ObjectiveBased on functional near-infrared spectroscopy (fNIRS), we investigated the brain activity characteristics of gross motor tasks in children with autism spectrum disorder (ASD) and motor dysfunctions (MDs) to provide a theoretical basis for further understanding the mechanism of MDs in children with ASD and designing targeted intervention programs from a central perspective. MethodsAccording to the inclusion and exclusion criteria, 48 children with ASD accompanied by MDs were recruited into the ASD group and 40 children with typically developing (TD) into the TD group. The fNIRS device was used to collect the information of blood oxygen changes in the cortical motor-related brain regions during single-handed bag throwing and tiptoe walking, and the differences in brain activation and functional connectivity between the two groups of children were analyzed from the perspective of brain activation and functional connectivity. ResultsCompared to the TD group, in the object manipulative motor task (one-handed bag throwing), the ASD group showed significantly reduced activation in both left sensorimotor cortex (SMC) and right secondary visual cortex (V2) (P<0.05), whereas the right pre-motor and supplementary motor cortex (PMC&SMA) had significantly higher activation (P<0.01) and showed bilateral brain region activity; in terms of brain functional integration, there was a significant decrease in the strength of brain functional connectivity (P<0.05) and was mainly associated with dorsolateral prefrontal cortex (DLPFC) and V2. In the body stability motor task (tiptoe walking), the ASD group had significantly higher activation in motor-related brain regions such as the DLPFC, SMC, and PMC&SMA (P<0.05) and showed bilateral brain region activity; in terms of brain functional integration, the ASD group had lower strength of brain functional connectivity (P<0.05) and was mainly associated with PMC&SMA and V2. ConclusionChildren with ASD exhibit abnormal brain functional activity characteristics specific to different gross motor tasks in object manipulative and body stability, reflecting insufficient or excessive compensatory activation of local brain regions and impaired cross-regions integration, which may be a potential reason for the poorer gross motor performance of children with ASD, and meanwhile provides data support for further unraveling the mechanisms underlying the occurrence of MDs in the context of ASD and designing targeted intervention programs from a central perspective.

OBJECTIVE: To investigate the characteristics of Vitamin D (VitD) and bone metabolism in patients with knee osteoarthritis (KOA) concurrent with osteoporosis (OP). METHODS: A retrospective analysis was performed on 240 patients who were admitted to the orthopedics department between March 2019 and March 2024. Patients were stratified into four distinct groups according to their respective disease categories.There were 90 patients in the simple KOA group, comprising 13 males and 77 females, age ranged from 50 to 91 years old with an average of (68.48±8.96) years old. There were 90 patients in the simple OP group, comprising 7 males and 83 females, age ranged from 52 to 88 years old with an average of (69.60±8.94 )years old. There were 30 patients in the KOA with OP group, comprising 1 male and 29 females, age ranged from 51 to 91 years old with an average of(69.03±7.93) years old. There were 30 patients in the physical examination group, comprising 5 males and 25 females, age ranged from 53 to 79 years old with an average of(64.93±6.51) years old. The general data and the levels of osteocalcin (OC), β-CrossLaps, parathyroid hormone(PTH) and VitD in each group were observed. RESULTS: The level of VitD in KOA with OP group (19.62±10.38) ng·ml^-1 and OP group (20.65±10.50) ng·ml^-1 was lower than that in physical examination group (27.46±8.00) ng·ml^-1 and KOA group (24.01±9.11) ng·ml^-1 (P<0.05). There were significant differences in β- CrossLaps and PTH levels among the four groups (P<0.001, P=0.019, respectively), while there was no significant difference in OC levels (P=0.763). Compared with the two simple disease groups, the KOA with OP group had higher levels of β - CrossLaps(0.81±0.30) ng·ml^-1 (P<0.001). There were significant differences in β-CrossLaps and PTH between the simple KOA group(0.54±0.22) ng·ml^-1, (46.03±18.08) pg·ml^-1 and the physical examination group (0.44±0.19) ng·ml^-1, (36.65±9.63) pg·mL^-1(P=0.038;P=0.006). There was a significant difference in PTH between the OP group(43.85±14.30) ng·ml-1, and the physical examination group, P=0.004. There was a significant difference in Kallgren-Lawrence grading between KOA with OP group and KOA group (P=0.006). Within KOA with OP group, the differences of β-CrossLaps and VitD levels among different K-L grades were statistically significant (P=0.016). The level of OC, β-CrossLaps and PTH within KOA with OP group was significantly different at different VitD levels (P=0.013, P=0.033, P=0.046). CONCLUSION Patients with KOA complicated by OP exhibit greater disturbances in bone metabolism and reduced VitD levels, particularly reflected by elevated β-CrossLaps. These findings underscore the importance of early monitoring of bone turnover and VitD supplementation in advanced-stage KOA with bone loss.
Humans ; Female ; Male ; Middle Aged ; Aged ; Vitamin D/blood* ; Osteoporosis/complications* ; Aged, 80 and over ; Osteoarthritis, Knee/complications* ; Retrospective Studies ; Bone and Bones/metabolism* ; Parathyroid Hormone/metabolism* ; Osteocalcin/metabolism*

Hearing loss is one of the most prevalent sensory disorders affecting the human nervous system. Liquid-liquid phase separation (LLPS) is a physiological process that facilitates the reversible and dynamic assembly of biomolecular condensates. Increasing evidence suggests that LLPS plays a significant role in the pathogenesis of hereditary hearing loss. Nevertheless, there is a conspicuous lack of systematic investigations exploring the impact of LLPS abnormalities on the etiology of hereditary hearing loss. In this review, we examine the mechanisms by which dysfunctions in LLPS contribute to hereditary hearing loss, specifically focusing on its effects on mechanoelectrical transduction in hair bundles, transcriptional regulation, post-transcriptional modifications, the actin cytoskeleton, ion homeostasis within the inner ear, and energy and redox homeostasis. Furthermore, we evaluate the considerable potential of targeting LLPS as a therapeutic approach for hearing loss and propose innovative perspectives on LLPS that may guide future research initiatives in the field of auditory disorders.
Humans ; Animals ; Hearing Loss/physiopathology* ; Phase Separation

Accurate prediction of drug responses in cancer cell lines (CCLs) and transferable prediction of clinical drug responses using CCLs are two major tasks in personalized medicine. Despite the rapid advancements in existing computational methods for preclinical and clinical cancer drug response (CDR) prediction, challenges remain regarding the generalization of new drugs that are unseen in the training set. Herein, we propose a multimodal fusion deep learning (DL) model called drug-target and single-cell language based CDR (DTLCDR) to predict preclinical and clinical CDRs. The model integrates chemical descriptors, molecular graph representations, predicted protein target profiles of drugs, and cell line expression profiles with general knowledge from single cells. Among these features, a well-trained drug-target interaction (DTI) prediction model is used to generate target profiles of drugs, and a pretrained single-cell language model is integrated to provide general genomic knowledge. Comparison experiments on the cell line drug sensitivity dataset demonstrated that DTLCDR exhibited improved generalizability and robustness in predicting unseen drugs compared with previous state-of-the-art baseline methods. Further ablation studies verified the effectiveness of each component of our model, highlighting the significant contribution of target information to generalizability. Subsequently, the ability of DTLCDR to predict novel molecules was validated through in vitro cell experiments, demonstrating its potential for real-world applications. Moreover, DTLCDR was transferred to the clinical datasets, demonstrating satisfactory performance in the clinical data, regardless of whether the drugs were included in the cell line dataset. Overall, our results suggest that the DTLCDR is a promising tool for personalized drug discovery.

This study was aimed at developing an in vitro fluorescent substrate assay for the activity of leucyl aminopeptid-ase(LAP)from Echinococcus multilocularis and comparing it with the chemical chromogenic substrate enzyme activity assay.Through the establishment of reaction conditions for the fluorescent substrate-based in vitro enzyme activity assay,we com-pared the differences between the fluorescent substrate L-Leucine-7-amido-4-methylocoumarin(Leu-AMC)and the chemical chromogenic substrate L-Leucine-4-nitroanilide(Leu-pNA)through molecular docking,inhibition rates,and precision measures.Molecular docking revealed that the fluorescent substrate Leu-AMC had higher affinity for the protein than the chemical chromogenic substrate Leu-pNA.Through analysis of the effects of varying reaction conditions on fluorescence intensi-ty,we optimized the fluorescent substrate enzyme activity assay to demonstrate favorable performance at a reaction temperature of 37℃,a pH of 9.0,a protein concentration of 800 nmol/L,and a reaction duration of 60 minutes.Leu-AMC exhibited significant and distinct responses at a 5 μmol/L substrate concentration,under varying substrate conditions.The fluo-rescent substrate assay demonstrated more significant intergroup differences than the chemical chromogenic substrate assay when various inhibitors were added.This study established a fluorescence-based enzyme activity assay for leucyl aminopeptidase from Echinococcus multilocularis by using Leu-AMC as the substrate;this method demonstrated a more significant intergroup difference and sensitivity than the chemical chromogenic substrate assay.

Objective To systematically review and quantitatively analyze the safety of biologic agents for the clinical treatment of psoriasis during pregnancy and lactation.Methods The literature from start of database to June 27,2023,was searched in MEDLINE(PubMed),Embase,Cochrane Library,and Web of Science by two researcher.Quality of included studies was assessed by the quality evaluation tool of case series from Australian JBI Evidence Based Healthcare Centre.According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA),a systematic review and was conducted to assess pregnancy or breastfeeding outcomes in psoriasis patients exposed to biologics within 3 months prior to pregnancy,during pregnancy or breastfeeding.Data on pregnancy and exposure characteristics were pooled,and the prevalence of adverse pregnancy outcome was summarized using a random effects model.Results A total of 54 studies involving 1206 pregnancies in 1177 female patients with psoriasis exposed to biologic agents were included in the analysis.Systematic review results demonstrated that the majority of the exposures were limited to early pregnancy,with pooled spontaneous abortion rates,elective abortion rates,overall mortality,preterm birth rates,incidence of low birth weights,and congenital anomalies similar to those of general population(P>0.05).Furthermore,no serious adverse reactions were reported during lactation.Conclusions The use of biologic agents in pregnant and breastfeeding women with psoriasis does not significantly increase the risk of adverse pregnancy outcomes and does not affect neonatal health or growth.However,the limited available safety data underscores the necessity of further studies to establish the relationship between psoriasis,biologic agents,and pregnancy/lactation outcomes,thereby providing comprehensive guidance for clinical practice.

Accurate prediction of drug responses in cancer cell lines(CCLs)and transferable prediction of clinical drug responses using CCLs are two major tasks in personalized medicine.Despite the rapid advancements in existing computational methods for preclinical and clinical cancer drug response(CDR)prediction,chal-lenges remain regarding the generalization of new drugs that are unseen in the training set.Herein,we propose a multimodal fusion deep learning(DL)model called drug-target and single-cell language based CDR(DTLCDR)to predict preclinical and clinical CDRs.The model integrates chemical descriptors,mo-lecular graph representations,predicted protein target profiles of drugs,and cell line expression profiles with general knowledge from single cells.Among these features,a well-trained drug-target interaction(DTI)prediction model is used to generate target profiles of drugs,and a pretrained single-cell language model is integrated to provide general genomic knowledge.Comparison experiments on the cell line drug sensitivity dataset demonstrated that DTLCDR exhibited improved generalizability and robustness in predicting unseen drugs compared with previous state-of-the-art baseline methods.Further ablation studies verified the effectiveness of each component of our model,highlighting the significant contribution of target information to generalizability.Subsequently,the ability of DTLCDR to predict novel molecules was validated through in vitro cell experiments,demonstrating its potential for real-world applications.Moreover,DTLCDR was transferred to the clinical datasets,demonstrating satisfactory performance in the clinical data,regardless of whether the drugs were included in the cell line dataset.Overall,our results suggest that the DTLCDR is a promising tool for personalized drug discovery.

This study was aimed at developing an in vitro fluorescent substrate assay for the activity of leucyl aminopeptid-ase(LAP)from Echinococcus multilocularis and comparing it with the chemical chromogenic substrate enzyme activity assay.Through the establishment of reaction conditions for the fluorescent substrate-based in vitro enzyme activity assay,we com-pared the differences between the fluorescent substrate L-Leucine-7-amido-4-methylocoumarin(Leu-AMC)and the chemical chromogenic substrate L-Leucine-4-nitroanilide(Leu-pNA)through molecular docking,inhibition rates,and precision measures.Molecular docking revealed that the fluorescent substrate Leu-AMC had higher affinity for the protein than the chemical chromogenic substrate Leu-pNA.Through analysis of the effects of varying reaction conditions on fluorescence intensi-ty,we optimized the fluorescent substrate enzyme activity assay to demonstrate favorable performance at a reaction temperature of 37℃,a pH of 9.0,a protein concentration of 800 nmol/L,and a reaction duration of 60 minutes.Leu-AMC exhibited significant and distinct responses at a 5 μmol/L substrate concentration,under varying substrate conditions.The fluo-rescent substrate assay demonstrated more significant intergroup differences than the chemical chromogenic substrate assay when various inhibitors were added.This study established a fluorescence-based enzyme activity assay for leucyl aminopeptidase from Echinococcus multilocularis by using Leu-AMC as the substrate;this method demonstrated a more significant intergroup difference and sensitivity than the chemical chromogenic substrate assay.

AIM To analyze the constituents absorbed into blood and brain from Zhishe Tongluo Capsules.METHODS Sixteen rats were randomly assigned into four groups and given intragastric administration(3.1 g/kg),after which the cerebral ischemia-reperfusion injury(MACO)model was established,the blood and brain tissues were collected,and UHPLC-Q Exactive Focus MS/MS was adopted in the identification of prototype constituents.RESULTS Total 70 constituents were identified,20 of which were found in the blood,mainly including flavonoids,tanshinones and Ligusticum chuanxiong phthalides,and 7 of them could enter the brain through blood-brain barrier.Compared with the normal administration group,the MACO administration group demonstrated added constituents absorbed into blood containing 3-hydroxybenzoic acid,calycosin-7-glucoside,curcumenol,senkyunolide B,dihydrotanshinone I and cryptotanshinone;removed constituents absorbed into brain containing puerarin,elemicin,sedanolide,and added those containing salvianolic acid A,senkyunolide I,dihydrotanshinone I in the left brain tissues(infarcted side).CONCLUSION The constituents absorbed into blood and brain from Zhishe Tongluo Capsules,along with the enhanced absorptions of phthalides,quinones and phenols in MACO rats in vivo may be the active substances for treating cerebral infarction.

In this study, we designed and synthesized 12 novel aloperine derivatives with different core structures. Among them, compound 3 with a ten-membered ring core was obtained through a special ring expansion reaction after γ-H Huffman elimination of quaternary ammonium salt, and the structure was verified by X-single crystal diffraction. Furthermore, their antiviral activity against human β-coronavirus HCoV-OC43 was evaluated by CCK-8 assay. Quaternary ammonium salt 2a and 3 had a good inhibitory effect against HCoV-OC43, and 2a had the highest anti-HCoV-OC43 activity with an EC₅₀ values of 3.77 μmol·L^-1 and a SI value of over 53.1. Schrӧdinger molecular docking results showed that both 2a and 3 might display their anti-HCoV-OC43 activity by directly acting on host TMPRSS2 and SR-B1. The results expanded the structural types of endocyclic aloperine and the function against coronavirus, and provided useful scientific data for the development of pharmaceutical applications of these compounds.