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Conceptual replications are part and parcel of education science. Methodologically rigorous conceptual replication studies permit researchers to test and strengthen the generalizability of a study's initial findings. The current conceptual replication sought to replicate the efficacy of a small-group, first-grade mathematics intervention with 240 first-grade students with mathematics difficulties in a new geographical region. Participating students were randomized into one of three conditions: (a) 2:1 mathematics intervention group, (b) 5:1 mathematics intervention group, or (c) business-as-usual instruction. Relative to the original study, findings from the replication varied. When comparing the treatment groups to the control, results suggested positive effects on all outcome measures, including a follow-up assessment administered one year later. However, differences between the two treatment groups based on group size were not found in the mathematics outcome measures. Both groups also received commensurate levels of observed instructional interactions. Implications for unpacking contextual differences between original research and their replications as well as using future research to explore the quantity and quality of instructional interactions as ways to explain variation in findings of group size are discussed.

Building proficiency with fraction arithmetic poses a consistent challenge for students with learning difficulties or disabilities in mathematics. This article illustrates how teachers can use the number line model to support struggling learners in making sense of fraction arithmetic. Number lines are a powerful tool that can be used to help students represent and solve problems involving addition, subtraction, multiplication, and division with fractions while building conceptual understanding of the underlying operations. Evidence-based strategies for using number line models to teach fraction arithmetic concepts and skills are described and specific examples provided to illustrate how teachers can strategically integrate number line models with other mathematical representations to support the development of flexible understanding of fractions.

The effectiveness of Tier 2 interventions may depend on the variability of student skills within an intervention group. We investigated the effect of pretest variability within intervention groups using data from a large-scale study of ROOTS, a Tier 2 kindergarten mathematics intervention. Our research questions were as follows: Does mathematics pretest variability within ROOTS groups predict student gains from the intervention, and is this relationship moderated by (a) intervention group size (two- vs. five-student groups), (b) quality of explicit instruction, or (c) group-level initial skill? We found that ROOTS groups with greater pretest variability on a closely aligned mathematics measure experienced smaller gains from the intervention. This association was more impactful in larger intervention groups (i.e., five-student groups compared with two-student groups) and in groups with higher quality of explicit instruction. We unpack these findings and conclude with recommendations for practice and future research.

This study explored whether initial skill moderated outcomes of Promoting Algebra Readiness, a Tier 2 sixth-grade mathematics intervention targeting conceptual and procedural knowledge of fractions. The study analyzed data from a quasi-experimental pilot study in which at-risk students (N = 198) from Oregon middle schools were assigned to the treatment or control condition at the school level. Proximal and distal measures of math proficiency were collected in the fall (pretest) and spring (post-test). Analyses examined initial student achievement as a moderator of mathematics outcomes. Results indicated that intervention outcomes were not moderated by initial skill. Implications for tiered mathematics instruction and future mathematics intervention research are discussed. [For the corresponding grantee submission, see ED627362.]

High-quality Tier 1 instruction is frequently conceptualized as the "foundation" for other tiers of intervention within multitiered systems of support (MTSS) models. However, the vast majority of Tier 2 intervention studies do not account for Tier 1 variables when examining intervention effectiveness. The purpose of this study was to examine Tier 1 predictors, or "quality indicators," of differential responsiveness to Tier 2 mathematics intervention. Data were drawn from a large-scale data set where all teachers taught the Early Learning in Mathematics (Tier 1) core program across the academic year, and a subset of students were selected for the ROOTS (Tier 2) mathematics intervention. We examined the following Tier 1 variables: (a) classroom-level mathematics gains, (b) Tier 1 fidelity of implementation, (c) Tier 1 classroom management and instructional support, and (d) class size. Response to Tier 2 intervention was not significantly predicted by any of the Tier 1 variables examined; however, the pattern of Hedges' g effect sizes suggested that students with higher quality of Tier 1 instruction tended to benefit less from the Tier 2 ROOTS intervention. Results are discussed in the context of implications for research and practice. [For the corresponding grantee submission, see ED626857.]

This study investigated the technical characteristics of four early measurement curriculum-based measures (EM-CBMs) designed to assess concepts related to linear measurement and iteration. The sample consisted of 221 first grade students. Data were collected at two time points approximately 10 weeks apart. Reliability and concurrent and predictive validity correlations were in the low to moderate range. We discuss study results related to screening for risk status including limitations to the current work and future directions for research. Impact Statement: The importance of measurement in mathematics development is garnering increased attention. Exploring measures to screen students for risk status is critical to enable schools to allocate resources to students in need of intervention services. The findings in this manuscript represent a first exploratory attempt to develop screening measures in the area of measurement.

This pilot study examined the promise of a Tier 2 Grade 6 intervention program for students at risk for difficulties in mathematics. The study utilized a quasi-experimental design. The final sample included 112 students in treatment (Promoting Algebra Readiness) and 86 students in control (standard district practice) conditions. The Promoting Algebra Readiness program consisted of 93 lessons across four strands focused on key concepts and applications of fractions. Measures of mathematics achievement were collected at pretest and posttest. Feasibility and usability data indicated favorable impressions by users and strong levels of implementation fidelity. Gain scores of treatment students were significantly greater than those of control peers on two of four proximal measures of mathematics achievement. Positive nonsignificant effects were found on additional proximal and distal measures. Implications for educators delivering instruction for at-risk students in multitier service delivery models are discussed.

Abstract Serine proteases are involved in many biological processes and are associated with irritable bowel syndrome (IBS) pathology. An increase in serine protease activity has been widely reported in IBS patients. While most of the studies focused on host proteases, the contribution of microbial proteases are poorly studied. In the present study, we report the analysis of proteolytic activities in fecal samples from the first Tunisian cohort of IBS-M patients and healthy individuals. We demonstrated, for the first time, that metalloproteases activities were fourfold higher in fecal samples of IBS patients compared to controls. Of interest, the functional characterization of serine protease activities revealed a 50-fold increase in trypsin-like activities and a threefold in both elastase- and cathepsin G-like activities. Remarkably, we also showed a fourfold increase in proteinase 3-like activity in the case of IBS. This study also provides insight into the alteration of gut microbiota and its potential role in proteolytic modulation in IBS. Our results stressed the impact of the disequilibrium of serine proteases, metalloproteases and gut microbiota in IBS and the need of the further characterization of these targets to set out new therapeutic approaches.

A fundamental issue in regenerative medicine is whether there exist endogenous regulatory mechanisms that limit the speed and efficiency of the repair process. We report the existence of a maturation checkpoint during muscle regeneration that pauses myofibers at a neonatal stage. This checkpoint is regulated by the mitochondrial protein mitofusin 2 (Mfn2), the expression of which is activated in response to muscle injury. Mfn2 is required for growth and maturation of regenerating myofibers; in the absence of Mfn2, new myofibers arrested at a neonatal stage, characterized by centrally nucleated myofibers and loss of H3K27me3 repressive marks at the neonatal myosin heavy chain gene. A similar arrest at the neonatal stage was observed in infantile cases of human centronuclear myopathy. Mechanistically, Mfn2 upregulation suppressed expression of hypoxia-induced factor 1α (HIF1α), which is induced in the setting of muscle damage. Sustained HIF1α signaling blocked maturation of new myofibers at the neonatal-to-adult fate transition, revealing the existence of a checkpoint that delays muscle regeneration. Correspondingly, inhibition of HIF1α allowed myofibers to bypass the checkpoint, thereby accelerating the repair process. We conclude that skeletal muscle contains a regenerative checkpoint that regulates the speed of myofiber maturation in response to Mfn2 and HIF1α activity.

Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy. Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant. TOMM7, a nuclear gene, encodes a translocase in the outer mitochondrial membrane. The TOMM complex makes up the outer membrane pore, which is responsible for importing many preproteins into the mitochondria. A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism. We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts. We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features.

Mitochondrial electron transport chain (ETC) dysfunction due to mutations in the nuclear or mitochondrial genome is a common cause of metabolic disease in humans and displays striking tissue specificity depending on the affected gene. The mechanisms underlying tissue-specific phenotypes are not understood. Complex I (cI) is classically considered the entry point for electrons into the ETC, and in vitro experiments indicate that cI is required for basal respiration and maintenance of the NAD+/NADH ratio, an indicator of cellular redox status. This finding has largely not been tested in vivo. Here, we report that mitochondrial complex I is dispensable for homeostasis of the adult mouse liver; animals with hepatocyte-specific loss of cI function display no overt phenotypes or signs of liver damage, and maintain liver function, redox and oxygen status. Further analysis of cI-deficient livers did not reveal significant proteomic or metabolic changes, indicating little to no compensation is required in the setting of complex I loss. In contrast, complex IV (cIV) dysfunction in adult hepatocytes results in decreased liver function, impaired oxygen handling, steatosis, and liver damage, accompanied by significant metabolomic and proteomic perturbations. Our results support a model whereby complex I loss is tolerated in the mouse liver because hepatocytes use alternative electron donors to fuel the mitochondrial ETC.

A fundamental issue in regenerative medicine is whether there exist endogenous regulatory mechanisms that limit the speed and efficiency of the repair process. We report the existence of a maturation checkpoint during muscle regeneration that pauses myofibers at a neonatal stage. This checkpoint is regulated by the mitochondrial protein mitofusin 2 (Mfn2), the expression of which is activated in response to muscle injury. Mfn2 is required for growth and maturation of regenerating myofibers; in the absence of Mfn2, new myofibers arrested at a neonatal stage, characterized by centrally nucleated myofibers and loss of H3K27me3 repressive marks at the neonatal myosin heavy chain gene. A similar arrest at the neonatal stage was observed in infantile cases of human centronuclear myopathy. Mechanistically, Mfn2 upregulation suppressed expression of hypoxia-induced factor 1a (HIF1[alpha]), which is induced in the setting of muscle damage. Sustained HIF1[alpha] signaling blocked maturation of new myofibers at the neonatal-to-adult fate transition, revealing the existence of a checkpoint that delays muscle regeneration. Correspondingly, inhibition of HIF1[alpha] allowed myofibers to bypass the checkpoint, thereby accelerating the repair process. We conclude that skeletal muscle contains a regenerative checkpoint that regulates the speed of myofiber maturation in response to Mfn2 and HIF1[alpha] activity., Introduction In response to injury, skeletal muscle undergoes a synchronized sequence of events over several days, including clearance of muscle debris, revascularization of the damaged region, activation and proliferation of [...]

Multiple genetic loci have been reported for progeroid syndromes. However, the molecular defects in some extremely rare forms of progeria have yet to be elucidated. Here, we report a 21-year-old man of Chinese ancestry who has an autosomal recessive form of progeria, characterized by severe dwarfism, mandibular hypoplasia, hyperopia, and partial lipodystrophy. Analyses of exome sequencing data from the entire family revealed only 1 rare homozygous missense variant (c.86C>T; p.Pro29Leu) in TOMM7 in the proband, while the parents and 2 unaffected siblings were heterozygous for the variant. TOMM7, a nuclear gene, encodes a translocase in the outer mitochondrial membrane. The TOMM complex makes up the outer membrane pore, which is responsible for importing many preproteins into the mitochondria. A proteomic comparison of mitochondria from control and proband-derived cultured fibroblasts revealed an increase in abundance of several proteins involved in oxidative phosphorylation, as well as a reduction in abundance of proteins involved in phospholipid metabolism. We also observed elevated basal and maximal oxygen consumption rates in the fibroblasts from the proband as compared with control fibroblasts. We concluded that altered mitochondrial protein import due to biallelic loss-of-function TOMM7 can cause severe growth retardation and progeroid features., Introduction In the last 2 decades, considerable progress has been made in identifying the molecular genetic basis of several progeroid syndromes, including mandibuloacral dysplasia (MAD), mandibular hypoplasia, deafness and progeroid [...]

Conceptual replications are part and parcel of education science. Methodologically rigorous conceptual replication studies permit researchers to test and strengthen the generalizability of a study's initial findings. The current conceptual replication sought to replicate the efficacy of a small-group, first-grade mathematics intervention with 240 first-grade students with mathematics difficulties in a new geographical region. Participating students were randomized into one of three conditions: (a) 2:1 mathematics intervention group, (b) 5:1 mathematics intervention group, or (c) business-as-usual instruction. Relative to the original study, findings from the replication varied. When comparing the treatment groups to the control, results suggested positive effects on all outcome measures, including a follow-up assessment administered one year later. However, differences between the two treatment groups based on group size were not found in the mathematics outcome measures. Both groups also received commensurate levels of observed instructional interactions. Implications for unpacking contextual differences between original research and their replications as well as using future research to explore the quantity and quality of instructional interactions as ways to explain variation in findings of group size are discussed. [ABSTRACT FROM AUTHOR]

The following article discusses some problems in the translation of the German comic book “Der Fönig” into Polish. The main concern is to define the semantic dominant of the source text correctly and to find any adequate translation possibilities of language phenomena, which could contribute to problems in the translator’s work. As the source text has not been translated into Polish yet, the author presents his own translation proposals of two problematic fragments of the German original.

Kallikrein‐related peptidase 14 (KLK14) is one of the several secreted KLK serine proteases involved in prostate cancer (PCa) pathogenesis. While relatively understudied, recent reports have identified KLK14 as overexpressed during PCa development. However, the modulation of KLK14 expression during PCa progression and the molecular and biological functions of this protease in the prostate tumor microenvironment remain unknown. To determine the modulation of KLK14 expression during PCa progression, we analyzed the expression levels of KLK14 in patient samples using publicly available databases and immunohistochemistry. In order to delineate the molecular mechanisms involving KLK14 in PCa progression, we integrated proteomic, transcriptomic, and in vitro assays with the goal to identify substrates, related‐signaling pathways, and functional roles of this protease. We showed that KLK14 expression is elevated in advanced PCa, and particularly in metastasis. Additionally, KLK14 levels were found to be decreased in PCa tissues from patients responsive to neoadjuvant therapy compared to untreated patients. Furthermore, we also identified that KLK14 expression reoccurred in patients who developed castrate‐resistant PCa. The combination of proteomic and transcriptomic analysis as well as functional assays revealed several new KLK14 substrates (agrin, desmoglein 2, vitronectin, laminins) and KLK14‐regulated genes (Interleukin 32, midkine, SRY‐Box 9), particularly an involvement of the mitogen‐activated protein kinase 1 and interleukin 1 receptor pathways, and an involvement of KLK14 in the regulation of cellular migration, supporting its involvement in aggressive features of PCa progression. In conclusion, our work showed that KLK14 expression is associated with the development of aggressive PCa suggesting that targeting this protease could offer a novel route to limit the progression of prostate tumors. Additional work is necessary to determine the benefits and implications of targeting/cotargeting KLK14 in PCa as well as to determine the potential use of KLK14 expression as a predictor of PCa aggressiveness or response to treatment.

The effectiveness of Tier 2 interventions may depend on the variability of student skills within an intervention group. We investigated the effect of pretest variability within intervention groups using data from a large-scale study of ROOTS, a Tier 2 kindergarten mathematics intervention. Our research questions were as follows: Does mathematics pretest variability within ROOTS groups predict student gains from the intervention, and is this relationship moderated by (a) intervention group size (two- vs. five-student groups), (b) quality of explicit instruction, or (c) group-level initial skill? We found that ROOTS groups with greater pretest variability on a closely aligned mathematics measure experienced smaller gains from the intervention. This association was more impactful in larger intervention groups (i.e., five-student groups compared with two-student groups) and in groups with higher quality of explicit instruction. We unpack these findings and conclude with recommendations for practice and future research. [ABSTRACT FROM AUTHOR]