Osteoarthritis: the genesis of pain Fu, Kai; Robbins, Sarah R; McDougall, Jason J
Rheumatology,
05/2018, Volume:
57, Issue:
suppl_4
Journal Article
Peer reviewed
Open access
Abstract
OA is a painful joint disease that predominantly affects the elderly. Pain is the primary symptom of OA, and it can present as either intermittent or constant. OA pain mechanisms are complex ...and have only recently been determined. Both peripheral and central processes are involved in creating the OA pain experience, making targeted therapy problematic. Nociceptive, inflammatory and neuropathic pains are all known to occur in OA, but to varying degrees in a patient- and time-specific manner. A better understanding of these multifactorial components of OA pain will lead to the development of more effective and safer pain treatments.
The flaviviruses dengue virus (DENV) and Zika virus (ZIKV) are severe health threats with rapidly expanding ranges. To identify the host cell dependencies of DENV and ZIKV, we completed orthologous ...functional genomic screens using RNAi and CRISPR/Cas9 approaches. The screens recovered the ZIKV entry factor AXL as well as multiple host factors involved in endocytosis (RAB5C and RABGEF), heparin sulfation (NDST1 and EXT1), and transmembrane protein processing and maturation, including the endoplasmic reticulum membrane complex (EMC). We find that both flaviviruses require the EMC for their early stages of infection. Together, these studies generate a high-confidence, systems-wide view of human-flavivirus interactions and provide insights into the role of the EMC in flavivirus replication.
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•RNAi and CRISPR/Cas9 screens were used to find flavivirus dependencies•The screens recovered host factors involved in endocytosis and heparin sulfation•The EMC is required by DENV and ZIKV in the early stages of replication•These studies give a systems-wide view of human-flavivirus interactions
Savidis et al. identify DENV and ZIKV dependencies using orthologous RNAi and CRISPR/Cas9 approaches. Multiple host factors involved in endocytosis and transmembrane protein processing, including the endoplasmic reticulum membrane complex (EMC), are important for flaviviral replication. Together, their studies generate a systems-wide view of human-flavivirus interactions.
Modern medical and hygienic practices have greatly improved human health and longevity; however, increased human life span occurs concomitantly with the emergence of metabolic and age-related ...diseases. Studies over the past decade have strongly linked host inflammatory responses to the etiology of several metabolic diseases including atherosclerosis, type 2 diabetes (T2D), obesity, and gout. A common immunological factor to these diseases is the activation of the inflammasome and release of proinflammatory cytokines that promote disease progression. Here we review the molecular mechanism(s) of inflammasome activation in response to metabolic damage-associated molecular patterns (DAMPs) and discuss potential targets for therapeutic intervention.
Abstract Engineered nanoparticles have the potential to expand the breadth of pulmonary therapeutics, especially as respiratory vaccines. Notably, cationic nanoparticles have been demonstrated to ...produce superior local immune responses following pulmonary delivery; however, the cellular mechanisms of this increased response remain unknown. To this end, we systematically investigated the cellular response of lung APCS following pulmonary instillation of anionic and cationic charged nanoparticles. While nanoparticles of both surface charges were capable of trafficking to the draining lymph node and were readily internalized by alveolar macrophages, both CD11b and CD103 lung dendritic cell (DC) subtypes preferentially associated with cationic nanoparticles. Instillation of cationic nanoparticles resulted in the upregulation of Ccl2 and Cxc10 , which likely contributes to the recruitment of CD11b DCs to the lung. In total, these cellular mechanisms explain the increased efficacy of cationic formulations as a pulmonary vaccine carrier and provide critical benchmarks in the design of pulmonary vaccine nanoparticles.
Listeria monocytogenes is an important cause of maternal-fetal infections and serves as a model organism to study these important but poorly understood events. L. monocytogenes can infect ...non-phagocytic cells by two means: direct invasion and cell-to-cell spread. The relative contribution of each method to placental infection is controversial, as is the anatomical site of invasion. Here, we report for the first time the use of first trimester placental organ cultures to quantitatively analyze L. monocytogenes infection of the human placenta. Contrary to previous reports, we found that the syncytiotrophoblast, which constitutes most of the placental surface and is bathed in maternal blood, was highly resistant to L. monocytogenes infection by either internalin-mediated invasion or cell-to-cell spread. Instead, extravillous cytotrophoblasts-which anchor the placenta in the decidua (uterine lining) and abundantly express E-cadherin-served as the primary portal of entry for L. monocytogenes from both extracellular and intracellular compartments. Subsequent bacterial dissemination to the villous stroma, where fetal capillaries are found, was hampered by further cellular and histological barriers. Our study suggests the placenta has evolved multiple mechanisms to resist pathogen infection, especially from maternal blood. These findings provide a novel explanation why almost all placental pathogens have intracellular life cycles: they may need maternal cells to reach the decidua and infect the placenta.
Abstract Background Mesenchymal stem cells (MSCs) show differentiation capacity along mesenchymal lineages and have the potential to aid tissue regeneration. MSC transplantation strategies are ...therefore currently being assessed following injury to various organs. However, potential MSC migration to these organs after intravenous (IV) MSC injection continues to be impeded by cell trapping within the lung. Methods Mouse MSCs were isolated, purified, transfected with firefly luciferase, and labeled with CSFE. Their size was assessed in vitro. To estimate the diameter of mouse pulmonary capillaries, fluorescence-labeled microspheres of different sizes were injected with or without sodium nitroprusside (SN) pretreatment. The lungs were harvested after 30 seconds and mean numbers of trapped microspheres per high-power field (HPF) were calculated. After IV injection of MSC suspensions (with or without SN), their dynamic distribution was monitored by in vivo luciferine imaging as well as by histopathology. Results The diameter of suspended MSCs in vitro was 15 to 19 μm. Whereas nearly no 4-μm microspheres could be detected in lung sections, the numbers of trapped 10- and 15-μm microspheres could be significantly decreased by prior SN injection from 19.3 ± 11.1 to 6.0 ± 1.6 cells/HPF ( P = .004) and from 34.9 ± 11.9 to 25.6 ± 8.1 cells/HPF ( P = .028), respectively. Within seconds after MSC IV injection, the vast majority of cells was found in the lungs. However, cell trapping in the pulmonary microvasculature was significantly reduced by pre-treatment with SN. Conclusions We demonstrate that cell trapping in lungs can be reduced with IV SN pretreatment, increasing MSC passage through the lung capillaries, and potentially facilitating cell access to injured organs.
Plant breeding relies on crossing-over to create novel combinations of alleles needed to confer increased productivity and other desired traits in new varieties. However, crossover (CO) events are ...rare, as usually only one or two of them occur per chromosome in each generation. In addition, COs are not distributed evenly along chromosomes. In plants with large genomes, which includes most crops, COs are predominantly formed close to chromosome ends, and there are few COs in the large chromosome swaths around centromeres. This situation has created interest in engineering CO landscape to improve breeding efficiency. Methods have been developed to boost COs globally by altering expression of anti-recombination genes and increase CO rates in certain chromosome parts by changing DNA methylation patterns. In addition, progress is being made to devise methods to target COs to specific chromosome sites. We review these approaches and examine using simulations whether they indeed have the capacity to improve efficiency of breeding programs. We found that the current methods to alter CO landscape can produce enough benefits for breeding programs to be attractive. They can increase genetic gain in recurrent selection and significantly decrease linkage drag around donor loci in schemes to introgress a trait from unimproved germplasm to an elite line. Methods to target COs to specific genome sites were also found to provide advantage when introgressing a chromosome segment harboring a desirable quantitative trait loci. We recommend avenues for future research to facilitate implementation of these methods in breeding programs.
Informed behavior change as an HIV prevention tool has yielded unequal successes across populations. Despite decades of HIV education, some individuals remain at high risk. The mainstream media often ...portrays these risk factors as products of race and national borders; however, a rich body of recent literature proposes a host of complex social factors that influence behavior, including, but not limited to: poverty, income inequality, stigmatizing social institutions and health care access. We examined the relationship between numerous social indicators and HIV incidence across eighty large U.S. cities in 1990 and 2000. During this time, major correlating factors included income inequality, poverty, educational attainment, residential segregation and marriage rates. However, these ecological factors were weighted differentially across risk groups (e.g. heterosexual, intravenous drug use, men who have sex with men (MSM)). Heterosexual risk rose significantly with poor economic indicators, while MSM risk depended more heavily on anti-homosexual stigma (as measured by same-sex marriage laws). HIV incidence among black individuals correlated significantly with numerous economic factors but also with segregation and imbalances in the male:female ratio (often an effect of mass incarceration). Our results support an overall model of HIV ecology where poverty, income inequality and social inequality (in the form of institutionalized racism and anti-homosexual stigma) have over time developed into synergistic drivers of disease transmission in the U.S., inhibiting information-based prevention efforts. The relative weights of these distal factors vary over time and by HIV risk group. Our testable model may be more generally applicable within the U.S. and beyond.
Significance To our knowledge, no other nano-based vaccine delivery platform has directly assessed the effects of nanoparticle charge on pulmonary vaccination without affecting other physio/chemical ...particle characteristics and/or antigen loading. The Particle Replication in Non-Wetting Templates nanoparticle fabrication process is unique in that it allows for isolation of charge as the sole variable in these studies while maintaining all other physical and chemical parameters constant. We find that positively charged nanoparticles induce robust mucosal and systemic antibody responses following pulmonary administration, whereas negatively charged nanoparticles fail to do so. Therefore, our studies underscore the importance of considering nanoparticle charge as a critical design parameter when generating pulmonary-based vaccines and may have implications for particulate vaccination through other routes of administration.
Pulmonary immunization enhances local humoral and cell-mediated mucosal protection, which are critical for vaccination against lung-specific pathogens such as influenza or tuberculosis. A variety of nanoparticle (NP) formulations have been tested preclinically for pulmonary vaccine development, yet the role of NP surface charge on downstream immune responses remains poorly understood. We used the Particle Replication in Non-Wetting Templates (PRINT) process to synthesize hydrogel NPs that varied only in surface charge and otherwise maintained constant size, shape, and antigen loading. Pulmonary immunization with ovalbumin (OVA)-conjugated cationic NPs led to enhanced systemic and lung antibody titers compared with anionic NPs. Increased antibody production correlated with robust germinal center B-cell expansion and increased activated CD4 ⁺ T-cell populations in lung draining lymph nodes. Ex vivo treatment of dendritic cells (DCs) with OVA-conjugated cationic NPs induced robust antigen-specific T-cell proliferation with ∼100-fold more potency than soluble OVA alone. Enhanced T-cell expansion correlated with increased expression of surface MHCII, T-cell coactivating receptors, and key cytokines/chemokine expression by DCs treated with cationic NPs, which were not observed with anionic NPs or soluble OVA. Together, these studies highlight the importance of NP surface charge when designing pulmonary vaccines, and our findings support the notion that cationic NP platforms engender potent humoral and mucosal immune responses.
Genomic selection predicts the genomic estimated breeding values (GEBVs) of individuals not previously phenotyped. Several studies have investigated the accuracy of genomic predictions in maize but ...there is little empirical evidence on the practical performance of lines selected based on phenotype in comparison with those selected solely on GEBVs in advanced testcross yield trials. The main objectives of this study were to (1) empirically compare the performance of tropical maize hybrids selected through phenotypic selection (PS) and genomic selection (GS) under well-watered (WW) and managed drought stress (WS) conditions in Kenya, and (2) compare the cost-benefit analysis of GS and PS. For this study, we used two experimental maize data sets (stage I and stage II yield trials). The stage I data set consisted of 1492 doubled haploid (DH) lines genotyped with rAmpSeq SNPs. A subset of these lines (855) representing various DH populations within the stage I cohort was crossed with an individual single-cross tester chosen to complement each population. These testcross hybrids were evaluated in replicated trials under WW and WS conditions for grain yield and other agronomic traits, while the remaining 637 DH lines were predicted using the 855 lines as a training set. The second data set (stage II) consists of 348 DH lines from the first data set. Among these 348 best DH lines, 172 lines selected were solely based on GEBVs, and 176 lines were selected based on phenotypic performance. Each of the 348 DH lines were crossed with three common testers from complementary heterotic groups, and the resulting 1042 testcross hybrids and six commercial checks were evaluated in four to five WW locations and one WS condition in Kenya. For stage I trials, the cross-validated prediction accuracy for grain yield was 0.67 and 0.65 under WW and WS conditions, respectively. We found similar responses to selection using PS and GS for grain yield other agronomic traits under WW and WS conditions. The top 15% of hybrids advanced through GS and PS gave 21%-23% higher grain yield under WW and 51%-52% more grain yield under WS than the mean of the checks. The GS reduced the cost by 32% over the PS with similar selection gains. We concluded that the use of GS for yield under WW and WS conditions in maize can produce selection candidates with similar performance as those generated from conventional PS, but at a lower cost, and therefore, should be incorporated into maize breeding pipelines to increase breeding program efficiency.
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