iPSC-Derived Airway Epithelial Cells: Progress, Promise, and Challenges.

Induced pluripotent stem cells (iPSCs) generated from somatic cell sources are pluripotent and capable of indefinite expansion in vitro. They provide an unlimited source of cells that can be differentiated into lung progenitor cells for potential clinical use in pulmonary regenerative medicine. This review gives a comprehensive overview of recent progress toward the use of iPSCs to generate proximal and distal airway epithelial cells and mix lung organoids. Furthermore, their potential applications and future challenges for the field are discussed, with a focus on the technological hurdles that must be cleared before stem cell therapeutics can be used for clinical treatment.

Proteomics and metabolomics profiling reveal panels of circulating diagnostic biomarkers and molecular subtypes in stable COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disease with high morbidity and mortality, especially in advanced patients. We aimed to develop multi-omics panels of biomarkers for the diagnosis and explore its molecular subtypes. METHODS: A total of 40 stable patients with advanced COPD and 40 controls were enrolled in the study. Proteomics and metabolomics techniques were applied to identify potential biomarkers. An additional 29 COPD and 31 controls were enrolled for validation of the obtained proteomic signatures. Information on demographic, clinical manifestation, and blood test were collected. The ROC analyses were carried out to evaluate the diagnostic performance, and experimentally validated the final biomarkers on mild-to-moderate COPD. Next, molecular subtyping was performed using proteomics data. RESULTS: Theophylline, palmitoylethanolamide, hypoxanthine, and cadherin 5 (CDH5) could effectively diagnose advanced COPD with high accuracy (auROC = 0.98, sensitivity of 0.94, and specificity of 0.95). The performance of the diagnostic panel was superior to that of other single/combined results and blood tests. Proteome based stratification of COPD revealed three subtypes (I-III) related to different clinical outcomes and molecular feature: simplex COPD, COPD co-existing with bronchiectasis, and COPD largely co-existing with metabolic syndrome, respectively. Two discriminant models were established using the auROC of 0.96 (Principal Component Analysis, PCA) and 0.95 (the combination of RRM1 + SUPV3L1 + KRT78) in differentiating COPD and COPD with co-morbidities. Theophylline and CDH5 were exclusively elevated in advanced COPD but not in its mild form. CONCLUSIONS: This integrative multi-omics analysis provides a more comprehensive understanding of the molecular landscape of advanced COPD, which may suggest molecular targets for specialized therapy.

Smart Vehicle Path Planning Based on Modified PRM Algorithm.

Path planning is a very important step for mobile smart vehicles in complex environments. Sampling based planners such as the Probabilistic Roadmap Method (PRM) have been widely used for smart vehicle applications. However, there exist some shortcomings, such as low efficiency, low reuse rate of the roadmap, and a lack of guidance in the selection of sampling points. To solve the above problems, we designed a pseudo-random sampling strategy with the main spatial axis as the reference axis. We optimized the generation of sampling points, removed redundant sampling points, set the distance threshold between road points, adopted a two-way incremental method for collision detections, and optimized the number of collision detection calls to improve the construction efficiency of the roadmap. The key road points of the planned path were extracted as discrete control points of the Bessel curve, and the paths were smoothed to make the generated paths more consistent with the driving conditions of vehicles. The correctness of the modified PRM was verified and analyzed using MATLAB and ROS to build a test platform. Compared with the basic PRM algorithm, the modified PRM algorithm has advantages related to speed in constructing the roadmap, path planning, and path length.

Neuroprotective Effects of Salidroside in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD), the most common form of dementia worldwide, is characterized by pathological hallmarks like ß-amyloid peptide (Aß) and clinical manifestations including cognitive impairment, psychiatry disorders, and behavioral changes. Salidroside (Sal) extracted from Rhodiola rosea L. showed protective effects against Aß-induced neurotoxicity in a Drosophila AD model in our previous research. In the present study, daily doses of Sal were administered to APP/PS1 mice, a mouse model of AD, and several parameters were tested, including behavioral performance, Aß status, levels of synapse-related proteins, and levels of PI3K/Akt targets of mTOR cell signaling pathway proteins. The behavioral testing showed an improvement in locomotor activity in the APP/PS1 mice after the administration of Sal. Treatment with Sal decreased both the soluble and insoluble Aß levels and increased the expression of PSD95, NMDAR1, and calmodulin-dependent protein kinase II. The phosphatidylinositide PI3K/Akt/mTOR signaling was upregulated, which was in accordance with the above improvements from Sal treatment. Our findings suggested that Sal may protect the damaged synapses of the neurons in the APP/PS1 mice.

Alternaria tenuissima Causing Leaf Spot Disease on Amygdalus triloba in Xinjiang of China.

Amygdalus triloba (Rosaceae; previously Prunus triloba) is a deciduous, flowering shrub that is widely used in the greening and beautification of lawns, parks and courtyards in China. In late May 2019, a leaf spot disease of A. triloba was observed on approximately 35% of plants in the Xinjiang Alaer city (40˚33'20''N, 81˚17'19''E). The disease symptoms began as small, suborbicular, brown spots on the leaves. As the disease progressed, the spots enlarged and coalesced into large necrotic areas and resulted in premature defoliation. Leaf sections (5 x 5 mm) from infected leaves were surface - sterilized with 75% ethanol for 30 s and 0.1% HgCl2 for 1 min, rinsed three times in sterile distilled water and then incubated on potato dextrose agar (PDA). Fifteen fungal isolates showing similar morphological characteristics were obtained by single-spore isolation. On the PDA plates, all fungal colonies had a dark olive color with loose, cottony mycelium. On the potato carrot agar, the fungus formed unbranched spore chains, but occasionally formed one or two lateral branches. Conidiophores were short, hazel-colored, septae, arising singly, and measuring 15.1 to 61.8 × 1.8 to 4.2 µm (35.2 ± 1.4 × 2.3 ± 0.1 µm, n = 50). Mature conidia were ellipsoidal to ovoid with a short conical beak at the tip, light brown with zero to three longitudinal septa and one to five transverse septa, and measuring 19.3 to 30.8 × 7.2 to 12.5 µm (21.8 ± 0.3 × 9.5 ± 0.2 µm, n = 50). Based on the cultural and morphological traits, the pathogen was preliminary identified as Alternaria tenuissima (Simmons 2007). Genomic DNA was extracted from the representative isolate YALAR-1, and the internal transcribed spacer (ITS) region, the partial coding sequence of endopolygalacturonase (endoPG), the glyceradehyde -3- phosphate dehydrogenase (GAPDA), the partial region of the histone 3 (H3) genes were amplified using primers ITS1/ITS4 (White et al. 1990), PG2b/PG3a (Andrew et al. 2009), GDF1/GDR1 (Berbee et al. 1999) and H3-1a/H3-1b (Glass and Donaldson 1995), respectively. The amplicons were sequenced and deposited in GenBank [MT459807 (ITS), MT459808 (endoPG), MT459805 (GAPDA), MT459806 (H3)]. MegaBLAST analyses revealed that our ITS, endoPG, GAPDA, and H3 sequences were 99-100% identical to those of A. tenuissima isolates in GenBank [AF347032 (ITS), KP124026 (endoPG), AY278809 (GAPDA), KF997086 (H3)], confirming the identity of the pathogen as A. tenuissima. Pathogenicity tests were performed by inoculating the fungus onto healthy, mature leaves of A. triloba in the field. Twenty five leaves (five leaves/plant) were sprayed with spore suspensions (1 × 106 spores/ml) of each fungal pathogen, and the same number of leaves were sprayed with distilled water as controls. Inoculated and control leaves were covered with clear plastic bags for 3 days. The experiment was repeated three times. Twelve days after inoculation, the observed symptoms were similar to the original symptoms and the same fungal pathogen was reisolated from the inoculated leaves and identified as A. tenuissima based on morphological features and sequence analysis. The control leaves remained asymptomatic and no fungus was isolated from these leaves. Previously, a leaf spot of A. triloba caused by Alternaria brassicae was reported in Dalian, China (Xie et al. 2017). In order to control this disease effectively, further studies are needed on the biology and ecology of A. tenuissima and A. brassicae respectively. To our knowledge, this is the first report of A. tenuissima associated with leaf spot disease on A. triloba in China. In late September 2020, the diseased plant rate increased to 38% in Alaer city. If the disease control and prevention is neglected, the landscape of Alaer city will be affected seriously. So, in order to effectively control the spread of the disease, it is urgent now to study the sensitivity of pathogen to fungicide and carry out the field efficacy trials. References: Andrew, M., et al. 2009. Mycologia. 101:95. Berbee, M. L., et al. 1999. Mycologia. 91:964. Glass, N. L., and Donaldson, G. C. 1995. Appl. Environ. Microbiol. 61:1323. Simmons, E. G. 2007. Alternaria: An Identification Manual. CBS Fungal Biodiversity Centre, Utrecht, The Netherlands. White, T. J., et al. 1990. PCR Protocols: A Guide to Methods and Applications. Academic Press, San Diego, CA. Xie, Y., et al. 2017. Liaoning Agricultural Sciences. 6: 73.

Clinical Significance of Galactose-Deficient IgA1 by KM55 in Patients with IgA Nephropathy.

BACKGROUND: Aberrant galactose-deficient IgA1 molecules (Gd-IgA1) are important causal factors in IgA nephropathy (IgAN); however, the detection of Gd-IgA1 in IgAN is complicated and instable. A monoclonal antibody, KM55, which specifically recognizes Gd-IgA1 has been developed. In the present study, we further explored the clinical significance of Gd-IgA1 using KM55. METHODS: In this study, we enrolled 75 patients with IgAN and 80 healthy controls and detected the plasma Gd-IgA1 levels using the KM55 ELISA method. We also stained -mesangial Gd-IgA1 deposition using KM55. RESULTS: We observed that the levels of plasma Gd-IgA1 in IgAN patients were elevated compared to the corresponding levels of healthy controls. Patients were divided into 2 groups based on the median of Gd-IgA1. Patients with high Gd-IgA1 levels had significantly higher levels of uric acid (UA) and IgA. The other clinical manifestations demonstrated that there were no differences in age, sex, blood pressure, initial proteinuria, hematuria, estimated glomerular filtration rate and Oxford pathological classification between the 2 groups of patients. In addition, positive correlations were observed between Gd-IgA1 and Bb, C3a, C4d and MAC. Mesangial Gd-IgA1 was positive in IgAN but negative in the normal renal tissue adjacent to neoplasm. We next analyzed the correlation between plasma Gd-IgA1 and mesangial Gd-IgA1 deposition. The results showed that a high level of plasma Gd-IgA1 was related to the deposition of mesangial Gd-IgA1, although the difference was not significant. CONCLUSION: We verified the elevated level of plasma and -mesangial Gd-IgA1 in patients with IgAN by KM55, which provided an alternative, easy, and reliable tool for diagnosis and activity assessment of IgAN. The level of plasma Gd-IgA1 positively correlated with levels of UA, total IgA levels, and complement activation products.

A Comprehensive Multilocus Sequence Typing Scheme for Identification and Genotyping of Staphylococcus Strains.

Increasing clinical significance of coagulase-negative staphylococci requires effective methods for species identification and genotyping. In this study, six housekeeping genes (femA, ftsZ, gap, pyrH, rpoB, and tuf) with extensive allelic polymorphisms were identified and evaluated to develop a comprehensive multilocus sequence typing (MLST) scheme. Selected primers were capable of amplification of the six loci from all of the 180 Staphylococcus strains belonging to 18 different species. Sequence analysis of each locus (44-63 alleles) revealed higher nucleotide diversity than 16S rRNA (28 alleles). Phylogenetic analysis of the concatenated sequences (3054 bp) of the six loci provided accurate species identification and highly discriminatory typing for all the strains. Multilocus allelic analysis of the 180 Staphylococcus strains generated 103 different sequence profiles, suggesting high genetic diversity of the strains. For example, 30 S. aureus, 37 S. epidermidis, 32 S. haemolyticus, and 14 S. hominis strains were typed into 15, 21, 11, and 10 sequence profiles, respectively. Compared with published MLST schemes that restrict on a few particular species, this new scheme both achieved similar discrimination for typing S. aureus, S. epidermidis, S. haemolyticus, and S. hominis and provided sufficient discriminatory power for typing additional opportunistic species, such as S. cohnii, S. capitis, and S. warneri. Importantly, the comprehensive MLST scheme for Staphylococcus strains provides a better genotyping tool for understanding the phylogeny of coagulase-positive Staphylococcus aureus strains.

Stroke and Coronary Artery Disease Are Associated With Parkinson's Disease.

BACKGROUND: The relationship between vascular disease and Parkinson's disease (PD) is controversial. We performed a cross-sectional study to investigate the association of two common vascular diseases (stroke and coronary artery disease [CAD]) with Parkinson's disease. METHODS: We identified 63 and 62 PD cases in two population-based cohorts (Malu rural community and Wuliqiao urban community) and collected information of PD and non-PD by means of questionnaires. Logistic regression analysis was used to investigate the association between stroke, coronary artery disease and PD, after adjusting for age, sex, hypertension, diabetes mellitus, hypercholesterolemia, smoking status, alcohol consumption, tea consumption and body mass index. RESULTS: After adjustment for potential confounders, we found that CAD and stroke were associated with PD in the Malu rural community (CAD: odds ratio [OR]=7.11, 95% confidence intervals [CI]: 3.09-16.40, p<0.001; stroke: OR=6.77, 95% CI: 3.09-14.81, p<0.001) and stroke was associated with PD in the Wuliqiao urban community (OR=2.58, 95% CI: 1.36-4.89, p=0.004), especially in women. In a subgroup analysis of PD with age- and sex-matched controls, the results were similar in the Malu rural community (CAD: OR=12.72, 95% CI: 2.92-55.32, p=0.001; stroke: OR=6.26, 95% CI: 1.83-21.42, p=0.003), whereas in the Wuliqiao urban community the results were different in that CAD (but not stroke) was found to be associated with PD (CAD: OR=2.44, 95% CI: 1.09-5.47, p=0.03; stroke: OR=1.79, 95% CI: 0.77-4.17, p=0.18). CONCLUSIONS: Our study suggested that stroke and CAD are associated with PD in two Chinese population-based cohorts, indicating a probable vascular component in the pathogenesis of PD.

A comprehensive technology strategy for microbial identification and contamination investigation in the sterile drug manufacturing facility-a case study.

Objective: A comprehensive strategy for microbial identification and contamination investigation during sterile drug manufacturing was innovatively established in this study, mainly based on MALDI-TOF MS for the identification and complemented by sequencing technology on strain typing. Methods: It was implemented to monitor the bacterial contamination of a sterile drug manufacturing facility, including its bacterial distribution features and patterns. In three months, two hundred ninety-two samples were collected covering multiple critical components of raw materials, personnel, environment, and production water. Results: Based on our strategy, the bacterial profile across the production process was determined: 241/292 bacterial identities were obtained, and Staphylococcus spp. (40.25%), Micrococcus spp.(11.20%), Bacillus spp. (8.30%), Actinobacteria (5.81%), and Paenibacillus spp. (4.56%) are shown to be the most dominant microbial contaminants. With 75.8% species-level and 95.4% genus-level identification capability, MALDI-TOF MS was promising to be a first-line tool for environmental monitoring routine. Furthermore, to determine the source of the most frequently occurring Staphylococcus cohnii, which evidenced a widespread presence in the entire process, a more discriminating S. cohnii whole-genome SNP typing method was developed to track the transmission routes. Phylogenetic analysis based on SNP results indicated critical environment contamination is highly relevant to personnel flow in this case. The strain typing results provide robust and accurate information for the following risk assessment step and support effective preventive and corrective measures. Conclusion: In general, the strategy presented in this research will facilitate the development of improved production and environmental control processes for the pharmaceutical industry, and give insights about how to provide more sound and reliable evidence for the optimization of its control program.

MIST: A microbial identification and source tracking system for next-generation sequencing data.

The Professional Committee of Microbiology of the National Pharmacopoeia Commission organized the drafting of the Technical Guidelines for Microbial Whole Genome Sequencing (WGS), aiming to standardize the method process and technical indicators of microbial WGS and ensure the accuracy of sequencing and identification. On the basis of the Guidelines, we developed an integrated microbial identification and source tracking (MIST) system, which could meet the needs of microbial identification and contamination investigation in food and drug quality control. MIST integrates three analysis pipelines: 16S/18S/internal transcribed spacer amplicon-based microbial identification, WGS-based microbial identification, and single-nucleotide polymorphism-based microbial source tracking. MIST can analyze sequence data in a variety of formats, such as Fasta, base call file, and FASTQ. It can be connected to a high-throughput sequencing instrument to acquire sequencing data directly. We also developed a publicly accessible web server for MIST (http://syj.i-sanger.cn).

Proteomic profiling reveals a distinctive molecular signature for critically ill COVID-19 patients compared with asthma and chronic obstructive pulmonary disease.

OBJECTIVE: The mortality rate for critically ill COVID-19 cases was more than 80%. Nonetheless, research about the effect of common respiratory diseases on critically ill COVID-19 expression and outcomes is scarce. DESIGN: We performed proteomic analyses on airway mucus obtained by bronchoscopy from patients with severe COVID-19, or induced sputum from patients with chronic obstructive pulmonary disease (COPD), asthma, and healthy controls. RESULTS: Of the total identified and quantified proteins, 445 differentially expressed proteins (DEPs) were found in different comparison groups. In comparison with COPD, asthma, and controls, 11 proteins were uniquely present in COVID-19 patients. Apart from DEPs associated with COPD versus controls and asthma versus controls, there was a total of 59 DEPs specific to COVID-19 patients. Finally, the findings revealed that there were 8 overlapping proteins in COVID-19 patients, including C9, FGB, FGG, PRTN3, HBB, HBA1, IGLV3-19, and COTL1. Functional analyses revealed that most of them were associated with complement and coagulation cascades, platelet activation, or iron metabolism, and anemia-related pathways. CONCLUSIONS: This study provides fundamental data for identifying COVID-19-specific proteomic changes in comparison with COPD and asthma, which may suggest molecular targets for specialized therapy.

Effects of bone morphogenetic protein 4 on TGF-ß1-induced cell proliferation, apoptosis, activation and differentiation in mouse lung fibroblasts via ERK/p38 MAPK signaling pathway.

Fibroblasts, in particular myofibroblasts, are the critical effector cells in idiopathic pulmonary fibrosis (IPF), a deadly lung disease characterized by abnormal lung remodeling and the formation of "fibroblastic foci". Aberrant activation of TGF-ß1 is frequently encountered and promotes fibroblast proliferation, activation, and differentiation in pulmonary fibrosis. Hence, the inhibition of TGF-ß1-induced lung fibroblast activation holds promise as a therapeutic strategy for IPF. The present study aimed to investigate the potential effect and underlying mechanisms of bone morphogenetic protein 4 (BMP4) on TGF-ß1-induced proliferation, apoptosis, activation and myofibroblast differentiation of adult lung fibroblasts. Here, we demonstrated that BMP4 expression was significantly decreased in TGF-ß1-stimulated mouse primary lung fibroblasts (PLFs). BMP4 inhibited proliferation and apoptosis resistance of TGF-ß1-stimulated mouse PLFs. BMP4 suppressed TGF-ß1-induced fibroblast activation and differentiation in mouse PLFs. We also found that BMP4 inhibited TGF-ß1-induced ERK and p38 MAPK phosphorylation. Our findings indicate that BMP4 exerts its anti-fibrotic effects by regulating fibroblast proliferation, apoptosis, activation and differentiation via the inhibition of the ERK/p38 MAPK signaling pathway, and thus has a potential for the treatment of pulmonary fibrosis.

Gene Expression Trajectories from Normal Nonsmokers to COPD Smokers and Disease Progression Discriminant Modeling in Response to Cigarette Smoking.

Background: Cigarette smoking (CS) is considered to the predominant risk factor contributing to the etiopathogenesis of chronic obstructive pulmonary disease (COPD); meanwhile, genetic predisposition likely plays a role in determining disease susceptibility. Objectives: We aimed to investigate gene expression trajectories from normal nonsmokers to COPD smokers and disease progression discriminant modeling in response to cigarette smoking. Methods: Small airway epithelial samples of human with different smoking status using fiberoptic bronchoscopy and corresponding rat lung tissues following 0, 3, and 6 months of CS exposure were obtained. The expression of the significant overlapping genes between human and rats was confirmed in 16HBE cells, rat lung tissues, and human peripheral PBMC using qRT-PCR. Binary logistic regression analysis was carried out to establish discrimination models. Results: The integrated bioinformatic analysis of 8 human GEO datasets (293 individuals) and 9 rat transcriptome databases revealed 13 overlapping genes between humans and rats in response to smoking exposure during COPD progression. Of these, 5 genes (AKR1C3/Akr1c3, ERP27/Erp27, AHRR/Ahrr, KCNMB2/Kcnmb2, and MRC1/Mrc1) were consistently identified in both the human and rat and validated by qRT-PCR. Among them, ERP27/Erp27, KCNMB2/Kcnmb2, and MRC1/Mrc1 were newly identified. On the basis of the overlapping gene panel, discriminant models were established with the receiver operating characteristic curve (AUC) of 0.98 (AKR1C3/Akr1c3 + ERP27/Erp27) and 0.99 (AHRR/Ahrr + KCNMB2/Kcnmb2) in differentiating progressive COPD from normal nonsmokers. In addition, we also found that DEG obtained from each expression profile dataset was better than combined analysis as more genes could be identified. Conclusion: This study identified 5 DEG candidates of COPD progression in response to smoking and developed effective and convenient discriminant models that can accurately predict the disease progression.

Standardized Shiga-Toxin Encoding Genes Real-Time PCR Screening Methods Comparison and Development of an Internally Controlled Assay for Pan-stx2 Detection.

BACKGROUND: Various primer and probe sets have been developed and standardized, but certain sets may have low efficiency or miss some stx-subtypes. OBJECTIVE: To compare the efficiency of the recommended stx screening primers and probe sets in four standardized methods and develop a new primers and probe system with an internal amplification control (IAC) for all known stx2 subtypes. METHOD: The inclusivity and specificity of recommended screening primers and probe sets in four standardized methods were compared. A new pan-stx2 primer and probe set was adapted from the International Organization for Standardization (ISO) method for all known stx2 subtypes. The robustness of the new method was assessed in seven laboratories and also assessed in ground beef and bean sprout samples. RESULTS: None of the recommended screening primers and probe sets in the four standardized methods could efficiently amplify all the stx2 subtypes because of various mismatches in the primers or the probe sequences. A new primers and probe system adapted from the ISO method, through introducing degenerate bases in primers and probe sequences with an IAC, showed high amplification efficiency and specificity for all known stx2 subtypes in ground beef and bean sprouts samples. The specificity of the new method was assessed in seven laboratories and showed robust and consistent results. CONCLUSIONS: This study provided evidence for Shiga-toxin producing Escherichia coli (STEC) screening method development, and the newly developed primers and probes system should be considered in the revision of the standardized methods. HIGHLIGHTS: None of the recommended screening primer and probe set in the four official methods could efficiently amplify all the stx2 subtypes. A new developed primer and probe set showed high amplification efficiency and specificity for all known stx2 subtypes in fresh ground beef and bean sprouts samples. The newly developed stx2 screening system showed robustness and consistency during interlaboratory study.

Gastric Glomus Tumor: A Clinicopathologic and Immunohistochemical Study of 21 Cases.

Gastric glomus tumors (GGTs) are rare mesenchymal tumors. Most glomus tumors occur in the distal parts of the extremities. Here, we retrospectively analyzed the features of GGTs from two institutions. The histologic and clinical findings of all GGT cases from 2009 to 2018 were reviewed. The most common location was the antrum, the mean age of patients was 49.3 years, and the mean tumor size was 2.1 cm. Microscopically, small, round cell nodules surrounded the expansion of blood vessels in a nest pattern. Immunohistochemical assays for vimentin and smooth muscle actin (SMA) were positive, and assays for H-caldesmon and calponin were partially positive. GGT is rare and easily misdiagnosed before operation. However, immunohistochemistry is useful for the differential diagnosis. The majority of GGTs are benign, and local surgery achieving complete resection is the most effective treatment method.

MHC-DRB1 exon 2 polymorphism and its association with mycoplasma ovipneumonia resistance or susceptibility genotypes in sheep.

Major histocompatibility complex (MHC) polymorphisms are associated with animal and human diseases. However, only a few studies have reported an association between MHC polymorphisms and mycoplasma ovipneumonia (MO). In the present study, three resistance/susceptibility genotypes associated with MO were identified by polymerase chain reaction-restriction fragment length polymorphism genotyping, assessing the clinical and pathological features, and examining the immune factors. The current results showed that MvaI bb and HaeIII ee were dominant genotypes in the susceptible Hu population, while MO-resistant populations, Dorper and D 9 H hybrids, were dominated by the MvaI cc and HaeIII dd genotypes, suggesting that MvaI cc and HaeIII dd genotypes might be associated with the trait of MO resistance. Further, the clinical symptoms and pathological morphology in the susceptibility group infected with MO were more severe than those in the resistant groups infected similarly. The data on the changes in the immune factor responses were utilized to deduce the molecular mechanism underlying the MO resistance/susceptibility. The results showed that the susceptible genotypes promote the inflammatory responses by inducing a high expression of TNFa, IFNc, IL-4, IL-6, and IL-1b, while the resistant genotypes inhibit the inflammatory response by increasing the expression of IL-2 and IL-10 significantly. This finding would provide the theoretical guidance for propagating sheep breeds that are highly resistant to MO.

Neuritin-overexpressing transgenic mice demonstrate enhanced neuroregeneration capacity and improved spatial learning and memory recovery after ischemia-reperfusion injury.

Acute ischemia-reperfusion (IR)-induced brain injury is further exacerbated by a series of slower secondary pathogenic events, including delayed apoptosis due to neurotrophic factor deficiency. Neuritin, a neurotrophic factor regulating nervous system development and plasticity, is a potential therapeutic target for treatment of IR injury. In this study, Neuritin-overexpressing transgenic (Tg) mice were produced by pronuclear injection and offspring with high overexpression used to generate a line with stable inheritance for testing the neuroprotective capacity of Neuritin against transient global ischemia (TGI). Compared to wild-type mice, transgenic mice demonstrated reduced degradation of the DNA repair factor poly [ADP-ribose] polymerase 1 (PARP 1) in the hippocampus, indicating decreased hippocampal apoptosis rate, and a greater number of surviving hippocampal neurons during the first week post-TGI. In addition, Tg mice showed increased expression of the regeneration markers NF-200, synaptophysin, and GAP-43, and improved recovery of spatial learning and memory. Our findings exhibited that the window of opportunity of neural recovery in Neuritin transgenic mice group had a tendency to move ahead after TGI, which indicated that Neuritin can be used as a potential new therapeutic strategy for improving the outcome of cerebral ischemia injury.

The activated newborn neurons participate in enriched environment induced improvement of locomotor function in APP/PS1 mice.

INTRODUCTION: Alzheimer's disease (AD) is an age-related neurodegenerative disorder. One of the pathological features of AD is neuronal loss in brain regions associated with cognition, particularly the hippocampus. An enriched environment (EE) can facilitate neuronal plasticity and improve behaviors such as emotion, motor function, and cognition in AD. METHODS: After APP/PS1 mice were exposed to EE at an early stage (2 months of age), elevated plus maze performance and contextual fear conditioning were tested, and neurogenesis and the extent of activation in the hippocampus were observed. RESULTS: The results showed that, compared with that in the mice that experienced a standard environment, the cognition of the mice exposed to EE, as measured by contextual fear conditioning, was not statistically significant. However, based on their performance in the elevated plus maze, the index was increased in the mice, especially the APP/PS1 mice, exposed to EE. Consistent with the behavioral changes, the APP/PS1 mice exposed to EE showed an increased number of c-Fos-positive neurons and elevated neurogenesis in the dentate gyrus (DG) area. In addition, the activation of newborn neurons did not occur in the other three groups. CONCLUSIONS: These results indicate that the activation of newborn neurons may participate in the improvement of behavioral performance in APP/PS1 mice after EE.

Effect and safety of LCZ696 in the treatment of hypertension: A meta-analysis of 9 RCT studies.

BACKGROUND: LCZ696 has been introduced in patients with hypertension in several trials. Here, we performed a meta-analysis to evaluate the effect and safety of LCZ696 in hypertensive patients. METHODS: PubMed, Embase, the Cochrane Library and ClinicalTrials.gov databases were searched to identify the available randomized controlled trials (RCTs) investigating the effect and safety of LCZ696 in hypertension patients. The last search date was October 31, 2018. RESULTS: Nine RCTs with 6765 subjects were finally included, in which 8 trials compared the effect and safety between LCZ696 and angiotensin receptor antagonists (ARBs). Evidences showed LCZ696, compared with ARBs, achieved a better blood pressure control rate (OR 1.24, 95% CI: 1.14-1.35), specifically, LCZ696 were better at reducing systolic blood pressure [WMD -4.11 mmHg, 95% CI: (-5.13, -3.08) mmHg], diastolic blood pressure [WMD -1.79 mmHg, 95% CI: (-2.22, -1.37) mmHg], mean 24-hour ambulatory systolic blood pressure [WMD -3.24 mmHg, 95% CI: (-4.48, -1.99) mmHg] and mean 24-hour ambulatory diastolic blood pressure [WMD -1.25 mmHg, 95% CI: (-1.81, -0.69) mmHg]. There was no difference in the events of adverse events (risk ratio [RR] 1.01, 95% CI: 0.39-1.09), serious adverse events (RR 0.80, 95% CI: 0.52-1.22) and discontinuation of treatment for any adverse events (RR 0.79, 95% CI: 0.56-1.11) between LCZ696 group and ARB/placebo group, except LCZ696 reduced the rate of headaches (RR 0.69, 95% CI: 0.48-0.99) while increased cough (RR 2.12, 95% CI: 1.11-4.04; P = .02; I = 25%). CONCLUSION: Our finding provides evidence that LCZ 696 was more effective than ARB on blood pressure control and was safe enough in patients with hypertension.