Strongly Gapped Spin-Wave Excitation in the Insulating Phase of NaOsO3

NaOsO3 hosts a rare manifestation of a metal-insulator transition driven by magnetic correlations, placing the magnetic exchange interactions in a central role. We use resonant inelastic x-ray scattering to directly probe these magnetic exchange interactions. A dispersive and strongly gapped (58 meV) excitation is observed indicating appreciable spin-orbit coupling in this 5d3 system. The excitation is well described within a minimal model Hamiltonian with strong anisotropy and Heisenberg exchange (J1=J2=13.9 meV). The observed behavior places NaOsO3 on the boundary between localized and itinerant magnetism

Pregabalin for the treatment of syringomyelia-associated neuropathic pain in dogs: A randomised, placebo-controlled, double-masked clinical trial

Pregabalin is the first-line treatment for neuropathic pain (NeP) in humans. Dogs with Chiari-like malformation and syringomyelia (CM/SM) associated with NeP could benefit from pregabalin. The aim of this study was to evaluate the efficacy of pregabalin for NeP in dogs with CM/SM. Eight dogs with symptomatic CM/SM were included in a double-masked, randomised, crossover placebo–controlled clinical trial. All dogs received anti-inflammatory drugs as base-line treatment during placebo or pregabalin phase of 14 ± 4 days each. Analgesic efficacy was assessed with a daily numerical rating scale (NRS) recorded by dog owners (0–10, 10 = worst pain) and quantitative sensory testing at baseline, placebo and pregabalin phases. Blood samples were collected to report pregabalin exposure and to assess renal function. Daily NRS scores recorded by dog owners in the pregabalin group were lower than in the placebo group (P = 0.006). Mechanical thresholds were higher with pregabalin compared to baseline or placebo (P = 0.037, P < 0.001). Cold latency at 15 °C was prolonged on the neck and humeri with pregabalin compared to baseline (P < 0.001 for both) or placebo (P = 0.02, P = 0.0001). Cold latency at 0 °C was longer on pregabalin compared to baseline and placebo (P = 0.001, P = 0.004). There was no pregabalin accumulation between first and last dose. This study demonstrates the efficacy of pregabalin for the treatment of NeP due to CM/SM on daily pain scores recorded by dog owners. Pregabalin significantly reduced mechanical hyperalgesia, cold hyperalgesia (0 °C) and allodynia (15 °C) compared to placebo. Pregabalin was non-cumulative and well tolerated with occasional mild sedation

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Implementation of Fourier transform infrared spectroscopy for the rapid typing of uropathogenic Escherichia coli.

In this paper, we demonstrate that Fourier transform infrared (FT-IR) spectroscopy is able to discriminate rapidly between uropathogenic Escherichia coli (UPEC) of key lineages with only relatively simple sample preparation. A total of 95 bacteria from six different epidemiologically important multilocus sequence types (ST10, ST69, ST95, ST73, ST127 and ST131) were used in this project and principal component-discriminant function analysis (PC-DFA) of these samples produced clear separate clustering of isolates, based on the ST. Analysis of data using partial least squares-discriminant analysis (PLS-DA), incorporating cross-validation, indicated a high prediction accuracy of 91.19% for ST131. These results suggest that FT-IR spectroscopy could be a useful method for the rapid identification of members of important UPEC STs

Pathogen-Mediated Proteolysis of the Cell Death Regulator RIPK1 and the Host Defense Modulator RIPK2 in Human Aortic Endothelial Cells

Porphyromonas gingivalis is the primary etiologic agent of periodontal disease that is associated with other human chronic inflammatory diseases, including atherosclerosis. The ability of P. gingivalis to invade and persist within human aortic endothelial cells (HAEC) has been postulated to contribute to a low to moderate chronic state of inflammation, although how this is specifically achieved has not been well defined. In this study, we demonstrate that P. gingivalis infection of HAEC resulted in the rapid cleavage of receptor interacting protein 1 (RIPK1), a mediator of tumor necrosis factor (TNF) receptor-1 (TNF-R1)-induced cell activation or death, and RIPK2, a key mediator of both innate immune signaling and adaptive immunity. The cleavage of RIPK1 or RIPK2 was not observed in cells treated with apoptotic stimuli, or cells stimulated with agonists to TNF-R1, nucleotide oligomerization domain receptor 1(NOD1), NOD2, Toll-like receptor 2 (TLR2) or TLR4. P. gingivalis-induced cleavage of RIPK1 and RIPK2 was inhibited in the presence of a lysine-specific gingipain (Kgp) inhibitor. RIPK1 and RIPK2 cleavage was not observed in HAEC treated with an isogenic mutant deficient in the lysine-specific gingipain, confirming a role for Kgp in the cleavage of RIPK1 and RIPK2. Similar proteolysis of poly (ADP-ribose) polymerase (PARP) was observed. We also demonstrated direct proteolysis of RIPK2 by P. gingivalis in a cell-free system which was abrogated in the presence of a Kgp-specific protease inhibitor. Our studies thus reveal an important role for pathogen-mediated modification of cellular kinases as a potential strategy for bacterial persistence within target host cells, which is associated with low-grade chronic inflammation, a hallmark of pathogen-mediated chronic inflammatory disorders

Vaccinia Virus G8R Protein: A Structural Ortholog of Proliferating Cell Nuclear Antigen (PCNA)

BACKGROUND: Eukaryotic DNA replication involves the synthesis of both a DNA leading and lagging strand, the latter requiring several additional proteins including flap endonuclease (FEN-1) and proliferating cell nuclear antigen (PCNA) in order to remove RNA primers used in the synthesis of Okazaki fragments. Poxviruses are complex viruses (dsDNA genomes) that infect eukaryotes, but surprisingly little is known about the process of DNA replication. Given our previous results that the vaccinia virus (VACV) G5R protein may be structurally similar to a FEN-1-like protein and a recent finding that poxviruses encode a primase function, we undertook a series of in silico analyses to identify whether VACV also encodes a PCNA-like protein. RESULTS: An InterProScan of all VACV proteins using the JIPS software package was used to identify any PCNA-like proteins. The VACV G8R protein was identified as the only vaccinia protein that contained a PCNA-like sliding clamp motif. The VACV G8R protein plays a role in poxvirus late transcription and is known to interact with several other poxvirus proteins including itself. The secondary and tertiary structure of the VACV G8R protein was predicted and compared to the secondary and tertiary structure of both human and yeast PCNA proteins, and a high degree of similarity between all three proteins was noted. CONCLUSIONS: The structure of the VACV G8R protein is predicted to closely resemble the eukaryotic PCNA protein; it possesses several other features including a conserved ubiquitylation and SUMOylation site that suggest that, like its counterpart in T4 bacteriophage (gp45), it may function as a sliding clamp ushering transcription factors to RNA polymerase during late transcription