Role of Telemedicine Intervention in the Treatment of Patients with Chronic Heart Failure: A Systematic Review and Meta-analysis.

OBJECTIVE: Although telemedicine interventional therapy is an innovative method to reduce public medical burden and improve heart failure, its effectiveness is still controversial. This meta-analysis evaluates the role of telemedicine interventional therapy in the treatment of patients with chronic heart failure. METHODS: Relevant literature on telemedicine in chronic heart failure treatment was screened and extracted based on predefined criteria. Quality assessment used Cochrane Handbook 5.1.0 tool, and meta-analysis was conducted using R 4.2.2 software. RESULTS: Fifteen English-language articles were ultimately included in this meta-analysis. The risk bias evaluation determined that 4 articles were low-risk bias and 11 articles were unclear risk bias. The meta-analysis revealed that, compared to the routine intervention group, the all-cause hospitalization rate of patients in the telemedicine intervention group decreased [OR = 0.63, 95% CI (0.41; 0.96), P =.03], and the hospitalization rate of heart failure also decreased [OR = 0.70, 95% CI (0.48; 0.85), P <.01]. However, there were no differences in mortality [OR = 0.64, 95% CI (0.41; 1.01), P =.05], length of hospitalization [MD = -0.42, 95% CI (-1.22; 0.38), P =.31], number of emergency hospitalizations [MD = -0.09, 95% CI (-0.33; 0.15), P =.45], medication compliance [OR = 1.67, 95% CI (0.92; 3.02), P =.09], or MLHFQ scores [MD = -2.30, 95% CI (-6.16; 1.56), P =.24] among the patients. CONCLUSION: This meta-analysis showed that telemedicine reduced overall and heart failure-related hospitalizations in chronic heart failure patients, suggesting its value in clinical management. However, it did not significantly affect mortality, hospital stay length, emergency visits, medication adherence, or quality of life. This suggests the need to optimize specific aspects of telemedicine, identify key components, and develop strategies for better treatment outcomes.

Amelioration of diabetic nephropathy in mice by a single intravenous injection of human mesenchymal stromal cells at early and later disease stages is associated with restoration of autophagy.

BACKGROUND AND AIMS: Mesenchymal stromal cells (MSCs) a potentially effective disease-modulating therapy for diabetic nephropathy (DN) but their clinical translation has been hampered by incomplete understanding of the optimal timing of administration and in vivo mechanisms of action. This study aimed to elucidate the reno-protective potency and associated mechanisms of single intravenous injections of human umbilical cord-derived MSCs (hUC-MSCs) following shorter and longer durations of diabetes. METHODS: A streptozotocin (STZ)-induced model of diabetes and DN was established in C57BL/6 mice. In groups of diabetic animals, human (h)UC-MSCs or vehicle were injected intravenously at 8 or 16 weeks after STZ along with vehicle-injected non-diabetic animals. Diabetes-related kidney abnormalities was analyzed 2 weeks later by urine and serum biochemical assays, histology, transmission electron microscopy and immunohistochemistry. Serum concentrations of pro-inflammatory and pro-fibrotic cytokines were quantified by ELISA. The expression of autophagy-related proteins within the renal cortices was investigated by immunoblotting. Bio-distribution of hUC-MSCs in kidney and other organs was evaluated in diabetic mice by injection of fluorescent-labelled cells. RESULTS: Compared to non-diabetic controls, diabetic mice had increases in urine albumin creatinine ratio (uACR), mesangial matrix deposition, podocyte foot process effacement, glomerular basement membrane thickening and interstitial fibrosis as well as reduced podocyte numbers at both 10 and 18 weeks after STZ. Early (8 weeks) hUC-MSC injection was associated with reduced uACR and improvements in multiple glomerular and renal interstitial abnormalities as well as reduced serum IL-6, TNF-α, and TGF-ß1 compared to vehicle-injected animals. Later (16 weeks) hUC-MSC injection also resulted in reduction of diabetes-associated renal abnormalities and serum TGF-ß1 but not of serum IL-6 and TNF-α. At both time-points, the kidneys of vehicle-injected diabetic mice had higher ratio of p-mTOR to mTOR, increased abundance of p62, lower abundance of ULK1 and Atg12, and reduced ratio of LC3B to LC3A compared to non-diabetic animals, consistent with diabetes-associated suppression of autophagy. These changes were largely reversed in the kidneys of hUC-MSC-injected mice. In contrast, neither early nor later hUC-MSC injection had effects on blood glucose and body weight of diabetic animals. Small numbers of CM-Dil-labeled hUC-MSCs remained detectable in kidneys, lungs and liver of diabetic mice at 14 days after intravenous injection. CONCLUSIONS: Single intravenous injections of hUC-MSCs ameliorated glomerular abnormalities and interstitial fibrosis in a mouse model of STZ-induced diabetes without affecting hyperglycemia, whether administered at relatively short or longer duration of diabetes. At both time-points, the reno-protective effects of hUC-MSCs were associated with reduced circulating TGF-ß1 and restoration of intra-renal autophagy.

Combined transplantation of hiPSC-NSC and hMSC ameliorated neuroinflammation and promoted neuroregeneration in acute spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a serious clinical condition that has pathological changes such as increased neuroinflammation and nerve tissue damage, which eventually manifests as fibrosis of the injured segment and the development of a spinal cord cavity leading to loss of function. Cell-based therapy, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs) are promising treatment strategies for spinal cord injury via immunological regulation and neural replacement respectively. However, therapeutic efficacy is rare reported on combined transplantation of MSC and NSC in acute mice spinal cord injury even the potential reinforcement might be foreseen. Therefore, this study was conducted to investigate the safety and efficacy of co-transplanting of MSC and NSC sheets into an SCI mice model on the locomotor function and pathological changes of injured spinal cord. METHODS: To evaluate the therapeutic effects of combination cells, acute SCI mice model were established and combined transplantation of hiPSC-NSCs and hMSCs into the lesion site immediately after the injury. Basso mouse scale was used to perform the open-field tests of hind limb motor function at days post-operation (dpo) 1, 3, 5, and 7 after SCI and every week after surgery. Spinal cord and serum samples were collected at dpo 7, 14, and 28 to detect inflammatory and neurotrophic factors. Hematoxylin-eosin (H&E) staining, masson staining and transmission electron microscopy were used to evaluate the morphological changes, fibrosis area and ultrastructure of the spinal cord. RESULT: M&N transplantation reduced fibrosis formation and the inflammation level while promoting the secretion of nerve growth factor and brain-derived neurotrophic factor. We observed significant reduction in damaged tissue and cavity area, with dramatic improvement in the M&N group. Compared with the Con group, the M&N group exhibited significantly improved behaviors, particularly limb coordination. CONCLUSION: Combined transplantation of hiPSC-NSC and hMSC could significantly ameliorate neuroinflammation, promote neuroregeneration, and decrease spinal fibrosis degree in safe and effective pattern, which would be indicated as a novel potential cell treatment option.

The Contributions of the Endolysosomal Compartment and Autophagy to APOEɛ4 Allele-Mediated Increase in Alzheimer's Disease Risk.

Apolipoprotein E4 (APOE4), although yet-to-be fully understood, increases the risk and lowers the age of onset of Alzheimer's disease (AD), which is the major cause of dementia among elderly individuals. The endosome-lysosome and autophagy pathways, which are necessary for homeostasis in both neurons and glia, are dysregulated even in early AD. Nonetheless, the contributory roles of these pathways to developing AD-related pathologies in APOE4 individuals and models are unclear. Therefore, this review summarizes the dysregulations in the endosome-lysosome and autophagy pathways in APOE4 individuals and non-human models, and how these anomalies contribute to developing AD-relevant pathologies. The available literature suggests that APOE4 causes endosomal enlargement, increases endosomal acidification, impairs endosomal recycling, and downregulates exosome production. APOE4 impairs autophagy initiation and inhibits basal autophagy and autophagy flux. APOE4 promotes lysosome formation and trafficking and causes ApoE to accumulate in lysosomes. APOE4-mediated changes in the endosome, autophagosome and lysosome could promote AD-related features including Aß accumulation, tau hyperphosphorylation, glial dysfunction, lipid dyshomeostasis, and synaptic defects. ApoE4 protein could mediate APOE4-mediated endosome-lysosome-autophagy changes. ApoE4 impairs vesicle recycling and endosome trafficking, impairs the synthesis of autophagy genes, resists being dissociated from its receptors and degradation, and forms a stable folding intermediate that could disrupt lysosome structure. Drugs such as molecular correctors that target ApoE4 molecular structure and enhance autophagy may ameliorate the endosome-lysosome-autophagy-mediated increase in AD risk in APOE4 individuals.

The role of Shenqi Fuzheng injection as adjuvant therapy for breast cancer: an overview of systematic reviews and meta-analyses.

BACKGROUND: Breast cancer (BC) is the most frequent malignancy in the world. Chemotherapy (CT) is a common treatment for BC but is accompanied by toxicity and side effects. Shenqi Fuzheng Injection (SFI) is an adjuvant therapy with promising results in improving efficacy and reducing toxicity in clinical studies. This overview of systematic reviews and meta-analysis (SRs/MAs) aimed to summarize the benefits and evaluate the quality of evidence supporting SFI adjuvant as CT for BC. METHODS: A systematic search for SRs/MAs of randomized controlled trials (RCTs) on SFI treatment for BC was performed by searching PubMed, Web of Science, EMbase, Cochrane Library, CNKI, Wanfang, VIP, and SinoMed databases from inception to October 1, 2022. The quality of SRs/MAs was evaluated using AMSTAR-2, PRISMA 2020, ROBIS, and GRADE by two reviewers. The corrected covered area (CCA) was used to quantify the degree of duplication of the original SRs/MAs. Finally, quantitative analysis of RCTs was conducted using RevMan 5.4 software. This study was registered with PROSPERO, CRD42022377290. RESULTS: Six SRs/MAs including 61 RCTs with 5593 patients were included in this study. Studies were published between 2015 and 2019, the original RCTs ranged from 7-49, with sample sizes ranging from 336-1989. The quantitative meta-analysis found that adjuvant CT of SFI improved the clinical response rate (RR=1.37, 95% CI=1.28, 1.46; P<0.00001) and the KPS score (RR=1.66, 95% CI 1.54, 1.79, P<0.00001) of patients with BC. In terms of immune function, CD3+ (SMD=1.51, 95% CI 0.91, 2.10; P<0.00001), CD4+ (SMD=1.87, 95% CI 1.18, 2.56; P<0.00001), CD4+/CD8+ (SMD=0.86, 95% CI 0.48, 1.23; P<0.00001), and NK cell levels (SMD=0.94, 95% CI 0.63, 1.24; P<0.00001) in the adjuvant CT group SFI were better than those with CT alone. Adverse reactions following SFI adjuvant CT showed reduced incidence of leukopenia (RR=0.53, 95% CI 0.46, 0.62; P<0.00001) and gastrointestinal reactions (RR=0.48, 95% CI 0.39, 0.58; P<0.00001). However, the GRADE results showed 'very low' to 'moderate' evidence for the 42 outcomes, without high-quality evidence supporting them, limited mainly by deficiencies in the design of RCTs (42/42, 100.00%), inconsistency (19/42, 45.24%), publication bias (41/42, 97.62%), and inaccuracy (3/42, 7.14%). The unsatisfactory results of AMSTAR-2, PRISMA 2020, and ROBIS were limited to lack of registration of study protocols, explanation of inclusion basis of RCTs, description of funding sources for the included studies, incomplete search strategy and screening process, addressing heterogeneity and sensitivity, and reporting potential conflicts of interest. CONCLUSION: Adjuvant CT with SFI for BC had better benefits and a lower risk of adverse events. The methodology and quality of the evidence are generally low, highlighting a need of greater attention during study implementation. More objective and high-quality studies are needed to verify the efficacy of adjuvant CT with SFI in clinical decision-making for BC.

Neural Differentiation and spinal cord organoid generation from induced pluripotent stem cells (iPSCs) for ALS modelling and inflammatory screening.

C9orf72 genetic mutation is the most common genetic cause of ALS/FTD accompanied by abnormal protein insufficiency. Induced pluripotent stem cell (iPSC)-derived two-dimensional (2D) and three-dimensional (3D) cultures are providing new approaches. Therefore, this study established neuronal cell types and generated spinal cord organoids (SCOs) derived from C9orf72 knockdown human iPSCs to model ALS disease and screen the unrevealed phenotype. Wild-type (WT) iPSC lines from three healthy donor fibroblasts were established, and pluripotency and differentiation ability were identified by RT-PCR, immunofluorescence and flow cytometry. After infection by the lentivirus with C9orf72-targeting shRNA, stable C9-knockdown iPSC colonies were selected and differentiated into astrocytes, motor neurons and SCOs. Finally, we analyzed the extracted RNA-seq data of human C9 mutant/knockout iPSC-derived motor neurons and astrocytes from the GEO database and the inflammatory regulation-related genes in function and pathways. The expression of inflammatory factors was measured by qRT-PCR. The results showed that both WT-iPSCs and edited C9-iPSCs maintained a similar ability to differentiate into the three germ layers, astrocytes and motor neurons, forming SCOs in a 3D culture system. The constructed C9-SCOs have features of spinal cord development and multiple neuronal cell types, including sensory neurons, motor neurons, and other neurons. Based on the bioinformatics analysis, proinflammatory factors were confirmed to be upregulated in C9-iPSC-derived 2D cells and 3D cultured SCOs. The above differentiated models exhibited low C9orf72 expression and the pathological characteristics of ALS, especially neuroinflammation.

Assessment of early diabetic retinopathy severity using ultra-widefield Clarus versus conventional five-field and ultra-widefield Optos fundus imaging.

To compare early diabetic retinopathy (DR) severity level and the abilities in detecting early DR lesions among conventional five-field, ultrawide-field (UWF) Optos, and UWF Clarus fundus imaging methods. This was a single-center, prospective, clinic-based, and comparative study. In total, 157 consecutive patients with diabetes mellitus were enrolled in this study. All patients underwent comprehensive ophthalmological examinations. Following mydriasis, each eye was examined with conventional five-field, UWF Optos, and UWF Clarus fundus imaging methods. The initial UWF images were overlaid with a template mask that obscured the retina, which created a five-field view from UWF images (covered UWF images). The covered UWF images were then graded, after which the template mask was removed, and the original UWF images were also evaluated. All images were graded using the International Clinical DR severity scale. DR grades were compared and analyzed by weighted kappa statistics among the three fundus imaging methods. In total, 157 consecutive patients with diabetes (302 eyes) were enrolled in this study. Weighted kappa statistics for agreement were 0.471 (five-field vs. covered Optos), 0.809 (five-field vs. covered Clarus), 0.396 (covered Optos vs. covered Clarus), 0.463 (five-field vs. Optos), 0.521 (five-field vs. Clarus 133°), 0.500 (five-field vs. Clarus 200°), 0.323 (Optos vs. Clarus 133°), and 0.349 (Optos vs. Clarus 200°). The area under curve of covered Clarus images was higher than that of conventional five-field images at three different thresholds. Compared with conventional five-field and Optos fundus imaging methods, Clarus fundus imaging methods exhibited excellent performance in assessing early DR severity. Thus, Clarus fundus imaging methods were superior for early detection of DR.

Comparison of quantitative assessment and efficiency of diabetic retinopathy diagnosis using ETDRS seven-field imaging and two ultra-widefield imaging.

PURPOSE: This study compared the efficiency of diabetic retinopathy (DR) diagnosis and differences in the relative visible retinal area among the Early Treatment Diabetic Retinopathy Study (ETDRS) seven-field, ultra-widefield (UWF)-Optos, and UWF-Clarus fundus imaging methods. METHODS: This was a prospective and clinic-based comparative study. All patients underwent three fundus examinations, and all images were graded using the ETDRS severity scale. We compared and analysed the agreement of DR severity and the relative visible retinal area among the three fundus examination methods, and the number and type of lesions outside the ETDRS seven-field (peripheral lesions) between the two UWF imaging methods. RESULTS: A total of 202 patients (386 eyes) were included. Weighted kappa for the agreement between ETDRS seven-field and blinded Optos images was 0.485; between ETDRS seven-field and blinded Clarus images, 0.924; and between blinded Optos and Clarus images, 0.461. Blinded Clarus showed excellent performance when a ETDRS scale was used for grading the images. The relative visible retinal area for ETDRS seven-field images was 195 ± 28 disc area (DA); single Optos images, 371 ± 69 DA; single Clarus images, 261 ± 65 DA; two-montage Clarus images, 462 ± 112 DA; and four-montage Clarus images, 598 ± 139 DA. The relative visible retinal area was statistically significant between any two of the imaging systems used. In total, 2015 and 4200 peripheral lesions were detected in single Optos and Clarus images, respectively (P < 0.001). These peripheral lesions on two UWF images suggested a more severe DR level in approximately 10% and 12% of eyes, respectively. CONCLUSION: UWF-Clarus fundus imaging offers a suitable assessment approach for DR severity; it could improve DR diagnosis and has the potential to replace ETDRS seven-field imaging after additional clinical trials.

Processed meat, red meat, white meat, and digestive tract cancers: A two-sample Mendelian randomization study.

Background: Previous observational studies suggested inconsistent insights on the associations between meat intake and the risk of digestive tract cancers (DCTs). The causal effect of meat intake on DCTs is unclear. Methods: Two-sample Mendelian randomization (MR) was performed based on genome-wide association studies (GWAS) summary data from UK Biobank and FinnGen to evaluate the causal effect of meat intake [processed meat, red meat (pork, beef, and lamb), and white meat (poultry)] on DCTs (esophageal, stomach, liver, biliary tract, pancreatic, and colorectal cancers). The causal effects were estimated using a primary analysis that employed inverse-variance weighting (IVW) and complementary analysis that utilized MR-Egger weighted by the median. A sensitivity analysis was conducted using the Cochran Q statistic, a funnel plot, the MR-Egger intercept, and a leave-one-out approach. MR-PRESSO and Radial MR were performed to identify and remove outliers. To demonstrate direct causal effects, multivariable MR (MVMR) was applied. In addition, risk factors were introduced to explore potential mediators of the relationship between exposure and outcome. Results: The results of the univariable MR analysis indicated that genetically proxied processed meat intake was associated with an increased risk of colorectal cancer [IVW: odds ratio (OR) = 2.12, 95% confidence interval (CI) 1.07-4.19; P = 0.031]. The causal effect is consistent in MVMR (OR = 3.85, 95% CI 1.14-13.04; P = 0.030) after controlling for the influence of other types of exposure. The body mass index and total cholesterol did not mediate the causal effects described above. There was no evidence to support the causal effects of processed meat intake on other cancers, except for colorectal cancer. Similarly, there is no causal association between red meat, white meat intake, and DCTs. Conclusions: Our study reported that processed meat intake increases the risk of colorectal cancer rather than other DCTs. No causal relationship was observed between red and white meat intake and DCTs.

Clinical Significance of Plasma D-Dimer and Fibrinogen in Outcomes after Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: There is increasing evidence on the prognostic significance of D-dimer and fibrinolysis in stroke. However, the systematic analysis of their relationship with adverse outcomes after stroke is lacking. Herein, we comprehensively assessed the correlation of D-dimer and fibrinolysis with stroke outcomes through meta-analysis. METHODS: Studies for systematic literature review were retrieved from PubMed, EMBASE, and Cochrane Library databases. The association of D-dimer and fibrinolysis with outcomes of stroke patients was expressed as an odds ratio (OR) with 95% confidence intervals (95% CI). RESULTS: Totally, 52 studies comprising 21,473 stroke patients were included. The results showed that the high D-dimer level was significantly associated with peripheral venous thrombosis after stroke (OR 1.03, 95% CI 1.01-1.05), poor outcome (MRS >2) after stroke (OR 1.731, 95% CI 1.464-2.048), death after stroke (OR 2.367, 95% CI 1.737-3.224), stroke recurrence (OR 1.229, 95% CI 1.113-1.358), and early neurologic deterioration (NIHSS >4) (OR 1.791, 95% CI 1.117-2.870). Moreover, high fibrinogen level was significantly associated with poor outcome (MRS >2) after stroke (OR 1.650, 95% CI 1.314-2.071), death after stroke (OR 1.310, 95% CI 1.128-1.520), stroke recurrence (OR 1.228, 95% CI 1.166-1.422), early neurologic deterioration (NIHSS >4) (OR 2.381, 95% CI 1.156-4.904), and coronary events after stroke (OR 1.427, 95% CI 1.232-1.653). CONCLUSION: Fibrinogen and D-dimer may be associated with adverse outcomes in patients with stroke, suggesting that they may serve as possible biomarkers for post-stroke adverse outcomes.

hiPSC-Neural Stem/Progenitor Cell Transplantation Therapy for Spinal Cord Injury.

Spinal cord injury (SCI) is a catastrophic event that incurs substantial personal and social costs. The complex pathophysiology associated with SCI often limits the regeneration of nerve tissue at the injured site and leads to permanent nerve damage. With advances in stem cell biology, the field of regenerative medicine offers the hope of solving this challenging problem. Neural stem/progenitor cells (NSPCs) possess nerve regenerative and neuroprotective effects, and transplanting NSPCs in their optimized form into an injured area holds promising therapeutic potential for SCI. In this review, we summarize the advantages and disadvantages of NSPCs derived from different sources while highlighting the utility of NSPCs derived from induced pluripotent stem cells, an NSPC source with superior advantages, according to data from in vivo animal models and the latest clinical trials.

Lentiviral Transduction-based CRISPR/Cas9 Editing of Schistosoma mansoni Acetylcholinesterase.

Background: Recent studies on CRISPR/Cas9-mediated gene editing in Schistosoma mansoni have shed new light on the study and control of this parasitic helminth. However, the gene editing efficiency in this parasite is modest. Methods: To improve the efficiency of CRISPR/Cas9 genome editing in schistosomes, we used lentivirus, which has been effectively used for gene editing in mammalian cells, to deliver plasmid DNA encoding Cas9 nuclease, a sgRNA targeting acetylcholinesterase (SmAChE) and a mCherry fluorescence marker into schistosomes. Results: MCherry fluorescence was observed in transduced eggs, schistosomula, and adult worms, indicating that the CRISPR components had been delivered into these parasite stages by lentivirus. In addition, clearly changed phenotypes were observed in SmAChE-edited parasites, including decreased SmAChE activity, reduced hatching ability of edited eggs, and altered behavior of miracidia hatched from edited eggs. Next-generation sequencing analysis demonstrated that the lentiviral transduction-based CRISPR/Cas9 gene modifications in SmAChE-edited schistosomes were homology-directed repair predominant but with much lower efficiency than that obtained using electroporation (data previously published by our laboratory) for the delivery of CRISPR components. Conclusion: Taken together, electroporation is more efficient than lentiviral transduction in the delivery of CRISPR/Cas9 into schistosomes for programmed genome editing. The exploration of tactics for enhancing CRISPR/Cas9 gene editing provides the basis for the future improvement of programmed genome editing in S. mansoni.

Autophagy-Mediated Inflammatory Cytokine Secretion in Sporadic ALS Patient iPSC-Derived Astrocytes.

Background: Astrocytes can be involved in motor neuron toxicity in amyotrophic lateral sclerosis (ALS) induced by noncell autonomous effects, and inflammatory cytokines may play the main role in mediating this process. However, the etiology of aberrant cytokine secretion is unclear. The present study assessed possible involvement of the mTOR-autophagy pathway in aberrant cytokine secretion by ALS patient iPSC-derived astrocytes. Method and Results. PBMCs from sporadic ALS patients and control subjects were reprogrammed into iPSCs, which were then differentiated into astrocytes and/or motor neurons. Comparison with control astrocytes indicated that conditioned medium of ALS astrocytes reduced the viability of the control motor neurons (p < 0.05) assessed using the MTT assay. The results of ELISA showed that the concentrations of TNFα, IL1ß, and IL6 in cell culture medium of ALS astrocytes were increased (p < 0.05). ALS astrocytes had higher p62 and mTOR levels and lower LC3BII/LC3BI ratio and ULK1 and p-Beclin-1 (Ser15) levels (p < 0.05), indicating defective autophagy. Exogenous inhibition of the mTOR-autophagy pathway, but not the activation of the pathway in control subject astrocytes, increased the levels of p62 and mTOR and concentration of IL-1ß, TNF-α, and IL-6 in cell culture medium and decreased the LC3BII/LC3BI ratio and levels of ULK1 and p-Beclin-1 (Ser15), and these changes were comparable to those in ALS astrocytes. After 48 h of rapamycin (autophagy activator) and 3-methyladenine (autophagy inhibitor) treatments, the exogenous activation of the mTOR-autophagy pathway, but not inhibition of the pathway, in ALS astrocytes significantly reduced the concentrations of TNFα, IL1ß, and IL6 in cell culture medium and reduced the levels of p62, while increasing the levels of LC3B-II/LC3B-I, ULK1, and p-Beclin-1 (Ser15), and these changes were comparable to those in control subject astrocytes. Conclusion: Alteration in the mTOR/ULK1/Beclin-1 pathway regulated cytokine secretion in ALS astrocytes, which was able to lead to noncell autonomous toxicity. Autophagy activation mitigated cytokine secretion by ALS astrocytes.

Schistosoma mansoni Fibroblast Growth Factor Receptor A Orchestrates Multiple Functions in Schistosome Biology and in the Host-Parasite Interplay.

Stem cells play significant roles in driving the complex life cycle of Schistosoma mansoni. Fibroblast growth factor (FGF) receptor A (SmFGFRA) is essential for maintaining the integrity of schistosome stem cells. Using immunolocalization, we demonstrated that SmFGFRA was distributed abundantly in germinal/stem cells of different S. mansoni life stages including eggs, miracidia, cercariae, schistosomula and adult worms. Indeed, SmFGFRA was also localized amply in embryonic cells and in the perinuclear region of immature eggs; von Lichtenberg's layer and the neural mass of mature eggs; the ciliated surface and neural mass of miracidia; the tegument cytosol of cercariae, schistosomula and adult worms; and was present in abundance in the testis and vitellaria of adult worms of S. mansoni. The distribution pattern of SmFGFRA illustrates the importance of this molecule in maintaining stem cells, development of the nervous and reproductive system of schistosomes, and in the host-parasite interplay. We showed SmFGFRA can bind human FGFs, activating the mitogen activated protein kinase (MAPK) pathway of adult worms in vitro. Inhibition of FGF signaling by the specific tyrosine kinase inhibitor BIBF 1120 significantly reduced egg hatching ability and affected the behavior of miracidia hatched from the treated eggs, emphasizing the importance of FGF signaling in driving the life cycle of S. mansoni. Our findings provide increased understanding of the complex schistosome life cycle and host-parasite interactions, indicating components of the FGF signaling pathway may represent promising targets for developing new interventions against schistosomiasis.

Adsorption characteristics of strontium by bentonite colloids acting on claystone of candidate high-level radioactive waste geological disposal sites.

The bentonite colloid produced in the deep geological repository of high-level radioactive waste can directly affect the migration of radionuclide strontium when it acts on claystone. The adsorption characteristics of strontium were investigated on claystone with the presence or absence of bentonite colloids from the Suhongtu area of China. The effects of different influencing factors, such as pH and solid content, on the adsorption process were investigated by batch adsorption experiments, and spectroscopic techniques were used to characterize the samples before and after adsorption of strontium. The results show that the presence of bentonite colloids can promote the adsorption of strontium on claystone under alkaline conditions. and the general order kinetic model provided the best fit to the experimental data. Strontium is adsorbed on the surface of claystone and bentonite colloid by ion exchange and surface complexation. Most of the Sr2+ formed SrCO3 with CO32- after ion exchange with Ca2+ and Mg2+ in plagioclase and dolomite, and a small amount of Sr2+ was adsorbed by complexation with -OH, Al-O and Si-O. These results provide a scientific basis for predicting the migration of strontium in subsurface porous media and the siting of high-level radioactive waste repositories.

Identification of Age-associated Proteins and Functional Alterations in Human Retinal Pigment Epithelium.

Retinal pigment epithelium (RPE) has essential functions, such as nourishing and supporting the neural retina, and is of vital importance in the pathogenesis of age-related retinal degeneration. However, the exact molecular changes of RPE during aging remain poorly understood. Here, we isolated human primary RPE (hRPE) cells from 18 eye donors distributed over a wide age range (10-67 years old). A quantitative proteomic analysis was performed to analyze changes in their intracellular and secreted proteins. Age-group related subtypes and age-associated proteins were revealed and potential age-associated mechanisms were validated in ARPE-19 and hRPE cells. The results of proteomic data analysis and verifications suggest that RNF123- and RNF149-related protein ubiquitination plays an important role in protecting hRPE cells from oxidative damage during aging. In older hRPE cells, apoptotic signaling-related pathways were up-regulated, and endoplasmic reticulum organization was down-regulated both in the intracellular and secreted proteomes. Our work paints a detailed molecular picture of hRPE cells during the aging process and provides new insights into the molecular characteristics of RPE during aging and under other related clinical retinal conditions.

[Effects of Mijiandao suppository on intestinal laxation in rats and its mechanisms].

Objective: To investigate the effects of Mijian Daotong Bowel Suppository (MJDs) on the compound diphenoxylate induced constipation model of male rats and its mechanisms. Methods: Sixty SD male rats were randomly divided into blank group, model group, positive group and MJDs group. The constipation model was established by using compound diphenoxylate gavage. The rats in blank group and model group were treated with saline by enema, the rats in positive group and MJDs group were given Kaisailu and honey decoction laxative suppository by enema, respectively, once a day for 10 days. The body weight, fecal water content, gastric emptying rate (GER) and carbon ink propulsion rate (CIPR) of rats were observed during modeling and administration. The effects of MJDs on the pathological changes of colon tissue in constipation rats were investigated by hematoxylin-eosin (HE) staining. The effect of MJDs on 5-hydroxytryptamine (5-HT) in the colon of constipation rats was investigated by ELISA kit. The effects of MJDs on the expressions of aquaporins 3 (AQP3) and aquaporins 4 (AQP4) in the colon of constipation rats were detected by immunohistochemistry. Results: After 10 days of administration, compared with the blank group, the body weight, fecal water content, carbon ink propulsion rate and colon 5-HT content in the model group were decreased significantly, while the expression levels of AQP3 and AQP4 in the colon were increased significantly (P＜0.05, P＜0.01). Compared with the model group, the fecal water content and colon 5-HT content in the positive group were increased significantly, and the expressions of AQP3 and AQP4 in the colon were decreased significantly. The body weight, fecal water content and colon 5-HT content in the MJDs group were increased significantly, and the expressions of AQP3 and AQP4 was decreased significantly (P＜0.05, P＜0.01). Compared with the positive group, the fecal water content of the MJDs group was decreased significantly, and the expressions of AQP3 and AQP4 in the colon of the MJDs group was decreased significantly (P＜0.05, P＜0.01). Gastric emptying rate was not statistically significant difference between the groups. Conclusion: MJDs has good therapeutic effects on constipation, and its mechanisms may be related to up-regulating the content of 5-HT in the colon and down-regulating the expressions of AQP3 and AQP4 in the colon.

CRISPR interference for sequence-specific regulation of fibroblast growth factor receptor A in Schistosoma mansoni.

Employing the flatworm parasite Schistosoma mansoni as a model, we report the first application of CRISPR interference (CRISPRi) in parasitic helminths for loss-of-function studies targeting the SmfgfrA gene which encodes the stem cell marker, fibroblast growth factor receptor A (FGFRA). SmFGFRA is essential for maintaining schistosome stem cells and critical in the schistosome-host interplay. The SmfgfrA gene was targeted in S. mansoni adult worms, eggs and schistosomula using a catalytically dead Cas9 (dCas9) fused to a transcriptional repressor KRAB. We showed that SmfgfrA repression resulted in considerable phenotypic differences in the modulated parasites compared with controls, including reduced levels of SmfgfrA transcription and decreased protein expression of SmFGFRA, a decline in EdU (thymidine analog 5-ethynyl-2'-deoxyuridine, which specifically stains schistosome stem cells) signal, and an increase in cell apoptosis. Notably, reduced SmfgfrA transcription was evident in miracidia hatched from SmfgfrA-repressed eggs, and resulted in a significant change in miracidial behavior, indicative of a durable repression effect caused by CRISPRi. Intravenous injection of mice with SmfgfrA-repressed eggs resulted in granulomas that were markedly reduced in size and a decline in the level of serum IgE, emphasizing the importance of SmFGFRA in regulating the host immune response induced during schistosome infection. Our findings show the feasibility of applying CRISPRi for effective, targeted transcriptional repression in schistosomes, and provide the basis for employing CRISPRi to selectively perturb gene expression in parasitic helminths on a genome-wide scale.

A review on deep learning MRI reconstruction without fully sampled k-space.

BACKGROUND: Magnetic resonance imaging (MRI) is an effective auxiliary diagnostic method in clinical medicine, but it has always suffered from the problem of long acquisition time. Compressed sensing and parallel imaging are two common techniques to accelerate MRI reconstruction. Recently, deep learning provides a new direction for MRI, while most of them require a large number of data pairs for training. However, there are many scenarios where fully sampled k-space data cannot be obtained, which will seriously hinder the application of supervised learning. Therefore, deep learning without fully sampled data is indispensable. MAIN TEXT: In this review, we first introduce the forward model of MRI as a classic inverse problem, and briefly discuss the connection of traditional iterative methods to deep learning. Next, we will explain how to train reconstruction network without fully sampled data from the perspective of obtaining prior information. CONCLUSION: Although the reviewed methods are used for MRI reconstruction, they can also be extended to other areas where ground-truth is not available. Furthermore, we may anticipate that the combination of traditional methods and deep learning will produce better reconstruction results.

Blood-derived integration-free induced pluripotent stem cells (iPSCs) from one 53-years-old male donor with APOE-ε4/ε4 genotype.

Apolipoprotein E ε4 allele (APOE4) is a minor allele of the APOE gene associated with a higher risk for Alzheimer's Disease (AD) and Vascular Dementia (VD). While lipid deposition and chronic inflammation in glia are the commonalities between atherosclerosis, VD, and AD. Hence, we presented an iPSC line of an AD male donor suffering from Cerebrovascular Atherosclerosis with APOE-ε4/ε4 alleles background. Furthermore, we differentiated the iPSCs into astrocyte to explore pathogenesis in APOE4 related dementia. The characterized iPSC line expressed typical pluripotency markers and showed differentiation potential and normal karyotype.