The Hyaluronan Receptor for Endocytosis Mediates Hyaluronan-Dependent Signal Transduction via Extracellular Signal-Regulated Kinases

The hyaluronan (HA) receptor for endocytosis (HARE) mediates the endocytotic clearance of HA and other glycosaminoglycans from lymph and blood. Two isoforms of human HARE, 315- and 190-kDa, are highly expressed in sinusoidal endothelial cells of liver, lymph node, and spleen; HARE is also in specialized cells in the eye, heart, brain, and kidney. Here we determined whether HA binding to HARE initiates intracellular signaling in Flp-In 293 cells stably expressing either the 315- and 190-kDa HARE or the 190-kDa HARE alone. HARE was co-immunoprecipitated with extracellular signal-regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal protein kinase (JNK), and p38 members of the mitogen-activated protein kinase signaling cascade. ERK phosphorylation increased in a dose- and time-dependent manner when HA was added to cells expressing full-length or 190-kDa HARE, but not cells with vector-only or a HARE(ΔLink) construct with greatly decreased (~90%) HA uptake. HA did not induce phosphorylation of JNK or p38. A maximum increase in phospho-ERK1/2 occurred within 30 min at 5 μg/ml HA, and the response was dampened at \u3e20 μg/ml HA. HA binding did not increase the level of HARE-ERK complexes, but did increase HARE phosphorylation. These findings demonstrate a novel functional response, when HARE binds HA, that leads to activation of ERK1/2, important mediators of intracellular signal transduction

Implication of Complement System and its Regulators in Alzheimer’s Disease

Alzheimer’s disease (AD) is an age-related neurodegenerative disease that affects approximately 24 million people worldwide. A number of different risk factors have been implicated in AD, however, neuritic (amyloid) plaques are considered as one of the defining risk factors and pathological hallmarks of the disease. Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer's dementia. This review emphasizes on the dual key roles of complement system and complement regulators (CRegs) in disease pathology and progression. The particular focus of this review is on currently evolving strategies for design of complement inhibitors that might aid therapy by restoring the fine balance between activated components of complement system, thus improving the cognitive performance of patients. This review discusses these issues with a view to inspiring the development of new agents that could be useful for the treatment of AD

A REDCap-based model for electronic consent (eConsent): Moving toward a more personalized consent

Introduction: The updated common rule, for human subjects research, requires that consents begin with a \u27concise and focused\u27 presentation of the key information that will most likely help someone make a decision about whether to participate in a study (Menikoff, Kaneshiro, Pritchard. The New England Journal of Medicine. 2017; 376(7): 613-615.). We utilized a community-engaged technology development approach to inform feature options within the REDCap software platform centered around collection and storage of electronic consent (eConsent) to address issues of transparency, clinical trial efficiency, and regulatory compliance for informed consent (Harris, et al. Journal of Biomedical Informatics 2009; 42(2): 377-381.). eConsent may also improve recruitment and retention in clinical research studies by addressing: (1) barriers for accessing rural populations by facilitating remote consent and (2) cultural and literacy barriers by including optional explanatory material (e.g., defining terms by hovering over them with the cursor) or the choice of displaying different videos/images based on participant\u27s race, ethnicity, or educational level (Phillippi, et al. Journal of Obstetric, Gynecologic, and Neonatal Nursing. 2018; 47(4): 529-534.). Methods: We developed and pilot tested our eConsent framework to provide a personalized consent experience whereby users are guided through a consent document that utilizes avatars, contextual glossary information supplements, and videos, to facilitate communication of information. Results: The eConsent framework includes a portfolio of eight features, reviewed by community stakeholders, and tested at two academic medical centers. Conclusions: Early adoption and utilization of this eConsent framework have demonstrated acceptability. Next steps will emphasize testing efficacy of features to improve participant engagement with the consent process

Genome-level analyses of Mycobacterium bovis lineages reveal the role of SNPs and antisense transcription in differential gene expression

BACKGROUND: Bovine tuberculosis (bTB) is a disease with major implications for animal welfare and productivity, as well as having the potential for zoonotic transmission. In Great Britain (GB) alone, controlling bTB costs in the region of £100 million annually, with the current control scheme seemingly unable to stop the inexorable spread of infection. One aspect that may be driving the epidemic is evolution of the causative pathogen, Mycobacterium bovis. To understand the underlying genetic changes that may be responsible for this evolution, we performed a comprehensive genome-level analyses of 4 M. bovis strains that encompass the main molecular types of the pathogen circulating in GB. RESULTS: We have used a combination of genome sequencing, transcriptome analyses, and recombinant DNA technology to define genetic differences across the major M. bovis lineages circulating in GB that may give rise to phenotypic differences of practical importance. The genomes of three M. bovis field isolates were sequenced using Illumina sequencing technology and strain specific differences in gene expression were measured during in vitro growth and in ex vivo bovine alveolar macrophages using a whole genome amplicon microarray and a whole genome tiled oligonucleotide microarray. SNP/small base pair insertion and deletions and gene expression data were overlaid onto the genomic sequence of the fully sequenced strain of M. bovis 2122/97 to link observed strain specific genomic differences with differences in RNA expression. CONCLUSIONS: We show that while these strains show extensive similarities in their genetic make-up and gene expression profiles, they exhibit distinct expression of a subset of genes. We provide genomic, transcriptomic and functional data to show that synonymous point mutations (sSNPs) on the coding strand can lead to the expression of antisense transcripts on the opposing strand, a finding with implications for how we define a 'silent’ nucleotide change. Furthermore, we show that transcriptomic data based solely on amplicon arrays can generate spurious results in terms of gene expression profiles due to hybridisation of antisense transcripts. Overall our data suggest that subtle genetic differences, such as sSNPS, may have important consequences for gene expression and subsequent phenotype

Phenomenological model of elastic distortions near the spin-Peierls transition in CuGeO3CuGeO_3

A phenomenological model of the Landau type forms the basis for a study of elastic distortions near the spin-Peierls transition $T_c$ in $CuGeO_3$. The atomic displacements proposed by Hirota {\it et al.} [Phys. Rev. Lett. {\bf 73}, 736 (1994)] are accounted for by the model which includes linear coupling between $Cu$ and $O$ distortions. $Cu$ displacements are seen to be responsible for anomalies in the elastic properties {\it at} $T_c$, whereas incipient $O$ distortions give rise to temperature dependence below $T_c$. A discussion of possible critical behavior is also made.Comment: 1 figure available upon reques

Are Thiel-embalmed Cadavers Effective Tools in Educating Medical Students to Perform Knee Arthrocentesis?

INTRODUCTION: The purposes of this study are to determine whether Thiel-embalmed cadavers are an effective educational tool in teaching medical students to perform knee arthrocentesis, to compare the use of Thiel-embalmed cadavers to formalin-embalmed cadavers in arthrocentesis education, and to determine whether the use of Thiel-embalmed cadavers is potentially generalizable to the instruction of other orthopedic procedures. METHODS: Sixty-eight third-year medical students participated in the study. The participants first completed a pre-survey to assess their prior experience with arthrocentesis procedures and Thiel-embalmed cadavers. Participants then attended an instructional session where the knee arthrocentesis procedure was demonstrated on a Thiel-embalmed cadaver. Participants then individually performed the simulated knee arthrocentesis procedure twice: once on a Thiel-embalmed cadaver and once on a formalin-embalmed cadaver. Success of each attempt was determined through the visualization of aspirated joint fluid. Following the laboratory session, each participant completed a post-survey to determine whether the session improved their perceived confidence in performing knee arthrocentesis, if they preferred the use of Thiel-embalmed cadavers or formalin-embalmed cadavers as a teaching tool, and if they believed simulated practice using Thiel-embalmed cadavers would be effective for learning other orthopedic procedural skills. RESULTS: Sixty-eight students participated in the laboratory session and successfully completed both pre- and post-course surveys. 96% of participants reported that they felt confident performing knee arthrocentesis under physician supervision following their participation in the laboratory session (versus 15% of participants in the pre-survey). 96% of participants reported that the Thiel-embalmed cadavers provided a more realistic teaching model than formalin-embalmed cadavers for learning knee arthrocentesis. 100% of participants believed the incorporation of simulated practice using Thiel-embalmed cadavers is an effective method in teaching students to perform knee arthrocentesis. 100% of participants reported that they would participate in future sessions using Thiel-embalmed cadavers to learn and practice other orthopedic procedural techniques. DISCUSSION: This study used a moderate sample size of third-year medical students to provide data regarding the suitability of using Thiel cadavers in arthrocentesis education. Results indicate that Thiel cadavers are effective tools in teaching medical students to perform knee arthrocentesis, that students preferred the Thiel cadavers to the formalin cadavers, and that the use of Thiel cadavers is a safe, engaging, and high-quality teaching modality for demonstrating proper arthrocentesis procedural technique to medical students. Since this study looked specifically at teaching knee arthrocentesis to medical students, it is uncertain whether the benefits of Thiel cadavers are generalizable to the education of other orthopedic procedures and subject groups such as residents, fellows, and practicing physicians. Further studies should be performed to assess whether Thiel cadavers are beneficial in teaching other orthopaedic procedures and if these benefits extend to other subject groups

Periodontitis and cognitive decline in Alzheimer's disease.

Periodontitis is common in the elderly and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro-inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer's disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer's disease. We aimed to determine if periodontitis in Alzheimer's disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer's Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer's Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation

Fatty acids linked to cardiovascular mortality are associated with risk factors

Background. Although saturated fatty acids (FAs) have been linked to cardiovascular mortality, it is not clear whether this outcome is attributable solely to their effects on low-density lipoprotein cholesterol (LDL-C) or whether other risk factors are also associated with FAs. The Western Alaskan Native population, with its rapidly changing lifestyles, shift in diet from unsaturated to saturated fatty acids and dramatic increase in cardiovascular disease (CVD), presents an opportunity to elucidate any associations between specific FAs and known CVD risk factors. Objective. We tested the hypothesis that the specific FAs previously identified as related to CVD mortality are also associated with individual CVD risk factors. Methods. In this community-based, cross-sectional study, relative proportions of FAs in plasma and red blood cell membranes were compared with CVD risk factors in a sample of 758 men and women aged ]35 years. Linear regression analyses were used to analyze relations between specific FAs and CVD risk factors (LDL-C, high-density lipoprotein cholesterol, triglycerides, C-reactive protein, systolic blood pressure, diastolic blood pressure, heart rate, body mass index, fasting glucose and fasting insulin, 2-hour glucose and 2-hour insulin). Results. The specific saturated FAs previously identified as related to CVD mortality, the palmitic and myristic acids, were adversely associated with most CVD risk factors, whereas unsaturated linoleic acid (18:2n-6) and the marine n-3 FAs were not associated or were beneficially associated with CVD risk factors. Conclusions. The results suggest that CVD risk factors are more extensively affected by individual FAs than hitherto recognized, and that risk for CVD,MI and stroke can be reduced by reducing the intake of palmitate, myristic acid and simple carbohydrates and improved by greater intake of linoleic acid and marine n-3 FAs