Objectives: . This study aimed to explore the role of the Pcdh15 gene in hearing maintenance and to examine the effects of its deficiency on cochlear structure, cochlear function, and hearing loss in mice. Methods: . CRISPR/Cas9 technology was used to generate Pcdh15 knockout (KO) mice. Auditory function was evaluated using hearing tests, while histological approaches were employed to assess morphological changes in cochlear hair cells and spiral ganglion neurons (SGNs). RNA sequencing (RNA-seq) was performed on cochlear tissue from postnatal day 18 (P18) wild-type (WT) and Pcdh15 KO mice to identify differentially expressed genes (DEGs). These DEGs were subjected to functional annotation and pathway analysis, with particular emphasis on oxidative phosphorylation (OXPHOS). Reactive oxygen species (ROS) levels were quantified using flow cytometry and DCFH-DA assays. Results: . Pcdh15 KO mice exhibited progressive sensorineural hearing loss, which worsened to profound deafness by P18. Notably, cochlear hair cells and SGNs showed substantial loss and pronounced morphological abnormalities, particularly within the basal high-frequency region. RNA-seq analysis identified 1,359 DEGs, including 1,024 downregulated and 335 upregulated genes. Pathway analysis indicated that Pcdh15 deficiency was associated with inhibition of the OXPHOS pathway, potentially disrupting mitochondrial respiratory chain complexes I, III, IV, and V and thereby impairing energy production and ATP metabolism. In addition, early-stage cochleae from KO mice demonstrated elevated ROS levels and increased oxidative stress, suggesting that redox imbalance may contribute to hearing damage. Conclusion . Pcdh15 plays a critical role in hearing maintenance. Its deficiency is associated with severe hearing loss and marked cochlear abnormalities, which are linked to inhibition of OXPHOS, disruption of energy metabolism, and exacerbation of oxidative stress. Together, these findings provide new insights into the mechanisms underlying hearing loss and suggest potential targets for therapeutic intervention.

This study aims to explore the effects of Buzhong Yiqi Decoction(BYD) on the cyclic guanosine monophosphate-adenosine monophosphate synthase(cGAS)-stimulator of interferon genes(STING) signaling pathway in the mouse model of autoimmune thyroiditis(AIT) and the mechanism of BYD in alleviating the immune injury. Forty-eight NOD.H-2~(h4) mice were assigned into normal, model, low-, medium-, and high-dose BYD, and selenium yeast tablets groups(n=8). Mice of 8 weeks old were treated with 0.05% sodium iodide solution for 8 weeks for the modeling of AIT and then administrated with corresponding drugs by gavage for 8 weeks before sampling. High performance liquid chromatography was employed to measure the astragaloside Ⅳ content in BYD. Hematoxylin-eosin staining was employed to observe the pathological changes in the mouse thyroid tissue. Enzyme-linked immunosorbent assay was employed to measure the serum levels of thyroid peroxidase antibody(TPO-Ab), thyroglobulin antibody(TgAb), and interferon-γ(IFN-γ). Flow cytometry was employed to detect the distribution of T cell subsets in the spleen. The immunohistochemical method was used to detect the expression of cGAS, STING, TANK-binding kinase 1(TBK1), and interferon regulatory factor 3(IRF3). Real-time PCR and Western blot were employed to determine the mRNA and protein levels, respectively, of markers related to the cGAS-STING signaling pathway in the thyroid tissue. The results showed that the content of astragaloside Ⅳ in BYD was(7.06±0.08) mg·mL~(-1). Compared with the normal group, the model group showed disrupted structures of thyroid follicular epithelial cells, massive infiltration of lymphocytes, and elevated levels of TgAb and TPO-Ab. Compared with the model group, the four treatment groups showed intact epithelial cells, reduced lymphocyte infiltration, and lowered levels of TgAb and TPO-Ab. Compared with the normal group, the model group showed increases in the proportions of Th1 and Th17 cells, a decrease in the proportion of Th2 cells, and an increase in the IFN-γ level. Compared with the model group, the four treatment groups presented decreased proportions of Th1 and Th17 cells and lowered levels of IFN-γ, and the medium-dose BYD group showed an increase in the proportion of Th2 cells. Compared with the normal group, the modeling up-regulated the mRNA levels of cGAS, STING, TBK1, and IRF3 and the protein levels of cGAS, p-STING, p-TBK1, and p-IRF3. Compared with the model group, the four treatment groups showed reduced levels of cGAS, STING, TBK1, and IRF3-positive products, down-regulated mRNA levels of cGAS, STING, and TBK1, and down-regulated protein levels of cGAS and p-STING. The high-dose BYD group showed down-regulations in the mRNA level of IRF3 and the protein levels of p-TBK1 and p-IRF3. The above results indicate that BYD can repair the imbalance of T cell subsets, alleviate immune injury, and reduce thyroid lymphocyte infiltration in AIT mice by inhibiting the cGAS-STING signaling pathway.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Signal Transduction/drug effects* ; Thyroiditis, Autoimmune/metabolism* ; Mice ; Membrane Proteins/metabolism* ; Mice, Inbred NOD ; Humans ; Female ; Nucleotidyltransferases/metabolism* ; Male ; Disease Models, Animal

This paper aimed to explore the effects of Duzhong Decoction(DZD)-containing serum on the proliferation and osteoblast differentiation of MC3T3-E1 cells through L-type voltage-gated calcium channels(L-VGCCs). L-VGCCs inhibitors, nifedipine and verapamil, were used to block L-VGCCs in osteoblasts. MC3T3-E1 cells were divided into a control group, a low-dose DZD-containing serum(L-DZD) group, a medium-dose DZD-containing serum(M-DZD) group, a high-dose DZD-containing serum(H-DZD) group, a nifedipine group, a H-DZD + nifedipine group, verapamil group, and a H-DZD + verapamil group. The CCK-8 method was used for cell proliferation analysis, alkaline phosphatase(ALP) assay kits for intracellular ALP activity measurement, Western blot for protein expression level in cells, real-time fluorescence quantitative PCR technology for intracellular mRNA expression level determination, fluorescence spectrophotometer for free Ca~(2+) concentration determination in osteoblasts, and alizarin red staining(ARS) for mineralized nodule formation in osteoblasts. The experimental results show that compared to the control group, DZD groups can promote MC3T3-E1 cell proliferation, ALP activity, and mineralized nodule formation, increase intracellular Ca~(2+) concentrations, and upregulate the protein expression of bone morphogenetic protein 2(BMP2), collagen Ⅰ(COL1), α2 subunit protein of L-VGCCs(L-VGCCα2), and the mRNA expression of Runt-related transcription factor 2(RUNX2), and BMP2. After blocking L-VGCCs with nifedipine and verapamil, the intervention effects of DZD-containing serum were inhibited to varying degrees. Both nifedipine and verapamil could inhibit ALP activity, reduce mineralized nodule areas, and downregulate the expression of bone formation-related proteins. Moreover, the effects of DZD-containing serum on increasing MC3T3-E1 cell proliferation, osteoblast differentiation, and Ca~(2+) concentrations, upregulating the mRNA expression of osteoprotegerin(OPG) and protein expression of phosphorylated protein kinase B(p-Akt) and phosphorylated forkhead box protein O1(p-FOXO1), and upregulating phosphatase and tensin homolog(PTEN) expression were reversed by nifedipine. The results indicate that DZD-containing serum can increase the Ca~(2+) concentration in MC3T3-E1 cells to promote bone formation, which may be mediated by L-VGCCs and the PTEN/Akt/FoxO1 signaling pathway, providing a new perspective on the mechanism of DZD in treating osteoporosis.
Animals ; Osteoblasts/metabolism* ; Cell Proliferation/drug effects* ; Cell Differentiation/drug effects* ; Mice ; Drugs, Chinese Herbal/pharmacology* ; Calcium Channels, L-Type/genetics* ; Alkaline Phosphatase/genetics* ; Serum/chemistry* ; Cell Line ; Osteogenesis/drug effects* ; Bone Morphogenetic Protein 2/genetics*

OBJECTIVES: To investigate the relationship between the polygenic risks for various psychiatric disorders and clinical and neuropsychological characteristics in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Using a cross-sectional design, 285 children with ADHD and 107 healthy controls were assessed using the Child Behavior Checklist, the Behavior Rating Inventory of Executive Function for parents, the Wechsler Intelligence Scale for Children, Fourth Edition, and the Cambridge Neuropsychological Test Automated Battery. Blood samples were collected for genetic data. Polygenic risk scores (PRSs) for various psychiatric disorders were calculated using the PRSice-2 software. RESULTS: Compared with the healthy controls, the children with ADHD displayed significantly higher PRSs for ADHD, major depressive disorder, anxiety disorder, and obsessive-compulsive disorder (P<0.05). In terms of daily-life executive function, ADHD-related PRS was significantly correlated with the working memory factor; panic disorder-related PRS was significantly correlated with the initiation factor; bipolar disorder-related PRS was significantly correlated with the shift factor; schizophrenia-related PRS was significantly correlated with the inhibition, emotional control, initiation, working memory, planning, organization, and monitoring factors (P<0.05). The PRS related to anxiety disorders was negatively correlated with total IQ and processing speed index (P<0.05). The PRS related to obsessive-compulsive disorder was negatively correlated with the processing speed index and positively correlated with the stop-signal reaction time index of the stop-signal task (P<0.05). CONCLUSIONS PRSs for various psychiatric disorders are closely correlated with the behavioral and cognitive characteristics in children with ADHD, which provides more insights into the heterogeneity of ADHD.
Humans ; Attention Deficit Disorder with Hyperactivity/genetics* ; Child ; Male ; Female ; Cross-Sectional Studies ; Neuropsychological Tests ; Multifactorial Inheritance ; Adolescent ; Mental Disorders/etiology* ; Executive Function ; Genetic Risk Score

Spine fracture and dislocation are common traumatic spinal conditions that often require surgical intervention due to compromised spinal stability. Surgical approaches include anterior, posterior, and combined anterior-posterior spinal procedures. According to the specific surgical requirements, patients may be placed in the prone position or repositioned between prone and supine positions during surgery. Intraoperative repositioning has become an essential step in patient positioning. However, during repositioning, patients with spinal fracture and dislocation are at increased risk for complications such as hemodynamic instability, nerve injury, and pressure injuries to the skin and soft tissue. Notably, due to the instability of the spinal cord, even minor manipulations can further exacerbate the damage, potentially leading to severe outcomes like paraplegia. Although the current clinical guidelines provide instructive recommendations for standard position, there remains no specific protocols for intraoperative repositioning in patients with spine fracture and dislocation. With a concern for the lack of clinical studies on positioning techniques, risk prevention, and operational norms for special patients, no applicable guidelines or standards are available. A consensus was required to provide clinical reference, meet the requirements of surgical treatment, and minimize the safety risks of patients caused by improper placement of positions. Professional Committee of Operating Room Nursing of Shaanxi Nursing Association organized experts in nursing management and operating room nursing from major hospitals across China to formulate Expert consensus on intraoperative repositioning for patients with spinal fracture and dislocation ( version 2025). The consensus provides 11 recommendations covering pre-repositioning preparation, intraoperative maneuvers, and post-repositioning observation, aiming to provide references for clinical standardization of the intraoperative repositioning process and protection of patients′ safety.

Objective:To explore the effects of umbilical moxibustion combined with a multi-component exercise program on perioperative rehabilitation in frail elderly patients with intertrochanteric fractures so as to provide evidence-based basis for optimizing clinical rehabilitation nursing pathways.Methods:A quasi-experimental study design was used. Convenience sampling was applied to frail select elderly patients with intertrochanteric femoral fractures, who were admitted to Zhengzhou Orthopedic Hospital from January to October 2024. According to their admission time, the patients were divided into four groups: conventional nursing group, umbilical moxibustion group (conventional nursing+umbilical moxibustion), exercise group (conventional nursing+multicomponent exercise), and combination group (conventional nursing+umbilical moxibustion combined with multicomponent exercise), with 31 patients in each group. All the patients underwent internal fixation with proximal femoral nail antirotation under anesthesia. The umbilical moxibustion protocol focused on Shenque acupoint, combined with liver-kidney-nourishing Chinese herbal powder, with each session lasting 20 minutes. The multi-component exercise program was designed in phases, including resistance, balance, and aerobic training. The Harris hip score (HHS), Tilburg frailty indicator (TFI), falls efficacy scale-international (FES-I), and Chinese version of the short form-36 health survey (SF-36) scores were compared among the four groups preoperatively, at 1 month, 3 months postoperatively, and at the last follow-up.Results:A total of 124 elderly patients were involved, including 50 males and 74 females, aged 60-80 years [(71.8±5.0)years]. All the patients were followed up for 6 months. The results of generalized estimating equation showed that the HHS, TFI, FES-I, and SF-36 scores differed significantly in terms of group effect, time effect, and interaction effect among the four groups across all the time points ( P<0.05). Simple effect analysis indicated no significant differences in preoperative HHS, TFI, FES-I, or SF-36 scores among the four groups ( P>0.05). The HHS scores at 1 and 3 months postoperatively were (54.3±5.1)points and (65.7±6.3)points in the umbilical moxibustion group, (61.3±5.3)points and (74.5±6.8)points in the exercise group, and (66.5±5.2)points and (86.3±6.7)points in the combination group, which were all significantly higher than (50.2±4.5)points and (60.7±5.1)points in the conventional nursing group ( P<0.05), with the combination group showing higher scores than the umbilical moxibustion group and exercise group ( P<0.05). At the last follow-up, the HHS score was (77.3±6.0)points in the conventional nursing group and (77.0±5.9)points in the umbilical moxibustion group ( P>0.05); the score was (83.8±4.7)points in the exercise group and (91.4±3.5)points in the combination group, which were significantly higher than that in the conventional nursing group ( P<0.05), with the combination group showing higher score than those in the umbilical moxibustion group and exercise group ( P<0.05). At 1 month, 3 months postoperatively, and at the last follow-up, the TFI total scores were 5.0(3.0, 7.0)points, 3.0(1.0, 5.0)points, and 3.0(0.0, 4.0)points in the umbilical moxibustion group, 4.0(1.0, 6.0)points, 2.0(0.0, 5.0)points, and 2.0(0.0, 3.0)points in the exercise group, and 2.0(0.0, 5.0)points, 1.0(0.0, 2.0)points, and 0.0(0.0, 1.0)points in the combination group, which were all significantly lower than those in the conventional nursing group [7.0(5.0, 10.0)points, 7.0(5.0, 9.0)points, and 6.0(5.0, 8.0)points, respectively] ( P<0.05), with the combination group showing lower scores than the umbilical moxibustion group and exercise group ( P<0.05). The physical and social dimension scores of TFI at 1 month, 3 months postoperatively, and at the last follow-up were significantly lower in the umbilical moxibustion group, exercise group, and combination group than those in the conventional nursing group ( P<0.05), with the combination group showing the lower scores than those in the umbilical moxibustion group and exercise group ( P<0.05). At 1 month postoperatively, no statistically significant difference was observed among the four groups in the psychological dimension scores of TFI ( P>0.05). At 3 months postoperatively and at the last follow-up, the psychological dimension scores of TFI in the umbilical moxibustion group, exercise group, and combination group were all lower than those in the conventional nursing group ( P<0.05), with the combination group showing the lower scores than those in the umbilical moxibustion group and exercise group ( P<0.05). At 1 month, 3 months postoperatively, and at the last follow-up, the FES-I scores were (45.3±4.3)points, (40.9±3.9)points, and (33.9±2.8)points, respectively in the umbilical moxibustion group, (38.7±3.8)points, (32.9±3.6)points, and (30.3±2.2)points, respectively in the exercise group, and (34.2±3.6)points, (30.2±2.6)points, and (27.9±1.3)points, respectively in the combination group, which were all significantly lower than those in the conventional nursing group [(50.9±4.9)points, (50.0±4.9)points, and (40.7±4.2)points] ( P<0.05), with the combination group showing lower scores than those in the umbilical moxibustion group and exercise group ( P<0.05). At 1 month, 3 months postoperatively, and at the last follow-up, the SF-36 physical health scores were (60.6±3.7)points, (76.1±3.5)points, and (78.4±2.6)points, respectively in the umbilical moxibustion group, (57.6±3.7)points, (78.4±3.7)points, and (80.4±3.1)points, respectively in the exercise group, and (65.7±3.1)points, (85.9±2.9)points, and (87.4±2.2)points, respectively in the combination group, which were all significantly higher than those in the conventional nursing group [(47.5±4.6)points, (65.9±4.6)points, and (68.3±4.4)points] ( P<0.05), with the combination group showing higher scores than those in the umbilical moxibustion group and exercise group ( P<0.05). At 1 month, 3 months postoperatively, and at the last follow-up, the SF-36 mental health scores were (59.7±4.1)points, (74.5±3.6)points, and (76.2±3.0)points, respectively in the umbilical moxibustion group, (59.4±4.6)points, (74.1±3.8)points, and (74.4±3.9)points, respectively in the exercise group, and (66.9±4.1)points, (81.6±3.3)points, and (79.9±3.7)points, respectively in the combination group, which were all significantly higher than those in the conventional nursing group [(52.8±5.2)points, (64.0±4.9)points, and (65.3±5.1)points] ( P<0.05), with the combination group showing higher scores than those in the umbilical moxibustion group and exercise group ( P<0.05). Conclusion:For elderly patients with intertrochanteric femoral fracture combined with frailty, umbilical moxibustion combined with a multi-component exercise program can significantly improve hip function, reduce frailty and fall risk, and enhance quality of life.

Direct compression is an ideal method for tablet preparation, but it requires the powder's high functional properties. The functional properties of the powder during compression directly affect the quality of the tablet. 15 parameters such as Py, FES-8KN, FES-12KN, FES-16KN, CR-8KN, CR-12KN, and CR-16KN were used as the characteristic variables in this paper. Unsupervised learning methods like principal component analysis, cluster analysis, and factor analysis were applied to analyze and classify the compression behavior data of 36 traditional Chinese medicine powders. The results showed that both different dimensionality reduction classification methods could effectively differentiate the compression behavior characteristics of 36 traditional Chinese medicine compound powders. The hierarchical cluster analysis results showed a better agreement with the actual compression phenomena of the powders, where group 1 was high elasticity and low compressibility, group 2 was easily compressed and hard to break, group 3 was excellent compressibility and compactibility. This study is expected to provide references and ideas for predicting the behavior of traditional Chinese medicine powders and the screening of tablet formulations.

Aim To investigate the neuroprotective effect of Takeda G protein-coupled receptor-5(TGR5)activated by INT-777 on hypoxic-ischemic encephalop-athy(HIE)in neonatal rats.Methods Seven-day-old SD rats were randomly divided into the sham opera-tion group(Sham,S),model group(HIE,G),INT-777 low-dose(L),medium-dose(M),and high-dose(H)groups.The modified Rice-Vanucci method was used to construct the HIE model and Intranasal admin-istration 1 h after modeling.Short-term neurobehavioral tests were performed 48 h after modeling to evaluate the neurological function of neonatal rats,TTC staining was used to determine the volume of cerebral infarction,dry and wet specific gravity was used to determine the brain water content,ferrous ion kit was used to deter-mine the brain ferrous ion content,HE staining was used to observe the pathological damage of brain tis-sue,Nissl staining was used to observe the loss of Nissl substance,Transmission electron microscopy(TEM)was used to observe the mitochondrial morphological changes of cortical neurons,and Western blot was em-ployed to detect the expression of ferroptosis-related proteins TFR1 and GPX4.Results Compared with group S,group G had increased short-term neurobehav-ioral test consumption time,higher scores,increased cerebral infarct volume,brain water content,and brain ferrous iron content,significant brain tissue damage on the affected side,severe loss of Nissl substance,smaller neuronal mitochondria,decreased mitochondrial cris-tae,and increased expression of TFR1 and reduced ex-pression of GPX4.Compared with group G,the INT-777 administration group had a shorter consumption time for short-term neurobehavioral tests,lower scores,the cerebral infarction volume,brain water content,and brain ferrous ion content decreased,the brain tissue damage on the affected side was reduced,and there was insignificant loss of Nissl substance,larger neuronal mi-tochondrial volume,increased mitochondrial cristae,re-duced expression of TFR1,and increased expression of GPX4.Conclusions INT-777 agonist TGR5 has a protective effect against hypoxic-ischemic encephalopa-thy in neonatal rats,and its mechanism of action may be related to the inhibition of neuronal ferroptosis.

Objective:To compare the efficacy, safety, and cost-effectiveness of the trastuzumab originator (HST) versus its biosimilar (HLX02) combined with pertuzumab and chemotherapy as neoadjuvant treatment in patients with HER-2-positive breast cancer.Methods:This retrospective cohort study included 175 patients with HER-2-positive breast cancer who received neoadjuvant therapy followed by curative surgery at the Cancer Hospital Chinese Academy of Medical Sciences between October 2020 and January 2024. Patients were divided into two groups based on the trastuzumab formulation used: the HST group ( n=89) and the HLX02 group ( n=86).The efficacy, safety, and trastuzumab-related treatment costs were compared between the two groups. Moreover, using Logistic regression model to identify the factors influencing total pathological complete response (tpCR) rates. Results:There were statistically significant differences in clinical T stage and surgical approach between the HST and HLX02 groups ( P＜0.05). Other clinicopathological characteristics, such as age and histological grade, showed no statistically significant differences ( P＞0.05), with most baseline characteristics remaining balanced between the two groups. There were no significant differences in tpCR rates ( P=0.957) or Miller-Payne (MP) grading rates ( P=0.991) between the HST and HLX02 groups. The tpCR rates for the two groups were 55.1% (49/89) and 54.7% (47/86), respectively. The rates of achieving grade 5 (G5) in the postoperative MP pathological grading system were 55.1% (49/89) and 55.8% (48/86), respectively, with no statistically significant difference ( P=0.991). Univariate and multivariate Logistic regression analyses showed that hormone receptor status is an independent risk factor affecting tpCR ( OR=0.31, 95% CI; 0.16-0.61, P＜0.001). The incidence of adverse event during neoadjuvant therapy was similar between the groups, with no occurrences of trastuzumab-related cardiac toxicity. The HLX02 regimen showed a lower cost-effectiveness ratio (586.48 vs. 604.96) and reduced trastuzumab treatment costs during neoadjuvant therapy compared to HST [tpCR:(31 208.37±2 191.00) CNY vs. (33 224.49±2 741.00) CNY; non-tpCR: 33 030.05±5 787.00) CNY vs. (33 412.50±4 203.00) CNY, P＜0.05]. Conclusions:In the neoadjuvant treatment of early-stage HER-2-positive breast cancer, HLX02 combined with pertuzumab and chemotherapy demonstrates similar efficacy and safety to the trastuzumab originator, while offering a significant cost advantage.