Whole-genome analysis of noncoding genetic variations identifies multiscale regulatory element perturbations associated with Hirschsprung disease.

It is widely recognized that noncoding genetic variants play important roles in many human diseases, but there are multiple challenges that hinder the identification of functional disease-associated noncoding variants. The number of noncoding variants can be many times that of coding variants; many of them are not functional but in linkage disequilibrium with the functional ones; different variants can have epistatic effects; different variants can affect the same genes or pathways in different individuals; and some variants are related to each other not by affecting the same gene but by affecting the binding of the same upstream regulator. To overcome these difficulties, we propose a novel analysis framework that considers convergent impacts of different genetic variants on protein binding, which provides multiscale information about disease-associated perturbations of regulatory elements, genes, and pathways. Applying it to our whole-genome sequencing data of 918 short-segment Hirschsprung disease patients and matched controls, we identify various novel genes not detected by standard single-variant and region-based tests, functionally centering on neural crest migration and development. Our framework also identifies upstream regulators whose binding is influenced by the noncoding variants. Using human neural crest cells, we confirm cell stage-specific regulatory roles of three top novel regulatory elements on our list, respectively in the RET, RASGEF1A, and PIK3C2B loci. In the PIK3C2B regulatory element, we further show that a noncoding variant found only in the patients affects the binding of the gliogenesis regulator NFIA, with a corresponding up-regulation of multiple genes in the same topologically associating domain.

Longitudinal comparison of direct medical cost, radiological and health-related quality of life treatment outcomes between traditional growing rods and magnetically controlled growing rods from preoperative to maturity.

BACKGROUND: Magnetically controlled growing rods (MCGR) have replaced traditional growing rods (TGR) in the past decade, however, a comparison of their direct costs and treatment outcomes based on real longitudinal data is lacking. This study aims to compare the direct cost and treatment outcomes between TGR and MCGR, whilst incorporating complications, reoperations and changes in health-related quality of life (HRQoL) throughout the entire treatment course. METHODS: Patients with early onset scoliosis (EOS) who underwent initial growing rod surgery between 2003 and 2016 at a tertiary scoliosis clinic were studied with longitudinal data. Accumulated direct medical costs were calculated based on the unit cost of surgeries of each TGR and MCGR, costs incurred for any rod exchange or remedial surgery for post-operative complication. Treatment outcomes were evaluated via: Patient's HRQoL using SRS-22r questionnaire, and radiological parameters (including major curve correction, spine length gains, spinal balance) throughout the treatment until maturity. RESULTS: A total of 27 EOS patients (16 MCGR, 11 TGR) were studied. Total direct cost of index surgery for MCGR was HKD$223,108 versus lower cost of HKD$135,184 for TGR (p < 0.001). At 2-3 years post-index surgery, accumulative total direct medical cost of MCGR and TGR became most comparable (TGR:MCGR ratio = 1.010) and had reached neutrality between the two groups since. Radiological parameters had no intergroup differences at maturity. For HRQoL, TGR group had shown the trend of less pain (domain score mean difference: 0.53, p = 0.024) post-index surgery and better self-appearance (domain score mean difference: 1.08, p = 0.017) before fusion. Higher satisfaction with treatment (domain score mean difference: 0.76, p = 0.029) was demonstrated by TGR patients at fusion/maturity. MCGR had negative (rs = -0.693) versus TGR's positive (rs = 0.989) correlations (p < 0.05) of cost and SRS-22r total scores at 2-3 years post-index surgery. CONCLUSIONS: From index surgery to maturity, TGR demonstrated better satisfaction with treatment by patients and comparable overall HRQoL with MCGR during the treatment course, as MCGR did not show apparent benefit despite less surgeries and cost neutrality between the two groups at 2-3 years post-index surgery.

Detection of Norovirus Variant GII.4 Hong Kong in Asia and Europe, 2017-2019.

We report a new norovirus GII.4 variant, GII.4 Hong Kong, with low-level circulation in 4 Eurasia countries since mid-2017. Amino acid substitutions in key residues on the virus capsid associated with the emergence of pandemic noroviruses suggest that GII.4 Hong Kong has the potential to become the next pandemic variant.

Multidisciplinary programme for rehabilitation of chronic low back pain - factors predicting successful return to work.

BACKGROUND: There are no clear indicators for predicting return to work for patients with chronic low back pain (LBP). We aim to report the outcomes of a 14-week multidisciplinary programme targeting patients with chronic LBP who failed conventional physiotherapy to provide functional rehabilitation. Also, this study will identify factors predicting successful return to work (RTW). METHODS: A collected cohort of patients with chronic LBP was consecutively enrolled into the programme from 1996 to 2014. All recruited patients failed to RTW despite at least 3 months of conservative treatment. Patient underwent weekly multidisciplinary sessions with physiotherapists, occupational therapists and clinical psychologists. Patient perceived function was considered the primary outcome of the programme. Patients were assessed for their sitting, standing and walking tolerance. Oswestry Disability Index (ODI) and Spinal Function Sort Score (SFSS) were used to assess patient perceived disability. RESULTS: One hundred and fifty-eight patients were recruited. After the programme, statistically significant improvement was found in ODI (47.5 to 45.0, p = 0.01) and SFSS (98.0 to 109.5, p <  0.001). There was statistically significant improvement (p <  0.01) in sitting, standing, walking tolerance and straight leg raise tests. 47.4% of the patients were able to meet their work demand. Multivariate logistic regression model (R2 = 59.5%, χ2 (9) = 85.640, p <  0.001) demonstrated that lower initial job demand level and higher patient-perceived back function correlated with greater likelihood of returning to work. CONCLUSION: The results of this study may support the use of this multidisciplinary programme to improve patient function and return to work.

Activation of Hedgehog Signaling Promotes Development of Mouse and Human Enteric Neural Crest Cells, Based on Single-Cell Transcriptome Analyses.

BACKGROUND & AIMS: It has been a challenge to develop fully functioning cells from human pluripotent stem cells (hPSCs). We investigated how activation of hedgehog signaling regulates derivation of enteric neural crest (NC) cells from hPSCs. METHODS: We analyzed transcriptomes of mouse and hPSC-derived enteric NCs using single-cell RNA sequencing (scRNA-seq) to identify the changes in expression associated with lineage differentiation. Intestine tissues were collected from Tg(GBS-GFP), Sufuf/f; Wnt1-cre, Ptch1+/-, and Gli3Δ699/Δ699 mice and analyzed by flow cytometry and immunofluorescence for levels of messenger RNAs encoding factors in the hedgehog signaling pathway during differentiation of enteric NCs. Human NC cells (HNK-1+p75NTR+) were derived from IMR90 and UE02302 hPSC lines. hPSCs were incubated with a hedgehog agonist (smoothened agonist [SAG]) and antagonists (cyclopamine) and analyzed for differentiation. hPSC-based innervated colonic organoids were derived from these hPSC lines and analyzed by immunofluorescence and neuromuscular coupling assay for expression of neuronal subtype markers and assessment of the functional maturity of the hPSC-derived neurons, respectively. RESULTS: Single-cell RNA sequencing analysis showed that neural fate acquisition by human and mouse enteric NC cells requires reduced expression of NC- and cell cycle-specific genes and up-regulation of neuronal or glial lineage-specific genes. Activation of the hedgehog pathway was associated with progression of mouse enteric NCs to the more mature state along the neuronal and glial lineage differentiation trajectories. Activation of the hedgehog pathway promoted development of cultured hPSCs into NCs of greater neurogenic potential by activating expression of genes in the neurogenic lineage. The hedgehog agonist increased differentiation of hPSCs into cells of the neuronal lineage by up-regulating expression of GLI2 target genes, including INSM1, NHLH1, and various bHLH family members. The hedgehog agonist increased expression of late neuronal markers and neuronal activities in hPSC-derived neurons. CONCLUSIONS: In enteric NCs from humans and mice, activation of hedgehog signaling promotes differentiation into neurons by promoting cell-state transition, expression of genes in the neurogenic lineage, and functional maturity of enteric neurons.

Identification of Genes Associated With Hirschsprung Disease, Based on Whole-Genome Sequence Analysis, and Potential Effects on Enteric Nervous System Development.

BACKGROUND & AIMS: Hirschsprung disease, or congenital aganglionosis, is believed to be oligogenic-that is, caused by multiple genetic factors. We performed whole-genome sequence analyses of patients with Hirschsprung disease to identify genetic factors that contribute to disease development and analyzed the functional effects of these variants. METHODS: We performed whole-genome sequence analyses of 443 patients with short-segment disease, recruited from hospitals in China and Vietnam, and 493 ethnically matched individuals without Hirschsprung disease (controls). We performed genome-wide association analyses and gene-based rare-variant burden tests to identify rare and common disease-associated variants and study their interactions. We obtained induced pluripotent stem cell (iPSC) lines from 4 patients with Hirschsprung disease and 2 control individuals, and we used these to generate enteric neural crest cells for transcriptomic analyses. We assessed the neuronal lineage differentiation capability of iPSC-derived enteric neural crest cells using an in vitro differentiation assay. RESULTS: We identified 4 susceptibility loci, including 1 in the phospholipase D1 gene (PLD1) (P = 7.4 × 10-7). The patients had a significant excess of rare protein-altering variants in genes previously associated with Hirschsprung disease and in the ß-secretase 2 gene (BACE2) (P = 2.9 × 10-6). The epistatic effects of common and rare variants across these loci provided a sensitized background that increased risk for the disease. In studies of the iPSCs, we observed common and distinct pathways associated with variants in RET that affect risk. In functional assays, we found variants in BACE2 to protect enteric neurons from apoptosis. We propose that alterations in BACE1 signaling via amyloid ß precursor protein and BACE2 contribute to pathogenesis of Hirschsprung disease. CONCLUSIONS: In whole-genome sequence analyses of patients with Hirschsprung disease, we identified rare and common variants associated with disease risk. Using iPSC cells, we discovered some functional effects of these variants.

Oxyhemoglobin changes in the prefrontal cortex in response to cognitive tasks: a systematic review.

PURPOSE OF THE STUDY: the aim of this study was to synthesize PFC fNIRS outcomes on the effects of cognitive tasks compared to resting/baseline tasks in healthy adults from studies utilizing a pre/post design. MATERIAL AND METHODS: original research studies were searched from seven databases (MEDLINE, EMBASE, CENTRAL, CINAHL, SCOPUS, PEDro and PubMed). Subsequently, two independent reviewers screened the titles and abstracts followed by full-text reviews to assess the studies' eligibility. RESULTS: eleven studies met the inclusion criteria and had data abstracted and quality assessed. Methodology varied considerably and yet cognitive tasks resulted in the ΔO2Hb increasing in 8 of the 11 and ΔHHb decreasing in 8 of 8 studies that reported this outcome. The cognitive tasks from 10 of the 11 studies were classified as "Working Memory" and "Verbal Fluency Tasks". CONCLUSIONS: although, the data comparison was challenging provided the heterogeneity in methodology, the results across studies were similar.

Correction of Hirschsprung-Associated Mutations in Human Induced Pluripotent Stem Cells Via Clustered Regularly Interspaced Short Palindromic Repeats/Cas9, Restores Neural Crest Cell Function.

BACKGROUND & AIMS: Hirschsprung disease is caused by failure of enteric neural crest cells (ENCCs) to fully colonize the bowel, leading to bowel obstruction and megacolon. Heterozygous mutations in the coding region of the RET gene cause a severe form of Hirschsprung disease (total colonic aganglionosis). However, 80% of HSCR patients have short-segment Hirschsprung disease (S-HSCR), which has not been associated with genetic factors. We sought to identify mutations associated with S-HSCR, and used the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing system to determine how mutations affect ENCC function. METHODS: We created induced pluripotent stem cell (iPSC) lines from 1 patient with total colonic aganglionosis (with the G731del mutation in RET) and from 2 patients with S-HSCR (without a RET mutation), as well as RET+/- and RET-/- iPSCs. IMR90-iPSC cells were used as the control cell line. Migration and differentiation capacities of iPSC-derived ENCCs were analyzed in differentiation and migration assays. We searched for mutation(s) associated with S-HSCR by combining genetic and transcriptome data from patient blood- and iPSC-derived ENCCs, respectively. Mutations in the iPSCs were corrected using the CRISPR/Cas9 system. RESULTS: ENCCs derived from all iPSC lines, but not control iPSCs, had defects in migration and neuronal lineage differentiation. RET mutations were associated with differentiation and migration defects of ENCCs in vitro. Genetic and transcriptome analyses associated a mutation in the vinculin gene (VCL M209L) with S-HSCR. CRISPR/Cas9 correction of the RET G731del and VCL M209L mutations in iPSCs restored the differentiation and migration capacities of ENCCs. CONCLUSIONS: We identified mutations in VCL associated with S-HSCR. Correction of this mutation in iPSC using CRISPR/Cas9 editing, as well as the RET G731del mutation that causes Hirschsprung disease with total colonic aganglionosis, restored ENCC function. Our study demonstrates how human iPSCs can be used to identify disease-associated mutations and determine how they affect cell functions and contribute to pathogenesis.

Responsiveness of the EuroQoL 5-dimension (EQ-5D) in adolescent idiopathic scoliosis.

PURPOSE: To test the responsiveness of the EuroQoL 5-dimension (EQ-5D) utility scores for adolescent idiopathic scoliosis (AIS). METHODS: A baseline sample of 227 AIS patients was recruited between August and October 2015, and was surveyed prospectively to 9-12 months follow-up. EQ-5D-5L utility scores were derived using a two-step approach: (1) cross-walking from five-level responses to three-level responses and (2) applying the EQ-5D-3L Chinese population value set. An anchor approach was adopted to assess the responsiveness of EQ-5D. Effect size statistics (standardized effect size and standardized response mean) and independent t test were used to assess the responsiveness, as well as to analyze the ability of measures to detect score changes with global health condition changes or discriminate between the worsened and unchanged/improved groups. RESULTS: Approximately two-thirds of follow-up patients (64.2%) reported no change in global health condition based on the self-reported health anchor, whilst 4.6 and 31.3% of patients rated worse and better in current health condition compared to baseline, respectively. In the subgroup where health worsened, EQ-5D utility scores were responsive to detect negative changes. EQ-5D utility scores had slight improvement in the group where health improved, despite a high mean score of 0.92 at baseline. Neither statistical significance nor moderate-large effect size was observed in mean changes among unchanged group. Responsiveness property of the EQ-5D utility score was generally satisfactory with respect to each health condition group. CONCLUSIONS: EQ-5D is found to be able to capture positive changes, and responsive in detecting important clinical changes in the improved group of this AIS population.

Dysregulation of clathrin promotes thyroid cell growth and contributes to multinodular goiter pathogenesis.

A germline mutation (A339V) in thyroid transcription factor-1 (TITF1/NKX2.1) was shown to be associated with multinodular goiter (MNG) and papillary thyroid carcinoma (PTC) pathogenesis. The overexpression of A339V TTF1 significantly promoted hormone-independent growth of the normal thyroid cells, representing a cause of MNG and/or PTC. Nevertheless, the underlying mechanism still remains unclear. In this study, we used liquid chromatography (LC)-tandem mass spectrometry (MS/MS)-based shotgun proteomics comparing the global protein expression profiles of normal thyroid cells (PCCL3) that overexpressed the wild-type or A339V TTF1 to identify key proteins implicated in this process. Proteomic pathway analysis revealed that the aberrant activation of epidermal growth factor (EGF) signaling is significantly associated with the overexpression of A339V TTF1 in PCCL3, and clathrin heavy chain (Chc) is the most significantly up-regulated protein of the pathway. Intriguingly, dysregulated Chc expression facilitated a nuclear accumulation of pStat3, leading to an enhanced cell proliferation of the A339V clones. Down-regulation and abrogation of Chc-mediated cellular trafficking, respectively, by knocking-down Chc and ectopic expression of a dominant-negative (DN) form of Chc could significantly reduce the nuclear pStat3 and rescue the aberrant cell proliferation of the A339V clones. Subsequent expression analysis further revealed that CHC and pSTAT3 are co-overexpressed in 66.7% (10/15) MNG. Taken together, our results suggest that the A339V TTF1 mutant protein up-regulates the cellular expression of Chc, resulting in a constitutive activation of Stat3 pathway, and prompting the aberrant growth of thyroid cells. This extensive growth signal may promote the development of MNG.

Social Support Predicts Hearing Aid Satisfaction.

OBJECTIVES: The goals of the current research were to determine: (1) whether there is a relationship between perceived social support and hearing aid satisfaction, and (2) how well perceived social support predicts hearing aid satisfaction relative to other correlates previously identified in the literature. DESIGN: In study 1, 173 adult ((Equation is included in full-text article.)age = 68.9 years; SD = 13.4) users of hearing aids completed a survey assessing attitudes toward health, hearing, and hearing aids, as well as a questionnaire assessing Big-Five personality factors (Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism) either using paper and pencil or the Internet. In a follow-up study designed to replicate and extend the results from study 1, 161 adult ((Equation is included in full-text article.)age = 32.8 years; SD = 13.3) users of hearing aids completed a similar survey on the Internet. In study 2, participants also completed a measure of hearing aid benefit and reported the style of their hearing aid. RESULTS: In studies 1 and 2, perceived social support was significantly correlated with hearing aid satisfaction (respectively, r = 0.34, r = 0.51, ps < 0.001). The results of a regression analysis revealed that in study 1, 22% of the variance in hearing aid satisfaction scores was predicted by perceived social support, satisfaction with one's hearing health care provider, duration of daily hearing aid use, and openness. In study 2, 43% of the variance in hearing aid satisfaction was predicted by perceived social support, hearing aid benefit, neuroticism, and hearing aid style. Overall, perceived social support was the best predictor of hearing aid satisfaction in both studies. After controlling for response style (i.e., acquiescence or the tendency to respond positively), the correlation between perceived social support and hearing aid satisfaction remained the same in study 1 (r = 0.34, p < 0.001) and was lower in study 2 (r = 0.39, p < 0.001), although the change in correlation was not significant. CONCLUSIONS: The results from study 1 provide evidence to suggest that perceived social support is a significant predictor of satisfaction with hearing aids, a finding that was replicated in a different sample of participants investigated in study 2. A significant relationship between perceived social support and hearing aid satisfaction was observed in both studies, even though the composition of the two samples differed in terms of age, relationship status, income, proportion of individuals with unilateral versus bilateral hearing impairment, and lifetime experience with hearing aids. The results from both studies 1 and 2 provide no support for the claim that participant response style accounts for the relationship between hearing aid satisfaction and perceived social support.

Cytokeratin 15 is a novel and independent predictor of poor outcome in luminal B HER2-negative breast carcinomas.

Cytokeratin 15 (CK15) has been described as a stem cell marker in human organs and its expression is seen in breast tissue. CK15 expression is associated with aggressive features in endometrial and oesophageal cancers, but data on the breast are lacking. This study aims to investigate the clinicopathological associations and prognostic significance of CK15 in breast carcinomas. A multi-institute cohort of breast carcinomas were retrieved. Clinicopathological and outcome data were obtained and compared with immunohistochemical expression CK15 and a panel of biomarkers. In total, 1,476 cases were included, with an expression rate of 3.5%, preferentially expressed in luminal subtypes (p=0.024), with luminal B carcinomas being the highest (4.7%), as opposed to basal-like (1%) and HER2-overexpressed carcinomas (0%). Except for nodal stage (p=0.013) and nodal metastasis (p=0.048), oestrogen (p=0.035) and progesterone receptor (p=0.001) positivity, there were no associations with other clinicopathological parameters. A trend was observed with shorter breast cancer specific survival (BCSS) in CK15-positive luminal B carcinomas (p=0.062). On further subgroup multivariate analysis of luminal B HER2-negative carcinomas, CK15 expression exhibited robust correlation with shorter BCSS (HR=9.004, p=0.001) and disease-free survival (HR=7.085, p<0.001). Restricted to luminal breast carcinomas, specifically luminal B HER2-negative, CK15 is demonstrated to be a robust independent predictor of higher risk of recurrence and shorter survival, with potential as a clinical prognostic marker and an exclusive stem cell marker for this subgroup of carcinomas.

Tregs delivered post-myocardial infarction adopt an injury-specific phenotype promoting cardiac repair via macrophages in mice.

Regulatory T cells (Tregs) are key immune regulators that have shown promise in enhancing cardiac repair post-MI, although the mechanisms remain elusive. Here, we show that rapidly increasing Treg number in the circulation post-MI via systemic administration of exogenous Tregs improves cardiac function in male mice, by limiting cardiomyocyte death and reducing fibrosis. Mechanistically, exogenous Tregs quickly home to the infarcted heart and adopt an injury-specific transcriptome that mediates repair by modulating monocytes/macrophages. Specially, Tregs lead to a reduction in pro-inflammatory Ly6CHi CCR2+ monocytes/macrophages accompanied by a rapid shift of macrophages towards a pro-repair phenotype. Additionally, exogenous Treg-derived factors, including nidogen-1 and IL-10, along with a decrease in cardiac CD8+ T cell number, mediate the reduction of the pro-inflammatory monocyte/macrophage subset in the heart. Supporting the pivotal role of IL-10, exogenous Tregs knocked out for IL-10 lose their pro-repair capabilities. Together, this study highlights the beneficial use of a Treg-based therapeutic approach for cardiac repair with important mechanistic insights that could facilitate the development of novel immunotherapies for MI.

Organoid models of breathing disorders reveal patterning defect of hindbrain neurons caused by PHOX2B-PARMs.

Retrotrapezoid nucleus (RTN) neurons in the brainstem regulate the ventilatory response to hypercarbia. It is unclear how PHOX2B-polyalanine repeat mutations (PHOX2B-PARMs) alter the function of PHOX2B and perturb the formation of RTN neurons. Here, we generated human brainstem organoids (HBSOs) with RTN-like neurons from human pluripotent stem cells. Single-cell transcriptomics revealed that expression of PHOX2B+7Ala PARM alters the differentiation trajectories of the hindbrain neurons and hampers the formation of the RTN-like neurons in HBSOs. With the unguided cerebral organoids (HCOs), PHOX2B+7Ala PARM interrupted the patterning of PHOX2B+ neurons with dysregulation of Hedgehog pathway and HOX genes. With complementary use of HBSOs and HCOs with a patient and two mutant induced pluripotent stem cell lines carrying different polyalanine repetition in PHOX2B, we further defined the association between the length of polyalanine repetition and malformation of RTN-respiratory center and demonstrated the potential toxic gain of function of PHOX2B-PARMs, highlighting the uniqueness of these organoid models for disease modeling.

Transcriptomics of Hirschsprung disease patient-derived enteric neural crest cells reveals a role for oxidative phosphorylation.

Hirschsprung disease is characterized by the absence of enteric neurons caused by the defects of enteric neural crest cells, leading to intestinal obstruction. Here, using induced pluripotent stem cell-based models of Hirschsprung and single-cell transcriptomic analysis, we identify a gene set of 118 genes commonly dysregulated in all patient enteric neural crest cells, and suggest HDAC1 may be a key regulator of these genes. Furthermore, upregulation of RNA splicing mediators and enhanced alternative splicing events are associated with severe form of Hirschsprung. In particular, the higher inclusion rate of exon 9 in PTBP1 and the perturbed expression of a PTBP1-target, PKM, are significantly enriched in these patient cells, and associated with the defective oxidative phosphorylation and impaired neurogenesis. Hedgehog-induced oxidative phosphorylation significantly enhances the survival and differentiation capacity of patient cells. In sum, we define various factors associated with Hirschsprung pathogenesis and demonstrate the implications of oxidative phosphorylation in enteric neural crest development and HSCR pathogenesis.

Consumer perspectives on grab bars: A Canadian national survey of grab bar acceptability in homes.

Given the prevalence and severity of bathroom falls and injuries across age groups, there is growing interest in policy-level approaches to bathroom fall prevention. Grab bars reduce fall risk during bathing transfers and improve bathing accessibility for adults of all ages and abilities. However, they are frequently absent from bathing environments, even in the homes of individuals who have a specific need for a grab bar. While mandatory bathroom grab bar installation has been suggested, it is unclear whether this would be supported by Canadians. The purpose of this study was to characterize Canadian public perceptions on the installation and use of grab bars in home bathrooms. We surveyed 443 Canadians about whether they currently had a grab bar and their perspectives on grab bar policy. 65.4% of respondents did not have a grab bar. However, 88.5% of respondents would allow a grab bar to be installed in their bathroom at no cost to them, only 11.5% of respondents would object to grab bar installation becoming mandatory in new builds, and 85.6% of respondents would use a grab bar if it were installed in their bathroom. Responses were affected by age (in four groups: 18-39, 40-59, 60-79, and 80+ years), self-reported impairment, and home ownership status. Older adults, respondents who reported having impairments, and home owners were more likely to respond favorably toward grab bars. Based on these results, the majority of Canadians would respond positively to policy mandating bathroom grab bars in new homes.

Learning structural alternations: What guides learners' generalization?

Some word-order alternations observed across the world's languages are constrained by specific verb choice, whereas one type of word-order alternation (i.e., scrambling) frequently seen in free word order languages is not lexically-dependent on the verb. Three novel-language learning experiments explore whether speakers latently respect this generalization. If learners show conservativeness that closely reflects statistics from the input, then it would support usage-based and statistical accounts; alternatively, if learners have linguistic biases that allow them to generalize beyond statistics and show generalization similar to typological patterns, then it would support an internal bias account. In each of the three experiments, two groups of English monolinguals learned a Korean-English hybrid language with structural alternations analogous to those found in different categories of natural languages, as defined by whether the language allows scrambling and whether alternations are lexically-dependent on the verb. Learners' generalization patterns in subsequent picture description and acceptability judgment tasks were analyzed. Comprehension data consistently showed that the group which learned alternations found in natural languages with relatively rigid word orders tended to be more verb-wise conservative than the group that learned alternations found in languages with relatively free word orders. Production data trended in the same direction as the comprehension data. Thus, our results suggest that learners have linguistic biases that mirror typological differences that help learners go beyond simple statistics tracking.

ICT-Supported Home-Based Learning in K-12: a Systematic Review of Research and Implementation.

With the integration of technology in teaching and learning, online learning is not a new instructional strategy in the education landscape. However, the onset of the Covid-19 pandemic has necessitated the implementation of Home-based Learning (HBL) for educators, parents, and students on an unprecedented duration and scale. The notions and the factors associated with the implementation of HBL are yet fully investigated. As such, this study aims to shed light on the prerequisites needed for implementing HBL and suggest its future research direction. The methodology involves a systematic review of the existing studies on ICT-supported formal learning outside the classroom and to identify the prerequisites of HBL from various perspectives of the students, teachers, and parents. By doing so, this report will provide a deeper understanding of the multiple components of HBL and how it is to be taken into consideration when implementing HBL from both the theoretical and practical standpoint.

Ciliary protein Kif7 regulates Gli and Ezh2 for initiating the neuronal differentiation of enteric neural crest cells during development.

Gastrointestinal motility disorders occur frequently in patients with ciliopathy, but the underlying genetic link is unclear. The ciliary protein Kif7 can positively or negatively regulate Hedgehog signaling in different cellular contexts. Mice with neural crest cell (NCC)­specific Kif7 deficiency show a marked reduction of enteric NOS+ inhibitory neurons. Malformation of enteric nervous system (ENS) causes growth retardation and gut motility defect in mice. Mechanistically, Kif7 inhibits Gli2 in enteric NCCs (ENCCs), where Gli2 positively regulates the expression of Ezh2 by inhibiting the miR124-mediated suppression. In developing ENCCs, Ezh2 is a master regulator of 102 core genes underlying ENCC differentiation. Deletion of Gli2 or inhibition of Ezh2 favors the neurogenic lineage differentiation of mouse and human ENCCs and rescues the ENS defects of Kif7 mutants. In summary, Hedgehog signal, via Kif7-Gli-Ezh2, controls the timely expressions of the core genes to mediate the differentiation of ENCCs.

Genome Sequence of a Human Norovirus GII.4 Hong Kong[P31] Variant in Hong Kong, China.

We report the nearly complete genome of a norovirus GII.4 Hong Kong[P31] variant (GII strain Hu/HK/2019/GII.4 Hong Kong[P31]/CUHK-NS-2200) that was detected in a patient with gastroenteritis in August 2019. The genome was sequenced by metagenomic next-generation sequencing and was found to have 92.8% nucleotide similarity to the closest GII.4 norovirus sequence in GenBank.