Astrocytic expression of Yes-associated protein (YAP) regulates retinal neovascularization in a mouse model of oxygen-induced retinopathy.

Pathological neovascularization is the hallmark of many vascular oculopathies. There is still a great deal of uncertainty surrounding retinal neovascularization research. A working hypothesis that astrocytic Yes-associated protein (YAP) act as a key factor in retinal neovascularization was proposed. And our study was conducted to verified this hypothesis. In vivo, we successfully generated mice deficient in YAP in astrocytes (YAPf/f GFAP-Cre mice) and set up oxygen-induced retinopathy (OIR) model. Pathological neovascularization was evaluated by immunofluorescence staining and western blotting. In vitro, cultured retinal astrocytes were transfected with YAP siRNA. Enzyme-linked immunosorbent assay (ELISA) and western blot were used to determine the proteins in the supernatants and cells. The results showed that YAP was upregulated and activated in the OIR mice retinas. Conditional ablation of YAP aggravated pathological neovascularization, along with the upregulation of vascular endothelial growth factor A (VEGF-A) and monocyte chemoattractant protein-1 (MCP-1). Studies in vitro confirmed that the knockdown of YAP in astrocytes lead to increases in VEGF-A and MCP-1 levels, thus enhancing pro-angiogenic capability of YAP-deficit astrocytes. In conclusion, astrocytic YAP alleviates retinal pathological angiogenesis by inhibiting the over-activation of astrocytes, which suppresses excessive VEGF-A production and neuroinflammation.

TRANS-ACTING SIRNA3-derived short interfering RNAs confer cleavage of mRNAs in rice.

Plant TRANS-ACTING SIRNA3 (TAS3)-derived short interfering RNAs (siRNAs) include tasiR-AUXIN RESPONSE FACTORs (ARFs), which are functionally conserved in targeting ARF genes, and a set of non-tasiR-ARF siRNAs, which have rarely been studied. In this study, TAS3 siRNAs were systematically characterized in rice (Oryza sativa). Small RNA sequencing results showed that an overwhelming majority of TAS3 siRNAs belong to the non-tasiR-ARF group, while tasiR-ARFs occupy a diminutive fraction. Phylogenetic analysis of TAS3 genes across dicot and monocot plants revealed that the siRNA-generating regions were highly conserved in grass species, especially in the Oryzoideae. Target genes were identified for not only tasiR-ARFs but also non-tasiR-ARF siRNAs by analyzing rice Parallel Analysis of RNA Ends datasets, and some of these siRNA-target interactions were experimentally confirmed using tas3 mutants generated by genome editing. Consistent with the de-repression of target genes, phenotypic alterations were observed for mutants in three TAS3 loci in comparison to wild-type rice. The regulatory role of ribosomes in the TAS3 siRNA-target interactions was further revealed by the fact that TAS3 siRNA-mediated target cleavage, in particular tasiR-ARFs targeting ARF2/3/14/15, occurred extensively in rice polysome samples. Altogether, our study sheds light into TAS3 genes in plants and expands our knowledge about rice TAS3 siRNA-target interactions.

Prophylactic donor lymphocyte infusion after haploidentical hematopoietic cell transplantation and post-transplant cyclophosphamide for treatment of high-risk myeloid neoplasms in children: A retrospective study.

BACKGROUND: Post-transplant cyclophosphamide (PTCy) has been recommended for prevention of graft-versus-host disease (GvHD) following haploidentical hematopoietic cell transplantation (haplo-HCT) for treatment of malignant blood diseases, but disease relapse remains a problem. Although donor lymphocyte infusion (DLI) is reported to be effective for treating post-transplantation relapse, the efficacy and safety of prophylactic-DLI (pro-DLI) post haplo-HCT, and PTCy in pediatric patients with hematological malignancies is unknown. METHODS: We retrospectively analyzed the outcomes of 54 pediatric patients with high-risk myeloid neoplasms who received a PTCy regimen for GvHD prophylaxis and pro-DLI after haploidentical peripheral blood stem cell transplantation. The high-risk myeloid neoplasms in this cohort included acute myeloid leukemia (n = 46) and myelodysplastic syndromes (n = 8). RESULTS: Median follow-up was for 19.7 (range: 3.4-46.6) months. The cumulative incidences of grade II-IV and III-IV acute GvHD were 37.0% (95% CI: 22.7%-48.7%) and 16.7% (95% CI: 6.1%-26.0%), respectively. There were no graft-failure events, and the 2-year rate of moderate/severe chronic GvHD was 8.1% (95% CI: 0%-16.7%). The 2-year non-relapse mortality, relapse, disease-free survival, GvHD-free relapse-free survival, and overall survival rates were 5.1% (95% CI: 0%-11.7%), 16.6% (95% CI: 5.3%-26.6%), 78.9% (95% CI: 68.0%-91.6%), 62.2% (95% CI: 49.4%-78.3%), and 87.3% (95% CI: 78.3%-97.4%), respectively. CONCLUSIONS: Prophylactic donor lymphocyte infusion in the setting of haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide appears to be effective and safe in pediatric patients with high-risk myeloid neoplasms.

Unlocking the transformative power of mentoring for youth development in communities, schools, and talent domains.

Mentoring is a highly individualized educational measure that can support youth development in communities, schools, and talent domains. Depending on the target population, goals, structure, and medium, mentoring for youths can differ considerably. This article first reviews the main types of mentoring programs and practices for youth development in communities, schools, and talent domains. Despite the popularity of mentoring programs, many programs fail to realize the full potential of mentoring as meta-analyses consistently show relatively small effects of mentoring. The discrepancy between the potential and actual effect of mentoring is referred to as the mentoring paradox. Crucial aspects that are held responsible for the mentoring paradox, such as adequate planning and implementation of mentoring programs, adherence to research-based mentoring practices, as well as quality assurance of mentoring programs through systematic program research and evaluation are described. Finally, implications on how to professionalize mentoring are provided for different stakeholders.

SPP1 facilitates cell migration and invasion by targeting COL11A1 in lung adenocarcinoma.

BACKGROUND: Secreted phosphoprotein 1 (SPP1), an extracellular secreted glycol phosphoprotein, is closely related to tumor biologies, such as proliferation, migration, and invasion. However, the role and biological function of SPP1 in lung adenocarcinoma (LUAD) was still ambiguous. METHODS: SPP1 expression in LUAD tissues and its associations with clinical features and prognosis was investigated using meta-analysis, immunohistochemistry (IHC) staining methods, and quantitative real-time polymerase chain reaction (qRT-PCR). Moreover, the potential mechanism related to SPP1 was identified by using the Gene Set Enrichment Analysis (GSEA) method. A series of function assays were conducted to determine the biological role of SPP1 in LUAD cell migration and invasion in vitro and vivo. The co-expressed genes of SPP1 were obtained and verified by western blot assays. The influence of SPP1 on Collagen type XI alpha 1 (COL11A1) expression and epithelial-mesenchymal transition (EMT) markers was analyzed using western blot assays. RESULTS: The expression of SPP1 in LUAD tissues and cells was significantly higher than that in normal tissues and cells. And positively associations of SPP1 expression with TNM stage, lymph node metastasis, and invasion depth were observed. Patients with high SPP1 expression had unfavorable survival. The multivariable Cox regression analysis revealed that SPP1 expression was an independent prognostic factor of LUAD patients. Furthermore, downregulation of SPP1 could inhibit cell migration and invasion both in vitro and vivo, reduce the expression of epithelial marker (E-cadherin), and increase the expression of mesenchymal markers (N-cadherin and vimentin). Using bioinformatics and western blot assays, we confirmed that COL11A1 acted as the downstream of SPP1, and SPP1 knockdown could significantly downregulate the COL11A1 expression. Importantly, suppression of cell migration and invasion and the expression changes of EMT markers induced by SPP1 downregulation could be reversed by COL11A1 overexpression. CONCLUSIONS: SPP1 facilitates cell migration and invasion by upregulating COL11A1 expression and that acts as a potential biomarker of metastasis and prognosis for LUAD.

Dry eye symptoms in interferon regulatory factor 3-deficient mice due to herpes simplex virus infection in harderian gland and lacrimal gland.

PURPOSE: Dry eye syndrome (DES) is a multifactorial ocular disorder. The possible pathogens and pathogenic mechanisms for virus-related dry eye disease are largely unknown. The current study aimed to provide evidence for mechanisms contributing to DES induced by herpes simplex virus (HSV) infection in the harderian gland (HG) and lacrimal gland (LG). METHODS: We recorded the dry eye-like cornea pathology of irf3-/- mice infected with HSV-1 till 8 months of age. The slit-lamp and confocal microscopy was used to observe the corneal defects. TUNEL was used to detect the corneal apoptosis. Human corneas suffered from herpes stromal keratitis (HSK) were also analyzed as a comparison. Then, we measure the aqueous tear production with a phenol red thread test in irf3-/-mice, and recorded their tear film breakup time. HGs and LGs were sectioned and analyzed using HE and oil-red-O staining. For molecular signaling pathway analysis, we used mRNA sequencing to explore the related gene ontology. Western blotting (WB) and real-time reverse transcription-quantitative polymerase chain reaction were used to verify the level of the Akt signaling pathway and related inflammatory factors. RESULTS: Inoculated irf3-/- mice tended to develop dry eye-like symptoms, such as corneal keratinization, corneal cell apoptosis, and tear reduction. The HGs and LGs of irf3-/- mice showed increased level of HSV-1, and exhibited inflammatory pathological changes and impaired function, which explained the damaged tear film. WB and mRNA sequencing indicated that enhanced PI3K-Akt pathway in irf3-/- mice might account for the higher susceptibility to HSV infection. CONCLUSIONS: We observed evidence of DES in irf3-/- mice induced by HSV-1 infection in the HGs and LGs, which may introduce a potential novel target for DES treatment.

Comparative ribosome profiling reveals distinct translational landscapes of salt-sensitive and -tolerant rice.

BACKGROUND: Soil salinization represents a serious threat to global rice production. Although significant research has been conducted to understand salt stress at the genomic, transcriptomic and proteomic levels, few studies have focused on the translatomic responses to this stress. Recent studies have suggested that transcriptional and translational responses to salt stress can often operate independently. RESULTS: We sequenced RNA and ribosome-protected fragments (RPFs) from the salt-sensitive rice (O. sativa L.) cultivar 'Nipponbare' (NB) and the salt-tolerant cultivar 'Sea Rice 86' (SR86) under normal and salt stress conditions. A large discordance between salt-induced transcriptomic and translatomic alterations was found in both cultivars, with more translationally regulated genes being observed in SR86 in comparison to NB. A biased ribosome occupancy, wherein RPF depth gradually increased from the 5' ends to the 3' ends of coding regions, was revealed in NB and SR86. This pattern was strengthened by salt stress, particularly in SR86. On the contrary, the strength of ribosome stalling was accelerated in salt-stressed NB but decreased in SR86. CONCLUSIONS: This study revealed that translational reprogramming represents an important layer of salt stress responses in rice, and the salt-tolerant cultivar SR86 adopts a more flexible translationally adaptive strategy to cope with salt stress compared to the salt susceptible cultivar NB. The differences in translational dynamics between NB and SR86 may derive from their differing levels of ribosome stalling under salt stress.

Regression analysis of current status data with latent variables.

Current status data occur in many fields including demographical, epidemiological, financial, medical, and sociological studies. We consider the regression analysis of current status data with latent variables. The proposed model consists of a factor analytic model for characterizing latent variables through their multiple surrogates and an additive hazard model for examining potential covariate effects on the hazards of interest in the presence of current status data. We develop a borrow-strength estimation procedure that incorporates the expectation-maximization algorithm and correlated estimating equations. The consistency and asymptotic normality of the proposed estimators are established. A simulation study is conducted to evaluate the finite sample performance of the proposed method. A real-life study on the chronic kidney disease of type 2 diabetic patients is presented.

Integrin CD11b Deficiency Aggravates Retinal Microglial Activation and RGCs Degeneration After Acute Optic Nerve Injury.

Neuroinflammation plays a vital role in the process of a variety of retinal ganglion cells (RGCs) degenerative diseases including traumatic optic neuropathy (TON). Retinal microglial activation is believed as a harbinger of TON, and robust microglial activation can aggravate trauma-induced RGCs degeneration, which ultimately leads to RGCs loss. Toll like receptor 4 (TLR4)-triggered inflammation is of great importance in retinal inflammatory response after optic nerve injury. CD11b on macrophage and brain microglia can inhibit TLR4-triggered inflammation. However, the functional role of CD11b in retinal microglia is not well understood. Here, using an optic nerve crush model and CD11b gene deficient mice, we found that CD11b protein expression was mainly on retinal microglia, significantly increased after optic nerve injury, and still maintained at a high level till at least 28 days post crush. Compared with wild type mice, following acute optic nerve injury, CD11b deficient retinae exhibited more exacerbated microglial activation, accelerated RGCs degeneration, less growth associated protein-43 expression, as well as more proinflammatory cytokines such as interleukin-6 and tumor necrosis factor α while less anti-inflammatory factors such as arginase-1 and interleukin-10 production. We conclude that CD11b is essential in regulating retinal microglial activation and neuroinflammatory responses after acute optic nerve injury, which is critical for subsequent RGCs degeneration and loss.

Relationship of Blood Eosinophils with Fractional Exhaled Nitric Oxide and Pulmonary Function Parameters in Chronic Obstructive Pulmonary Disease (COPD) Exacerbation.

BACKGROUND The 2018 Global Initiative for Chronic Obstructive Lung Disease Report reveals that the blood eosinophil count could forecast the risk of flare-ups. This study explored the correlations of blood eosinophils with fractional exhaled nitric oxide (FeNO) and pulmonary function parameters in acute exacerbation of chronic obstructive pulmonary disease (AECOPD). MATERIAL AND METHODS The data of patients with AECOPD at our hospital admitted between July 2018 and June 2019 were retrospectively analyzed. All patients were stratified into an eosinophilic group (≥2%) or a noneosinophilic group (<2%) based on the peripheral eosinophil count per centum. Cross-sectional analysis was performed to compare clinical characteristics, percentage of eosinophils, FeNO, and pulmonary function between the 2 groups. RESULTS After applying the inclusion/exclusion criteria, 247 patients were included. FeNO values were higher in eosinophilic group (n=97) than in noneosinophilic group (n=150) (P=0.005). The forced expiratory volume in 1 second% predicted (FEV1% predicted), FEV1, and forced vital capacity (FVC) were higher in the eosinophilic group than in the noneosinophilic group (P=0.043; P=0.040; and P=0.011, respectively). Blood eosinophilia showed positive correlations with FeNO (P=0.004) and spirometry variables (FEV1 [% predicted], P=0.003; FEV1, P<0.001; and FVC, P<0.001). An FeNO level of 22.5 ppb was the best cutoff value to predict blood eosinophilia (P=0.000). CONCLUSIONS Blood eosinophil count is a likely biomarker that can predict positive relationship with FeNO values and pulmonary function parameters.

[A clinical epidemiological investigation of neonatal acute respiratory distress syndrome in southwest Hubei, China].

OBJECTIVE: To investigate the clinical features and outcome of neonatal acute respiratory distress syndrome (ARDS) in southwest Hubei, China. METHODS: According to the Montreux definition of neonatal ARDS, a retrospective clinical epidemiological investigation was performed on the medical data of neonates with ARDS who were admitted to Department of Neonatology/Pediatrics in 17 level 2 or level 3 hospitals in southwest Hubei from January to December, 2017. RESULTS: A total of 7 150 neonates were admitted to the 17 hospitals in southwest Hubei during 2017 and 66 (0.92%) were diagnosed with ARDS. Among the 66 neonates with ARDS, 23 (35%) had mild ARDS, 28 (42%) had moderate ARDS, and 15 (23%) had severe ARDS. The main primary diseases for neonatal ARDS were perinatal asphyxia in 23 neonates (35%), pneumonia in 18 neonates (27%), sepsis in 12 neonates (18%), and meconium aspiration syndrome in 10 neonates (15%). Among the 66 neonates with ARDS, 10 neonates (15%) were born to the mothers with an age of ≥35 years, 30 neonates (45%) suffered from intrauterine distress, 32 neonates (49%) had a 1-minute Apgar score of 0 to 7 points, 24 neonates (36%) had abnormal fetal heart monitoring results, and 21 neonates (32%) experienced meconium staining of amniotic fluid. Intraventricular hemorrhage was the most common comorbidity (12 neonates), followed by neonatal shock (9 neonates) and patent ductus arteriosus (8 neonates). All 66 neonates with ARDS were treated with mechanical ventilation in addition to the treatment for primary diseases. Among the 66 neonates with ARDS, 10 died, with a mortality rate of 15% (10/66), and 56 neonates were improved or cured, with a survival rate of 85% (56/66). CONCLUSIONS: Neonatal ARDS in southwest Hubei is mostly mild or moderate. Perinatal asphyxia and infection may be the main causes of neonatal ARDS in this area. Intraventricular hemorrhage is the most common comorbidity. Neonates with ARDS tend to have a high survival rate after multimodality treatment.

Quality-adjusted survival of nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone among treatment-naive patients with advanced melanoma: a quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis.

PURPOSE: To compare the quality-adjusted survival of nivolumab plus ipilimumab combination and nivolumab alone versus ipilimumab alone among treatment-naive patients with advanced melanoma based on a minimum 36-month follow-up from the CheckMate 067 trial. METHODS: Overall survival was partitioned into time without symptoms of progression or toxicity (TWiST), time with treatment-related grade ≥ 3 adverse events after randomization but before progression (TOX), and time from progression until end of follow-up or death (REL). Mean quality-adjusted TWiST (Q-TWiST) was calculated by multiplying the mean time spent in each health state by a utility of 1.0 for TWiST and 0.5 for TOX and REL. Sensitivity analyses included varying utilities of TOX and REL; Q-TWiST gains at different follow-up times were calculated using EQ-5D-3L utilities from the trial. Relative Q-TWiST gain of ≥ 10% was considered clinically important. RESULTS: Compared with ipilimumab-treated patients, those who received nivolumab + ipilimumab combination had significantly longer TWiST and TOX but shorter REL; nivolumab-treated patients had significantly longer TWiST, shorter REL, and shorter but statistically nonsignificant TOX. Mean Q-TWiST was highest for nivolumab + ipilimumab (23.5 months; 95% CI 21.9-25.2), followed by nivolumab (21.8 months; 95% CI 20.2-23.4) and ipilimumab (15.3 months; 95% CI 13.9-16.6). Relative Q-TWiST gains were favorable and clinically important for nivolumab + ipilimumab combination (+ 36.81%) and nivolumab alone (+ 29.18%) versus ipilimumab alone. Relative gains increased with follow-up from 3 to 40 months for all comparisons. These gains remained consistent in magnitude and direction in the different sensitivity analyses. CONCLUSIONS: Nivolumab + ipilimumab combination and nivolumab alone resulted in a statistically significant and clinically important improvement in quality-adjusted survival compared with ipilimumab alone.

Comparative Efficacy of Budesonide/Formoterol with Budesonide, Formoterol or Placebo for Stable Chronic Obstructive Pulmonary Disease: A Meta-Analysis.

BACKGROUND The 2018 Global Initiative for Chronic Obstructive Lung Disease publication suggested that the combination of bronchodilator therapy of inhaled glucocorticoid/long-acting ß2 adrenoceptor agonist is more effective in improving pulmonary function and health status in the treatment of patients with acute exacerbations than the individual components; however, it is not known whether this also the case for stable chronic obstructive pulmonary disease (COPD). The purpose of this meta-analysis was to evaluate the effectiveness of budesonide/formoterol in the maintenance and relief therapy of patients with stable COPD. MATERIAL AND METHODS An electronic search of the literature in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials was undertaken to identify published randomized controlled trials (RCTs) of ≥12 weeks duration comparing the budesonide/formoterol, with budesonide, formoterol, or placebo in the treatment of patients with stable COPD. The identified RCTs were reviewed. The mean difference (MD) with corresponding 95% confidence interval (CI) was used to pool the results. RESULTS Seven high quality studies with RCTs met the inclusion criteria for meta-analysis. Compared with budesonide alone, the combination therapy of budesonide/formoterol showed significant improvement in the following spirometric indices: pre-dose forced expiratory volume in 1 second (FEV1) (SMD: 0.26, 95% CI: 0.18, 0.34; P=0.000). In addition, versus formoterol alone, budesonide/formoterol was associated with a significant increase in pre-dose FEV1 (SMD: 0.12, 95% CI: 0.07, 0.17; P=0.000). A similar pattern was also evident in the comparison to placebo, where budesonide/formoterol yielded greater increase in pre-dose FEV1 (SMD: 0.24, 95% CI: 0.18, 0.30; P=0.000). Moreover, compared with other controls, the combination of budesonide-formoterol significantly improved morning peak expiratory flow and evening peak expiratory flow, significantly reduced the total score of St. George's Respiratory Questionnaire. CONCLUSIONS For stable COPD patients, compared with controls (monocomponents or placebo), budesonide/formoterol improved pulmonary function and health status. Future larger long-term RCTs are warranted to assess the beneficial clinical efficacy of budesonide/formoterol in COPD patients.

Exploring Compensations for Demographic Disadvantage in Science Talent Development.

This study explores factors enhancing the likelihood that three demographically disadvantaged groups of selective science high school graduates would complete a university STEM degree 4-6 years later. The target groups are labeled as disadvantaged in terms of STEM pipeline persistence compared to school peers, and include: (1) women, (2) those without a parent in a STEM field, and (3) those whose parents were not educated beyond high school. Employing Social Cognitive Career Theory as a conceptual framework, we focus on two categories of factors. Individual factors incorporate motivation and career intention brought to the high school experience. Environmental factors include graduates' high school experiences related to their STEM interest and capacity development. The individual variables include: STEM career intentions prior to high school, motivation for attending a specialized science high school, and motivation for pursuing advanced science courses in high school. Environmental factors include whether participants partook in an authentic research experience, had a mentor, felt they belonged at the school, maintained their interest in STEM as well as perceived intellectual capacity for STEM throughout high school. The results have promising implications for educational policy associated with STEM talented students.

[Incidence of neonatal asphyxia and contributing factors for the develpment of severe asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture: a multicenter study].

OBJECTIVE: To investigate the incidence of neonatal asphyxia and possible contributing factors for the development of severe asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture, China. METHODS: A total of 16 hospitals in Hubei Enshi Tujia and Miao Autonomous Prefecture were selected as research centers. A retrospective analysis was performed for the clinical data of 22 294 live births in these 16 hospitals from January to December, 2016 to investigate the incidence rate of neonatal asphyxia and possible contributing factors for the development of severe asphyxia. RESULTS: Of the 22 294 neonates born alive, 733 (3.29%) were diagnosed with neonatal asphyxia, among whom 627 had mild asphyxia and 106 had severe asphyxia. The neonates with low maternal education level, maternal anemia during pregnancy, chorioamnionitis, abnormal amniotic fluid, abnormal umbilical cord, placenta previa, placental abruption, Tujia Minority, preterm birth, and low birth weight had a higher incidence of severe asphyxia (P<0.05). CONCLUSIONS: The incidence rate of neonatal asphyxia in Hubei Enshi Tujia and Miao Autonomous Prefecture is higher. Low maternal education level, maternal anemia during pregnancy, chorioamnionitis, abnormal amniotic fluid, abnormal umbilical cord, placenta previa, placental abruption, Tujia Minority, preterm birth, and low birth weight may be related to the development of severe neonatal asphyxia.

MicroRNA-378a-5p promotes trophoblast cell survival, migration and invasion by targeting Nodal.

Nodal is a member of the transforming growth factor-ß superfamily that plays crucial roles during embryogenesis. Recently, we have reported that Nodal inhibits trophoblast cell proliferation, migration and invasion, but induces apoptosis in the human placenta. In this study, we examined the regulation of Nodal by microRNAs. In silico analysis of Nodal 3'UTR revealed a potential binding site for miR-378a-5p. In luciferase reporter assays, we found that miR-378a-5p suppressed the luciferase activity of a reporter plasmid containing Nodal 3'UTR but this suppressive effect was completely abolished when the predicted target site was mutated. Western blot analysis showed that miR-378a-5p decreased whereas anti-miR-378a-5p increased Nodal protein levels. These results indicate that miR-378a-5p targets Nodal 3'UTR to repress its expression. Stable transfection of the miR-378a-5p precursor, mir-378a, into HTR8/SVneo cells enhanced cell survival, proliferation, migration and invasion. Transient transfection of mature miR-378a-5p mimic, and to a lesser extent, siRNA targeting Nodal, produced similar effects. However, anti-miR-378a-5p inhibited cell migration and invasion. In addition, overexpression of Nodal reversed the invasion-promoting effect of miR-378a-5p. Furthermore, miR-378a-5p enhanced, whereas anti-miR-378a-5p suppressed, the outgrowth and spreading of extravillous trophoblast cells in first trimester placental explants. Finally, miR-378a-5p was detected in human placenta throughout different stages of gestation and in preterm pregnancies, placental miR-378a-5p levels were lower in preeclamptic patients than in healthy controls. Taken together, these findings strongly suggest that miR-378a-5p plays an important role in human placental development by regulating trophoblast cell growth, survival, migration and invasion, and that miR-378a-5p exerts these effects, at least in part, through the suppression of Nodal expression.

Attracting and developing STEMM talent toward excellence and innovation.

This article provides an overview of science, technology, engineering, mathematics, and medical sciences (STEMM) talent development from first exposure to a STEMM domain to achieving eminence and innovation. To this end, a resource-oriented model of STEMM talent development is proposed as a framework. It includes a three-stage phase model based on Bloom (1985), with the main focus on interest development in the first stage, skill acquisition toward expertise and excellence in the second stage, and style formation toward eminence and innovation in the final stage. A literature review shows that from an educational perspective, each phase is mainly characterized by the focus that Bloom postulated. However, it is important that all three stages (i.e., interest development, skill acquisition, and style formation) occur in a stage-typical manner. To explain how these primary objectives of STEMM development can be supported through STEMM talent education, Ziegler and Stoeger's (2011) educational and learning capital framework is used in the proposed resource-based model. A literature review shows that consistent provisioning of the resources specified in the model is necessary for individuals to complete a learning pathway to STEMM eminence and innovation.

Effect of astrocyte GPER on the optic nerve inflammatory response following optic nerve injury in mice.

Activated astrocytes are a primary source of inflammatory factors following traumatic optic neuropathy (TON). Accumulation of inflammatory factors in this context leads to increased axonal damage and loss of retinal ganglion cells (RGCs). Therefore, in the present study, we explored the role of the astrocyte G protein-coupled estrogen receptor (GPER) in regulating inflammatory factors following optic nerve crush (ONC), and analyzed its potential regulatory mechanisms. Overall, our results showed that GPER was abundantly expressed in the optic nerve, and co-localized with glial fibrillary acidic proteins (GFAP). Exogenous administration of G-1 led to a significant reduction in astrocyte activation and expression of inflammation-related factors (including IL-1ß, TNF-α, NFκB, and p-NFκB). Additionally, it dramatically increased the survival of RGCs. In contrast, astrocytes were activated to a greater extent by exogenous G15 administration; however, RGCs survival was significantly reduced. In vitro, GPER activation significantly reduced astrocyte activation and the release of inflammation-related factors. In conclusion, activation of astrocyte GPER significantly reduced ONC inflammation levels, and should be explored as a potential target pathway for protecting the optic nerve and RGCs after TON.

A novel capsid-XL32-derived adeno-associated virus serotype prompts retinal tropism and ameliorates choroidal neovascularization.

Gene therapy has been adapted, from the laboratory to the clinic, to treat retinopathies. In contrast to subretinal route, intravitreal delivery of AAV vectors displays the advantage of bypassing surgical injuries, but the viral particles are more prone to be nullified by the host neutralizing factors. To minimize such suppression of therapeutic effect, especially in terms of AAV2 and its derivatives, we introduced three serine-to-glycine mutations, based on the phosphorylation sites identified by mass spectrum analysis, to the XL32 capsid to generate a novel serotype named AAVYC5. Via intravitreal administration, AAVYC5 was transduced more effectively into multiple retinal layers compared with AAV2 and XL32. AAVYC5 also enabled successful delivery of anti-angiogenic molecules to rescue laser-induced choroidal neovascularization and astrogliosis in mice and non-human primates. Furthermore, we detected fewer neutralizing antibodies and binding IgG in human sera against AAVYC5 than those specific for AAV2 and XL32. Our results thus implicate this capsid-optimized AAVYC5 as a promising vector suitable for a wide population, particularly those with undesirable AAV2 seroreactivity.