PARP1 ADP-ribosylates lysine residues of the core histone tails

The chromatin-associated enzyme PARP1 has previously been suggested to ADP-ribosylate histones, but the specific ADP-ribose acceptor sites have remained enigmatic. Here, we show that PARP1 covalently ADP-ribosylates the amino-terminal histone tails of all core histones. Using biochemical tools and novel electron transfer dissociation mass spectrometric protocols, we identify for the first time K13 of H2A, K30 of H2B, K27 and K37 of H3, as well as K16 of H4 as ADP-ribose acceptor sites. Multiple explicit water molecular dynamics simulations of the H4 tail peptide into the catalytic cleft of PARP1 indicate that two stable intermolecular salt bridges hold the peptide in an orientation that allows K16 ADP-ribosylation. Consistent with a functional cross-talk between ADP-ribosylation and other histone tail modifications, acetylation of H4K16 inhibits ADP-ribosylation by PARP1. Taken together, our computational and experimental results provide strong evidence that PARP1 modifies important regulatory lysines of the core histone tails

Memory-Based Mismatch Response to Frequency Changes in Rats

Any occasional changes in the acoustic environment are of potential importance for survival. In humans, the preattentive detection of such changes generates the mismatch negativity (MMN) component of event-related brain potentials. MMN is elicited to rare changes (‘deviants’) in a series of otherwise regularly repeating stimuli (‘standards’). Deviant stimuli are detected on the basis of a neural comparison process between the input from the current stimulus and the sensory memory trace of the standard stimuli. It is, however, unclear to what extent animals show a similar comparison process in response to auditory changes. To resolve this issue, epidural potentials were recorded above the primary auditory cortex of urethane-anesthetized rats. In an oddball condition, tone frequency was used to differentiate deviants interspersed randomly among a standard tone. Mismatch responses were observed at 60–100 ms after stimulus onset for frequency increases of 5% and 12.5% but not for similarly descending deviants. The response diminished when the silent inter-stimulus interval was increased from 375 ms to 600 ms for +5% deviants and from 600 ms to 1000 ms for +12.5% deviants. In comparison to the oddball condition the response also diminished in a control condition in which no repetitive standards were presented (equiprobable condition). These findings suggest that the rat mismatch response is similar to the human MMN and indicate that anesthetized rats provide a valuable model for studies of central auditory processing

Final 15 articles - full data set

Three excel sheets of data analysi

PRISMA flow chart

PRISMA flow showing the handling of articles during resource selectio

Cultural inequalities in access to Early Intervention for Psychosis services in the UK

A review of existing literature on access to EIP services in the UK for ethnic minority populations such as British South Asian

Grey search triage and results

Because the grey search was conducted outside of Covidence, the data were logged and triaged in an Excel database

Discovery of the TLR7/8 Antagonist MHV370 for Treatment of Systemic Autoimmune Diseases.

Toll-like receptor (TLR) 7 and TLR8 are endosomal sensors of the innate immune system that are activated by GU-rich single stranded RNA (ssRNA). Multiple genetic and functional lines of evidence link chronic activation of TLR7/8 to the pathogenesis of systemic autoimmune diseases (sAID) such as Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE). This makes targeting TLR7/8-induced inflammation with small-molecule inhibitors an attractive approach for the treatment of patients suffering from systemic autoimmune diseases. Here, we describe how structure-based optimization of compound 2 resulted in the discovery of 34 (MHV370, (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide). Its in vivo activity allows for further profiling toward clinical trials in patients with autoimmune disorders, and a Phase 2 proof of concept study of MHV370 has been initiated, testing its safety and efficacy in patients with Sjögren's syndrome and mixed connective tissue disease