Six Principles of Language Development: Implications for Second Language Learners

The number of children growing up in dual language environments is increasing in the United States. Despite the apparent benefits of speaking two languages, children learning English as a second language (ESL) often face struggles, as they may experience poverty and impoverished language input at home. Early exposure to a rich language environment is crucial for ESL children’s academic success. This article explores how six evidenced-based principles of language learning can be used to provide support for ESL children.     

Maternal fructose intake during pregnancy modulates hepatic and hypothalamic AMP‐activated protein kinase signalling in a sex‐specific manner in offspring

Dietary fructose ingestion during gestation affects carbohydrate metabolism in the offspring. In the present study, we investigated the effects of excess fructose intake during pregnancy on hepatic and hypothalamic AMP‐activated kinase (AMPK) expression and phosphorylation, as well as hepatic glucose‐6‐phosphatase (G6Pase) activity in offspring. Pregnant Wistar rats received normal chow and 100 g/L fructose solution or normal water during gestation ad libitum. On gestational Day 21, some dams were killed and plasma samples and fetuses were collected. The remaining dams received normal water after spontaneous delivery during lactation. Pups were killed on postnatal Day 22 and the plasma, liver and hypothalamus were collected and analysed. Plasma glucose and insulin levels increased in female but not male offspring in the fructose group. Although the mRNA and total protein levels of AMPKα were unchanged, levels of phosphorylated AMPKα protein in the fructose group of female offspring were significantly lower in the liver and 4.6‐fold higher in the hypothalamus. The hepatic protein level of sirtuin 1, which is involved in AMPK phosphorylation and activation, was significantly reduced in the fructose group of female offspring. The activity of G6Pase, which plays a role in gluconeogenesis, was significantly enhanced in the liver of female offspring from fructose‐fed dams. These changes were not observed in male offspring. In conclusion, we found that excessively high fructose intake during pregnancy may modulate the hepatic and hypothalamic AMPK signalling pathways in female offspring after birth.     

Highly efficient induction of primate iPS cells by combining RNA transfection and chemical compounds

Induced pluripotent stem (iPS) cells hold great promise for regenerative medicine and the treatment of various diseases. Before proceeding to clinical trials, it is important to test the efficacy and safety of iPS cell‐based treatments using experimental animals. The common marmoset is a new world monkey widely used in biomedical studies. However, efficient methods that could generate iPS cells from a variety of cells have not been established. Here, we report that marmoset cells are efficiently reprogrammed into iPS cells by combining RNA transfection and chemical compounds. Using this novel combination, we generate transgene integration‐free marmoset iPS cells from a variety of cells that are difficult to reprogram using conventional RNA transfection method. Furthermore, we show this is similarly effective for human and cynomolgus monkey iPS cell generation. Thus, the addition of chemical compounds during RNA transfection greatly facilitates reprogramming and efficient generation of completely integration‐free safe iPS cells in primates, particularly from difficult‐to‐reprogram cells.     

Inverse Association between Sodium Channel-Blocking Antiepileptic Drug Use and Cancer: Data Mining of Spontaneous Reporting and Claims Databases

Purpose: Voltage-gated sodium channels (VGSCs) are drug targets for the treatment of epilepsy. Recently, a decreased risk of cancer associated with sodium channel-blocking antiepileptic drugs (AEDs) has become a research focus of interest. The purpose of this study was to test the hypothesis that the use of sodium channel-blocking AEDs are inversely associated with cancer, using different methodologies, algorithms, and databases.Methods: A total of 65,146,507 drug-reaction pairs from the first quarter of 2004 through the end of 2013 were downloaded from the US Food and Drug Administration Adverse Event Reporting System. The reporting odds ratio (ROR) and information component (IC) were used to detect an inverse association between AEDs and cancer. Upper limits of the 95% confidence interval (CI) of < 1 and < 0 for the ROR and IC, respectively, signified inverse associations. Furthermore, using a claims database, which contains 3 million insured persons, an event sequence symmetry analysis (ESSA) was performed to identify an inverse association between AEDs and cancer over the period of January 2005 to May 2014. The upper limit of the 95% CI of adjusted sequence ratio (ASR) < 1 signified an inverse association.Results: In the FAERS database analyses, significant inverse associations were found between sodium channel-blocking AEDs and individual cancers. In the claims database analyses, sodium channel-blocking AED use was inversely associated with diagnoses of colorectal cancer, lung cancer, gastric cancer, and hematological malignancies, with ASRs of 0.72 (95% CI: 0.60 - 0.86), 0.65 (0.51 - 0.81), 0.80 (0.65 - 0.98), and 0.50 (0.37 - 0.66), respectively. Positive associations between sodium channel-blocking AEDs and cancer were not found in the study.Conclusion: Multi-methodological approaches using different methodologies, algorithms, and databases suggest that sodium channel-blocking AED use is inversely associated with colorectal cancer, lung cancer, gastric cancer, and hematological malignancies.     

Dual regulation of NR2B and NR2C expression by NMDA receptor activation in mouse cerebellar granule cell cultures

In the developing cerebellum, switching of the subunit composition of NMDA receptors occurs in granule cells from NR2B-containing receptors to NR2C-containing ones. We investigated the mechanisms underlying switching of NR2B and NR2C subunit composition in primary cultures of mouse granule cells at the physiological KCl concentration (5 mM). Granule cells extensively extended their neuritic processes 48 h after having been cultured in serum-free medium containing 5 mM KCl. Consistent with this morphological change, NR2B mRNA and NR2C mRNA were down- and up-regulated, respectively, in the granule cells. This dual regulation of the two mRNAs was abrogated by blocking excitation of granule cells with TTX. This neuronal activity–dependent regulation of NR2B and NR2C mRNAs was abolished by the addition of selective antagonists of AMPA receptors and NMDA receptors. Furthermore, the dual regulation of NR2B and NR2C mRNAs in TTX-treated cells was restored by the addition of NMDA in the presence of the AMPA receptor antagonist, but not by that of AMPA in the presence of the NMDA receptor antagonist. Importantly, the NMDA receptor activation drove the NR2B/NR2C switching of NMDA receptors in the cell-surface membrane of granule cells. This investigation demonstrates that stimulation of NMDA receptors in conjunction with the AMPA receptor–mediated excitation of granule cells plays a key role in functional subunit switching of NMDA receptors in maturing granule cells at the physiological KCl concentration.     

Species differences in intestinal metabolic activities of cytochrome P450 isoforms between cynomolgus monkeys and humans

The oral bioavailability of some drugs is markedly lower in cynomolgus monkeys than in humans. One of the reasons for the low bioavailability in cynomolgus monkeys may be the higher metabolic activity of intestinal CYP3A; however, the species differences in intestinal metabolic activities of other CYP isoforms between cynomolgus monkeys and humans are not well known. In the present study, we investigated the intrinsic clearance (CL(int)) values in pooled intestinal microsomes from cynomolgus monkeys and humans using 25 substrates of human CYP1A2, CYP2J2, CYP2C, and CYP2D6. As in humans, intestinal CL(int) values of human CYP1A2 and CYP2D6 substrates in cynomolgus monkeys were low. On the other hand, intestinal CL(int) values of human CYP2J2 and CYP2C substrates in cynomolgus monkeys were greatly higher than those in humans. Using immunoinhibitory antibodies and chemical inhibitors, we showed that the higher intestinal CL(int) values of the human CYP2J2 and CYP2C substrates in cynomolgus monkeys might be caused by monkey CYP4F and CYP2C subfamily members, respectively. In conclusion, there is a possibility that the greatly higher metabolic activity of CYP2C and CYP4F in cynomolgus monkey intestine is one of the causes of the species difference of intestinal first-pass metabolism between cynomolgus monkeys and humans.     

The impact of H1N1 influenza A virus pandemic on the blood donations in Hyogo Prefecture,Japan

BACKGROUND: The impact of the H1N1 influenza on blood donation is unknown. STUDY DESIGN AND METHODS: We examined number of blood donors presenting to blood donation centers or bloodmobiles using a blood donation database of Red Cross Hyogo Prefectural Blood Center between 4 weeks before and after May 16, 2009, respectively, when the first case of H1N1 influenza was confirmed in Kobe. The numbers of blood donors per donation site (i.e., blood donation centers and bloodmobiles) and per blood products (i.e., red blood cells [RBCs], platelet [PLT]‐poor plasma, and PLTs) were also examined. RESULTS: The number of blood donors decreased by 21% and whole blood donations declined by 1329 units within 1 week of the first case of H1N1 influenza. While number of blood donors showed a rapid decrease, blood donations returned to the normal level within 1 week. This quick recovery was attributed to the diligent efforts made by Red Cross Centers, including the use of e‐mail to encourage blood donation, on‐the‐street campaigns, and requesting new bloodmobile drives in workplaces and universities. RBCs that were donated in bloodmobiles was predominantly affected; the number of blood donors in bloodmobiles decreased by 39%. CONCLUSION: H1N1 influenza pandemic had a great but transient impact on blood donation.     

The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition

Substantial numbers of variants of unknown significance (VUSs) have been identified in BRCA1/2 through genetic testing, which poses a significant clinical challenge because the contribution of these VUSs to cancer predisposition has not yet been determined. Here, we report 10 Japanese patients from seven families with breast or ovarian cancer harboring the BRCA2 c.7847C>T (p.Ser2616Phe) variant that was interpreted as a VUS. This variant recurs only in families from Japan and has not been reported in the global general population databases. A Japanese patient with Fanconi anemia with compound heterozygous variants c.7847C>T (p.Ser2616Phe) and c.475+1G>A in BRCA2 was reported. In silico predictions and quantitative cosegregation analysis suggest a high probability of pathogenicity. The clinical features of the variant carriers were not specific to, but were consistent with, those of patients with hereditary breast and ovarian cancer. A validated functional assay, called the mixed-all-nominated-in-one-BRCA (MANO-B) method and the accurate BRCA companion diagnostic (ABCD) test, demonstrated the deleterious effects of the variant. Altogether, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, this variant satisfied the “PS3,” “PM2,” “PM3,” and “PP3” criteria. We thus conclude that the BRCA2 c.7847C>T (p.Ser2616Phe) variant is a “likely pathogenic” variant that is specifically observed in the Japanese population, leading to a breast and ovarian cancer predisposition.