Sanpian decoction ameliorates cerebral ischemia-reperfusion injury by regulating SIRT1/ERK/HIF-1α pathway through in silico analysis and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Cerebral ischemia-reperfusion injury (CIRI) is a complex pathophysiological process involving multiple factors, and becomes the footstone of rehabilitation after ischemic stroke. Sanpian decoction (SPD) has exhibited protective effects against CIRI, migraine, and other cerebral vascular diseases. However, the underlying mechanisms have not been completely elucidated. AIM OF THE STUDY: This study sought to explore the potential mechanisms underlying the effect of SPD against CIRI. MATERIALS AND METHODS: High-performance liquid chromatography (HPLC) and ultra-high-performance liquid chromatography (UPLC) were carried out to determine the chemical constituents of SPD. A network pharmacology approach combined with experimental verification was conducted to elucidate SPD's multi-component, multi-target, and multi-pathway mechanisms in CIRI occurrence. The pharmacodynamics of the decoction was evaluated by establishing the rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). In vivo and in vitro experiments were carried out, and the therapeutic effects of SPD were performed using 2,3,5-triphenyltetrazolium chloride (TTC) staining, hematoxylin-eosin (HE) staining, and Nissl staining. We used terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and flow cytometry to evaluate cortex apoptosis. The quantification of mRNA and corresponding proteins were performed using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot respectively. RESULTS: Our research showed that pretreatment with SPD improved neurological function and inhibited CIRI. Network pharmacology revealed that the hypoxia-inducible factor-1 (HIF-1) signaling pathway and mitogen-activated protein kinase (MAPK) signaling pathway-mediated apoptosis may be associated with CIRI. In vivo and in vitro experiments, we confirmed that SPD increased cerebral blood flow, improved neural function, and reduced neural apoptosis via up-regulating the expression of sirtuin 1 (SIRT1) and down-regulating phospho-extracellular regulated protein kinases (p-ERK)/ERK and HIF-1α levels in CIRI rats. CONCLUSION: Taken together, the present study systematically revealed the potential targets and signaling pathways of SPD in the treatment of CIRI using in silico prediction and verified the therapeutic effects of SPD against CIRI via ameliorating apoptosis by regulating SIRT1/ERK/HIF-1α.

Epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China: a hospital-based retrospective study.

Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death. China has the largest population of patients with traumatic spinal cord injury. Previous studies of traumatic spinal cord injury in China have mostly been regional in scope; national-level studies have been rare. To the best of our knowledge, no national-level study of treatment status and economic burden has been performed. This retrospective study aimed to examine the epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China at the national level. We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China. Patient epidemiological and clinical features, treatment status, and total and daily costs were recorded. Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program. The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall (annual percentage change, -0.5% and 2.1%, respectively). A total of 10,053 (74.7%) patients underwent surgery. Only 2.8% of patients who underwent surgery did so within 24 hours of injury. A total of 2005 (14.9%) patients were treated with high-dose (≥ 500 mg) methylprednisolone sodium succinate/methylprednisolone (MPSS/MP); 615 (4.6%) received it within 8 hours. The total cost for acute traumatic spinal cord injury decreased over the study period (-4.7%), while daily cost did not significantly change (1.0% increase). Our findings indicate that public health initiatives should aim at improving hospitals' ability to complete early surgery within 24 hours, which is associated with improved sensorimotor recovery, increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.

[Retracted] Effect of CCL2 siRNA on proliferation and apoptosis in the U251 human glioma cell line.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the VEGF western blotting data shown in Fig. 4A on p. 3392 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes.  Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received a reply.The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 16: 3387­3394, 2017; DOI: 10.3892/mmr.2017.6995].

A golgi-targeting and polarity-specific fluorescent probe for the diagnosis of cancer and fatty liver in living cells and tissues.

Elucidating the intrinsic relationship between diseases and Golgi apparatus polarity remains a great challenge owing to the lack of the Golgi-specific fluorescent probe for polarity. Until now, the visualization of abnormal Golgi apparatus polarity in clinical cancer patient samples has not been achieved. To meet this urgent challenge, we facilely synthesized a robust Golgi-targeting and polarity-specific fluorescent probe (GCSP), which consists of an electron-acceptor solvatochromic coumarin 343 and an electron-donor Golgi-targeting group phenylsulfonamide. Owing to the typical D-π-A molecular configuration with unique intramolecular charge transfer effect, GCSP exhibits high sensitivity to polarity change in different solvents. Moreover, we revealed that GCSP possessed a satisfactory ability to sensitively monitor Golgi apparatus polarity changes in living cells. Using GCSP, we have successfully shown that Golgi apparatus polarity may serve as an ubiquitous marker for cancer and fatty liver detection. Surprisingly, the visualization of Golgi polarity has been achieved not only at the cellular levels, but also in clinical tissue samples from cancer patients, thus holding great potential in the clinical diagnosis of human cancer. All these features render GCSP an effective tool for the accurate diagnosis of Golgi apparatus related diseases.

Human Umbilical Cord Mesenchymal Stem Cells Alleviate Rat Knee Osteoarthritis via Activating Wnt/ ß-catenin Signaling Pathway.

BACKGROUND: Osteoarthritis (OA) is a chronic disease characterized by joint cartilage degeneration, destruction, and osteogenic hyperplasia. Human umbilical cord mesenchymal stem cells (hUCMSCs) have attracted increasing research interest due to their high clonogenic, proliferative, and migratory potential, as well as their improved secretion of relevant chondrogenic factors. This study evaluated the therapeutic potential and underlying mechanism of hUC-MSCs in alleviating pathological symptoms of OA. METHODS: For the in vivo study, OA rats were established by the Hulth method to observe the therapeutic effect of intra-articular injection of hUC-MSCs. X-ray tests, gross observations, and histological and immunohistochemical assessments were conducted in rats. Levels of interleukin-1 beta (IL-1ß), IL-6, matrix metalloproteinase-13 (MMP-13), and tissue inhibitor matrix metalloproteinase-1 in rats' synovial fluid were measured using enzyme-linked immunosorbent assay kits. For the in vitro study, hUC-MSCs and chondrocytes were cultured to explore the effect and underlying mechanisms of hUC-MSCs on OA. Apoptosis, proliferation, and glycosaminoglycan (GAG) were measured in the chondrocytes. The relative expression of aggrecan, COL-2, and SOX-9 mRNA was quantified by real-time polymerase chain reaction. Expressions of Wnt/ß-catenin signaling molecules were measured by Western blot. RESULTS: We found that intra-articular injection of hUC-MSCs reduced the combined score, increased the expression of collagen II, and decreased the expression of MMP-13, IL-1ß, and IL-6 in rat knee joints. Additionally, hUC-MSCs increased the content of GAGs, inhibited chondrocyte apoptosis, and promoted chondrocyte proliferation. The expression of aggrecan, COL-2, and SOX-9 mRNA in chondrocytes was promoted by hUC-MSCs via activation of the Wnt/ß-catenin signaling pathway. CONCLUSION: Overall, this study demonstrated that hUC-MSCs induce the secretion of some cytokines via the paracrine function to activate the Wnt/ß-catenin signaling pathway to reduce the pathological condition of OA and maintain the proper expression of cytokines and extracellular matrix proteins.

The iron matters: Aged microplastics disrupted the iron homeostasis in the liver organoids.

Plastic products undergo artificial and unintentional aging during daily use, causing the presence of aged microplastics (aMP). Humans are inevitably exposed to aMP. Liver is one of the critical target organs of MP through oral intake, however, limited research has focused on the hepatic toxicity of aMP compared to pristine MP (pMP). We utilized the human pluripotent stem cells-derived liver organoids (LOs) to compare the cytotoxicity of pristine polystyrene microplastics (pPS) (1 µm, carbonyl index 0.08) and aged polystyrene microplastics (aPS) (1 µm, carbonyl index 0.20) ranged from 20 to 200 ng/mL. Our findings indicate that aPS was more cytotoxic than pPS. We explored the disrupted iron homeostasis in terms of the [Fe2+] and [Fe3+] levels, iron storage and transport. A "vector-like effect" induced by aPS has been preliminarily suggested by the correlated change in total iron level and co-localization of PS and ferritin light chain (FTL) in the LOs following exposure to aPS and ferric ammonium citrate (FAC) individually and combinedly. In addition, we observed abnormal mitochondrial morphology, elevated lipid peroxidation, and declined GSH peroxidase activity, together with the declined expression of transferrin receptor (TFRC) and elevated expressions of SLC7A11, FTL. The gene handled iron transport and iron use were disrupted by aPS. Moreover, we employed FAC to introduce iron overload and Nacetylcysteine (NAC) to protect the lipid peroxidation. In aPS + FAC group, aggravated effects could be observed in aspects of [Fe2+] level, lipid peroxidation, and compromised expression levels of iron homeostasis-related markers, in contrast, in aPS + NAC group, most of changes recovered but the hepatocytoxicity remained. Specifically, a dimorphic change in elevated FTL and decreased ferritin heavy chain (FTH1) caused by 50 ng/mL aMP (57.33 ± 3.57 items/mL, equivalent to human intake level), indicated a specific response to low-dose aMP.

Abnormal changes of dynamic topological characteristics in patients with major depressive disorder.

BACKGROUND: Most studies have detected abnormalities of static topological characteristics in major depressive disorder (MDD). However, whether dynamic alternations in brain topology are influenced by MDD remains unknown. METHODS: An approach was proposed to capture the dynamic topological characteristics with sliding-window and graph theory for a large data sample from the REST-meta-MDD project. RESULTS: It was shown that patients with MDD were characterized by decreased nodal efficiency of the left orbitofrontal cortex. The temporal variability of topological characteristics was focused on the left opercular part of inferior frontal gyrus, and the right part of middle frontal gyrus, inferior parietal gyrus, precuneus and thalamus. LIMITATIONS: Future studies need larger and diverse samples to explore the relationship between dynamic topological network characteristics and MDD symptoms. CONCLUSIONS: The results support that the altered dynamic topology in cortex of frontal and parietal lobes and thalamus during resting-state activity may be involved in the neuropathological mechanism of MDD.

Sustainable inflammatory activation following spinal cord injury is driven by thrombin-mediated dynamic expression of astrocytic chemokines.

Acute spinal cord injury (SCI) always results in sustainable recruitment of inflammatory cells driven by sequentially generated chemokines, thereby eliciting excessive neuroinflammation. However, the underlying mechanism of temporally produced chemokines remains elusive. Reactive astrocytes are known to be the main sources of chemokines at the lesion site, which can be immediately activated by thrombin following SCI. In the present study, SCI was shown to induce a sequential production of chemokines CCL2 and CCL5 from astrocytes, which were associated with a persistent infiltration of macrophages/microglia. The rapidly induced CCL2 and later induced CCL5 from astrocytes were regulated by thrombin at the damaged tissues. Investigation of the regulatory mechanism revealed that thrombin facilitated astrocytic CCL2 production through activation of ERK/JNK/NF­κB pathway, whereas promoted CCL5 production through PLCß3/NF­κB and ERK/JNK/NF­κB signal pathway. Inhibition of thrombin activity significantly decreased production of astrocytic CCL2 and CCL5, and reduced the accumulation of macrophages/microglia at the lesion site. Accordingly, the locomotor function of rats was remarkably improved. The present study has provided a new regulatory mechanism on thrombin-mediated sequential production of astrocytic chemokines, which might be beneficial for clinical therapy of CNS neuroinflammation.

Remodeling of the liver fibrosis microenvironment based on nilotinib-loaded multicatalytic nanozymes with boosted antifibrogenic activity.

Liver fibrosis is a reversible pathological process caused by chronic liver damage and a major risk factor for hepatocellular carcinoma (HCC). Hepatic stellate cell (HSC) activation is considered the main target for liver fibrosis therapy. However, the efficiency of this strategy is limited due to the complex microenvironment of liver fibrosis, including excessive extracellular matrix (ECM) deposition and hypoxia-induced imbalanced ECM metabolism. Herein, nilotinib (NIL)-loaded hyaluronic acid (HA)-coated Ag@Pt nanotriangular nanozymes (APNH NTs) were developed to inhibit HSCs activation and remodel the microenvironment of liver fibrosis. APNH NTs efficiently eliminated intrahepatic reactive oxygen species (ROS) due to their inherent superoxide dismutase (SOD) and catalase (CAT) activities, thereby downregulating the expression of NADPH oxidase-4 (NOX-4) and inhibiting HSCs activation. Simultaneously, the oxygen produced by the APNH NTs further alleviated the hypoxic microenvironment. Importantly, the released NIL promoted collagen depletion by suppressing the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), thus synergistically remodeling the microenvironment of liver fibrosis. Notably, an in vivo study in CCl4-induced mice revealed that APNH NTs exhibited significant antifibrogenic effects without obvious long-term toxicity. Taken together, the data from this work suggest that treatment with the synthesized APNH NTs provides an enlightening strategy for remodeling the microenvironment of liver fibrosis with boosted antifibrogenic activity.

Evaluation of prescription review and feedback policy on rational antibiotic use in primary healthcare settings in Beijing, China: a qualitative study using the Theoretical Domains Framework and the behaviour change wheel.

Objectives: To decelerate antibiotic resistance driven by inappropriate antibiotic prescribing, a prescription review and feedback (PRF) policy is implemented in primary healthcare institutions (PHIs) in Beijing, China. However, evaluation of PRF implementation in PHIs is scarce. This study aims to systematically identify the barriers and facilitators of PRF policy implementation to provide evidence for antimicrobial stewardship. Methods: We conducted key informant interviews with 40 stakeholders engaged in the implementation of PRF in Beijing, including physicians, pharmacists and administrators. Interviews were audio recorded and transcribed verbatim. We coded the interview transcripts and mapped informant views to domains of the Theoretical Domains Framework. We then used a behaviour change wheel to suggest possible behavioural interventions. Results: Procedural knowledge (Knowledge) and skills (Skill) of PRF were possessed by stakeholders. They felt responsible to promote the appropriate use of antibiotics (Social/professional role and identity) and believed that PRF could help to change inappropriate provider behaviours (Behavioural regulation) in prescribing antibiotics (Beliefs about consequences) under increased intention on antibiotic use (Stages of change). Moreover, informants called for a more unified review standard to enhance PRF implementation (Goals). Frequently identified barriers to PRF included inadequate capacity (Skill), using punishment mechanism (Behaviour regulation), reaching consistently lower antibiotic prescription rates (Goals), lack of resources (Environmental context and resources) and perceived pressure coming from patients (Social influences). Conclusions: Stakeholders believed that PRF implementation promoted the rational use of antibiotics at PHIs in Beijing. Still, PRF was hampered by inconsistencies in review process and resources needed for PRF implementation.

Gaussian clustering and quantification of the sperm chromatin dispersion test using convolutional neural networks.

Sperm DNA fragmentation is a sign of sperm nuclear damage. The sperm chromatin dispersion (SCD) test is a reliable and economical method for the evaluation of DNA fragmentation. However, the cut-off value for differentiation of DNA fragmented sperms is fixed at 1/3 with limited statistical justification, making the SCD test a semi-quantitative method that gives user-dependent results. We construct a collection of deep neural networks to automate the evaluation of bright-field images for SCD tests. The model can detect valid sperm nuclei and their locations from the input images captured with a 20× objective and predict the geometric parameters of the halo ring. We construct an annotated dataset consisting of N = 3120 images. The ResNet 18 based network reaches an average precision (AP50) of 91.3%, a true positive rate of 96.67%, and a true negative rate of 96.72%. The distribution of relative halo radii is fit to the multi-peak Gaussian function (p > 0.99). DNA fragmentation is regarded as those with a relative halo radius 1.6 standard deviations smaller than the mean of a normal cluster. In conclusion, we have established a deep neural network based model for the automation and quantification of the SCD test that is ready for clinical application. The DNA fragmentation index is determined using Gaussian clustering, reflecting the natural distribution of halo geometry and is more tolerable to disturbances and sample conditions, which we believe will greatly improve the clinical significance of the SCD test.

Recent advances in the involvement of epigenetics in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease that manifests as skin rash, arthritis, lymphadenopathy, and multiple organ lesions. Epigenetics, including DNA methylation, histone modification, and non-coding RNA regulation, mainly affect the function and characteristics of cells through the regulation of gene transcription or translation. Increasing evidence indicates that there are a variety of complex epigenetic effects in patients with SLE, which interfere with the differentiation and function of T, and B lymphocytes, monocytes, and neutrophils, and enhance the expression of SLE-associated pathogenic genes. This paper summarizes our currently knowledge regarding pathogenesis of SLE, and introduces current advances in the epigenetic regulation of SLE from three aspects: immune function, inflammatory response, and lupus complications. We propose that epigenetic changes could be used as potential biomarkers and therapeutic targets of SLE.

1,25(OH)2 D3 inhibits Lewis lung cancer cell migration via NHE1-sensitive metabolic reprograming.

High prevalence and metastasis rates are characteristics of lung cancer. Glycolysis provides energy for the development and metastasis of cancer cells. The 1,25-dihydroxy vitamin D3 (1,25(OH)2 D3 ) has been linked to reducing cancer risk and regulates various physiological functions. We hypothesized that 1,25(OH)2 D3 could be associated with the expression and activity of Na+ /H+ exchanger isoform 1 (NHE1) of Lewis lung cancer cells, thus regulating glycolysis as well as migration by actin reorganization. Followed by online public data analysis, Vitamin D3 receptor, the receptor of 1,25(OH)2 D3 has been proved to be abundant in lung cancers. We demonstrated that 1,25(OH)2 D3 treatment suppressed transcript levels, protein levels, and activity of NHE1 in LLC cells. Furthermore, 1,25(OH)2 D3 treatment resets the metabolic balance between glycolysis and OXPHOS, mainly including reducing glycolytic enzymes expression and lactate production. In vivo experiments showed the inhibition effects on tumor growth as well. Therefore, we concluded that 1,25(OH)2 D3 could amend the NHE1 function, which leads to metabolic reprogramming and cytoskeleton reconstruction, finally inhibits the cell migration.

Polymyxin B sulfate inhalable microparticles with high-lectin-affinity sugar carriers for efficient treatment of biofilm-associated pulmonary infections.

Pulmonary infections caused by multidrug-resistant bacteria have become a significant threat to human health. Bacterial biofilms exacerbate the persistence and recurrence of pulmonary infections, hindering the accessibility and effectiveness of antibiotics. In this study, a dry powder inhalation (DPI) consisting of polymyxin B sulfate (PMBS) inhalable microparticles and high-lectin-affinity (HLA) sugar (i.e., raffinose) carriers was developed for treating pulmonary infections and targeting bacterial lectins essential for biofilm growth. The formulated PMBS-HLA DPIs exhibited particle sizes of approximately 3 µm, and surface roughness varied according to the drug-to-carrier ratio. Formulation F5 (PMBS: raffinose = 10:90) demonstrated the highest fine particle fraction (FPF) value (64.86%), signifying its substantially enhanced aerosol performance, potentially attributable to moderate roughness and smallest mass median aerodynamic particle size. The efficacy of PMBS-HLA DPIs in inhibiting biofilm formation and eradicating mature biofilms was significantly improved with the addition of raffinose, suggesting the effectiveness of lectin-binding strategy for combating bacterial biofilm-associated infections. In rat models with acute and chronic pulmonary infections, F5 demonstrated superior bacterial killing and amelioration of inflammatory responses compared to spray-dried PMBS (F0). In conclusion, our HLA carrier-based formulation presents considerable potential for the efficient treatment of multidrug-resistant bacterial biofilm-associated pulmonary infections.

Repression of LSD1 potentiates homologous recombination-proficient ovarian cancer to PARP inhibitors through down-regulation of BRCA1/2 and RAD51.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively active in ovarian cancer (OC) with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other DNA repair pathway members. We sought molecular targeted therapy that induce HRD in HR-proficient cells to induce synthetic lethality with PARPi and extend the utility of PARPi. Here, we demonstrate that lysine-specific demethylase 1 (LSD1) is an important regulator for OC. Importantly, genetic depletion or pharmacological inhibition of LSD1 induces HRD and sensitizes HR-proficient OC cells to PARPi in vitro and in multiple in vivo models. Mechanistically, LSD1 inhibition directly impairs transcription of BRCA1/2 and RAD51, three genes essential for HR, dependently of its canonical demethylase function. Collectively, our work indicates combination with LSD1 inhibitor could greatly expand the utility of PARPi to patients with HR-proficient tumor, warranting assessment in human clinical trials.

The sonic hedgehog pathway suppresses oxidative stress and senescence in nucleus pulposus cells to alleviate intervertebral disc degeneration via GPX4.

Disruption of intervertebral disc (IVD) homeostasis caused by oxidative stress and nucleus pulposus cell (NPC) senescence is a main cause of intervertebral disc degeneration (IDD). The sonic hedgehog (Shh) pathway plays an important role in IVD development, but its roles in IDD are unknown. This study aimed to investigate the effects of the Shh pathway on the alleviation of IDD and the related mechanisms. In vivo, the effect of the Shh pathway on IVD homeostasis was studied by intraperitoneal injection of recombinant Shh (rShh) and GANT61 based on puncture-induced IDD. GANT61, lentivirus-coated sh-Gli1 and rShh were used to investigate the role and mechanism of the Shh pathway in NPCs based on senescence induced by Braco19 and oxidative stress induced by TBHP. Shh pathway expression decreased, and senescence and oxidative stress increased with age. Intraperitoneal injection of rShh activated the Shh pathway to suppress oxidative stress and NPC senescence and consequently alleviated needle puncture-induced IDD. In vitro, the Shh pathway upregulated glutathione peroxidase 4 (GPX4) expression to suppress oxidative stress and senescence in NPCs. Moreover, GPX4 suppression in NPCs by si-GPX4 significantly reduced the protective effect of the Shh pathway on oxidative stress and senescence in NPCs. Our results demonstrate for the first time that the Shh pathway plays a key role in the alleviation of IDD by suppressing oxidative stress and cell senescence in NP tissues. This study provides a new potential target for the prevention and reversal of IDD.

Who might encounter hard-braking while speeding? Analysis for regular speeders using low-frequency taxi trajectories on arterial roads and explainable AI.

Regular speeders are those who commit speeding recidivism during a period. Among their speeding behaviors, some occurring in specific scenarios may cause more hazards to road users. Therefore, there is a need to evaluate the driving risks if the regular speeders have different speeding propensities. This study considers speeding-related hard-braking events (SHEs) as a safety surrogate measure and recognizes the regular speeders who encounter at least one SHEs during the study period as risky individuals. To identify speeding behaviors and hard-braking events from low-frequency GPS trajectories, we compare the average travel speed between pairwise adjacent GPS points to the posted speed limit and examine the speed curve and the corresponding travel distance between these GPS points, respectively. Thereafter, a logistic model, XGBoost, and three 1D Convolutional Neural Networks (CNNs) including AlexNet CNN, Mini-AlexNet CNN, and Simple CNN are respectively developed to recognize the regular speeders who encountered SHEs based on their speeding propensities. The proposed Mini-AlexNet CNN achieves a global F1-score of 91% and recall of 90% on the testing data, which are superior to other models. Further, the study uses the Shapley Additive exPlanation (SHAP) framework to visually interpret the contribution of speeding propensities on SHE likelihood. It is found that speeding by 50% or greater for no more than 285 m is the most dangerous kind among all the speeding behaviors. Speeding on roads without bicycle lanes or on roads with roadside parking and excessive accesses increases the probability of encountering SHEs. Based on the analyses, we put forward tailored recommendations that aim to restrict hazard-related speeding behaviors rather than speeding behaviors of all kinds.

Transient vacuolar changes of the crystalline lens in patients using a dispersive ophthalmic viscosurgical device.

AIM: To report the clinical prognosis and pathological findings of accidental lens vacuolar changes in eyes with intraoperative exposure to a dispersive ophthalmic viscosurgical device (OVD). METHODS: Two patients who developed transient lens vacuolar changes during uneventful persistent pupillary membrane (PPM) removal surgery were presented and followed up. This event was speculated to be associated with an intraoperative dispersive OVD DisCoVisc (hyaluronic acid 1.6%-chondroitin sulfate 4.0%) exposure. Then, to provide the pathological basis for our speculation, another four cataract patients were randomly exposed to different OVDs, and their anterior lens capsules were investigated with transmission electron microscopy (TEM). RESULTS: After months, the subcapsular vacuoles in both PPM cases were gradually disappeared without visual deterioration. For the cataract patients, similar lens changes were observed intraoperatively in those exposed to a dispersive DisCoVisc but not a cohesive OVD IVIZ (sodium hyaluronate gel 1.0%). In addition, marked ultrastructural changes, including chromatin condensation, extensive cytoplasmic vacuoles, and obvious intercellular space between lens epithelial cells in the anterior lens capsules of all eyes exposed to DisCoVisc, were observed by TEM. CONCLUSION: The lens vacuolar changes may be associated with a dispersive OVD exposure. Therefore, it is not preferable to use dispersive OVDs in patients with transparent lenses or without the intention of lens extraction. In addition, close follow-ups instead of immediate lens extraction are recommended for the occurrence of similar lens lesions.

Homocysteine Combined with Apolipoprotein B as Serum Biomarkers for Predicting Carotid Atherosclerosis in the Oldest-Old.

Background: The measurement of serum biomarkers is a promising decision aid in the assessment of atherosclerosis. However, data on the levels and epidemiological distribution of serum biomarkers of carotid atherosclerosis (CAS) in the oldest-old are limited. This study aimed to investigate the characteristics of CAS serum biomarkers in the oldest-old over 80 and explore their predictive value for CAS. Methods: As part of the China Hainan Centenarian Cohort Study, a total of 1565 individuals over 80 years old were included. Atherosclerosis was assessed by carotid plaque and carotid intima-media thickness. Serum biomarker levels, demographic indicators, and physical examination indicators were detected. Prediction factors correlated to the CAS were explored by logistic regression and verified by receiver operating characteristic curve analysis. Multivariate regression models were fitted, along with subgroup analysis and robustness tests. Results: Among the oldest-old population, 83.5% (1306) had CAS. In a fully adjusted multivariate logistic regression model, systolic blood pressure (SBP), heart rhythm (HR), serum homocysteine (Hcy), and apolipoprotein B (ApoB) levels were significantly and positively associated with CAS in the oldest-old (PS < 0.001). ROC analysis indicated that the combination of serum Hcy, ApoB, SBP, and HR increased the predictive value for CAS in the oldest-old (area under the curve: 0.856, 95% CI: 0.803-0.879; sensitivity: 81.8%; specificity: 85.9%). Conclusion: SBP, HR, Hcy and ApoB are independent risk factors for CAS in the oldest-old. The specific set of biomarkers and their combination with other risk markers may be a promising strategy for assessing CAS in the elderly, especially in global aging.

Downhill running and caloric restriction attenuate insulin resistance associated skeletal muscle atrophy via the promotion of M2-like macrophages through TRIB3-AKT pathway.

BACKGROUD: Downhill running has recently become a promising exercise modality for metabolic syndrome, but the effect and precise mechanism of downhill running training on insulin resistance (IR) induced skeletal muscle atrophy remains unclear. The current study aimed to explore the benefits of downhill running training accompanied by a low-fat diet on skeletal muscle atrophy in IR mice and its possible mechanisms. METHODS: For in vivo study, high-fat diet (HFD) -induced IR mice were submitted to the downhill running training or/and caloric restriction for 8 weeks. In vitro study was performed using co-cultured RAW264.7 macrophages and C2C12 myoblasts model. Glucose tolerance test (GTT), insulin tolerance test (ITT), immunofluorescence staining, western blot analysis, hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assay (ELISA), Cell counting kit-8 (CCK-8) assays and glucose uptake assays were employed to explore the benefits and possible mechanisms of downhill running training accompanied by a low-fat diet on IR mice. RESULTS: Our data revealed that HFD induces IR, which leading to skeletal muscle atrophy. Downhill running accompanied by caloric restriction mitigated HFD-induced IR and improve skeletal muscle atrophy. Further study suggested that descended TRIB3 mediated the favorable impact of downhill running on IR induced skeletal muscle atrophy by suppressing M1-like macrophages and promoting M2-like macrophages. Macrophages-specific knockdown of TRIB3 exerted similar effects on the macrophage polarization and IR related myogenesis to downhill running training accompanied by caloric restriction. In contrast, macrophages-specific overexpression of TRIB3 descended phosphorylation of AKT, further activated M1-like macrophages and aggravated IR related inhibition of myogenesis. CONCLUSIONS: This finding demonstrated the beneficial effects of downhill running training and caloric restriction on IR related skeletal muscle atrophy by promoting M2-like macrophages through TRIB3-AKT pathway.