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Cisplatin (CDDP)-based chemotherapy is the first-line treatment for muscle-invasive and metastatic bladder cancer, yet most patients rapidly develop resistance. N6-methyladenosine (m6A) methylation is a pervasive RNA modification, and its specific role and potential mechanism in the regulation of CDDP chemosensitivity in bladder cancer remain unclear. Furthermore, studies have not yet fully elucidated whether circular RNA (circRNA) can directly regulate m6A modification of mRNA. Here we report upregulation of a novel circRNA, hsa_circ_0008399 (circ0008399), by eukaryotic translation initiation factor 4A3 (EIF4A3) in bladder cancer tissues and cell lines. Functionally, circ0008399 inhibited apoptosis of bladder cancer cells. Mechanistically, circ0008399 bound Wilms' tumor 1–associating protein (WTAP) to promote formation of the WTAP/METTL3/METTL14 m6A methyltransferase complex. Circ0008399 increased expression of TNF alpha-induced protein 3 (TNFAIP3) by increasing its mRNA stability in an m6A-dependent manner. In patients with bladder cancer, high expression of circ0008399 and WTAP was associated with poor outcomes. Importantly, activation of the circ0008399/WTAP/TNFAIP3 pathway decreased bladder cancer chemosensitivity to CDDP, and targeting the circ0008399/WTAP/TNFAIP3 axis enhanced the CDDP efficacy. Collectively, these findings give novel insights into circRNA-mediated regulation of m6A modifications and provide potential therapeutic targets for bladder cancer.Significance:A newly characterized circRNA circ0008399 binds WTAP to modulate expression of target RNA through m6A modification and reduce cisplatin sensitivity in bladder cancer, implicating the potential therapeutic value of targeting this axis.

Cisplatin (CDDP)-based chemotherapy is the first-line treatment for muscle-invasive and metastatic bladder cancer, yet most patients rapidly develop resistance. N6-methyladenosine (m6A) methylation is a pervasive RNA modification, and its specific role and potential mechanism in the regulation of CDDP chemosensitivity in bladder cancer remain unclear. Furthermore, studies have not yet fully elucidated whether circular RNA (circRNA) can directly regulate m6A modification of mRNA. Here we report upregulation of a novel circRNA, hsa_circ_0008399 (circ0008399), by eukaryotic translation initiation factor 4A3 (EIF4A3) in bladder cancer tissues and cell lines. Functionally, circ0008399 inhibited apoptosis of bladder cancer cells. Mechanistically, circ0008399 bound Wilms' tumor 1–associating protein (WTAP) to promote formation of the WTAP/METTL3/METTL14 m6A methyltransferase complex. Circ0008399 increased expression of TNF alpha-induced protein 3 (TNFAIP3) by increasing its mRNA stability in an m6A-dependent manner. In patients with bladder cancer, high expression of circ0008399 and WTAP was associated with poor outcomes. Importantly, activation of the circ0008399/WTAP/TNFAIP3 pathway decreased bladder cancer chemosensitivity to CDDP, and targeting the circ0008399/WTAP/TNFAIP3 axis enhanced the CDDP efficacy. Collectively, these findings give novel insights into circRNA-mediated regulation of m6A modifications and provide potential therapeutic targets for bladder cancer. Significance: A newly characterized circRNA circ0008399 binds WTAP to modulate expression of target RNA through m6A modification and reduce cisplatin sensitivity in bladder cancer, implicating the potential therapeutic value of targeting this axis.

Background This study sought to investigate incidence and risk factors for acute kidney injury (AKI) in hospitalized COVID-19. Methods In this retrospective study, we enrolled 823 COVID-19 patients with at least two evaluations of renal function during hospitalization from four hospitals in Wuhan, China between February 2020 and April 2020. Clinical and laboratory parameters at the time of admission and follow-up data were recorded. Systemic renal tubular dysfunction was evaluated via 24-h urine collections in a subgroup of 55 patients. Results In total, 823 patients were enrolled (50.5% male) with a mean age of 60.9 ± 14.9 years. AKI occurred in 38 (40.9%) ICU cases but only 6 (0.8%) non-ICU cases. Using forward stepwise Cox regression analysis, we found eight independent risk factors for AKI including decreased platelet level, lower albumin level, lower phosphorus level, higher level of lactate dehydrogenase (LDH), procalcitonin, C-reactive protein (CRP), urea, and prothrombin time (PT) on admission. For every 0.1 mmol/L decreases in serum phosphorus level, patients had a 1.34-fold (95% CI 1.14–1.58) increased risk of AKI. Patients with hypophosphatemia were likely to be older and with lower lymphocyte count, lower serum albumin level, lower uric acid, higher LDH, and higher CRP. Furthermore, serum phosphorus level was positively correlated with phosphate tubular maximum per volume of filtrate (TmP/GFR) (Pearson r = 0.66, p

Objective To observe the role of connective tissue growth factor (CTGF) and collagen synthesis in anti-pulmonary fibrosis (PF) by Kiwi fruit essence(unsaturated fatty acid of actinidia chinesis planch seed oil)in rats. Methods Sixty male SD rats were randomly divided into control group, model group, Kiwi fruit essence (60, 120, 240 mg/kg) treatment groups, and 5 mg/kg prednisone acetate group, with 10 animals in each group. Rats in control group were intratracheally administered with 9 g/L sodium chloride solution, and animals in other groups were intratracheally administered with bleomycin A5 to establish PF model. From the second day on, rats in the latter 4 groups were intragastrically treated with Kiwi fruit essence of 60, 120 and 240 mg/kg and prednisone acetate of 5 mg/kg, respectively. Rats in control and model groups were treated with 9 g/L sodium chloride solution once a day. All rats were sacrificed on day 28, and then pulmonary tissues were removed. The extent of PF lesions were evaluated using HE and Masson staining. The contents of hydroxyproline (HYP) were measured by a commercial kit. The mRNA expressions of CTGF and α-smooth muscle actin (α-SMA) in pulmonary tissues was detected by quantitative real-time PCR. The protein expressions of CTGF, α-SMA, collagen type 1 (Col1) and Col3 were measured by Western blotting. The protein levels of CTGF were analyzed using immunohistochemical staining. Results Compared with the model group, the alveolitis and PF extent in 60, 120, 240 mg/kg Kiwi fruit essence treatment groups as well as 5 mg/kg prednisone acetate group were significantly alleviated, and the content of HYP and the expression of CTGF, α-SMA, Col1 and Col3 decreased. The changes of above indicators were dose-dependent among the (60, 120, 240) mg/kg Kiwi fruit essence treatment groups. Moreover, the above indicators were found higher in (60, 120) mg/kg Kiwi fruit essence treatment groups than those in 5 mg/kg prednisone acetate group, which, however, showed no significantly difference between 240 mg/kg Kiwi fruit essence treatment group and 5 mg/kg prednisone acetate group. Conclusion Kiwi fruit essence down-regulates CTGF expression and decreases the levels of α-SMA, leading to inhibition of Col1 and Col3 synthesis and alleviation of PF.

Aim: Recovery of damaged mucosal surfaces following inflammatory insult requires diverse regenerative mechanisms that remain poorly defined. Previously, we demonstrated that the reparative actions of Trefoil Factor 3 (TFF3) depend upon the enigmatic receptor, leucine rich repeat and immunoglobulin-like domain containing nogo receptor 2 (LINGO2). This study examined the related orphan receptor LINGO3 in the context of intestinal tissue damage to determine whether LINGO family members are generally important for mucosal wound healing and maintenance of the intestinal stem cell (ISC) compartment needed for turnover of mucosal epithelium.Methods and Results: We find that LINGO3 is broadly expressed on human enterocytes and sparsely on discrete cells within the crypt niche, that contains ISCs. Loss of function studies indicate that LINGO3 is involved in recovery of normal intestinal architecture following dextran sodium sulfate (DSS)-induced colitis, and that LINGO3 is needed for therapeutic action of the long acting TFF2 fusion protein (TFF2-Fc), including a number of signaling pathways critical for cell proliferation and wound repair. LINGO3-TFF2 protein-protein interactions were relatively weak however and LINGO3 was only partially responsible for TFF2 induced MAPK signaling suggesting additional un-identified components of a receptor complex. However, deficiency in either TFF2 or LINGO3 abrogated budding/growth of intestinal organoids and reduced expression of the intestinal ISC gene leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), indicating homologous roles for these proteins in tissue regeneration, possibly via regulation of ISCs in the crypt niche.Conclusion: We propose that LINGO3 serves a previously unappreciated role in promoting mucosal wound healing.

Maize is a globally valuable commodity and one of the most extensively studied genetic model organisms. However, we know surprisingly little about the extent and potential utility of the genetic variation found in the wild relatives of maize. Here, we characterize a high-density genomic variation map from 744 genomes encompassing maize and all wild taxa of the genus Zea, identifying over 70 million single nucleotide polymorphisms (SNPs) and nearly 9 million Insertion/Deletion (InDel) polymorphisms. The variation map reveals evidence of selection within taxa displaying novel adaptations to traits such as waterlogging, perenniality and regrowth. We focus in detail on adaptive alleles in highland teosinte and temperate maize and highlight the key role of flowering time related pathways in highland and high latitude adaptation. To show how this data can identify useful genetic variants, we generated and characterized novel mutant alleles for two flowering time candidate genes. This work provides the most extensive sampling to date of the genetic diversity of the genus Zea, resolving questions on evolution and identifying adaptive variants for direct use in modern breeding.

The pitch-based activated carbon fibers with nickel sulfide nanoparticles (ACF/NiS) were designed by in situ polymerization of ethylene tar with the addition of nickel nitrate followed by melt spinning, stabilization, carbonization, steam activation, and vulcanization processes. The ACF/NiS with hierarchical pore structure and abundant active sites was used as an anode material to improve Coulombic efficiency and increase capacity of potassium-ion batteries (PIBs). The results showed the obtained ACF/NiS with excellent specific surface area of 1552 m2 g-1 and high mesopore volume contribution of 38%, which delivered a high initial Coulombic efficiency of 84.22%, a high capacity of 292.5 mAh g-1, and retained 95.7% capacity retention after 200 cycles at 0.5 A g-1 current density. The NiS provided abundant active sites for the adsorption of potassium-ion, and the rich hierarchical structure shortened the electrolyte penetration path and expanded the storage space of potassium-ion, making it easier to store potassium-ion inside the ACF/NiS anode to obtain a better performance. This work presented one strategy for designing the hierarchical pore structure of pitch-based ACF to boost the capacity storage of PIBs and revealed that ACF-based carbon materials served as potential anodes for high-performance PIBs.

Introduction Acute kidney injury (AKI) in coronavirus disease 2019 (COVID-19) patients is associated with poor prognosis. Early prediction and intervention of AKI are vital for improving clinical outcome of COVID-19 patients. As lack of tools for early AKI detection in COVID-19 patients, this study aimed to validate the USCD-Mayo risk score in predicting hospital-acquired AKI in an extended multi-center COVID-19 cohort. Methods Five hundred seventy-two COVID-19 patients from Wuhan Tongji Hospital Guanggu Branch, Wuhan Leishenshan Hospital, and Wuhan No. Ninth Hospital was enrolled for this study. Patients who developed AKI or reached an outcome of recovery or death during the study period were included. Predictors were evaluated according to data extracted from medical records. Results Of all patients, a total of 44 (8%) developed AKI. The UCSD-Mayo risk score achieved excellent discrimination in predicting AKI with the C-statistic of 0.88 (95%CI: 0.84–0.91). Next, we determined the UCSD-Mayo risk score had good overall performance (Nagelkerke R2 = 0.32) and calibration in our cohort. Further analysis showed that the UCSD-Mayo risk score performed well in subgroups defined by gender, age, and several chronic comorbidities. However, the discrimination of the UCSD-Mayo risk score in ICU patients and patients with mechanical ventilation was not good which might be resulted from different risk factors of these patients. Conclusions We validated the performance of UCSD-Mayo risk score in predicting hospital-acquired AKI in COVID-19 patients was excellent except for patients from ICU or patients with mechanical ventilation.

Introduction Familial IgA nephropathy (IgAN) has been widely reported. However, its clinicohistologic characteristics and long-term prognosis are not clear. Methods A total of 348 familial IgAN cases from 167 independent families were recruited and their clinicohistologic characteristics as well as lifetime risk of end-stage renal disease (ESRD) were compared to 1116 sporadic IgAN patients from the same geographic region. Results Of all familial IgAN patients, 60 (17%) came from 32 single-generation (SG; all affected individuals are siblings) families, whereas 286 (82%) came from 134 multiple-generation (MG; affected individuals were present in at least 2 consecutive generations) families. The lifetime ESRD risk was significantly higher in familial patients than sporadic ones after adjusting by gender (hazard ratio [HR]=1.40, 95% confidence interval [CI]: 1.12–1.74, P = 0.004), with 5 years younger in median ESRD age (60 years vs. 65 years in familial and sporadic cases separately). Interestingly, among familial patients, we found cases from SG families (vs. MG families: HR = 2.62, 95% CI: 1.59–4.31, P < 0.001) or with early onset (onset age, Graphical abstract

The dissimilar self-piercing riveted (SPR) joints between aluminium-lithium alloy (AL1420) and titanium (TA1) sheets were investigated. The effects of the overlap form and rivet hardness on the forming structures, quasi-static and fatigue characteristics of the considered dissimilar joints were analysed systematically. A new curve-fitting method was adopted to fit the fatigue data of SPR joints. The results show that the potential weak areas in the forming structures could be changed using different overlap forms or rivet hardness. The overlap form for the dissimilar joints plays a more important role on the joint strength compared to the rivet hardness, but has little influence on the energy absorption. The fatigue property of the dissimilar joints is improved with the rivet hardness increased and the joints taken TA1 as the locked sheet possess a better fatigue life. The rivet hardness presents an obvious influence on the fatigue fracture path. The forming structures of the dissimilar joints are significantly affected by the overlap forms, which finally results in the fatigue fracture originated in different initiation sites.

Ear length (EL), which is controlled by quantitative trait loci (QTLs), is an important component of grain yield and as such is a key target trait in maize breeding. However, very few EL QTLs have been cloned, and their molecular mechanisms are largely unknown. Here, using a genome wide association study (GWAS), we identified a QTL, YIGE1, which encodes an unknown protein that regulates EL by affecting pistillate floret number. Overexpression of YIGE1 increased female inflorescence meristem (IM) size, increased EL and kernel number per row (KNPR), and thus enhanced grain yield. By contrast, CRISPR/Cas9 knockout and Mutator insertion mutant lines of YIGE1 displayed decreased IM size and EL. A single-nucleotide polymorphism (SNP) located in the regulatory region of YIGE1 had a large effect on its promoter strength, which positively affected EL by increasing gene expression. Further analysis shows that YIGE1 may be involved in sugar and auxin signal pathways to regulate maize ear development, thus affecting IM activity and floret production in maize inflorescence morphogenesis. These findings provide new insights into ear development and will ultimately facilitate maize molecular breeding.

Accumulating evidence has revealed that the dysregulation of circular RNAs (circRNAs) plays crucial roles in the occurrence and progression of cancers. However, the aberrant expression profile and dysfunction of circRNAs in non-small cell lung cancer (NSCLC) have not been fully explored. Herein, we discovered that a circRNA, hsa_circ_0001666 (circ0001666), was highly expressed in NSCLC tissues and cell lines, and it was positively correlated with NSCLC tumor pathological grade and lymph node metastasis. Moreover, Kaplan-Meier survival analysis implied that NSCLC patients with high circ0001666 expression were negatively correlated with favorable survival. Functionally, circ0001666 could promote migration and invasion of NSCLC cells

In the past, H2O2 has been used as an oxidant when Ti-based materials are used as catalysts at ambient conditions. However, H2O2 suffers from high cost and safety concerns. Therefore, replacing H2O2 with O2 has been highly desired. In this study, a Ti-based bi-MOF, MIL-125(Ti)@NH2-MIL-125(Ti) has been synthesized through the internal extended growth of MIL-125(Ti) on NH2-MIL-125(Ti). This Ti-based bi-MOF performed in sequence to synergistically catalyze the oxidative desulfurization (ODS) reaction with O2. In this bi-MOF catalyst, MIL-125(Ti) is partly embedded and well distributed on the surface of NH2-MIL-125(Ti). NH2-MIL-125(Ti) serves as a catalyst for the production of H2O2 from O2/methanol under visible light, while MIL-125(Ti) serves as an ODS catalyst. The ODS over MIL-125(Ti) is the most effective as the in situ generated H2O2 could be used fully, and the consumed H2O2 (ODS reaction) also promotes further H2O2 production through the Le Chatelier's principle. MIL-125(Ti) and NH2-MIL-125(Ti) exist in close proximity in the bi-MOF material, which leads to an increase in the catalytic efficiency by 2.5-fold in comparison to that obtained from their physical mixture.

As a new type of gear transmission developed in recent years, curve-face gear transmission has not appeared before. In order to solve the problem of root bending strength of the eccentric straight and helical curve face gear, a calculating method of the tooth root bending strength was proposed. According to the principle of space meshing, differential geometry and design of machinery, the parametric equations of pitch curve was obtained, the pressure angle and the contact ratio in the meshing process were derived. The plane equivalent pitch curve was obtained, and the formula for calculating the equivalent tooth form factor and the equivalent stress correction factor was acquired. The calculation method of the bending strength of the gear pair was established, and the influence of the basic structural parameters on the bending stress was also analyzed in detail. The position of the stress hazard of the eccentric curve-face gear was determined. Through the finite element analysis and transmission experiment, the accuracy of the calculation method of strength of the gear pair was verified.

The detection of emerging trends is of great interest to many stakeholders such as government and industry. Previous research focused on the machine learning, network analysis and time series analysis based on the bibliometrics data and made a promising progress. However, these approaches inevitably have time delay problems. For the reason that leader papers of "emerging topics" share the similar characters with the "cover papers", this study present a novel approach to translate the "emerging topics" detection to "cover paper" prediction. By using "AdaBoost model" and topic model, we construct a machine learning framework to imitate the top journal (chief) editor's judgement to select cover paper from material science. The results of our prediction were validated by consulting with field experts. This approach was also suitable for the Nature, Science, and Cell journals.

Tumor-associated macrophages have emerged as crucial factors for metastases. Microglia are indispensable components of the brain microenvironment and play vital roles in brain metastasis (BM). However, the underlying mechanism of how activated microglia promote brain metastasis of non-small cell lung cancer (NSCLC) remains elusive. Here, we purified cell lines with brain-metastatic tropism and employed a co-culture system to reveal their communication with microglia. By single-cell RNA-sequencing and transcriptome difference analysis, we identified IL6 as the key regulator in brain-metastatic cells (A549-F3) to induce anti-inflammatory microglia via JAK2/STAT3 signaling, which in turn promoted the colonization process in metastatic A549-F3 cells. In our clinical samples, patients with higher levels of IL6 in serum showed higher propensity for brain metastasis. Additionally, the TCGA (The Cancer Genome Atlas) data revealed that NSCLC patients with a lower level of IL6 had a longer overall survival time compared to those with a higher level of IL6. Overall, our data indicate that the targeting of IL6/JAK2/STAT3 signaling in activated microglia may be a promising new approach for inhibiting brain metastasis in NSCLC patients.

Additional file 10: Supplementary Table S5.

Additional file 9: Supplementary Table S4.

Cellular, biochemical, and structural investigation of the MyoVa/MICAL1 complex reveals an intracellular cargo-unloading mechanism., Motor-mediated intracellular trafficking requires motors to position cargoes at proper locations. Myosin Va (MyoVa), an actin-based motor, is a classic model for studying cargo transport. However, the molecular basis underlying cargo unloading in MyoVa-mediated transport has remained enigmatic. We have identified MICAL1, an F-actin disassembly regulator, as a binding partner of MyoVa and shown that MICAL1-MyoVa interaction is critical for localization of MyoVa at the midbody. By binding to MICAL1, MyoVa-mediated transport is terminated, resulting in vesicle unloading at the midbody for efficient cytokinesis. The MyoVa/MICAL1 complex structure reveals that MICAL1 and F-actin assembly factors, Spires, share an overlapped binding surface on MyoVa, suggesting a regulatory role of F-actin dynamics in cargo unloading. Down-regulating F-actin disassembly by a MICAL1 mutant significantly reduces MyoVa and vesicles accumulating at the midbody. Collectively, our findings demonstrate that MyoVa binds to MICAL1 at the midbody destination and triggers F-actin disassembly to unload the vesicle cargo.

Metastasis is the fundamental cause of cancer mortality, but there are still very few anti-metastatic drugs available. Endosomal trafficking has been implicated in tumor metastasis, and we have previously found that small chemical vacuolin-1 (V1) potently inhibits autophagosome-lysosome fusion and general endosomal-lysosomal degradation. Here, we assessed the anti-metastatic activity of V1 both in vitro and in vivo. V1 significantly inhibits colony formation, migration, and invasion of various cancer cells in vitro. It also compromises the assembly-disassembly dynamics of focal adhesions (FAs) by inhibiting the recycling and degradation of integrins. In various experimental or transgenic mouse models, V1 significantly suppresses the metastasis and/or tumor growth of breast cancer or melanoma. We further identified capping protein Zβ (CapZβ) as a V1 binding protein and showed that it is required for the V1-mediated inhibition of migration and metastasis of cancer cells. Collectively, our results indicate that V1 targets CapZβ to inhibit endosomal trafficking and metastasis.

Demyelination is a common pathological feature of a large number of neurodegenerative diseases including multiple sclerosis and Huntington's disease (HD). Laquinimod (LAQ) has been found to have therapeutic effects on multiple sclerosis and HD. However, the mechanism underlying LAQ's therapeutic effects remains unknown. Using HD mice that selectively express mutant huntingtin in oligodendrocytes and show demyelination, we found that LAQ reduces the Ser259 phosphorylation on myelin regulatory factor (MYRF), an oligodendrocyte-specific transcription factor promoting the expression of myelin-associated genes. The reduced MYRF phosphorylation inhibits MYRF's binding to mutant huntingtin and increases the expression of myelin-associated genes. We also found that PRKG2, a cGMP-activated protein kinase subunit II, promotes the Ser259-MYRF phosphorylation and that knocking down PRKG2 increased myelin-associated protein's expression in HD mice. Our findings suggest that PRKG2-regulated phosphorylation of MYRF is involved in demyelination and can serve as a potential therapeutic target for reducing demyelination.

Multi-granulation decision-theoretic rough set (MG-DTRS) is a generalisation of the multi-granulation rough set (MGRS) model through integrating the related properties of MGRSs and decision-theoretic rough sets (DTRSs), and it can realise decision analysis and processing of information systems from multiple perspectives and multi-level. Taking the optimistic MG-DTRS and the pessimistic MG-DTRS model as an example, MG-DTRS model and its related properties were discussed according to the DTRSs which construct positive, boundary and negative regions on the basis of two thresholds given by experts. Especially, the positive decision and its properties in MG-DTRS model were analysed. At the same time, it was found and proved that the positive decision is monotonic with the change of granularity in MG-DTRS model. Further, the granular structure selection problem was investigated under the MG-DTRS model, the concept of α-decision granularity importance was introduced and a granularity reduction algorithm based on the positive decision holding for MG-DTRS model was designed and constructed. Finally, an example was given to prove that the algorithm is effective, and it has a small time complexity.

Jinlong capsule (JLC), a type of herbal medicine, is considered to be a promising adjuvant therapy for hepatocellular carcinoma (HC). Although an analysis of the published literature has been performed, the exact effects and safety of JLC are yet to be systematically investigated. Therefore, a wide-ranging systematic search of electronic databases to draw conclusions was performed. Data from 29 trials, including 2488 patients with advanced HC, were analyzed. The results indicated that, compared with conventional treatment alone, the combination of conventional treatment and JLC markedly improved overall patient response (odds ratio (OR) 2.06 [95% confidence interval (CI) 1.71–2.49]; P0.05). In summary, results of this meta-analysis suggest that the combination of conventional treatment and JLC is more effective for the treatment of HC than conventional treatment alone.

Maize (Zea mays) is one of the most important crops in the world. However, few agronomically important maize genes have been cloned and used for trait improvement, due to its complex genome and genetic architecture. Here, we integrated multiplexed CRISPR/Cas9-based high-throughput targeted mutagenesis with genetic mapping and genomic approaches to successfully target 743 candidate genes corresponding to traits relevant for agronomy and nutrition. After low-cost barcode-based deep sequencing, 412 edited sequences covering 118 genes were precisely identified from individuals showing clear phenotypic changes. The profiles of the associated gene-editing events were similar to those identified in human cell lines and consequently are predictable using an existing algorithm originally designed for human studies. We observed unexpected but frequent homology-directed repair through endogenous templates that was likely caused by spatial contact between distinct chromosomes. Based on the characterization and interpretation of gene function from several examples, we demonstrate that the integration of forward and reverse genetics via a targeted mutagenesis library promises rapid validation of important agronomic genes for crops with complex genomes. Beyond specific findings, this study also guides further optimization of high-throughput CRISPR experiments in plants.

Growing evidence has revealed that brain pericytes are multifunctional and contribute to the pathogenesis of a number of neurological disorders. However, the role of pericytes in cerebral ischemia, and especially the pathophysiological alterations in pericytes, remains unclear. In the present study, our aim was to determine whether the proliferation of pericytes is affected by cerebral ischemia and, if so, to identify the underlying mechanism(s). Cultured brain pericytes subjected to oxygen-glucose deprivation (OGD) were used as our model of cerebral ischemia; the protein expression levels of cyclin D1, cyclin E, cdk4, and cyclin B1 were determined by Western blot analysis, and cell cycle analysis was assessed by flow cytometry. The OGD treatment reduced the brain pericyte proliferation by causing G2/M phase arrest and downregulating the protein levels of cyclin D1, cyclin E, cdk4, and cyclin B1. Further studies demonstrated a simultaneous decrease in the activity of extracellular regulated protein kinases (ERK), suggesting a critical role of the ERK signaling cascade in the inhibition of OGD-induced pericyte proliferation. We suggest that OGD inhibition of the proliferation of brain pericytes is associated with the inactivation of the ERK signaling pathway, which arrests them in the G2/M phase.

In chicks, the diurnal patterns of retinal dopamine synthesis and release are associated with refractive development. To assess the within-day patterns of dopamine release, we assayed vitreal levels of DOPAC (3,4-dihydroxyphenylacetic acid) using high performance liquid chromatography with electrochemical detection, at 4-hour intervals over 24 hours in eyes with experimental manipulations that change ocular growth rates. Chicks were reared under a 12 hour light/12 hour dark cycle; experiments began at 12 days of age. Output was assessed by modelling using the robust variance structure of Generalized Estimating Equations. CONTINUOUS SPECTACLE LENS-DEFOCUS OR FORM DEPRIVATION: One group experienced non-restricted visual input to both eyes and served as untreated “normal” controls. Three experimental cohorts underwent monocular visual alterations known to alter eye growth and refraction: wearing a diffuser, a negative lens or a positive lens. After one full day of device-wear, chicks were euthanized at 4-hour intervals over 24 hours (8 birds per time/condition). BRIEF HYPEROPIC DEFOCUS: Chicks wore negative lenses for only 2 daily hours either in the morning (starting at ZT 0; n=16) or mid-day (starting at ZT 4; n=8) for 3 days. Vitreal DOPAC was assayed. In chicks with bilateral non-restricted vision, or with continuous defocus or form-deprivation, there was a diurnal variation in vitreal DOPAC levels for all eyes (p

Purpose Stimulated by evidence implicating diurnal/circadian rhythms and light in refractive development, we studied the expression over 24 hours of selected clock and circadian rhythm-related genes in retina/retinal pigment epithelium (RPE) and choroid of experimental ametropias in chicks. Methods Newly hatched chicks, entrained to a 12-hour light/dark cycle for 12 to 14 days, either experienced nonrestricted vision OU (i.e., in both eyes) or received an image-blurring diffuser or a minus 10-diopter (D) or a plus 10-D defocusing lens over one eye. Starting 1 day later and at 4-hour intervals for 24 hours, the retina/RPE and choroid were separately dissected. Without pooling, total RNA was extracted, converted to cDNA, and assayed by quantitative PCR for the expression of the following genes: Opn4m, Clock, Npas2, Per3, Cry1, Arntl, and Mtnr1a. Results The expression of each gene in retina/RPE and in choroid of eyes with nonrestricted vision OU varied over 24 hours, with equal levels OU for most genes and times. Altered visual input influenced gene expression in complex patterns that varied by gene, visual input, time, and eye, affecting experimental eyes with altered vision and also contralateral eyes with nonrestricted vision. Discussion Altering visual input in ways known to induce ametropias alters the retinal/RPE and choroidal expression of circadian rhythm-related genes, further linking circadian biology with eye growth regulation. While further investigations are needed, studying circadian processes may help understand refractive mechanisms and the increasing myopia prevalence in contemporary societies where lighting patterns can desynchronize endogenous rhythms from the natural environmental light/dark cycle.

The fatigue characterization and failure modes of self-piercing riveted joints in titanium plates were studied experimentally. The self-piercing riveting (SPR) process was optimised to improve the forming quality, mechanical property and failure behaviour of titanium joints through the comparative trials. The crack propagation mechanisms and fretting behaviours are quite different for different failure modes and analysed in detail from macro- and micro-perspective. The static and fatigue properties are both enhanced and the failure mode of rivet fracture is avoided for the optimised joints. The failures of upper sheet fracture and lower sheet fracture occur in the fatigue tests. Heavy fretting wear exists precisely at the critical faying interfaces and results in the fatigue crack initiations. The fatigue crack initiates at the faying interface between both sheets for the upper sheet fracture and propagates to both sides of the upper sheet simultaneously. Concerning the lower sheet fracture, the fatigue crack initiates at the faying interface between the rivet and the lower sheet, and then propagates to the close side of the lower sheet in the first stage, extends to the far side in the second stage.

The new technique of pre-holed self-piercing riveting (PH-SPR) was proposed to improve the dissimilar joining of the carbon fibre reinforced polymer (CFRP) laminate and the commercially pure titanium (TA1) sheet. The joint quality, strength, failure behaviour and forming structure of the PH-SPR joints were analysed comparing with the regular SPR (R-SPR) joints. The effects of process parameters on the PH-SPR joint were discussed systematically and experimentally. It was concluded that a better mechanical interlock could be obtained using PH-SPR. The joint strength of the PH-SPR joints failed in the rivet pulled out was superior to those failed in the composite layer torn. Comparing with the R-SPR joints, a better hardening effect to the TA1 sheet and a relatively lower strength loss to the rivet brought a better joint strength for the PH-SPR joints. For the PH-SPR process, the joint strength is highly dependent on the interlock length, and the static failure mode of the joints was affected largely by the rivet head height. The remaining bottom thickness and interlock length was mainly determined by the plastic deformation capacity of the metallic sheet, and the rivet head height was primarily influenced by the joining force.

With the increasingly energy and environmental problems, photoelectrochemical (PEC) water splitting has recently attracted a great deal of attention. The slow oxygen evolution reaction (OER) involved in O–H bond breaking and attendant O O bond formation has restricted the efficiency of PEC water splitting. Herein, we demonstrate for the first time that the Eu2O3 can work as OER catalyst to significantly promote the performance of PEC water splitting. Because of its surface valance transition, the Eu2O3/ZnO shows an obvious water oxidation peak at 1.90 V vs. RHE, with a cathodic shift of around 200 mV to that of ZnO. The Eu2O3/ZnO can also yield a current density of 3.5 times larger than that of ZnO. Furthermore, similar enhancements can be also observed for the TiO2 and BiVO4, confirming the Eu2O3 is a general and efficient OER catalyst for improving the PEC performance. Such OER catalyst of Eu2O3 may bring new opportunities for the development of PEC cells with superior performance.

To achieve optimal performance of fuel cells and metal-air batteries, searching the cost-effective catalysts with enhanced activity and durability for oxygen reduction reaction (ORR) is highly pursued. We present a new and scalable approach to synthesize low-cost Co and N co-doped C (CoNC) catalysts from sustainable organic-rich chitosan waste. The CoNC designed here involves in chelation between the chitosan and Co ions, shows superior ORR activity. The XPS spectra demonstrate the kinds of ORR active N sites are of high content in the CoNC, which lead to preferable catalytic activity. The TEM images show more highly dispersion of Co, N and C in the CoNC, which contributes to the high ORR activity. The CoNC catalysts exhibit a remarkable limiting current of ∼5.36 mA cm−2 and positive onset potential of −0.105 V (vs. Ag/AgCl), both of which are comparable to those of the commercial Pt/C. Additionally, the optimal CoNC also possesses prominent durability and tolerance of methanol.

CD38 is a multifunctional membrane enzyme and the main mammalian ADP-ribosyl cyclase, which catalyzes the synthesis and hydrolysis of cADPR, a potent endogenous Ca2+ mobilizing messenger. Here, we explored the role of CD38 in the neural differentiation of mouse embryonic stem cells (ESCs). We found that the expression of CD38 was decreased during the differentiation of mouse ESCs initiated by adherent monoculture. Perturbing the CD38/cADPR signaling by either CD38 knockdown or treatment of cADPR antagonists inhibited the neural commitment of mouse ESCs, whereas overexpression of CD38 promoted it. Moreover, CD38 knockdown dampened reactive oxygen species (ROS) production during neural differentiation of ESCs by inhibiting NADPH oxidase activity, while CD38 overexpression enhanced it. Similarly, application of hydrogen peroxide mitigated the inhibitory effects of CD38 knockdown on neural differentiation of ESCs. Taken together, our data indicate that the CD38 signaling pathway is required for neural differentiation of mouse ESCs by modulating ROS production. Stem Cells 2015;33:2664–2673