Identification of novel potential homologous repair deficiency-associated genes in pancreatic adenocarcinoma via WGCNA coexpression network analysis and machine learning.

Homologous repair deficiency (HRD) impedes double-strand break repair, which is a common driver of carcinogenesis. Positive HRD status can be used as theranostic markers of response to platinum- and PARP inhibitor-based chemotherapies. Here, we aimed to fully investigate the therapeutic and prognostic potential of HRD in pancreatic adenocarcinoma (PAAD) and identify effective biomarkers related to HRD using comprehensive bioinformatics analysis. The HRD score was defined as the unweighted sum of the LOH, TAI, and LST scores, and it was obtained based on the previous literature. To characterize PAAD immune infiltration subtypes, the "ConsensusClusterPlus" package in R was used to conduct unsupervised clustering. A WGCNA was conducted to elucidate the gene coexpression modules and hub genes in the HRD-related gene module of PAAD. The functional enrichment study was performed using Metascape. LASSO analysis was performed using the "glmnet" package in R, while the random forest algorithm was realized using the "randomForest" package in R. The prognostic variables were evaluated using univariate Cox analysis. The prognostic risk model was built using the LASSO approach. ROC curve and KM survival analyses were performed to assess the prognostic potential of the risk model. The half-maximal inhibitory concentration (IC50) of the PARP inhibitors was estimated using the "pRRophetic" package in R and the Genomics of Drug Sensitivity in Cancer database. The "rms" package in R was used to create the nomogram. A high HRD score indicated a poor prognosis and an advanced clinical process in PAAD patients. PAAD tumors with high HRD levels revealed significant T helper lymphocyte depletion, upregulated levels of cancer stem cells, and increased sensitivity to rucaparib, Olaparib, and veliparib. Using WGCNA, 11 coexpression modules were obtained. The red module and 122 hub genes were identified as the most correlated with HRD in PAAD. Functional enrichment analysis revealed that the 122 hub genes were mainly concentrated in cell cycle pathways. One novel HRD-related gene signature consisting of CKS1B, HJURP, and TPX2 were screened via LASSO analysis and a random forest algorithm, and they were validated using independent validation sets. No direct association between HRD and CKS1B, HJURP, or TPX2 has not been reported in the literature so far. Thus, these findings indicated that CKS1B, HJURP, and TPX2 have potential as diagnostic and prognostic biomarkers for PAAD. We constructed a novel HRD-related prognostic model that provides new insights into PAAD prognosis and immunotherapy. Based on bioinformatics analysis, we comprehensively explored the therapeutic and prognostic potential of HRD in PAAD. One novel HRD-related gene signature consisting of CKS1B, HJURP, and TPX2 were identified through the combination of WGCNA, LASSO analysis and a random forest algorithm. A novel HRD-related risk model that can predict clinical prognosis and immunotherapeutic response in PAAD patients was constructed.

SPINT2 is involved in the proliferation, migration and phenotypic switching of aortic smooth muscle cells: Implications for the pathogenesis of thoracic aortic dissection.

Thoracic aortic dissection (TAD) is a severe and extremely dangerous cardiovascular disease. Proliferation, migration and phenotypic switching of vascular smooth muscle cells (SMCs) are major pathogenetic mechanisms involved in the development of TAD. The present study was designed to investigate the expression and potential function of serine peptidase inhibitor Kunitz type 2 (SPINT2) in TAD. The gene expression profile data for ascending aorta from patients with TAD were downloaded from the GEO database with the accession number GSE52093. Bioinformatics analysis using GEO2R indicated that the differentially expressed SPINT2 was prominently decreased in TAD. The expression levels of SPINT2 mRNA and protein in aortic dissection specimens and normal aorta tissues were measured using reverse transcription-quantitative PCR and western blotting. SPINT2 expression was downregulated in clinical samples from aortic dissection specimens of patients with TAD compared with the corresponding expression noted in tissues derived from patients without TAD. In vitro, platelet-derived growth factor BB (PDGF-BB) was applied to induce the isolated primary mouse aortic SMC phenotypic modulation (a significant upregulation in the expression levels of synthetic markers), and the SMCs were infected with the adenoviral vector, Ad-SPINT2, to construct SPINT2-overexpressed cell lines. SMC viability was detected by an MTT assay and SMC proliferation was detected via the presence of Ki-67-positive cells (immunofluorescence staining). To explore the effects of SPINT2 on SMC migration, a wound healing assay was conducted. ELISA and western blotting assays were used to measure the content and expression levels of MMP-2 and MMP-9. The expression levels of vimentin, collagen I, α-SMA and SM22α were measured using western blotting. The PDGF-BB-induced proliferation and migration of SMCs were recovered by SPINT2 overexpression. The increase in the expression levels of SPINT2 reduced the expression levels of active matrix metalloproteinases (MMPs), MMP-2 and MMP-9. Overexpression of SPINT2 suppressed SMC switching from a contractile to a synthetic type, as evidenced by decreased vimentin and collagen I expression levels along with increased α-smooth muscle actin and smooth muscle protein 22-α expression levels. Furthermore, activation of ERK was inhibited in SPINT2-overexpressing SMCs. A specific ERK agonist, 12-O-tetradecanoylphorbol-13-acetate, reversed the SPINT2-mediated inhibition of SMC migration and the phenotypic switching. Collectively, the data indicated that SPINT2 was implicated in the proliferation, migration and phenotypic switching of aortic SMCs, suggesting that it may be involved in TAD progression.

Inception Convolution and Feature Fusion for Person Search.

With the rapid advancement of deep learning theory and hardware device computing capacity, computer vision tasks, such as object detection and instance segmentation, have entered a revolutionary phase in recent years. As a result, extremely challenging integrated tasks, such as person search, might develop quickly. The majority of efficient network frameworks, such as Seq-Net, are based on Faster R-CNN. However, because of the parallel structure of Faster R-CNN, the performance of re-ID can be significantly impacted by the single-layer, low resolution, and occasionally overlooked check feature diagrams retrieved during pedestrian detection. To address these issues, this paper proposed a person search methodology based on an inception convolution and feature fusion module (IC-FFM) using Seq-Net (Sequential End-to-end Network) as the benchmark. First, we replaced the general convolution in ResNet-50 with the new inception convolution module (ICM), allowing the convolution operation to effectively and dynamically distribute various channels. Then, to improve the accuracy of information extraction, the feature fusion module (FFM) was created to combine multi-level information using various levels of convolution. Finally, Bounding Box regression was created using convolution and the double-head module (DHM), which considerably enhanced the accuracy of pedestrian retrieval by combining global and fine-grained information. Experiments on CHUK-SYSU and PRW datasets showed that our method has higher accuracy than Seq-Net. In addition, our method is simpler and can be easily integrated into existing two-stage frameworks.

Association between iron status and incident coronary artery disease: a population based-cohort study.

Disorders of iron metabolism has been implicated in cardiovascular disease. However, the association of serum iron stores and coronary artery disease (CAD) remains inconsistent. Here, we investigated the associations of serum iron metabolism with the incidence of CAD, the severity of coronary artery stenosis, metabolic biomarkers, and the risk of major adverse cardiovascular event (MACE). A total of 643 CAD patients and 643 healthy controls were enrolled to assess the associations of serum iron status with the presence of CAD, the severity of CAD, and the risk of MACE. Serum iron metabolism and other metabolic markers were measured in all subjects. All statistical analyses were analyzed using SPSS22.0 software and STATA statistical package. Serum level of iron metabolism markers, including serum iron, unsaturated transferrin iron binding capacity (UIBC), Total iron binding capacity (TIBC) levels, in CAD groups was significantly lower than the control group (P < 0.001). UIBC and TIBC were negatively correlated with ferritin in both sexes. Each unit increase of serum iron and TIBC were found to have a protective role for CAD in women (iron: OR 0.794, 95% CI (0.647-0.973), TIBC: OR 0.891, 95% CI (0.795-0.999), P < 0.05). However, high ferritin level was significant associated the CAD incident in both sexes (OR 1.029, 95% CI (1.002-1.058) in men, OR 1.013, 95% CI (1.0-1.025) in women, P < 0.05). Serum iron metabolism markers exhibited no significant association with the severity of CAD. Increased serum level of iron and TIBC levels were found to have a protective role for CAD in women, but not in men. Elevated serum ferritin is independently and positively associated with CAD in men and women.

A construction and comprehensive analysis of the immune-related core ceRNA network and infiltrating immune cells in peripheral arterial occlusive disease.

Background: Peripheral arterial occlusive disease (PAOD) is a peripheral artery disorder that increases with age and often leads to an elevated risk of cardiovascular events. The purposes of this study were to explore the underlying competing endogenous RNA (ceRNA)-related mechanism of PAOD and identify the corresponding immune cell infiltration patterns. Methods: An available gene expression profile (GSE57691 datasets) was downloaded from the GEO database. Differentially expressed (DE) mRNAs and lncRNAs were screened between 9 PAOD and 10 control samples. Then, the lncRNA-miRNA-mRNA ceRNA network was constructed on the basis of the interactions generated from the miRcode, TargetScan, miRDB, and miRTarBase databases. The functional enrichment and protein-protein interaction analyses of mRNAs in the ceRNA network were performed. Immune-related core mRNAs were screened out through the Venn method. The compositional patterns of the 22 types of immune cell fraction in PAOD were estimated through the CIBERSORT algorithm. The final ceRNA network and immune infiltration were validated using clinical tissue samples. Finally, the correlation between immune cells and mRNAs in the final ceRNA network was analyzed. Results: Totally, 67 DE_lncRNAs and 1197 DE_mRNAs were identified, of which 130 DE_mRNAs (91 downregulated and 39 upregulated) were lncRNA-related. The gene ontology enrichment analysis showed that those down- and upregulated genes were involved in dephosphorylation and regulation of translation, respectively. The final immune-related core ceRNA network included one lncRNA (LINC00221), two miRNAs (miR-17-5p and miR-20b-5p), and one mRNA (CREB1). Meanwhile, we found that monocytes and M1 macrophages were the main immune cell subpopulations in PAOD. After verification, these predictions were consistent with experimental results. Moreover, CREB1 was positively correlated with naive B cells (R = 0.55, p = 0.035) and monocytes (R = 0.52, p = 0.049) and negatively correlated with M1 macrophages (R = -0.72, p = 0.004), resting mast cells (R = -0.66, p = 0.009), memory B cells (R = -0.55, p = 0.035), and plasma cells (R = -0.52, p = 0.047). Conclusion: In general, we proposed that the immune-related core ceRNA network (LINC00221, miR-17-5p, miR-20b-5p, and CREB1) and infiltrating immune cells (monocytes and M1 macrophages) could help further explore the molecular mechanisms of PAOD.

pH/Thermosensitive dual-responsive hydrogel based sequential delivery for site-specific acute limb ischemia treatment.

Acute limb ischemia (ALI) is the most severe manifestation of peripheral artery disease, accompanied by pH/temperature-microenvironment changes in two different phases. In the acute phase, temperature and pH are significantly decreased, and reactive oxygen species (ROS) are excessively generated owing to the sharp reduction of blood perfusion. Afterwards, in the chronic phase, although the temperature gradually recovers, angiogenesis is delayed due to chronic vascular injury, skeletal muscle cell apoptosis and endothelial cell dysfunction. Current therapeutic strategies mainly focus on recanalization; however, their effects on scavenging ROS in the acute phase and promoting angiogenesis in the chronic phase are quite limited. Herein, an injectable pH and temperature dual-responsive poloxamer 407 (PF127)/hydroxymethyl cellulose (HPMC)/sodium alginate (SA)-derived hydrogel (FHSgel), encapsulating melatonin and diallyl trisulfide-loaded biodegradable hollow mesoporous silica nanoparticles (DATS@dHMSNs), is developed, which can intelligently respond to the different phases of ALI. In the acute phase of ischemia, the decreased pH results in the rapid release of melatonin to scavenge excessive ischemia-induced ROS. On the other hand, in the chronic repair phase, the recovered temperature triggers the sustained release of DATS@dHMSNs from the FHSgel, thus generating hydrogen sulfide (H2S) to enhance the angiogenesis and microcirculation reconstruction of ischemic limbs.

Selenite capture by MIL-101 (Fe) through FeOSe bonds at free coordination Fe sites.

Selective immobilization of SeO32- is highly desired for the remediation of Se-contaminated water. Thus, the irreversible sorption of SeO32- ions by adsorbents through unique coordination bonds with high affinity is needed. Herein, we demonstrated that Fe-based metal-organic framework (MOF) (Fe-MIL-101) with free coordination sites (FCSs) enabled selective and irreversible capture of SeO32- ions from aqueous solution with fast kinetics and a high uptake capacity of 183.7 mg∙g-1, owing to large MOF apertures and substantial numbers of FCSs as capture sites through forming Fe-O-Se bonds. Meanwhile, Fe-MIL-101 maintained excellent performance in a broad pH range (4-11) and high selectivity for SeO32- ions in the presence of excessive competitive anions (e.g., CO32-, PO43-). Density functional theory (DFT) calculation, extended X-ray absorption fine structure (EXAFS), and Mössbauer fittings confirmed that the capture on Fe-MIL-101 was through the Fe-O-Se coordination bonds between FCSs and SeO32-. Moreover, Fe-MIL-101 could effectively remove SeO32- in simulated natural water and sewage by overcoming the influence of co-existing ions and organic matters. This study highlights new opportunities for the design of MOF-based materials for removing toxic and radioactive anions with irreversibility and high selectivity from natural and waste water.

A versatile and low-toxicity material for photothermal therapy in deeper tissues.

The limited depth of the near infrared (NIR) response is one of the major flaws of the present photothermal therapy (PTT). In this article, thermosensitive polyurethane urea (TPUU) was synthesized by polymerization. Subsequent experiments showed that, compared with classical photosensitizers, TPUU has higher photothermal effects and lower cytotoxicity. These valuable properties could make the present PTT research provide more therapeutic options among different tissues and organs. As a practical example, TPUU was applied to regulate the intestinal flora through external NIR irradiation, which implied its promising expanded applications in deeper tissues.

Serum Complement C1q Activity Is Associated With Obstructive Coronary Artery Disease.

Background: Complement C1q plays a dual role in the atherosclerosis. Previous studies showed inconsistent results about the association of serum C1q levels and coronary artery disease (CAD). Here, we explored the associations of serum C1q activity with CAD, coronary stenosis severity, cardiovascular biomarkers, and 1-year restenosis after coronary artery revascularization. Methods: We enrolled 956 CAD patients and 677 controls to evaluate the associations of serum complement C1q activity to the presence and severity of obstructive CAD and non-obstructive CAD. Serum C1q activity and the concentrations of laboratory markers were measured in all subjects. All the data were analyzed using SPSS22.0 software. Results: Serum C1q activity in Obstructive CAD and Non-Obstructive CAD groups was significantly higher than the control group (195.52 ± 48.31 kU/L and 195.42 ± 51.25 kU/L vs. 183.44 ± 31.75 kU/L, P < 0.05). Greater C1q activity was significantly correlated with higher total cholesterol (TC) and triglyceride (TG) levels. C1q activity was associated with an increased Odds Ratio (OR) of CAD (OR = 1.322, 95% CI 1.168-1.496, P < 0.05) and 1-year restenosis after revascularization (the highest OR = 3.544, 95% CI 1.089-12.702, P < 0.05). Complement C1q activity was not correlated with Gensini score in the Obstructive CAD group after adjustment for confounders. C1q activity has low value in predicting the incidence of CAD. Conclusion: Serum complement C1q activity is associated with obstructive CAD.

Hyperthermia-triggered UK release nanovectors for deep venous thrombosis therapy.

Deep vein thrombosis (DVT) is a common and lethal complication of surgery. In the clinic, thrombolytic drugs are primarily used for treating DVT. However, the utilization of thrombolytic drugs is limited due to the risk of urokinase (UK)-related hemorrhagic complications. In this paper, a binary eutectic phase-change fatty acid composed of lauric acid and stearic acid was used to block the pores of gold-mesoporous silica core-shell nanoparticles, so as to deliver thrombolytic drugs. The eutectic mixture has a well-defined melting point at 39.2 °C, which can be used as a biocompatible phase-change material for hyperthermia-triggered drug release. The prepared system presents remarkable photothermal effects due to the gold nanoparticles and quick drug release in response to near-infrared irradiation (NIR). In addition, localized hyperthermia could also enhance the lysis of the thrombus. The thrombolytic effect of this system was evaluated in vitro and in vivo. Herein, a rabbit femoral vein thrombosis model was first built for imitating thrombolysis in vivo. The B-ultrasound was then used to monitor the changes in the thrombus after treatment. The results indicated that the reported system could be potentially used to deliver thrombotic drugs in the clinic.

Effect of Remote Ischemic Preconditioning on Patients Undergoing Elective Major Vascular Surgery: A Systematic Review and Meta-analysis.

BACKGROUND: Whether remote ischemic preconditioning (RIPC), through several cycles of ischemia-reperfusion, can generate endogenous protective substances to protect patients undergoing elective major vascular surgery remains unclear. The results derived from many randomized controlled trials (RCTs) have been discrepant. METHODS: PubMed (1966 to May 2018) and EMBASE (1966 to May 2018) databases were searched to identify all published RCTs that assessed the effect of RIPC in patients undergoing elective major vascular surgery. Then, we performed a systematic review and meta-analysis to merge the outcomes of RIPC procedures from each RCT, which included all-cause mortality, myocardial infarction (MI), acute kidney injury (AKI), and/or new-onset arrhythmia. RESULTS: A total of 909 patients were enrolled from 10 eligible studies that were conducted from 2007 through 2016. A fixed effect model was utilized in this study to pool each effect size. Pooled analyses of all RCTs showed that RIPC did not reduce the incidence of all-cause mortality (pooled risk ratio [RR] 1.36, 95% confidence interval [CI] 0.63-2.92, P = 0.56), MI (pooled RR 0.77, 95% CI 0.48-1.22, P = 0.38), AKI (pooled RR 0.93, 95% CI 0.68-1.27, P = 0.10), or new-onset arrhythmia (pooled RR 1.47, 95% CI 0.83-2.60, P = 0.52) compared with the control treatment. The publication bias detected by Begg's test was low. CONCLUSIONS: There is no prominent evidence to support the hypothesis that RIPC can provide perioperative protection to patients undergoing elective major vascular surgery. Therefore, the routine use of RIPC to reduce the incidence of perioperative complications of these operations may not be recommended.

3D printed zirconia ceramic hip joint with precise structure and broad-spectrum antibacterial properties.

Background: Nowadays, zirconia ceramic implants are widely used as a kind of hip prosthesis material because of their excellent biocompatibility and long-term wear resistance. However, the hip joint is one of the major joints with complex 3D morphological structure and greatly individual differences, which usually causes great material waste during the process of surgical selection of prosthesis. Methods: In this paper, by combining ceramic 3D printing technology with antibacterial nano-modification, zirconia ceramic implant material was obtained with precise 3D structure and effective antibacterial properties. Among which, two technical problems (fragile and sintering induced irregular shrinkage) of 3D printed ceramics were effectively minimized by optimizing the reaction conditions and selective area inversing compensation. Through in vivo and in vitro experiments, it was confirmed that the as prepared hip prosthesis could precisely matched the corresponding parts, which also exhibited good biocompatibility and impressive antibacterial activities. Results: 1) Two inherent technical problems (fragile and sintering induced irregular shrinkage) of 3D printed ceramics were effectively minimized by optimizing the reaction conditions and selective area inversing compensation. 2) It could be seen that the surface of the ZrO2 material was covered with a layer of ZnO nano-particles. A universal testing machine was used to measure the tensile, bending and compression experiments of ceramic samples. It could be found that the proposed ZnO modification had no significant effect on the mechanical properties of ZrO2 ceramics. 3) According to the plate counting results, ceramics modified with ZnO exhibited significantly higher antibacterial efficiency than pure ZrO2 ceramics, the ZrO2-ZnO ceramics had a significant killing effect 8 hours. 4) The removed implants and the tissue surrounding the implant were subjected to HE staining. For ZrO2-ZnO ceramics, inflammation was slight, while for pure ZrO2 ceramics, the inflammatory response could be seen that the antibacterial rate of the ZrO2-ZnO ceramics was significantly better than that of the pure ZrO2 ceramics group. 5) It could be seen that the cytotoxicity did not increase proportionally with the increase of concentration, all of viability were still above 80%. This suggested that our materials were safe and could be applied as a type of potential biomaterial in the future. 6) Further animal studies demonstrated that the implant was in good position without dislocation. This resulted implied that the proposed method can achieve accurate 3D printing preparation of ceramic joints. In addition, the femurs and surrounding muscles around the implant were then sectioned and HE stained. Results of muscle tissue sections further showed no significant tissue abnormalities, and the growth of new bone tissue was observed in the sections of bone tissue. Conclusion: 1) The ceramic 3D printing technology combined with antibacterial nano-modification can quickly customize the ideal implant material with precise structure, wear-resistant and effective antibacterial properties. 2) Two inherent technical problems (fragile and sintering induced irregular shrinkage) of 3D printed ceramics were effectively minimized by optimizing the reaction conditions and selective area inversing compensation. 3) ZnO nano-materials were modified on the ceramic surface, which could effectively killing pathogenic bacteria.

A magnetically modified black phosphorus nanosheet-based heparin delivery platform for preventing DVT accurately.

A new heparin targeting delivery platform was developed based on iron oxide (Fe3O4) nanoparticles and polyethyleneimine (PEI) functionalized black phosphorus nanosheets (BP NSs). Both in and ex vivo studies suggested that this drug delivery platform (PEI/Fe3O4@BP NSs) possessed high heparin loading capacity (≈450%), accurate magnetic enrichment capacity, and good biocompatibility. With the aid of near-infrared (NIR) laser irradiation, this BP NS based delivery platform could further enhance the photothermal thrombolysis effect. Most importantly, the experiments in vivo confirmed that the proposed PEI/Fe3O4@BP NSs could considerably prolong the effective drug concentration duration of heparin. By which means, accurate, long-acting, and effective thromboprophylaxis could be accomplished with limited drug dosage, which could radically reduce the perniciousness of drug overdose.

Exercise training improves motor skill learning via selective activation of mTOR.

Physical exercise improves learning and memory, but little in vivo evidence has been provided to illustrate the molecular mechanisms. Here, we show that chronic treadmill exercise activates the mechanistic target of rapamycin (mTOR) pathway in mouse motor cortex. Both ex vivo and in vivo recordings suggest that mTOR activation leads to potentiated postsynaptic excitation and enhanced neuronal activity of layer 5 pyramidal neurons after exercise, in association with increased oligodendrogenesis and axonal myelination. Exercise training also increases dendritic spine formation and motor learning. Together, exercise activates mTOR pathway, which is necessary for spinogenesis, neuronal activation, and axonal myelination leading to improved motor learning. This model provides new insights for neural network adaptations through exercises and supports the intervention of cognitive deficits using exercise training.

ZnO and Hydroxyapatite-Modified Magnesium Implant with a Broad Spectrum of Antibacterial Properties and a Unique Minimally Invasive Defined Degrading Capability.

ZnO and hydroxyapatite-based membranes have been proposed to improve the antibacterial properties and anticorrosion capabilities of the magnesium implant, simultaneously. More importantly, the concept of minimally invasive surgery has been introduced to define the degradation timing of the as-modified magnesium implant. With the aid of a Kirschner wire, the as-prepared membrane could immediately change from the "protective layer" to the "degradation accelerator" of the implant material. The subsequent studies have implied that this membrane could be a promising avenue to create a biocompatible and lightweight implant material with a valuable personal customized degradable timing capability.

Selective Capture of Toxic Selenite Anions by Bismuth-based Metal-Organic Frameworks.

Chemically durable and effective absorbent materials for selenite (SeO32- ) remain highly desirable for contamination remediation. Now a bismuth-based metal-organic framework (Bi-MOF, CAU-17) was used as adsorbent to capture SeO32- anions from aqueous solution with ultrahigh adsorption capacity of 255.3 mg g-1 and fast kinetics. Furthermore, the adsorbent showed excellent selectivity for SeO32- and was able to work steadily in a broad pH range of 4-11. Density functional theory (DFT) calculation, XANES modeling, and EXAFS fitting suggested that SeO32- anions were immobilized by forming Bi-O-Se bonds (T-3 structural model) though splitting the O-Bi-O bond in the crystal structure, leading to a structural transformation of CAU-17 in the solid state.

Neuroprotective effects of methyl 3,4 dihydroxybenzoate in a mouse model of retinitis pigmentosa.

Retinitis pigmentosa is a photoreceptor-degenerative disease that is currently untreatable and eventually causes blindness. Methyl 3,4 dihydroxybenzoate (MDHB) is a small molecule that exerts neuroprotective effects in vitro. The present study tests whether MDHB protects the retina of rd10 mice, a model of retinitis pigmentosa. MDHB or an equal volume of vehicle was intraperitoneally injected in rd10 mice daily from postnatal day 12 (P12) to P26. Retinal morphology was evaluated by immunostaining, and retinal function by electroretinogram (ERG) and by visual behavior. TUNEL, Iba1, GFAP staining and western blotting were applied to explore the neuroprotective mechanism of MDHB in retina. MDHB treatment significantly promoted photoreceptor survival and preserved cone morphology compared to the untreated animals. The visual behavior and ERG responses were also greatly enhanced in MDHB-treated rd10 mice. Mechanistically, following MDHB treatment, the number of TUNEL-positive cells was decreased in rd10 retina, and the expression of brain-derived neurotrophic factor (BDNF) protein and phosphorylated tropomyosin-related kinase B (TrkB) receptor were increased. Furthermore, blocking TrkB using the antagonist ANA-12 prevented the protective effect of MDHB on photoreceptor survival and structure. MDHB treatment also inhibited microglial activation and Muller cell gliosis in rd10 retina. In conclusion, MDHB treatment delays retinal degeneration in rd10 mice and preserves retinal structure and functions. These effects are likely mediated by the BDNF-TrkB pathway. Due to its neurotrophic effects and ability to reduce reactive gliosis, MDHB may be useful to treat degenerative diseases in retina and brain.

Regulatory Roles of Anoctamin-6 in Human Trabecular Meshwork Cells.

Purpose: Trabecular meshwork (TM) cell volume is a determinant of aqueous humor outflow resistance, and thereby IOP. Regulation of TM cell volume depends on chloride ion (Cl-) release through swelling-activated channels (ICl,Swell), whose pore is formed by LRRC8 proteins. Chloride ion release through swelling-activated channels has been reported to be regulated by calcium-activated anoctamins, but this finding is controversial. Particularly uncertain has been the effect of anoctamin Ano6, reported as a Ca2+-activated Cl- (CaCC) or cation channel in other cells. The current study tested whether anoctamin activity modifies volume regulation of primary TM cell cultures and cell lines. Methods: Gene expression was studied with quantitative PCR, supplemented by reverse-transcriptase PCR and Western immunoblots. Currents were measured by ruptured whole-cell patch clamping and volume by electronic cell sizing. Results: Primary TM cell cultures and the TM5 and GTM3 cell lines expressed Ano6 3 to 4 orders of magnitude higher than the other anoctamin CaCCs (Ano1 and Ano2). Ionomycin increased cell Ca2+ and activated macroscopic currents conforming to CaCCs in other cells, but displayed significantly more positive mean reversal potentials (+5 to +12 mV) than those displayed by ICl,Swell (-14 to -21 mV) in the same cells. Nonselective CaCC inhibitors (tannic acid>CaCCinh-A01) and transient Ano6 knockdown strongly inhibited ionomycin-activated currents, ICl,Swell and the regulatory volume response to hyposmotic swelling. Conclusions: Ionomycin activates CaCCs associated with net cation movement in TM cells. These currents, ICl,Swell, and cell volume are regulated by Ano6. The findings suggest a novel clinically-relevant approach for altering cell volume, and thereby outflow resistance, by targeting Ano6.

Transgenerational Inheritance of Paternal Neurobehavioral Phenotypes: Stress, Addiction, Ageing and Metabolism.

Epigenetic modulation is found to get involved in multiple neurobehavioral processes. It is believed that different types of environmental stimuli could alter the epigenome of the whole brain or related neural circuits, subsequently contributing to the long-lasting neural plasticity of certain behavioral phenotypes. While the maternal influence on the health of offsprings has been long recognized, recent findings highlight an alternative way for neurobehavioral phenotypes to be passed on to the next generation, i.e., through the male germ line. In this review, we focus specifically on the transgenerational modulation induced by environmental stress, drugs of abuse, and other physical or mental changes (e.g., ageing, metabolism, fear) in fathers, and recapitulate the underlying mechanisms potentially mediating the alterations in epigenome or gene expression of offsprings. Together, these findings suggest that the inheritance of phenotypic traits through male germ-line epigenome may represent the unique manner of adaptation during evolution. Hence, more attention should be paid to the paternal health, given its equivalently important role in affecting neurobehaviors of descendants.

Rapid discrimination of malignant lesions from normal gastric tissues utilizing Raman spectroscopy system: a meta-analysis.

OBJECTIVES: To systematically analyze the diagnostic accuracy of Raman spectroscopy system (RAS) in the rapid diagnosis of gastric cancer with histopathology as the reference standard. METHODS: We searched a wide range of electronic databases for all published researches that assessed the diagnostic accuracy of RAS to detect gastric carcinoma. Full papers were obtained for potentially eligible studies and evaluated according to predefined criteria. The Quality Assessment of Diagnostic Accuracy Studies checklist was used to assess the quality of included studies. From each study, we extracted information on diagnostic performance of RAS. After exploring heterogeneity, we adopted a random effects model to pool related effect sizes. RESULTS: The initial literature search identified 257 reference articles in which 15 relevant articles with 15 data sets were selected and reviewed. The pooled sensitivity and specificity of RAS in diagnosing gastric cancer were 0.89 (95 % CI 0.84-0.92) and 0.92 (95 % CI 0.88-0.95), respectively. The positive likelihood ratio, the negative likelihood ratio, and the area under the curve were 10 (95 % CI 6.5-15.3), 0.13 (95 % CI 0.08-0.22), and 0.96 (95 % CI 0.94-0.97), respectively. All the pooled estimates, calculated by random and fixed effect models, were similar. There was no evidence of considerable publication bias. CONCLUSIONS: RAS is an objective and sensitive optical diagnostic technology for detecting gastric cancer and has advantages of being noninvasive to the body, real-time diagnosis, and ease of use. Consequently, it does deserve to be recommended.