation.

Because ozone (O3) is a significant air pollutant, advanced O3 elimination technologies, particularly those under high-humidity conditions, have become an essential research focus. In this study, a nickel-iron layered double hydroxide (NiFe-LDH) was modified via intercalation with octanoate to develop an effective hydrophobic catalyst (NiFe-OAa-LDH) for O3 decomposition. The NiFe-OAa-LDH catalyst sustained its O3 decomposition rate of >98% for 48 h under conditions of 90% relative humidity, 840 L/(g·h) space velocity, and 100 ppm inlet O3 concentration. Moreover, it maintained a decomposition rate of 90% even when tested at a higher airflow rate of 2500 L/(g·h). Based on the changes induced by the Ni-OII to Ni-OIII bonds in NiFe-OAa-LDH during O3 treatment, catalytic O3 decomposition was proposed to occur in two stages. The first stage involved the reaction between the hydroxyl groups and O3, leading to the breakage of the O-H bonds, formation of NiOOH, and structural changes in the catalyst. This transformation resulted in the formation of abundant and stable hydrogen vacancies. According to density functional theory calculations, O3 can be effectively decomposed at the hydrogen vacancies with a low energy barrier during the second stage. This study provides new insights into O3 decomposition.

Silica-supported ionic liquid for efficient gaseous arsenic oxide removal through hydrogen bonding.

The emission of highly-toxic gaseous As2O3 (As2O3 (g)) from nonferrous metal smelting poses environmental concerns. In this study, we prepared an adsorbent (SMIL-X) by loading an ionic liquid (IL) ([HOEtMI]NTf2) into MCM-41 through an impregnation-evaporation process and then applied it to adsorb As2O3 (g). SMIL-20% exhibited an As2O3 (g) adsorption capacity of 35.48 mg/g at 400 °C, which was 490% times higher than that of neat MCM-41. Characterization of SMIL-X indicated that the IL was mainly supported on MCM-41 through O-H…O bonds formed between the hydroxyl groups (-OH) and the silanol groups (Si-OH) and the O-H…F bonds formed between the C-F groups and the Si-OH groups. The hydrogen bonds significantly contributed to the adsorption of As2O3 (g), with -NH and -OH groups forming hydrogen bonds with As-O species (i.e., N-H…O and O-H…O). This showed superior performance to traditional adsorbents that rely on van der Waals forces and chemisorption. Moreover, after exposure to high concentrations of SO2, the adsorption capacities remained at 76% of their initial values, demonstrating some sulfur resistance. This study presents an excellent adsorbent for the purification of As2O3 (g) and shows promising application potential for treating flue gas emitted by nonferrous metal smelting processes.

Majie Cataplasm Alleviates Asthma by Regulating Th1/Th2/Treg/Th17 Balance.

INTRODUCTION: T cells play a critical role in inflammatory diseases. The aim of the present study was to investigate the effects of Majie cataplasm (MJC) on asthma and to propose a possible mechanism involved in this process. METHODS: Airway inflammation, infiltration of inflammatory cells, levels of interleukin (IL)-4, IL-10, IL-17, and interferon (IFN)-γ, levels of Th2, Treg, Th17, and Th1 cells, and the expressions of IL-4, IL-10, IL-17, IFN-γ, GATA binding protein 3 (GATA-3), Foxp3, RAR-related orphan receptor gamma (RORγt), and T-bet were detected. RESULT: MJC treatment reduced lung airway resistance and inflammatory infiltration in lung tissues. MJC treatment also reduced the numbers of eosinophils and neutrophils in the blood and bronchoalveolar lavage fluid (BALF). The levels of IL-4 and IL-17 in the blood, BALF, and lungs were suppressed by MJC, and IFN-γ and IL-10 were increased. Furthermore, MJC suppressed the percentage of Th2 and Th17 and increased the percentage of Th1 and Treg in spleen cells. In addition, MJC can inhibit asthma by increasing expressions of IFN-γ, IL-10, T-bet, and Foxp3, as well as decreasing expressions of IL-4, IL-17, GATA-3, and RORγt. CONCLUSION: MJC may improve airway hyperresponsiveness and inflammation by regulating Th1/Th2/Treg/Th17 balance in ovalbumin-induced rats. And MJC may be a new source of anti-asthma drugs.

A fully autonomous robotic ultrasound system for thyroid scanning.

The current thyroid ultrasound relies heavily on the experience and skills of the sonographer and the expertise of the radiologist, and the process is physically and cognitively exhausting. In this paper, we report a fully autonomous robotic ultrasound system, which is able to scan thyroid regions without human assistance and identify malignant nod- ules. In this system, human skeleton point recognition, reinforcement learning, and force feedback are used to deal with the difficulties in locating thyroid targets. The orientation of the ultrasound probe is adjusted dynamically via Bayesian optimization. Experimental results on human participants demonstrated that this system can perform high-quality ultrasound scans, close to manual scans obtained by clinicians. Additionally, it has the potential to detect thyroid nodules and provide data on nodule characteristics for American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) calculation.

Hypercholesterolemia and the Increased Risk of Vascular Dementia: a Cholesterol Perspective.

PURPOSE OF REVIEW: Vascular dementia (VaD) is the second most prevalent type of dementia after Alzheimer's disease.Hypercholesterolemia may increase the risk of dementia, but the association between cholesterol and cognitive function is very complex. From the perspective of peripheral and brain cholesterol, we review the relationship between hypercholesterolemia and increased risk of VaD and how the use of lipid-lowering therapies affects cognition. RECENT FINDINGS: Epidemiologic studies show since 1980, non-HDL-C levels of individuals has increased rapidly in Asian countries.The study has suggested that vascular risk factors increase the risk of VaD, such as disordered lipid metabolism. Dyslipidemia has been found to interact with chronic cerebral hypoperfusion to promote inflammation resulting in cognitive dysfunction in the brain.Hypercholesterolemia may be a risk factor for VaD. Inflammation could potentially serve as a link between hypercholesterolemia and VaD. Additionally, the potential impact of lipid-lowering therapy on cognitive function is also worth considering. Finding strategies to prevent and treat VaD is critical given the aging of the population to lessen the load on society. Currently, controlling underlying vascular risk factors is considered one of the most effective methods of preventing VaD. Understanding the relationship between abnormal cholesterol levels and VaD, as well as discovering potential serum biomarkers, is important for the early prevention and treatment of VaD.

AIDA-1/ANKS1B Binds to the SynGAP Family RasGAPs with High Affinity and Specificity.

AIDA-1, encoded by ANKS1B, is an abundant postsynaptic scaffold protein essential for brain development. Mutations of ANKS1B are closely associated with various psychiatric disorders. However, very little is known regarding the molecular mechanisms underlying AIDA-1's involvements under physiological and pathophysiological conditions. Here, we discovered an interaction between AIDA-1 and the SynGAP family Ras-GTPase activating protein (GAP) via affinity purification using AIDA-1d as the bait. Biochemical studies showed that the PTB domain of AIDA-1 binds to an extended NPx[F/Y]-motif of the SynGAP family proteins with high affinities. The high-resolution crystal structure of AIDA-1 PTB domain in complex with the SynGAP NPxF-motif revealed the molecular mechanism governing the specific interaction between AIDA-1 and SynGAP. Our study not only explains why patients with ANKS1B or SYNGAP1 mutations share overlapping clinical phenotypes, but also allows identification of new AIDA-1 binding targets such as Ras and Rab interactors.

Enhancing AsH3 Detoxification via Electron-Deficient [NiIII-OH (µ-O)] in a Nickel-Modified NaY Zeolite: A Pathway toward As0 Products.

The transformation of toxic arsine (AsH3) gas into valuable elemental arsenic (As0) from industrial exhaust gases is important for achieving sustainable development goals. Although advanced arsenic removal catalysts can improve the removal efficiency of AsH3, toxic arsenic oxides generated during this process have not received adequate attention. In light of this, a novel approach for obtaining stable As0 products was proposed by performing controlled moderate oxidation. We designed a tailored Ni-based catalyst through an acid etching approach to alter interactions between Ni and NaY. As a result, the 1Ni/NaY-H catalyst yielded an unprecedented proportion of As0 as the major product (65%), which is superior to those of other reported catalysts that only produced arsenic oxides. Density functional theory calculations clarified that Ni species changed the electronic structure of oxygen atoms, and the formed [NiIII-OH (µ-O)] active centers facilitated the adsorption of AsH2*, AsH*, and As* reaction intermediates for As-H bond cleavage, thereby decreasing the direct reactivity of oxygen with the arsenic intermediates. This work presents pioneering insights into inhibiting excessive oxidation during AsH3 removal, demonstrating potential environmental applications for recovery of As0 from toxic AsH3.

Seasonal patterns in Chinese population: Validating the seasonal pattern assessment questionnaire and exploring associations with psychiatric diagnoses and biological rhythms.

Seasonal patterns (SP) exert a notable influence on the course and prognosis of patients with affective disorders, serving as a specifier in diagnosis. However, there is limited exploration of seasonality among psychotic patients, and the distinctions in seasonality among psychiatric patients remain unclear. In this study, we enrolled 198 psychiatric patients with anxiety and depressive disorders (A&D), bipolar disorder (BD), and schizophrenia (SZ), as well as healthy college students. Online questionnaires, including the Seasonal Pattern Assessment Questionnaire (SPAQ) for seasonality, the Morningness and Eveningness Questionnaire-5 (MEQ-5) for chronotypes, and the Pittsburgh Sleep Quality Index (PSQI), were administered. The validity and reliability of the Chinese version of the SPAQ were thoroughly analyzed, revealing a Cronbach's alpha of 0.896 with a two-factor structure. Results indicated that higher seasonality was correlated with poorer sleep quality and a more delayed chronotype (p < 0.05). Significant monthly variations were particularly evident in BD, specifically in mood, appetite, weight, social activities, and sleep dimensions (p < 0.001). In summary, the Chinese version of SPAQ is validated, demonstrating moderate correlations between seasonality, chronotype, and sleep quality. BD patients exhibited the strongest seasonality, while mood disorder patients displayed more delayed chronotypes than SZ.

Lysosome passivation triggered by silver nanoparticles enhances subcellular-targeted drug therapy.

Frequently, subcellular-targeted drugs tend to accumulate in lysosomes after cellular absorption, a process termed the lysosomal trap. This accumulation often interferes with the drug's ability to bind to its target, resulting in decreased efficiency. Existing methods for addressing lysosome-induced drug resistance mainly involve improving the structures of small molecules or enveloping drugs in nanomaterials. Nonetheless, these approaches can lead to changes in the drug structure or potentially trigger unexpected reactions within organisms. To address these issues, we introduced a strategy that involves inactivating the lysosome with the use of Ag nanoparticles (Cy3.5@Ag NPs). In this method, the Cy3.5@Ag NPs gradually accumulate inside lysosomes, leading to permeation of the lysosomal membrane and subsequent lysosomal inactivation. In addition, Cy3.5@Ag NPs also significantly affected the motility of lysosomes and induced the occurrence of lysosome passivation. Importantly, coincubating Cy3.5@Ag NPs with various subcellular-targeted drugs was found to significantly increase the efficiency of these treatments. Our strategy illustrates the potential of using lysosomal inactivation to enhance drug efficacy, providing a promising therapeutic strategy for cancer.

Cu/Biochar Bifunctional Catalytic Removal of COS and H2S:H2O Dissociation and CuO Anchoring Enhanced by Pyridine N.

Economic and environmentally friendly strategies are needed to promote the bifunctional catalytic removal of carbonyl sulfide (COS) by hydrolysis and hydrogen sulfide (H2S) by oxidation. N doping is considered to be an effective strategy, but the essential and intrinsic role of N dopants in catalysts is still not well understood. Herein, the conjugation of urea and biochar during Cu/biochar annealing produced pyridine N, which increased the combined COS/H2S capacity of the catalyst from 260.7 to 374.8 mg·g-1 and enhanced the turnover frequency of H2S from 2.50 × 10-4 to 5.35 × 10-4 s-1. The nucleophilic nature of pyridine N enhances the moderate basic sites of the catalyst, enabling the attack of protons and strong H2O dissociation. Moreover, pyridine N also forms cavity sites that anchor CuO, improving Cu dispersion and generating more reactive oxygen species. By providing original insight into the pyridine N-induced bifunctional catalytic removal of COS/H2S in a slightly oxygenated and humid atmosphere, this study offers valuable guidance for further C═S and C-S bond-breaking in the degradation of sulfur-containing pollutants.

Novel biallelic SASS6 variants associated with primary microcephaly and fetal growth restriction.

Primary microcephaly is characterized by a head circumference prenatally or at birth that falls below three standard deviations from age-, ethnic-, and sex-specific norms. Genetic defects are one of the underlying causes of primary microcephaly. Since 2014, five variants of the SASS6 gene have been identified as the cause of MCPH 14 in three reported families. In this study, we present the genetic findings of members of a nonconsanguineous Chinese couple with a history of microcephaly and fetal growth restriction (FGR) during their first pregnancy. Utilizing trio whole-exome sequencing, we identified compound heterozygous variants involving a frameshift NM_194292.3:c.450_453del p.(Lys150AsnfsTer7) variant and a splice region NM_194292.3:c.1674+3A>G variant within the SASS6 gene in the affected fetus. Moreover, reverse transcriptase-polymerase chain reaction from RNA of the mother's peripheral blood leukocytes revealed that the c.1674+3A>G variant led to the skipping of exon 14 and an inframe deletion. To the best of our knowledge, the association between FGR and SASS6-related microcephaly has not been reported, and our findings confirm the pivotal role of SASS6 in microcephaly pathogenesis and reveal an expanded view of the phenotype and mutation spectrum associated with this gene.

The effect of transcranial direct current stimulation (tDCS) on cognitive function recovery in patients with depression following electroconvulsive therapy (ECT): protocol for a randomized controlled trial.

BACKGROUND: Electroconvulsive therapy (ECT) is a highly effective treatment for depressive disorder. However, the use of ECT is limited by its cognitive side effects (CSEs), and no specific intervention has been developed to address this problem. As transcranial direct current stimulation (tDCS) is a safe and useful tool for improving cognitive function, the main objective of this study was to explore the ability to use tDCS after ECT to ameliorate the cognitive side effects. METHODS: 60 eligible participants will be recruited within two days after completing ECT course and randomly assigned to receive either active or sham stimulation in a blinded, parallel-design trial and continue their usual pharmacotherapy. The tDCS protocol consists of 30-min sessions at 2 mA, 5 times per week for 2 consecutive weeks, applied through 15-cm2 electrodes. An anode will be placed over the left dorsolateral prefrontal cortex (DLPFC), and a cathode will be placed over the right supraorbital cortex. Cognitive function and depressive symptoms will be assessed before the first stimulation (T0), after the final stimulation (T1), 2 weeks after the final stimulation (T2), and 4 weeks after the final stimulation (T3) using the Cambridge Neuropsychological Test Automated Battery (CANTAB). DISCUSSION: We describe a novel clinical trial to explore whether the administration of tDCS after completing ECT course can accelerates recovery from the CSEs. We hypothesized that the active group would recover faster from the CSEs and be superior to the sham group. If our hypothesis is supported, the use of tDCS could benefit eligible patients who are reluctant to receive ECT and reduce the risk of self-inflicted or suicide due to delays in treatment. TRIAL REGISTRATION DETAILS: The trial protocol is registered with https://www.chictr.org.cn/ under protocol registration number ChiCTR2300071147 (date of registration: 05.06.2023). Recruitment will start in November 2023.

Chiral Supramolecular Nanofibers Regulated Tumor-Derived Exosomes Secretion for Constructing an Anti-Tumor Extracellular Microenvironment.

Tumor-derived exosomes (TDEs) induced extracellular microenvironment has recently been validated to be critical for tumor progression and metastasis, however, remodeling it for oncotherapy still remains a major challenge due to difficulty in regulation of TDEs secretion. Herein, the supramolecular chiral nanofibers, composed of L/D -phenylalanine derivates (L/D-Phe) and linear hyaluronic acid (HA), are successfully employed to construct TDEs induced anti-tumor extracellular microenvironment. The left-handed L-Phe @HA nanofibers significantly inhibit TDEs secretion into extracellular microenvironment, which results in suppression of tumor proliferation and metastasis in vitro and vivo. Biological assays and theoretical modeling reveal that these results are mainly attributed to strong adsorption of the key exosomes transporters (Ras-related protein Rab-27A and synaptosome-associated protein 23) on left-handed L-Phe @HA nanofibers via enhanced stereoselective interaction, leading to degradation and phosphorylated dropping of exosomes transporters. Subsequently, transfer function of exosomes transporters is limited, which causes remarkable inhibition of TDEs secretion. These findings provide a promising novel insight of chiral functional materials to establish an anti-tumor extracellular microenvironment via regulation of TDEs secretion.

CVaR-Constrained Policy Optimization for Safe Reinforcement Learning.

Current constrained reinforcement learning (RL) methods guarantee constraint satisfaction only in expectation, which is inadequate for safety-critical decision problems. Since a constraint satisfied in expectation remains a high probability of exceeding the cost threshold, solving constrained RL problems with high probabilities of satisfaction is critical for RL safety. In this work, we consider the safety criterion as a constraint on the conditional value-at-risk (CVaR) of cumulative costs, and propose the CVaR-constrained policy optimization algorithm (CVaR-CPO) to maximize the expected return while ensuring agents pay attention to the upper tail of constraint costs. According to the bound on the CVaR-related performance between two policies, we first reformulate the CVaR-constrained problem in augmented state space using the state extension procedure and the trust-region method. CVaR-CPO then derives the optimal update policy by applying the Lagrangian method to the constrained optimization problem. In addition, CVaR-CPO utilizes the distribution of constraint costs to provide an efficient quantile-based estimation of the CVaR-related value function. We conduct experiments on constrained control tasks to show that the proposed method can produce behaviors that satisfy safety constraints, and achieve comparable performance to most safe RL (SRL) methods.

Tumor keratin 15 expression links with less extent of invasion and better prognosis in papillary thyroid cancer patients receiving tumor resection.

OBJECTIVE: Keratin 15 (KRT15) is identified as a useful biomarker in several solid tumors, while its clinical role in papillary thyroid cancer (PTC) remains unknown. Herein, this study is intended to explore the correlation of tumor KRT15 with clinical features and survival in PTC patients who received tumor resection. METHODS: This study retrospectively screened 350 PTC patients who received tumor resection and 50 thyroid benign lesions (TBL) patients. KRT15 in formalin-fixed paraffin-embedded lesion specimens of all subjects was detected by immunohistochemistry (IHC). RESULTS: KRT15 was reduced in PTC patients compared to TBL patients (P < 0.001). Furthermore, KRT15 was negatively associated with tumor size (P = 0.017), extrathyroidal invasion (P = 0.007), pathological tumor (pT) stage (P < 0.001), and postoperative radioiodine application (P = 0.008) in PTC patients. Regarding prognostic value, high KRT15 (cut-off by an IHC value of 3) is linked with prolonged accumulating disease-free survival (DFS) (P = 0.008) and overall survival (OS) (P = 0.008) in PTC patients. Also, the multivariate Cox regression model showed that high KRT15 (vs. low) was an independent factor for longer DFS (hazard ratio = 0.433, P = 0.049), but not for OS (P > 0.050) in PTC patients. Subgroup analyses revealed that KRT15 possessed a better prognostic value in PTC patients with age ≥ 55 years, tumor size > 4 cm, pathological node stage 1, or pathological tumor-node-metastasis stage ≤ 2 (all P < 0.050). CONCLUSION: Increased tumor KRT15 associates with a lower invasive degree, prolonged DFS, and OS, revealing its prognostic utility in PTC patients undergoing tumor resection.

Prenatal diagnosis and preimplantation genetics testing of 3M syndrome in a Chinese family with novel biallelic variants of CUL7.

BACKGROUND: 3M syndrome is a rare autosomal recessive developmental disorder characterized by pre and postnatal growth deficiency, dysmorphic facial features, and normal intelligence. 3M syndrome should be suspected in a proband with a combination of characteristic or recognizable dysmorphic features. The diagnosis of 3M syndrome could be confirmed by identifying biallelic variants in CUL7, OBSL1, or CCDC8. METHODS: Whole-exome sequencing (WES) was performed to identify genetic causes. Reverse-transcription polymerase chain reaction (RT-PCR) was performed to detect aberrant splicing events. Haplotypes were constructed using multiplex PCR and sequencing. Variants of the parental haplotype and target likely pathogenic variants were detected by PCR and Sanger sequencing from the embryos. Copy number variant (CNV) detection was performed by next-generation sequencing. RESULTS: We present the case of a nonconsanguineous Chinese couple with one abnormal pregnancy, where the fetus showed 3M phenotypes of shortened long bones. WES identified two novel heterozygous mutations in CUL7: NM_014780.5:c.354del (p.Gln119ArgfsTer52) and NM_014780.5:c.1373-15G>A. RT-PCR from RNA of the mother's peripheral blood leucocytes showed that c.1373-15G>A caused the insertion of a 13-bp extra intron sequence and encoded the mutant p.Leu459ProfsTer25. Both variants were classified as likely pathogenic according to ACMG/AMP guidelines and Clinical Genome Resource specifications. During genetic counseling, the options of prenatal diagnosis through chorionic villus sampling or amniocentesis, adoption, sperm donation, and electing not to reproduce, as well as preimplantation genetic testing for monogenic disorders (PGT-M), were discussed. The couple hopes to conceive a child of their own and refused to accept the 25% risk during the next pregnancy and opted for PGT-M. They finally successfully delivered a healthy baby through PGT-M. CONCLUSION: This study expanded the mutation spectrum of CUL7, detected the aberrant splicing event of CUL7 via RT-PCR, constructed the haplotype for PGT-M, and demonstrated the successful delivery of a healthy baby using PGT-M.

Causal relationship between psoriasis vulgaris and dementia: Insights from Mendelian randomization analysis.

Many clinical studies have demonstrated a correlation between psoriasis vulgaris and dementia, yet this correlation remains controversial. Our study employed the Mendelian randomization (MR) method to investigate the causal relationship between psoriasis vulgaris and dementia. Data were obtained from the summary statistics of the genome-wide association studies from IEU-OpenGWAS project database. In univariate Mendelian randomization (UVMR) analysis, psoriasis vulgaris was used as exposure. Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD) and frontotemporal dementia (FTD) served as the outcomes. In multivariate Mendelian randomization (MVMR) analysis, VaD served as the outcome. The first MVMR analysis used psoriasis vulgaris, mean platelet volume (MPV), platelet distribution width (PDW) and platelet count (PLT) as exposures. The second MVMR analysis used psoriasis vulgaris, vitamin D level and 25 hydroxyvitamin D level as exposures. The main analysis employed the inverse variance weighted method, and the outcomes were evaluated by odds ratio (OR) and 95% confidence interval (95% CI). In UVMR analysis, the results depicted that psoriasis vulgaris was associated with VaD (OR: 0.903, 95% CI: 0.818-0.996, p = 0.041). The results revealed insignificant associations between psoriasis vulgaris and other dementia types. After adjusting the effects of MPV, PDW and PLT in MVMR analysis, the association between psoriasis vulgaris and VaD was no longer significant (p = 0.164). Similarly, after adjusting the effects of vitamin D level and 25 hydroxyvitamin D level in MVMR analysis, the association between psoriasis vulgaris and VaD was also no longer significant (p = 0.533). Our study suggests that psoriasis vulgaris may potentially decrease VaD incidence. However, the causal association between psoriasis vulgaris and VaD may be impeded by platelet-related indices, vitamin D level and 25 hydroxyvitamin D level.

Chiral Supramolecular Hydrogel Enhanced Transdermal Delivery of Sodium Aescinate to Modulate M1 Macrophage Polarization Against Lymphedema.

Sodium aescinate (SA) shows great potential for treating lymphedema since it can regulate the expression of cytokines in M1 macrophages, however, it is commonly administered intravenously in clinical practice and often accompanied by severe toxic side effects and short metabolic cycles. Herein, SA-loaded chiral supramolecular hydrogels are prepared to prove the curative effects of SA on lymphedema and enhance its safety and transdermal transmission efficiency. In vitro studies demonstrate that SA- loaded chiral supramolecular hydrogels can modulate local immune responses by inhibiting M1 macrophage polarization. Typically, these chiral hydrogels can significantly increase the permeability of SA with good biocompatibility due to the high enantioselectivity between chiral gelators and stratum corneum and L-type hydrogels are found to have preferable drug penetration over D-type hydrogels. In vivo studies show that topical delivery of SA via chiral hydrogels results in dramatic therapeutic effects on lymphedema. Specifically, it can downregulate the level of inflammatory cytokines, reduce the development of fibrosis, and promote the regeneration of lymphatic vessels. This study initiates the use of SA for lymphedema treatment and for the creation of an effective chiral biological platform for improved topical administration.