Deubiquitylating Enzymes and DNA Damage Response Pathways

Covalent post-translational modification of proteins by ubiquitin and ubiquitin-like factors has emerged as a general mechanism to regulate myriad intra-cellular processes. The addition and removal of ubiquitin or ubiquitin-like proteins from factors has recently been demonstrated as a key mechanism to modulate DNA damage response (DDR) pathways. It is thus, timely to evaluate the potential for ubiquitin pathway enzymes as DDR drug targets for therapeutic intervention. The synthetic lethal approach provides exciting opportunities for the development of targeted therapies to treat cancer: most tumours have lost critical DDR pathways, and thus rely more heavily on the remaining pathways, while normal tissues are still equipped with all DDR pathways. Here, we review key deubiquitylating enzymes (DUBs) involved in DDR pathways, and describe how targeting DUBs may lead to selective therapies to treat cancer patients

VennPlex--a novel Venn diagram program for comparing and visualizing datasets with differentially regulated datapoints.

With the development of increasingly large and complex genomic and proteomic data sets, an enhancement in the complexity of available Venn diagram analytical programs is becoming increasingly important. Current freely available Venn diagram programs often fail to represent extra complexity among datasets, such as regulation pattern differences between different groups. Here we describe the development of VennPlex, a program that illustrates the often diverse numerical interactions among multiple, high-complexity datasets, using up to four data sets. VennPlex includes versatile output features, where grouped data points in specific regions can be easily exported into a spreadsheet. This program is able to facilitate the analysis of two to four gene sets and their corresponding expression values in a user-friendly manner. To demonstrate its unique experimental utility we applied VennPlex to a complex paradigm, i.e. a comparison of the effect of multiple oxygen tension environments (1–20% ambient oxygen) upon gene transcription of primary rat astrocytes. VennPlex accurately dissects complex data sets reliably into easily identifiable groups for straightforward analysis and data output. This program, which is an improvement over currently available Venn diagram programs, is able to rapidly extract important datasets that represent the variety of expression patterns available within the data sets, showing potential applications in fields like genomics, proteomics, and bioinformatics

Investigation and management of an outbreak of Salmonella Typhimurium DT8 associated with duck eggs, Ireland 2009 to 2011.

Salmonella Typhimurium DT8 was a very rare cause of human illness in Ireland between 2000 and 2008, with only four human isolates from three patients being identified. Over a 19-month period between August 2009 and February 2011, 34 confirmed cases and one probable case of Salmonella Typhimurium DT8 were detected, all of which had an MLVA pattern 2-10-NA-12-212 or a closely related pattern. The epidemiological investigations strongly supported a linkbetween illness and exposure to duck eggs. Moreover, S. Typhimurium with an MLVA pattern indistinguishable (or closely related) to the isolates from human cases, was identified in 22 commercial and backyard duck flocks, twelve of which were linked with known human cases. A range of control measures were taken at farm level, and advice was provided to consumers on the hygienic handling and cooking of duck eggs. Although no definitive link was established with a concurrent duck egg-related outbreak of S. Typhimurium DT8 in the United Kingdom, it seems likely that the two events were related. It may be appropriate for other countries with a tradition of consuming duck eggs to consider the need for measures to reduce the risk of similar outbreaks

2-Acetyl­pyridinium bromanilate

In the crystal of the title mol­ecular salt (systematic name: 2-acetyl­pyridinium 2,5-dibromo-4-hydr­oxy-3,6-dioxocyclo­hexa-1,4-dienolate), C7H8NO+·C6HBr2O4 −, centrosymmetric rings consisting of two cations and two anions are formed, with the components linked by alternating O—H⋯O and N—H⋯O hydrogen bonds. Short O⋯Br contacts [3.243 (2) and 3.359 (2) Å] may help to consolidate the packing

5-benzamidoisoquinolin-1-ones and 5-(ω-carboxyalkyl)isoquinolin-1-ones as isoform-selective inhibitors of poly(ADP-ribose) polymerase 2 (PARP-2)

PARP-2 is a member of the poly(ADP-ribose) polymerase family, with some activities similar to those of PARP-1 but with other distinct roles. Two series of isoquinolin-1-ones were designed, synthesized, and evaluated as selective inhibitors of PARP-2, using the structures of the catalytic sites of the isoforms. A new efficient synthesis of 5-aminoisoquinolin-1-one was developed, and acylation with acyl chlorides gave 5-acylaminoisoquinolin-1-ones. By examination of isoquinolin-1-ones with carboxylates tethered to the 5-position, Heck coupling of 5-iodoisoquinolin-1-one furnished the 5-CH═CHCO2H compound for reduction to the 5-propanoic acid. Alkylation of 5-aminoisoquinolin-1-one under mildly basic conditions, followed by hydrolysis, gave 5-(carboxymethylamino)isoquinolin-1-one, whereas it was alkylated at 2-N with methyl propenoate and strong base. Compounds were assayed in vitro for inhibition of PARP-1 and PARP-2, using FlashPlate and solution-phase assays, respectively. The 5-benzamidoisoquinolin-1-ones were more selective for inhibition of PARP-2, whereas the 5-(ω-carboxyalkyl)isoquinolin-1-ones were less so. 5-Benzamidoisoquinolin-1-one is the most PARP-2-selective compound (IC50(PARP-1)/IC50(PARP-2) = 9.3) to date, in a comparative study

Dissemination of extensively drug-resistant NDM-producing Providencia stuartii in Europe linked to patients transferred from Ukraine, March 2022 to March 2023

BackgroundThe war in Ukraine led to migration of Ukrainian people. Early 2022, several European national surveillance systems detected multidrug-resistant (MDR) bacteria related to Ukrainian patients.AimTo investigate the genomic epidemiology of New Delhi metallo-β-lactamase (NDM)-producing Providencia stuartii from Ukrainian patients among European countries.MethodsWhole-genome sequencing of 66 isolates sampled in 2022-2023 in 10 European countries enabled whole-genome multilocus sequence typing (wgMLST), identification of resistance genes, replicons, and plasmid reconstructions. Five blaNDM-1-carrying-P. stuartii isolates underwent antimicrobial susceptibility testing (AST). Transferability to Escherichia coli of a blaNDM-1-carrying plasmid from a patient strain was assessed. Epidemiological characteristics of patients with NDM-producing P. stuartii were gathered by questionnaire.ResultswgMLST of the 66 isolates revealed two genetic clusters unrelated to Ukraine and three linked to Ukrainian patients. Of these three, two comprised blaNDM-1-carrying-P. stuartii and the third blaNDM-5-carrying-P. stuartii. The blaNDM-1 clusters (PstCluster-001, n = 22 isolates; PstCluster-002, n = 8 isolates) comprised strains from seven and four countries, respectively. The blaNDM-5 cluster (PstCluster-003) included 13 isolates from six countries. PstCluster-001 and PstCluster-002 isolates carried an MDR plasmid harbouring blaNDM-1,blaOXA-10, blaCMY-16, rmtC and armA, which was transferrable in vitro and, for some Ukrainian patients, shared by other Enterobacterales. AST revealed PstCluster-001 isolates to be extensively drug-resistant (XDR), but susceptible to cefiderocol and aztreonam-avibactam. Patients with data on age (n = 41) were 19-74 years old; of 49 with information on sex, 38 were male.ConclusionXDR P. stuartii were introduced into European countries, requiring increased awareness and precautions when treating patients from conflict-affected areas.</p

Dissemination of extensively drug-resistant NDM-producing Providencia stuartii in Europe linked to patients transferred from Ukraine, March 2022 to March 2023

BackgroundThe war in Ukraine led to migration of Ukrainian people. Early 2022, several European national surveillance systems detected multidrug-resistant (MDR) bacteria related to Ukrainian patients.AimTo investigate the genomic epidemiology of New Delhi metallo-β-lactamase (NDM)-producing Providencia stuartii from Ukrainian patients among European countries.MethodsWhole-genome sequencing of 66 isolates sampled in 2022-2023 in 10 European countries enabled whole-genome multilocus sequence typing (wgMLST), identification of resistance genes, replicons, and plasmid reconstructions. Five blaNDM-1-carrying-P. stuartii isolates underwent antimicrobial susceptibility testing (AST). Transferability to Escherichia coli of a blaNDM-1-carrying plasmid from a patient strain was assessed. Epidemiological characteristics of patients with NDM-producing P. stuartii were gathered by questionnaire.ResultswgMLST of the 66 isolates revealed two genetic clusters unrelated to Ukraine and three linked to Ukrainian patients. Of these three, two comprised blaNDM-1-carrying-P. stuartii and the third blaNDM-5-carrying-P. stuartii. The blaNDM-1 clusters (PstCluster-001, n = 22 isolates; PstCluster-002, n = 8 isolates) comprised strains from seven and four countries, respectively. The blaNDM-5 cluster (PstCluster-003) included 13 isolates from six countries. PstCluster-001 and PstCluster-002 isolates carried an MDR plasmid harbouring blaNDM-1,blaOXA-10, blaCMY-16, rmtC and armA, which was transferrable in vitro and, for some Ukrainian patients, shared by other Enterobacterales. AST revealed PstCluster-001 isolates to be extensively drug-resistant (XDR), but susceptible to cefiderocol and aztreonam-avibactam. Patients with data on age (n = 41) were 19-74 years old; of 49 with information on sex, 38 were male.ConclusionXDR P. stuartii were introduced into European countries, requiring increased awareness and precautions when treating patients from conflict-affected areas.</p

A nearby m star with three transiting super-earths discovered by k2

I. J. M. Crossfied, “A Nearby M Star with Three Transiting Super-Earths Discovered by K2”, The Astrophysical Journal, Vol 804(1), April 2015. © 2015. The American Astronomical Society.Small, cool planets represent the typical end-products of planetary formation. Studying the architectures of these systems, measuring planet masses and radii, and observing these planets' atmospheres during transit directly informs theories of planet assembly, migration, and evolution. Here we report the discovery of three small planets orbiting a bright (Ks = 8.6 mag) M0 dwarf using data collected as part of K2, the new ecliptic survey using the re-purposed Kepler spacecraft. Stellar spectroscopy and K2 photometry indicate that the system hosts three transiting planets with radii 1.5-2.1 , straddling the transition region between rocky and increasingly volatile-dominated compositions. With orbital periods of 10-45 days the planets receive just 1.5-10x the flux incident on Earth, making these some of the coolest small planets known orbiting a nearby star; planet d is located near the inner edge of the system's habitable zone. The bright, low-mass star makes this system an excellent laboratory to determine the planets' masses via Doppler spectroscopy and to constrain their atmospheric compositions via transit spectroscopy. This discovery demonstrates the ability of K2 and future space-based transit searches to find many fascinating objects of interest.Peer reviewe