PP-DDP: a privacy-preserving outsourcing framework for solving the double digest problem.

BACKGROUND: As one of the fundamental problems in bioinformatics, the double digest problem (DDP) focuses on reordering genetic fragments in a proper sequence. Although many algorithms for dealing with the DDP problem were proposed during the past decades, it is believed that solving DDP is still very time-consuming work due to the strongly NP-completeness of DDP. However, none of these algorithms consider the privacy issue of the DDP data that contains critical business interests and is collected with days or even months of gel-electrophoresis experiments. Thus, the DDP data owners are reluctant to deploy the task of solving DDP over cloud. RESULTS: Our main motivation in this paper is to design a secure outsourcing computation framework for solving the DDP problem. We at first propose a privacy-preserving outsourcing framework for handling the DDP problem by using a cloud server; Then, to enable the cloud server to solve the DDP instances over ciphertexts, an order-preserving homomorphic index scheme (OPHI) is tailored from an order-preserving encryption scheme published at CCS 2012; And finally, our previous work on solving DDP problem, a quantum inspired genetic algorithm (QIGA), is merged into our outsourcing framework, with the supporting of the proposed OPHI scheme. Moreover, after the execution of QIGA at the cloud server side, the optimal solution, i.e. two mapping sequences, would be transferred publicly to the data owner. Security analysis shows that from these sequences, none can learn any information about the original DDP data. Performance analysis shows that the communication cost and the computational workload for both the client side and the server side are reasonable. In particular, our experiments show that PP-DDP can find optional solutions with a high success rate towards typical test DDP instances and random DDP instances, and PP-DDP takes less running time than DDmap, SK05 and GM12, while keeping the privacy of the original DDP data. CONCLUSION: The proposed outsourcing framework, PP-DDP, is secure and effective for solving the DDP problem.

Deep Stacking Network for Intrusion Detection.

Preventing network intrusion is the essential requirement of network security. In recent years, people have conducted a lot of research on network intrusion detection systems. However, with the increasing number of advanced threat attacks, traditional intrusion detection mechanisms have defects and it is still indispensable to design a powerful intrusion detection system. This paper researches the NSL-KDD data set and analyzes the latest developments and existing problems in the field of intrusion detection technology. For unbalanced distribution and feature redundancy of the data set used for training, some training samples are under-sampling and feature selection processing. To improve the detection effect, a Deep Stacking Network model is proposed, which combines the classification results of multiple basic classifiers to improve the classification accuracy. In the experiment, we screened and compared the performance of various mainstream classifiers and found that the four models of the decision tree, k-nearest neighbors, deep neural network and random forests have outstanding detection performance and meet the needs of different classification effects. Among them, the classification accuracy of the decision tree reaches 86.1%. The classification effect of the Deeping Stacking Network, a fusion model composed of four classifiers, has been further improved and the accuracy reaches 86.8%. Compared with the intrusion detection system of other research papers, the proposed model effectively improves the detection performance and has made significant improvements in network intrusion detection.

ViTT: Vision Transformer Tracker.

This paper presents a new model for multi-object tracking (MOT) with a transformer. MOT is a spatiotemporal correlation task among interest objects and one of the crucial technologies of multi-unmanned aerial vehicles (Multi-UAV). The transformer is a self-attentional codec architecture that has been successfully used in natural language processing and is emerging in computer vision. This study proposes the Vision Transformer Tracker (ViTT), which uses a transformer encoder as the backbone and takes images directly as input. Compared with convolution networks, it can model global context at every encoder layer from the beginning, which addresses the challenges of occlusion and complex scenarios. The model simultaneously outputs object locations and corresponding appearance embeddings in a shared network through multi-task learning. Our work demonstrates the superiority and effectiveness of transformer-based networks in complex computer vision tasks and paves the way for applying the pure transformer in MOT. We evaluated the proposed model on the MOT16 dataset, achieving 65.7% MOTA, and obtained a competitive result compared with other typical multi-object trackers.

An Efficient Alert Aggregation Method Based on Conditional Rough Entropy and Knowledge Granularity.

With the emergence of network security issues, various security devices that generate a large number of logs and alerts are widely used. This paper proposes an alert aggregation scheme that is based on conditional rough entropy and knowledge granularity to solve the problem of repetitive and redundant alert information in network security devices. Firstly, we use conditional rough entropy and knowledge granularity to determine the attribute weights. This method can determine the different important attributes and their weights for different types of attacks. We can calculate the similarity value of two alerts by weighting based on the results of attribute weighting. Subsequently, the sliding time window method is used to aggregate the alerts whose similarity value is larger than a threshold, which is set to reduce the redundant alerts. Finally, the proposed scheme is applied to the CIC-IDS 2018 dataset and the DARPA 98 dataset. The experimental results show that this method can effectively reduce the redundant alerts and improve the efficiency of data processing, thus providing accurate and concise data for the next stage of alert fusion and analysis.

Statistic Experience Based Adaptive One-Shot Detector (EAO) for Camera Sensing System.

Object detection in a camera sensing system has been addressed by researchers in the field of image processing. Highly-developed techniques provide researchers with great opportunities to recognize objects by applying different algorithms. This paper proposes an object recognition model, named Statistic Experience-based Adaptive One-shot Detector (EAO), based on convolutional neural network. The proposed model makes use of spectral clustering to make detection dataset, generates prior boxes for object bounding and assigns prior boxes based on multi-resolution. The model is constructed and trained for improving the detection precision and the processing speed. Experiments are conducted on classical images datasets while the results demonstrate the superiority of EAO in terms of effectiveness and efficiency. Working performance of the EAO is verified by comparing it to several state-of-the-art approaches, which makes it a promising method for the development of the camera sensing technique.

TSNARE1 polymorphisms are associated with schizophrenia susceptibility in Han Chinese.

t-SNARE domain containing 1 gene (TSNARE1) is located at human chromosome 8q24.3, and may play a crucial role in intracellular protein transport and synaptic transmission. Recently, a large-scale meta-analysis of genome-wide association study dataset identified that rs10098073 and rs4129585, two single nucleotide polymorphisms (SNPs) within TSNARE1, were closely associated with the risk of schizophrenia in Caucasians. However, this finding has not been validated in other populations or ethnic groups thus far. In the current study, we conducted a case-control study to confirm the association of these two SNPs with the schizophrenia risk in a Han Chinese population comprising 440 schizophrenia patients and 450 control subjects. According to the genotype data of Han Chinese from Beijing in 1,000 Genomes Project database, rs10098073 and rs4129585 were located in one haplotype block and were in almost complete linkage disequilibrium (D' = 1, r (2) ≥ 0.952). Therefore, only rs10098073 was selected for the subsequent analysis. We showed for the first time that the minor allele (A) of rs10098073 was associated with a reduced risk of schizophrenia (OR = 0.753; 95 % CI 0.613-0.924; P = 0.007). Furthermore, we found that the A allele of rs10098073 reduced the schizophrenia risk through a recessive manner (A/A vs. A/C + C/C, OR = 0.563; 95 % CI 0.357-0.89; P = 0.013, P Bonferroni corrected = 0.026) rather than a dominant manner (A/A + A/C vs. C/C, OR = 0.762; 95 % CI 0.586-0.992; P = 0.043, P Bonferroni corrected = 0.086). Taken together, these findings demonstrate a significant association between TSNARE1 polymorphisms and schizophrenia risk in a Han Chinese population, suggesting TSNARE1 may represent a susceptibility gene for this disease.

Activation of double-stranded RNA-dependent protein kinase inhibits proliferation of pancreatic ß-cells.

Double-stranded RNA-dependent protein kinase (PKR) is revealed to participate in the development of insulin resistance in peripheral tissues in type 2 diabetes (T2DM). Meanwhile, PKR is also characterized as a critical regulator of cell proliferation. To date, no study has focused on the impact of PKR on the proliferation of pancreatic ß-cells. Here, we adopted insulinoma cell lines and mice islet ß-cells to investigate: (1) the effects of glucolipotoxicity and pro-inflammatory cytokines on PKR activation; (2) the effects of PKR on proliferation of pancreatic ß-cells and its underlying mechanisms; (3) the actions of PKR on pro-proliferative effects of IGF-I and its underlying pathway. Our results provided the first evidence that PKR can be activated by glucolipitoxicity and pro-inflammatory cytokines in pancreatic ß-cells, and activated PKR significantly inhibited cell proliferation by arresting cell cycle at G1 phase. Reductions in cyclin D1 and D2 as well as increases in p27 and p53 were associated with the anti-proliferative effects of PKR, and proteasome-dependent degradation took part in the reduction of cyclin D1 and D2. Besides, PKR activation abrogated the pro-proliferative effects of IGF-I by activating JNK and disrupting IRS1/PI3K/Akt signaling pathway. These findings indicate that the anti-proliferative actions of PKR on pancreatic ß-cells may contribute to the pathogenesis of T2DM.

Early activation of nSMase2/ceramide pathway in astrocytes is involved in ischemia-associated neuronal damage via inflammation in rat hippocampi.

BACKGROUND: Ceramide accumulation is considered a contributing factor to neuronal dysfunction and damage. However, the underlying mechanisms that occur following ischemic insult are still unclear. METHODS: In the present study, we established cerebral ischemia models using four-vessel occlusion and oxygen-glucose deprivation methods. The hippocampus neural cells were subjected to immunohistochemistry and immunofluorescence staining for ceramide and neutral sphingomyelinase 2 (nSMase2) levels; immunoprecipitation and immunoblot analysis for nSMase2, receptor for activated C kinase 1 (RACK1), embryonic ectoderm development (EED), p38 mitogen-activated protein kinase (p38MAPK) and phosphorylated p38MAPK expression; SMase assay for nSMase and acid sphingomyelinase (aSMase) activity; real-time reverse transcription polymerase chain reaction for cytokine expression; and Nissl, microtubule-associated protein 2 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling staining. RESULTS: We found considerable production of ceramide in astrocytes, but not in neurons, during early cerebral ischemia. This was accompanied by the induction of nSMase (but not aSMase) activity in the rat hippocampi. The inhibition of nSMase2 activity effectively reduced ceramide accumulation in astrocytes and alleviated neuronal damage to some extent. Meanwhile, the expression levels of proinflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and IL-6, were found to be upregulated, which may have played an import role in neuronal damage mediated by the nSMase2/ceramide pathway. Although enhanced binding of nSMase2 with RACK1 and EED were also observed after cerebral ischemia, nSMase2 activity was not blocked by the TNF-α receptor inhibitor through RACK1/EED signaling. p38MAPK, but not protein kinase Cζ or protein phosphatase 2B, was able to induce nSMase2 activation after ischemia. p38MAPK can be induced by A2B adenosine receptor (A2BAR) activity. CONCLUSIONS: These results indicate that the inhibition of ceramide production in astrocytes by targeting A2BAR/p38MAPK/nSMase2 signaling may represent a viable approach for attenuating inflammatory responses and neuronal damage after cerebral ischemia.

[Protective effect of H2S pretreatment on cerebral ischemia-reperfusion injury and its mechanisms in rats].

OBJECTIVE: To investigate the protective effect of H2S pretreatment after cerebral schemia/reperfusion injury and its mechanisms in rats. METHODS: The rat model of global cerebral ischemia/reperfusion injury was established by bilateral common carotid arteries occlusion combined with hemorrhagic hypotension.30 rats were randomly divided into four groups(1)sham group(n=5),in which rats received sham surgery only,with their bilateral vertebral artery and bilateral common carotid artery exposed but without ischemia treatment;(2)global cerebral ischemia/reperfusion model group(IR group,n=5),in which the global cerebral ischemia was induced by 10-min occlusion of bilateral common carotid arteries combined with hypotension;(3)H2S pretreatment group(n=15),in which H2S(12,24,48 Μmol/kg)was intraperitoneally injected before operation;(4)NaCl pretreatment group(n=5),in which the rats were intraperitoneally injected with saline 30 minutes before operation.The activities of superoxide dismutase(SOD)and the levels of malondialdeehyde(MDA)in brain were measured by spectrophotometry.Brain water content was detected.The expression of heat shock protein 70(HSP70) in the hippocampus was determined by Western blotting. RESULTS: The SOD activities were significant increased in groups pretreated with 12Μmol/kg H2S(P=0.042),24Μmol/kg H2S(P=0.002),and 48Μmol/kg H2S(P=0.000),and the SOD activity was significantly lower in the ischemia group than in the Sham group(P=0.003).The MDA activities in the 24Μmol/kg group(P=0.026)and the 48Μmol/kg group(P=0.015)groups were significantly lower than in the IR group.The brain water content was decreased in H2S pretreatment group(24Μmol/kg and 48 Μmol/kg)compared with IR group(P=0.018,P=0.008),and it was also significantly higher in the IR group than in the sham group(P=0.009).The expression of HSP70 were decreased in H2S pretreatment group(24 Μmol/kg)compared with the IR group(P=0.000),and the expression of HSP70 were significantly higher in the IR group than in HSP70 group(P=0.000).The expression of HSP70 also significantly differed between NaCl group and HSP70 group(P=0.000). CONCLUSION: H2S has protective effects on cerebral ischemia and reperfusion,which may be achieved by improving SOD activity,removing oxygen free radicals,inhibiting lipid peroxidation,and down-regulating the expression of HSP70 in the hippocampus.

Clinical value for the detection of fetal chromosomal deletions/duplications by noninvasive prenatal testing in clinical practice.

OBJECTIVE: This study was to report the experiences on the clinical value of noninvasive prenatal testing (NIPT) for the screening of fetal chromosomal deletions/duplications. METHODS: We performed a retrospective analysis of a cohort of 20,439 pregnancies undergoing NIPT from March 2017 to September 2020 at a single center. Patients with positive NIPT results for fetal chromosomal deletions or duplications had options of invasive diagnostic testing or no further testing. The data were complied from all cases with positive NIPT results for chromosomal deletions/duplications. The positive predictive value (PPV) was calculated from tabulated data. RESULTS: In this cohort, positive NIPT results for fetal chromosomal deletions/duplications were found in 60 pregnant women. Of the positive samples, further invasive testing was performed in 39 cases, in which 9 cases were found to be true positive. The overall PPV for chromosomal deletions/duplications was 23.1%. In addition, fetal structural anomaly was found by ultrasound examination in three cases, in which the chromosomal deletions/duplications of three cases were not verified. Moreover, an unexpected pathogenic 8p23.3 deletion was identified by invasive testing in 1 fetus with a false positive NIPT screen for 3q27.3q29 duplication. CONCLUSIONS: In summary, positive NIPT results of chromosomal deletions/duplications were not uncommon in clinical practice, whereas the PPV for the testing was low. Hence, potential risks and high percentage of false positives for these abnormal NIPT results might be informed to pregnant women before the choice made of invasive testing.

Long Noncoding RNA TUG1 Promotes Autophagy-Associated Paclitaxel Resistance by Sponging miR-29b-3p in Ovarian Cancer Cells.

PURPOSE: Paclitaxel (PTX) is a first-line chemotherapeutic agent for treating ovarian cancer. However, PTX resistance has become a major obstacle in ovarian cancer therapy. The underlying mechanism associated with PTX resistance is still unclear. PATIENTS AND METHODS: We used qPCR to detect taurine up-regulated 1 (TUG1) expression in normal ovarian tissues and ovarian tumor tissues. A combination of small interfering RNA (siRNA), cell counting kit 8 (CCK8), colony formation assay and nude mouse model were used to detect the effect of TUG1 on ovarian cancer cell PTX-resistance. Autophagy/cytotoxicity dual staining assay, luciferase reporter assay, Western blot and RNA-binding protein immunoprecipitation assay were used for further mechanistic studies. RESULTS: TUG1 is highly expressed not only in ovarian tumor tissues compared with normal ovarian tissues but also in the chemo-resistant group compared with the sensitive group. Knockdown of TUG1 by siRNA decreased ovarian cancer cell and xenograft tumor PTX resistance with or without PTX treatment. Moreover, deletion of TUG1 in ovarian cancer cells decreased autophagosome formation and increased apoptosis as demonstrated by autophagy/cytotoxicity dual staining and Western blot assays. Furthermore, microRNA-29b-3p (miR-29b-3p) was found as the direct target of TUG1. Additionally, TUG1 could directly bind Ago2, a key protein of the RNA-induced silencing complex. CONCLUSION: Our findings suggest that TUG1, through targeting miR-29b-3p, induces autophagy and consequently results in PTX resistance in ovarian cancer.

Quantitative assessment of serum heat shock protein 27 for the diagnosis of epithelial ovarian cancer using targeted proteomics coupled with immunoaffinity enrichment.

BACKGROUND: Heat shock protein 27 (HSP27) may take part in the epithelial ovarian cancer (EOC) malignant process because it is elevated in the serum of EOC patients, suggesting that HSP27 may serve as an EOC biomarker to complement the standard serum carbohydrate antigen 125 (CA125) test. Thus, accurate quantification of serum HSP27 would assist the diagnosis of EOC. METHODS: Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based targeted proteomics coupled with an immunoaffinity enrichment assay was developed and validated to monitor HSP27 concentrations in serum. RESULTS: Tryptic peptide 80QLSSGVSEIR89 was selected as a surrogate analyte for quantification, and an immuno-depleted serum extract was used as a surrogate matrix. Immunoaffinity enrichment was effective for protein enrichment and sensitivity enhancement, and the resulting LOQ was 500 pg/ml (>10-fold increase). Then, serum HSP27 concentrations in EOC patients, benign ovarian tumors patients and healthy volunteers were accurately determined to be 4.95 ±â€¯0.37 ng/ml, 2.98 ±â€¯0.16 ng/ml and 2.82 ±â€¯0.15 ng/ml, respectively, suggesting that the EOC samples had significantly higher concentrations of HSP27 than a sample from benign ovarian tumor patients. The experimental values for the samples were compared with those obtained from enzyme-linked immune sorbent assays (ELISAs). The ROC curve analysis showed that the combined area under the curve (AUC) for CA125 and HSP27 was 0.88, which is significantly superior to that of CA125 alone. CONCLUSIONS: Targeted proteomics coupled with immunoaffinity enrichment may provide more accurate quantification of low-abundant proteins.

Application of karyotype analysis combined with BACs-on-Beads for prenatal diagnosis.

This study explored the clinical application of karyotype analysis combined with BACs-on-Beads (BoBs) technology in prenatal diagnosis. A total of 558 pregnant women who were admitted to Xuzhou Maternity and Child Health Care Hospital from July 2015 to June 2017 were enrolled in this study. All the subjects underwent amniocentesis. BoBs assay was performed for subjects in the observation group, and karyotype analysis was performed for subjects in the control group. The main technical indicators of subjects in the two groups were summarized, and cases of chromosome abnormalities were further evaluated. Clinical follow-up of their pregnancy and neonatal birth was undertaken. Finally, the chromosomal manifestations of these patients were compared with those of normal male and normal female, as well as common chromosomal abnormalities. All 558 pregnant women underwent amniocentesis again. Karyotype analysis combined with BoBs assay of amniotic fluid was performed. Cases of chromosomal abnormalities detected were: 75 cases of trisomy 21, 20 cases of trisomy 18, 1 case of trisomy 13, 27 cases of sex chromosomal abnormalities, 12 cases of balanced chromosome translocation, and 2 cases of chromosome microdeletion. The results indicated that karyotype analysis combined with BoBs technology for prenatal diagnosis was easy to perform, and provided quick results with high accuracy. The two testing methods were complementary to each other, which significantly improved the diagnostic rate of chromosomal abnormalities thus reducing birth defects and guiding continued pregnancy of high-risk pregnant women.

Common Polymorphisms Within QPCT Gene Are Associated with the Susceptibility of Schizophrenia in a Han Chinese Population.

A recent genome-wide association study conducted in Caucasians has identified glutaminyl-peptide cyclotransferase (QPCT) gene as a susceptibility gene for schizophrenia, as its common single nucleotide polymorphism (SNP) rs2373000 was significantly associated with the risk of this disease. To date, this finding has not been validated in other populations or ethnic groups. The aim of this study was to investigate the association of common SNPs spanning QPCT gene with the susceptibility of schizophrenia in a Han Chinese population comprising 440 schizophrenia patients and 450 control subjects. A total of 6 tagSNPs including rs2373000 was selected and then genotyped in our sample. Although the relation between rs2373000 and the risk of schizophrenia was not successfully replicated, we showed for the first time that the minor allele (C) of rs3770752 was associated with a reduced risk of schizophrenia (odds ratio (OR) = 0.645; 95 % confidence interval (CI) 0.486-0.855; P corrected = 0.012) in our cohorts. Meanwhile, this allele seemed to modify the schizophrenia risk through a dominant manner (CC + CT vs. TT, OR = 0.625; 95 % CI 0.457-0.854; P corrected = 0.03). In addition, we found that the minor allele (T) of rs3770748 remarkably reduced the schizophrenia risk via a recessive manner (TT vs. TC + CC, OR = 0.618; 95 % CI: 0.449-0.851; P corrected = 0.03). Taken together, these findings demonstrate a significant association between common SNPs within QPCT gene and schizophrenia risk in a Han Chinese population, suggesting QPCT gene may represent a susceptibility gene for this disease.

rs11098403 polymorphism near NDST3 is associated with a reduced risk of schizophrenia in a Han Chinese population.

A recent genome-wide association study indicated that rs11098403, a single nucleotide polymorphism in the vicinity of NDST3, was strongly associated with the risk of schizophrenia in Caucasians. However, this relation has not been validated in other populations or ethnic groups. Herein, we conducted a case-control study to investigate the association of rs11098403 polymorphism with the schizophrenia risk in a Han Chinese population comprising 440 schizophrenia patients and 450 control subjects. For the first time, we showed that the minor allele (G) of rs11098403 is closely associated with a reduced risk of schizophrenia (OR=0.614; 95% CI: 0.453-0.833; P=0.002; Power=0.832). Meanwhile, the G allele of rs11098403 seemed to reduce the schizophrenia risk via a dominant manner (GG+AG vs. AA, OR=0.526; 95% CI: 0.374-0.74; P<0.001). Furthermore, this association was further confirmed using an independent replication sample containing 267 schizophrenia patients and 400 control subjects with a Han Chinese descent (OR=0.652; 95% CI: 0.469-0.907; P=0.011; Power=0.772). Taken together, these findings demonstrate a significant association between rs11098403 and schizophrenia risk in Han Chinese, confirming the data that previously obtained from Caucasians.

Triggering receptor expressed on myeloid cells 2 knockdown exacerbates aging-related neuroinflammation and cognitive deficiency in senescence-accelerated mouse prone 8 mice.

As a major characteristic of aging process, neuroinflammation is involved in the pathogenesis of several aging-related diseases including Alzheimer's disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a newly identified risk gene for AD, which regulates inflammatory process in peripheral tissues via modulating the release of inflammatory cytokines. However, the role of TREM2 in aging-related neuroinflammation, cognitive deficiency, and AD-like neuropathology is unclear so far. Here, we detected the protein levels of TREM2 in brain of 3-, 7-, and 11-month-old senescence-accelerated mouse prone 8 (SAMP8) mice and observed that TREM2 levels were increased during aging process. We then knocked down TREM2 expression in brain of SAMP8 mice by nonviral RNA interference and found a significant increase in proinflammatory cytokines including tumor necrosis factor-α and interleukin (IL)-6, which was accompanied by a reduction in IL-10. Meanwhile, more obvious neuronal and synaptic losses and cognitive impairment were observed. These findings indicate that TREM2 may play a protective role against aging-related neuroinflammation and cognitive impairment.

Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer's disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for Alzheimer's disease (AD), as its low-frequency variants increase the risk of this disease with an odds ratio similar to that of an APOE ɛ4 allele. To date, the expression and biologic functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was upregulated in microglia during disease progression. For the first time, we provided in vitro and in vivo evidence that this upregulation was attributed to the increased amyloid-ß (Aß)(1-42) levels in the brain. By knockdown and overexpression of TREM2 in cultured primary microglia, we revealed that TREM2 modulated microglial functions under AD context, as it facilitated Aß(1-42) phagocytosis and inhibited Aß(1-42)-triggered proinflammatory responses. Meanwhile, this modulation was dependent on DAP12, the adapter protein of TREM2. More importantly, overexpression of TREM2 in the brain of APPswe/PS1dE9 mice markedly ameliorated AD-related neuropathology including Aß deposition, neuroinflammation, and neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive functions. Taken together, our data suggest that the upregulation of TREM2 serves as a compensatory response to Aß(1-42) and subsequently protects against AD progression by modulation of microglia functions. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a potential therapeutic target for this disease.

MiR-21 involve in ERK-mediated upregulation of MMP9 in the rat hippocampus following cerebral ischemia.

Matrix metallinoprotease-9 (MMP9) plays a key role in the pathogenesis of post-ischemic blood brain barrier (BBB) disruption and the formation of lesions after cerebral ischemia. In this study we investigate the effect of brain-specific miRNAs on MMP-9 protein level in the rat hippocampus following cerebral ischemia and its underlying mechanism. Cerebral ischemia significantly upregulated miR-21 and -224 in the hippocampus; however, expression of miR-122 and -338-3p was not significantly affected by ischemia. Silencing of miR-21, but not -224, reduced MMP9 protein level after cerebral ischemia. Downregulation of extracellular signal-regulated kinase (ERK) signaling using the ERK inhibitor U0126 and the calcium-channel blocker ketamine inhibited the upregulation of miR-21 expression and MMP9 protein level after cerebral ischemia. The study suggests that cerebral ischemia up-regulates expression level of miR-21, which is involved in ERK-stimulated upregulation of MMP9 following cerebral ischemia via a calcium-dependent mechanism.

Elevated toll-like receptor 3 inhibits pancreatic ß-cell proliferation through G1 phase cell cycle arrest.

Activation of the innate and acquired immune systems plays an important role in chronic inflammatory diseases and conditions such as obesity, insulin resistance, type 2 diabetes mellitus and atherosclerosis, with additional roles in regulation of cell proliferation and survival. Here, we provide evidence that TLR3 can respond to nutrient signals and induce loss of ß-cell mass through induction of G1 cycle arrest. Activation of TLR3 by polyinosinic-polycytidylic acid [poly (I:C)] was shown to trigger the decline of cyclin D1/2 protein levels in pancreatic ß-cell lines, which could be reversed by the proteasome inhibitor MG132. P38 was also found to interfere with this degradation which may be associated with G1 cycle arrest. Moreover, inhibitory effects of TLR3 on ß-cell growth were supported by gene silencing of TRIF, which could inhibit p38 activity in response to poly (I:C) stimuli. These results support a role for TLR3 in ß-cell mass loss in metabolic surplus and raise the possibility that TRIF/p38 signaling may be involved in G1 phase cycle arrest through ubiquitin/proteasome-dependent degradation of cyclin D.

Inhibition of autophagy contributes to ischemic postconditioning-induced neuroprotection against focal cerebral ischemia in rats.

BACKGROUND: Ischemic postconditioning (IPOC), or relief of ischemia in a stuttered manner, has emerged as an innovative treatment strategy to reduce programmed cell death, attenuate ischemic injuries, and improve neurological outcomes. However, the mechanisms involved have not been completely elucidated. Recent studies indicate that autophagy is a type of programmed cell death that plays elusive roles in controlling neuronal damage and metabolic homeostasis. This study aims to determine the role of autophagy in IPOC-induced neuroprotection against focal cerebral ischemia in rats. METHODOLOGY/PRINCIPAL FINDINGS: A focal cerebral ischemic model with permanent middle cerebral artery (MCA) occlusion plus transient common carotid artery (CCA) occlusion was established. The autophagosomes and the expressions of LC3/Beclin 1/p62 were evaluated for their contribution to the activation of autophagy. We found that autophagy was markedly induced with the upregulation of LC3/Beclin 1 and downregulation of p62 in the penumbra at various time intervals following ischemia. IPOC, performed at the onset of reperfusion, reduced infarct size, mitigated brain edema, inhibited the induction of LC3/Beclin 1 and reversed the reduction of p62 simultaneously. Rapamycin, an inducer of autophagy, partially reversed all the aforementioned effects induced by IPOC. Conversely, autophagy inhibitor 3-methyladenine (3-MA) attenuated the ischemic insults, inhibited the activation of autophagy, and elevated the expression of anti-apoptotic protein Bcl-2, to an extent comparable to IPOC. CONCLUSIONS/SIGNIFICANCE: The present study suggests that inhibition of the autophagic pathway plays a key role in IPOC-induced neuroprotection against focal cerebral ischemia. Thus, pharmacological inhibition of autophagy may provide a novel therapeutic strategy for the treatment of stroke.