Abstract
The reciprocal nature of spoken interaction means that participants constantly alternate between speaker and listener roles. However, listener or recipient actions—also known as interactive ...listening (IL)—are somewhat underrepresented in language tests. In conventional listening tests, they are not directly assessed. In speaking tests, they have often been overshadowed by an emphasis on production features or subsumed under broader constructs such as interactional competence. This article is an effort to represent the rich IL phenomena that can be found in peer interactive speaking assessments, where the candidate–candidate format and discussion task offer opportunities to elicit and assess IL. Taking a close look at candidate discourse and nonverbal actions through a conversation analytic approach, the analysis focuses on three IL features (i) listenership displays, (ii) contingent responses, and (iii) collaborative completions, and unpacks their relative strength in evidencing listener understanding. This article concludes by making a case for revisiting the role of IL, calling for more explicit inclusion of IL in L2 assessment as well as pedagogy.
The ability to interact with others has gained recognition as part of the L2 speaking construct in the assessment literature and in high- and low-stakes speaking assessments. This paper first ...presents a review of the literature on interactional competence (IC) in L2 learning and assessment. It then discusses a particular feature – producing responses contingent on previous speakers’ contributions – that emerged as a de facto construct feature of IC, oriented to both candidates and examiners within the school-based group speaking assessment in the Hong Kong Diploma of Secondary Education (HKDSE) English Language Examination. Previous studies have, similarly, argued for the importance of responding to or linking one’s own talk to previous speakers’ contributions as a way of demonstrating comprehension of co-participants’ talk. However, what counts as such a response has yet to be explored systematically. This paper presents a conversation analytic study of the candidate discourse in the assessed group interactions, identifying three conversational actions through which student-candidates construct contingent responses to co-participants. The thick description about the nature of contingent responses lays the groundwork for further empirical investigations on the relevance of this IC feature and its proficiency implications.
Update on KMT2B-Related Dystonia Zech, Michael; Lam, Daniel D.; Winkelmann, Juliane
Current neurology and neuroscience reports,
11/2019, Volume:
19, Issue:
11
Journal Article
Peer reviewed
Purpose of Review
To summarize the molecular and clinical findings of
KMT2B
-related dystonia (DYT-
KMT2B
), a newly identified genetic dystonia syndrome.
Recent Findings
Since first described in ...2016, 66 different
KMT2B
-affecting variants, encompassing a set of frameshift, nonsense, splice-site, missense, and deletion mutations, have been reported in 76 patients. Most mutations are de novo and expected to mediate epigenetic dysregulation by inducing
KMT2B
haploinsufficiency. DYT-
KMT2B
is characterized phenotypically by limb-onset childhood dystonia that tends to spread progressively, resulting in generalized dystonia with cranio-cervical involvement. Co-occuring signs such as intellectual disability are frequently observed. Sustained response to deep brain stimulation (DBS), including restoration of independent ambulation, is seen in 93% (27/29) of patients.
Summary
DYT-
KMT2B
is emerging as a prevalent monogenic dystonia. Childhood-onset dystonia presentations should prompt a search for
KMT2B
mutations, preferentially via next-generation-sequencing and genomic-array technologies, to enable specific counseling and treatment. Prospective multicenter studies are desirable to establish
KMT2B
mutational status as a DBS outcome predictor.
•Discrete neuronal populations are sufficient for driving appetite and satiety.•These neurons are regulated by sensory, hormonal, and exogenous signals.•Specific brain circuits are directly ...implicated in appetite regulation.•Natural neuronal activity dynamics reflect food-related behaviours.
Obesity results from the consumption of food in excess of bodily energy requirements, with the excess energy stored as adipose tissue. Sequelae of obesity, such as heart disease and type 2 diabetes, consistently rank among the top causes of death worldwide. The global prevalence of obesity highlights the urgency of understanding the mechanisms regulating hunger and satiety. Appetite, defined as the motivational drive to obtain food, is regulated by a complex neurocircuitry which integrates a variety of interoceptive signals to gauge nutritional state and guide appropriate levels of food-seeking. Here we review key recent developments in the identification of cell groups, neural circuits, endogenous and exogenous substances, and intracellular signaling pathways which drive hunger and satiety. We also consider particularly promising pharmacological targets for appetite modulation.
Abstract Feedback penetrates many walks of our lives, and its importance in L2 teaching and assessment is well recognised. However, while corrective feedback and writing feedback have been the focus ...of much L2 research and classroom practice, there seems relatively little attention to feedback on spoken interactional skills. Concomitantly, translating research on interactional competence (IC) to classroom practice has been a glacial process. Aiming at supporting teachers in providing assessment feedback and teaching IC in the classroom, this article introduces worked examples of peer interactions as a feedback and learning resource. Adopting a procedure used in conversation analytic (CA) research, the worked examples are designed to guide learners to notice and understand IC features in context, at a less cognitively demanding pace for processing, and promote learners’ active engagement with the feedback or teaching focus. The article concludes with suggestions for teachers to develop similar resources for their local contexts.
Large surveys of galaxy clusters with the Hubble Space Telescope (HST) and Spitzer, including the Cluster Lensing And Supernova survey with Hubble and the Frontier Fields, have demonstrated the power ...of strong gravitational lensing to efficiently deliver large samples of high-redshift galaxies. We extend this strategy through a wider, shallower survey named RELICS, the Reionization Lensing Cluster Survey, described here. Our 188-orbit Hubble Treasury Program observed 41 clusters at 0.182 ≤ z ≤ 0.972 with Advanced Camera for Surveys (ACS) and WFC3/IR imaging spanning 0.4-1.7 m. We selected 21 of the most massive clusters known based on Planck PSZ2 estimates and 20 additional clusters based on observed or inferred lensing strength. RELICS observed 46 WFC3/IR pointings (∼200 arcmin2) each with two orbits divided among four filters (F105W, F125W, F140W, and F160W) and ACS imaging as needed to achieve single-orbit depth in each of three filters (F435W, F606W, and F814W). As previously reported by Salmon et al., we discovered over 300 z ∼ 6-10 candidates, including the brightest z ∼ 6 candidates known, and the most distant spatially resolved lensed arc known at z ∼ 10. Spitzer IRAC imaging (945 hr awarded, plus 100 archival, spanning 3.0-5.0 m) has crucially enabled us to distinguish z ∼ 10 candidates from z ∼ 2 interlopers. For each cluster, two HST observing epochs were staggered by about a month, enabling us to discover 11 supernovae, including 3 lensed supernovae, which we followed up with 20 orbits from our program. Reduced HST images, catalogs, and lens models are available on MAST, and reduced Spitzer images are available on IRSA.
We previously piloted the concept of a Connectivity Map (CMap), whereby genes, drugs, and disease states are connected by virtue of common gene-expression signatures. Here, we report more than a ...1,000-fold scale-up of the CMap as part of the NIH LINCS Consortium, made possible by a new, low-cost, high-throughput reduced representation expression profiling method that we term L1000. We show that L1000 is highly reproducible, comparable to RNA sequencing, and suitable for computational inference of the expression levels of 81% of non-measured transcripts. We further show that the expanded CMap can be used to discover mechanism of action of small molecules, functionally annotate genetic variants of disease genes, and inform clinical trials. The 1.3 million L1000 profiles described here, as well as tools for their analysis, are available at https://clue.io.
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•A new gene expression profiling method, L1000, dramatically lowers cost•The Connectivity Map now includes 1.3 million publicly accessible L1000 profiles•Facilitates discovery of small-molecule mechanism and annotation of genetic variants•The work establishes feasibility and utility of a truly comprehensive Connectivity Map
The next generation Connectivity Map, a large-scale compendium of functional perturbations in cultured human cells coupled to a gene-expression readout, facilitates the discovery of connections between genes, drugs, and diseases.
Cas9 is commonly introduced into cell lines to enable CRISPR-Cas9-mediated genome editing. Here, we studied the genetic and transcriptional consequences of Cas9 expression itself. Gene expression ...profiling of 165 pairs of human cancer cell lines and their Cas9-expressing derivatives revealed upregulation of the p53 pathway upon introduction of Cas9, specifically in wild-type TP53 (TP53-WT) cell lines. This was confirmed at the messenger RNA and protein levels. Moreover, elevated levels of DNA repair were observed in Cas9-expressing cell lines. Genetic characterization of 42 cell line pairs showed that introduction of Cas9 can lead to the emergence and expansion of p53-inactivating mutations. This was confirmed by competition experiments in isogenic TP53-WT and TP53-null (TP53
) cell lines. Lastly, Cas9 was less active in TP53-WT than in TP53-mutant cell lines, and Cas9-induced p53 pathway activation affected cellular sensitivity to both genetic and chemical perturbations. These findings may have broad implications for the proper use of CRISPR-Cas9-mediated genome editing.
Isolated dystonia is a disorder characterized by involuntary twisting postures arising from sustained muscle contractions. Although autosomal-dominant mutations in TOR1A, THAP1, and GNAL have been ...found in some cases, the molecular mechanisms underlying isolated dystonia are largely unknown. In addition, although emphasis has been placed on dominant isolated dystonia, the disorder is also transmitted as a recessive trait, for which no mutations have been defined. Using whole-exome sequencing in a recessive isolated dystonia-affected kindred, we identified disease-segregating compound heterozygous mutations in COL6A3, a collagen VI gene associated previously with muscular dystrophy. Genetic screening of a further 367 isolated dystonia subjects revealed two additional recessive pedigrees harboring compound heterozygous mutations in COL6A3. Strikingly, all affected individuals had at least one pathogenic allele in exon 41, including an exon-skipping mutation that induced an in-frame deletion. We tested the hypothesis that disruption of this exon is pathognomonic for isolated dystonia by inducing a series of in-frame deletions in zebrafish embryos. Consistent with our human genetics data, suppression of the exon 41 ortholog caused deficits in axonal outgrowth, whereas suppression of other exons phenocopied collagen deposition mutants. All recessive mutation carriers demonstrated early-onset segmental isolated dystonia without muscular disease. Finally, we show that Col6a3 is expressed in neurons, with relevant mRNA levels detectable throughout the adult mouse brain. Taken together, our data indicate that loss-of-function mutations affecting a specific region of COL6A3 cause recessive isolated dystonia with underlying neurodevelopmental deficits and highlight the brain extracellular matrix as a contributor to dystonia pathogenesis.
Cell-specific expression of many genes is conveyed by multiple enhancers, with each individual enhancer controlling a particular expression domain. In contrast, multiple enhancers drive similar ...expression patterns of some genes involved in embryonic development, suggesting regulatory redundancy. Work in Drosophila has indicated that functionally overlapping enhancers canalize development by buffering gene expression against environmental and genetic disturbances. However, little is known about regulatory redundancy in vertebrates and in genes mainly expressed during adulthood. Here we study nPE1 and nPE2, two phylogenetically conserved mammalian enhancers that drive expression of the proopiomelanocortin gene (Pomc) to the same set of hypothalamic neurons. The simultaneous deletion of both enhancers abolished Pomc expression at all ages and induced a profound metabolic dysfunction including early-onset extreme obesity. Targeted inactivation of either nPE1 or nPE2 led to very low levels of Pomc expression during early embryonic development indicating that both enhancers function synergistically. In adult mice, however, Pomc expression is controlled additively by both enhancers, with nPE1 being responsible for ∼80% and nPE2 for ∼20% of Pomc transcription. Consequently, nPE1 knockout mice exhibit mild obesity whereas nPE2-deficient mice maintain a normal body weight. These results suggest that nPE2-driven Pomc expression is compensated by nPE1 at later stages of development, essentially rescuing the earlier phenotype of nPE2 deficiency. Together, these results reveal that cooperative interactions between the enhancers confer robustness of Pomc expression against gene regulatory disturbances and preclude deleterious metabolic phenotypes caused by Pomc deficiency in adulthood. Thus, our study demonstrates that enhancer redundancy can be used by genes that control adult physiology in mammals and underlines the potential significance of regulatory sequence mutations in common diseases.
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