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Fendrr synergizes with Wnt signalling to regulate fibrosis related genes during lung development
(2021)
Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via a RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and find that this FendrrBox is partially required for Fendrr function in vivo. We find that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs, associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in fibroblasts. We find that Fendrr with the Wnt signaling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signaling in lung fibrosis.
Cannabis is the most commonly used illicit drug in the world. However due to a changing legal landscape, and rising interest in therapeutic utility, there is an increasing trend in (long-term) use and possibly, cannabis impairment. Importantly, a growing body of evidence suggests regular cannabis users develop tolerance to the impairing, as well as the rewarding, effects of the drug. However, the neuroadaptations that may underlie cannabis tolerance remain unclear. Therefore, this double-blind, randomized, placebo controlled, cross-over study assessed the acute influence of cannabis on brain and behavioral outcomes in two distinct cannabis user groups. Twelve occasional (OUs) and 12 chronic (CUs) cannabis users received acute doses of cannabis (300 μg/kg THC) and placebo, and underwent ultra-high field functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS). In OUs, cannabis induced significant neurometabolic alterations in reward circuitry, namely decrements in functional connectivity and increments in striatal glutamate concentrations, which were associated with increases in subjective high and decreases in performance on a sustained attention task. Such changes were absent in CUs. The finding that cannabis altered circuitry and distorted behavior in OUs, but not CUs, suggests reduced responsiveness of the reward circuitry to cannabis intoxication in chronic users Taken together, the results suggest a pharmacodynamic mechanism for the development of tolerance to cannabis impairment.
Bone vasculature provides protection and signals necessary to control stem cell quiescence and renewal1. Specifically, type H capillaries, which highly express Endomucin, constitute the endothelial niche supporting a microenvironment of osteoprogenitors and long-term hematopoietic stem cells2–4. The age-dependent decline in type H endothelial cells was shown to be associated with bone dysregulation and accumulation of hematopoietic stem cells, which display cell-intrinsic alterations and reduced functionality3. The regulation of bone vasculature by chronic diseases, such as heart failure is unknown. Here, we describe the effects of myocardial infarction and post-infarction heart failure on the vascular bone cell composition. We demonstrate an age-independent loss of type H bone endothelium in heart failure after myocardial infarction in both mice and in humans. Using single-cell RNA sequencing, we delineate the transcriptional heterogeneity of human bone marrow endothelium showing increased expression of inflammatory genes, including IL1B and MYC, in ischemic heart failure. Inhibition of NLRP3-dependent IL-1β production partially prevents the post-myocardial infarction loss of type H vasculature in mice. These results provide a rationale for using anti-inflammatory therapies to prevent or reverse the deterioration of vascular bone function in ischemic heart disease.
Understanding the complexity of transcriptional regulation is a major goal of computational biology. Because experimental linkage of regulatory sites to genes is challenging, computational methods considering epigenomics data have been proposed to create tissue-specific regulatory maps. However, we showed that these approaches are not well suited to account for the variations of the regulatory landscape between cell-types. To overcome these drawbacks, we developed a new method called STITCHIT, that identifies and links putative regulatory sites to genes. Within STITCHIT, we consider the chromatin accessibility signal of all samples jointly to identify regions exhibiting a signal variation related to the expression of a distinct gene. STITCHIT outperforms previous approaches in various validation experiments and was used with a genome-wide CRISPR-Cas9 screen to prioritize novel doxorubicin-resistance genes and their associated non-coding regulatory regions. We believe that our work paves the way for a more refined understanding of transcriptional regulation at the gene-level.
Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using in vitro microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs immediately resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases.
Coronavirus disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and can affect multiple organs, among which is the circulatory system. Inflammation and mortality risk markers were previously detected in COVID-19 plasma and red blood cells (RBCs) metabolic and proteomic profiles. Additionally, biophysical properties, such as deformability, were found to be changed during the infection. Based on such data, we aim to better characterize RBC functions in COVID-19. We evaluate the flow properties of RBCs in severe COVID-19 patients admitted to the intensive care unit by using in vitro microfluidic techniques and automated methods, including artificial neural networks, for an unbiased RBC analysis. We find strong flow and RBC shape impairment in COVID-19 samples and demonstrate that such changes are reversible upon suspension of COVID-19 RBCs in healthy plasma. Vice versa, healthy RBCs immediately resemble COVID-19 RBCs when suspended in COVID-19 plasma. Proteomics and metabolomics analyses allow us to detect the effect of plasma exchanges on both plasma and RBCs and demonstrate a new role of RBCs in maintaining plasma equilibria at the expense of their flow properties. Our findings provide a framework for further investigations of clinical relevance for therapies against COVID-19 and possibly other infectious diseases.
In this special issue of Matrix Biology centered on proteoglycan biology we have assembled a blend of articles focused on the state-of-the-art of proteoglycanology. The field has greatly expanded in the past three decades and now encompasses all the areas of biology. This special issue is divided into five chapters describing hyaluronan metabolism, biosynthetic and catabolic pathways of proteoglycans and their roles in inflammation, cancer, repair and development. We hope that the new original work and the reviews from recognized leaders will stimulate investigations in this exciting and fertile field of research.
Background: Trauma-related guilt and shame are crucial for the development and maintenance of PTSD (posttraumatic stress disorder). We developed an intervention combining cognitive techniques with loving-kindness meditations (C-METTA) that specifically target these emotions. C-METTA is an intervention of six weekly individual treatment sessions followed by a four-week practice phase.
Objective: This study examined C-METTA in a proof-of-concept study within a randomized wait-list controlled trial.
Method: We randomly assigned 32 trauma-exposed patients with a DSM-5 diagnosis to C-METTA or a wait-list condition (WL). Primary outcomes were clinician-rated PTSD symptoms (CAPS-5) and trauma-related guilt and shame. Secondary outcomes included psychopathology, self-criticism, well-being, and self-compassion. Outcomes were assessed before the intervention phase and after the practice phase.
Results: Mixed-design analyses showed greater reductions in C-METTA versus WL in clinician-rated PTSD symptoms (d = −1.09), guilt (d = −2.85), shame (d = −2.14), psychopathology and self-criticism.
Conclusion: Our findings support positive outcomes of C-METTA and might contribute to improved care for patients with stress-related disorders. The study was registered in the German Clinical Trials Register (DRKS00023470).
HIGHLIGHTS
C-METTA is an intervention that addresses trauma-related guilt and shame and combines cognitive interventions with loving-kindness meditations.
A proof-of-concept study was conducted examining C-METTA in a wait-list randomized controlled trial
C-METTA led to reductions in trauma-related guilt and shame and PTSD symptoms.
The small GTPases H, K, and NRAS are molecular switches that are indispensable for proper regulation of cellular proliferation and growth. Mutations in this family of proteins are associated with cancer and result in aberrant activation of signaling processes caused by a deregulated recruitment of downstream effector proteins. In this study, we engineered novel variants of the Ras-binding domain (RBD) of the kinase CRAF. These variants bound with high affinity to the effector binding site of active Ras. Structural characterization showed how the newly identified mutations cooperate to enhance affinity to the effector binding site compared to RBDwt. The engineered RBD variants closely mimic the interaction mode of naturally occurring Ras effectors and as dominant negative affinity reagent block their activation. Experiments with cancer cells showed that expression of these RBD variants inhibits Ras signaling leading to a reduced growth and inductions of apoptosis. Using the optimized RBD variants, we stratified patient-derived colorectal cancer organoids according to Ras dependency, which showed that the presence of Ras mutations was insufficient to predict sensitivity to Ras inhibition.
Attention-Deficit/Hyperactivity Disorder (ADHD) is frequently comorbid with other psychiatric disorders and also with somatic conditions, such as obesity. In addition to the clinical overlap, significant genetic correlations have been found between ADHD and obesity as well as body mass index (BMI). The biological mechanisms driving this association are largely unknown, but some candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the link between ADHD and obesity measures. Using the largest GWAS summary statistics currently available for ADHD (N=53,293), BMI (N=681,275), and obesity (N=98,697), we first tested the association of dopaminergic and circadian rhythm gene sets with each phenotype. This hypothesis-driven approach showed that the dopaminergic gene set was associated with both ADHD (P=5.81×10−3) and BMI (P=1.63×10−5), while the circadian rhythm gene set was associated with BMI only (P=1.28×10−3). We then took a data-driven approach by conducting genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. This approach further supported the implication of dopaminergic signaling in the link between ADHD and obesity measures, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was significantly enriched in both the ADHD-BMI and ADHD-obesity gene-based meta-analysis results. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering the shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of preventive interventions and/or efficient treatment of these conditions.