No evidence that playing a linear number board game improves numerical skills beyond teaching as usual: A randomized controlled trial in 4- to 5-year-old primary school children

Early numerical skills are important not only for later mathematical achievement but for overall achievement and are associated with later income, health, and quality of life. Socioeconomic disparities in numerical skills are visible before children begin school, and widen throughout schooling. It is, therefore, important to support the development of early numerical skills in children from lower socioeconomic backgrounds. Previous studies have highlighted the effectiveness of linear number board games for improving early numerical skills, and the beneficial effect of counting backward as well as forward. We designed a number board game that required children to place number cards in order on a line, either forward-only or forward and backward in small groups in the classroom. The game’s effectiveness was evaluated in 4- to 5-year-old children from schools located in socioeconomically disadvantaged areas. Children were randomly allocated to one of three conditions: playing the number game forward-only (n = 82), playing the number game forward and backward (i.e., bidirectional condition; n = 82), or an alphabet game (active control, n = 85). After eight gameplay sessions across 5 weeks, children’s numerical and letter-sound knowledge skills improved, but there was no significant effect of the intervention condition. Neither forward nor bidirectional number line games (nor the alphabet game) added benefits beyond the learning already happening in the classroom. Short linear board game interventions may be effective compared to control groups who received minimal or absent numerical education, but they fail to provide an additional advantage when children are already learning mathematics in school.</p

How do Socioeconomic Attainment Gaps in Early Mathematical Ability Arise?

Socioeconomic attainment gaps in mathematical ability are evident before children begin school, and widen over time. Little is known about why early attainment gaps emerge. Two cross-sectional correlational studies were conducted in 2018–2019 with socioeconomically diverse preschoolers, to explore four factors that might explain why attainment gaps arise: working memory, inhibitory control, verbal ability, and frequency of home mathematical activities (N = 304, 54% female; 84% White, 10% Asian, 1% black African, 1% Kurdish, 4% mixed ethnicity). Inhibitory control and verbal ability emerged as indirect factors in the relation between socioeconomic status and mathematical ability, but neither working memory nor home activities did. We discuss the implications this has for future research to understand, and work towards narrowing attainment gaps

How do Socioeconomic Attainment Gaps in Early Mathematical Ability Arise?

The socioeconomic attainment gap in mathematical ability is evident before children begin school and widens over time. Little is known about why this early attainment gap emerges. Two studies were conducted in 3- and 4-year-olds, to explore four possible factors that may explain why attainment gaps arise: working memory, inhibitory control, verbal ability, and frequency of home mathematical activities (N = 304, 54% female from a range of ethnic backgrounds but predominantly White British [76%]). Inhibitory control and verbal ability emerged as indirect factors in the relation between socioeconomic status and early mathematical ability, but neither working memory nor home mathematical activities did. These studies provide important insights about how the early attainment gap in mathematical ability may arise

Breast-Specific Epigenetic Regulation of DeltaNp73 and Its Role in DNA-Damage-Response of BRCA1-Mutated Human Mammary Epithelial Cells

The function of BRCA1/2 proteins is essential for maintaining genomic integrity in all cell types. However, why women who carry deleterious germline mutations in BRCA face an extremely high risk of developing breast and ovarian cancers specifically has remained an enigma. We propose that breast-specific epigenetic modifications, which regulate tissue differentiation, could team up with BRCA deficiency and affect tissue susceptibility to cancer. In earlier work, we compared genome-wide methylation profiles of various normal epithelial tissues and identified breast-specific methylated gene promoter regions. Here, we focused on deltaNp73, the truncated isoform of p73, which possesses antiapoptotic and pro-oncogenic functions. We showed that the promoter of deltaNp73 is unmethylated in normal human breast epithelium and methylated in various other normal epithelial tissues and cell types. Accordingly, deltaNp73 was markedly induced by DNA damage in human mammary epithelial cells (HMECs) but not in other epithelial cell types. Moreover, the induction of deltaNp73 protected HMECs from DNA damage-induced cell death, and this effect was more substantial in HMECs from BRCA1 mutation carriers. Notably, when BRCA1 was knocked down in MCF10A, a non-malignant breast epithelial cell line, both deltaNp73 induction and its protective effect from cell death were augmented upon DNA damage. Interestingly, deltaNp73 induction also resulted in inhibition of BRCA1 and BRCA2 expression following DNA damage. In conclusion, breast-specific induction of deltaNp73 promotes survival of BRCA1-deficient mammary epithelial cells upon DNA damage. This might result in the accumulation of genomic alterations and allow the outgrowth of breast cancers. These findings indicate deltaNp73 as a potential modifier of breast cancer susceptibility in BRCA1 mutation carriers and may stimulate novel strategies of prevention and treatment for these high-risk women

Loss of glycine transporter 1 causes a subtype of glycine encephalopathy with arthrogryposis and mildly elevated cerebrospinal fluid glycine

Glycine is a major neurotransmitter that activates inhibitory glycine receptors and is a co-agonist for excitatory glutamatergic N-methyl-D-aspartate (NMDA) receptors. Two transporters, GLYT1 and GLYT2, regulate extracellular glycine concentrations within the CNS. Dysregulation of the extracellular glycine has been associated with hyperekplexia and nonketotic hyperglycinemia. Here, we report four individuals from two families who presented at birth with facial dysmorphism, encephalopathy, arthrogryposis, hypotonia progressing to hypertonicity with startle-like clonus, and respiratory failure. Only one individual survived the respiratory failure and was weaned off ventilation but has significant global developmental delay. Mildly elevated cerebrospinal fluid (CSF) glycine and normal serum glycine were observed in two individuals. In both families, we identified truncating mutations in SLC6A9, encoding GLYT1. We demonstrate that pharmacologic or genetic abolishment of GlyT1 activity in mice leads to mildly elevated glycine in the CSF but not in blood. Additionally, previously reported slc6a9-null mice and zebrafish mutants also display phenotypes consistent with the affected individuals we examined. Our data suggest that truncating SLC6A9 mutations lead to a distinct human neurological syndrome hallmarked by mildly elevated CSF glycine and normal serum glycine

Tissue Specific DNA Methylation in Normal Human Breast Epithelium and in Breast Cancer

<div><p>Cancer is a heterogeneous and tissue-specific disease. Thus, the tissue of origin reflects on the natural history of the disease and dictates the therapeutic approach. It is suggested that tissue differentiation, mediated mostly by epigenetic modifications, could guide tissue-specific susceptibility and protective mechanisms against cancer. Here we studied breast specific methylation in purified normal epithelium and its reflection in breast cancers. We established genome wide methylation profiles of various normal epithelial tissues and identified 110 genes that were differentially methylated in normal breast epithelium. A number of these genes also showed methylation alterations in breast cancers. We elaborated on one of them, TRIM29 (ATDC), and showed that its promoter was hypo-methylated in normal breast epithelium and heavily methylated in other normal epithelial tissues. Moreover, in breast carcinomas methylation increased and expression decreased whereas the reverse was noted for multiple other carcinomas. Interestingly, TRIM29 regulation in breast tumors clustered according to the PAM50 classification. Thus, it was repressed in the estrogen receptor positive tumors, particularly in the more proliferative luminal B subtype. This goes in line with previous reports indicating tumor suppressive activity of TRIM29 in estrogen receptor positive luminal breast cells in contrast to oncogenic function in pancreatic and lung cancers. Overall, these findings emphasize the linkage between breast specific epigenetic regulation and tissue specificity of cancer.</p></div

TRIM29 promoter methylation and gene expression varies in normal epithelial tissues.

<p>(<b>A&C</b>) Q-MSP at TRIM29 promoter in (<b>A</b>) various human normal tissues enriched for epithelium and (<b>C</b>) purified human normal epithelial cells. The same tissue samples studied by the Illumina methylation array were included in (A). Q-MSP amplicon overlapped with the sequence of Illumina probe #cg13625403 used for array analysis (<b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091805#pone.0091805.s005" target="_blank">Table S4</a></b>). (<b>B&D</b>) The same samples were used for gene expression analysis by qRT-PCR that showed inverse correlation with promoter methylation (RNA was not available for fallopian tube and urinary bladder). HMEC- human mammary epithelial cells, HPEpiC-prostate, OvEC-ovarian, HCEpiC- colon, HUtEpiC-uterine, HREC-renal. (<b>E</b>) Data from Illumina Infinium methylation450K array obtained from ENCODE showed similar pattern of TRIM29 promoter methylation in additional purified human normal epithelial cells. Methylation at 5 Illumina probes is shown: 1.cg20655548 2.cg12201660 3.cg17971587 4.cg13285004 5.cg13625403 (<b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091805#pone.0091805.s005" target="_blank">Table S4B</a></b>). Each row refers to one individual.</p

Bidirectional “switch” in TRIM29 regulation from normal epithelium to the respective carcinomas.

<p>TCGA data analysis: (<b>A</b>) TRIM29 promoter methylation (average of 5 Illumina probes, <b><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0091805#pone.0091805.s005" target="_blank">Table S4B</a></b>) in normal and in cancer tissues. Partial methylation was noted in breast and prostate normal tissues that increased in the respective cancers. In contrast, for the other tissue-types, methylation was high in the normal tissues and decreased in the respective carcinomas. (<b>B</b>) For breast and prostate cancers, increase in promoter methylation was associated with decrease in gene expression whereas the opposite was noted for the other tissues. BRCA = breast carcinoma, PRAD = prostate adenocarcinoma, LUSC = lung squamous cell carcinoma, BLCA = bladder carcinoma, PAAD = pancreatic adenocarcinoma, COAD = colon adenocarcinoma, READ = rectal adenocarcinoma UCEC = uterine-cervix carcinoma. Number of samples indicated at the bottom, <b>***</b>p<0.0001, NS – not significant, P-values between groups were calculated using Welch's corrected t-test.</p

Genome-wide methylation analysis of various normal human epithelial tissues.

<p>Pearson correlation coefficient was calculated (<b>A</b>) between the right and the left breast and (<b>B</b>) between breast epithelium and WBC of the same woman. (<b>C</b>) Principal Component Analysis (PCA) grouped 15 tissue samples by their global methylation resemblance into 5 clusters that corresponded with the origin of the tissues.</p