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Abstract Background The triglyceride–glucose (TyG) index has demonstrated correlations with adverse clinical outcomes in patients with ischaemic stroke, coronary heart disease and cardiac failure. However, its association with overall mortality in individuals concurrently experiencing heart failure (HF) and chronic kidney disease (CKD) remains inadequately explored. Methods Utilizing the Medical Information Mart for Intensive Care IV (Version 2.2) repository, subjects underwent quartile stratification based on the TyG index. The primary endpoint was all‐cause mortality during hospitalization. Cox proportional hazard models were employed to examine the correlation between TyG and all‐cause mortality in HF patients with CKD. Evaluation involved Kaplan–Meier (KM) analysis and restricted cubic splines (RCSs) to compare mortality rates during hospitalization and 1 year after admission across cohorts with varying TyG index levels. Results A cohort of 1537 HF and CKD patients participated. Cox regression analysis revealed elevated TyG levels as an independent risk factor for both in‐hospital and 1 year mortality. RCS analysis indicated a rising, non‐linear association between TyG levels and all‐cause mortality (P value for non‐linear

Abstract Background Frailty and its components are proposed to associate with kidney function, but little attention is paid to the significance of changes in their status on rapid loss of kidney function. This study aimed to investigate the association between changes in frailty and its components status with rapid loss of renal function. Methods This study used data from China Health and Retirement Longitudinal Study (CHARLS). Frailty status was measured using the Fried frailty phenotype (FP) scale, including five components: slowness, weakness, exhaustion, inactivity, and shrinking. Frailty status was further classified into three levels: robust (0 component), prefrail (1–2 components) and frail (3–5 components). Changes in frailty status were assessed by frailty status at baseline and 4- year follow-up. Rapid loss of kidney function was defined as a rate of estimate glomerular filtration rate(eGFR) decline ≥ 4 ml/min per 1.73 m2per year. Logistic regression models were performed to assess the association between changes in frailty status and its components status with rapid eGFR decline. Results A total of 2705 participants were included with 316 (11.68%) participants categorized as rapid eGFR decline during the 4-year follow-up. Compared with baseline prefrail participants who progressed to frail, prefrail participants who maintained prefrail or recovered to robust status had decreased risks of rapid eGFR decline (stable prefrail status, OR = 0.608, 95% CI: 0.396–0.953; recover to robust, OR = 0.476, 95% CI: 0.266–0.846). In contrast, among baseline robust or frail participants, we did not find changes in frailty status significantly affect the risks of rapid loss of kidney function. Moreover, participants who experienced incident weakness showed the significant relationship with an increased risk of rapid eGFR decline (OR = 1.531, 95% CI: 1.051–2.198) compared to stable non-weakness participants. Other changes of frailty components status did not significantly affect the risks of rapid eGFR decline. Conclusions The progression of frailty status increases the risks of rapid eGFR decline among prefrail populations. Preventing weakness, may benefit kidney function.

Alzheimer’s disease is a prominent chronic neurodegenerative condition characterized by a gradual decline in memory leading to dementia. Growing evidence suggests that Alzheimer’s disease is associated with accumulating various amyloid-β oligomers in the brain, influenced by complex genetic and environmental factors. The memory and cognitive deficits observed during the prodromal and mild cognitive impairment phases of Alzheimer’s disease are believed to primarily result from synaptic dysfunction. Throughout life, environmental factors can lead to enduring changes in gene expression and the emergence of brain disorders. These changes, known as epigenetic modifications, also play a crucial role in regulating the formation of synapses and their adaptability in response to neuronal activity. In this context, we highlight recent advances in understanding the roles played by key components of the epigenetic machinery, specifically DNA methylation, histone modification, and microRNAs, in the development of Alzheimer’s disease, synaptic function, and activity-dependent synaptic plasticity. Moreover, we explore various strategies, including enriched environments, exposure to non-invasive brain stimulation, and the use of pharmacological agents, aimed at improving synaptic function and enhancing long-term potentiation, a process integral to epigenetic mechanisms. Lastly, we deliberate on the development of effective epigenetic agents and safe therapeutic approaches for managing Alzheimer’s disease. We suggest that addressing Alzheimer’s disease may require distinct tailored epigenetic drugs targeting different disease stages or pathways rather than relying on a single drug.

Abstract Freeze-thaw cycles and compactness are two critical factors that significantly affect the engineering properties and safety of building foundations, especially in seasonally frozen regions. This paper investigated the effects of freeze-thaw cycles on the shear strength of naturally strongly chlorine saline soil with the compactness of 85%, 90% and 95%. Three soil samples with different compactness were made. Size and mass changes were measured and recorded during freeze-thaw cycles. Shear strength under different vertical pressures was determined by direct shear tests, and the cohesion and friction angle were measured and discussed. Microstructure characteristic changes of saline soil samples were observed using scanning electron microscopy under different freeze-thaw cycles. Furthermore, numerical software was used to calculate the subsoil-bearing capacity and settlement of the electric tower foundation in the Qarhan Salt Lake region under different freeze-thaw cycles. Results show that the low-density soil shows thaw settlement deformation, but the high-density soil shows frost-heaving deformation with the increase in freeze-thaw cycles. The shear strength of the soil samples first increases and then decreases with the increase in freeze-thaw cycles. After 30 freeze-thaw cycles, the friction angle of soil samples is 28.3%, 29.2% and 29.6% lower than the soil samples without freeze-thaw cycle, the cohesion of soil samples is 71.4%, 60.1% and 54.4% lower than the samples without freeze-thaw cycle, and the cohesion and friction angle of soil samples with different compactness are close to each other. Microstructural changes indicate that the freeze-thaw cycle leads to the breakage of coarse particles and the aggregation of fine particles. Correspondingly, the structure type of soil changes from a granular stacked structure to a cemented-aggregated system. Besides, the quality loss of soil samples is at about 2% during the freeze-thaw cycles. Results suggest that there may be an optimal compactness between 90 and 95%, on the premise of meeting the design requirements and economic benefits. This study can provide theoretical guidance for foundation engineering constructions in seasonally frozen regions.

Abstract Background In recent years, the role of altered cellular metabolism in tumor progression has attracted widespread attention. Related metabolic enzymes have also been considered as potential cancer therapeutic targets. Serine hydroxymethyltransferase 2 (SHMT2) has been reported to be upregulated in several cancers and associated with poor prognosis. However, there are few studies of SHMT2 in esophageal cancer (EC), and the related functions and mechanisms also need to be further explored. Methods In this study, we first analyzed SHMT2 expression in EC by online database and clinical samples. Then, the biological functions of SHMT2 in EC were investigated by cell and animal experiments. The intracellular m6A methylation modification levels were also evaluated by MeRIP. Linked genes and mechanisms of SHMT2 were analyzed by bioinformatics and rescue experiments. Results We found that SHMT2 expression was abnormally upregulated in EC and associated with poor prognosis. Functionally, SHMT2 silencing suppressed c-myc expression in an m6A-dependent manner, thereby blocking the proliferation, migration, invasion and immune escape abilities of EC cells. Mechanistically, SHMT2 encouraged the accumulation of methyl donor SAM through a one-carbon metabolic network, thereby regulating the m6A modification and stability of c-myc mRNA in a METTL3/FTO/ALKBH5/IGF2BP2-dependent way. In vivo animal experiments also demonstrated that SHMT2 mediated MYC expression by m6A-methylation modification, thus boosting EC tumorigenesis. Conclusion In conclusion, our data illustrated that SHMT2 regulated malignant progression and immune escape of EC cell through c-myc m6A modification. These revealed mechanisms related to SHMT2 in EC and maybe offer promise for the development of new therapeutic approaches.

Exudate management is of significant clinical value for the treatment of acute wound. Various wound dressings have been developed to restore the function of injured tissues and promote wound healing, but proper exploiting the healing factors inside exudate and achieving anti-adhesion wound care remains a challenge. Herein, we present a novel multi-functional composite dressing (MCD) by coupling supernatant lyophilized powder of mesenchymal stem cells (MSC-SLP) with a sandwich-structured wound dressing (SWD). The developed MCDs demonstrated unique unidirectional drainage capability, stable anti-adhesion characteristics, and improved wound healing performance. The designed SWD with both superhydrophobic inner surface and liquid-absorption ability of mid layer enables the dressings exhibit desired anti-adhesion property to neoformative granulation tissues, favorable shielding effect to exogenous bacteria, as well as appropriate exudate-retaining capability and unidirectional exudate-absorption property. The introduction of MSC-SLP in SWD was demonstrated to further improve wound healing quality. Compared to medical gauze, the synergic effect of SWD and MSC-SLP significantly accelerates wound healing rate by over 30%, avoids tissue avulsion when changing dressings, and produces a flat-smooth closure surface. More importantly, the wound treated with MCDs presents more skin accessory organs and blood vessels in regenerated tissues than other groups. In vivo/vitro biocompatibility evaluations indicated little toxicity, demonstrating the biosecurity of the developed dressings. The proposed method offers great potential in clinical applications particularly for chronic wound treatments.

Abstract Objectives To investigate the correlation between serum angiopoietin‐like protein 4 (ANGPTL4) levels, white matter hyperintensity (WMH), and cognitive impairment (CI) in patients with cerebral small vessel disease (CSVD). Methods This cross‐sectional study enrolled 171 patients with CSVD who attended the First Affiliated Hospital of Xinxiang Medical University from December 2021 to July 2022. All subjects underwent a 3.0T head magnetic resonance imaging, neuropsychology assessment, and blood sampling. Serum ANGPTL4 levels were detected by enzyme‐linked immunosorbent assay and the severity of WMH was assessed by the Fazekas scale. According to the Montreal Cognitive Assessment (MoCA) scale, subjects were divided into normal cognition group (NC, n = 80) and CI group (n = 91). According to the total Fazekas scores, subjects were divided into a mild WMH group (n = 84), a moderate WMH group (n = 70), and a severe WMH group (n = 17). Results Serum ANGPTL4 levels were significantly higher in the CI group than in the NC group (p

Summary: The survival outcomes of patients with chest wall sarcomas (CWS) were evaluated after receiving wide excision and chest wall reconstruction by using three-dimensional printed (3DP) implants. The survival outcomes evaluating the effect of 3DP implants for chest wall reconstruction is lacking. Here, forty-nine patients with CWS underwent radical wide excision and chest wall reconstruction using 3DP implants. The surgical data and long-term survival outcomes were collected and analyzed. With a median follow-up of 36 months, the disease-free survival (DFS) and overall survival (OS) were 31.7% and 58.5%, respectively. In addition, the 3-year DFS and OS can be significantly differentiated using the classification criteria of tumor grade, tumor size tumor area. Hence, wide excision and chest wall reconstruction using three-dimensional printed implants are a safe and effective treatment for chest wall sarcoma. The novel classification criteria of tumor size and area have the potential to predict the prognosis of CWS.

Abstract Background The optimal treatment for multiple brain metastases has been recently controversially discussed.This study was aimed to explore the feasibility of Hippocampus-Avoidance Whole-Brain Radiotherapy plus a simultaneous integrated boost (HA-WBRT + SIB) in patients with multiple brain metastases and assess tumor control in comparison with Hippocampus-Avoidance Whole-Brain Radiotherapy (HA-WBRT) alone for brain metastases. Methods In this study, 63 patients with multiple brain metastases (≥ 4 metastases) had undergone HA-WBRT + SIB between January 2016 and December 2020 in the observation group:HA-WBRT (30 Gy in 12 fractions, the maximum dose of the hippocampus ≤ 14 Gy) plus a simultaneous integrated boost (48 Gy in 12 fractions) for brain metastases.Overall Survival (OS), Median survival,intracranial control (IC = control within the entire brain), intracranial progression-free survival (iPFS) and adverse events were compared with the control group (a HA-WBRT retrospective cohort) by propensity score matching analysis. Results After 1:1 propensity score matching,there were 56 patients in each group (the observation group, the control group). OS, median survival and iPFS were significantly longer in the observation group (18.4 vs. 10.9 months, P0.05). Conclusions HA-WBRT + SIB resulted in better OS,median survival, IC, iPFS, an acceptable risk of radiation response, and a potential way of declining neurocognitive adverse events, which may be a better treatment for patients with multiple brain metastases.

Abstract Objectives Although postoperative radiotherapy (PORT) could reduce the incidence of local recurrence in patients with IIIA-N2 non-small cell lung cancer (NSCLC), the role of PORT on survival in patients with surgically treated stage IIIA-N2 NSCLC remains controversial. Therefore, this study was designed to evaluate the effect of PORT on survival for patients with surgically treated stage IIIA-N2 NSCLC. Materials and methods This study population was chosen from the Surveillance, Epidemiology, and End Results database. The Cox proportional hazards regression analysis was used to determine significant contributors to overall survival (OS) and cancer special survival (CSS) outcomes. To balance baseline characteristics between the non-PORT group and PORT group, propensity score matching (PSM) with 1:1 propensity nearest-neighbor match by 0.001 matching tolerance was conducted by R software. Furthermore, a Kaplan–Meier curve was used to visualize the OS and CSS between the PORT group and non-PORT group survival probability. Results Of all evaluated cases, 4511 with IIIA-N2 NSCLC were eligible for inclusion, of which 1920 were enrolled into the PORT group. On univariate analysis and multivariate analysis, sex, age, year of diagnosis, race, histologic type, T stage, PORT, use of chemotherapy, and positive regional nodes were significantly associated with OS and CSS in IIIA-N2 NSCLC (P

Abstract In Parkinson’s disease and other synucleinopathies, the elevation of α-synuclein phosphorylated at Serine129 (pS129) is a widely cited marker of pathology. However, the physiological role for pS129 has remained undefined. Here we use multiple approaches to show for the first time that pS129 functions as a physiological regulator of neuronal activity. Neuronal activity triggers a sustained increase of pS129 in cultured neurons (200% within 4 h). In accord, brain pS129 is elevated in environmentally enriched mice exhibiting enhanced long-term potentiation. Activity-dependent α-synuclein phosphorylation is S129-specific, reversible, confers no cytotoxicity, and accumulates at synapsin-containing presynaptic boutons. Mechanistically, our findings are consistent with a model in which neuronal stimulation enhances Plk2 kinase activity via a calcium/calcineurin pathway to counteract PP2A phosphatase activity for efficient phosphorylation of membrane-bound α-synuclein. Patch clamping of rat SNCA −/− neurons expressing exogenous wild-type or phospho-incompetent (S129A) α-synuclein suggests that pS129 fine-tunes the balance between excitatory and inhibitory neuronal currents. Consistently, our novel S129A knock-in (S129AKI) mice exhibit impaired hippocampal plasticity. The discovery of a key physiological function for pS129 has implications for understanding the role of α-synuclein in neurotransmission and adds nuance to the interpretation of pS129 as a synucleinopathy biomarker.

ObjectiveThe study investigated the correlation and predictive value between the severity of cerebral microbleeds (CMBs) and the level of serum High Mobility Group Protein B1 (HMGB1) and the occurrence of cognitive impairment in patients with cerebral small vessel disease (CSVD).MethodsA total of 139 patients with CSVD admitted to the Department of Neurology of the First Affiliated Hospital of Xinxiang Medical University from December 2020 to December 2022 were selected as study subjects. The Montreal Cognitive Assessment (MoCA) scale was used to assess the cognitive function and was divided into the cognitive impairment group and the cognitive normal group. Magnetic Resonance Imaging (MRI) and Susceptibility Weighted Imaging (SWI) were used to screen and assess the severity of CMBs. Serum HMGB1 levels of CSVD patients were measured by enzyme linked immunosorbent assay (ELISA). Multivariable logistic regression analysis was used to explore risk factors for cognitive impairment and CMBs. Pearson correlation analysis was used to investigate the correlation between HMGB1 and cognitive function. Receiver Operating Characteristics (ROC) curves were used to assess the predictive value of HMGB1 for the occurrence of cognitive impairment in patients with CMBs.ResultsHigh Mobility Group Protein B1, uric acid (UA), glycosylated hemoglobin (HbA1c), CMBs, lacunar cerebral infarction (LI), years of education, and history of hypertension were risk factors for cognitive impairment (P < 0.05); HMGB1 was significantly and negatively associated with total MoCA score, visuospatial/executive ability, and delayed recall ability (P < 0.05). HMGB1 was significantly and positively correlated with the number of CMBs (P < 0.05). The area under the ROC curve for HMGB1 predicting cognitive impairment in patients with CMBs was 0.807 (P < 0.001).ConclusionSerum HMGB1 levels are associated with the development of cognitive impairment in CSVD patients, and serum HMGB1 levels have a high predictive value for the development of cognitive impairment in CSVD patients with combined CMBs, which can be used for early clinical identification and intervention of vascular cognitive impairment.

The occurrence of polycyclic aromatic hydrocarbon (PAH) derivatives in the environment is of growing concern because they exhibit higher toxicity than their parent PAHs. This study evaluated the large-scale occurrence and spatiotemporal distribution of 16 PAHs and 14 oxygenated PAHs (OPAHs) in urban agricultural soils from seven districts of Guangzhou City, China. Linear correlation analysis was conducted to explore the relationship between PAH and OPAH occurrence and a series of parameters. The compositional analysis, principal component analysis, diagnostic ratios, and principal component analysis coupled with a multiple linear regression model were used to identify the sources of PAHs and OPAHs in the soils. The average concentrations of ΣPAHs and ΣOPAHs (59.6 ± 31.1–213 ± 115.5 μg/kg) during the flood season were significantly higher than those during the dry season (42.1 ± 13.3–157.2 ± 98.2 μg/kg), which were due to relatively strong wet deposition during the flood season and weak secondary reactions during the dry season. Linear correlation analysis showed that soil properties, industrial activities, and agricultural activities (r = 0.27–0.96, p

Electrically driven magnetization switch has attracted much attention in the new spintronic memory, especially for spin–orbit torque (SOT)-based magnetic random access memory (MRAM). However, the published models are facing limitations with the continuous shrinkage of the feature size down to nanoscale. Also, the thermal effect caused by switching operation is non-negligible. Therefore, an effective model is needed to represent the switching dynamic of the device concerning the influences of the nanoscale and the thermal effect. In the paper, a compact model of three-terminal SOT-driven switching is established. The influence of the voltage-controlled magnetic anisotropy (VCMA) and spin transfer torque (STT) effect induced by bias voltage on the field-free SOT-driven switching is considered by numerically solving the LLG equations. Furthermore, a 3D model of the SOT-MTJ device is established by finite element method to trace the thermoelectric behavior inside the device. The thermoelectric behavior is integrated into the compact model to show the influence of the temperature on the switching behavior, highlighting the importance of the thermal effect for the realistic modelling of SOT-driven switching. Finally, a novel voltage pulse scheme is proposed, which can effectively shorten the switching time and improve the reliability of the device. The established model could provide strategies and guidelines for next-generation memory design and application.

Cerebral small vascular disease (CSVD) is a common type of cerebrovascular disease, and an important cause of vascular cognitive impairment (VCI) and stroke. The disease burden is expected to increase further as a result of population aging, an ongoing high prevalence of risk factors (e.g., hypertension), and inadequate management. Due to the poor understanding of pathophysiology in CSVD, there is no effective preventive or therapeutic approach for CSVD. Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that is related to the occurrence and development of vascular dysfunction diseases. Therefore, MIF may contribute to the pathogenesis of CSVD and VCI. Here, reviewed MIF participation in chronic cerebral ischemia-hypoperfusion and neurodegeneration pathology, including new evidence for CSVD, and its potential role in protection against VCI.

This work reports a novel carrier flotation protocol for removing scaling cations from an oilfield produced water source which significantly reduces the collector consumption by employing natural minerals such as quartz, montmorillonite and talcum as the scaling cations carriers. The scaling cations uptake onto all carrier minerals exhibited homogeneous and monolayer adsorption, which was mainly dominated by physisorption. After adding oleate collector, the scaling cations removal rate was further enhanced, which was attributed to its high affinity with the scaling cations. Notably, the talcum flotation process simultaneously offered a high scaling cations removal rate (76.1%) and mineral recovery rate (98.3%), which achieved a sediment yield reduction of 72.2%. By summarizing the characterization results, the scaling cations removal mechanisms were also proposed. Moreover, high regeneration efficiencies (86.1% and 84.8% for quartz and talcum regeneration within three cycles) were achieved by the proposed regeneration protocol. This carrier flotation protocol with its low collector consumption offered technical promise for scaling cations removal from oilfield produced water. HIGHLIGHTS Novel carrier flotation protocol to remove scaling cations from produced water.; Outstanding scaling inhibition and carrier mineral recycle efficiencies simultaneously achieved.; Comprehensive removal mechanisms of scaling cations are explored.; Spent carrier minerals could be effectively regenerated.;

Hepatopulmonary syndrome (HPS) is a serious pulmonary vascular complication that causes respiratory insufficiency in patients with chronic liver diseases. HPS is characterized by two central pathogenic features—intrapulmonary vascular dilatation (IPVD) and angiogenesis. Endothelial glycocalyx (eGCX) is a gel-like layer covering the luminal surface of blood vessels which is involved in a variety of physiological and pathophysiological processes including controlling vascular tone and angiogenesis. In terms of lung disorders, it has been well established that eGCX contributes to dysregulated vascular contraction and impaired blood-gas barrier and fluid clearance, and thus might underlie the pathogenesis of HPS. Additionally, pharmacological interventions targeting eGCX are dramatically on the rise. In this review, we aim to elucidate the potential role of eGCX in IPVD and angiogenesis and describe the possible degradation-reconstitution equilibrium of eGCX during HPS through a highlight of recent literature. These studies strongly underscore the therapeutic rationale in targeting eGCX for the treatment of HPS.

Early cognitive impairment in Alzheimer's disease may result in part from synaptic dysfunction caused by the accumulation oligomeric assemblies of amyloid β-protein (Aβ). Changes in hippocampal function seem critical for cognitive impairment in early Alzheimer's disease (AD). Diffusible oligomers of Aβ (oAβ) have been shown to block canonical long-term potentiation (LTP) in the CA1 area of hippocampus, but whether there is also a direct effect of oAβ on synaptic transmission and plasticity at synapses between mossy fibers (axons) from the dentate gyrus granule cells and CA3 pyramidal neurons (mf-CA3 synapses) is unknown. Studies in APP transgenic mice have suggested an age-dependent impairment of mossy fiber LTP. Here we report that although endogenous AD brain-derived soluble oAβ had no effect on mossy-fiber basal transmission, it strongly impaired paired-pulse facilitation in the mossy fiber pathway and presynaptic mossy fiber LTP (mf-LTP). Selective activation of both β1 and β2 adrenergic receptors and their downstream cAMP/PKA signaling pathway prevented oAβ-mediated inhibition of mf-LTP. Unexpectedly, activation of the cGMP/PKG signaling pathway also prevented oAβ-impaired mf-LTP. Our results reveal certain specific pharmacological targets to ameliorate human oAβ-mediated impairment at the mf-CA3 synapse.

Olfactory ensheathing cells (OECs) are a special type of glial cell in the olfactory system, which exhibit neuroprotective, immunomodulatory, and angiogenic effects. Although many studies have focused on the reversal of demyelination and axonal degeneration (during spinal cord injury) by OECs, few reports have focused on the ability of OECs to repair ischemic nerve injury. This article reviews the protective effects of OEC transplantation in ischemic stroke and provides a theoretical basis and new strategy for OEC transplantation in the treatment of ischemic stroke.

(1) Objective: To investigate the relationship between serum macrophage migration inhibitory factor (MIF) level and white matter hyperintensity (WMH) and executive function (EF) in cerebral small vascular disease (CSVD), and assess the impact and predictive value of MIF level and Fazekas scores in CSVD-related cognitive impairment (CI) (CSVD-CI); (2) Methods: A total of 117 patients with WMH admitted to the First Affiliated Hospital of Xinxiang Medical College from January 2022 to August 2022 were enrolled. According to the Montreal cognitive assessment (MoCA) scale, subjects were divided into a normal cognitive group and an impaired group. All subjects required serum MIF level, 3.0 T MRI, and neuropsychological evaluation to investigate the risk factors for CDVD-CI, analyze the correlation between MIF level, WMH, and EF, and to analyze the diagnostic value of MIF and WMH degree in predicting CSVD-CI; (3) Results: 1. Fazekas score and MIF level were the risk factors of CSVD-CI. 2. The Fazekas score was negatively correlated with MoCA score, positively correlated with Stroop C-Time, Stroop C-Mistake, Stroop interference effects (SIE)-Time, SIE-Mistake, and color trails test (CTT) interference effects (CIE) (B-A). 3. The MIF level was positively correlated with Fazekas score, Stroop C-Time, SIE-Time, CTT B-Time, and CIE (B-A), and negatively correlated with MoCA score. 4. Fazekas score and MIF level were significant factors for diagnosing CSVD-CI; (4) Conclusion: The Fazekas score and MIF level may be the risk factors of CSVD-CI, and they are closely correlated to CI, especially the EF, and they have diagnostic value for CSVD-CI.

Cerebral small vessel disease (CSVD) refers to a type of syndrome caused by lesions in perforating arteries, small veins, small arteries, or capillaries, resulting in clinical, imaging, or pathological alterations. The occurrence and development of CSVD are related to various cerebrovascular risk factors, such as metabolism and genetic factors. CSVD is diagnosed based on brain imaging biomarkers; however, biomarkers capable of predicting and diagnosing CSVD early in its progression have not been found. Exploring biomarkers closely related to disease progression is of great significance for early diagnosis, prognosis, prevention, and treatment of CSVD. This article examines the research progress of CSVD biomarkers, from inflammatory biomarkers, coagulation and fibrinolysis markers, biomarkers of endothelial dysfunction, biomarkers related to cerebrospinal fluid, and gene markers.

Cerebral small vessel disease (CSVD) is a pathophysiological process involving small arteries such as cerebellar arteries, arterioles, capillaries, and veinlets. Imaging features vary; they are mainly composed of recent subcortical infarcts, lacunes of presumed vascular origin, white matter hyperintensities (WMHs) of presumed vascular origin, cerebral microbleeds, enlarged perivascular spaces, and global and regional brain atrophy. CSVD is a common cause of vascular cognitive dysfunction, and in its end stage, dementia often develops. CSVD has been a major research hotspot; however, its causes are poorly understood. Neuroimaging markers of CSVD can be used as the basis for etiological analysis. This review highlights the relevance of neuroimaging markers and cognitive impairment, providing a new direction for the early recognition, treatment, and prevention of cognitive dysfunction in small cerebral angiopathy.

GLT-1, the major glutamate transporter in the mammalian central nervous system, is expressed in presynaptic terminals that use glutamate as a neurotransmitter, in addition to astrocytes. It is widely assumed that glutamate homeostasis is regulated primarily by glutamate transporters expressed in astrocytes, leaving the function of GLT-1 in neurons relatively unexplored. We generated conditional GLT-1 knockout (KO) mouse lines to understand the cell-specific functions of GLT-1. We found that stimulus-evoked field extracellular postsynaptic potentials (fEPSPs) recorded in the CA1 region of the hippocampus were normal in the astrocytic GLT-1 KO but were reduced and often absent in the neuronal GLT-1 KO at 40 weeks. The failure of fEPSP generation in the neuronal GLT-1 KO was also observed in slices from 20 weeks old mice but not consistently from 10 weeks old mice. Using an extracellular FRET-based glutamate sensor, we found no difference in stimulus-evoked glutamate accumulation in the neuronal GLT-1 KO, suggesting a postsynaptic cause of the transmission failure. We hypothesized that excitotoxicity underlies the failure of functional recovery of slices from the neuronal GLT-1 KO. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist MK801, when present in the ACSF during the recovery period following cutting of slices, promoted full restoration of fEPSP generation. The inclusion of an enzymatic glutamate scavenging system in the ACSF conferred partial protection. Excitotoxicity might be due to excess release or accumulation of excitatory amino acids, or to metabolic perturbation resulting in increased vulnerability to NMDA receptor activation. Previous studies have demonstrated a defect in the utilization of glutamate by synaptic mitochondria and aspartate production in the synGLT-1 KO in vivo, and we found evidence for similar metabolic perturbations in the slice preparation. In addition, mitochondrial cristae density was higher in synaptic mitochondria in the CA1 region in 20–25 weeks old synGLT-1 KO mice in the CA1 region, suggesting compensation for loss of axon terminal GLT-1 by increased mitochondrial efficiency. These data suggest that GLT-1 expressed in presynaptic terminals serves an important role in the regulation of vulnerability to excitotoxicity, and this regulation may be related to the metabolic role of GLT-1 expressed in glutamatergic axon terminals.

Background: Matrix metalloproteinase-9 (MMP-9) is a significant protease required for synaptic plasticity, learning, and memory. Yet, the role of MMP-9 in the occurrence and development of cognitive decline after ischemic stroke is not fully understood. In this study, we used clinical data experiments to further investigate whether MMP-9 and genetic polymorphism are associated with post-stroke cognitive impairment or dementia (PSCID). Materials and Methods: A total of 148 patients with PSCID confirmed by the Montreal Cognitive Assessment (MoCA) 3 months after onset (PSCID group) were included in the study. The MMP-9 rs3918242 polymorphisms were analyzed using polymerase chain reaction coupled with restriction fragment length polymorphism, and the serum level of MMP-9 was measured using enzyme-linked immunosorbent assay (ELISA). The same manipulations have been done on 169 ischemic stroke patients without cognitive impairment (NCI group) and 150 normal controls (NC group). Results: The expression level of serum MMP-9 in the PSCID group and NCI group was higher compared to the NC group, and the levels in the PSCID group were higher than that in the NCI group (all p < 0.05). Diabetes mellitus, hyperhomocysteinemia, and increased serum MMP-9 levels were the main risk factors of cognitive impairment after ischemic stroke. The serum level of MMP-9 was negatively correlated with the MoCA score, including visual-spatial executive, naming, attention, language, and delayed recall. Genetic polymorphism showed that TC genotype with MMP-9 rs3918242 and CC genotype were associated with a significantly increased risk of PSCID; moreover, the TC genotype significantly increased the risk of cognitive impairment. In the TCCC genotype of MMP-9 rs3918242, diabetes mellitus and hyperhomocysteinemia were associated with the increased risk of PSCID; also, hyperhomocysteinemia could increase the risk of cognitive impairment. Conclusions: MMP-9 level and MMP-9 rs3918242 polymorphism have an important role in the occurrence and development of post-stroke cognitive impairment or dementia (PSCID).

Early degradation of cast-in-situ concrete induced by multiple internal–external sulfate combined attacks significantly affects the development of concrete strength. An experimental study regarding the effects of Ca2+ on the early degradation of cast-in-situ mortars subjected to internal–external sulfate and magnesium combined attacks is investigated in this paper. In particular, a specific method for accurately simulating the degradation of cast-in-situ structures was proposed in this experiment. Physical properties (including weight, size changes, and porosity), mechanical properties (including flexural strength and compressive strength), sulfate concentration, and microstructural properties were monitored during 28 days of immersion. The results show that an internal sulfate and magnesium combined attack (ISA-IMA) obviously retards the development of early strength and accelerates the degradation induced by external sulfate attack (ESA). The diffusion path of sulfate ions from outside is blocked by flake-shaped magnesium hydrates, delaying the penetration of external sulfate attacks. However, it is far from neutralizing the strength loss induced by an internal magnesium attack (IMA) at an early age. Premixed excessive Ca2+ would improve the strength development and pore structure of concrete or mortar, enhancing durability against corrosive conditions.

Titanium alloy (Ti) has been widely used in aerospace industry due to excellent mechanical properties and the demands of Ti parts with a high length-to-diameter ratio and a large diameter are increasing. However, deep hole drilling of large-diameter Ti holes is usually both time-consuming and cost-consuming due to a series of problems such as unfavorable chip removal, helical structure on the hole surface, poor hole precision and severe tool wear. This paper reports on the cutting mechanism and experimental results of low-frequency vibration-assisted single-lip drilling (LFVASLD) of large-diameter Ti holes (Ø17mm) for the first time. In this paper, a novel rotary low-frequency vibration device was developed and the vibration generation mechanism was analyzed. Thereafter, the material removal mechanism of LFVASLD was established. Then, the comparative experiments between LFVASLD and conventional single-lip drilling (CSLD) of Ti were conducted. The experimental results show that, compared with CSLD, LFVASLD can significantly prolong the drilling depth by 9 times due to reduced tool wear and alleviate helical structure on the hole surface due to the separated cutting mode. Furthermore, the influence of drilling parameters in LFVASLD on hole quality were also investigated. It is concluded that, the LFVASLD method is suitable for deep hole drilling of large-diameter titanium alloy and the developed rotary low-frequency vibration device can be used as a machine tool accessory to significantly improve the processing capacity in the industrial practice.

Recently, the high-dimensional negative binomial regression (NBR) for count data has been widely used in many scientific fields. However, most studies assumed the dispersion parameter as a constant, which may not be satisfied in practice. This paper studies the variable selection and dispersion estimation for the heterogeneous NBR models, which model the dispersion parameter as a function. Specifically, we proposed a double regression and applied a double ℓ1-penalty to both regressions. Under the restricted eigenvalue conditions, we prove the oracle inequalities for the lasso estimators of two partial regression coefficients for the first time, using concentration inequalities of empirical processes. Furthermore, derived from the oracle inequalities, the consistency and convergence rate for the estimators are the theoretical guarantees for further statistical inference. Finally, both simulations and a real data analysis demonstrate that the new methods are effective.

Abstract Pathologic, biochemical and genetic evidence indicates that accumulation and aggregation of amyloid β-proteins (Aβ) is a critical factor in the pathogenesis of Alzheimer’s disease (AD). Several therapeutic interventions attempting to lower Aβ have failed to ameliorate cognitive decline in patients with clinical AD significantly, but most such approaches target only one or two facets of Aβ production/clearance/toxicity and do not consider the heterogeneity of human Aβ species. As synaptic dysfunction may be among the earliest deficits in AD, we used hippocampal long-term potentiation (LTP) as a sensitive indicator of the early neurotoxic effects of Aβ species. Here we confirmed prior findings that soluble Aβ oligomers, much more than fibrillar amyloid plaque cores or Aβ monomers, disrupt synaptic function. Interestingly, not all (84%) human AD brain extracts are able to inhibit LTP and the degree of LTP impairment by AD brain extracts does not correlate with Aβ levels detected by standard ELISAs. Bioactive AD brain extracts also induce neurotoxicity in iPSC-derived human neurons. Shorter forms of Aβ (including Aβ1–37, Aβ1–38, Aβ1–39), pre-Aβ APP fragments (− 30 to − 1) and N-terminally extended Aβs (− 30 to + 40) each showed much less synaptotoxicity than longer Aβs (Aβ1–42 - Aβ1–46). We found that antibodies which target the N-terminus, not the C-terminus, efficiently rescued Aβ oligomer-impaired LTP and oligomer-facilitated LTD. Our data suggest that preventing soluble Aβ oligomer formation and targeting their N-terminal residues with antibodies could be an attractive combined therapeutic approach.

MicroRNAs (miRNAs) are involved in human glioblastoma (GB). MiR-935 has been reported to have both tumor-inhibiting and tumorigenesis effects, but its role in GB remains unclear. Because of the high mortality and morbidity associated with the malignancy of GB, a deeper understanding of the molecular crosstalk that occurs in GB is needed to identify new potential targets for treatment. At present, the mechanism of GB at the molecular level is not fully understood. With the aid of bioinformatic analysis, miR-935 was significantly downregulated in GB, and it presented a poorer outcome. In the glioma cell line and in the nude mice model, the miR-935 inhibited cell proliferation by modulating cell circles in vitro and in vivo. Then, the target genes of miR-935 were analyzed by using the online database, and the direct binding was tested with a luciferase analysis. FZD6 was found to be the direct target of miR-935. The effect of miR-935 was recovered by the overexpression of FZD6 in vitro. In addition, the negative correlation of miR-935 and the expression of FZD6 were confirmed in our clinical samples, and the expression of FZD6 has a strong correlation with tumor malignancy and prognosis. This study showed that miR-935 directly inhibited the expression of FZD6 and inhibited the cell proliferation, thereby suppressing the development of GB, suggesting that miR-935 is a cancer suppressor miRNA and may become a prognostic biomarker or a promising potential therapeutic target for human GBs.

As the most common cause of progressive cognitive decline in humans, Alzheimer's disease (AD) has been intensively studied, but the mechanisms underlying its profound synaptic dysfunction remain unclear. Here we confirm that exposing wild-type mice to an enriched environment (EE) facilitates signaling in the hippocampus that promotes long-term potentiation (LTP). Exposing the hippocampus of mice kept in standard housing to soluble Aβ oligomers impairs LTP, but EE can fully prevent this. Mechanistically, the key molecular features of the EE benefit are an upregulation of miRNA-132 and an inhibition of histone deacetylase (HDAC) signaling. Specifically, soluble Aβ oligomers decreased miR-132 expression and increased HDAC3 levels in cultured primary neurons. Further, we provide evidence that HDAC3 is a direct target of miR-132. Overexpressing miR-132 or injecting an HDAC3 inhibitor into mice in standard housing mimics the benefits of EE in enhancing hippocampal LTP and preventing hippocampal impairment by Aβ oligomers in vivo. We conclude that EE enhances hippocampal synaptic plasticity by upregulating miRNA-132 and reducing HDAC3 signaling in a way that counteracts the synaptotoxicity of human Aβ oligomers. Our findings provide a rationale for prolonged exposure to cognitive novelty and/or epigenetic modulation to lessen the progressive effects of Aβ accumulation during human brain aging.

Background: Anemia is extremely common among dialysis patients and underlies some of the symptoms associated with reduced kidney function, including fatigue, depression, reduced exercise tolerance, and dyspnea. Objectives: A clearer cognition of the prognosistic impact of hemoglobin (Hb) or hematocrit (Hct) target for the outcomes of dialysis patients is urgent. This article aims to establish the suitable hemoglobin in order to provide clinical guidance. Methods: MEDLINE, EmBase, the Cochrane Library and other databases were searched with both MeSH terms and keywords to gather randomized controlled trials that assessed all-cause mortality, cardiovascular events, fistula thrombosis, infectious diseases and transfusion among dialysis-dependent patients using erythropoiesis-stimulating agents. The meta-analysis was accomplished via Revman 5.3 version. Findings: Totally, nine eligible studies were included, with study subjects involving 3228 patients. There was a significantly higher risk of fistula thrombosis without heterogeneity (RR 1.34, 95% CI 1.15–1.55; p

Summary: Soluble Aβ oligomers (oAβs) contribute importantly to synaptotoxicity in Alzheimer disease (AD), but the mechanisms related to heterogeneity of synaptic functions at local circuits remain elusive. Nearly all studies of the effects of oAβs on hippocampal synaptic plasticity have only examined homosynaptic plasticity. Here we stimulated the Schaffer collaterals and then simultaneously recorded in stratum radiatum (apical dendrites) and stratum oriens (basal dendrites) of CA1 neurons. We found that the apical dendrites are significantly more vulnerable to oAβ-mediated synaptic dysfunction: the heterosynaptic basal dendritic long-term potentiation (LTP) remained unchanged, whereas the homosynaptic apical LTP was impaired. However, the heterosynaptic basal dendritic plasticity induced by either spaced 10-Hz bursts or low-frequency (1-Hz) stimulation was disrupted by oAβs in a mGluR5-dependent manner. These results suggest that different firing patterns in the same neurons may be selectively altered by soluble oAβs in an early phase of AD, before frank neurodegeneration. : Neuroscience; Cellular Neuroscience; Disease Subject Areas: Neuroscience, Cellular Neuroscience, Disease

Abstract Background Accurate assessment of kidney function is clinically important, but estimates of glomerular filtration rate (GFR) by regression are imprecise. Methods We hypothesized that ensemble learning could improve precision. A total of 1419 participants were enrolled, with 1002 in the development dataset and 417 in the external validation dataset. GFR was independently estimated from age, sex and serum creatinine using an artificial neural network (ANN), support vector machine (SVM), regression, and ensemble learning. GFR was measured by 99mTc-DTPA renal dynamic imaging calibrated with dual plasma sample 99mTc-DTPA GFR. Results Mean measured GFRs were 70.0 ml/min/1.73 m2 in the developmental and 53.4 ml/min/1.73 m2 in the external validation cohorts. In the external validation cohort, precision was better in the ensemble model of the ANN, SVM and regression equation (IQR = 13.5 ml/min/1.73 m2) than in the new regression model (IQR = 14.0 ml/min/1.73 m2, P 0.05 for all comparisons of the new regression equation and the other new models. Conclusions An ensemble learning model including three variables, the average ANN, SVM, and regression equation values, was more precise than the new regression model. A more complex ensemble learning strategy may further improve GFR estimates.

AMPA receptors (AMPARs) mediate fast excitatory synaptic transmission and are crucial for synaptic plasticity, learning, and memory. However, the molecular control of AMPAR stability and its neurophysiological significance remain unclear. Here, we report that AMPARs are subject to lysine acetylation at their C termini. Acetylation reduces AMPAR internalization and degradation, leading to increased cell-surface localization and prolonged receptor half-life. Through competition for the same lysine residues, acetylation intensity is inversely related to the levels of AMPAR ubiquitination. We find that sirtuin 2 (SIRT2) acts as an AMPAR deacetylase regulating AMPAR trafficking and proteostasis. SIRT2 knockout mice (Sirt2−/−) show marked upregulation in AMPAR acetylation and protein accumulation. Both Sirt2−/− mice and mice expressing acetylation mimetic GluA1 show aberrant synaptic plasticity, accompanied by impaired learning and memory. These findings establish SIRT2-regulated lysine acetylation as a form of AMPAR post-translational modification that regulates its turnover, as well as synaptic plasticity and cognitive function.

Epileptic activity may be more prevalent in early stage Alzheimer's disease (AD) than previously believed. Several studies report spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Aβ accumulation. The mechanism by which Aβ-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials (fEPSP) in stratum radiatum and population spikes (PSs) in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble Aβ oligomers (oAβ) blocked hippocampal LTP and EPSP–spike (E–S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oAβ elevated glutamate levels in the hippocampal slice medium. Recording the PS revealed that oAβ increased PS frequency and reduced LTP, and this LTP deficit was occluded by pretreatment with the GABAA antagonist picrotoxin. Whole-cell recordings showed that oAβ significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oAβ impairment of hippocampal LTP. Finally, treating slices with two antiepileptic drugs rescued the LTP inhibition induced by oAβ. We conclude that soluble Aβ oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity.

Dyslipidemia is often detected in patients with chronic kidney disease (CKD). Previous studies of the relationship between lipid profiles and kidney function have yielded variable results. We aimed to investigate the correlation between serum lipid levels and kidney function evaluated by measured glomerular filtration rate (mGFR) in Chinese patients with CKD.A cross-sectional study was conducted on 2036 Chinese CKD patients who had mGFR. Linear regression analysis was performed to evaluate the correlation between different serum lipid levels and mGFR, while logistic regression analysis was used to investigate the association between CKD stages and the risk of different types of dyslipidemia.The mean age was 55 years and the mean mGFR was 63 mL/min/1.73m2. After adjusting for some confounders (age, gender, body mass index, a history of diabetes, fasting glucose, a history of hypertension, systolic blood pressure, diastolic blood pressure, smoking status, hemoglobin, serum potassium, serum albumin, and serum uric acid), serum triglyceride level showed a negative correlation with mGFR (β = -0.006, P = 0.006) in linear regression analysis, and CKD stages were positively related to the risk of hypertriglyceridemia (odds ratios were 1.329, 1.868, 2.514 and P were 0.046, < 0.001, < 0.001 for CKD stage 2, 3, 4/5, respectively) in logistic regression anlysis.Serum triglyceride level is independently association with mGFR. Patients with reduced kidney function are more likely to have higher serum triglyceride levels. Further longitudinal, multicenter and well-conducted studies are needed to provide more evidence.

Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic (DA) neurons in the substantial nigra pars compacta. Increasing evidence showed that Wnt/β-catenin pathway and the orphan nuclear receptor Nurr1 play crucial roles in the survival and functional maintenance of DA neurons in the midbrain and GSK-3β antagonists LiCl and SB216763 were used to activate Wnt/β-catenin pathway experimentally. However, the detail mechanism underlying the neuroprotection against apoptosis on DA neuron is still unclear and the interaction between Wnt/β-catenin and Nurr1 remains undisclosed. In this study, using cell biological assay we investigated the function of Wnt/β-catenin and its crosstalk with Nurr1 on the course of PC12 cell degeneration in vitro. Our data showed that PC12 cell viability was inhibited by rotenone, but attenuated by GSK-3β antagonists LiCl or SB216763. The activity of Wnt/β-catenin pathway was deregulated on exposure of rotenone in a concentration-dependent manner. After the interference of β-catenin with siRNA, LiCl or SB216763 failed to protect PC12 cells from apoptosis by the rotenone toxicity. Our data confirmed that Wnt/β-catenin signaling activated by LiCl or SB216763 enhanced Nurr1 expression to 2.75 ± 0.55 and 4.06 ± 0.41 folds respectively compared with control detected by real-time PCR and the interaction of β-catenin with Nurr1 was identified by co-immunoprecipitate analysis. In conclusion, the data suggested that Wnt/β-catenin and Nurr1 are crucial factors in the survival of DA neurons, and the activation of Wnt/β-catenin pathway exerts protective effects on DA neurons partly by mean of a co-active pattern with Nurr1. This finding may shed a light on the potential treatment of Parkinson disease.

The Heusler alloy Ti2CrGe is a stable L21 phase with antiferromagnetic ordering. With band-gap energy (∼ 0.18 eV) obtained from a first-principles calculation, it belongs to the group of narrow band gap semiconductor. The band-gap energy decreases with increasing lattice compression and disappears until a strain of −5%; moreover, gap contraction only occurs in the spin-down states, leading to half-metallic character at the −5% strain. The Ti1, Ti2, and Cr moments all exhibit linear changes in behavior within strains of −5%– +5%. Nevertheless, the total zero moment is robust for these strains. The imaginary part of the dielectric function for both up and down spin states shows a clear onset energy, indicating a corresponding electronic gap for the two spin channels.

In order to secure high strength and high elongation of suspension parts, it is critical to predict shrinkage porosity quantitatively. A new simulation method for quantitative prediction of shrinkage porosity when replenishing molten metal has been proposed for squeeze casting process. To examine the accuracy of the calculation model, the proposed method was applied to a plate model.

Sevelamer hydrochloride is used widely, but its impact upon cardiovascular calcification, cardiovascular mortality, all-cause mortality and hospitalization is not known.Primary outcome was cardiovascular calcification (coronary artery calcification scores (CACS) and aortic calcification scores (ACS)). Secondary outcomes were serum characteristics, hospitalization, cardiovascular mortality and all-cause mortality. Risk ratio (RR), mean differences and standard mean difference with 95% confidence intervals (CIs) were pooled using random- or fixed-effects models.We identified 31 studies (on 23 randomized controlled trials with 4395 participants). An analysis pooling showed a significant decrease in serum levels of phosphate with calcium-based phosphate binders (CBPBs) by 0.17 mg/dL [mean difference (MD), 95% CI, 0.03, 0.31] than sevelamer. A significant difference in the change of CACS by -102.66 [MD: 95% CI, -159.51, -45.80] and ACS by -1008.73 [MD, 95% CI, -1664.75, -352.72] between sevelamer and CBPBs was observed. Prevalence of hypercalcemia (serum levels of calcium >10.2-10.5 mg/dL and >11.0 mg/dL) was significantly smaller for sevelamer (RR = 0.44, 95% CI, 0.33, 0.58; RR = 0.24, 95% CI, 0.14, 0.40). No significant difference was found in hospitalization, all-cause mortality or cardiovascular mortality.This meta-analysis suggests that sevelamer benefits dialysis patients in terms of CACS, ACS and hypercalcemia.