Dimensions of coping and anxiety symptoms in a community sample of young children

Coping style plays an important role in children’s wellbeing. This paper describes the patterns of associations between children’s self-reported coping styles and symptoms of anxiety in order to determine whether particular dimensions are associated with better adjustment. Participants were 2566 children (1268 girls, 1298 boys) aged 7–11 years attending 15 schools in the South East of England. Results showed that aspects of coping were differentially associated with children’s self-reported anxiety. Patterns of association also varied by age and gender. Dimensions of coping were shown to form distinct adaptive and maladaptive coping styles which were also differentially associated with anxiety. Analysis of these styles indicated that it is the absence of maladaptive coping strategies, rather than the presence of adaptive strategies, that is significant in emotional wellbeing. These findings suggest that interventions designed to reduce or extinguish maladaptive coping styles may be of particular benefit in facilitating emotional wellbeing

Important Interactions Promoting Recognition of Peptide Ligands at the Binding Pocket of the PDZ Signaling Domain of AF6

Afadin (AF6) is a scaffolding protein involved in the formation of protein complexes at tight and adherens junctions. AF6 plays vital roles in many cellular processes, such as structural development, cellular organization, directional cell movement, and polarity. The PDZ domain participates in multiple signaling networks to initiate and maintain cellular polarity, to facilitate protein trafficking, and allow neuronal communications; thus, misregulated PDZ domain-dependent pathways can induce cells to become cancerous. AF6 interacts with many other proteins via its PDZ signaling domain and exhibits multimodal specificity. The PDZ signaling domain of AF6 (AF6_PDZ) binds predominantly hydrophobic peptide ligands. A biological array binding study has shown that AF6_PDZ can also recognize peptide ligands that contain diverse features compared to those of cognate sequence. The plasticity of the AF6_PDZ to recognize chemically diverse ligands raises questions regarding how AF6_PDZ achieves specificity in peptide recognition, as well as which binding pocket interactions are important for peptide binding. Structures of the AF6_PDZ with several biological peptide ligands highlight intermolecular interactions that stabilize these ligands at the binding pocket. We hypothesize that these interactions play a key role in recruiting the ligand to a “hot spot” on the AF6_PDZ surface and promote binding. This hypothesis predicts that changing the interactions by introducing mutations into the peptide sequence will alter the peptide binding affinity. The protein-peptide interactions in this project were studied predominantly with 1H-15N-heteronuclear single quantum coherence nuclear magnetic resonance (HSQC NMR) titration. We selected two non-cognate peptides suspected of binding to AF6_PDZ but found that these peptides only weakly interact with AF6_PDZ. Based on this result, we suggest that AF6_PDZ cannot recognize peptide with a deviated residue at the extreme C-terminal position of the peptide (P0). In specific, an arginine or a proline amino acid is likely not preferable residue at this position of the peptide. Using knowledge-based approach, we introduced a valine at the P0 of the peptide, successfully restoring binding. This result highlights the crucial role of the valine in promote binding. The disassociation constants KD for binding interaction of AF6_PDZ with cognate peptide (Class I ligand) and designed peptide (Class II ligand) are 154 µM and 26.4 µM respectively, and these values are consistent with what others have observed previously. We also studied shifted motif ligands, in which we investigated whether AF6_PDZ can accommodate ligands with an additional C-terminal residue to the P0 valine. We conclude that the AF6_PDZ does not have the ability to recognize these peptides, and the shifted motif binding mode is likely not relevant for AF6_PDZ in biological environment. Comparison of available structures reveals the possibility that αA helix of AF6_PDZ may impose some structural constraint, and thereby inhibit the protein recognition of shifted motif peptides. We also suggest that the list of the top 100 binding sequences from the peptide screening experiment does not reflect all biological binders; thus, this list needs to be used with precaution in future experiments. Altogether, we confirm the important interactions that the valine at P0 forms at the binding pocket and these interactions help targeting the peptide to the binding pocket to promote binding. This finding will aid scientists in designing therapeutic drugs that targets the AF6_PDZ, in specific, and PDZ-domain containing proteins, in generally

Defining Epidermal Basal Cell States during Skin Homeostasis and Wound Healing Using Single-Cell Transcriptomics.

Our knowledge of transcriptional heterogeneities in epithelial stem and progenitor cell compartments is limited. Epidermal basal cells sustain cutaneous tissue maintenance and drive wound healing. Previous studies have probed basal cell heterogeneity in stem and progenitor potential, but a comprehensive dissection of basal cell dynamics during differentiation is lacking. Using single-cell RNA sequencing coupled with RNAScope and fluorescence lifetime imaging, we identify three non-proliferative and one proliferative basal cell state in homeostatic skin that differ in metabolic preference and become spatially partitioned during wound re-epithelialization. Pseudotemporal trajectory and RNA velocity analyses predict a quasi-linear differentiation hierarchy where basal cells progress from Col17a1Hi/Trp63Hi state to early-response state, proliferate at the juncture of these two states, or become growth arrested before differentiating into spinous cells. Wound healing induces plasticity manifested by dynamic basal-spinous interconversions at multiple basal transcriptional states. Our study provides a systematic view of epidermal cellular dynamics, supporting a revised "hierarchical-lineage" model of homeostasis

Exposure of agriculture workers to pesticides: the effect of heat on protective glove performance and skin exposure to dichlorvos

Dichlorvos is a toxic organophosphate insecticide that is used in agriculture and other insecticide applications. Dermal uptake is a known exposure route for dichlorvos and chemical protective gloves are commonly utilized. Chemical handling and application may occur in a variety of thermal environments, and the rates of both chemical permeation through gloves and transdermal penetration may vary significantly with temperature. There has been no published research on the temperature-dependent kinetics of these processes for dichlorvos and thus, this study reports on the effects of hot conditions for the concentrated and application strength chemical. Dichlorvos breakthrough times for non-disposable polyvinyl chloride (PVC) gloves at 60 °C were approximately halved compared to 25 °C for the concentrate (2 vs. 4 h) and more than halved at application strength (3 vs. >8 h). From permeation experiments covering 15–60 °C, there was a 460-fold increase in cumulative permeation over 8 h for the concentrated dichlorvos and the estimated activation energy halved. Elevated temperature was also shown to be a significant factor for human skin penetration increasing the cumulative penetration of concentrate dichlorvos from 179 ± 37 to 1315 ± 362 µg/cm² (p = 0.0032) and application strength from 29.8 ± 5.7 to 115 ± 19 µg/cm² (p = 0.0131). This work illustrates the important role temperature plays in glove performance and health risk via dermal exposure. As such, it is important to consider in-use conditions of temperature when implementing chemical hygiene programs.Leigh Thredgold, Sharyn Gaskin , Chloe Quy and Dino Pisaniell

Preemptive analgesic effect of intrathecal applications of neuroactive steroids in a rodent model of post-surgical pain: Evidence for the role of T-type calcium channels

Preemptive management of post-incisional pain remains challenging. Here, we examined the role of preemptive use of neuroactive steroids with activity on low-voltage activated T-type C

Risk of acquired drug resistance during short-course directly observed treatment of tuberculosis in an area with high levels of drug resistance.

BACKGROUND: Data on the performance of standardized short-course directly observed treatment (DOTS) of tuberculosis (TB) in areas with high levels of drug resistance and on the potential impact of DOTS on amplification of resistance are limited. Therefore, we analyzed treatment results from a cross-sectional sample of patients with TB enrolled in a DOTS program in an area with high levels of drug resistance in Uzbekistan and Turkmenistan in Central Asia. METHODS: Sputum samples for testing for susceptibility to 5 first-line drugs and for molecular typing were obtained from patients starting treatment in 8 districts. Patients with sputum smear results positive for TB at the end of the intensive phase of treatment and/or at 2 months into the continuation phase were tested again. RESULTS. Among 382 patients with diagnoses of TB, 62 did not respond well to treatment and were found to be infected with an identical Mycobacterium tuberculosis strain when tested again; 19 of these patients had strains that developed new or additional drug resistance. Amplification occurred in only 1.2% of patients with initially susceptible or monoresistant TB strains, but it occurred in 17% of those with polyresistant strains (but not multidrug-resistant strains, defined as strains with resistance to at least isoniazid and rifampicin) and in 7% of those with multidrug-resistant strains at diagnosis. Overall, 3.5% of the patients not initially infected with multidrug-resistant TB strains developed such strains during treatment. Amplification of resistance, however, was found only in polyresistant Beijing genotype strains. CONCLUSIONS: High levels of amplification of drug resistance demonstrated under well-established DOTS program conditions reinforce the need for implementation of DOTS-Plus for multidrug-resistant TB in areas with high levels of drug resistance. The strong association of Beijing genotype and amplification in situations of preexisting resistance is striking and may underlie the strong association between this genotype and drug resistance

Clinical Outcomes of Intraoperative Radiation Therapy for Extremity Sarcomas

Purpose. Radiation of extremity lesions, a key component of limb-sparing therapy, presents particular challenges, with significant risks of toxicities. We sought to explore the efficacy of intraoperative radiation therapy (IORT) in the treatment of soft tissue sarcomas of the extremities. Patients. Between 1995 and 2001, 17 patients received IORT for soft tissue sarcomas of the extremities. Indications for IORT included recurrent tumors in a previously radiated field or tumors adjacent to critical structures. Results. Gross total resections were achieved in all 17 patients. Two patients experienced locoregional relapses, six patients recurred at metastatic sites, and one patient died without recurrence. Thirty-six month estimates for locoregional control, disease free survival, and overall survival were 86%, 50%, and 78%, respectively. IORT was extremely well tolerated, with no toxicities referable to IORT. Conclusions. For patients with soft tissue sarcomas of the extremities, IORT used as a boost to EBRT provides excellent local control, with limited acute toxicities

On the evaluation of strain energy release rate of cement-bone bonded joints under mode II loading

Bone cements based on poly(methylmethacrylate) (PMMA) are primarily used in joint replacement surgeries. In the fixation of joint replacement, the self-curing cement fills constitutes a very important interface. To understand and improve the interaction between cortical bone and bone cement it is essential to characterize the mechanical properties of cement-bone bonded joints in full detail. In this study, the end-notched flexure test was used in the context of pure mode II fracture characterisation of cement-bone bonded joints. A data reduction scheme based on crack equivalent concept was employed to overcome the difficulties inherent to crack length monitoring during damage propagation. A finite element method combined with a cohesive zone model was first used to validate numerically the adopted method. The procedure was subsequently applied to experimental results to determine the fracture toughness of cement-bone bonded joints under pure mode II loading. The consistency of the obtained results leads to the conclusion that the adopted procedure is adequate to carry out fracture characterisation of these joints under pure mode II loading. The innovative aspect of the present work lies in the application of cohesive zone modelling approach to PMMA-based cement-bone bonded joints

Animal-related factors associated with moderate-to-severe diarrhea in children younger than five years in western Kenya: A matched case-control study

Background Diarrheal disease remains among the leading causes of global mortality in children younger than 5 years. Exposure to domestic animals may be a risk factor for diarrheal disease. The objectives of this study were to identify animal-related exposures associated with cases of moderate-to-severe diarrhea (MSD) in children in rural western Kenya, and to identify the major zoonotic enteric pathogens present in domestic animals residing in the homesteads of case and control children. Methodology/Principal findings We characterized animal-related exposures in a subset of case and control children (n = 73 pairs matched on age, sex and location) with reported animal presence at home enrolled in the Global Enteric Multicenter Study in western Kenya, and analysed these for an association with MSD. We identified potentially zoonotic enteric pathogens in pooled fecal specimens collected from domestic animals resident at children’s homesteads. Variables that were associated with decreased risk of MSD were washing hands after animal contact (matched odds ratio [MOR] = 0.2; 95% CI 0.08–0.7), and presence of adult sheep that were not confined in a pen overnight (MOR = 0.1; 0.02–0.5). Variables that were associated with increased risk of MSD were increasing number of sheep owned (MOR = 1.2; 1.0–1.5), frequent observation of fresh rodent excreta (feces/urine) outside the house (MOR = 7.5; 1.5–37.2), and participation of the child in providing water to chickens (MOR = 3.8; 1.2–12.2). Of 691 pooled specimens collected from 2,174 domestic animals, 159 pools (23%) tested positive for one or more potentially zoonotic enteric pathogens (Campylobacter jejuni, C. coli, non-typhoidal Salmonella, diarrheagenic E. coli, Giardia, Cryptosporidium, or rotavirus). We did not find any association between the presence of particular pathogens in household animals, and MSD in children. Conclusions and significance Public health agencies should continue to promote frequent hand washing, including after animal contact, to reduce the risk of MSD. Future studies should address specific causal relations of MSD with sheep and chicken husbandry practices, and with the presence of rodents