Regulation of hepatocyte phospholipid peroxidation signaling by a Chinese patent medicine against psychological stress-induced liver injury.

BACKGROUND: Psychological stress is associated with various diseases including liver dysfunction, yet effective intervention strategies remain lacking due to the unrevealed pathogenesis mechanism. PURPOSE: This study aims to explore the relevance between BMAL1-controlled circadian rhythms and lipoxygenase 15 (ALOX15)-mediated phospholipids peroxidation in psychological stress-induced liver injury, and to investigate whether hepatocyte phospholipid peroxidation signaling is involved in the hepatoprotective effects of a Chinese patent medicine, Pien Tze Huang (PZH). METHODS: Restraint stress models were established to investigate the underlying molecular mechanisms of psychological stress-induced liver injury and the hepatoprotective effects of PZH. Redox lipidomics based on liquid chromatography-tandem mass spectrometry was applied for lipid profiling. RESULTS: The present study discovered that acute restraint stress could induce liver injury. Notably, lipidomic analysis confirmed that phospholipid peroxidation was accumulated in the livers of stressed mice. Additionally, the essential core circadian clock gene Brain and Muscle Arnt-like Protein-1 (Bmal1) was altered in stressed mice. Circadian disruption in mice, as well as BMAL1-overexpression in human HepaRG cells, also appeared to have a significant increase in phospholipid peroxidation, suggesting that stress-induced liver injury is closely related to circadian rhythm and phospholipid peroxidation. Subsequently, arachidonate 15-lipoxygenase (ALOX15), a critical enzyme that contributed to phospholipid peroxidation, was screened as a potential regulatory target of BMAL1. Mechanistically, BMAL1 promoted ALOX15 expression via direct binding to an E-box-like motif in the promoter. Finally, this study revealed that PZH treatment significantly relieved pathological symptoms of psychological stress-induced liver injury with a potential mechanism of alleviating ALOX15-mediated phospholipid peroxidation. CONCLUSION: Our findings illustrate the critical role of BMAL1-triggered phospholipid peroxidation in psychological stress-induced liver injury and provide new insight into treating psychological stress-associated liver diseases by TCM intervention.

Rapid visualization of PD-L1 expression level in glioblastoma immune microenvironment via machine learning cascade-based Raman histopathology.

INTRODUCTION: Combination immunotherapy holds promise for improving survival in responsive glioblastoma (GBM) patients. Programmed death-ligand 1 (PD-L1) expression in immune microenvironment (IME) is the most important predictive biomarker for immunotherapy. Due to the heterogeneous distribution of PD-L1, post-operative histopathology fails to accurately capture its expression in residual tumors, making intra-operative diagnosis crucial for GBM treatment strategies. However, the current methods for evaluating the expression of PD-L1 are still time-consuming. OBJECTIVE: To overcome the PD-L1 heterogeneity and enable rapid, accurate, and label-free imaging of PD-L1 expression level in GBM IME at the tissue level. METHODS: We proposed a novel intra-operative diagnostic method, Machine Learning Cascade (MLC)-based Raman histopathology, which uses a coordinate localization system (CLS), hierarchical clustering analysis (HCA), support vector machine (SVM), and similarity analysis (SA). This method enables visualization of PD-L1 expression in glioma cells, CD8+ T cells, macrophages, and normal cells in addition to the tumor/normal boundary. The study quantified PD-L1 expression levels using the tumor proportion, combined positive, and cellular composition scores (TPS, CPS, and CCS, respectively) based on Raman data. Furthermore, the association between Raman spectral features and biomolecules was examined biochemically. RESULTS: The entire process from signal collection to visualization could be completed within 30 min. In an orthotopic glioma mouse model, the MLC-based Raman histopathology demonstrated a high average accuracy (0.990) for identifying different cells and exhibited strong concordance with multiplex immunofluorescence (84.31 %) and traditional pathologists' scoring (R2 ≥ 0.9). Moreover, the peak intensities at 837 and 874 cm-1 showed a positive linear correlation with PD-L1 expression level. CONCLUSIONS: This study introduced a new and extendable diagnostic method to achieve rapid and accurate visualization of PD-L1 expression in GBM IMB at the tissular level, leading to great potential in GBM intraoperative diagnosis for guiding surgery and post-operative immunotherapy.

Design and synthesis of 1H-benzo[d]imidazole selective HDAC6 inhibitors with potential therapy for multiple myeloma.

Pan-HDAC inhibitors exhibit significant inhibitory activity against multiple myeloma, however, their clinical applications have been hampered by substantial toxic side effects. In contrast, selective HDAC6 inhibitors have demonstrated effectiveness in treating multiple myeloma. Compounds belonging to the class of 1H-benzo[d]imidazole hydroxamic acids have been identified as novel HDAC6 inhibitors, with the benzimidazole group serving as a specific linker for these inhibitors. Notably, compound 30 has exhibited outstanding HDAC6 inhibitory activity (IC50 = 4.63 nM) and superior antiproliferative effects against human multiple myeloma cells, specifically RPMI-8226. Moreover, it has been shown to induce cell cycle arrest in the G2 phase and promote apoptosis through the mitochondrial pathway. In a myeloma RPMI-8226 xenograft model, compound 30 has demonstrated significant in vivo antitumor efficacy (T/C = 34.8%) when administered as a standalone drug, with no observable cytotoxicity. These findings underscore the immense potential of compound 30 as a promising therapeutic agent for the treatment of multiple myeloma.

Hosimosines A-E, structurally diverse cytisine derivatives from the seeds of Ormosia hosiei Hemsl. et Wils.

Ormosia hosiei Hemsl. et Wils (Fabaceae family) is an arbor species endemic to China. The seeds of O. hosiei have been used as traditional Chinese medicine to treat hernia, abdominal pain, blood stasis and amenorrhea. Cytisine-like and angustifoline type alkaloids were main components identified from this plant. In our research on the bioactive alkaloids from the promising Chinese medicinal plants, four new angustifoline type alkaloids (1-4) and a new cytisine-like alkaloid (5), named hosimosine A-E, together with 13 known analogues (6-18) were isolated from the seeds of O. hosiei. Their structures were elucidated by the extensive spectroscopic methods, especially the interpretation of NMR spectra and specific rotations, along with the methods of NMR and ECD calculation. Compounds 1-4 were identified as two pairs of epimers, whose relative configurations were deduced from density functional theory (DFT) calculations of NMR chemical shifts and DP4+ analysis, and absolute configurations were determined by comparison of their experimental and theoretical ECD spectra. Compound 5 displayed two sets of NMR data caused by the existence of tautomeric forms. Compounds 14, 17 and 18 were determined to be enantiomers of literature compounds. Some of the isolates exhibited moderate cytotoxic effects against HepG2, A2780 and MCF-7 cells.

[Research progress on chemical structures and pharmacological effects of natural cytisine and its derivatives].

Cytisine derivatives are a group of alkaloids containing the structural core of cytisine, which are mainly distributed in Fabaceae plants with a wide range of pharmacological activities, such as resisting inflammation, tumors, and viruses, and affecting the central nervous system. At present, a total of 193 natural cytisine and its derivatives have been reported, all of which are derived from L-lysine. In this study, natural cytisine derivatives were classified into eight types, namely cytisine type, sparteine type, albine type, angustifoline type, camoensidine type, cytisine-like type, tsukushinamine type, and lupanacosmine type. This study reviewed the research progress on the structures, plant sources, biosynthesis, and pharmacological activities of alkaloids of various types.

GPX4 deficiency-dependent phospholipid peroxidation drives motor deficits of ALS.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by oxidative stress that triggers motor neurons loss in the brain and spinal cord. However, the mechanisms underlying the exact role of oxidative stress in ALS-associated neural degeneration are not definitively established. Oxidative stress-generated phospholipid peroxides are known to have extensive physiological and pathological consequences to tissues. Here, we discovered that the deficiency of glutathione peroxidase 4 (GPX4), an essential antioxidant peroxidase, led to the accumulation of phospholipid peroxides and resulted in a loss of motor neurons in spinal cords of ALS mice. Mutant human SOD1G93A transgenic mice were intrathecally injected with neuron-targeted adeno-associated virus (AAV) expressing GPX4 (GPX4-AAV) or phospholipid peroxidation inhibitor, ferrostatin-1. The results showed that impaired motor performance and neural loss induced by SOD1G93A toxicity in the lumbar spine were substantially alleviated by ferrostatin-1 treatment and AAV-mediated GPX4 delivery. In addition, the denervation of neuron-muscle junction and spinal atrophy in ALS mice were rescued by neural GPX4 overexpression, suggesting that GPX4 is essential for the motor neural maintenance and function. In comparison, conditional knockdown of Gpx4 in the spinal cords of Gpx4fl/fl mice triggered an obvious increase of phospholipid peroxides and the occurrence of ALS-like motor phenotype. Altogether, our findings underscore the importance of GPX4 in maintaining phospholipid redox homeostasis in the spinal cord and presents GPX4 as an attractive therapeutic target for ALS treatment.

Effect of Lactobacillus plantarum ZFM4 in Helicobacter pylori-infected C57BL/6 mice: prevention is better than cure.

Objectives: This study was performed to explore the preventive and therapeutic effects of Lactobacillus plantarum ZFM4 on H. pylori infections of the stomach tissue in C57BL/6 mice. Methods: In this study, 40 specific-pathogen-free female C57BL/6 mice were randomly divided into five groups, namely, the control, ZFM4 pretreatment) ZFM4 pretreatment before H. pylori infected), model (H. pylori infected), triple therapy (H. pylori infected and treated with triple therapy), and ZFM4 treatment groups (H. pylori infected and treated with ZFM4). The preventive and therapeutic effects of Lactobacillus plantarum ZFM4 were evaluated in H. pylori-infected C57BL/6 mice by assessing gastric tissue morphology, inflammatory cytokine levels, microbial composition, and microbial diversity. Results: Lactobacillus plantarum ZFM4 was able to survive in low gastric pH and play a role in preventing H. pylori infection. This was evident from a reduction in both, the gastric inflammatory response and expression of inflammatory factors caused by H. pylori infection. Lactobacillus plantarum ZFM4 could also inhibit the growth of H. pylori via its beneficial impact on the gastric microbiota. Conclusion: Our findings suggest that Lactobacillus plantarum ZFM4 offers superior preventive effects against H. pylori infections when used alone. However, the therapeutic effect on established infections is weaker. Further clinical trials are needed to confirm the specific dosage, duration, and other aspects of administration.

Phospholipid peroxidation inhibits autophagy via stimulating the delipidation of oxidized LC3-PE.

Phospholipid peroxidation of polyunsaturated fatty acids at the bis-allylic position drives ferroptosis. Here we identify a novel role for phospholipid peroxidation in the inhibition of autophagy. Using in vitro and in vivo models, we report that phospholipid peroxidation induced by glutathione peroxidase-4 inhibition and arachidonate 15-lipoxygenase overexpression leads to overload of peroxidized phospholipids and culminate in inhibition of autophagy. Functional and lipidomics analysis further demonstrated that inhibition of autophagy was associated with an increase of peroxidized phosphatidylethanolamine (PE) conjugated LC3. We further demonstrate that autophagy inhibition occurred due to preferential cleavage of peroxidized LC3-PE by ATG4B to yield delipidated LC3. Mouse models of phospholipid peroxidation and autophagy additionally supported a role for peroxidized PE in autophagy inhibition. Our results agree with the recognized role of endoplasmic reticulum as the primary source for autophagosomal membranes. In summary, our studies demonstrated that phospholipid peroxidation inhibited autophagy via stimulating the ATG4B-mediated delipidation of peroxidized LC3-PE.

The mutation spectrum of Parkinson-disease-related genes in early-onset Parkinson's disease in ethnic Chinese.

BACKGROUND AND PURPOSE: Recent genetic progress has shown many causative/risk genes linked to Parkinson's disease (PD), mainly in patients of European ancestry. The study aimed to investigate the PD-related genes and determine the mutational spectrum of early-onset PD in ethnic Chinese. METHODS: In this study, whole-exome sequencing and/or gene dosage analysis were performed in 704 early-onset PD (EOPD) patients (onset age ≤45 years) and 1866 controls. Twenty-six PD-related genes and 20 other genes linked to neurodegenerative and lysosome diseases were analysed. RESULTS: Eighty-two (11.6%, 82/704) EOPD patients carrying rare pathogenic/likely pathogenic variants in PD-related genes were identified. The mutation frequency in autosomal recessive inheritance EOPD (42.9%, 27/63) was much higher than that in autosomal dominant inheritance EOPD (0.9%, 12/110) or sporadic EOPD (8.1%, 43/531). Bi-allelic mutations in PRKN were the most frequent, accounting for 5.1% of EOPD cases. Three common pathogenic variants, p.A53V in SNCA, p.G284R in PRKN and p.P53Afs*38 in CHCHD2, occur exclusively in Asians. The putative damaging variants from GBA, PRKN, DJ1, PLA2G6 and GCH1 contributed to the collective risk for EOPD. Notably, the protein-truncating variants in CHCHD2 were enriched in EOPD, especially for p.P53Afs*38, which was also found in three patients from an independent cohort of patients with late-onset PD (n = 1300). Functional experiments confirmed that truncated CHCHD2 variants cause loss of function and are linked to mitochondrial dysfunction. CONCLUSIONS: Our study reveals that the genetic spectrum of EOPD in Chinese, which may help develop genetic scanning strategies, provided more evidence supporting CHCHD2 in PD.

[Two novel cephalotaxine-type alkaloids from Cephalotaxus sinensis].

Silica gel, octadecyl-silica(ODS), Sephadex LH-20, and semi-preparative high performance liquid chromatography(HPLC) was performed to isolate nine cephalotaxine-type alkaloids from Cephalotaxus sinensis: 8-oxodeoxyharringtonine(1), 8-oxonordeoxyharringtonine(2), cephafortunine A(3), 8-oxocephalotaxine(4), deoxyharringtonine(5), acetylcephalotaxine(6), cephalotaxine(7), epicephalotaxine(8), and cephalotaxinone(9). Compounds 1 and 2 were identified for the first time and their structures were determined by high-resolution-electrospray ionization-mass spectrometry(HR-ESI-MS), nuclear magnetic resonance(NMR), and electronic circular dichroism(ECD). Compounds 1-3 and 5 significantly inhibited the transcription of nuclear factor kappa B(NF-κB), with the half-maximal inhibitory concentration(IC_(50)) of(3.91±0.70),(2.99±0.45),(7.84±0.51), and(1.46±0.17) µmol·L~(-1), respectively.

Comparative Study between ZOOMit and Conventional Intravoxel Incoherent Motion MRI for Assessing Parotid Gland Abnormalities in Patients with Early- or Mid-Stage Sjögren's Syndrome.

OBJECTIVE: To compare the reproducibility and performance of quantitative metrics between ZOOMit and conventional intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) in the diagnosis of early- and mid-stage Sjögren's syndrome (SS). MATERIALS AND METHODS: Twenty-two patients (mean age ± standard deviation, 52.0 ± 10.8 years; male:female, 2:20) with early- or mid-stage SS and 20 healthy controls (46.9 ± 14.6 years; male:female, 7:13) were prospectively enrolled in our study. ZOOMit IVIM and conventional IVIM MRI were performed simultaneously in all individuals using a 3T scanner. Quantitative IVIM parameters - including tissue diffusivity (D), pseudodiffusion coefficient (D*), and perfusion fraction (f) - inter- and intra-observer reproducibility in measuring these parameters, and their ability to distinguish patients with SS from healthy individuals were assessed and compared between ZOOMit IVIM and conventional IVIM methods, appropriately. MR gland nodular grade (MRG) was also examined. RESULTS: Inter- and intra-observer reproducibility was better with ZOOMit imaging than with conventional IVIM imaging (ZOOMit vs. conventional, intraclass correlation coefficient of 0.897-0.941 vs. 0.667-0.782 for inter-observer reproducibility and 0.891-0.968 vs. 0.814-0.853 for intra-observer reproducibility). Significant differences in ZOOMit f, ZOOMit D*, conventional D*, and MRG between patients with SS and healthy individuals (all p < 0.05) were observed. ZOOMit D* outperformed conventional D* in diagnosing early- and mid-stage SS (area under receiver operating curve, 0.867 and 0.658, respectively; p = 0.002). The combination of ZOOMit D*, MRG, and ZOOMit f as a new diagnostic index for SS, increased diagnostic area under the curve to 0.961, which was higher than that of any single parameter (all p < 0.01). CONCLUSION: Considering its better reproducibility and performance, ZOOMit IVIM may be preferred over conventional IVIM MRI, and may subsequently improve the ability to diagnose early- and mid-stage SS.

[Using changes of left cardiac functional parameters and CPET evaluated the clinical effectiveness of individualized precise exercise overall program management of chronic disease I --Analysis between groups].

Objective: To explore and study the clinical usefulness of continuous dynamic recording of left cardiac function changes forevaluation the improvement in patients with chronic disease after 3 months of intensive control of individualized precision exercise overall manage program. Methods: From 2018 to 2021, 21 patients with chronic cardiovascular and cerebrovascular metabolic diseases mainly controlled by our team were selected to complete the cardiopulmonary exercise test (CPET) and Non-invasive synchronous cardiac function detector (N-ISCFD), electrocardiogram, radial pulse wave, jugular pulse wave and cardiogram data were continuously recorded for 50s.According to the titration results under CPET and continuous functional parameters monitoring, a holistic plan with individualized moderate exercise intensity as the core was developed for 3 months of intensive management, and then N-ISCFD data collection was repeatedafter signing the informed consent. All N-ISCFD data were analyzed in the 50s according to the optimal report mode of Fuwai Hospital and 52 cardiac functional indexes were calculated. The data before and after the enhanced control were compared and the paired T-test was used to statistically analyze the changes of groups. Results: Twenty-one patients with chronic diseases (16 male and 5 female) were (54.05±12.77,29~75) years, BMI (25.53±4.04,16.62~31.7) kg/m2.Comparison with baseline,the whole group analysis: ①The body weight, BMI, systolic blood pressure and diastolic blood pressure of patients were significantly decreased(P＜0.01).②CPET Peak VO2 was (64.93±24.22, 26.96~103.48) %Pred before enhanced control, and (85.22±30.31, 43.95~140.48) %Pred after enhanced control, and increased (35.09±27.87, 0.12~129.35) % after enhanced control compared with before enhanced control. The AT, Peak VO2/HR, Peak Work Rate, OUEP, FVC, FEV1, FEV3/FVC% and MVV were significantly increased (P＜0.01) and the Lowest VE/VCO2 and VE/VCO2 Slope were significantly decreased(P＜0.01).③Core indicators of left heart function:Ejection fraction was significantly increased from (0.60±0.12,0.40~0.88) to(0.66±0.09, 0.53~0.87)(P＜ 0.01), by (12.39±14.90,-12.32~41.11)%. The total peripheral resistance was significantly decreased from (1579.52±425.45,779.46~2409.61) G/(cm4·s),to(1340.44±261.49,756.05~1827.01) G/(cm4·s)(P＜0.01), by (12.00±17.27,37.79~28.61) %.The left stroke index, cardiac total power, ejective pressure and left ventricular end diastolic volumewere significantly improved (P＜0.05).The change analysis of each indicator for each patient is shown in the individualized analysis section of this study. Conclusion: Use CPET and continuous functional monitoring we can safely and effectively develop the overall program of individualized exercise in patients with chronic diseases. Long-term intensive management and control can safely and effectively significantly improve the cardiovascular function of patients. Continuous dynamic recording of changes in left and right cardiac functional parameters can be a simple way to supplement CPET to evaluate cardiovascular function.

Assessment of kidney function in chronic kidney disease by combining diffusion tensor imaging and total kidney volume.

OBJECTIVE: This study aimed to investigate the value and feasibility of combining fractional anisotropy (FA) values from diffusion tensor imaging (DTI) and total kidney volume (TKV) for the assessment of kidney function in chronic kidney disease (CKD). MATERIALS AND METHODS: Fifty-one patients were included in this study. All MRI examinations were performed with a 3.0 T scanner. DTI was used to measure FA values, and TKV was obtained from DTI and T2-weighted imaging (T2WI). Patients were divided into three groups (mild, moderate, severe) according to eGFR, which was calculated with serum creatinine. Differences in the FA values of the cortex and medulla were analysed among the three groups, and the relationships of FA values, TKV, and the product of the FA values and TKV with eGFR were analysed. Receiver operating characteristic (ROC) curve analysis was used to compare the diagnostic efficiency of the FA values, TKV, and the product of the FA values and TKV for kidney function in different CKD stages. RESULTS: Medullary FA values (m-FA), TKV, and the product of the m-FA values and TKV (m-FA-TKV) were significantly correlated with eGFR (r = 0.653, 0.685, and 0.797, respectively; all P < 0.001). ROC curve analysis showed that m-FA-TKV exhibited better diagnostic performance than m-FA values (P = 0.022). CONCLUSION: m-FA-TKV obtained by DTI significantly improves the accuracy of kidney function assessment in CKD patients.

Precise anatomical localization and classification of rib fractures on CT using a convolutional neural network.

OBJECTIVE: To develop a convolutional neural network (CNN) model for the detection, precise anatomical localization (right 1-12th and left 1-12th) and classification (fresh, healing and old fractures) of rib fractures automatically, and to compare the performance with the experienced radiologists. MATERIALS AND METHODS: A total of 640 rib fracture patients with 340,501 annotations were retrospectively collected from three hospitals. They consisted of a classification training dataset (n = 482), a localization training dataset (n = 30), an internal testing dataset (n = 90) and an external testing dataset (n = 38). RetinaNet with rib localization postprocessing and the result merging technique were employed to structure the CNN model. ROC curve, free-response ROC curve, AUC, precision, recall, and F1-score were calculated to choose the better option between model I (training classification and localization data together) and model II (adding an additional classification model to model I). RESULTS: The detection and classification performance of rib fractures was better in model II than in model I. The sensitivity of localization reached 97.11% and 94.87% on the right and left ribs, respectively. In the external dataset with different CT scanner and slice thickness, model II showed better diagnostic performance. Moreover, the CNN model was superior in diagnosing fresh and healing fractures to 5 radiologists and consumed shorter diagnosis time. CONCLUSIONS: Our CNN model was capable of detection, precise anatomical localization, and classification of rib fractures automatically.

Role of genetics in amyotrophic lateral sclerosis: a large cohort study in Chinese mainland population.

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.

Aberrant functional and effective connectivity of the frontostriatal network in unilateral acute tinnitus patients with hearing loss.

PURPOSE: The present study combined resting-state functional connectivity (FC) and Granger causality analysis (GCA) to explore frontostriatal network dysfunction in unilateral acute tinnitus (AT) patients with hearing loss. METHODS: The participants included 42 AT patients and 43 healthy control (HC) subjects who underwent resting-state functional magnetic resonance imaging (fMRI) scans. Based on the seed regions in the frontostriatal network, FC and GCA were conducted between the AT patients and HC subjects. Correlation analyses were used to examine correlations among altered FC values, GCA values, and clinical features in AT patients. RESULTS: Compared with HCs, AT patients showed a general reduction in FC between the seed regions in the frontostriatal network and nonauditory areas, including the frontal cortices, midcingulate cortex (MCC), supramarginal gyrus, and postcentral gyrus (PoCG). Using the GCA algorithm, we detected abnormal effective connectivity (EC) in the inferior occipital gyrus, MCC, Cerebelum_Crus1, and PoCG. Furthermore, correlations between disrupted FC/EC and clinical characteristics, especially tinnitus distress-related characteristics, were found in AT patients. CONCLUSIONS: Our work demonstrated abnormal FC and EC between the frontostriatal network and several nonauditory regions in AT patients with hearing loss, suggesting that multiple large-scale network dysfunctions and interactions are involved in the perception of tinnitus. These findings not only enhance the current understanding of the frontostriatal network in tinnitus but also serve as a reminder of the importance of focusing on tinnitus at an early stage.

Abieshanesides A and B, two unique ent-18,19-dinoricetexane diterpenoid glycosides from Abies beshanzuensis M.H. Wu.

Two unprecedented ent-18,19-dinoricetexane diterpenoid glycosides, named abieshanesides A (1) and B (2), together with seven known compounds, have been isolated from the dead trunks and branches of Abies beshanzuensis M.H. Wu. To our knowledge, abieshanesides A and B represent the first ent-18,19-dinoricetexane diterpenoid glycosides found in natural sources. Their structures and absolute configurations were elucidated by using a combination of spectroscopic techniques and comparison of experimental and calculated electronic circular dichroism (ECD) data. The MTT experiments showed that (E)-resveratrol (7) could inhibit viability of MH7A cells with the IC50 value of 12.5 µM. Compound 7 was able to block MH7A cell proliferation and was associated with G0/G1-phase cell cycle arrest. Flow cytometric analysis showed that the treatment by 7 significantly induced the proliferation of MH7A cells in a dose-dependent manner.

Discovery of new genetic loci for male sexual orientation in Han population.

Epidemiological studies have demonstrated that the genetic factors partly influence the development of same-sex sexual behavior, but most genetic studies have focused on people of primarily European ancestry, potentially missing important biological insights. Here, we performed a two-stage genome-wide association study (GWAS) with a total sample of 1478 homosexual males and 3313 heterosexual males in Han Chinese populations and identified two genetic loci (rs17320865, Xq27.3, FMR1NB, Pmeta = 8.36 × 10-8, OR = 1.29; rs7259428, 19q12, ZNF536, Pmeta = 7.58 × 10-8, OR = 0.75) showing consistent association with male sexual orientation. A fixed-effect meta-analysis including individuals of Han Chinese (n = 4791) and European ancestries (n = 408,995) revealed 3 genome-wide significant loci of same-sex sexual behavior (rs9677294, 2p22.1, SLC8A1, Pmeta = 1.95 × 10-8; rs2414487, 15q21.3, LOC145783, Pmeta = 4.53 × 10-9; rs2106525, 7q31.1, MDFIC, Pmeta = 6.24 × 10-9). These findings may provide new insights into the genetic basis of male sexual orientation from a wider population scope. Furthermore, we defined the average ZNF536-immunoreactivity (ZNF536-ir) concentration in the suprachiasmatic nucleus (SCN) as lower in homosexual individuals than in heterosexual individuals (0.011 ± 0.001 vs 0.021 ± 0.004, P = 0.013) in a postmortem study. In addition, compared with heterosexuals, the percentage of ZNF536 stained area in the SCN was also smaller in the homosexuals (0.075 ± 0.040 vs 0.137 ± 0.103, P = 0.043). More homosexual preference was observed in FMR1NB-knockout mice and we also found significant differences in the expression of serotonin, dopamine, and inflammation pathways that were reported to be related to sexual orientation when comparing CRISPR-mediated FMR1NB knockout mice to matched wild-type target C57 male mice.

[Individualization analysis of pulse wave shape characteristics before and after single precise power exercise in young healthy subjects].

Objective: To observe and study the resting radial artery pulse wave and the pulse wave changes after a single individualized exercise in young healthy normal subjects. Methods: We selected 16 young healthy graduate students, advanced training doctors, and visiting scholars from Fuwai Hospital without any disease diagnosis and low daily exercise. They first completed the symptom-restricted limit cardiopulmonary exercise testing (CPET). A single individualized exercise with Δ50% power as the exercise intensity was completed within one week after CPET. We measured and recorded 50 s pulse wave data before exercise and 10 min, 20 min, 30min after exercise, let the instrument automatically fix the point and then manually recheck to obtain each pulse wave characteristic point: starting point (B), main wave peak point (P1), trough of a repulse point (PL), crest of a repulse point (P2), and end point (E), and the raw data of the abscissa (time T) and ordinate (amplitude Y) corresponding to each point were derived from the instrument. We treated the end point E of the previous pulse wave as the start point B of the next wave, returned TB to zero, and got the main observation indicators: YB, YP1, YPL, YP2 and TP1, TPL, TP2, TE, and calculated out ΔYP1 (YP1-YB), ΔYPL (YPL-YB), ΔYP2 (YP2-YB), TE-TPL, (TE-TPL)/TPL, pulse rate, S1 (the slope of main wave ascending branch), S2 (the slope of dicrotic ascending branch), ΔYP2-ΔYPL and TP2-TPL as secondary observation indicators; defined the dicrotic wave with obvious crest as YP2>YPL, and calculated the occurrence rate of dicrotic wave with obvious crest (number of waveforms with YP2>YPL in 50 s /total number of waveforms×100%). We analyzed individually the 50 s pulse wave data of each subject before and after exercise, and then averaged all the data for overall analysis. Results: ①16 healthy young subjects (males 10, females 6), age (30.6±6.4, 24~48) years old; height (170.4±8.2, 160~188) cm; body mass (63.9±12.8, 43~87) kg. ②YB (87.2±5.8, 78.1~95.9), YP1 (223.5±15.8, 192.7~242.3), YPL (122.8±7.8, 110.0~133.8), YP2 (131.4±4.9, 116.7~137.5), TP1 (126.2±42.2, 94.2~280.0), TPL (360.2±44.8, 311.5~507.3), TP2 (432.4±50.8, 376.2~589.0), TE (899.7±86.9, 728.3~1042.0). ΔYP1 (136.3±19.9, 96.8~ 158.6), ΔYPL (35.7±10.7, 16.0~55.7), ΔYP2 (44.3±8.1, 22.5~56.5), TE-TPL (539.5±79.3, 405.9~691.3), (TE-TPL)/TPL (1.5±0.3, 0.8~2.0), pulse rate (67.3±6.6, 57.6~82.4), S1 (1.1±0.2, 0.6~1.4), S2 (0.1±0.1, 0.0~0.2), ΔYP2-ΔYPL (8.6±6.1, 0.9 ~19.8), TP2-TPL (72.3±19.9, 38.3~108.4). ③10 min after exercise, YPL (97.0±13.2 vs 122.8±7.8), YP2 (109.6±12.8 vs 131.4±4.9), ΔYPL (6.6±9.8 vs 35.7±10.7), ΔYP2 (19.3±11.2 vs 44.3±8.1), TE (667.8±123.1 vs 899.7±86.9), TE-TPL (330.2±128.4 vs 539.5±79.3), (TE-TPL)/TPL (1.0±0.4 vs 1.5±0.3) decreased, while the pulse rate (92.2± 14.0 vs 67.3±6.6), ΔYP2-ΔYPL (12.7±9.7 vs 8.6±6.1), TP2-TPL (98.0±38.1 vs 72.3±19.9) increased (all P<0.05). The trend of pulse wave changes at 20 min and 30 min after exercise was consistent with that at 10 min after exercise, but from 20 min, most of the indicators gradually recovered to the resting level before exercise. ④The incidence of dicrotic waves with obvious peaks in 16 young healthy persons at rest was 94.5%, and increased at 10 min (96.3%), 20 min (98.5%), and 30 min (99.8%) after exercise (all P<0.01). Among them, the incidence of dicrotic waves with obvious peaks before and after exercise was maintained at about 100% in 10 subjects. The appearance rate of 2 cases had reached 100% before exercise, but it decreased at 10 minutes after exercise, and then continued to increase, at 30 minutes recovered to 100%. Three subjects had a low resting rate and started to increase after exercise. In 1 case, the rate was low only 20 minutes after exercise, considering the influence of human factors. Conclusion: The influence of exercise on the pulse wave of normal people is mainly reflected in the dicrotic wave. On the whole, after a single precise power exercise, the position of the dicrotic wave is reduced, the amplitude is deepened, and the appearance rate of the dicrotic wave with obvious crest is generally increased, and this change can be maintained for at least 30 minutes. From an individual point of view, the response trend of each subject is different.