The complex interplay between endoplasmic reticulum stress and the NLRP3 inflammasome: a potential therapeutic target for inflammatory disorders.

Inflammation is the result of a complex network of cellular and molecular interactions and mechanisms that facilitate immune protection against intrinsic and extrinsic stimuli, particularly pathogens, to maintain homeostasis and promote tissue healing. However, dysregulation in the immune system elicits excess/abnormal inflammation resulting in unintended tissue damage and causes major inflammatory diseases including asthma, chronic obstructive pulmonary disease, atherosclerosis, inflammatory bowel diseases, sarcoidosis and rheumatoid arthritis. It is now widely accepted that both endoplasmic reticulum (ER) stress and inflammasomes play critical roles in activating inflammatory signalling cascades. Notably, evidence is mounting for the involvement of ER stress in exacerbating inflammasome-induced inflammatory cascades, which may provide a new axis for therapeutic targeting in a range of inflammatory disorders. Here, we comprehensively review the roles, mechanisms and interactions of both ER stress and inflammasomes, as well as their interconnected relationships in inflammatory signalling cascades. We also discuss novel therapeutic strategies that are being developed to treat ER stress- and inflammasome-related inflammatory disorders

Inter-examiner reliability of the diagnosis of cervical pillar hyperplasia (CPH) and the correlation between CPH and spinal degenerative joint disease (DJD)

BACKGROUND: Cervical pillar hyperplasia (CPH) is a recently described phenomenon of unknown aetiology. Its clinical importance is poorly understood at the present time; therefore, the objective of this study was to determine (1) the inter-examiner reliability of detecting CPH and (2) if there is a clinically important correlation (r > 0.4) between the number of cervical spine levels showing signs of degenerative joint disease (DJD) and CPH. METHODS: The sample consisted of 320 radiographs of human male and female subjects who ranged from 40 to 79 years of age. The inter-examiner reliability of assessing the presence/absence of pillar hyperplasia was evaluated on 50 neutral lateral radiographs by two examiners using line drawings and it was quantified using the kappa coefficient of concordance. To determine the presence/absence of hyperplastic pillars as well as the presence/absence of DJD at each intervertebral disc and zygapophysial joint, 320 AP open mouth, AP lower cervical and neutral lateral radiographs were then examined. The unpaired t-test at the 5% level of significance was performed to test for a statistically significant difference between the number of levels affected by DJD in patients with and without hyperplasia. The Spearman's rho at the 5% level of significance was performed to quantify the correlation between DJD and age. RESULTS: The inter-examiner reliability of detecting cervical pillar hyperplasia was moderate with a kappa coefficient of 0.51. The unpaired t-test indicated that there was no statistically significant difference (p > 0.05) between the presence/absence of cervical pillar hyperplasia and the number of levels affected by DJD in an age-matched population, regardless of whether all elements were considered together, or the discs and facets were analyzed separately. A Spearman correlation rank of 0.67 (p < 0.05) suggested a moderately strong correlation between the number of elements (i.e. discs/facets) affected, and the age of the individual. CONCLUSION: Cervical pillar hyperplasia is a reasonable concept that requires further research. Its evaluation is easy to learn and acceptably reliable. Previous research has suggested that CPH may affect the cervical lordosis, and therefore, alter biomechanics which may result in premature DJD. This current study, however, indicates that, globally, CPH does not appear to be related to the development of DJD

The extraordinary evolutionary history of the reticuloendotheliosis viruses

The reticuloendotheliosis viruses (REVs) comprise several closely related amphotropic retroviruses isolated from birds. These viruses exhibit several highly unusual characteristics that have not so far been adequately explained, including their extremely close relationship to mammalian retroviruses, and their presence as endogenous sequences within the genomes of certain large DNA viruses. We present evidence for an iatrogenic origin of REVs that accounts for these phenomena. Firstly, we identify endogenous retroviral fossils in mammalian genomes that share a unique recombinant structure with REVs—unequivocally demonstrating that REVs derive directly from mammalian retroviruses. Secondly, through sequencing of archived REV isolates, we confirm that contaminated Plasmodium lophurae stocks have been the source of multiple REV outbreaks in experimentally infected birds. Finally, we show that both phylogenetic and historical evidence support a scenario wherein REVs originated as mammalian retroviruses that were accidentally introduced into avian hosts in the late 1930s, during experimental studies of P. lophurae, and subsequently integrated into the fowlpox virus (FWPV) and gallid herpesvirus type 2 (GHV-2) genomes, generating recombinant DNA viruses that now circulate in wild birds and poultry. Our findings provide a novel perspective on the origin and evolution of REV, and indicate that horizontal gene transfer between virus families can expand the impact of iatrogenic transmission events

Species' geographic distributions through time: Playing catchup with changing climates

This is the author's accepted manuscript.Species’ ranges are often treated as a rather fixed characteristic, rather than a fluid, ever-changing manifestation of their ecological requirements and dispersal abilities. Paleontologists generally have had a more flexible point of view on this issue than neontologists, but each perspective can improve by appreciating the other. Here, we provide an overview of paleontological and neontological perspectives on species’ geographic distributions, focusing on what can be learned about historical variations in distributions. The cross-disciplinary view, we hope, offers some novel perspectives on species-level biogeography

Problems with studying wolf predation on small prey in summer via global positioning system collars

We attempted to study predation on various-sized prey by a male and female wolf (Canis lupus) with global positioning system (GPS) collars programmed to acquire locations every 10 min in the Superior National Forest of Minnesota. During May to August 2007, we investigated 147 clusters of locations (31% of the total) and found evidence of predation on a white-tailed deer (Odocoileus virginianus) fawn and yearling, a beaver (Castor canadensis), ruffed grouse (Bonasa umbellus), and fisher (Martes pennanti) and scavenging on a road-killed deer and other carrion. However, we missed finding many prey items and discuss the problems associated with trying to conduct such a study

A Genome-Wide Analysis of Promoter-Mediated Phenotypic Noise in Escherichia coli

Gene expression is subject to random perturbations that lead to fluctuations in the rate of protein production. As a consequence, for any given protein, genetically identical organisms living in a constant environment will contain different amounts of that particular protein, resulting in different phenotypes. This phenomenon is known as “phenotypic noise.” In bacterial systems, previous studies have shown that, for specific genes, both transcriptional and translational processes affect phenotypic noise. Here, we focus on how the promoter regions of genes affect noise and ask whether levels of promoter-mediated noise are correlated with genes' functional attributes, using data for over 60% of all promoters in Escherichia coli. We find that essential genes and genes with a high degree of evolutionary conservation have promoters that confer low levels of noise. We also find that the level of noise cannot be attributed to the evolutionary time that different genes have spent in the genome of E. coli. In contrast to previous results in eukaryotes, we find no association between promoter-mediated noise and gene expression plasticity. These results are consistent with the hypothesis that, in bacteria, natural selection can act to reduce gene expression noise and that some of this noise is controlled through the sequence of the promoter region alon

Spatial and Temporal Variability of Macroinvertebrates in Spawning and Non-Spawning Habitats during a Salmon Run in Southeast Alaska

Spawning salmon create patches of disturbance through redd digging which can reduce macroinvertebrate abundance and biomass in spawning habitat. We asked whether displaced invertebrates use non-spawning habitats as refugia in streams. Our study explored how the spatial and temporal distribution of macroinvertebrates changed during a pink salmon (Oncorhynchus gorbuscha) spawning run and compared macroinvertebrates in spawning (riffle) and non-spawning (refugia) habitats in an Alaskan stream. Potential refugia included: pools, stream margins and the hyporheic zone, and we also sampled invertebrate drift. We predicted that macroinvertebrates would decline in riffles and increase in drift and refugia habitats during salmon spawning. We observed a reduction in the density, biomass and taxonomic richness of macroinvertebrates in riffles during spawning. There was no change in pool and margin invertebrate communities, except insect biomass declined in pools during the spawning period. Macroinvertebrate density was greater in the hyporheic zone and macroinvertebrate density and richness increased in the drift during spawning. We observed significant invertebrate declines within spawning habitat; however in non-spawning habitat, there were less pronounced changes in invertebrate density and richness. The results observed may be due to spawning-related disturbances, insect phenology, or other variables. We propose that certain in-stream habitats could be important for the persistence of macroinvertebrates during salmon spawning in a Southeast Alaskan stream

Association between adherence to calcium-channel blocker and statin medications and likelihood of cardiovascular events among US managed care enrollees

<p>Abstract</p> <p>Background</p> <p>Prior studies have found that patients taking single-pill amlodipine/atorvastatin (SPAA) have greater likelihood of adherence at 6 months than those taking 2-pill calcium-channel blocker and statin combinations (CCB/statin). This study examines whether this adherence benefit results in fewer cardiovascular (CV) events.</p> <p>Methods</p> <p>A retrospective cohort study was conducted using administrative claims data from the IMS LifeLink: US Health Plan Claims database, identifying adults already taking CCB or statin (but not both) who had an index event of either initiating treatment with SPAA or adding CCB to statin (or vice versa) between April 1, 2004 to August 31, 2005. Inclusion criteria included age 18+ years, continuously enrolled for minimum of 6 months prior and 18 months following treatment initiation, >1 diagnosis of hypertension, and no prescription claims for SPAA or added CCB or statin for 6 months prior. Exclusion criteria included >1 claim with missing or invalid days supplied, age 65+ years and not enrolled in Medicare Advantage, or history of prior CV events, cancer diagnosis, or chronic renal failure. The primary outcome measure was the rate of CV events (myocardial infarction, heart failure, angina, other ischemic heart disease, stroke, peripheral vascular disease, or revascularization procedure) from 6 to 18 months following index date, analyzed at three levels: 1) all adherent vs. non-adherent patients, 2) SPAA vs. dual-pill patients (regardless of adherence level), and 3) adherent SPAA, adherent dual-pill, and non-adherent SPAA patients vs. non-adherent dual-pill patients.</p> <p>Results</p> <p>Of 1,537 SPAA patients, 56.5% were adherent at 6 months, compared with 21.4% of the 17,910 CCB/statin patients (p < 0.001). Logistic regression found SPAA patients more likely to be adherent (OR = 4.7, p < 0.001) than CCB/statin patients. In Cox proportional hazards models, being adherent to either regimen was associated with significantly lower risk of CV event (HR = 0.77, p = 0.003). A similar effect was seen for SPAA vs. CCB/statin patients (HR = 0.68, p = 0.02). In a combined model, the risk of CV events was significantly lower for adherent CCB/statin patients (HR = 0.79, p = 0.01) and adherent SPAA patients (HR = 0.61, p = 0.03) compared to non-adherent CCB/statin patients.</p> <p>Conclusions</p> <p>Patients receiving SPAA rather than a 2-pill CCB/statin regimen are more likely to be adherent. In turn, adherence to CCB and statin medications is associated with lower risk of CV events in primary prevention patients.</p

Measurement of Exclusive B Decays to Final States Containing a Charmed Baryon

Using data collected by the CLEO detector in the Upsilon(4S) region, we report new measurements of the exclusive decays of B mesons into final states of the type Lambda_c^+ p-bar n(pi), where n=0,1,2,3. We find signals in modes with one, two and three pions and an upper limit for the two body decay Lambda_c^+ pbar. We also make the first measurements of exclusive decays of B mesons to Sigma_c p-bar n(pi), where n=0,1,2. We find signals in modes with one and two pions and an upper limit for the two body decay Sigma_c p-bar. Measurements of these modes shed light on the mechanisms involved in B decays to baryons.Comment: 11 pages postscript, also available through http://w4.lns.cornell.edu/public/CLNS, submitted to PR