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Infection by Kaposi sarcoma-associated herpesvirus (KSHV) can cause severe consequences, such as cancers and lymphoproliferative diseases. Whole inactivated viruses (WIV) with chemically destroyed genetic materials have been used as antigens in several licensed vaccines. During KSHV productive replication, virus-like vesicles (VLVs) that lack capsids and viral genomes are generated along with virions. Here, we investigated the immunogenicity of KSHV VLVs produced from a viral mutant that was defective in capsid formation and DNA packaging. Mice immunized with adjuvanted VLVs generated KSHV-specific T cell and antibody responses. Neutralization of KSHV infection by the VLV immune serum was low but was markedly enhanced in the presence of the complement system. Complement-enhanced neutralization and complement deposition on KSHV-infected cells was dependent on antibodies targeting viral open reading frame 4 (ORF4). However, limited complement-mediated enhancement was detected in the sera of a small cohort of KSHV-infected humans which contained few neutralizing antibodies. Therefore, vaccination that induces antibody effector functions can potentially improve infection-induced humoral immunity. Overall, our study highlights a potential benefit of engaging complement-mediated antibody functions in future KSHV vaccine development. IMPORTANCE KSHV is a virus that can lead to cancer after infection. A vaccine that prevents KSHV infection or transmission would be helpful in preventing the development of these cancers. We investigated KSHV VLV as an immunogen for vaccination. We determined that antibodies targeting the viral protein ORF4 induced by VLV immunization could engage the complement system and neutralize viral infection. However, ORF4-specific antibodies were seldom detected in the sera of KSHV-infected humans. Moreover, these human sera did not potently trigger complement-mediated neutralization, indicating an improvement that immunization can confer. Our study suggests a new antibody-mediated mechanism to control KSHV infection and underscores the benefit of activating the complement system in a future KSHV vaccine.

The purpose of this study was to investigate the mediating effect of student achievement in mathematics and science in individuals' intergenerational social mobility between parental socioeconomic status (SES) and their future occupational prestige. We also examined the mediating effect of other factors, such as parental expectation for educational attainment. The Longitudinal Study of American Youth (LSAY) 1987-1994 and 2007-2011 data (a sample of 5,945 high school students) were analyzed with structural equation modeling. Our results indicated that high school student achievement in mathematics and science significantly mediated students' intergenerational social mobility between parental SES and their future occupational prestige. Also, achievement in mathematics and science had a lesser effect than students' expectations for future education.

Given the growing trend toward using technology to assess student learning, this investigation examined test mode comparability of student achievement scores obtained from paper-pencil and computerized assessments of statewide End-of-Course and End-of-Grade examinations in the subject areas of high school biology and eighth-grade English Language Arts and math. Propensity score matching was used to generate comparable groups of students who were assessed using paper-pencil or computer-based formats. T-tests and generalized linear models were further used to examine test mode effect. Analyses revealed a small test mode effect for all three subjects such that students using the paper-based format achieved higher scores than students using the computer-based format. The findings are germane to school districts transitioning to computerized assessments and investigating test mode comparability.

Ribosome is a vital molecular machine for protein translation in the cell. Defects in several ribosomal proteins including RPS19, RPL11 and RPS14 have been observed in two types of anemia: Diamond Blackfan Anemia and 5q- syndrome. In zebrafish, deficiency of these ribosomal proteins shows similar anemic phenotype. It remains to be determined if any other ribosome proteins are similarly involved in regulating erythropoiesis. Here we generated mutations in zebrafish rps9, a rarely studied ribosomal protein gene, and investigated its function. Analysis of this mutant demonstrates that rps9 disruption leads to impairment of erythrocyte maturation, resulting in anemia. In addition, the overall phenotype including the anemic state is p53-dependent in rps9 mutants. Furthermore, this anemic state can be partially relieved by the treatment of L-leucine, and dexamethasone, which have been previously used in rescuing the phenotype of other ribosomal protein mutants. Finally, by comparing the phenotype, we show that there are considerable differences in morphology, cytomorphology, and hemoglobin levels for four ribosomal protein mutants in zebrafish. Based on the observed difference, we suggest that the level of anemic severity correlates with the delayed status of erythrocyte maturation in zebrafish models.

Research on school leadership suggests that both principal and teacher leadership are important for school improvement. However, few studies have studied the interaction of principal and teacher leadership as separate but linked systems in how they relate to student outcomes. In this study, we examine how leadership pathways are related in the context of high schools and compare findings to research in elementary schools. Using survey and administrative data from high schools in a large urban context, the paper explores direct and indirect pathways from leadership to student achievement growth. The results indicate that there are 2 pathways through which principal leadership is related to student learning in high schools. One pathway is mediated by teacher leadership, whereas the second pathway does not include teacher leadership. We find that similar to elementary schools, the learning climate is the only organizational factor that links principal and teacher leadership with student achievement. [This article was published in "School Effectiveness and School Improvement," (EJ1149257).]

The del(5q) myelodysplastic syndrome (MDS) is a distinct subtype of MDS, associated with deletion of the ribosomal protein S14 (RPS14) gene that results in macrocytic anemia. This study sought to identify novel targets for the treatment of patients with del(5q) MDS by performing an in vivo drug screen using an rps14-deficient zebrafish model. From this, we identified the secreted gelatinase matrix metalloproteinase 9 (MMP9). MMP9 inhibitors significantly improved the erythroid defect in rps14-deficient zebrafish. Similarly, treatment with MMP9 inhibitors increased the number of colony forming unit-erythroid colonies and the CD71+ erythroid population from RPS14 knockdown human BMCD34+ cells. Importantly, we found that MMP9 expression is upregulated in RPS14-deficient cells by monocyte chemoattractant protein 1. Double knockdown of MMP9 and RPS14 increased the CD71+ population compared with RPS14 single knockdown, suggesting that increased expression of MMP9 contributes to the erythroid defect observed in RPS14-deficient cells. In addition, transforming growth factor β (TGF-β) signaling is activated in RPS14 knockdown cells, and treatment with SB431542, a TGF-β inhibitor, improved the defective erythroid development of RPS14-deficient models. We found that recombinant MMP9 treatment decreases the CD71+ population through increased SMAD2/3 phosphorylation, suggesting that MMP9 directly activates TGF-β signaling in RPS14-deficient cells. Finally, we confirmed that MMP9 inhibitors reduce SMAD2/3 phosphorylation in RPS14-deficient cells to rescue the erythroid defect. In summary, these study results support a novel role for MMP9 in the pathogenesis of del(5q) MDS and the potential for the clinical use of MMP9 inhibitors in the treatment of patients with del(5q) MDS.

Despite decades of educational reforms, the achievement gap based on socioeconomic status (SES) persists in the United States. Not only does the SES-based achievement gap persist, it has also been widening. This study focused on the role of students, hypothesizing that students might reduce the SES-based achievement gap by increasing their learning time and persistence. I used both ANOVA and two-level hierarchical linear models (HLM) to analyze the Program for International Student Assessment (PISA) United States data. The findings suggested that students viewing themselves to be persistent were likely to perform better than those viewing themselves to be less persistent. Also increased time learning in school was associated with increased achievement. However, high-SES students generally spent more time learning in school and viewed themselves to be more persistent. Thus learning time and persistence were not likely to address the SES constraint on achievement for a majority of low-SES students unless schools provided them extra classes and learning opportunities.

Although mental health concerns are common among children and adolescents, youth-serving adults often feel underprepared in responding to these challenges. Youth Mental Health First Aid (YMHFA) is a training program designed to teach adults how to assist youths experiencing mental health or addiction challenges. This pilot program evaluation study examined the outcomes of YMHFA associated with adult knowledge, confidence, beliefs, and behaviors. Participants included 2,180 individuals in Ohio who attended a YMHFA training between January 2015 and August 2016; most participants were White women and represented professions in the field of education. Results revealed that YMHFA participants became more confident, willing to help, aware of support and resources, and accepting of individuals with mental health conditions three months posttraining. A high percentage of YMHFA participants also reported applying YMHFA Action Steps at 3, 6, 9, and 12 months after the training. Demographic differences (by race, gender, age, and occupation) in the adult outcomes associated with YMHFA training did not emerge when removing the effects of other participant variables. Limitations, future directions for research, and implications for school psychology practice are discussed in this Service Delivery Brief.

Regenerative medicine holds great promise for both degenerative diseases and traumatic tissue injury which represent significant challenges to the health care system. Hearing loss, which affects hundreds of millions of people worldwide, is caused primarily by a permanent loss of the mechanosensory receptors of the inner ear known as hair cells. This failure to regenerate hair cells after loss is limited to mammals, while all other non-mammalian vertebrates tested were able to completely regenerate these mechanosensory receptors after injury. To understand the mechanism of hair cell regeneration and its association with regeneration of other tissues, we performed a guided mutagenesis screen using zebrafish lateral line hair cells as a screening platform to identify genes that are essential for hair cell regeneration, and further investigated how genes essential for hair cell regeneration were involved in the regeneration of other tissues. We created genetic mutations either by retroviral insertion or CRISPR/Cas9 approaches, and developed a high-throughput screening pipeline for analyzing hair cell development and regeneration. We screened 254 gene mutations and identified 7 genes specifically affecting hair cell regeneration. These hair cell regeneration genes fell into distinct and somewhat surprising functional categories. By examining the regeneration of caudal fin and liver, we found these hair cell regeneration genes often also affected other types of tissue regeneration. Therefore, our results demonstrate guided screening is an effective approach to discover regeneration candidates, and hair cell regeneration is associated with other tissue regeneration.

This study examined the characteristics of teacher incentive pay programs in the United States. Using the 2007-08 SASS data set, it found an inverse relationship between union influence and districts' incentive pay offerings. Large and ethnically diverse districts in urban areas that did not meet the requirements for Adequate Yearly Progress as defined under the "No Child Left Behind Act" are more likely to offer a larger number of economic incentives. Although rural districts are likely to reward teachers in hard-to-staff schools, they are not more likely to reward teachers who are certified by the National Board or who teach in the subject areas of shortage, nor are they more likely to offer multiple financial incentives.

Precise genetic modifications in model animals are essential for biomedical research. Here, we report a programmable "base editing" system to induce precise base conversion with high efficiency in zebrafish. Using cytidine deaminase fused to Cas9 nickase, up to 28% of site-specific single-base mutations are achieved in multiple gene loci. In addition, an engineered Cas9-VQR variant with 5'-NGA PAM specificities is used to induce base conversion in zebrafish. This shows that Cas9 variants can be used to expand the utility of this technology. Collectively, the targeted base editing system represents a strategy for precise and effective genome editing in zebrafish.The use of base editing enables precise genetic modifications in model animals. Here the authors show high efficient single-base editing in zebrafish using modified Cas9 and its VQR variant with an altered PAM specificity.

[This corrects the article DOI: 10.1371/journal.pgen.1006481.].

ATP6V1H is a component of a large protein complex with vacuolar ATPase (V-ATPase) activity. We identified two generations of individuals in which short stature and osteoporosis co-segregated with a mutation in ATP6V1H. Since V-ATPases are highly conserved between human and zebrafish, we generated loss-of-function mutants in atp6v1h in zebrafish through CRISPR/Cas9-mediated gene knockout. Homozygous mutant atp6v1h zebrafish exhibited a severe reduction in the number of mature calcified bone cells and a dramatic increase in the expression of mmp9 and mmp13. Heterozygous adults showed curved vertebra that lack calcified centrum structure and reduced bone mass and density. Treatment of mutant embryos with small molecule inhibitors of MMP9 and MMP13 significantly restored bone mass in the atp6v1h mutants. These studies have uncovered a new, ATP6V1H-mediated pathway that regulates bone formation, and defines a new mechanism of disease that leads to bone loss. We propose that MMP9/MMP13 could be therapeutic targets for patients with this rare genetic disease.

After injury, zebrafish can restore many tissues that do not regenerate well in mammals, making it a useful vertebrate model for studying regenerative biology. We performed a systematic screen to identify genes essential for hair cell regeneration in zebrafish, and found that the heat shock protein Hspd1 (Hsp60) has a critical role in the regeneration of hair cells and amputated caudal fins. We showed HSP60-injected extracellularly promoted cell proliferation and regeneration in both hair cells and caudal fins. We showed that hspd1 mutant was deficient in leukocyte infiltration at the site of injury. Topical application of HSP60 in a diabetic mouse skin wound model dramatically accelerated wound healing compared with controls. Stimulation of human peripheral blood mononuclear cells with HSP60 triggered a specific induction of M2 phase CD163-positive monocytes. Our results demonstrate that the normally intracellular chaperonin HSP60 has an extracellular signalling function in injury inflammation and tissue regeneration, likely through promoting the M2 phase for macrophages.

Glucose is the primary energy source for eukaryotic cells and the predominant substrate for the brain. GLUT3 is essential for trans-placental glucose transport and highly expressed in the mammalian brain. To further elucidate the role of GLUT3 in embryonic development, we utilized the vertebrate whole animal model system of Danio rerio as a tractable system for defining the cellular and molecular mechanisms altered by impaired glucose transport and metabolism related to perturbed expression of GLUT3. The comparable orthologue of human GLUT3 was identified and the expression of this gene abrogated during early embryonic development. In a dose-dependent manner embryonic brain development was disrupted resulting in a phenotype of aberrant brain organogenesis, associated with embryonic growth restriction and increased cellular apoptosis. Rescue of the morphant phenotype was achieved by providing exogenous GLUT3 mRNA. We conclude that GLUT3 is critically important for brain organogenesis and embryonic growth. Disruption of GLUT3 is responsible for the phenotypic spectrum of embryonic growth restriction to demise and neural apoptosis with microcephaly.

The purpose of this study was to examine whether school disciplinary climate and grit predicted low socioeconomic status (SES) students being high achievers in mathematics and science with a representative sample of 15-year-old students in the United States. Our analysis, using a two-level logistic hierarchical linear model (HLM), indicated both disciplinary climate and grit were significantly associated with low-SES students' high achievement in math and science. Low-SES students who perceived themselves as having a higher level of grit and whose classrooms had better disciplinary climate were much more likely to be high achievers. This finding provided supplemental evidence to the limited number of existing studies which suggest achievement gaps could be narrowed by addressing school climate and student grit. In conclusion, we discussed what implications this study could offer for future educational research and policy.

Research on school leadership suggests that both principal and teacher leadership are important for school improvement. However, few studies have studied the interaction of principal and teacher leadership as separate but linked systems in how they relate to student outcomes. In this study, we examine how leadership pathways are related in the context of high schools and compare findings to research in elementary schools. Using survey and administrative data from high schools in a large urban context, the paper explores direct and indirect pathways from leadership to student achievement growth. The results indicate that there are 2 pathways through which principal leadership is related to student learning in high schools. One pathway is mediated by teacher leadership, whereas the second pathway does not include teacher leadership. We find that similar to elementary schools, the learning climate is the only organizational factor that links principal and teacher leadership with student achievement.

School principals can play an important role in promoting teacher leadership by delegating authority and empowering teachers in ways that allow them influence in key organizational decisions and processes. However, it is unclear whether instruction and student learning are enhanced by promoting teacher influence in all aspects of school organization or whether it is better for principals to directly work on certain processes while delegating influence on others. We compare pathways from principal leadership through school organizational processes to student outcomes that include teacher influence as a mediating factor to pathways that do not include teachers' influence. Our results suggest that effective principals use teacher leadership to improve the school learning climate while they work directly on professional development and school program coherence.

The authors' purpose was to examine the relationship between three forms of cultural capital--the embodied, the objectified, and the institutionalized--and student performance in mathematics and science. Their analysis of Trends in International Mathematics and Science Study 2011 data from 32 countries and regions revealed that parental expectation (the embodied cultural capital) had the strongest association with student performance. Parental education (the institutionalized cultural capital) and book possession (the objectified cultural capital) were also significant, with some exceptions. However, their relationship with student performance was relatively weaker. This suggested that the significant relationship between cultural capital and student performance holds in the 32 countries included in the sample, about 4 decades after Bourdieu first introduced the concept (i.e., students with higher parental cultural capital are more likely to perform better in mathematics and science).

BackgroundNXT2 is a member of NXT family proteins that are generally involved in exporting nuclear RNA in eukaryotic cells. It is not known if NXT2 has any function in specific biological processes.ResultsA zebrafish mutant exhibiting specific heart defects during embryogenesis was generated by animal cloning-mediated retroviral insertions. Molecular analysis indicated that the mutant phenotype was caused by a disruption of NXT2. Whole-mount RNA in situ hybridization showed that NXT2 transcripts were clearly detectable in embryonic heart as well as other tissues. Further analysis revealed that expression level of one form of alternative splicing NXT2 mRNA transcripts was significantly reduced, resulting in deficient myocardial cell differentiation and the malformation of cardiac valve at the atrioventricular boundary. The defects could be reproduced by morpholino anti-sense oligo knockdown of NXT2.ConclusionNXT2 has a critical role in maintaining morphogenetic integrity of embryonic heart in vertebrate species.

Since the publication of the Coleman report in 1966, research on the role of schools in influencing student achievement relative to the role of family background has generated considerable interest and controversy. A large volume of international and comparative research has also been devoted to studying school effects on student achievement. Relatively few studies have examined international differences in the importance of schools in bridging achievement gaps based on socioeconomic status (SES). Using PISA 2012 data, this study examines the role of schools in bridging within-school SES gaps in achievement and compares findings across 61 countries. Contrary to prior research, we find that schools may have limited ability in bridging SES gaps that exist within schools. We also find that across all countries included in the study, specific factors such as the school's learning environment and school context are not systematically associated with within-school SES gaps.

Our study sought to understand changes in gender inequality in education across four generations of rural Chinese women's educational experiences in a small community in southern China. The 24 interviews and numerous informal conversations with 12 women showed that gender-based favouritism for men and against women undergirded family expectations, support, and decisions about women's formal education, but this manifested in different ways over generations. It appeared as strict gender division of labour within families, control, or ignorance of women's access to schooling, participants' emotional trauma, lower expectations of daughters' schoolwork, and gender-discriminating language in schools.

Given the growing trend toward using technology to assess student learning, this investigation examined test mode comparability of student achievement scores obtained from paper-pencil and computerized assessments of statewide End-of-Course and End-of-Grade examinations in the subject areas of high school biology and eighth-grade English Language Arts and math. Propensity score matching was used to generate comparable groups of students who were assessed using paper-pencil or computer-based formats. T-tests and generalized linear models were further used to examine test mode effect. Analyses revealed a small test mode effect for all three subjects such that students using the paper-based format achieved higher scores than students using the computer-based format. The findings are germane to school districts transitioning to computerized assessments and investigating test mode comparability. [ABSTRACT FROM AUTHOR]