CRISPR editing demonstrates rs10490924 raised oxidative stress in iPSC-derived retinal cells from patients with ARMS2/HTRA1-related AMD.

Genome-wide association studies (GWAS) have identified genetic risk loci for age-related macular degeneration (AMD) on the chromosome 10q26 (Chr10) locus and are tightly linked: the A69S (G>T) rs10490924 single-nucleotide variant (SNV) and the AATAA-rich insertion-deletion (indel, del443/ins54), which are found in the age-related maculopathy susceptibility 2 (ARMS2) gene, and the G512A (G>A) rs11200638 SNV, which is found in the high-temperature requirement A serine peptidase 1 (HTRA1) promoter. The fourth variant is Y402H complement factor H (CFH), which directs CFH signaling. CRISPR manipulation of retinal pigment epithelium (RPE) cells may allow one to isolate the effects of the individual SNV and thus identify SNV-specific effects on cell phenotype. Clustered regularly interspaced short palindromic repeats (CRISPR) editing demonstrates that rs10490924 raised oxidative stress in induced pluripotent stem cell (iPSC)-derived retinal cells from patients with AMD. Sodium phenylbutyrate preferentially reverses the cell death caused by ARMS2 rs10490924 but not HTRA1 rs11200638. This study serves as a proof of concept for the use of patient-specific iPSCs for functional annotation of tightly linked GWAS to study the etiology of a late-onset disease phenotype. More importantly, we demonstrate that antioxidant administration may be useful for reducing reactive oxidative stress in AMD, a prevalent late-onset neurodegenerative disorder.

Sulfonic Acid-Functionalized Graphdiyne for Effective Li-S Battery Separators.

Lithium-sulfur (Li-S) batteries enable a promising high-energy-storage system while facing practical challenges regarding lithium dendrites and lithium polysulfides (LiPSs) shuttling. Herein, a fascinating SO3H-functionalized graphdiyne (SOGDY) was developed by grafting SO3H onto GDY to modify the separator in Li-S batteries. It realizes structure-retained material transformation, that is, SOGDY retains the crystalline all-carbon network and uniform subnanopores from the initial GDY. The abundant SO3H and uniform pores create a rapid Li+ transport relay station, benefit rapid Li+ transport and even lithium deposition, and prevent lithium dendrite growth. The spatial obstruction and strong polar adsorption sites from SO3H effectively inhibit LiPS shuttling. Additionally, SOGDY establishes a fast electron-transfer pathway to facilitate the LiPS conversion. The SOGDY/PP separator exhibited steady cycling at 1 mA cm-2 over 3500 h in the Li∥Li symmetric battery and achieved outstanding low-temperature and high-rate performance in the Li-S battery with a high initial specific capacity of 804.5 mA h g-1 and a final capacity of 504.9 mA h g-1 after 500 cycles at 3 C and -10 °C. This work demonstrates that introducing a stable all-carbon network and uniform functionalized nanopores is an effective strategy to modify the Li-S battery separator.

Long-term vitamin A supplementation in a preclinical mouse model for RhoD190N-associated retinitis pigmentosa.

Retinitis pigmentosa (RP) is caused by one of many possible gene mutations. The National Institutes of Health recommends high daily doses of vitamin A palmitate for RP patients. There is a critical knowledge gap surrounding the therapeutic applicability of vitamin A to patients with the different subtypes of the disease. Here, we present a case report of a patient with RP caused by a p.D190N mutation in Rhodopsin (RHO) associated with abnormally high quantitative autofluorescence values after long-term vitamin A supplementation. We investigated the effects of vitamin A treatment strategy on RP caused by the p.D190N mutation in RHO by exposing Rhodopsin p.D190N (RhoD190N/+) and wild-type (WT) mice to experimental vitamin A-supplemented and standard control diets. The patient's case suggests that the vitamin A treatment strategy should be further studied to determine its effect on RP caused by p.D190N mutation in RHO and other mutations. Our mouse experiments revealed that RhoD190N/+ mice on the vitamin A diet exhibited higher levels of autofluorescence and lipofuscin metabolites compared to WT mice on the same diet and isogenic controls on the standard control diet. Vitamin A supplementation diminished photoreceptor function in RhoD190N/+ mice while preserving cone response in WT mice. Our findings highlight the importance of more investigations into the efficacy of clinical treatments like vitamin A for patients with certain genetic subtypes of disease and of genotyping in the precision care of inherited retinal degenerations.

Par3L, a polarity protein, promotes M1 macrophage polarization and aggravates atherosclerosis in mice via p65 and ERK activation.

Proinflammatory M1 macrophages are critical for the progression of atherosclerosis. The Par3-like protein (Par3L) is a homolog of the Par3 family involved in cell polarity establishment. Par3L has been shown to maintain the stemness of mammary stem cells and promote the survival of colorectal cancer cells. In this study, we investigated the roles of the polar protein Par3L in M1 macrophage polarization and atherosclerosis. To induce atherosclerosis, Apoe-/- mice were fed with an atherosclerotic Western diet for 8 or 16 weeks. We showed that Par3L expression was significantly increased in human and mouse atherosclerotic plaques. In primary mouse macrophages, oxidized low-density lipoprotein (oxLDL, 50 µg/mL) time-dependently increased Par3L expression. In Apoe-/- mice, adenovirus-mediated Par3L overexpression aggravated atherosclerotic plaque formation accompanied by increased M1 macrophages in atherosclerotic plaques and bone marrow. In mouse bone marrow-derived macrophages (BMDMs) or peritoneal macrophages (PMs), we revealed that Par3L overexpression promoted LPS and IFNγ-induced M1 macrophage polarization by activating p65 and extracellular signal-regulated kinase (ERK) rather than p38 and JNK signaling. Our results uncover a previously unidentified role for the polarity protein Par3L in aggravating atherosclerosis and favoring M1 macrophage polarization, suggesting that Par3L may serve as a potential therapeutic target for atherosclerosis.

Fluspirilene exerts an anti-glioblastoma effect through suppression of the FOXM1-KIF20A axis.

Given the infiltrative nature of human glioblastoma (GBM), cocktail drug therapy will remain a vital tool for the treatment of the disease. We investigated fluspirilene, perphenazine, and sulpiride, three classic anti-schizophrenic drugs, as possible anti-GBM agents. The CCK-8 assay demonstrated that fluspirilene possesses the most outstanding anti-GBM effect. We performed molecular mechanisms studies in vitro and an orthotopic xenograft model in mice. Fluspirilene inhibited proliferation and migration in vitro in U87MG and U251 GBM cell lines. Flow cytometry demonstrated that treatment increased apoptosis and cells accumulated in the G2/M phase. Our analysis of publicly available expression data for several cell lines treated with the drug led to the identification of several genes, including KIF20A, that are downregulated by fluspirilene and lead to growth inhibition/apoptosis. We also demonstrated that siRNA knockdown of KIF20A, a member of the kinesin family, attenuated cell proliferation in GBM cells and an orthotopic xenograft model in mice. A regulator of KIF20A, the oncogenic transcription factor FOXM1, was identified using the String database, which harbors protein interaction networks. In fluspirilene-treated cells, FOXM1 protein was decreased, indicating that KIF20A was downregulated in the presence of the drug due to decreased FOXM1 protein. These results demonstrate that fluspirilene is an effective anti-GBM agent that works by suppressing the FOXM1-KIF20A oncogenic axis.

Research on collaborative development mechanism of multiple stakeholders in medical institutions based on rough set.

Reducing doctor-patient conflict is an important part of coordinating doctor-patient disputes and easing doctor-patient relationship, which is conducive to building a harmonious medical environment and promoting the healthy development of medical undertakings. This paper constructs a multi-decision-maker mixed conflict model based on rough set theory, puts forward the matrix operation expression of the conflict degree theory in the Pawlak model, and gives a more objective and scientific evaluation function. Combined with hot issues of doctor-patient conflict, the proposed multi-decision-maker mixed conflict model is applied to doctor-patient conflict, examines the doctor-patient relationship in the medical institution system from multiple internal perspectives, and calculates feasible solutions in the conflict system. The results show that high medical quality, high standardize medication, high institutional efficiency, high staff efficiency, high hospital benefits, high hospital revenue, medium employee development, medium equipment development, or high medical quality, high standardize medication, high institutional efficiency, medium staff efficiency, medium hospital benefits, high hospital revenue, high employee development, and high equipment development are important conditions for building a harmonious medical environment and reducing doctor-patient conflicts.

Dynamic Changes and Effects of H2S, IGF-1, and GH in the Traumatic Brain Injury.

The aim of this study was to examine the expression changes of H2S, IGF-1, and GH in traumatic brain injury (TBI) patients and to detect their neuroprotective functions after TBI. In this study, we first collected cerebrospinal fluid (CSF) and plasma from TBI patients at different times after injury and evaluated the concentrations of H2S, IGF-1, and GH. In vitro studies were using the scratch-induced injury model and cell-cell interaction model (HT22 hippocampal neurons co-cultured with LPS-induced BV2 microglia cells). In vivo studies were using the controlled cortical impact (CCI) model in mice. Cell viability was assessed by CCK-8 assay. Pro-inflammatory cytokines expression was determined by qRT-PCR, ELISA, and nitric oxide production. Western blot was performed to assess the expression of CBS, CSE, IGF-1, and GHRH. Moreover, the recovery of TBI mice was evaluated for behavioral function by applying the modified Neurological Severity Score (mNSS), the Rotarod test, and the Morris water maze. We discovered that serum H2S, CSF H2S, and serum IGF-1 concentrations were all adversely associated with the severity of the TBI, while the concentrations of IGF-1 and GH in CSF and GH in the serum were all positively related to TBI severity. Experiments in vitro and in vivo indicated that treatment with NaHS (H2S donor), IGF-1, and MR-409 (GHRH agonist) showed protective effects after TBI. This study gives novel information on the functions of H2S, IGF-1, and GH in TBI.

Metal-N Coordination in Lithium-Sulfur Batteries: Inhibiting Catalyst Passivation.

Lithium-sulfur (Li-S) batteries exhibit great potential as the next-generation energy storage techniques. Application of catalyst is widely adopted to accelerate the redox kinetics of polysulfide conversion reactions and improve battery performance. Although significant attention has been devoted to seeking new catalysts, the problem of catalyst passivation remains underexplored. Herein, we find that metal-N coordination has a previously overlooked role in preventing the catalyst passivation. In the case of nickel, the Ni catalyst reacts with S8 to produce NiSx compounds on the surface, leading to catalyst passivation and slow the kinetics of LiPSs conversion. In contrast, when Ni is coordinated with N (typically Ni-N4), S8 remains stable on the surface. The Ni-N4 exhibits excellent resistance to passivation and rapid kinetics of LiPSs conversion. Consequently, the sulfur cathode with Ni-N4 exhibits a high rate capability of 604.11 mAh g-1 at 3 C and maintains a low capacity decay rate of 0.046 % per cycle over 1000 cycles at 2 C. Furthermore, preventing S passivation in M-N coordination applies not only to Ni-N4 but also to various coordination numbers and transition metals. This study reveals a new aspect of metal-N coordination in inhibiting catalyst passivation, improving our understanding of catalysts in Li-S batteries.

Preliminary identification of soil fungi for the degradation of polyurethane film.

Polyurethane (PU) is a versatile plastic that boasts high environmental resistance. The biodegradation of PU has become a hot topic of research aimed at finding ways to potentially solve PU pollutants. Identifying microorganisms capable of efficiently degrading PU plastics is pivotal for the development of a green recycling process for PU. This study aimed to isolate and characterize PU-degrading fungi from the soil of a waste transfer station in Luoyang, China. We isolated four different fungal strains from the soil. Among the isolates, the P2072 and P2073 strains were identified as Rhizopus oryzae (internal transcribed spacer identity, 99.66%) and Alternaria alternata (internal transcribed spacer identity, 99.81%), respectively, through microscopic, morphologic, as well as 18S rRNA sequencing. The degradation ability of strains P2072 and P2073 was analyzed through measurement of weight loss, and they exhibited a degradation rate of 2.7% and 3.3%, respectively, for the PU films after 2 months' growth in mineral salt medium (MSM) with PU films as the sole carbon source. In addition, the P2073 strain exhibited protease activity in the presence of PU. To our knowledge, R. oryzae has never been reported as a PU-degrading fungus. This study provides a new perspective on the biodegradation of PU.

Development of multidimensional water poverty in the Yangtze River Economic Belt, China.

As a basic natural and strategic resource, water is of great significance to the sustainable development of economies and societies. Owing to population growth, industrialization, the acceleration of urbanization, and global warming, water poverty is gradually increasing in some parts of the world. Effectively assessing water poverty from different dimensions is still a serious challenge for global water resources planning. This paper establishes a framework of multidimensional water poverty (MWP) from six dimensions: water management, water technology, water assets, water welfare, water resources, and water environment. The measurement model of MWP is built based on the Back Propagation Neural Network (BPNN), and the Spatial Correlation Analysis tool is used to visualize the spatial effects of MWP. The Yangtze River Economic Belt (YREB) was used as a case study and the main factors affecting the MWP of the YREB were determined by the Geodetector. When analyzing the results the following observations were made: (1) In terms of time distribution, the level of MWP in the YREB has gradually increased, and the poverty gap between the upper reaches, as well as the middle and lower reaches, shows an increasing trend. (2) With respect to spatial distribution, there is a continuously increasing agglomeration effect that shows a gradient-increasing distribution pattern of "West-Central-East." (3) The MWP in the YREB is mainly affected by these indicators in the three dimensions consisting of water resources, water technology, and water management. Specifically, R&D expenditure as a percentage of GDP, the proportion of water-saving irrigation area in the cultivable land area, the urban daily wastewater treatment capacity, the land surface water resources per capita, and the groundwater resources per capita play an important role in the MWP. Based on the above findings, targeted policy recommendations are proposed to alleviate the MWP in the YREB.

[Latest Findings on the Role of CD47 in Tumor Immune Evasion and Related Targeted Therapies].

CD47 is an immunoglobulin that is overexpressed on the surface of a variety of cancer cells. CD47 forms a signaling complex with signal regulatory protein alpha (SIRPα), prompting the escape of cancer cells from macrophage-mediated phagocytosis. In recent years, CD47 has been shown to be highly expressed in many types of solid tumors and is associated with poor prognosis in patients. More and more studies have shown that inhibition of the CD47-SIRPα signaling pathway can promote adaptive immune responses and enhance the phagocytosis of tumor cells by macrophages. Humanized anti-CD47 IgG4 monoclonal antibody has been studied in clinical trials for the treatment of a variety of advanced solid tumors and lymphomas, demonstrating a sound safety profile and achieving partial remission in some patients. In this review we discuss the structure and function of CD47 and the mechanism of CD47 regulation in tumors, summarize the research progress in therapeutic antibody drugs targeting CD47 and a bottleneck in research that targeted drugs are more prone to result in serious adverse effects, and evaluated the potential of the applying CD47-SIRPα signaling pathway in anti-cancer therapy.

Antiatherosclerotic effect of dehydrocorydaline on ApoE-/- mice: inhibition of macrophage inflammation.

Despite improvements in cardiovascular disease (CVD) outcomes by cholesterol-lowering statin therapy, the high rate of CVD is still a great concern worldwide. Dehydrocorydaline (DHC) is an alkaloidal compound isolated from the traditional Chinese herb Corydalis yanhusuo. Emerging evidence shows that DHC has anti-inflammatory and antithrombotic benefits, but whether DHC exerts any antiatherosclerotic effects remains unclear. Our study revealed that intraperitoneal (i.p.) injection of DHC in apolipoprotein E-deficient (ApoE-/-) mice not only inhibited atherosclerosis development but also improved aortic compliance and increased plaque stability. In addition, DHC attenuated systemic and vascular inflammation in ApoE-/- mice. As macrophage inflammation plays an essential role in the pathogenesis of atherosclerosis, we next examined the direct effects of DHC on bone marrow-derived macrophages (BMDMs) in vitro. Our RNA-seq data revealed that DHC dramatically decreased the levels of proinflammatory gene clusters. We verified that DHC significantly downregulated proinflammatory interleukin (IL)-1ß and IL-18 mRNA levels in a time- and concentration-dependent manner. Furthermore, DHC decreased lipopolysaccharide (LPS)-induced inflammation in BMDMs, as evidenced by the reduced protein levels of CD80, iNOS, NLRP3, IL-1ß, and IL-18. Importantly, DHC attenuated LPS-induced activation of p65 and the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Thus, we conclude that DHC ameliorates atherosclerosis in ApoE-/- mice by inhibiting inflammation, likely by targeting macrophage p65- and ERK1/2-mediated pathways.

A Dpagt1 Missense Variant Causes Degenerative Retinopathy without Myasthenic Syndrome in Mice.

Congenital disorders of glycosylation (CDG) are a heterogenous group of primarily autosomal recessive mendelian diseases caused by disruptions in the synthesis of lipid-linked oligosaccharides and their transfer to proteins. CDGs usually affect multiple organ systems and vary in presentation, even within families. There is currently no cure, and treatment is aimed at ameliorating symptoms and improving quality of life. Here, we describe a chemically induced mouse mutant, tvrm76, with early-onset photoreceptor degeneration. The recessive mutation was mapped to Chromosome 9 and associated with a missense mutation in the Dpagt1 gene encoding UDP-N-acetyl-D-glucosamine:dolichyl-phosphate N-acetyl-D-glucosaminephosphotransferase (EC 2.7.8.15). The mutation is predicted to cause a substitution of aspartic acid with glycine at residue 166 of DPAGT1. This represents the first viable animal model of a Dpagt1 mutation and a novel phenotype for a CDG. The increased expression of Ddit3, and elevated levels of HSPA5 (BiP) suggest the presence of early-onset endoplasmic reticulum (ER) stress. These changes were associated with the induction of photoreceptor apoptosis in tvrm76 retinas. Mutations in human DPAGT1 cause myasthenic syndrome-13 and severe forms of a congenital disorder of glycosylation Type Ij. In contrast, Dpagt1tvrm76 homozygous mice present with congenital photoreceptor degeneration without overt muscle or muscular junction involvement. Our results suggest the possibility of DPAGT1 mutations in human patients that present primarily with retinitis pigmentosa, with little or no muscle disease. Variants in DPAGT1 should be considered when evaluating cases of non-syndromic retinal degeneration.

Spatial-temporal variation and driving factors decomposition of agricultural grey water footprint in China.

The management of agricultural water pollution is crucial to alleviate the water crisis and promote regional sustainable development. Therefore, it is necessary to clarify the spatial-temporal variation characteristics of the agricultural grey water footprint (GWF) and accurately identify its main influencing factors, aiming at formulating differentiated regional management strategies. Based on this, the agricultural GWFs of 31 provincial regions in China from 2011 to 2019 were firstly calculated, and then the spatial-temporal variation characteristics of agricultural GWF were analyzed using the ArcGIS software and Standard Deviational Ellipse (SDE) method. Finally, the Generalized Divisia Index Method (GDIM) was creatively introduced to decompose the factors of agricultural GWF change and their respective contributions at the national and provincial levels. The main results are as follow: (1) Agricultural GWF in China decreased on the whole and showed significant provincial differences. Among them, the agricultural GWF of Henan Province was the largest while that of Shanghai City was the smallest. Compared with 2011, most provinces saw a decrease in agricultural GWF in 2019 while Yunnan, Tibet, Qinghai, Ningxia and Xinjiang Provinces achieved growth. (2) Areas with higher agricultural GDP generally had higher agricultural GWF. The spatial distribution of agricultural GWF and breeding GWF generally tended to be consistent, with the lower value in northwest and southeast of China and higher value in the northeast and southwest of China. Meanwhile, the mean center of SDE of agricultural GWF was located in Henan Province from 2011 to 2018, and shifted to Shaanxi Province in 2019, showing a slight northwest shift. (3) Agricultural GWF intensity and agricultural GDP had the largest restraining effect and driving effect on agricultural GWF growth, respectively. Additionally, China has achieved decoupling between agricultural GWF and agricultural GDP, reflecting that the patterns of agricultural production and consumption have become more sustainable. The findings of this study can provide important decision-making insights for agricultural water pollution management and industry adjustment.

The circular RNA circSLC7A11 functions as a mir-330-3p sponge to accelerate hepatocellular carcinoma progression by regulating cyclin-dependent kinase 1 expression.

BACKGROUND: Circular RNAs (circRNAs), which are endogenous non-coding RNAs, are associated with various biological processes including development, homeostatic maintenance, and pathological responses. Accumulating evidence has implicated non-coding RNAs in cancer progression, and the role of circRNAs in particular has drawn wide attention. However, circRNA expression patterns and functions in hepatocellular carcinoma (HCC) remain poorly understood. METHODS: CircRNA sequencing was performed to screen differentially expressed circRNAs in HCC. Northern blotting, quantitative real-time polymerase chain reaction, nucleocytoplasmic fractionation, and fluorescence in situ hybridization analyses were conducted to evaluate the expression and localization of circSLC7A11 in HCC tissues and cells. CircSLC7A11 expression levels were modified in cultured HCC cell lines to explore the association between the expression of circSLC7A11 and the malignant behavior of these cells using several cell-based assays. The modified cells were implanted into immunocompetent nude mice to assess tumor growth and metastasis in vivo. We applied bioinformatics methods, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays to explore the mechanisms of circSLC7A11 in HCC. RESULTS: CircSLC7A11 (hsa_circ_0070975) was conserved and dramatically overexpressed in HCC tissues and cells. HCC patients showing high circSLC7A11 expression had worse prognoses. Our in vitro and in vivo experiments showed that circSLC7A11 markedly accelerated HCC progression and metastasis through the circSLC7A11/miR-330-3p/CDK1 axis. CONCLUSIONS: The acceleration of HCC progression and metastasis by circSLC7A11 through the circSLC7A11/miR-330-3p/CDK1 axis suggests that circSLC7A11 is a potential novel diagnostic and therapeutic target for HCC treatment.

Self-Supervised Joint Learning Fault Diagnosis Method Based on Three-Channel Vibration Images.

The accuracy of bearing fault diagnosis is of great significance for the reliable operation of rotating machinery. In recent years, increasing attention has been paid to intelligent fault diagnosis techniques based on deep learning. However, most of these methods are based on supervised learning with a large amount of labeled data, which is a challenge for industrial applications. To reduce the dependence on labeled data, a self-supervised joint learning (SSJL) fault diagnosis method based on three-channel vibration images is proposed. The method combines self-supervised learning with supervised learning, makes full use of unlabeled data to learn fault features, and further improves the feature recognition rate by transforming the data into three-channel vibration images. The validity of the method was verified using two typical data sets from a motor bearing. Experimental results show that this method has higher diagnostic accuracy for small quantities of labeled data and is superior to the existing methods.

Mouse Models of Achromatopsia in Addressing Temporal "Point of No Return" in Gene-Therapy.

Achromatopsia is characterized by amblyopia, photophobia, nystagmus, and color blindness. Previous animal models of achromatopsia have shown promising results using gene augmentation to restore cone function. However, the optimal therapeutic window to elicit recovery remains unknown. Here, we attempted two rounds of gene augmentation to generate recoverable mouse models of achromatopsia including a Cnga3 model with a knock-in stop cassette in intron 5 using Easi-CRISPR (Efficient additions with ssDNA inserts-CRISPR) and targeted embryonic stem (ES) cells. This model demonstrated that only 20% of CNGA3 levels in homozygotes derived from target ES cells remained, as compared to normal CNGA3 levels. Despite the low percentage of remaining protein, the knock-in mouse model continued to generate normal cone phototransduction. Our results showed that a small amount of normal CNGA3 protein is sufficient to form "functional" CNG channels and achieve physiological demand for proper cone phototransduction. Thus, it can be concluded that mutating the Cnga3 locus to disrupt the functional tetrameric CNG channels may ultimately require more potent STOP cassettes to generate a reversible achromatopsia mouse model. Our data also possess implications for future CNGA3-associated achromatopsia clinical trials, whereby restoration of only 20% functional CNGA3 protein may be sufficient to form functional CNG channels and thus rescue cone response.

Reduced expression of proteolipid protein 2 increases ER stress-induced apoptosis and autophagy in glioblastoma.

Proteolipid protein 2 (PLP2) is an integral ion channel membrane protein of the endoplasmic reticulum. The protein has been shown to be highly expressed in many cancer types, but its importance in glioma progression is poorly understood. Using publicly available datasets (Rembrandt, TCGA and CGGA), we found that the expression of PLP2 was significantly higher in high-grade gliomas than in low-grade gliomas. We confirmed these results at the protein level through IHC staining of high-grade (n = 56) and low-grade glioma biopsies (n = 16). Kaplan-Meier analysis demonstrated that increased PLP2 expression was associated with poorer patient survival. In functional experiments, siRNA and shRNA PLP2 knockdown induced ER stress and increased apoptosis and autophagy in U87 and U251 glioma cell lines. Inhibition of autophagy with chloroquine augmented apoptotic cell death in U87- and U251-siPLP2 cells. Finally, intracranial xenografts derived from U87- and U251-shPLP2 cells revealed that loss of PLP2 reduced glioma growth in vivo. Our results therefore indicate that increased PLP2 expression promotes GBM growth and that PLP2 represents a potential future therapeutic target.

An FRMD4B variant suppresses dysplastic photoreceptor lesions in models of enhanced S-cone syndrome and of Nrl deficiency.

Photoreceptor dysplasia, characterized by formation of folds and (pseudo-)rosettes in the outer retina, is associated with loss of functional nuclear receptor subfamily 2 group E member 3 (NR2E3) and neural retina leucine-zipper (NRL) in both humans and mice. A sensitized chemical mutagenesis study to identify genetic modifiers that suppress photoreceptor dysplasia in Nr2e3rd7mutant mice identified line Tvrm222, which exhibits a normal fundus appearance in the presence of the rd7 mutation. The Tvrm222 modifier of Nr2e3rd7/rd7 was localized to Chromosome 6 and identified as a missense mutation in the FERM domain containing 4B (Frmd4b) gene. The variant is predicted to cause the substitution of a serine residue 938 with proline (S938P). The Frmd4bTvrm222 allele was also found to suppress outer nuclear layer (ONL) rosettes in Nrl-/- mice. Fragmentation of the external limiting membrane (ELM), normally observed in rd7 and Nrl-/-mouse retinas, was absent in the presence of the Frmd4bTvrm222 allele. FRMD4B, a binding partner of cytohesin 3, is proposed to participate in cell junction remodeling. Its biological function in photoreceptor dysplasia has not been previously examined. In vitro experiments showed that the FRMD4B938P variant fails to be efficiently recruited to the cell surface upon insulin stimulation. In addition, we found a reduction in protein kinase B phosphorylation and increased levels of cell junction proteins, Catenin beta 1 and tight junction protein 1, associated with the cell membrane in Tvrm222 retinas. Taken together, this study reveals a critical role of FRMD4B in maintaining ELM integrity and in rescuing morphological abnormalities of the ONL in photoreceptor dysplasia.

An evolutionary game analysis of governments' decision-making behaviors and factors influencing watershed ecological compensation in China.

As a way to coordinate the interests of multi-government and solve the problem of transboundary water pollution, watershed ecological compensation system has been promoted in China. It is necessary to understand the influencing factors of watershed ecological compensation from the perspective of how interactions occur between different governments. This paper analyses the interaction among upstream governments, downstream governments and the central government in the Eastern Route of South-to-North Water Transfer Project, using evolutionary game theory. In particular, how ecological benefits are distributed between upstream and downstream governments is analyzed. Simultaneously, numerical simulation is used to analyze the effects of influencing factors on governments' behaviors. The results show that: (1) the initial willingness of governments to corporate affect their final behaviors; (2) upstream and downstream governments cannot spontaneously cooperate to implement watershed ecological compensation system without supervision of the central government; (3) opportunity costs only have a significant impact on upstream governments; (4) punishment on downstream governments can effectively influence the behaviors of governments at all levels; (5) high ecological compensation fee improve downstream governments' willness not to pay; (6) upstream governments get about 78% of ecological benefits due to the implementation of watershed ecological compensation system.