Ditransitive structures in child language acquisition: An investigation of production and comprehension in children aged five to seven.

The aim of the present study was to investigate the acquisition of ditransitive structures beyond production. We conducted an elicitation task (production) and a picture-sentence matching task measuring accuracy and response times (comprehension). We examined German five-to seven-year-old typically developing children and an adult control group. Our data showed quasi-perfect performance in comprehension in adults and in those children who had already mastered ditransitives productively. However, children who had not yet mastered the production of ditransitives showed comprehension abilities preceding production abilities. Unlike adults, in the comprehension task children did not react explicitly before the end of the auditory stimulus.

The role of age and timing in bilingual assessment: non-word repetition, subject-verb agreement and case marking in L1 and eL2 children with and without SLI.

Diagnostics in bilingual children is challenging, due to an overlap of production patterns in typically developing (TD) bilingual children and monolingual children with specific language impairment (SLI). To screen bilingual children effectively, the Language Impairment Testing in Multilingual Settings (LITMUS) tools were developed in an international project. The present study tests three of these tools for their suitability and diagnostic accuracy for early second language learners (eL2) of German, aged six to eight years. The study focuses on the timing in first language (L1) TD acquisition, investigating early and late acquisition phenomena of the morphosyntactic domain (subject-verb agreement [SVA], and case marking), combined with a non-word repetition (NWR) task targeting phonological complexity. The study aims at evaluating these three LITMUS-tools regarding their diagnostic accuracy, compared to a standardised assessment tool (LiSe-DaZ).To this end, forty-two children were tested using the LITMUS-tools, namely, contrastive case marking (CCM), supplemented by an elicitation task for the prepositional case, SVA and NWR. Four groups of children participated: eL2 children with SLI (mean age 7;6, mean age of onset 3;1), eL2 children with TD (mean age 7;10, mean age of onset 2;11), L1 TD children (mean age 7;3) and L1 SLI children (mean age 7;2). Results show NWR and SVA as suitable markers and the LITMUS-tools as suitable screenings. Conversely, CCM does not disentangle SLI from TD in the investigated bilingual population by this age.

SUMO pathway inhibition targets an aggressive pancreatic cancer subtype.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies. DESIGN: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC. RESULTS: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition. CONCLUSION: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.

Supporting second language acquisition of bilingual preschool children through professionalization of caregivers in specialized preschool programs.

The aim of the present study was to investigate the effectiveness of a training program on language support strategies and dialogic reading for caregivers working in specialized preschool programs. These programs serve children without a regular childcare place who grow up with one or more languages other than German as the environmental language. Recent studies investigating the development of children attending these programs found only moderate improvements in German receptive language skills, while language support quality of the programs was rated as average. We assessed receptive second language competencies in vocabulary and grammar of n = 48 children and language support competencies of n = 15 caregivers using an interventional pre-posttest design. Receptive vocabulary skills of children supported by trained caregivers (intervention group) were compared to children supported by untrained caregivers (control group, n = 43). We found that both children's and caregivers' competencies increased from pre- to posttest, whereas the control group's receptive vocabulary skills did not increase noticeably. The caregivers' language support competencies influenced the increase of children's receptive grammar but not vocabulary skills. The comparison between the intervention group and control group consistently showed no effect of group membership on children's receptive vocabulary acquisition over time. Since the control group data came from a secondary analysis, only receptive vocabulary skills could be compared. The preliminary results of our study suggest that a caregivers' training on language support strategies and dialogic reading in everyday educational situations support bilingual children's grammar acquisition.

Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma.

SUMOylation is a post-translational modification of proteins that regulates these proteins' localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we here identify the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to Poly-ADP-Ribose-Polymerase (PARP) inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma.

Corrigendum: The Bilingual Native Speaker Competence: Evidence From Explicit and Implicit Language Knowledge Using Elicited Production, Sentence-Picture Matching, and Pupillometry.

[This corrects the article DOI: 10.3389/fpsyg.2021.717379.].

The Bilingual Native Speaker Competence: Evidence From Explicit and Implicit Language Knowledge Using Elicited Production, Sentence-Picture Matching, and Pupillometry.

The present pilot study investigated potential effects of early and late child bilingualism in highly proficient adult bilinguals. It has been shown that some early second language (eL2) speakers stagnate when it comes to complex linguistic phenomena and that they display subtle difficulties in adulthood. Therefore, we have chosen the complex structure of double object constructions. We investigate the long-term achievement in a combined-method approach using elicited production, explicit comprehension by sentence-picture matching and a measure of implicit linguistic knowledge, namely pupillometry. This eye tracking method is suitable for measuring implicit reactions of the pupils to unexpected or ungrammatical stimuli. For production, ditransitive structures were elicited by means of a game. For comprehension, a sentence-picture matching task was conducted. Two pictures were shown on a monitor that were equal with respect to the involved objects, but the thematic roles of direct and indirect objects were interchanged. Items were controlled for length, gender, animacy, semantic likelihood and word order. Reaction times and accuracy scores were analyzed. To this end, N = 18 bilingual adult speakers of German (+ another language, mean age: 26.5) with different ages of onset participated in this study and were compared to N = 26 monolingual German adult speakers (mean age 23.9). All participants had a proficiency of German above 89% correct in placement and cloze tests. Results show fully comparable productive and comprehensive competencies in monolinguals and bilinguals including the reaction times in the sentence-picture matching task and a word order effect on the reaction times in both groups. In the pupillometry task, we found monolinguals and bilinguals to be sensitive to differing conditions with respect to grammatical and ungrammatical utterances. However, we find between group differences in pupil dilations in that bilinguals react differently to strong grammatical violations than monolinguals. These results are discussed with respect to the term of native speaker competence and the variation within both groups.

CXCR4 hyperactivation cooperates with TCL1 in CLL development and aggressiveness.

Aberrant CXCR4 activity has been implicated in lymphoma pathogenesis, disease progression, and resistance to therapies. Using a mouse model with a gain-of-function CXCR4 mutation (CXCR4C1013G) that hyperactivates CXCR4 signaling, we identified CXCR4 as a crucial activator of multiple key oncogenic pathways. CXCR4 hyperactivation resulted in an expansion of transitional B1 lymphocytes, which represent the precursors of chronic lymphocytic leukemia (CLL). Indeed, CXCR4 hyperactivation led to a significant acceleration of disease onset and a more aggressive phenotype in the murine Eµ-TCL1 CLL model. Hyperactivated CXCR4 signaling cooperated with TCL1 to cause a distinct oncogenic transcriptional program in B cells, characterized by PLK1/FOXM1-associated pathways. In accordance, Eµ-TCL1;CXCR4C1013G B cells enriched a transcriptional signature from patients with Richter's syndrome, an aggressive transformation of CLL. Notably, MYC activation in aggressive lymphoma was associated with increased CXCR4 expression. In line with this finding, additional hyperactive CXCR4 signaling in the Eµ-Myc mouse, a model of aggressive B-cell cancer, did not impact survival. In summary, we here identify CXCR4 hyperactivation as a co-driver of an aggressive lymphoma phenotype.

Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma.

Aberrant activity of the glycoprotein 130 130/JAK/STAT3 (gp130/JAK/STAT3) signaling axis is a recurrent event in inflammation and cancer. In particular, it is associated with a wide range of hematological malignancies, including multiple myeloma and leukemia. Novel targeted therapies have only been successful for some subtypes of these malignancies, underlining the need for developing robust mouse models to better dissect the role of this pathway in specific tumorigenic processes. Here, we investigated the role of selective gp130/JAK/STAT3 activation by generating a conditional mouse model. This model targeted constitutively active, cell-autonomous gp130 activity to B cells, as well as to the entire hematopoietic system. We found that regardless of the timing of activation in B cells, constitutively active gp130 signaling resulted in the formation specifically of mature B cell lymphomas and plasma cell disorders with full penetrance, only with different latencies, where infiltrating CD138+ cells were a dominant feature in every tumor. Furthermore, constitutively active gp130 signaling in all adult hematopoietic cells also led to the development specifically of largely mature, aggressive B cell cancers, again with a high penetrance of CD138+ tumors. Importantly, gp130 activity abrogated the differentiation block induced by a B cell-targeted Myc transgene and resulted in a complete penetrance of the gp130-associated, CD138+, mature B cell lymphoma phenotype. Thus, gp130 signaling selectively provides a strong growth and differentiation advantage for mature B cells and directs lymphomagenesis specifically toward terminally differentiated B cell cancers.

PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice.

B-cell lymphoma (BCL) is the most common hematologic malignancy. While sequencing studies gave insights into BCL genetics, identification of non-mutated cancer genes remains challenging. Here, we describe PiggyBac transposon tools and mouse models for recessive screening and show their application to study clonal B-cell lymphomagenesis. In a genome-wide screen, we discover BCL genes related to diverse molecular processes, including signaling, transcriptional regulation, chromatin regulation, or RNA metabolism. Cross-species analyses show the efficiency of the screen to pinpoint human cancer drivers altered by non-genetic mechanisms, including clinically relevant genes dysregulated epigenetically, transcriptionally, or post-transcriptionally in human BCL. We also describe a CRISPR/Cas9-based in vivo platform for BCL functional genomics, and validate discovered genes, such as Rfx7, a transcription factor, and Phip, a chromatin regulator, which suppress lymphomagenesis in mice. Our study gives comprehensive insights into the molecular landscapes of BCL and underlines the power of genome-scale screening to inform biology.

German dative case marking in monolingual and simultaneous bilingual children with and without SLI.

This study explores the role of German dative case marking in disentangling effects of specific language impairment (SLI) and bilingualism. Longitudinal data of German-Italian bilingual children with SLI (N = 3) is compared to cross-sectional data (N = 42) of monolingual and bilingual typically developing (TD) children and monolingual children with SLI (ages four and seven). Spontaneous and elicited speech data is analysed in terms of target-like dative case marking in German. Results show differences between the acquisition of case marking of pronouns and of full Determiner Phrases (DPs). Regarding the target-like dative case marking in total, there were no differences found between bilingual TD, monolingual and bilingual children with SLI by the age of four. They demonstrated a similar delay when compared to monolingual TD children. By the age of seven, however, bilingual TD children 'catch up' with their monolingual peers. Children with SLI do not master the acquisition of dative case marking by this age. Cumulative effects of bilingualism and SLI were not found neither in younger nor in older bilingual children. These findings underline the importance of further research on linguistic markers and of distinguishing between effects of SLI and bilingualism.

Epitope mapping via selection of anti-FVIII antibody-specific phage-presented peptide ligands that mimic the antibody binding sites.

The most serious complication in today's treatment of congenital haemophilia A is the development of neutralising antibodies (inhibitors) against factor VIII (FVIII). Although FVIII inhibitors can be eliminated by immune tolerance induction (ITI) based on repeated administration of high doses of FVIII, 20-30% of patients fail to become tolerant. Persistence of FVIII inhibitors is associated with increased morbidity and mortality. Data from recent studies provide evidence for a potential association between ITI outcome and epitope specificity of FVIII inhibitors. Nevertheless the determination of epitopes and their clinical relevance has not yet been established. In this study a general strategy for the identification of anti-FVIII antibody epitopes in haemophilia A patient plasma was to be demonstrated. Phage-displayed peptide libraries were screened against anti-FVIII antibodies to isolate specific peptides. Peptide specificity was confirmed by FVIII-sensitive ELISA binding. Peptide residues essential for antibody binding were identified by mutational analysis and epitopes were predicted via FVIII homology search. The proposed mapping strategy was validated for the monoclonal murine antibody (mAb) 2-76. Binding studies with FVIII variants confirmed the location of the predicted epitope at the level of individual amino acids. In addition, anti-FVIII antibody-specific peptide ligands were selected for 10 haemophilia A patients with FVIII inhibitors. Detailed epitope mapping for three of them showed binding sites on the A2, A3 and C2 domains. Precise epitope mapping of anti-FVIII antibodies using antibody-specific peptide ligands can be a useful approach to identify antigenic sites on FVIII.

Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas.

Loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1) or deregulated expression of the oncogene BCL6 occurs in a large proportion of diffuse large B cell lymphoma (DLBCL) cases. However, targeted mutation of either gene in mice leads to only slow and infrequent development of malignant lymphoma, and despite frequent mutation of BCL6 in activated B cells of healthy individuals, lymphoma development is rare. Here we show that T cells prevent the development of overt lymphoma in mice caused by Blimp1 deficiency or overexpression of Bcl6 in the B cell lineage. Impairment of T cell control results in rapid development of DLBCL-like disease, which can be eradicated by polyclonal CD8(+) T cells in a T cell receptor-, CD28- and Fas ligand-dependent manner. Thus, malignant transformation of mature B cells requires mutations that impair intrinsic differentiation processes and permit escape from T cell-mediated tumor surveillance.