Longxuetongluo Capsule alleviate ischemia/reperfusion induced cardiomyocyte apoptosis through modulating oxidative stress and mitochondrial dysfunction.

BACKGROUND: Chinese dragon's blood, the red resin of Dracaena cochinchinensis (Lour.) S. C. Chen., is widely used to treat cardiovascular and cerebrovascular diseases in China. Longxuetongluo Capsule (LTC) is a total phenolic compound extracted from Chinese dragon's blood, currently used in treating ischemic stroke. Myocardial injury can be aggravated after reperfusion of ischemic myocardium, which is called myocardial ischemia-reperfusion injury (MIRI), and the mechanism of MIRI is complex. However, the exact effect and mechanism of LTC on MIRI are still unclear. We explore the effect of LTC on alleviating MIRI based on mitochondrial dysfunction and oxidative stress. AIM OF THE STUDY: To explore the cardioprotective mechanism of LTC against MIRI. MATERIALS AND METHODS: A rat MIRI model was constructed through ligation of the left anterior descending coronary artery, and LTC was given continuously for 28 days before surgery. The H9c2 cardiomyocyte injury model was induced by oxygen-glucose deprivation/reperfusion (OGD/R), and LTC was given 24 h before OGD. Myocardial ischemia areas were detected with 2,3,5-triphenyltetrazolium chloride (TTC) staining. Cardiac histopathological changes were detected with hematoxylin-eosin (HE) staining. And biochemical indexes were detected with serum biochemical kit. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) staining and flow cytometry were used to detect apoptosis. Fluorescent probes were used to observe reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm), Ca2+and other indexes. MitoTracker staining and immunofluorescence were used to observe the morphology of mitochondria and translocation of dynamin-related protein 1 (Drp1). Finally, immunohistochemistry and Western blotting were used to examine the expression of proteins related to apoptosis, mitochondrial fission and fusion and oxidative stress. RESULTS: LTC could ameliorate cardiac pathological changes, decrease myocardial infarct area and the content or level of relevant serum cardiac enzymes, indicating that LTC could alleviate MIRI. Meanwhile, LTC could inhibit cardiomyocyte apoptosis via regulating apoptosis-related protein expression, and it could restore mitochondrial morphology, maintain ΔΨm, inhibit mitochondrial ROS generation and Ca2+ accumulation, increase the expression of mitochondrial fusion protein 2 (Mfn2), decrease the level of phosphorylation dynamin-related protein 1 (p-Drp1), and regulate ATP synthesis, thereby significantly ameliorating mitochondrial dysfunction. Moreover, LTC significantly reduced the expression of NADPH oxidase 2 (NOX2), NADPH oxidase 4 (NOX4) and neutrophil cytosolic factor 2 (NOXA2/p67phox), and reduced ROS production. CONCLUSION: The study demonstrated that LTC could inhibit MIRI induced cardiomyocyte apoptosis by inhibiting ROS generation and mitochondrial dysfunction, and these fundings suggested that LTC can be used to alleviate MIRI, which provides a potential therapeutic approach for future treatment of MIRI.

Correlation between Circle of Willis configuration and intracranial arterial dolichoectasia, and genetic contributions.

OBJECTIVES: Intracranial arterial dolichoectasia (IADE) is characterized by the dilation, elongation, and tortuosity of intracranial arteries. We aimed to investigate the association between variations of the Circle of Willis (COW) and IADE in the general population, as well as estimate the genetic correlation between COW variations and IADE. METHODS: A total of 981 individuals from a population-based cohort were included. Brain magnetic resonance angiography was performed to assess COW variants and measure the diameters of intracranial arteries. IADE was defined as a total intracranial volume-adjusted diameter ≥ 2 standard deviations. Logistic regression models were used to analyze the association between COW variations and IADE. The heritability and genetic correlation were estimated using genome-wide complex trait analysis (GCTA) based on single nucleotide polymorphism (SNP) array data. RESULTS: The prevalence of IADE was 6.2 %. Hypoplastic/absent A1 segments were associated with an increase in contralateral ICA diameter (ß ± SE, 0.279 ± 0.049; p = 0.001) and a decrease in ipsilateral ICA diameter (ß ± SE, -0.300 ± 0.050; p = 0.001). Fetal-type posterior cerebral artery (FTP) was associated with a larger ICA diameter (ß ± SE, 0.326 ± 0.048; p = 0.001) and a smaller BA diameter (ß ± SE, -0.662 ± 0.043; p = 0.001). FTP revealed a positive genetic correlation with ICA dilation (rG = 0.259 ± 0.175; p = 0.0009) and a negative genetic correlation with BA dilation (rG = -0.192 ± 0.153, p = 0.015). CONCLUSIONS: There was an association between COW variations and larger intracranial arterial diameters in the general population. Genetic factors may play a role in the development of intracranial arterial dilation and the formation of COW variants.

Genome-Wide Mendelian Randomization Study Reveals Druggable Genes for Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease (CSVD) is a group of neurological disorders that affect the small blood vessels within the brain, for which no effective treatments are currently available. We conducted a Mendelian randomization (MR) study to identify candidate therapeutic genes for CSVD. METHODS: We retrieved genome-wide association study data from 6 recently conducted, extensive investigations focusing on CSVD magnetic resonance imaging markers and performed a 2-sample MR analysis to assess the potential causal effects of gene expression and protein level within druggable genes on CSVD in blood and brain tissues. Colocalization analyses and repeat studies were undertaken to verify the relationship. Additionally, mediation analysis was conducted to explore the potential mechanisms involving druggable genes and known risk factors for CSVD. Finally, phenome-wide MR analyses were applied to evaluate the potential adverse effects related to the identified druggable genes for CSVD treatment. RESULTS: Overall, 5 druggable genes consistently showed associations with CSVD in MR analyses across both the discovery and validation cohorts. Notably, the ALDH2 and KLHL24 genes were identified as associated with CSVD in both blood and brain tissues, whereas the genes ADRB1, BTN3A2, and EFEMP1 were exclusively detected in brain tissue. Moreover, mediation analysis elucidated the proportion of the total effects mediated by CSVD risk factors through candidate druggable genes, which ranged from 5.5% to 18.5%, and offered potential explanations for the observed results. A comprehensive phenome-wide MR analysis further emphasized both the therapeutic benefits and potential side effects of targeting these candidate druggable genes. CONCLUSIONS: This study provides genetic evidence supporting the potential therapeutic benefits of targeting druggable genes for treating CSVD, which will be useful for prioritizing CSVD drug development.

[Effects of epimedium total flavone capsules on post-stroke cognitive impairment in rats].

To investigate the effect of epimedium total flavone capsules on post-stroke cognitive impairment(PSCI) in rats. The transient middle cerebral artery occlusion(tMCAO) model was constructed on selected rats, and rats with impaired neurological function were randomly divided into the model group, low, middle, and high dose groups of epimedium total flavone capsules, and nimodipine tablet group. The cognitive function of rats was measured after administration. Pathological changes in brain tissue were observed after hematoxylin-eosin staining(HE). Neuronal nuclei(NeuN) and glial fibrillary acidic protein(GFAP) distribution in brain tissue were tested by immunofluorescent staining. The level of amyloid beta 1-42(Aß_(1-42)), neuron specific enolase(NSE), acetylcholine(ACH), dopamine(DA), 5-hydroxytryptamine(5-HT), norepinephrine(NE), interleukin-1ß(IL-1ß), tumor necrosis factor-α(TNF-α), and hypersensitive C-reactive protein(hs-CRP) in rat serum was tested. Moreover, Western blot was utilized to test the expression of nuclear factor-kappaB(NF-κB), p-NF-κB, alpha inhibitor of NF-κB(IκBα) protein, and p-IκBα protein in the hippocampus. The experimental results showed that epimedium total flavone capsules can improve the cognitive function of model rats, and the mechanism may be related to the regulation of the expression of p-IκBα and p-NF-κB proteins, so as to inhibit inflammatory response induced by ischemia-reperfusion.

[Clinical affect of contralateral knee pain on patients undergoing total knee arthroplasty].

OBJECTIVE: To evaluate the effect of contralateral knee pain on joint dysfunction and treatment satisfaction on the operative side 1 year after total knee arthroplasty（TKA） in patients with osteoarthritis. METHODS: From March 2019 to January 2021, 635 patients underwent TKA including 296 males and 339 females, with an average age of （69.33±9.38） years old, the duration of symptoms was （1.15±0.44） years. According to the degree of pain visual analogue scale（VAS） in the contralateral knee joint 12 months after operation, the patients were divided into three groups, 423 patients with no or mild pain（VAS 0 to 3）, 105 patients with moderate pain（VAS 4 to 6）, 107 patients with severe pain（VAS 7 to 10）. The related factors of knee function and satisfaction score 12 months after operation were analyzed and compared on different contralateral knee pain levels. RESULTS: The contralateral knee pain VAS was significantly reduced after TKA. Old age, high body mass index, high WOMAC scores of postoperative knee joint, moderate and severe pain of contralateral knee joint were the risk factors of dissatisfaction （P<0.05）, OR were 1.285, 1.665, 2.319, 1.863 respectively. The high degree of knee pain on the operation side and the ladder room in the home environment were the risk factors for the high WOMAC scores 1 year after discharge（P<0.05）. Adherence to exercise and functional training after discharge were the protective factors for patients with high WOMAC scores 1 year after discharge（P<0.05）, OR were 3.016, 1.738, 0.619, 0.574 respectively. CONCLUSION: TKA can alleviate the pain of contralateral knee joint. Contralateral knee pain does not affect the WOMAC scores after TKA, but it will reduce the treatment satisfaction of patients.

Transcriptomic and network analysis identifies shared and unique pathways and immune changes across fibrotic interstitial lung diseases.

BACKGROUND: Interstitial lung disease (ILD) encompasses a diverse group of disorders characterized by chronic inflammation and fibrosis of the pulmonary interstitium. Three ILDs, namely idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (fHP), and connective tissue disease-associated ILD (CTD-ILD), exhibit similar progressive fibrosis phenotypes, yet possess distinct etiologies, encouraging us to explore their different underlying mechanisms. METHODS: Transcriptome data of fibrotic lung tissues from patients with IPF, fHP, and CTD-ILD were subjected to functional annotation, network, and pathway analyses. Additionally, we employed the xCell deconvolution algorithm to predict immune cell infiltration in patients with fibrotic ILDs and healthy controls. RESULTS: We identified a shared progressive fibrosis-related module in these diseases which was related to extracellular matrix (ECM) degradation and production and potentially regulated by the p53 family transcription factors. In IPF, neuron-related processes emerged as a critical specific mechanism in functional enrichment. In fHP, we observed that B cell signaling and immunoglobulin A (IgA) production may act as predominant processes, which was further verified by B cell infiltration and the central role of CD19 gene. In CTD-ILD, active chemokine processes were enriched, and active dendritic cells (aDCs) were predicted to infiltrate the lung tissues. CONCLUSIONS: This study revealed shared and specific molecular and cellular pathways among IPF, fHP, and CTD-ILD, providing a basis for understanding their pathogenesis and identifying potential therapeutic targets.

[Research and development practice of traditional Chinese medicine based on network target theory and technology].

Network targets theory and technology have transcended the limitations of the "single gene, single target" model, aiming to decipher the mechanisms of traditional Chinese medicine(TCM) based on biological network from the perspective of informatics and system. As the core of TCM network pharmacology, with the development of computer science and high-throughput experimental techniques, the network target theory and technology are beginning to exhibit a trend of organic integration with artificial intelligence technology and high-throughput multi-modal multi-omics experimental techniques. Taking the network target analysis of TCM like Yinqiao Qingre Tablets as a typical case, network target theory and technology have achieved the systematic construction, in-depth analysis, and high-throughput multi-modal multi-omics validation of multi-level biological networks spanning from traditional Chinese and Western phenotypes to tissues, cells, molecules, and traditional Chinese and Western medicines. This development helps to address critical issues in the analysis of mechanisms of TCM, including the discovery of key targets, identification of functional components, discovery of synergistic effects among compound ingredients, and elucidation of the regulatory mechanisms of formulae. It provides powerful theoretical and technological support for advancing clinical precision diagnosis and treatment, precise positioning of TCM, and precise research and development of TCM. Thus, a new paradigm of TCM research gradually emerges, combining big data and artificial intelligence(AI) with the integration of human experience and scientific evidence.

A-to-I RNA Editing in Klebsiella pneumoniae Regulates Quorum Sensing and Affects Cell Growth and Virulence.

Millions of adenosine (A) to inosine (I) RNA editing events are reported and well-studied in eukaryotes; however, many features and functions remain unclear in prokaryotes. By combining PacBio Sequel, Illumina whole-genome sequencing, and RNA Sequencing data of two Klebsiella pneumoniae strains with different virulence, a total of 13 RNA editing events are identified. The RNA editing event of badR is focused, which shows a significant difference in editing levels in the two K. pneumoniae strains and is predicted to be a transcription factor. A hard-coded Cys is mutated on DNA to simulate the effect of complete editing of badR. Transcriptome analysis identifies the cellular quorum sensing (QS) pathway as the most dramatic change, demonstrating the dynamic regulation of RNA editing on badR related to coordinated collective behavior. Indeed, a significant difference in autoinducer 2 activity and cell growth is detected when the cells reach the stationary phase. Additionally, the mutant strain shows significantly lower virulence than the WT strain in the Galleria mellonella infection model. Furthermore, RNA editing regulation of badR is highly conserved across K. pneumoniae strains. Overall, this work provides new insights into posttranscriptional regulation in bacteria.

Integrated bioinformatics analysis identifies shared immune changes between ischemic stroke and COVID 19.

Although COVID-19 is primarily a respiratory disease, its neurological complications, such as ischemic stroke (IS), have aroused growing concerns and reports. However, the molecular mechanisms that underlie IS and COVID-19 are not well understood. Therefore, we implemented transcriptomic analysis from eight GEO datasets consist of 1191 samples to detect common pathways and molecular biomarkers in IS and COVID-19 that help understand the linkage between them. Differentially expressed genes (DEGs) were detected for IS and COVID-19 separately for finding shared mechanisms and we found that immune-related pathways were outlined with statistical significance. JAK2, which was identified as a hub gene, was supposed to be a potential therapeutic gene targets during the immunological process of COVID-19 and IS. Besides, we found a decrease in the proportion of CD8+ T and T helper 2 cells in the peripheral circulation of both COVID and IS patients, and NCR3 expression was significantly correlated with this change. In conclusion, we demonstrated that transcriptomic analyses reported in this study could make a deeper understanding of the common mechanism and might be promising for effective therapeutic for IS and COVID-19.

Mechanism of Ferroptosis in Chinese Medicine Treatment of Heart Failure： A Review / 中国实验方剂学杂志

Heart failure is the final stage of heart disease caused by a variety of etiologies and has a high morbidity， mortality， and disability rate， making it a major challenge in the field of medicine. Cardiomyocytes， the most basic unit of the heart， are irreversible in nature and can be damaged or necrotic in various ways in the presence of heart failure. Myocardial cell injury is also an important cause of cardiac dysfunction and affects the prognosis and quality of life of patients. Therefore， reducing the level of myocardial cell damage and delaying the process of cell death can help patients with heart failure lessen the extent of cardiac damage and improve their prognosis， thereby lowering the incidence of death and disability and times of hospitalization. Ferroptosis is a new form of cell death that has been widely concerned in recent years， with studies confirming its occurrence in cardiac myocytes. As a modifiable form of cell death， interfering with ferroptosis can modulate the extent of injury and death in cardiac myocytes. Studies have shown that the inhibition of iron death has a protective effect on cardiomyocytes， thereby alleviating heart failure. Chinese medicine has been widely used in the clinical treatment of heart failure， and has the advantages of multiple approaches and entry points， with significant therapeutic effects， low side effects， and low medical costs. It also reduces the clinical side effects of western medicine， with good clinical results. The use of Chinese medicine to modulate ferroptosis may be a new direction for the future treatment of heart failure. This paper briefly elaborated on the mechanism of ferroptosis， investigated the role of ferroptosis in heart failure， and discussed the current status of research on ferroptosis in Chinese medicine interventions in heart failure， to provide references for further improving the efficacy of Chinese medicine in the treatment of heart failure.

Research on applying genetic and environmental risk score in risk-adapted colorectal cancer screening / 中华流行病学杂志

Objective: To evaluate the effectiveness of a risk-adapted colorectal cancer screening strategy constructed utilizing genetic and environmental risk score (ERS). Methods: A polygenic risk score (PRS) was constructed based on 20 previously published single nucleotide polymorphisms for colorectal cancer in East Asian populations, using 2 160 samples with MassARRAY test results from a multicenter randomized controlled trial of colorectal cancer screening in China. The ERS was calculated using the Asia-Pacific Colorectal Screening Score system. Logistic regression was used to analyze the association between PRS alone and PRS combined with ERS and colorectal neoplasms risk, respectively. We also designed a risk-adapted screening strategy based on PRS and ERS (high-risk participants undergo a single colonoscopy, low-risk participants undergo an annual fecal immunochemical test, and those with positive results undergo further diagnostic colonoscopy) and compared its effectiveness with the all-acceptance colonoscopy strategy. Results: The high PRS group had a 26% increased risk of colorectal neoplasms compared with the low PRS group (OR=1.26, 95%CI: 1.03-1.54, P=0.026). Participants with the highest PRS and ERS were 3.03 times more likely to develop advanced colorectal neoplasms than those with the lowest score (95%CI: 1.87-4.90, P<0.001). As the risk-adapted screening simulation reached the third round, the detection rate of the PRS combined with ERS strategy was not statistically different from the all-acceptance colonoscopy strategy (8.79% vs. 10.46%, P=0.075) and had a higher positive predictive value (14.11% vs. 10.46%, P<0.001) and lower number of colonoscopies per advanced neoplasms detected (7.1 vs. 9.6, P<0.001). Conclusion: The risk-adapted screening strategy combining PRS and ERS helps achieve population risk stratification and better effectiveness than the traditional colonoscopy-based screening strategy.

Research and development practice of traditional Chinese medicine based on network target theory and technology / 中国中药杂志

Network targets theory and technology have transcended the limitations of the "single gene, single target" model, aiming to decipher the mechanisms of traditional Chinese medicine(TCM) based on biological network from the perspective of informatics and system. As the core of TCM network pharmacology, with the development of computer science and high-throughput experimental techniques, the network target theory and technology are beginning to exhibit a trend of organic integration with artificial intelligence technology and high-throughput multi-modal multi-omics experimental techniques. Taking the network target analysis of TCM like Yinqiao Qingre Tablets as a typical case, network target theory and technology have achieved the systematic construction, in-depth analysis, and high-throughput multi-modal multi-omics validation of multi-level biological networks spanning from traditional Chinese and Western phenotypes to tissues, cells, molecules, and traditional Chinese and Western medicines. This development helps to address critical issues in the analysis of mechanisms of TCM, including the discovery of key targets, identification of functional components, discovery of synergistic effects among compound ingredients, and elucidation of the regulatory mechanisms of formulae. It provides powerful theoretical and technological support for advancing clinical precision diagnosis and treatment, precise positioning of TCM, and precise research and development of TCM. Thus, a new paradigm of TCM research gradually emerges, combining big data and artificial intelligence(AI) with the integration of human experience and scientific evidence.

Transcriptomic analysis identifies shared biological foundations between ischemic stroke and Alzheimer's disease.

Aim: Alzheimer's disease (AD) and ischemic stroke (IS), two major neurological diseases, are suggested to be associated in clinical and pathophysiological levels. Previous studies have provided some insights into the possible genetic mechanisms behind the correlation between AD and IS, but this issue is still not clear. We implemented transcriptomic analysis to detect common hub genes and pathways to help promote the understanding of this issue. Materials and methods: Four gene expression profiling datasets (GSE16561, GSE58294, GSE63060, and GSE63061) of peripheral whole blood, which contain 108 IS samples, 284 AD samples, and 285 matched controls, were employed to detect differentially expressed genes (DEGs) for AD and IS, which were further analyzed for shared biological pathways, candidate drugs, and transcription factors. Protein-protein interaction (PPI) network and drug-target interaction analysis were applied to identify hub genes and drug targets, respectively. Result verification was done with other independent datasets (GSE37587, GSE46480, and GSE140829). The difference in proportions of various immune cells in the peripheral blood of AD and IS patients were evaluated using CIBERSORT. Results: We identified 74 DEGs and 18 biological processes with statistical significance shared by AD and IS, 9 of which were immune-related pathways. Five hub genes scored high in the topological analysis of the PPI network, and we also found eight drug target genes and candidate drugs which were associated with AD and IS. As for immunological changes, an increase in the proportion of M0 macrophages was found in the peripheral circulation of both AD and IS patients, and SOD1 expression was significantly correlated with this change. Conclusion: Collectively, the common DEGs and shared pathways found in this study suggest a potential shared etiology between AD and IS, behind which immune system, particularly the M0 macrophage elevation, might have important roles. While, the shared hub genes, potential therapeutic gene targets and drugs reported in this study provide promising treatment strategies for AD and IS.

Diversity analysis of leaf endophytic fungi and rhizosphere soil fungi of Korean Epimedium at different growth stages.

BACKGROUND: Rhizosphere fungi and endophytic fungi play key roles in plant growth and development; however, their role in the growth of Epimedium koreanum Nakai at different stages remains unclear. Here, we used the Illumina MiSeq system, a high-throughput sequencing technology, to study the endophytic fungi and rhizosphere microbiome of Korean Epimedium. RESULTS: Epimedium koreanum Nakai rhizosphere soil and leaves had highly diverse fungal communities during the growth process. The relative abundance of soil fungi in the rhizosphere stage was higher than that of leaf endophytic fungi in the early growth stage, but the overall abundance was basically equal. Sebacina is a significantly divergent fungal genera, and Sebacina sp. are present among leaf fungi species in the rhizosphere soil of Epimedium koreanum Nakai. Sebacina sp. can move to each other in rhizosphere soil fungi and leaf endophytes. VIF (variance inflation factor) analysis showed that soluble salt, whole nitrogen, alkaline lysis nitrogen, whole phosphorus, total potassium, and fast-acting potassium are useful environmental factors for rhizosphere soil and leaf endophytic fungi: potassium, total nitrogen, whole phosphorus, and three environmental factors were significantly and positively associated with the relative abundance of Sebacina sp. CONCLUSIONS: (1) This study is the first to clarify the species diversity of fungi in Epimedium koreanum Nakai leaf and rhizosphere soil. (2) Different fungal communities of rhizosphere soil fungi and leaf endophytic fungi at different growth stages of Epimedium koreanum Nakai were examined. (3) Sebacina sp. can move to each other between rhizosphere soil fungi and leaf endophytic fungi. (4) Nitrogen, phosphorus and potassium elements in the environment have a significant positive effect on the relative abundance of Sebacina sp.

Differential Regulation of the Immune System in Peripheral Blood Following Ischemic Stroke.

Method: 108 IS samples and 47 matched controls were obtained from the GEO database. Immune-related genes (IRGs) and their associated drugs were collected from the ImmPort and PharmGBK databases, respectively. Random forest (RF) regression and least absolute shrinkage and selection operator (LASSO) logistic regression were applied to identify immune-related genetic biomarkers (IRGBs) of IS, and accuracy was verified using neural network models. Finally, proportion changes of various immune cells in peripheral blood of IS patients were evaluated using CIBERSORT and xCell and correlation analyses were performed between IRGBs and differentially distributed immune cells. Results: A total of 537 genes were differentially expressed between IS and control samples. Four immune-related differential expressed genes identified by regression analysis presented strong predictive power (AUC = 0.909) which we suggeseted them as immune-related genetic biomarkers (IRGBs). We also demonstrated six immune-related genes targeted by known drugs. In addition, post-IS immune system presented an increase in the proportion of innate immune cells and a decrease in adaptive immune cells in the peripheral circulation, and IRGBs showing significance were associated with this process. Conclusion: The study identified CARD11, ICAM2, VIM, and CD19 as immune-related genetic biomarkers of IS. Six immune-related DEGs targeted by known drugs were found and provide new candidate drug targets for modulating the post-IS immune system. The innate immune cells and adaptive immune cells are diversified in the post-IS immune system, and IRGBs might play important role during this process.

Investigating the Genetic Characteristics of Hippocampal Volume and Plasma ß-Amyloid in a Chinese Community-Dwelling Population.

BACKGROUND AND OBJECTIVES: The genetic characteristics and correlations of hippocampal volume and plasm Aß, probable endophenotypes for dementia, remain to be explored in Chinese community cohort. Using whole-exome sequencing and SNP-array genotyping, we sought to identify rare and common variants and genes influencing these two endophenotypes, and calculate their heritability and genetic correlation. METHODS: Association analyses with both whole-exome sequencing and SNP-array genotyping data were performed for hippocampal volumes and plasm Aß with mixed-effect linear regression model adjusted for sex, age, and total intracranial volume or APOE ε4 while considering familial relatedness. We also performed gene-level analysis for common and gene-burden analysis for rare variants. Heritability and genetic correlation were further examined. RESULTS: Totally 1,261 participants from a Chinese community cohort were included and we identified one gene, PTPRT, for hippocampal volume, with the top significant SNPs by whole genome-wide association study. rs6030076 (P=5.48×10-8, ß=-0.092, SE=0.017) from whole-exome sequencing and rs6030088 (P=8.24×10-9, ß=-105.22 SE=18.09) from SNP-array data, both located in this gene. Gene-burden analysis based on rare mutations detected 6 genes to be significantly associated with Aß. The SNP-based heritability was 0.43±0.13 for hippocampal volume and 0.2-0.3 for plasma Aß. The SNP-based genetic correlation between hippocampal volume and plasma Aß were negative. DISCUSSION: In this study, we identified several SNPs and one gene, PTPRT, which were not reported in previous GWASs, associated with hippocampal volume. Besides, the heritability and the genetic correlation gave an overview of hippocampal volume and plasma Aß. Our findings provide insights into the mechanisms behind the individual variances in these endophenotypes.

[Influence of hemoglobin level(Hb) on survival and prognosis of elderly hip fracture at admission].

OBJECTIVE: To analyze the relationship between hemoglobin(Hb) level on admission and survival prognosis of patients with hip fracture. METHODS: From February 2016 to October 2018, 249 elderly patients with hip fracture were surgically treated including 62 males and 187 females;the age ranged from 60 to 91(73.67±10.52) years;the time from injury to operation was (6.79±2.27) d. The clinical and laboratory examination results were collected. The Hb level at admission and the mortality at 30, 90, 180 and 360 days after operation were observed. According to the Hb level at admission, the patients were divided into Hb<120 g/L and Hb≥120 g/L groups. The survival conditions of the two groups at 30, 90, 180 and 360 days after operation were compared and analyzed. Logistic regression was used to analyze the effect of Hb level on death 30, 90, 180 and 360 days after operation. RESULTS: The mortality rates at 30, 90, 180 and 360 days after operation were 5.22%, 9.24%, 16.87% and 20.48% respectively. The level of Hb at admission was a risk factor for prognosis and death 30, 90, 180 and 360 days after operation(P<0.05). The OR(95% CI) were 2.431(1.475-4.006), 2.625(1.468-4.695), 2.276(1.320-3.925) and 2.082(1.221-3.551) respectively. CONCLUSION: The level of Hb at admission can affect the survival and prognosis of elderly patients with hip fracture. We should further study how to manage the level of Hb before operation.

Influence of hemoglobin level(Hb) on survival and prognosis of elderly hip fracture at admission / 中国骨伤

OBJECTIVE@#To analyze the relationship between hemoglobin(Hb) level on admission and survival prognosis of patients with hip fracture.@*METHODS@#From February 2016 to October 2018, 249 elderly patients with hip fracture were surgically treated including 62 males and 187 females;the age ranged from 60 to 91(73.67±10.52) years;the time from injury to operation was (6.79±2.27) d. The clinical and laboratory examination results were collected. The Hb level at admission and the mortality at 30, 90, 180 and 360 days after operation were observed. According to the Hb level at admission, the patients were divided into Hb<120 g/L and Hb≥120 g/L groups. The survival conditions of the two groups at 30, 90, 180 and 360 days after operation were compared and analyzed. Logistic regression was used to analyze the effect of Hb level on death 30, 90, 180 and 360 days after operation.@*RESULTS@#The mortality rates at 30, 90, 180 and 360 days after operation were 5.22%, 9.24%, 16.87% and 20.48% respectively. The level of Hb at admission was a risk factor for prognosis and death 30, 90, 180 and 360 days after operation(P<0.05). The OR(95% CI) were 2.431(1.475-4.006), 2.625(1.468-4.695), 2.276(1.320-3.925) and 2.082(1.221-3.551) respectively.@*CONCLUSION@#The level of Hb at admission can affect the survival and prognosis of elderly patients with hip fracture. We should further study how to manage the level of Hb before operation.

Mutational landscape and genetic signatures of cell-free DNA in tumour-induced osteomalacia.

Tumour-induced osteomalacia (TIO) is a very rare paraneoplastic syndrome with bone pain, fractures and muscle weakness, which is mostly caused by phosphaturic mesenchymal tumours (PMTs). Cell-free DNA (cfDNA) has been regarded as a non-invasive liquid biopsy for many malignant tumours. However, it has not been studied in benign tumours, which prompted us to adopt the targeted next-generation sequencing approach to compare cfDNAs of 4 TIO patients, four patients with bone metastasis (BM) and 10 healthy controls. The mutational landscapes of cfDNA in TIO and BM groups were similar in the spectrum of allele frequencies and mutation types. Markedly, deleterious missense mutations in FGFR1 and loss-of-function mutations in MED12 were found in 3/4 TIO patients but none of BM patients. The gene ontology analysis strongly supported that these mutated genes found in TIOs would play a potential role in PMTs' process. The genetic signatures and corresponding change in expression of FGFR1 and FGF23 were further validated in PMT tissues from a test cohort of another three TIO patients. In summary, we reported the first study of the mutational landscape and genetic signatures of cfDNA in TIO/PMTs.

Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1.

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS). METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort. RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject with MPLS, a more complicated fibrillinopathy, and two subjects with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro. CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.