👤 Lea Thaler

The SARS-CoV-2 pandemic highlighted the need for broad-spectrum antivirals to increase our preparedness. Patients often require treatment by the time that blocking virus replication is less effective. Therefore, therapy should not only aim to inhibit the virus, but also to suppress pathogenic host responses, e.g., leading to microvascular changes and pulmonary damage. Clinical studies have previously linked SARS-CoV-2 infection to pathogenic intussusceptive angiogenesis in the lungs, involving the upregulation of angiogenic factors such as ANGPTL4. The β-blocker propranolol is used to suppress aberrant ANGPTL4 expression in the treatment of hemangiomas. Therefore, we investigated the effect of propranolol on SARS-CoV-2 infection and the expression of ANGPTL4. SARS-CoV-2 upregulated ANGPTL4 in endothelial and other cells, which could be suppressed with R-propranolol. The compound also inhibited the replication of SARS-CoV-2 in Vero-E6 cells and reduced the viral load by up to ~2 logs in various cell lines and primary human airway epithelial cultures. R-propranolol was as effective as S-propranolol but lacks the latter's undesired β-blocker activity. R-propranolol also inhibited SARS-CoV and MERS-CoV. It inhibited a post-entry step of the replication cycle, likely via host factors. The broad-spectrum antiviral effect and suppression of factors involved in pathogenic angiogenesis make R-propranolol an interesting molecule to further explore for the treatment of coronavirus infections. Show less

Recent studies have reported altered methylation levels at disorder-relevant DNA sites in people who are ill with Anorexia Nervosa (AN) compared to findings in people with no eating disorder (ED) or in whom AN has remitted. The preceding implies state-related influences upon gene expression in people with AN. This study further examined this notion. We measured genome-wide DNA methylation in 145 women with active AN, 49 showing stable one-year remission of AN, and 64 with no ED. Comparisons revealed 205 differentially methylated sites between active and no ED groups, and 162 differentially methylated sites between active and remitted groups ( Findings corroborate earlier results suggesting reversible DNA methylation alterations in AN, and point to particular genes at which epigenetic mechanisms may act to shape AN phenomenology. Show less

VPS35 and VPS13 have been associated with Parkinson's disease (PD), and their shared phenotype in yeast when reduced in function is abnormal vacuolar transport. We aim to test if additional potentially deleterious variants in other genes that share this phenotype can modify the risk for PD. 77 VPS and VPS-related genes were analyzed using whole-genome-sequencing data from 202 PD patients of Ashkenazi Jewish (AJ) ancestry. Filtering was done based on quality and functionality scores. Ten variants in nine genes were further genotyped in 1200 consecutively recruited unrelated AJ-PD patients, and allele frequencies and odds ratio calculated compared to gnomAD-AJ-non-neuro database, in un-stratified (n = 1200) and stratified manner (LRRK2-G2019S-PD patients (n = 145), GBA-PD patients (n = 235), and non-carriers of these mutations (NC, n = 787)). Five variants in PIK3C3, VPS11, AP1G2, HGS and VPS13D were significantly associated with PD-risk. PIK3C3-R768W showed a significant association in an un-stratified (all PDs) analysis, as well as in stratified (LRRK2, GBA, and NC) analyses (Odds ratios = 2.71, 5.32, 3.26. and 2.19 with p = 0.0015, 0.002, 0.0287, and 0.0447, respectively). AP1G2-R563W was significantly associated in LRRK2-carriers (OR = 3.69, p = 0.006) while VPS13D-D2932N was significantly associated in GBA-carriers (OR = 5.45, p = 0.0027). VPS11-C846G and HGS-S243Y were significantly associated in NC (OR = 2.48 and 2.06, with p = 0.022 and 0.0163, respectively). Variants in genes involved in vesicle-mediated protein transport and recycling pathways, including autophagy and mitophagy, may differentially modify PD-risk in LRRK2-carriers, GBA carriers, or NC. Specifically, PIK3C3-R768W is a PD-risk allele, with the highest effect size in LRRK2-G2019S carriers. These results suggest oligogenic effect that may depends on the genetic background of the patient. An unbiased burden of mutations approach in these genes should be evaluated in additional PD and control groups. The mechanisms by which these novel variants interact and increase PD-risk should be researched in depth for better tailoring therapeutic intervention for PD prevention or slowing disease progression. Show less

Epigenetic regulatory proteins support mammalian development, cancer, aging and tissue repair by controlling many cellular processes including stem cell self-renewal, lineage-commitment and senescence in both skeletal and non-skeletal tissues. We review here our knowledge of epigenetic regulatory protein complexes that support the formation of inaccessible heterochromatin and suppress expression of cell and tissue-type specific biomarkers during development. Maintenance and formation of heterochromatin critically depends on epigenetic regulators that recognize histone 3 lysine trimethylation at residues K9 and K27 (respectively, H3K9me3 and H3K27me3), which represent transcriptionally suppressive epigenetic marks. Three chromobox proteins (i.e., CBX1, CBX3 or CBX5) associated with the heterochromatin protein 1 (HP1) complex are methyl readers that interpret H3K9me3 marks which are mediated by H3K9 methyltransferases (i.e., SUV39H1 or SUV39H2). Other chromobox proteins (i.e., CBX2, CBX4, CBX6, CBX7 and CBX8) recognize H3K27me3, which is deposited by Polycomb Repressive Complex 2 (PRC2; a complex containing SUZ12, EED, RBAP46/48 and the methyl transferases EZH1 or EZH2). This second set of CBX proteins resides in PRC1, which has many subunits including other polycomb group factors (PCGF1, PCGF2, PCGF3, PCGF4, PCGF5, PCGF6), human polyhomeotic homologs (HPH1, HPH2, HPH3) and E3-ubiquitin ligases (RING1 or RING2). The latter enzymes catalyze the subsequent mono-ubiquitination of lysine 119 in H2A (H2AK119ub). We discuss biological, cellular and molecular functions of CBX proteins and their physiological and pathological activities in non-skeletal cells and tissues in anticipation of new discoveries on novel roles for CBX proteins in bone formation and skeletal development. Show less