Abnormal small heat shock protein interactions involving neuropathy-associated HSP22 (HSPB8) mutants

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154632/1/fsb2fj065911fje.pd

Acute phase protein response in an experimental model of ovine caseous lymphadenitis

<p>Abstract</p> <p>Background</p> <p>Caseous lymphadenitis (CLA) is a disease of small ruminants caused by <it>Corynebacterium pseudotuberculosis</it>. The pathogenesis of CLA is a slow process, and produces a chronic rather than an acute disease state. Acute phase proteins (APP) such as haptoglobin (Hp) serum amyloid A (SAA) and α₁acid glycoprotein (AGP) are produced by the liver and released into the circulation in response to pro-inflammatory cytokines. The concentration of Hp in serum increases in experimental CLA but it is not known if SAA and AGP respond in parallel or have differing response profiles.</p> <p>Results</p> <p>The concentration in serum of Hp, SAA and AGP in 6 sheep challenged with 2 × 10⁵cells of <it>C. pseudotuberculosis </it>showed significant increases (P < 0.05) compared to 3 unchallenged control sheep. By day 7 post infection. (p.i.) the Hp and SAA concentrations reached mean (± SEM) values of 1.65 ± 0.21 g/L and 18.1 ± 5.2 mg/L respectively. Thereafter, their concentrations fell with no significant difference to those of the control sheep by day 18 p.i.. In contrast, the serum AGP concentration in infected sheep continued to rise to a peak of 0.38 ± 0.05 g/L on day 13 p.i., after which a slow decline occurred, although the mean concentration remained significantly higher (P < 0.05) than the control group up to 29 days p.i.. Specific IgG to phospholidase D of <it>C. pseudotuberculosis </it>became detectable at 11 days p.i. and continued to rise throughout the experiment.</p> <p>Conclusion</p> <p>The serum concentrations of Hp, SAA and AGP were raised in sheep in an experimental model of CLA. An extended response was found for AGP which occurred at a point when the infection was likely to have been transforming from an acute to a chronic phase. The results suggest that AGP could have a role as a marker for chronic conditions in sheep.</p

A Phase II Basket Trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609) in Patients with Nonpancreatic Neuroendocrine Tumors.

PurposeImmune checkpoint blockade has improved outcomes across tumor types; little is known about the efficacy of these agents in rare tumors. We report the results of the (nonpancreatic) neuroendocrine neoplasm cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART).Patients and methodsWe performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab plus nivolumab across multiple rare tumor cohorts, with the (nonpancreatic) neuroendocrine cohort reported here. Response assessment by grade was not prespecified. The primary endpoint was overall response rate [ORR; RECIST v1.1; complete response (CR) and partial response (PR)]; secondary endpoints included progression-free survival (PFS), overall survival (OS), stable disease &gt;6 months, and toxicity.ResultsThirty-two eligible patients received therapy; 18 (56%) had high-grade disease. Most common primary sites were gastrointestinal (47%; N = 15) and lung (19%; N = 6). The overall ORR was 25% [95% confidence interval (CI) 13-64%; CR, 3%, N = 1; PR, 22%, N = 7]. Patients with high-grade neuroendocrine carcinoma had an ORR of 44% (8/18 patients) versus 0% in low/intermediate grade tumors (0/14 patients; P = 0.004). The 6-month PFS was 31% (95% CI, 19%-52%); median OS was 11 months (95% CI, 6-∞). The most common toxicities were hypothyroidism (31%), fatigue (28%), and nausea (28%), with alanine aminotransferase elevation (9%) as the most common grade 3/4 immune-related adverse event, and no grade 5 events.ConclusionsIpilimumab plus nivolumab demonstrated a 44% ORR in patients with nonpancreatic high-grade neuroendocrine carcinoma, with 0% ORR in low/intermediate grade disease

Using Model Test Data to Assess VIV Factor of Safety for SCR and TTR in GOM

This paper presents results obtained as part of the DeepStar Phase 10 program on VIV Factors of Safety. The objective was to develop a general methodology to calibrate Factors of Safety for VIV-induced fatigue and to apply it to partially straked risers. This was achieved using reliability methods, accepted industry VIV prediction software and state-of-the-art model test experiments. Most oil companies use a Factor of Safety of 20 when predicting VIV damage using VIV software tools. There are numerous software tools currently in use in industry to predict VIV damage to straked risers and each of them will have different accuracy, and therefore an intrinsic level of conservatism. Understanding the level of conservatism in different VIV prediction software is therefore critical to determining what Factor of Safety to use. This study benchmarks the latest generation of industry accepted VIV design tools at the time of the study (2011): SHEAR7v4.6, VIVAv6.5 and VIVANAv3.7.24 against high quality VIV data from three separate straked riser experiments. A bias distribution (predicted to measured VIV damage results) is obtained for each software tool as a function of the strake coverage. A novel reliability framework approach is then developed to incorporate all uncertainties associated with VIV fatigue prediction into a limit state function, including variability in met-ocean conditions and variability in the fatigue resistance of the material characterized by a design S-N curve. The limit state function is analyzed using First Order Reliability Methods to develop Factors of Safety for target probabilities of failure. The general method is then applied on two case studies involving an SCR and TTR in Gulf of Mexico loop currents, but it can be easily extended to different locations and riser configurations. The resulting FoS range from about 1 to 15 for most software, and are lower than industry standards for VIV prediction. The FoS do not vary markedly for different riser configurations, indicating the possibility of reducing excess conservatism when predicting VIV damage on straked risers.DeepStar (Consortium)SHEAR7 JI

Multiperspectival designs and processes in interpretative phenomenological analysis research

Researchers using interpretative phenomenological analysis (IPA) within applied research typically use homogenous samples exploring shared perspectives on a single phenomenon of interest. This article explores the challenges and opportunities involved with developing rigorous and epistemologically coherent research designs for capturing more complex and systemic experiential phenomena, through the use of multiple perspectives to explore the same phenomenon. We outline a series of multiple perspective designs and analytic procedures that can be adapted and used across many diverse settings and populations. Whilst building upon existing approaches within qualitative methods and IPA, these designs and procedures are intended to scaffold clear routes to practical application, psychological intervention, the design of behaviour change interventions, and other recommendations for policy and practice. We discuss a variety of conceptual antecedents which situate these designs within phenomenology, pluralistic idiography, qualitative psychology, and wider debates within psychology and other social and behavioural sciences

Building genomic infrastructure: Sequencing platinum-standard reference-quality genomes of all cetacean species.

International audienc

Evaluation of the Impact of the I-66 Active Traffic Management System: Phase II

In early 2013, construction began on a Virginia Department of Transportation (VDOT) project to install an Active Traffic Management (ATM) system on I-66 from US 29 in Centreville to the Capital Beltway (I-495). Construction was completed in September 2015. This project was intended to improve safety and operations on I-66 without physically expanding the roadway through better management of the existing facility. The main components of the installed system included advisory variable speed limits (AVSL), lane use control signals (LUCS), and hard shoulder running (HSR)

Genomic and functional determinants of host spectrum in Group B Streptococcus

Group B Streptococcus (GBS) is a major human and animal pathogen that threatens public health and food security. Spill-over and spill-back between host species is possible due to adaptation and amplification of GBS in new niches but the evolutionary and functional mechanisms underpinning those phenomena are poorly known. Based on analysis of 1,254 curated genomes from all major GBS host species and six continents, we found that the global GBS population comprises host-generalist, host-adapted and host-restricted sublineages, which are found across host groups, preferentially within one host group, or exclusively within one host group, respectively, and show distinct levels of recombination. Strikingly, the association of GBS genomes with the three major host groups (humans, cattle, fish) is driven by a single accessory gene cluster per host, regardless of sublineage or the breadth of host spectrum. Moreover, those gene clusters are shared with other streptococcal species occupying the same niche and are functionally relevant for host tropism. Our findings demonstrate (1) the heterogeneity of genome plasticity within a bacterial species of public health importance, enabling the identification of high-risk clones; (2) the contribution of inter-species gene transmission to the evolution of GBS; and (3) the importance of considering the role of animal hosts, and the accessory gene pool associated with their microbiota, in the evolution of multi-host bacterial pathogens. Collectively, these phenomena may explain the adaptation and clonal expansion of GBS in animal reservoirs and the risk of spill-over and spill-back between animals and humans.</p