Mechanisms of regulation and diversification of deubiquitylating enzyme function

Deubiquitinating enzymes (DUBs) are proteases that reverse protein ubiquitylation and therefore modulate the outcome of this posttranslational modification. DUBs regulate a variety of intracellular processes, including protein turnover, signalling pathways and the DNA damage response. They have also been linked to a number of human diseases, such as cancer, and inflammatory and neurodegenerative disorders. Although we are beginning to better appreciate the role of DUBs in basic cell biology and their importance for human health, there are still many unknowns. Central among these is the conundrum of how the small number of ∼100 DUBs encoded in the human genome is capable of regulating the thousands of ubiquitin modification sites detected at steady-state conditions in human cells. This Commentary addresses the biological mechanisms employed to modulate and expand the functions of DUBs, and sets directions for future research aimed at elucidating the details of these fascinating processes

Acquisition of a Unique Onshore/Offshore Geophysical and Geochemical Dataset in the Northern Malawi (Nyasa) Rift

The Study of Extension and maGmatism in Malawi aNd Tanzania (SEGMeNT) project acquired a comprehensive suite of geophysical and geochemical datasets across the northern Malawi (Nyasa) rift in the East Africa rift system. Onshore/offshore active and passive seismic data, long‐period and wideband magnetotelluric data, continuous Global Positioning System data, and geochemical samples were acquired between 2012 and 2016. This combination of data is intended to elucidate the sedimentary, crustal, and upper‐mantle architecture of the rift, patterns of active deformation, and the origin and age of rift‐related magmatism. A unique component of our program was the acquisition of seismic data in Lake Malawi, including seismic reflection, onshore/offshore wide‐angle seismic reflection/refraction, and broadband seismic data from lake‐bottom seismometers, a towed streamer, and a large towed air‐gun source

Linear ubiquitination in immunity

Linear ubiquitination is a post-translational protein modification recently discovered to be crucial for innate and adaptive immune signaling. The function of linear ubiquitin chains is regulated at multiple levels: generation, recognition, and removal. These chains are generated by the linear ubiquitin chain assembly complex (LUBAC), the only known ubiquitin E3 capable of forming the linear ubiquitin linkage de novo. LUBAC is not only relevant for activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs) in various signaling pathways, but importantly, it also regulates cell death downstream of immune receptors capable of inducing this response. Recognition of the linear ubiquitin linkage is specifically mediated by certain ubiquitin receptors, which is crucial for translation into the intended signaling outputs. LUBAC deficiency results in attenuated gene activation and increased cell death, causing pathologic conditions in both, mice, and humans. Removal of ubiquitin chains is mediated by deubiquitinases (DUBs). Two of them, OTULIN and CYLD, are constitutively associated with LUBAC. Here, we review the current knowledge on linear ubiquitination in immune signaling pathways and the biochemical mechanisms as to how linear polyubiquitin exerts its functions distinctly from those of other ubiquitin linkage types

Morchella australiana sp. nov., an apparent Australian endemic from New South Wales and Victoria

An abundant fruiting of a black morel was encountered in temperate northwestern New South Wales (NSW), Australia, during a mycological survey in Sep 2010. The site was west of the Great Dividing Range in a young, dry sclerophyll forest dominated by Eucalyptus and Callitris north of Coonabarabran in an area known as the Pilliga Scrub. Although the Pilliga Scrub is characterized by frequent and often large, intense wildfires, the site showed no sign of recent fire, which suggests this species is not a postfire morel. Caps of the Morchella elata-like morel were brown with blackish ridges supported by a pubescent stipe that became brown at maturity. Because no morel has been described as native to Australia, the collections were subjected to multilocus molecular phylogenetic and morphological analyses to assess its identity. Results of these analyses indicated that our collection, together with collections from NSW and Victoria, represented a novel, genealogically exclusive lineage, which is described and illustrated here as Morchella australiana T. F. Elliott, Bougher, O’Donnell & Trappe, sp. nov.Keywords: Morchellaceae, Callitris, Morels, Pezizales, Eucalyptus, Ascomycota, Western Australi

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10−8) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10−8). The top IBC association for SBP was rs2012318 (P= 6.4 × 10−6) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10−6) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexit

Partial gamma-ray production cross sections for (n,xng) reactions in natural argon from 1 - 30 MeV

Background: Neutron-induced backgrounds are a significant concern for experiments that require extremely low levels of radioactive backgrounds such as direct dark matter searches and neutrinoless double-beta decay experiments. Unmeasured neutron scattering cross sections are often accounted for incorrectly in Monte Carlo simulations. Purpose: Determine partial gamma-ray production cross sections for (n,xng) reactions in natural argon for incident neutron energies between 1 and 30 MeV. Methods: The broad spectrum neutron beam at the Los Alamos Neutron Science Center (LANSCE) was used used for the measurement. Neutron energies were determined using time-of-flight and resulting gamma rays from neutron-induced reactions were detected using the GErmanium Array for Neutron Induced Excitations (GEANIE). Results: Partial gamma-ray cross sections were measured for six excited states in Ar-40 and two excited states in Ar-39. Measured (n,xng) cross sections were compared to the TALYS and CoH3 nuclear reaction codes. Conclusions: These new measurements will help to identify potential backgrounds in neutrinoless double-beta decay and dark matter experiments that use argon as a detection medium or shielding. The measurements will also aid in the identification of neutron interactions in these experiments through the detection of gamma rays produced by (n,xng) reactions.Comment: 25 pages, 6 figure

Translation of genomics into routine cardiological practice:insights from a European Society of Cardiology Cardiovascular Round Table

Cardiovascular diseases (CVD) remain the leading cause of death globally and there is an urgent need for innovative approaches to treatment. One emerging avenue is genetic therapies, which hold particular promise for diseases with a monogenic basis. Gene silencing techniques using antisense oligonucleotides or ribonucleic acid interference strategies are currently at the forefront of genetic therapies in CVD, with several ribonucleic acid-targeted therapies already approved for the treatment of conditions such as familial hypercholesterolaemia and transthyretin amyloidosis. For diseases caused by loss-of-function genetic variants, there is growing interest in gene therapy, applying either gene replacement strategies using adeno-associated virus vectors or gene editing strategies using tools such as the clustered regularly interspaced short palindromic repeats and clustered regularly interspaced short palindromic repeats-associated protein-9 system. Preclinical studies have highlighted the potential of this technology in CVD and promising data are beginning to emerge from early-phase clinical trials. During a European Society of Cardiology Cardiovascular Round Table workshop, the challenges of translating these novel therapeutic strategies to the routine cardiology clinic were discussed. Several key priorities were identified, including the need for disease-specific preclinical models, precision diagnostics, adequately powered clinical trials with meaningful endpoints, and enhanced education of healthcare professionals and patients. The Cardiovascular Round Table also considered the role of polygenic risk scores in risk stratification and how these can potentially be implemented in clinical practice.</p