Evidence for an inositol hexakisphosphate-dependent role for Ku in mammalian nonhomologous end joining that is independent of its role in the DNA-dependent protein kinase

Nonhomologous end-joining (NHEJ) is an important pathway for the repair of DNA double-strand breaks (DSBs) and plays a critical role in maintaining genomic stability in mammalian cells. While Ku70/80 (Ku) functions in NHEJ as part of the DNA-dependent protein kinase (DNA-PK), genetic evidence indicates that the role of Ku in NHEJ goes beyond its participation in DNA-PK. Inositol hexakisphosphate (IP6) was previously found to stimulate NHEJ in vitro and Ku was identified as an IP6-binding factor. Through mutational analysis, we identified a bipartite IP6-binding site in Ku and generated IP6-binding mutants that ranged from 1.22% to 58.48% of wild-type binding. Significantly, these Ku IP6-binding mutants were impaired for participation in NHEJ in vitro and we observed a positive correlation between IP6 binding and NHEJ. Ku IP6-binding mutants were separation-of-function mutants that bound DNA and activated DNA-PK as well as wild-type Ku. Our observations identify a hitherto undefined IP6-binding site in Ku and show that this interaction is important for DSB repair by NHEJ in vitro. Moreover, these data indicate that in addition to binding of exposed DNA termini and activation of DNA-PK, the Ku heterodimer plays a role in mammalian NHEJ that is regulated by binding of IP6

Using Extra-Linguistic Material for Mandarin-French Verbal Constructions Comparison

International audienceSystematic cross-linguistic studies of verbs syntactic-semantic behaviors for ty-pologically distant languages such as Mandarin Chinese and French are difficult to conduct.Such studies are nevertheless necessary due to the crucial role that verbal constructions playin the mental lexicon. This paper addresses the problem by combining psycho-linguisticsand computational methods. Psycho-linguistics provides us with a bilingual corpus that fea-tures verbal construction associated with carefully built extra-linguistic material (short videoclips). Computational approaches bring us distributional semantic models (DSM) to measurethe distance between linguistic elements in the extra-linguistic space. These models allowsfor cross-linguistic measures that we evaluate against manually annotated data. In this pa-per, we discuss the results, potential shortcomings involving cultural variability and how tomeasure such bias

The generalized parton distributions of the nucleon in the NJL model based on the Faddeev approach

We study the generalized parton distributions, including the helicity-flip ones, using Nambu-Jona-Lasinio model based on a relativistic Faddeev approach with `static approximation'. Sum rules relating the generalized parton distributions to nucleon electromagnetic form factors are satisfied. Moreover, quark-antiquark contributions in the region $-\xi<x<\xi$ are non-vanishing. Our results are qualitatively similar to those calculated with Radyushkin's double distribution ansatz using forward parton distribution functions calculated in the NJL model as inputs.Comment: 35 pages, 15 figure

Evaluating the health-related quality of life of the rare disease population in Hong Kong using EQ-5D 3-level

Objectives This study aimed to establish a normative profile of health-related quality of life (HRQOL) of the rare disease (RD) population in Hong Kong (HK) and identify potential predictors. Methods Between March 2020 and October 2020, patients with RD and caregivers were recruited through Rare Disease Hong Kong, the largest RD patient group alliance in HK. HRQOL was derived using the EQ-5D 3-Level with reference to the established HK value set. Utility scores were stratified according to demographics and disease-related information. Multiple linear regression was performed to explore the associations between patient characteristics and HRQOL. Results A total of 286 patients, covering 107 unique RDs, reported a mean utility score of 0.53 (SD 0.36). Thirty patients (10.5%) reported negative utility scores, indicating worse-than-death health states. More problems were recorded in the “usual activities” and “self-care” dimensions. Univariate analyses revealed that neurologic diseases, high out-of-pocket expenditure, home modification, and living in public housing or subdivided flats/units were significantly associated with lower HRQOL. A total of 99 caregivers reported a mean utility score of 0.78 (SD 0.17), which was significantly associated with the utility score of patients they took care of (r = 0.32; P = .001). Conclusions The normative profile of the RD population was established, which revealed lower HRQOL in the RD population than other chronic disease groups and general population in HK. Findings were corroborated by evidence from other cohorts using EQ-5D, combined as part of a meta-analysis. Identifying predictors highlight areas that should be prioritized to improve HRQOL of RD population through clinical and psychosocial dimensions

Visiting urban green space as a climate-change adaptation strategy: Exploring push factors in a push–pull framework

Urban green space (UGS) offers users multiple ecosystem services and amenities. This study investigated whether residents used UGS visitation in summer as a sustainable measure to tackle hot weather and associated climate-change impacts in humid-subtropical Hong Kong. Attributes of the indoor residential environment, seldom examined in park-visitation studies, were evaluated as push factors to visit UGS through a push–pull theoretical framework. A questionnaire survey of 483 respondents targeted urban park users. The results indicated that UGS visit frequency and stay duration were relatively low in hot summer. Ordinal multiple regression showed that indoor living conditions, residence location, living routine, and habit and personal health impacts were significantly correlated with UGS visits. Interdependence between push and pull factors was detected, demonstrating that intrinsic UGS environmental conditions could constrain UGS visits despite the motivations of push factors. The results indicated the need to improve the microclimate-regulating function in UGS. It could be achieved mainly by optimizing the nature-based design to promote UGS as an adaptive measure to combat the thermal stress brought by climate change. The findings yielded hints to shape visiting habits and suggestions to improve UGS management

Danggui Buxue Tang – A Chinese herbal decoction activates the phosphorylations of extracellular signal-regulated kinase and estrogen receptor α in cultured MCF-7 cells

AbstractDanggui Buxue Tang (DBT), a Chinese herbal decoction used to treat ailments in women, contains Radix Astragali (Huangqi; RA) and Radix Angelicae Sinensis (Danggui; RAS). The weight ratio of RA to RAS used in DBT must be 5:1 as stipulated as early as AD 1247; however, DBT’s mechanism of action has never been described. Here, the estrogenic effects of DBT were investigated by determining the phosphorylations of estrogen receptor α (ERα) and extracellular signal-regulated kinase 1/2 (Erk1/2) in cultured MCF-7 cells. The application of DBT triggered the phosphorylation of ERα and Erk1/2 in a time-dependent manner. In contrast to the effect of estrogen, DBT triggered ERα phosphorylation at both S118 and S167. This DBT-specific phosphorylation was not triggered by an extract of one of the individual herbs, or by mixing the extracts of RA and RAS. DBT-induced downstream signals are described here. These signals suggest the uniqueness of this Chinese herbal decoction that requires a well-defined formulation

Hydrophobic and ionic-interactions in bulk and confined water with implications for collapse and folding of proteins

Water and water-mediated interactions determine thermodynamic and kinetics of protein folding, protein aggregation and self-assembly in confined spaces. To obtain insights into the role of water in the context of folding problems, we describe computer simulations of a few related model systems. The dynamics of collapse of eicosane shows that upon expulsion of water the linear hydrocarbon chain adopts an ordered helical hairpin structure with 1.5 turns. The structure of dimer of eicosane molecules has two well ordered helical hairpins that are stacked perpendicular to each other. As a prelude to studying folding in confined spaces we used simulations to understand changes in hydrophobic and ionic interactions in nano droplets. Solvation of hydrophobic and charged species change drastically in nano water droplets. Hydrophobic species are localized at the boundary. The tendency of ions to be at the boundary where water density is low increases as the charge density decreases. Interaction between hydrophobic, polar, and charged residue are also profoundly altered in confined spaces. Using the results of computer simulations and accounting for loss of chain entropy upon confinement we argue and then demonstrate, using simulations in explicit water, that ordered states of generic amphiphilic peptide sequences should be stabilized in cylindrical nanopores