Deciphering disease signatures and molecular targets in vascular Ehlers-Danlos syndrome through transcriptome and miRNome sequencing of dermal fibroblasts

Vascular Ehlers-Danlos syndrome (vEDS) is a severe connective tissue disorder caused by dominant mutations in the COL3A1 gene encoding type III collagen (COLLIII). COLLIII is primarily found in blood vessels and hollow organs, and its deficiency leads to soft connective tissues fragility, resulting in life-threatening arterial and organ ruptures. There are no current targeted therapies available. Although the disease usually results from COLLIII misfolding due to triple helix structure disruption, the underlying pathomechanisms are largely unknown. To address this knowledge gap, we performed a comprehensive transcriptome analysis using RNA- and miRNA-seq on a large cohort of dermal fibroblasts from vEDS patients and healthy donors. Our investigation revealed an intricate interplay between proteostasis abnormalities, inefficient endoplasmic reticulum stress response, and compromised autophagy, which may significantly impact the molecular pathology. We also present the first detailed miRNAs expression profile in patient cells, demonstrating that several aberrantly expressed miRNAs can disrupt critical cellular functions involved in vEDS pathophysiology, such as autophagy, proteostasis, and mTOR signaling. Target prediction and regulatory networks analyses suggested potential interactions among miRNAs, lncRNAs, and candidate target genes linked to extracellular matrix organization and autophagy-lysosome pathway. Our results highlight the importance of understanding the functional role of ncRNAs in vEDS pathogenesis, shedding light on possible miRNAs and lncRNAs signatures and their functional implications for dysregulated pathways related to disease. Deciphering this complex molecular network of RNA interactions may yield additional evidence for potential disease biomolecules and targets, assisting in the design of effective patient treatment strategies

Optical properties of high quality Cu2ZnSnSe4 thin films

Cu2ZnSnSe4 thin films, fabricated on bare or molybdenum coated glass substrates by magnetron sputtering and selenisation, were studied by a range of techniques. Photoluminescence spectra reveal an excitonic peak and two phonon replicas of a donor-acceptor pair (DAP) recombination. Its acceptor and donor ionisation energies are 27 and 7 meV, respectively. This demonstrates that high-quality Cu2ZnSnSe4 thin films can be fabricated. An experimental value for the longitudinal optical phonon energy of 28 meV was estimated. The band gap energy of 1.01 eV at room temperature was determined using optical absorption spectr

Clinical and molecular characterization of 40 patients with classic Ehlers--Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations.

Classic Ehlers-Danlos syndrome (cEDS) is a rare autosomal dominant connective tissue disorder that is primarily characterized by skin hyperextensibility, abnormal wound healing/atrophic scars, and joint hypermobility. A recent study demonstrated that more than 90% of patients who satisfy all of these major criteria harbor a type V collagen (COLLV) defect. This cohort included 40 patients with cEDS who were clinically diagnosed according to the Villefranche nosology. The flowchart that was adopted for mutation detection consisted of sequencing the COL5A1 gene and, if no mutation was detected, COL5A2 analysis. In the negative patients the presence of large genomic rearrangements in COL5A1 was investigated using MLPA, and positive results were confirmed via SNP-array analysis. We report the clinical and molecular characterization of 40 patients from 28 families, consisting of 14 pediatric patients and 26 adults. A family history of cEDS was present in 9 patients. The majority of the patients fulfilled all the major diagnostic criteria for cEDS; atrophic scars were absent in 2 females, skin hyperextensibility was not detected in a male and joint hypermobility was negative in 8 patients (20% of the entire cohort). Wide inter- and intra-familial phenotypic heterogeneity was observed. We identified causal mutations with a detection rate of approximately 93%. In 25/28 probands, COL5A1 or COL5A2 mutations were detected. Twenty-one mutations were in the COL5A1 gene, 18 of which were novel (2 recurrent). Of these, 16 mutations led to nonsense-mediated mRNA decay (NMD) and to COLLV haploinsufficiency and 5 mutations were structural. Two novel COL5A2 splice mutations were detected in patients with the most severe phenotypes. The known p. (Arg312Cys) mutation in the COL1A1 gene was identified in one patient with vascular-like cEDS. Our findings highlight that the three major criteria for cEDS are useful and sufficient for cEDS clinical diagnosis in the large majority of the patients. The borderline patients for whom these criteria fail can be diagnosed when minor signs of connective tissue diseases and family history are present and when genetic testing reveals a defect in COLLV. Our data also confirm that COL5A1 and COL5A2 are the major, if not the only, genes involved in cEDS

The Relationship Between Depressive Symptoms and Social Cognitive Processing in Partners of Long-Term Breast Cancer Survivors

Purpose/Objectives: To determine 1) if depressive symptoms in partners of long-term breast cancer survivors (BCS) could be predicted by social cognitive processing theory, and 2) if partners of younger and older breast cancer survivors were differentially affected by the cancer experience. Design: A cross-sectional, descriptive study utilizing self-report questionnaires. Setting: Indiana University and 97 ECOG-ACRIN sites. Sample: Partners of breast cancer survivors (n=508) diagnosed 3-8 years prior. Methods: Secondary data mediation analyses were conducted to determine if cognitive processing mediated the relationship between social constraints and depressive symptoms. Age-related differences on all scales were tested. Main Research Variables: Depressive symptoms; secondary variables included social constraints, cognitive processing (avoidance and intrusive thoughts), and potentially confounding variables. Findings: Cognitive processing mediated the relationship between social constraints and depressive symptoms for partners (F(5,498)= 19.911, R2=.167, p<.001). Partners of young BCS reported worse outcomes on all measures than partners of older breast cancer survivors Conclusions: As predicted by the social cognitive processing theory, cognitive processing mediated the relationship between social constraints and depressive symptoms. Furthermore, partners of younger BCS fared worse on social constraints, intrusive thoughts and depressive symptoms than partners of older BCS. Implications for Nursing: Results provide support for using the social cognitive processing theory in intervention design with partners of long-term BCS to decrease depressive symptoms. Knowledge Translation: • Partners of long-term BCS report clinically significant depression. • Partners of younger BCS report higher levels of depressive symptoms than the national average and than partners of older survivors. • Addressing social constraints within the dyad may improve depressive symptoms.This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA189828, CA180795, CA37403, CA35199, CA17145 and CA49883, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Research reported in this publication was supported by the National Institute of Nursing Research of the National Institutes of Health under Award Number F31NR013822, and by the National Cancer Institute of the National Institutes of Health under Award Numbers K05CA175048 and R25CA117865. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, including the National Cancer Institute or the National Institute of Nursing Research

Structural Phase Transition at High Temperatures in Solid Molecular Hydrogen and Deuterium

We study the effect of temperature up to 1000K on the structure of dense molecular para-hydrogen and ortho-deuterium, using the path-integral Monte Carlo method. We find a structural phase transition from orientationally disordered hexagonal close packed (hcp) to an orthorhombic structure of Cmca symmetry before melting. The transition is basically induced by thermal fluctuations, but quantum fluctuations of protons (deuterons) are important in determining the transition temperature through effectively hardening the intermolecular interaction. We estimate the phase line between hcp and Cmca phases as well as the melting line of the Cmca solid.Comment: 8 pages, 7 figures; accepted in Phys. Rev.

A Low Cost Luminescent Solar Concentrator

Abstract Two commercially available, ultra-low cost plastics, doped with fluorescent dyes, are presented as novel materials to be used to in luminescent solar concentrator systems. Investigation of the optical properties of the plastics reveals favourable performance characteristics including significant Stoke&apos;s shifts and negligible spectral overlap of the emission and absorption spectra. These attributes are supported by experimentally determined optical efficiencies of 9.8% and 16.8%. Limited absorption/emission spectral overlap indicates that self-absorption is a low loss mechanism in these devices. This is confirmed by a weak red shift as the photon path length in the LSC is increased. Finally, the potential for this type of LSC is considered in the context of indoor photovoltaics and solid state lighting

Factors associated with depressive symptoms in young long-term breast cancer survivors

Purpose Long-term breast cancer survivors frequently report distress (i.e., depressive symptoms) that impacts their quality of life. Previous studies have found that negative social interactions (“social constraints”) from partners contribute to long-term, unresolved cycling of intrusive thoughts and cognitive avoidance, resulting in psychological distress. However, these relationships have not been tested in long-term breast cancer survivors. Furthermore, the effect of partners’ depressive symptoms on the survivors’ depressive symptoms has not been tested within the context of these relationships. Therefore, the purpose of this study was to test relationships between breast cancer survivors’ depressive symptoms and (1) social constraints, cognitive avoidance, and intrusive thoughts, and (2) partners’ depressive symptoms. Methods Data were from a cross-sectional descriptive study of breast cancer survivors (N = 222) 3–8 years post-diagnosis and their partners, who completed surveys assessing demographic characteristics, social constraints, intrusive thoughts, cognitive avoidance, and depressive symptoms. Structural equation modeling confirmatory path analyses were conducted to determine significant relationships between survivors’ depressive symptoms and all other variables. Results Our model fits the data well. Breast cancer survivors’ depressive symptoms were predicted by social constraints and intrusive thoughts. The relationship between survivors’ depressive symptoms and partners’ depressive symptoms was close but not significant. Conclusions As hypothesized, depressive symptoms were predicted by social constraints and intrusive thoughts. Further research is needed to understand the possible relationship between survivors’ long-term depressive symptoms and cognitive avoidance and partners’ depressive symptoms. Our findings highlight the negative impact of social constraints from partners on psychological outcomes in long-term breast cancer survivors

Long-Term Fear of Recurrence in Young Breast Cancer Survivors and Partners

Background Fear of a breast cancer recurrence is the most prevalent and disruptive source of distress for long-term survivors and their partners. However, few studies have focused on predictors of fear of recurrence. The aim of this study is to test the efficacy of the Social Cognitive Processing Theory (SCPT) in predicting fear of recurrence in long-term breast cancer survivors diagnosed at age 45 years or younger and their partners. Methods In a large cross-sectional study, breast cancer survivors (n = 222) 3–8 years from diagnosis and their partners completed a survey assessing demographic characteristics, fear of recurrence, social constraints, and cognitive processing (intrusive thoughts and cognitive avoidance). Mediation analyses were conducted for survivors and partners separately to determine if cognitive processing would mediate the relationship between social constraints and fear of recurrence. Results Cognitive processing mediated the relationship between social constraints and fear of recurrence both for survivors [F(3,213) = 47.541, R2 = 0.401, p < 0.001] and partners [F(3,215) = 27.917, R2 = 0.280, p < 0.001). Demographic variables were not significant predictors of fear of recurrence. Conclusions As predicted, cognitive processing mediated the relationship between social constraints and fear of recurrence. Results expand the utility of the SCPT in long-term survivors and their partners by supporting its use in intervention design.Acknowledgement: This research was supported by an American Cancer Society grant: RSGPB-04-089-01-PBP. This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported in part by Public Health Service Grants CA189828, CA180795 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Research reported in this publication was supported by the National Institute of Nursing Research of the National Institutes of Health under Award Number F31NR013822. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number K05CA175048. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

Microbial community functioning during plant litter decomposition

International audienceAbstract Microbial life in soil is fueled by dissolved organic matter (DOM) that leaches from the litter layer. It is well known that decomposer communities adapt to the available litter source, but it remains unclear if they functionally compete or synergistically address different litter types. Therefore, we decomposed beech, oak, pine and grass litter from two geologically distinct sites in a lab-scale decomposition experiment. We performed a correlative network analysis on the results of direct infusion HR-MS DOM analysis and cross-validated functional predictions from 16S rRNA gene amplicon sequencing and with DOM and metaproteomic analyses. Here we show that many functions are redundantly distributed within decomposer communities and that their relative expression is rapidly optimized to address litter-specific properties. However, community changes are likely forced by antagonistic mechanisms as we identified several natural antibiotics in DOM. As a consequence, the decomposer community is specializing towards the litter source and the state of decomposition (community divergence) but showing similar litter metabolomes (metabolome convergence). Our multi-omics-based results highlight that DOM not only fuels microbial life, but it additionally holds meta-metabolomic information on the functioning of ecosystems