In Time with the Beat: Entrainment in Patients with Phonological Impairment, Apraxia of Speech, and Parkinson’s Disease

In the present study, we investigated if individuals with neurogenic speech sound impairments of three types, Parkinson’s dysarthria, apraxia of speech, and aphasic phonological impairment, accommodate their speech to the natural speech rhythm of an auditory model, and if so, whether the effect is more significant after hearing metrically regular sentences as compared to those with an irregular pattern. This question builds on theories of rhythmic entrainment, assuming that sensorimotor predictions of upcoming events allow humans to synchronize their actions with an external rhythm. To investigate entrainment effects, we conducted a sentence completion task relating participants’ response latencies to the spoken rhythm of the prime heard immediately before. A further research question was if the perceived rhythm interacts with the rhythm of the participants’ own productions, i.e., the trochaic or iambic stress pattern of disyllabic target words. For a control group of healthy speakers, our study revealed evidence for entrainment when trochaic target words were preceded by regularly stressed prime sentences. Persons with Parkinson’s dysarthria showed a pattern similar to that of the healthy individuals. For the patient groups with apraxia of speech and with phonological impairment, considerably longer response latencies with differing patterns were observed. Trochaic target words were initiated with significantly shorter latencies, whereas the metrical regularity of prime sentences had no consistent impact on response latencies and did not interact with the stress pattern of the target words to be produced. The absence of an entrainment in these patients may be explained by the more severe difficulties in initiating speech at all. We discuss the results in terms of clinical implications for diagnostics and therapy in neurogenic speech disorders. View Full-Tex

Reading Fluency in Children and Adolescents Who Stutter

Speech fluency is a major challenge for young persons who stutter. Reading aloud, in particular, puts high demands on fluency, not only regarding online text decoding and articulation, but also in terms of prosodic performance. A written text has to be segmented into a number of prosodic phrases with appropriate breaks. The present study examines to what extent reading fluency (decoding ability, articulation rate, and prosodic phrasing) may be altered in children (9–12 years) and adolescents (13–17 years) who stutter compared to matched control participants. Read speech of 52 children and adolescents who do and do not stutter was analyzed. Children and adolescents who stutter did not differ from their matched control groups regarding reading accuracy and articulation rate. However, children who stutter produced shorter pauses than their matched peers. Results on prosodic phrasing showed that children who stutter produced more major phrases than the control group and more intermediate phrases than adolescents who stutter. Participants who stutter also displayed a higher number of breath pauses. Generally, the number of disfluencies during reading was related to slower articulation rates and more prosodic boundaries. Furthermore, we found age-related changes in general measures of reading fluency (decoding ability and articulation rate), as well as the overall strength of prosodic boundaries and number of breath pauses. This study provides evidence for developmental stages in prosodic phrasing as well as for alterations in reading fluency in children who stutter

Mammary stem cells have myoepithelial cell properties.

Contractile myoepithelial cells dominate the basal layer of the mammary epithelium and are considered to be differentiated cells. However, we observe that up to 54% of single basal cells can form colonies when seeded into adherent culture in the presence of agents that disrupt actin-myosin interactions, and on average, 65% of the single-cell-derived basal colonies can repopulate a mammary gland when transplanted in vivo. This indicates that a high proportion of basal myoepithelial cells can give rise to a mammary repopulating unit (MRU). We demonstrate that myoepithelial cells, flow-sorted using two independent myoepithelial-specific reporter strategies, have MRU capacity. Using an inducible lineage-tracing approach we follow the progeny of myoepithelial cells that express α-smooth muscle actin and show that they function as long-lived lineage-restricted stem cells in the virgin state and during pregnancy.This work was funded by Cancer Research UK, Breast Cancer Campaign, the University of Cambridge, Hutchison Whampoa Limited, La Ligue Nationale Contre le Cancer (Equipe Labelisée 2013) and a grant from Agence Nationale de la Recherche ANR- 08-BLAN-0078-01 to M.A.G.This is the author accepted manuscript. The final version is available from Nature at http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3025.html

Evolutionary Dynamics of Co-Segregating Gene Clusters Associated with Complex Diseases

BACKGROUND: The distribution of human disease-associated mutations is not random across the human genome. Despite the fact that natural selection continually removes disease-associated mutations, an enrichment of these variants can be observed in regions of low recombination. There are a number of mechanisms by which such a clustering could occur, including genetic perturbations or demographic effects within different populations. Recent genome-wide association studies (GWAS) suggest that single nucleotide polymorphisms (SNPs) associated with complex disease traits are not randomly distributed throughout the genome, but tend to cluster in regions of low recombination. PRINCIPAL FINDINGS: Here we investigated whether deleterious mutations have accumulated in regions of low recombination due to the impact of recent positive selection and genetic hitchhiking. Using publicly available data on common complex diseases and population demography, we observed an enrichment of hitchhiked disease associations in conserved gene clusters subject to selection pressure. Evolutionary analysis revealed that these conserved gene clusters arose by multiple concerted rearrangements events across the vertebrate lineage. We observed distinct clustering of disease-associated SNPs in evolutionary rearranged regions of low recombination and high gene density, which harbor genes involved in immunity, that is, the interleukin cluster on 5q31 or RhoA on 3p21. CONCLUSIONS: Our results suggest that multiple lineage specific rearrangements led to a physical clustering of functionally related and linked genes exhibiting an enrichment of susceptibility loci for complex traits. This implies that besides recent evolutionary adaptations other evolutionary dynamics have played a role in the formation of linked gene clusters associated with complex disease traits

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Molecular Modes of Action of an Aqueous <i>Nerium oleander</i> Extract in Cancer Cells In Vitro and In Vivo

Cancer drug resistance remains a major obstacle in clinical oncology. As most anticancer drugs are of natural origin, we investigated the anticancer potential of a standardized cold-water leaf extract from Nerium oleander L., termed Breastin. The phytochemical characterization by nuclear magnetic resonance spectroscopy (NMR) and low- and high-resolution mass spectrometry revealed several monoglycosidic cardenolides as major constituents (adynerin, neritaloside, odoroside A, odoroside H, oleandrin, and vanderoside). Breastin inhibited the growth of 14 cell lines from hematopoietic tumors and 5 of 6 carcinomas. Remarkably, the cellular responsiveness of odoroside H and neritaloside was not correlated with all other classical drug resistance mechanisms, i.e., ATP-binding cassette transporters (ABCB1, ABCB5, ABCC1, ABCG2), oncogenes (EGFR, RAS), tumor suppressors (TP53, WT1), and others (GSTP1, HSP90, proliferation rate), in 59 tumor cell lines of the National Cancer Institute (NCI, USA), indicating that Breastin may indeed bypass drug resistance. COMPARE analyses with 153 anticancer agents in 74 tumor cell lines of the Oncotest panel revealed frequent correlations of Breastin with mitosis-inhibiting drugs. Using tubulin-GFP-transfected U2OS cells and confocal microscopy, it was found that the microtubule-disturbing effect of Breastin was comparable to that of the tubulin-depolymerizing drug paclitaxel. This result was verified by a tubulin polymerization assay in vitro and molecular docking in silico. Proteome profiling of 3171 proteins in the NCI panel revealed protein subsets whose expression significantly correlated with cellular responsiveness to odoroside H and neritaloside, indicating that protein expression profiles can be identified to predict the sensitivity or resistance of tumor cells to Breastin constituents. Breastin moderately inhibited breast cancer xenograft tumors in vivo. Remarkably, in contrast to what was observed with paclitaxel monotherapy, the combination of paclitaxel and Breastin prevented tumor relapse, indicating Breastin’s potential for drug combination regimens