Alterations in gut microbiota contribute to cognitive deficits induced by chronic infection of Toxoplasma gondii.

Chronic infection with Toxoplasma gondii (T. gondii) emerges as a risk factor for neurodegenerative diseases in animals and humans. However, the underlying mechanisms are largely unknown. We aimed to investigate whether gut microbiota and its metabolites play a role in T. gondii-induced cognitive deficits. We found that T. gondii infection induced cognitive deficits in mice, which was characterized by synaptic ultrastructure impairment and neuroinflammation in the hippocampus. Moreover, the infection led to gut microbiota dysbiosis, barrier integrity impairment, and inflammation in the colon. Interestingly, broad-spectrum antibiotic ablation of gut microbiota attenuated the adverse effects of the parasitic infection on the cognitive function in mice; cognitive deficits and hippocampal pathological changes were transferred from the infected mice to control mice by fecal microbiota transplantation. In addition, the abundance of butyrate-producing bacteria and the production of serum butyrate were decreased in infected mice. Interestingly, dietary supplementation of butyrate ameliorated T. gondii-induced cognitive impairment in mice. Notably, compared to the healthy controls, decreased butyrate production was observed in the serum of human subjects with high levels of anti-T. gondii IgG. Overall, this study demonstrates that gut microbiota is a key regulator of T. gondii-induced cognitive impairment.

Long-term Intravital Investigation of an Orthotopic Glioma Mouse Model via Optical Coherence Tomography Angiography.

BACKGROUND/AIM: Probing brain tumor microvasculature holds significant importance in both basic cancer research and medical practice for tracking tumor development and assessing treatment outcomes. However, few imaging methods commonly used in clinics can noninvasively monitor the brain microvascular network at high precision and without exogenous contrast agents in vivo. The present study aimed to investigate the characteristics of microvasculature during brain tumor development in an orthotopic glioma mouse model. MATERIALS AND METHODS: An orthotopic glioma mouse model was established by surgical orthotopic implantation of U87-MG-luc cells into the mouse brain. Then, optical coherence tomography angiography (OCTA) was utilized to characterize the microvasculature progression within 14 days. RESULTS: The orthotopic glioma mouse model evaluated by bioluminescence imaging and MRI was successfully generated. As the tumor grew, the microvessels within the tumor area slowly decreased, progressing from the center to the periphery for 14 days. CONCLUSION: This study highlights the potential of OCTA as a useful tool to noninvasively visualize the brain microvascular network at high precision and without any exogenous contrast agents in vivo.

Exploring the Oncogenic Potential of TIMM8A: A Crucial Factor in Breast Cancer Tumorigenesis.

BACKGROUND: Female breast cancer has become the world's most common malignant tumor, displacing lung malignancy, and the incidence of malignant tumors has increased continuously in recent decades. However, the underlying molecular mechanisms of breast tumorigenesis have not been fully elucidated. By consulting the literature, we discovered that the TIMM8A gene could affect oxidative stress and apoptosis in patients with Mohr-Tranebjærg syndrome. However, the biological function of TIMM8A has yet to be explored. MATERIALS AND METHODS: We investigated the expression level of TIMM8A via bioinformatic analysis and performed immunohistochemistry, diagnostic value, immune infiltration, functional enrichment, and survival analyses. Nonetheless, in vitro, additional experiments were performed. We explored whether TIMM8A expression was greater in breast tumors than in nearby normal tissues through qRT‒PCR. The expression of TIMM8A was knocked down by siRNA. Then, we conducted proliferation tests (CCK-8 experiment and colony formation) and Transwell assays (migration and invasion assays) to determine the specific biological functions of TIMM8A in the MDA-MB-231 and BT-549 cell lines. RESULTS: Tumor samples exhibited higher TIMM8A expression and exon expression, whereas normal tissues had higher TIMM8A methylation. The expression level of TIMM8A was linked to immune infiltration and survival, making it a valuable prognostic indicator and effective diagnostic tool. Functional enrichment analysis of TIMM8A indicated potential pathways through which it may play a role. In vitro experiments demonstrated that suppressing TIMM8A significantly inhibited the viability, colony formation, migration, and invasion of breast carcinoma cell lines. CONCLUSION: This study revealed that TIMM8A is an oncogene and is critical for the tumorigenesis of breast carcinoma.

GNPNAT1 is a Biomarker That Predicts a Poor Prognosis of Breast Cancer.

Background: Breast cancer (BC) is increasingly becoming the primary reason for death in women, which sounded the alarm. Thus, finding a novel management target for BC is imminent. Materials and Methods: The data on gene expression and clinicopathological characteristics were downloaded from The Cancer Genome Atlas (TCGA). The expression of GNPNAT1 in 40 paired breast cancer and adjacent tissues was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Univariate and Multivariate logistic regression methodology was applied to analyze the prognostic factors for lymph node metastasis (LNM). Based on the status of breast cancer-relative receptors, patients were distributed into six groups, and then the Kaplan-Meier survival analysis with a Log rank test was applied to investigate the involvement among the expression of GNPNAT1 and overall survival (OS). Results: We found higher expression of GNPNAT1 was connected with poor survival in breast cancer by COX regulation analysis. GO, KEGG, and GSEA analysis prompted that GNPNAT1 was connected with the defense mechanism of cells, cell proliferation, and division. Immunization infiltration analysis showed that high GNPNAT1 was negatively connected with 16 immunization infiltration cell types and positively connected with four immunization infiltration cell types. Conclusion: As a whole, our results indicated that GNPNAT1 might be a probable biomarker for diagnosis and prognosis in breast cancer.

Intravital photoacoustic brain stimulation with high-precision.

Significance: Neural regulation at high precision vitally contributes to propelling fundamental understanding in the field of neuroscience and providing innovative clinical treatment options. Recently, photoacoustic brain stimulation has emerged as a cutting-edge method for precise neuromodulation and shows great potential for clinical application. Aim: The goal of this perspective is to outline the advancements in photoacoustic brain stimulation in recent years. And, we also provide an outlook delineating several prospective paths through which this burgeoning approach may be substantively refined for augmented capability and wider implementations. Approach: First, the mechanisms of photoacoustic generation as well as the potential mechanisms of photoacoustic brain stimulation are provided and discussed. Then, the state-of-the-art achievements corresponding to this technology are reviewed. Finally, future directions for photoacoustic technology in neuromodulation are provided. Results: Intensive research endeavors have prompted substantial advancements in photoacoustic brain stimulation, illuminating the unique advantages of this modality for noninvasive and high-precision neuromodulation via a nongenetic way. It is envisaged that further technology optimization and randomized prospective clinical trials will enable a wide acceptance of photoacoustic brain stimulation in clinical practice. Conclusions: The innovative practice of photoacoustic technology serves as a multifaceted neuromodulation approach, possessing noninvasive, high-accuracy, and nongenetic characteristics. It has a great potential that could considerably enhance not only the fundamental underpinnings of neuroscience research but also its practical implementations in a clinical setting.

Prognostic impact of lung ultrasound detected B-lines on hospitalised ischaemic heart failure with mildly reduced ejection fraction patients.

OBJECTIVES: Prognostic impact of lung ultrasound-derived B-lines (LUS-BL) in heart failure with mildly reduced left ventricular ejection fraction (HFmrEF) patients remains elusive. We evaluated the correlation between LUS-BL and prognosis in HFmrEF patients. METHODS: This is a subgroup analysis based on our previously published retrospective study with 1691 HFmrEF patients. This subgroup analysis involved 574 patients with LUS-BL results at admission. After discharge, patients underwent clinical follow-up for a minimum of 1 year through telephone, clinical visits or community visits. The primary endpoint was defined as cardiovascular (CV) event, including CV-related mortality or HF hospitalisation at 90 days and 1 year after discharge. RESULTS: CV event at 90 days was significantly increased with higher LUS-BL number (0, 1-2, 3-9 and ≥10: 20%, 14%, 18% and 33%, p=0.008), while CV event rate at 1 year was similar among groups (45% vs 45% vs 42% vs 50%, p=0.573). Older age, hypertension (HR=2.06, 95% CI 1.31 to 3.25), higher right ventricular diameter (>23 mm, HR=2.008, 95% CI 1.37 to 2.94), increased ratio of early transmitral flow velocity to early mitral annular velocity (>24, HR=1.79, 95% CI 1.11 to 2.26) and higher LUS-BL number (>11, HR=1.510, 95% CI 1.01 to 2.26) were identified as independent determinants associated with increased risk of CV event at 90 days after discharge. The Harrell's C-Statistic analysis, based on the Cox regression models, demonstrated a significant improvement in the predictive ability of the model that incorporated both clinical and echocardiographic risk factors along with LUS-BL (areas under the curve (AUC)=0.72) compared with the model comprising only clinical risk factors and LUS-BL (AUC=0.69, p=0.036), or to the model with echocardiographic risk factors and LUS-BL (AUC=0.68, p=0.025). CONCLUSION: In HFmrEF patients with ischaemic heart disease, admission LUS-BL>11 is independently associated with an increased risk of CV event at 90 days following discharge.

Dapagliflozin impedes endothelial cell senescence by activating the SIRT1 signaling pathway in type 2 diabetes.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) clinically reduce atherosclerosis and lower blood pressure. However, their impact on endothelial dysfunction in type 2 diabetes (T2D) remains unclear. In this study, we investigated the protective effect and underlying mechanism of the SGLT2 inhibitor dapagliflozin in diabetes. Methods: Vascular reactivity was measured to assess the vasoprotective effect of dapagliflozin in a mouse model of high glucose (HG)-induced T2D. Pulse wave velocity was measured to quantify arterial stiffness. Protein expression was assessed by western blotting and immunofluorescence, oxidative stress was evaluated using dihydroethidium, nitric oxide was evaluated using the Griess reaction, and cellular senescence was assessed based on senescence-associated beta-galactosidase (SA-ß-gal) activity and the expression of senescence markers. Furthermore, the endothelial nitric oxide synthase (eNOS) acetylation status was determined and eNOS interactions with SIRT1 were evaluated by coimmunoprecipitation assays. Results: Dapagliflozin protected against impaired endothelium-dependent vasorelaxation and improved arterial stiffness in the mouse model of T2D; mouse aortas had significantly reduced levels of senescence activity and senescence-associated inflammatory factors. HG-induced increases in senescence activity, protein marker levels, and oxidative stress in vitro were all ameliorated by dapagliflozin. The decreases in eNOS phosphorylation and nitric oxide (NO) production in senescent endothelial cells were restored by dapagliflozin. SIRT1 expression was reduced in HG-induced senescent endothelial cells, and dapagliflozin restored SIRT1 expression. SIRT1 inhibition diminished the antisenescence effects of dapagliflozin. Coimmunoprecipitation showed that SIRT1 was physically associated with eNOS, suggesting that the effects of dapagliflozin are dependent on SIRT1 activation. Conclusion: These findings indicate that dapagliflozin protects against endothelial cell senescence by regulating SIRT1 signaling in diabetic mice.

Role of cGAS-STING signaling pathway in cardiometabolic diseases. / cGAS-STINGé€šè·¯åœ¨ä»£è°¢æ€§å¿ƒè¡€ç®¡ç–¾ç— ä¸­çš„ä½œç”¨.

Cardiometabolic disease is a common clinical syndrome with exact causal relationship between the aberrant of glucose/lipid metabolism and cardiovascular disfunction, but its pathogenesis is unclear. Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon gene (STING) signaling pathway regulates the activation of innate immunity by sensing intracellular double stranded DNA. Metabolic risk factors drive the activation of cGAS-STING pathway through mitochondrial DNA, nuclear DNA and endoplasmic reticulum stress. In addition, the activation of the cGAS-STING pathway triggers chronic sterile inflammation, excessive activation of autophagy, senescence and apoptosis in related cells of cardiovascular system. These changes induced by cGAS-STING pathway might be implicated in the onset and deterioration of cardiometabolic disease. Therefore, the targeting intervention of cGAS-STING signaling pathway may emerge as a novel treatment for cardiometabolic disease.

Ultrasensitive Photocathodic Biosensor Based on the Cu2O/PTB7-Th/PDA+ Composite with Enhanced Photoelectrochemical Performance for the Detection of MicroRNA-375-3p.

Herein, an ultrasensitive photocathodic biosensor was fabricated based on Cu2O/PTB7-Th/PDA+ photoactive materials with high photocarrier separation efficiency for the detection of microRNA-375-3p. Impressively, the photocathodic signal of the Cu2O material was significantly enhanced by using PTB7-Th as an energy level-matching photoactive material to enhance the bulk charge separation and N,N-bis (2-(trimethylammoniumiodide) propylene) perylene-3,4,9,10-tetracarboxydiimide (PDA+) as an interfacial charge transfer mediator to efficiently suppress charge recombination at the photoelectrode/electrolyte interface. Compared with the pristine Cu2O as a photocathode, the obtained Cu2O/PTB7-Th/PDA+ exhibited a 17 times higher photocathodic signal. As a proof of concept, a PEC biosensor was fabricated by using Cu2O/PTB7-Th/PDA+ as a photoactive material and a target-triggered 3D DNA walker integrated with the dumbbell hybridization chain reaction (DHCR) as a signal amplifier to achieve the sensitive detection of microRNA-375-3p with a detection limit of 0.3 fM. This work provided a method to increase the photocurrent signal and the sensitivity of PEC-sensing platforms for the detection of biomarkers and disease diagnosis.

A facile synthesis of FeS/Fe3C nanoparticles highly dispersed on in situ grown N-doped CNTs as cathode electrocatalysts for microbial fuel cells.

A novel composite of iron sulfide, iron carbide and nitrogen carbides (Nano-FeS/Fe3C@NCNTs) as a cathode electrocatalyst for microbial fuel cells (MFCs) is synthesized by a one-pot solid state reaction, which yields a unique configuration of FeS/Fe3C nanoparticles highly dispersed on in situ grown nitrogen-doped carbon nanotubes (NCNTs). The highly dispersed FeS/Fe3C nanoparticles possess large active sites, while the NCNTs provide an electronically conductive network. Consequently, the resultant Nano-FeS/Fe3C@NCNTs exhibit excellent electrocatalytic activity towards the oxygen reduction reaction (ORR), with a half-wave potential close to that of Pt/C (about 0.88 V vs. RHE), and enable MFCs to deliver a power density of 1.28 W m-2 after two weeks' operation, which is higher than that of MFCs with Pt/C as the cathode electrocatalyst (1.02 W m-2). Theoretical calculations and experimental data demonstrate that there is a synergistic effect between Fe3C and FeS in Nano-FeS/Fe3C@NCNTs. Fe3C presents a strong attraction and electron-donating tendency to oxygen molecules, serving as the main active component, while FeS reduces charge transfer resistance by transferring electrons to Fe3C, synergistically improving the kinetics of the ORR and power density of MFCs.

Impact of signs and symptoms on the prognosis of patients with HFmrEF.

BACKGROUND: Worsening of heart failure (HF) symptoms is the leading cause of medical contact and hospitalization of patients with mildly reduced ejection fraction (HFmrEF). The prognostic value of signs and symptoms for patients with HFmrEF is currently unclear. This study investigated the prognostic impact of signs and symptoms in HFmrEF patients. METHODS: A Cox proportional risk regression model analyzed the relationship between the number of signs/symptoms and outcomes in 1691 hospitalized HFmrEF patients. Ten significant signs and symptoms were included. Patients were divided into three groups (A: ≤2, B: 3-5, C: ≥6 signs/symptoms). Stratified analysis on male and female patients was performed. The primary endpoint was all-cause mortality, and the secondary outcome was a composite of cardiovascular death and heart failure readmission (CV events) post-discharge. RESULTS: After a median follow-up of 33 months, all-cause mortality occurred in 457 patients and CV events occurred in 977 patients. Incidence of all-cause mortality was 20.7%, 32.3%* and 49.4%*† in group A, B and C of male patients, (*P < 0.05 vs. A, †P < 0.05 vs. B) and 18.8%, 33.6% and 55.8%* in group A, B and C of female patients. Incidence of CV events was 64.8%, 70.1%* and 87.5%* in group A, B and C of male patients, 61.9%, 75.3%, and 86.1%* in group A, B and C of female patients. Multivariate Cox regression showed older age, renal insufficiency, higher number of signs and symptoms (≥ 3, hazard ratio [HR] 1.317, 95% confidence interval [CI] 1.070-1.621, P = 0.009; ≥6, HR 1.982, 95% CI 1.402-2.801, P < 0.001), myocardial infarction, stroke, faster heart rate on admission, and diabetes were independently associated with all-cause mortality(all P < 0.05). Similarly, higher number of signs and symptoms (≥ 3, HR 1.271, 95% CI 1.119-1.443, P < 0.001; ≥6, HR 1.955, 95% CI 1.524-2.508, P < 0.001), older age, renal insufficiency, atrial fibrillation, and diabetes were independently associated with cardiovascular events (all P < 0.05). CONCLUSIONS: Higher number of symptoms and signs is associated with increased risk of all-cause mortality and CV events in HFmrEF patients. Our results highlight the prognostic importance of careful inquiry on HF symptoms and related physical examination in HFmrEF patients.

Red blood cell count and risk of adverse outcomes in patients with mildly reduced left ventricular ejection fraction.

BACKGROUND: Anemia is associated with increased rates of heart failure (HF)-related mortality and hospitalization. No studies have focused on the association between the red blood cell (RBC) count and the prognosis of patients with HF with mildly reduced left ventricular ejection fraction (HFmrEF). We retrospectively analyzed the effect of the RBC count on outcome events in patients with HFmrEF. METHODS: We investigated the association of the RBC count with outcome events in 1691 patients with HFmrEF (mean age: 68 years; 35% female) in Xiangtan Central Hospital. Using Cox proportional hazards models, the RBC count was assessed as both a continuous and categorical variable. RESULTS: During follow-up (median: 33 months), cardiovascular death occurred in 168 patients (114 men and 54 women). After adjusting for established risk factors, each 1.0 × 1012 cell/L increase in the RBC count was associated with a 28% lower risk of cardiovascular death in men and a 43% lower risk in women. Patients with low RBC counts had a 0.5-fold higher risk of cardiovascular death than those with normal RBC counts. The hazard ratio for men was 1.42 (95% confidence interval [CI]: 1.07-1.89), and the hazard ratio for women was 1.79 (95% CI: 1.20-2.67). The RBC count was not significantly associated with the composite endpoint of cardiovascular death and HF readmission (cardiovascular events) (p > .05). CONCLUSIONS: A decreased RBC count is associated with increased cardiovascular mortality in patients with HFmrEF. Correcting a low RBC count might potentially reduce the risk of cardiovascular death in patients with HFmrEF.

Impact of atrial fibrillation on cerebro-cardiovascular outcome of heart failure with mildly-reduced ejection fraction.

AIMS: Atrial fibrillation (AF) and heart failure (HF) often co-exist and are closely intertwined. The impact of AF on the outcome of patients with heart failure with mildly-reduced ejection fraction (HFmrEF) is not fully clear. This study aimed to investigate the impact of AF on the outcomes of hospitalized HFmrEF patients. METHODS AND RESULTS: The study included 1691 consecutive patients with HFmrEF (mean 68.2 years, 64.8% male) including 296 AF patients. Patients completed 1 year and mean of 33 month clinical follow-up after discharge by telephone interview, clinical visit, or community visit. The primary endpoint was cerebro-cardiovascular events (CCE, composite of HF rehospitalization, stroke, or cardiovascular death). After propensity score matching, 296 patients were included into the AF group (mean 71.5 years) and 592 patients into the non-AF group (mean 70.6 years). After propensity score matching, CCE at 1 year (59.1% vs. 48.5%, P = 0.003) and at a mean of 33 month (77.0% vs. 70.6%, P = 0.043). AF was independently associated with increased CCE within 1 year (HR = 1.31, 95% CI 1.07 to 1.61, P = 0.010) and at 33 months (HR = 1.20, 95% CI 1.00 to 1.43, P = 0.050) post-discharge after adjusted for other clinical confounders including discharge heart rate, NT-proBNP, haemoglobin, and uric acid. CONCLUSIONS: AF is independently associated with an increased risk of CCE in HFmrEF patients within 1 year and at a mean of 33 months after discharge.

Astragaloside IV attenuates high glucose-induced NF-κB-mediated inflammation through activation of PI3K/AKT-ERK-dependent Nrf2/ARE signaling pathway in glomerular mesangial cells.

Inflammation is a key contributor to diabetic kidney disease pathogenesis, including reactive oxidation stress (ROS)-mediated nuclear factor-κB (NF-κB) signaling pathway. In this study, we examined the effect of Astragaloside IV (AS-IV) on anti-inflammatory and anti-oxidative properties under high glucose (HG) condition and the potential mechanism in glomerular mesangial cells (GMCs). We showed that AS-IV concentration-dependently reduced GMCs proliferation, restrained ROS release and hydrogen peroxide content, and suppressed pro-inflammatory cytokines as well as pro-fibrotic factors expression, which were associated with the inhibition of NF-κB and nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling activation. Accordingly, both NF-κB overexpression by using RNA plasmid and Nrf2 gene silencing by using RNA interference weakened the ability of AS-IV to ameliorate HG-induced oxidative stress, inflammation, and cell proliferation. Furthermore, phosphatidylinositide 3-kinases (PI3K)/serine/threonine protein kinase (Akt) and extracellular regulated protein kinases (ERK) signaling pathway regulated the process of AS-IV-induced Nrf2 activation and antioxidant capacity, which evidenced by using PI3K inhibitor LY294002 or ERK inhibitor PD98059 that largely abolished the AS-IV efficacy. Taken together, these results indicated that AS-IV protected against HG-induced GMCs damage by inhibiting ROS/NF-kB-induced increases of inflammatory cytokines, fibrosis biomarkers, and cell proliferation via up-regulation of Nrf2-dependent antioxidant enzyme expression, which were mediated by PI3K/Akt and ERK signaling pathway activation.

TSPTFBS 2.0: trans-species prediction of transcription factor binding sites and identification of their core motifs in plants.

Introduction: An emerging approach using promoter tiling deletion via genome editing is beginning to become popular in plants. Identifying the precise positions of core motifs within plant gene promoter is of great demand but they are still largely unknown. We previously developed TSPTFBS of 265 Arabidopsis transcription factor binding sites (TFBSs) prediction models, which now cannot meet the above demand of identifying the core motif. Methods: Here, we additionally introduced 104 maize and 20 rice TFBS datasets and utilized DenseNet for model construction on a large-scale dataset of a total of 389 plant TFs. More importantly, we combined three biological interpretability methods including DeepLIFT, in-silico tiling deletion, and in-silico mutagenesis to identify the potential core motifs of any given genomic region. Results: For the results, DenseNet not only has achieved greater predictability than baseline methods such as LS-GKM and MEME for above 389 TFs from Arabidopsis, maize and rice, but also has greater performance on trans-species prediction of a total of 15 TFs from other six plant species. A motif analysis based on TF-MoDISco and global importance analysis (GIA) further provide the biological implication of the core motif identified by three interpretability methods. Finally, we developed a pipeline of TSPTFBS 2.0, which integrates 389 DenseNet-based models of TF binding and the above three interpretability methods. Discussion: TSPTFBS 2.0 was implemented as a user-friendly web-server (http://www.hzau-hulab.com/TSPTFBS/), which can support important references for editing targets of any given plant promoters and it has great potentials to provide reliable editing target of genetic screen experiments in plants.

ARA-net: an attention-aware retinal atrophy segmentation network coping with fundus images.

Background: Accurately detecting and segmenting areas of retinal atrophy are paramount for early medical intervention in pathological myopia (PM). However, segmenting retinal atrophic areas based on a two-dimensional (2D) fundus image poses several challenges, such as blurred boundaries, irregular shapes, and size variation. To overcome these challenges, we have proposed an attention-aware retinal atrophy segmentation network (ARA-Net) to segment retinal atrophy areas from the 2D fundus image. Methods: In particular, the ARA-Net adopts a similar strategy as UNet to perform the area segmentation. Skip self-attention connection (SSA) block, comprising a shortcut and a parallel polarized self-attention (PPSA) block, has been proposed to deal with the challenges of blurred boundaries and irregular shapes of the retinal atrophic region. Further, we have proposed a multi-scale feature flow (MSFF) to challenge the size variation. We have added the flow between the SSA connection blocks, allowing for capturing considerable semantic information to detect retinal atrophy in various area sizes. Results: The proposed method has been validated on the Pathological Myopia (PALM) dataset. Experimental results demonstrate that our method yields a high dice coefficient (DICE) of 84.26%, Jaccard index (JAC) of 72.80%, and F1-score of 84.57%, which outperforms other methods significantly. Conclusion: Our results have demonstrated that ARA-Net is an effective and efficient approach for retinal atrophic area segmentation in PM.

Integrated analysis of coexpression and a tumor-specific ceRNA network revealed a potential prognostic biomarker in breast cancer.

Background: Breast cancer, a type of tumor associated with high heterogeneity, is top among the common malignancies threatening women's health worldwide. Emerging evidence suggests that competing endogenous RNA (ceRNA) plays a role in the molecular biological mechanisms related to the occurrence and development of cancer. However, the effect of the ceRNA network on breast cancer, especially the long non-coding RNA (lncRNA)-microRNA (miRNA)-messenger RNA (mRNA) regulatory network, has not been fully studied. Methods: To explore potential prognostic markers of breast cancer under ceRNA network, we first extracted the breast cancer expression profiles of lncRNAs, miRNAs and mRNAs and their corresponding clinical data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) database. Next, we selected breast cancer-related candidate genes by intersection of the differential expression analysis and the weighted gene coexpression network analysis (WGCNA). Then, we studied the interactions among lncRNAs, miRNAs, and mRNAs by means of multiMiR and starBase and then constructed a ceRNA network of 9 lncRNAs, 26 miRNAs, and 110 mRNAs. We established a prognostic risk formula by means of multivariable Cox regression analysis. Results: Based on public databases and evaluated via modeling, we identified the HOX antisense intergenic RNA (HOTAIR)-miR-130a-3p-high mobility group-box 3 (HMGB3) axis as a potential prognostic marker in breast cancer through a prognostic risk model we established using multivariable Cox analysis. Conclusions: For the first time, the potential interactions among HOTAIR, miR-130a-3p, and HMGB3 in the tumorigenesis were clarified, and these may provide novel prognostic value for breast cancer treatment.

Network-based drug repurposing for potential stroke therapy.

Stroke is the leading cause of death and disability worldwide, with a growing number of incidences in developing countries. However, there are currently few medical therapies for this disease. Emerged as an effective drug discovery strategy, drug repurposing which owns lower cost and shorter time, is able to identify new indications from existing drugs. In this study, we aimed at identifying potential drug candidates for stroke via computationally repurposing approved drugs from Drugbank database. We first developed a drug-target network of approved drugs, employed network-based approach to repurpose these drugs, and altogether identified 185 drug candidates for stroke. To validate the prediction accuracy of our network-based approach, we next systematically searched for previous literature, and found 68 out of 185 drug candidates (36.8 %) exerted therapeutic effects on stroke. We further selected several potential drug candidates with confirmed neuroprotective effects for testing their anti-stroke activity. Six drugs, including cinnarizine, orphenadrine, phenelzine, ketotifen, diclofenac and omeprazole, have exhibited good activity on oxygen-glucose deprivation/reoxygenation (OGD/R) induced BV2 cells. Finally, we showcased the anti-stroke mechanism of actions of cinnarizine and phenelzine via western blot and Olink inflammation panel. Experimental results revealed that they both played anti-stroke effects in the OGD/R induced BV2 cells via inhibiting the expressions of IL-6 and COX-2. In summary, this study provides efficient network-based methodologies for in silico identification of drug candidates toward stroke.

Sex differences in patients with heart failure and mildly reduced left ventricular ejection fraction.

Clinical studies on heart failure with mildly reduced left ventricular ejection fraction (HFmrEF) have gradually increased. However, studies on the prognostic differences between men and women among patients with HFmrEF are few, and no evidence on sex differences in such patients exists. Therefore, we retrospectively assessed the data of patients with HFmrEF using propensity score-matched analysis (PSMA). A total of 1691 patients with HFmrEF were enrolled in the Outcome of Discharged HFmrEF Patients study (OUDI-HF study), which included 1095 men and 596 women. After propensity score matching, we compared the difference in cardiovascular (CV) events (cardiovascular death or heart failure readmission) and all-cause mortality at 90 days and 1 year after discharge between men and women using Kaplan-Meier analysis and Cox regression. After PSMA, men with HFmrEF were 2.2 times more likely to die at 90 days than women with HFmrEF [hazard ratio (HR) 1.88; 95% confidence interval (95% CI) 1.03-3.46; P = 0.041]. However, there was no difference in the 90-day CV events (HR 0.96; 95% CI 0.75-1.22; P = 0.718). Similarly, there was no difference in all-cause mortality (HR 1.16; 95% CI 0.81-1.65; P = 0.417) and CV events (HR 0.98; 95% CI 0.83-1.16; P = 0.817) between men and women after 1 year. Among the patients with HFmrEF, men had a higher 90-day risk of all-cause mortality than women after hospital discharge, and this risk disappeared after 1 year.Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT05240118 (ESC Heart Failure. (2022). doi: https://doi.org/10.1002/ehf2.14044 ).

Reproducible Abnormalities and Diagnostic Generalizability of White Matter in Alzheimer's Disease.

Alzheimer's disease (AD) is associated with the impairment of white matter (WM) tracts. The current study aimed to verify the utility of WM as the neuroimaging marker of AD with multisite diffusion tensor imaging datasets [321 patients with AD, 265 patients with mild cognitive impairment (MCI), 279 normal controls (NC)], a unified pipeline, and independent site cross-validation. Automated fiber quantification was used to extract diffusion profiles along tracts. Random-effects meta-analyses showed a reproducible degeneration pattern in which fractional anisotropy significantly decreased in the AD and MCI groups compared with NC. Machine learning models using tract-based features showed good generalizability among independent site cross-validation. The diffusion metrics of the altered regions and the AD probability predicted by the models were highly correlated with cognitive ability in the AD and MCI groups. We highlighted the reproducibility and generalizability of the degeneration pattern of WM tracts in AD.