Search

Abstract Background Understanding the molecular mechanisms of Alzheimer’s disease (AD) has important clinical implications for guiding therapy. Impaired amyloid beta (Aβ) clearance is critical in the pathogenesis of sporadic AD, and blood monocytes play an important role in Aβ clearance in the periphery. However, the mechanism underlying the defective phagocytosis of Aβ by monocytes in AD remains unclear. Methods Initially, we collected whole blood samples from sporadic AD patients and isolated the monocytes for RNA sequencing analysis. By establishing APP/PS1 transgenic model mice with monocyte-specific cystatin F overexpression, we assessed the influence of monocyte-derived cystatin F on AD development. We further used a nondenaturing gel to identify the structure of the secreted cystatin F in plasma. Flow cytometry, enzyme-linked immunosorbent assays and laser scanning confocal microscopy were used to analyse the internalization of Aβ by monocytes. Pull down assays, bimolecular fluorescence complementation assays and total internal reflection fluorescence microscopy were used to determine the interactions and potential interactional amino acids between the cystatin F protein and Aβ. Finally, the cystatin F protein was purified and injected via the tail vein into 5XFAD mice to assess AD pathology. Results Our results demonstrated that the expression of the cystatin F protein was specifically increased in the monocytes of AD patients. Monocyte-derived cystatin F increased Aβ deposition and exacerbated cognitive deficits in APP/PS1 mice. Furthermore, secreted cystatin F in the plasma of AD patients has a dimeric structure that is closely related to clinical signs of AD. Moreover, we noted that the cystatin F dimer blocks the phagocytosis of Aβ by monocytes. Mechanistically, the cystatin F dimer physically interacts with Aβ to inhibit its recognition and internalization by monocytes through certain amino acid interactions between the cystatin F dimer and Aβ. We found that high levels of the cystatin F dimer protein in blood contributed to amyloid pathology and cognitive deficits as a risk factor in 5XFAD mice. Conclusions Our findings highlight that the cystatin F dimer plays a crucial role in regulating Aβ metabolism via its peripheral clearance pathway, providing us with a potential biomarker for diagnosis and potential target for therapeutic intervention.

Human bocavirus (HBoV) has been identified as a viral agent with a global presence, especially in young patients with gastrointestinal infections. In this study, we aimed to evaluate the epidemiological patterns of the HBoVs associated with acute gastroenteritis (AGE) in Taiwan. A total of 2994 AGE fecal samples from several diarrhea outbreaks from 2018 to 2022 were analyzed. From the samples, 73 positive samples were detected in three different bocaviruses: 30 (41.1%) were from HBoV1; 37 (50.7%) were from HBoV2; and 6 (8.2%) were from HBoV3, revealing the respective prevalences in AGE of 1%, 1.2%, and 0.2%. HBoV1 and HBoV2 were the two major epidemic agents of HBoVs in Taiwan during this study period and have seasonal distinct patterns with an epidemic peak from October to the following March. Phylogeny reconstruction and evaluation were implemented in Mega X; the results revealed that most HBoV1 strains in Taiwan appeared to be closely related to those strains from other Asian countries. The HBoV2 exhibited substantial genetic diversity and the HBoV3 genes showed discordance of groups.

We investigated the optical constants of thin films of the Nb25Mo25Ta25W25 alloy, which belongs to high-entropy alloys (HEAs), with a transmission terahertz (THz) measurement system and discovered that the refractive index, extinction coefficient, and conductivity of the HEA thin film measured in the range of 0.3–1.0 THz all increased as the thickness of the thin film increased (the thickness was maintained in the range between 10 and 40 nm). According to the experimental results, this alloy with a high refractive index is suitable for producing high-contrast gratings (HCGs). The principle behind achieving a high contrast with a high-reflection HEA grating is to harness the confined plasmonic energy within the grating, thereby enhancing the localized plasmonic energy within the grating. This work elucidates that we can not only fabricate THz components by controlling the thickness of the thin film but also utilize the high refractive index of this material to create HCGs.

Background: Inflammatory-coagulation dysfunction plays an increasingly important role in sepsis associated acute kidney injury (SAKI). This study aimed to investigate whether early heparin therapy improves survival in patients with SAKI.Methods: Patients with SAKI were identified from the Medical Information Mart for Intensive Care-IV database. The patients were divided into two groups: those who received heparin subcutaneously within 48 h after intensive care unit (ICU) admission and the control group, who received no heparin. The primary endpoint was ICU mortality, the secondary outcomes were 7-day, 14-day, 28-day, and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), and E-value analyses were performed.Results: The study included 5623 individuals with SAKI, 2410 of whom received heparin and 3213 of whom did not. There were significant effects on ICU and 28-day mortality in the overall population with PSM. MSCM further reinforces the efficacy of heparin administration reduces ICU mortality in the general population. Stratification analysis with MSCM showed that heparin administration was associated with decreased ICU mortality at various AKI stages. Heparin use was also associated with reduced 28-day mortality in patients with only female, age >60 years, and AKI stage 3, with HRs of 0.79, 0.77, and 0.60, respectively (p < 0.05). E-value analysis suggests robustness to unmeasured confounding.Conclusion: Early heparin therapy for patients with SAKI decreased ICU mortality. Further analysis demonstrated that heparin therapy was associated with reduced 28-day mortality rate in patients only among female, age > 60 years and AKI stage 3.

Ischemia-reperfusion (I/R) injury constitutes a significant risk factor for a range of diseases, including ischemic stroke, myocardial infarction, and trauma. Following the restoration of blood flow post-tissue ischemia, oxidative stress can lead to various forms of cell death, including necrosis, apoptosis, autophagy, and necroptosis. Recent evidence has highlighted the crucial role of mitochondrial dysfunction in I/R injury. Nevertheless, there remains much to be explored regarding the molecular signaling network governing cell death under conditions of oxidative stress. Voltage-dependent anion channel 1 (VDAC1), a major component in the outer mitochondrial membrane, is closely involved in the regulation of cell death. In a cellular model of oxygen-glucose deprivation and reoxygenation (OGD/R), which effectively simulates I/R injury in vitro, our study reveals that OGD/R induces VDAC1 oligomerization, consequently exacerbating cell death. Furthermore, we have revealed the translocation of mixed lineage kinase domain-like protein (MLKL) to the mitochondria, where it interacts with VDAC1 following OGD/R injury, leading to an increased mitochondrial membrane permeability. Notably, the inhibition of MLKL by necrosulfonamide hinders the binding of MLKL to VDAC1, primarily by affecting the membrane translocation of MLKL, and reduces OGD/R-induced VDAC1 oligomerization. Collectively, our findings provide preliminary evidence of the functional association between MLKL and VDAC1 in the regulation of necroptosis.

LncRNA (long non-coding RNA) H19 is a transcript of the H19 gene that is expressed during embryogenesis. We previously discovered a role for circular lncRNA H19 in the onset and prognosis of cerebral ischemic stroke. In this study, we used serum from patients with ischemic stroke, and mouse and cell culture models to elucidate the roles of plasma and neuronal exosomes in the regulatory effect of lncRNA H19 on insulin-like growth factor-1 and its mechanism in ischemic stroke, using western blotting, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assays. Plasma exosomal lncRNA H19 was negatively associated with blood levels of insulin-like growth factor-1 in samples from patients with cerebral ischemic stroke. In a mouse model, levels of exosomal lncRNA H19 were positively correlated with plasma and cerebral lncRNA H19. In a cell co-culture model, we confirmed that lncRNA H19 was transported from neurons to astrocytes by exosomes to induce downregulation of insulin-like growth factor-1 through the H19/let-7a/insulin-like growth factor-1 receptor axis. This study provides the first evidence for the transportation of lncRNA H19 by exosomes and the relationship between lncRNA H19 and insulin-like growth factor-1.

Background: Previous studies documented that heparin can inhibit the invasion and metastasis of tumors, but its role on outcomes in patients with solid malignancy complicated sepsis remains unclear.Methods: A retrospective cohort study was conducted in critically ill patients with solid malignancy associated sepsis from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary endpoint was intensive care unit (ICU) mortality, secondary outcomes were thrombosis and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), cox proportional hazards model, stratification analysis and E-value were used to account for baseline differences, time-varying confounding and unmeasured variables.Results: A total of 1,512 patients with solid malignancy complicated sepsis were enrolled, of which 683 in the heparin group with intensive care unit mortality, thrombosis rate and hospital mortality were 9.7%, 5.4%, 16.1%, and 829 in the non-heparin group with ICU mortality, thrombosis rate and hospital mortality were 14.6%, 12.5%, 22.6%. Similar results were observed on outcomes for patients with PSM (ICU mortality hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41–0.92), thrombosis rate (HR 0.42, 95% confidence interval 0.26–0.68); hospital mortality HR 0.70, 95% CI 0.50–0.99). marginal structural Cox model further reinforced the efficacy of heparin in reducing ICU mortality (HR 0.48, 95% CI 0.34–0.68). Logistic regression and Cox regression model showed heparin use also markedly reduced thrombosis (HR 0.42; 95% CI 0.26–0.68; p < 0.001) and hospital mortality (HR 0.70; 95% CI 0.50–0.99; p = 0.043). Stratification analysis with the MSCM showed an effect only those with digestive system cancer (HR 0.33, 95% CI 0.16–0.69).Conclusion: Early heparin therapy improved outcomes in critically ill patients with solid malignancy complicated sepsis. These results are evident especially in those with digestive system cancer. A prospective randomized controlled study should be designed to further assess the relevant findings.

Escherichia coli (E. coli) is the most common Gram-negative bacterial organism causing neonatal meningitis. The pathogenesis of E. coli meningitis, especially how E. coli escape the host immune defenses, remains to be clarified. Here we show that deletion of bacterial Lpp encoding lipoprotein significantly reduces the pathogenicity of E. coli K1 to induce high-degree of bacteremia necessary for meningitis. The Lpp-deleted E. coli K1 is found to be susceptible to the intracellular bactericidal activity of neutrophils, without affecting the release of neutrophil extracellular traps. The production of reactive oxygen species (ROS), representing the primary antimicrobial mechanism in neutrophils, is significantly increased in response to Lpp-deleted E. coli. We find this enhanced ROS response is associated with the membrane translocation of NADPH oxidase p47phox and p67phox in neutrophils. Then we constructed p47phox knockout mice and we found the incidence of bacteremia and meningitis in neonatal mice induced by Lpp-deleted E. coli is significantly recovered by p47phox knockout. Proteomic profile analysis show that Lpp deficiency induces upregulation of flagellar protein FliC in E. coli. We further demonstrate that FliC is required for the ROS induction in neutrophils by Lpp-deleted E. coli. Taken together, these data uncover the novel role of Lpp in facilitating intracellular survival of E. coli K1 within neutrophils. It can be inferred that Lpp of E. coli K1 is able to suppress FliC expression to restrain the activation of NADPH oxidase in neutrophils resulting in diminished bactericidal activity, thus protecting E. coli K1 from the elimination by neutrophils.

Abstract Objectives This research innovatively analyzed the marital transitions (i.e., divorce and widowhood) of older Taiwanese parents, their sleep problems and spousal specific characteristics (i.e., separate bedrooms for sleep and marital relationships) as well as their social and family connections, all of which were simultaneously reflected in emotional and social domains of loneliness. Methods Data are from 1645 older parents from Northern Taiwan. Loneliness was assessed by a De Jong-Gierveld short scale with emotional and social domains. We conducted multivariate logistic regression to examine the associations of marital transitions and family/social connections regarding sleep problems and psychological well-being with loneliness in social and emotional domains. Besides sleep problems and individual socioeconomic status, we included data on couples’ sleeping arrangements and marital relationships. Results Social loneliness was significantly associated with being divorced (AOR = 1.80, 95% CI 1.13–2.86) and living alone (AOR = 1.50, 95% CI 1.02–2.23). In contrast, strong family cohesion and frequent weekly contact with friends were associated with lower social loneliness. Married parents who slept in separate bedrooms were more likely than bed-sharing couples to feel emotional and social loneliness, despite adjusting for their sleep problems. Furthermore, satisfactory spousal relationships significantly decreased the magnitude of associations in the social domain. Discussion Our findings support significant associations between loneliness in later life and major marital transitions, family and social connections and sleep problems which differ in social and emotional domains. Independent of relationship satisfaction, separate bedrooms relate to higher risks of emotional loneliness in older adults.

Vehicle fault detection and diagnosis (VFDD) along with predictive maintenance (PdM) are indispensable for early diagnosis in order to prevent severe accidents due to mechanical malfunction in urban environments. This paper proposes an early voiceprint driving fault identification system using machine learning algorithms for classification. Previous studies have examined driving fault identification, but less attention has focused on using voiceprint features to locate corresponding faults. This research uses 43 different common vehicle mechanical malfunction condition voiceprint signals to construct the dataset. These datasets were filtered by linear predictive coefficient (LPC) and wavelet transform(WT). After the original voiceprint fault sounds were filtered and obtained the main fault characteristics, the deep neural network (DNN), convolutional neural network (CNN), and long short-term memory (LSTM) architectures are used for identification. The experimental results show that the accuracy of the CNN algorithm is the best for the LPC dataset. In addition, for the wavelet dataset, DNN has the best performance in terms of identification performance and training time. After cross-comparison of experimental results, the wavelet algorithm combined with DNN can improve the identification accuracy by up to 16.57% compared with other deep learning algorithms and reduce the model training time by up to 21.5% compared with other algorithms. Realizing the cross-comparison of recognition results through various machine learning methods, it is possible for the vehicle to proactively remind the driver of the real-time potential hazard of vehicle machinery failure.

The necessity of vehicle fault detection and diagnosis (VFDD) is one of the main goals and demands of the Internet of Vehicles (IoV) in autonomous applications. This paper integrates various machine learning algorithms, which are applied to the failure prediction and warning of various types of vehicles, such as the vehicle transmission system, abnormal engine operation, and tire condition prediction. This paper first discusses the three main AI algorithms, such as supervised learning, unsupervised learning, and reinforcement learning, and compares the advantages and disadvantages of each algorithm in the application of system prediction. In the second part, we summarize which artificial intelligence algorithm architectures are suitable for each system failure condition. According to the fault status of different vehicles, it is necessary to carry out the evaluation of the digital filtering process. At the same time, it is necessary to preconstruct its model analysis and adjust the parameter attributes, types, and number of samples of various vehicle prediction models according to the analysis results, followed by optimization to obtain various vehicle models. Finally, through a cross-comparison and sorting, the artificial intelligence failure prediction models can be obtained, which can correspond to the failure status of a certain car model and a certain system, thereby realizing a most appropriate AI model for a specific application.

Circular RNAs (circRNAs) have recently been discovered as a novel type of endogenous non-coding RNA that may regulate gene expression in mammals. In the central nervous system (CNS), circRNAs are relevant to many neurological disorders such as Alzheimer's disease (AD). In this study, we attempted to identify an aberrant circRNA, hsa_circ_0003391, which is significantly downregulated in the peripheral blood of patients with AD, and to explore the relationship between hsa_circ_0003391 and the clinical manifestation of AD. The expression of hsa_circ_0003391 had a specific decrease in the peripheral blood of patients with AD compared to those with other types of dementia. To evaluate the potential diagnostic value of the circRNA, we performed a receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) value was 0.7283 for hsa_circ_0003391, which was statistically significant. The natural form of hsa_circ_0003391 in the peripheral blood was a loop structure with good stability. We found a potential correlation between the expression of hsa_circ_0003391 and the clinical manifestations of AD. Bioinformatic analysis was carried out to predict the latent target microRNAs (miRNA) of hsa_circ_0003391. Furthermore, microRNAs targeted by hsa_circ_0003391 were successfully detected, and miR-574-5p had an expected elevation in the AD groups, suggesting that miR-574-5p might be a potential microRNA target for hsa_circ_0003391. Our results suggest that the downregulation of hsa_circ_0003391 in the peripheral blood has a potential relationship with AD. Our findings not only provide an important latent biomarker but also highlight an important perspective for the following study into AD pathogenesis. This may promote the process of novel therapeutics targeting non-coding RNA.

ObjectivesOrganotropism is primarily determined by tumor-derived exosomes. To date, the role of lung cancer cells-derived exosomes underlying the pre-metastatic niche formation is unclear.Materials and MethodsThe animal models of retro-orbital and intra-ventricular injection were constructed to administrate lung cancer cells-derived exosomes. Cytokine array was used to screen the cytokines released from brain endothelium after internalization of lung cancer cells-derived exosomes. The cellular co-culture system was established to mimic microglia-vascular niche contained lung cancer cells-derived exosomes. The levels of Dkk-1 and the activities of microglia were analyzed by qRT-PCR, western blot and immunofluorescence. In vivo selections of highly brain metastatic cells were performed to analyze the direct interaction of lung cancer cells with microglia.ResultsAnimal studies demonstrated that there was a suppressive signal transferred from brain endothelium to microglia after internalization of lung cancer cells-derived exosomes into brain endothelium, which caused an absolutely less M1 phenotypic microglia and a relatively more M2 phenotypic microglia. Further results indicated that lung cancer cells-derived exosomes induced a release of endogenous Dkk-1 from brain endothelium, which rendered microglia to acquire a pro-tumorigenic feature in pre-metastatic niche. Subsequently, the declines of Dkk-1 in metastatic lung cancer cells removed the suppression on microglia and enhanced microglial activation in metastatic niche.ConclusionOur findings shed a new light on the synergistic reaction of the different cells in “neurovascular units” toward the metastatic messages from lung cancer cells and provided a potential therapeutic pathway for lung cancer metastasis to brain.

Neonatal bacterial meningitis remains a life-threatening and causative sequelae disease in newborns, despite the effective usage of antibiotics and improved critical medical care. Polymorphonuclear leukocyte (PMN) transendothelial migration across the blood-brain barrier, one of the three hallmarks of bacterial meningitis, now is considered as a “double-edge sword”. When participating in host immune system defending against virulent pathogens, it results in tissue inflammation and following severe damage of central nervous system at the same time, which contributes to a disastrous consequence. Recently, several researches have focused on this multi-step process and the mechanism of how the virulent factors of different pathogens influence PMN migration. The great progression they made has enlightened a new research hotspot and a novel therapeutic strategy. This mini review outlines the determinants and progression of PMN transmigration in neonatal meningitis caused by different predominant pathogens.

Penetration of the blood–brain barrier (BBB) is crucial for development of E. coli-caused meningitis. Here, the authors show that a host membrane protein, Caspr1, acts as a receptor for a bacterial virulence factor to facilitate BBB penetration and entry of E. coli into brain neurons.

The activity of norovirus varies from season to season, and the effect of climate change on the incidence of norovirus outbreaks is a widely recognized yet poorly understood phenomenon. Investigation of the possible association between climatic factors and the incidence of norovirus is key to a better understanding of the epidemiology of norovirus and early prediction of norovirus outbreaks. In this study, clinical stool samples from acute gastroenteritis outbreaks were collected from January 2015 to June 2019 in Taiwan. Data analysis from our study indicated that more than half of the cases were reported in the winter and spring seasons, including those caused by norovirus of genotypes GII (genogroup II).2, GII.3, GII.6, and GII.17, and 45.1% of the patients who tested positive for norovirus were infected by the GII.4 norovirus in autumn. However, GII.6 norovirus accounted for a higher proportion of the cases reported in summer than any other strain. Temperature is a crucial factor influencing patterns of epidemic outbreaks caused by distinct genotypes of norovirus. The results of this study may help experts predict and issue early public warnings of norovirus transmission and understand the effect of climate change on norovirus outbreaks caused by different genotypes and occurring in different locations.

The expression of contactin-associated protein 1 (Caspr1) in brain microvascular endothelial cells (BMECs), one of the major cellular components of the neurovascular unit (NVU), has been revealed recently. However, the physiological role of Caspr1 in BMECs remains unclear. We previously reported the nonamyloidogenic processing of amyloid protein precursor (APP) pathway in the human BMECs (HBMECs). In this study, we found Caspr1 depletion reduced the levels of soluble amyloid protein precursor α (sAPPα) in the supernatant of HBMECs, which could be rescued by expression of full-length Caspr1. Our further results showed that ADAM9, the α-secretase essential for processing of APP to generate sAPPα, was decreased in Caspr1-depleted HBMECs. The reduced sAPPα secretion in Caspr1-depleted HBMECs was recovered by expression of exogenous ADAM9. Then, we identified that Caspr1 specifically regulates the expression of ADAM9, but not ADAM10 and ADAM17, at transcriptional level by nuclear factor-κB (NF-κB) signaling pathway. Caspr1 knockout attenuated the activation of NF-κB and prevented the nuclear translocation of p65 in brain endothelial cells, which was reversed by expression of full-length Caspr1. The reduced sAPPα production and ADAM9 expression upon Caspr1 depletion were effectively recovered by NF-κB agonist. The results of luciferase assays indicated that the NF-κB binding sites are located at −859 bp to −571 bp of ADAM9 promoter. Taken together, our results demonstrated that Caspr1 facilitates sAPPα production by transcriptional regulation of α-secretase ADAM9 in brain endothelial cells.

Soy isoflavones (SI) are phytochemicals with various biological activities. Acetaminophen can cause acute liver injury when overdosed. In this study, to investigate the effects of SI on the metabolism and toxicity of acetaminophen in liver, rats were fed a controlled diet with or without 120 mg/kg SI-rich product for 2 weeks and were then intraperitoneally injected with acetaminophen. Cytochrome P-450 (CYP), phase II enzymes, membrane transporters, and glutathione in liver were evaluated. Acetaminophen-induced elevations in plasma alanine aminotransferase activity and decreases in liver glutathione levels were ameliorated in rats treated with SI. SI reduced hepatic CYP2E1 and CYP3A activities and acetaminophen-protein adduct contents. Hepatic UDP-glucuronosyltransferase activity and urinary acetaminophen excretion were increased by SI after acetaminophen treatment. Protein expression of multidrug-resistance-associated protein 2/3 and connexin 32 in liver, however, was not changed by SI. Our results indicate that SI-rich product may act as functional food which can reduce acetaminophen-induced hepatotoxicity.

A novel interleaved high step-up DC–DC converter applied for applications in photovoltaic systems is proposed in this paper. The proposed configuration is composed of three-winding coupled inductors, voltage multiplier cells and a clamp circuit. The step-up voltage gain is effectively increased, owing to the voltage-stack and voltage-lift techniques using the voltage multiplier cells. The leakage inductor energy is recycled by the clamp circuit to avoid the voltage surge on a power switch. The low-voltage-rated power switches with low on-state resistances and costs can be used to decrease the conduction losses and increase the conversion efficiency when the voltage stresses of power switches for the converter are considerably lower than the high output voltage. The reverse-recovery problems of diodes are mitigated by the leakage inductances of the coupled inductors. Moreover, both the input current ripple and the current stress on each power switch are reduced, owing to the interleaved operation. The operating principle and steady-state analysis of the proposed converter are thoroughly presented herein. A controller network is designed to diminish the effect of the variations of input voltage and output load on the output voltage. Finally, the experimental results for a 1 kW prototype with 28–380 V voltage conversion are shown to demonstrate its effectiveness and performance.

ObjectivesMost researchers have examined forms of loneliness as discrete and emotional distress. The approach proposed in this study captures the reality that many persons experience more than one dimension of loneliness-varying degrees coupled with their psychological well-being in a family context. This study explores the latent structure of loneliness during young adulthood and its association with psychological well-being, as well as how these are related to their family characteristics in adolescence.MethodsData are from 2,748 young people, a cohort sample from the Taiwan Youth Project (TYP). Loneliness was assessed by a 6-item de Jong-Gierveld short scale with emotional and social loneliness domains. We describe the clustering between loneliness domains and psychological well-being, namely depressive symptoms, self-esteem, suicidal thoughts, and alcohol use using latent class cluster analysis. In addition to incorporating the Taiwanese family context, multivariate multinomial logistic regression models included data on family cohesion and parental guan (parental control) in adolescence. This might be associated with choices in partnership and childbearing, and influence loneliness in young adulthood.ResultsOur results demonstrate a three-cluster model of loneliness involving emotional loners, serious emotional loners, and severe emotional/social loners. We also found that a feeling of serious emotional loneliness and severe emotional/social loneliness were significantly associated with psychological well-being, even adjusting for individual characteristics. Among young adults who had a partner, the married adults were significantly less likely to feel serious emotional loneliness than those who were living alone. Furthermore, young adults with stronger family cohesion during early adolescence were less likely to suffer from serious emotional loneliness (Relative risk ratios [RRR] 0.77, 95% CI 0.65-0.91) and severe emotional/social loneliness (RRR 0.54, 95% CI 0.34-0.85) in young adulthood.DiscussionThis measurement strategy provides a foundation for future research into how experts can address loneliness clusters in order to better understand psychological well-being during young adulthood and family context in adolescence. This is important because our results suggest that the various loneliness domains do not occur independently, but rather are embedded in patterns and are associated with family characteristics.

Ischemic strokes often result in cerebral injury due to ischemia/reperfusion (I/R). Although the local inflammatory responses are known to play a primary role in the brain I/R injury, the underlying mechanism remains unclear. In the current study, we investigated the effect of brain endothelial Atg7 (autophagy related 7) depletion in the acute brain injury induced by ischemia and reperfusion. Endothelial knockout of Atg7 in mice (Atg7 eKO) was found to significantly attenuate both the infarct volume and the neurological defects induced by I/R when compared to the controls. In fact, brain inflammatory responses induced by I/R were alleviated by the Atg7 eKO. Furthermore, an increased expression of pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, and TNF-α, was observed in brain endothelial cells in response to oxygen/glucose depletion/reoxygenation, which was decreased by the shRNA-mediated Atg7 knockdown. Interestingly, Atg7 knockdown reduced IKKβ phosphorylation, leading to NF-κB deactivation and downregulation of the pro-inflammatory cytokines mRNA levels. Further, Atg7 transcriptional regulation function is independent of its role in autophagy. Taken together, our results demonstrated that brain endothelial Atg7 contributes to brain damage during I/R by modulating the expression of pro-inflammatory cytokines. Depletion of Atg7 in brain endothelium has a neuroprotective effect against the ischemia/reperfusion-induced acute cerebral injury during stroke.

AIM:To compare the curative effects between laser multi-point scanning and single-point multiple scanning for the treatment of non-proliferative diabetic retinopathy. METHODS:Fifty patients with non-proliferative diabetic retinopathy from January 2010 to January 2014 in our hospital were selected for the study, and were divided into two groups, the control group and the observation group, using a random number table. Twenty-five patients(43 eyes)in the observation group completed panretinal photocoagulation(PRP)therapy once by 577nm laser multi-point scanning. Twenty-five patients(41 eyes)in the control group completed PRP therapy by the single-point multiple scanning. The differences of average threshold sensitivity of visual field, F-ERG a/b wave amplitude, the clinical effective rates, the laser energy, the number of laser spot and the energy density between the two groups at various time points were compared.RESULTS:At 1d after the treatments, average threshold sensitivity of visual field was lower than those at 1d before treament, and the difference was statistically significant(t=2.421, P=0.017). The differences of average threshold sensitivity between the two groups at 1d before treatments, at 1d, 1, 2, 6, 12mo after treatments, were not statistically significant(P>0.05). The F-ERG a wave amplitude of both groups at 1d after treatments were lower than those of 1d before treatments, and the difference was statistically significant(t=2.319, P=0.025). There were no differences of the F-ERG b wave amplitude between both groups at 1d before treatments and at 1d, 1, 2, 6, 12mo after treatments(P>0.05). The F-ERG b wave amplitude of both groups at 1d after treatments were lower than those at 1d before treatments, and the difference was statistically significant(t=2.276, P=0.031). There were no differences between the two groups in terms of clinical effective rates and the number of laser spot(P>0.05). Laser energy used in the observation group was higher than that in the control group, the energy density was lower than that in the control group. The differences on the two items were statistically significant(P CONCLUSION:There is no significant difference on clinical efficacy between laser multi-point scanning and single-point multiple scanning of PRP therapy. But the energy density of multi-point scanning mode is lower, and the damage made by this mode is less.

1-(2,6-Dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)-propane hydrochloride (DDPH) is a novel antihypertensive agent based on structural characteristics of mexiletine and verapamine. We investigated the effect of DDPH on vasodilatation and neuroprotection in a rat model of cerebral ischemia in vivo, and a rabbit model of isolated basilar arteries in vitro. Our results show that DDPH (10 mg/kg) significantly increased hippocampal blood flow in vivo in cerebral ischemic rats, and exerted dose-dependent relaxation of isolated basilar arteries contracted by histamine or KCl in the in vitro rabbit model. DDPH (3 × 10 -5 M) also inhibited histamine-stimulated extracellular calcium influx and intracellular calcium release. Our findings suggest that DDPH has a vasodilative effect both in vivo and in vitro, which mediates a neuroprotective effect on ischemic nerve tissue.

This paper adopts an automated frequency-driven approach to identify frequently-used word combinations (i.e., lexical bundles) in academic writing. Lexical bundles retrieved from one corpus of published academic texts and two corpora of student academic writing (one L1, the other L2), were investigated both quantitatively and qualitatively. Published academic writing was found to exhibit the widest range of lexical bundles whereas L2 student writing showed the smallest range. Furthermore, some high-frequency expressions in published texts, such as in the context of, were underused in both student corpora, while the L2 student writers overused certain expressions (e.g., all over the world) which native academics rarely used. The findings drawn from structural and functional analyses of lexical bundles also have some pedagogical implications.

Amyloid-β (Aβ), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from sequential proteolytic cleavage of amyloid protein precursor (APP) by secretases. In this study, we found that cystatin C (CysC), a natural cysteine protease inhibitor, is able to reduce Aβ40 secretion in human brain microvascular endothelial cells (HBMEC). The CysC-induced Aβ40 reduction was caused by degradation of β-secretase BACE1 through the ubiquitin/proteasome pathway. In contrast, we found that CysC promoted secretion of soluble APPα indicating the activated non-amyloidogenic processing of APP in HBMEC. Further results revealed that α-secretase ADAM10, which was transcriptionally upregulated in response to CysC, was required for the CysC-induced sAPPα secretion. Knockdown of SIRT1 abolished CysC-triggered ADAM10 upregulation and sAPPα production. Taken together, our results demonstrated that exogenously applied CysC can direct amyloidogenic APP processing to non-amyloidgenic pathway in brain endothelial cells, mediated by proteasomal degradation of BACE1 and SIRT1-mediated ADAM10 upregulation. Our study unveils previously unrecognized protective role of CysC in APP processing.

BACKGROUND: Bone marrow-derived microglia that originates in part from hematopoietic cells, and more particularly from monocytes preferentially attach to amyloid deposition in brains of Alzheimer's disease (AD). However, the mechanism of monocytes recruited into the amyloid plaques with an accelerated process in AD is unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here we reported that monocytes from AD patients express significantly higher chemokine (C-X-C motif) ligand 1 (CXCL1) compared to age-matched controls. AD patient's monocytes or CXCL1-overexpressing THP-1 cells had enhanced ability of β-amyloid (Aβ)-induced transendothelial migration and Aβ-induced transendothelial migration for AD patient's monocytes or CXCL1-overexpressing THP-1 cells was almost abrogated by anti-CXCL1 antibody. Furthermore, monocytes derived from a transgenic mouse model of AD also expressed significantly higher CXCL1. CD11b⁺CD45(hi) population of cells that were recruited from the peripheral blood were markedly bolcked in APP mouse brain by anti-CXCL1 antibody. Accordingly, in response to Aβ, human brain microvascular endothelial cells (HBMEC) significantly up-regulated CXC chemokine receptor 2 (CXCR2) expression, which was the only identified receptor for CXCL1. In addition, a high level expression of CXCR2 in HBMEC significantly promoted the CXCL1-overexpressing THP-1 cells transendothelial migration, which could be was abrogated by anti-CXCR2 antibody. Further examination of possible mechanisms found that CXCL1-overexpressing THP-1 cells induced transendothelial electrical resistance decrease, horseradish peroxidase flux increase, ZO-1 discontinuous and occludin re-distribution from insoluble to soluble fraction through interacting with CXCR2. ROCK inhibitor, Y27632, could block CXCL1-overexpressing THP-1 cells transendothelial migration, whereas other inhibitors had no effects. CONCLUSIONS/SIGNIFICANCE: The present data indicate that monocytes derived from AD patients overexpressing CXCL1, which is a determinant for Aβ-induced transendothelial migration. CXCL1 expressed by monocytes and CXCR2 on HBMEC is involved in monocytes migrating from blood to brain in AD patients.

BACKGROUND: Abnormal zinc homeostasis is involved in β-amyloid (Aβ) plaque formation and, therefore, the zinc load is a contributing factor in Alzheimer's disease (AD). However, the involvement of zinc in amyloid precursor protein (APP) processing and Aβ deposition has not been well established in AD animal models in vivo. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, APP and presenilin 1 (PS1) double transgenic mice were treated with a high dose of zinc (20 mg/ml ZnSO4 in drinking water). This zinc treatment increased APP expression, enhanced amyloidogenic APP cleavage and Aβ deposition, and impaired spatial learning and memory in the transgenic mice. We further examined the effects of zinc overload on APP processing in SHSY-5Y cells overexpressing human APPsw. The zinc enhancement of APP expression and cleavage was further confirmed in vitro. CONCLUSIONS/SIGNIFICANCE: The present data indicate that excess zinc exposure could be a risk factor for AD pathological processes, and alteration of zinc homeostasis is a potential strategy for the prevention and treatment of AD.

A simple voltammetric method, employing Au nanoparticles modified glassy carbon electrode (AuNPs/ GCE), was developed for the determination of butylated hydroxylanisole (BHA), butylated hydroxytoluene (BHT), and tert-butylhydroquinone (TBHQ), the widely used synthetic phenolic antioxidants in foods. As a result, the electrochemical behavior of the antioxidants could be simultaneously detected only at the AuNPs/ GCE. The AuNPs/GCE allowed the detection of the three analytes at potentials lower than those observed at bare GCE. The stability and repeatability of the AuNPs/GCE were also confirmed in the study. Under the optimized conditions, the method presented a linear response in the concentration range of 0~330 mg/ L for TBHQ (R² = 0.9962), BHA (R² = 0.9974) and BHT (R² = 0.9968), respectively. The proposed method was effectively utilized to simultaneously quantify BHA, BHT, and TBHQ in various edible oil products. The obtained results were found to be consistent with those obtained through the high-performance liquid chromatography (HPLC) method. The analytical utility of the AuNPs/GCE-based sensor was evaluated through a recovery study, achieving an average recovery of 95.56% to 104.98% for the three antioxidants. These results indicated satisfactory precision and accuracy, suggesting the potential use of the developed electroanalytical method for detecting these antioxidants in food products. [ABSTRACT FROM AUTHOR]