Research paper: Wh-questions' expression in persianspeaking children: A comparison between spontaneous and elicited probes

Objectives: Studies have shown that most children before the age of 5 are capable to comprehend and express wh-questions in daily conversations. This study aimed at comparing the ability of wh-questions' production in 4-6-year-old children in spontaneous and elicited conditions. Methods: In this descriptive-analytic study, 72 (n=72) 4-6-year-old Persian-speaking children were selected randomly from kindergartens of Hamadan, Iran. Three different probes were used to evaluate the spontaneous and elicited conditions in the expression of questions with "what, where, who, why, and when". In the first probe, children were encouraged to ask questions spontaneously about experimental pictures. While in the second probe, the verbal prompt was presented about wh-questions, and wh-words were provided as key-words in the third probe. Repeated measures analysis of variance test with between-subjects' factors of sex (male, female) and age group (4-5 years, 5-6 years) and within-subjects' factor of the method (I, II, III) was performed in the study. Results: There was a main effect of probes in "where, who, and when" questions and the mean scores of the II and III probes were significantly higher than those of probe I. Children in probe I received higher scores for why questions than the other probes. "What" questions were expressed more by children in probe II. "Why, when, and where" scores were significantly higher for 5-6 years group than for 4-5 years group. There was no significant effect on all wh-questions. Discussion: The higher accuracy of wh-questions in probe II and III compared to probe I suggested that this competence is significantly developed by the use of elicited procedures (verbal prompt or providing wh-words as key-words) in comparison with no elicitation. © 2020 University of Social Welfare and Rehabilitation Sciences

RET PLCγ Phosphotyrosine Binding Domain Regulates Ca2+ Signaling and Neocortical Neuronal Migration

The receptor tyrosine kinase RET plays an essential role during embryogenesis in regulating cell proliferation, differentiation, and migration. Upon glial cell line-derived neurotrophic factor (GDNF) stimulation, RET can trigger multiple intracellular signaling pathways that in concert activate various downstream effectors. Here we report that the RET receptor induces calcium (Ca2+) signaling and regulates neocortical neuronal progenitor migration through the Phospholipase-C gamma (PLCγ) binding domain Tyr1015. This signaling cascade releases Ca2+ from the endoplasmic reticulum through the inositol 1,4,5-trisphosphate receptor and stimulates phosphorylation of ERK1/2 and CaMKII. A point mutation at Tyr1015 on RET or small interfering RNA gene silencing of PLCγ block the GDNF-induced signaling cascade. Delivery of the RET mutation to neuronal progenitors in the embryonic ventricular zone using in utero electroporation reveal that Tyr1015 is necessary for GDNF-stimulated migration of neurons to the cortical plate. These findings demonstrate a novel RET mediated signaling pathway that elevates cytosolic Ca2+ and modulates neuronal migration in the developing neocortex through the PLCγ binding domain Tyr1015

“We have been working overnight without sleeping”: traditional birth attendants’ practices and perceptions of post-partum care services in rural Tanzania

Background: In many low-income countries, formal post-partum care utilization is much lower than that of skilled delivery and antenatal care. While Traditional Birth Attendants (TBAs) might play a role in post-partum care, research exploring their attitudes and practices during this period is scarce. Therefore, the aim of this study was to explore TBAs’ practices and perceptions in post-partum care in rural Tanzania. Methods: Qualitative in-depth interview data were collected from eight untrained and three trained TBAs. Additionally, five multiparous women who were clients of untrained TBAs were also interviewed. Interviews were conducted in February 2013. Data were digitally recorded and transcribed verbatim. Qualitative content analysis was used to analyze data. Results: Our study found that TBAs take care of women during post-partum with rituals appreciated by women. They report lacking formal post-partum care training, which makes them ill-equipped to detect and handle post-partum complications. Despite their lack of preparation, they try to provide care for some post-partum complications which could put the health of the woman at risk. TBAs perceive that utilization of hospital-based post-partum services among women was only important for the baby and for managing complications which they cannot handle. They are poorly linked with the health system. Conclusions: This study found that the TBAs conducted close follow-ups and some of their practices were appreciated by women. However, the fact that they were trying to manage certain post-partum complications can put women at risk. These findings point out the need to enhance the communication between TBAs and the formal health system and to increase the quality of the TBA services, especially in terms of prompt referral, through provision of training, mentoring, monitoring and supervision of the TBA servic

Dcas Supports Cell Polarization and Cell-Cell Adhesion Complexes in Development

Mammalian Cas proteins regulate cell migration, division and survival, and are often deregulated in cancer. However, the presence of four paralogous Cas family members in mammals (BCAR1/p130Cas, EFS/Sin1, NEDD9/HEF1/Cas-L, and CASS4/HEPL) has limited their analysis in development. We deleted the single Drosophila Cas gene, Dcas, to probe the developmental function of Dcas. Loss of Dcas had limited effect on embryonal development. However, we found that Dcas is an important modulator of the severity of the developmental phenotypes of mutations affecting integrins (If and mew) and their downstream effectors Fak56D or Src42A. Strikingly, embryonic lethal Fak56D-Dcas double mutant embryos had extensive cell polarity defects, including mislocalization and reduced expression of E-cadherin. Further genetic analysis established that loss of Dcas modified the embryonal lethal phenotypes of embryos with mutations in E-cadherin (Shg) or its signaling partners p120- and β-catenin (Arm). These results support an important role for Cas proteins in cell-cell adhesion signaling in development

Levels of DNA methylation vary at CpG sites across the BRCA1 promoter, and differ according to triple negative and "BRCA-like" status, in both blood and tumour DNA

Triple negative breast cancer is typically an aggressive and difficult to treat subtype. It is often associated with loss of function of the BRCA1 gene, either through mutation, loss of heterozygosity or methylation. This study aimed to measure methylation of the BRCA1 gene promoter at individual CpG sites in blood, tumour and normal breast tissue, to assess whether levels were correlated between different tissues, and with triple negative receptor status, histopathological scoring for BRCA-like features and BRCA1 protein expression. Blood DNA methylation levels were significantly correlated with tumour methylation at 9 of 11 CpG sites examined (p<0.0007). The levels of tumour DNA methylation were significantly higher in triple negative tumours, and in tumours with high BRCA-like histopathological scores (10 of 11 CpG sites; p<0.01 and p<0.007 respectively). Similar results were observed in blood DNA (6 of 11 CpG sites; p<0.03 and 7 of 11 CpG sites; p<0.02 respectively). This study provides insight into the pattern of CpG methylation across the BRCA1 promoter, and supports previous studies suggesting that tumours with BRCA1 promoter methylation have similar features to those with BRCA1 mutations, and therefore may be suitable for the same targeted therapies

Immunophenotypic predictive profiling of BRCA1-associated breast cancer

The immunophenotypic predictive profile of BRCA1-associated cancers including major predictive markers, i.e., PARP-1, EGFR, c-kit, HER-2, and steroid hormones (ER/PR) that may have therapeutic relevance has not yet been reported in a comprehensive study. Using immunohistochemistry, we examined the expression of these proteins in a large cohort of BRCA1-associated breast cancers. PARP-1 immunoreactivity was found in 81.9%, EGFR in 43.6%, ER/PR in 17.9%, c-kit in 14.7%, and overexpression of HER-2 in 3.6% of cancers. For all markers studied, 8.2% of tumors were negative. Expression of only one predictive marker was found in 29.7% of cancers, and most frequently, it was PARP-1 (20.8%). In 62.1% of tumors, more than one predictive marker was expressed: PARP-1 and EGFR in 30.4%, PARP-1, and hormone receptors in 13.3% and PARP-1 with c-kit in 7.5% of all tumors. Coexpression of two or more other predictive markers was rare. There were significant differences in the median age at diagnosis of BRCA1-associated cancer between patients with ER+ vs. ER− and grades 1–2 vs. grade 3 tumors. These results demonstrate that BRCA1-associated cancers differ with respect to expression of proteins that are regarded as targets for specific therapies and that 92% of patients with BRCA1-associated cancers may benefit from one or several options for specific therapy (in addition to DNA damaging agents, e.g., cisplatin). About 8% of cancers which do not express therapeutic target proteins may not respond to such therapies. Knowledge of the immunophenotypic predictive profile may help with the recruitment of patients for trials of targeted therapies

The Centrosomal Kinase Plk1 Localizes to the Transition Zone of Primary Cilia and Induces Phosphorylation of Nephrocystin-1

Polo-like kinase (Plk1) plays a central role in regulating the cell cycle. Plk1-mediated phosphorylation is essential for centrosome maturation, and for numerous mitotic events. Although Plk1 localizes to multiple subcellular sites, a major site of action is the centrosomes, which supports mitotic functions in control of bipolar spindle formation. In G0 or G1 untransformed cells, the centriolar core of the centrosome differentiates into the basal body of the primary cilium. Primary cilia are antenna-like sensory organelles dynamically regulated during the cell cycle. Whether Plk1 has a role in ciliary biology has never been studied. Nephrocystin-1 (NPHP1) is a ciliary protein; loss of NPHP1 in humans causes nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. We here demonstrate that Plk1 colocalizes with nephrocystin-1 to the transition zone of primary cilia in epithelial cells. Plk1 co-immunoprecipitates with NPHP1, suggesting it is part of the nephrocystin protein complex. We identified a candidate Plk1 phosphorylation motif (D/E-X-S/T-φ-X-D/E) in nephrocystin-1, and demonstrated in vitro that Plk1 phosphorylates the nephrocystin N-terminus, which includes the specific PLK1 phosphorylation motif. Further, induced disassembly of primary cilia rapidly evoked Plk1 kinase activity, while small molecule inhibition of Plk1 activity or RNAi-mediated downregulation of Plk1 limited the first and second phase of ciliary disassembly. These data identify Plk1 as a novel transition zone signaling protein, suggest a function of Plk1 in cilia dynamics, and link Plk1 to the pathogenesis of NPH and potentially other cystic kidney diseases

BRCA1-mutated and basal-like breast cancers have similar aCGH profiles and a high incidence of protein truncating TP53 mutations

<p>Abstract</p> <p>Background</p> <p>Basal-like breast cancers (BLBC) are aggressive breast cancers for which, so far, no targeted therapy is available because they typically lack expression of hormone receptors and HER2. Phenotypic features of BLBCs, such as clinical presentation and early age of onset, resemble those of breast tumors from <it>BRCA1</it>-mutation carriers. The genomic instability of <it>BRCA1</it>-mutated tumors can be effectively targeted with DNA-damaging agents and poly-(ADP-ribose) polymerase 1 (PARP1) inhibitors. Molecular similarities between BLBCs and <it>BRCA1</it>-mutated tumors may therefore provide predictive markers for therapeutic response of BLBCs.</p> <p>Methods</p> <p>There are several known molecular features characteristic for <it>BRCA1</it>-mutated breast tumors: 1) increased numbers of genomic aberrations, 2) a distinct pattern of genomic aberrations, 3) a high frequency of <it>TP53 </it>mutations and 4) a high incidence of complex, protein-truncating <it>TP53 </it>mutations. We compared the frequency of <it>TP53 </it>mutations and the pattern and amount of genomic aberrations between <it>BRCA1</it>-mutated breast tumors, BLBCs and luminal breast tumors by <it>TP53 </it>gene sequencing and array-based comparative genomics hybridization (aCGH) analysis.</p> <p>Results</p> <p>We found that the high incidence of protein truncating <it>TP53 </it>mutations and the pattern and amount of genomic aberrations specific for BRCA1-mutated breast tumors are also characteristic for BLBCs and different from luminal breast tumors.</p> <p>Conclusions</p> <p>Complex, protein truncating TP53 mutations in BRCA1-mutated tumors may be a direct consequence of genomic instability caused by BRCA1 loss, therefore, the presence of these types of TP53 mutations in sporadic BLBCs might be a hallmark of BRCAness and a potential biomarker for sensitivity to PARP inhibition. Also, our data suggest that a small subset of genomic regions may be used to identify BRCA1-like BLBCs. BLBCs share molecular features that were previously found to be specific for BRCA1-mutated breast tumors. These features might be useful for the identification of tumors with increased sensitivity to (high-dose or dose-dense) alkylating agents and PARP inhibitors.</p

The TP53 Arg72Pro and MDM2 309G>T polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

Background: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. Methods: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. Results: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93–1.10, Ptrend=0.77; MDM2: HR=0.96, 95%CI: 0.84–1.09, Ptrend=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87–1.12, Ptrend=0.83; MDM2: HR=0.98, 95%CI: 0.80–1.21, Ptrend=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. Conclusion: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers. O M Sinilnikova1,2, A C Antoniou3, J Simard4, S Healey5, M Léoné1, D Sinnett6,7, A B Spurdle5, J Beesley5, X Chen5, kConFab8, M H Greene9, J T Loud9, F Lejbkowicz10, G Rennert10, S Dishon10, I L Andrulis11,12, OCGN11, S M Domchek13, K L Nathanson13, S Manoukian14, P Radice15,16, I Konstantopoulou17, I Blanco18, A L Laborde19, M Durán20, A Osorio21, J Benitez21, U Hamann22, F B L Hogervorst23, T A M van Os24, H J P Gille25, HEBON23, S Peock3, M Cook3, C Luccarini26, D G Evans27, F Lalloo27, R Eeles28, G Pichert29, R Davidson30, T Cole31, J Cook32, J Paterson33, C Brewer34, EMBRACE3, D J Hughes35, I Coupier36,37, S Giraud1, F Coulet38, C Colas38, F Soubrier38, E Rouleau39, I Bièche39, R Lidereau39, L Demange40, C Nogues40, H T Lynch41, GEMO1,2,42, R K Schmutzler43, B Versmold43, C Engel44, A Meindl45, N Arnold46, C Sutter47, H Deissler48, D Schaefer49, U G Froster50, GC-HBOC43,44,45,46,47,48,49,50, K Aittomäki51, H Nevanlinna52, L McGuffog3, D F Easton3, G Chenevix-Trench5 and D Stoppa-Lyonnet42 on behalf of the Consortium of Investigators of Modifiers of BRCA1/