CCN2 reduction mediates protective effects of BMP7 treatment in obstructive nephropathy

Treatment with rhBMP7 exerts profound protective effects in a wide variety of experimental models of renal disease. However, little is known about how these protective effects are mediated, and which cells in the kidney are targeted by exogenous rhBMP7 treatment. To determine if rhBMP7 increases glomerular and tubulointerstitial canonical BMP signaling, we performed Unilateral Ureteral Obstruction w(UUO, a widely used obstructive nephropathy model) in mice reporting transcriptional activity downstream of canonical BMP signaling by the expression of GFP under the BMP Responsive Element of the Id1 promoter (BRE:gfp mice). We also analysed the impact of rhBMP7 treatment on severity of the UUO phenotype, on TGFβ signaling, and on expression of CCN2 (CTGF). Despite profound protective effects with respect to morphological damage, macrophage infiltration, and fibrosis, no significant difference in GFP-expression was observed upon rhBMP7 administration. Also TGFβ signalling was similar in rhBMP7 and vehicle treated mice, but CCN2 expression in obstructed kidneys was significantly reduced by rhBMP7 treatment. Of note, in heterozygous CCN2 mice (CCN2+/−) treatment with rhBMP7 did not (further) reduce the severity of kidney damage in the UUO-model. These data suggest that protection against obstructive nephropathy by exogenous rhBMP7 treatment relies primarily on non-canonical BMP signaling, and may be mediated in large part by downregulation of CCN2 expression

Perspectives of older adults on co-management of low back pain by doctors of chiropractic and family medicine physicians: a focus group study.

BACKGROUND: While older adults may seek care for low back pain (LBP) from both medical doctors (MDs) and doctors of chiropractic (DCs), co-management between these providers is uncommon. The purposes of this study were to describe the preferences of older adults for LBP co-management by MDs and DCs and to identify their concerns for receiving care under such a treatment model. METHODS: We conducted 10 focus groups with 48 older adults who received LBP care in the past year. Interviews explored participants\u27 care seeking experiences, co-management preferences, and perceived challenges to successful implementation of a MD-DC co-management model. We analyzed the qualitative data using thematic content analysis. RESULTS: Older adults considered LBP co-management by MDs and DCs a positive approach as the professions have complementary strengths. Participants wanted providers who worked in a co-management model to talk openly and honestly about LBP, offer clear and consistent recommendations about treatment, and provide individualized care. Facilitators of MD-DC co-management included collegial relationships between providers, arrangements between doctors to support interdisciplinary referral, computer systems that allowed exchange of health information between clinics, and practice settings where providers worked in one location. Perceived barriers to the co-management of LBP included the financial costs associated with receiving care from multiple providers concurrently, duplication of tests or imaging, scheduling and transportation problems, and potential side effects of medication and chiropractic care. A few participants expressed concern that some providers would not support a patient-preferred co-managed care model. CONCLUSIONS: Older adults are interested in receiving LBP treatment co-managed by MDs and DCs. Older adults considered patient-centered communication, collegial interdisciplinary interactions between these providers, and administrative supports such as scheduling systems and health record sharing as key components for successful LBP co-management

Cyberinfrastructure for Life Sciences - iAnimal Resources for Genomics and Other Data Driven Biology

Whole genome sequence, SNPs, copy number variation, phenotypes and other “-omics” data underlie evidence-based estimations of breeding value. Unfortunately, the computational resources (data storage, high-performance computing, analysis pipelines, etc.) that exploit this knowledge are limited in availability – many investigations are therefore restricted to the commercial sector or well-funded academic programs. Cyberinfrastructure developed by the iPlant Collaborative (NSF-#DBI0735191) and its extension iAnimal (USDA-#2013-67015-21231) provides the animal breeding community a comprehensive and freely available platform for the storage, sharing, and analyses of large datasets – from genomes to phenotype data. iPlant/iAnimal tools support a variety of genotype-phenotype related analyses in a platform that accommodates every level of user – from breeder to bioinformatician. These tools have been used to develop scalable, accessible versions of common workflows required for applying sequencing to livestock genomics

Piezoelectric Ribbons Printed onto Rubber for Flexible Energy Conversion

The development of a method for integrating highly efficient energy conversion materials onto stretchable, biocompatible rubbers could yield breakthroughs in implantable or wearable energy harvesting systems. Being electromechanically coupled, piezoelectric crystals represent a particularly interesting subset of smart materials that function as sensors/actuators, bioMEMS devices, and energy converters. Yet, the crystallization of these materials generally requires high temperatures for maximally efficient performance, rendering them incompatible with temperature-sensitive plastics and rubbers. Here, we overcome these limitations by presenting a scalable and parallel process for transferring crystalline piezoelectric nanothick ribbons of lead zirconate titanate from host substrates onto flexible rubbers over macroscopic areas. Fundamental characterization of the ribbons by piezo-force microscopy indicates that their electromechanical energy conversion metrics are among the highest reported on a flexible medium. The excellent performance of the piezo-ribbon assemblies coupled with stretchable, biocompatible rubber may enable a host of exciting avenues in fundamental research and novel applications

Evaluation of tarsal injuries in C57BL/6J male mice.

Tarsal joint abnormalities have been observed in aged male mice on a C57BL background. This joint disease consists of calcaneal displacement, inflammation, and proliferation of car- tilage and connective tissue, that can progress to ankylosis of the joint. While tarsal pathol- ogy has been described previously in C57BL/6N substrains, as well as in STR/ort and B10. BR strain, no current literature describes this disease occurring in C57BL/6J mice. More importantly the behavioral features that may result from such a change to the joint have yet to be evaluated. This condition was observed in older male mice of the C57BL/6J lineage, around the age of 20 weeks or older, at a frequency of 1% of the population. To assess potential phenotypic sequela, this study sought to evaluate body weight, frailty assessment, home cage wheel running, dynamic weight bearing, and mechanical allodynia with and with- out the presence of pain relief with morphine. Overall mice with tarsal injuries had signifi- cantly higher frailty scores (p\u3c 0.05) and weighed less (p\u3c0.01) compared to unaffected mice. Affected mice had greater overall touch sensitivity (p\u3c0.05) and they placed more weight on their forelimbs (p\u3c0.01) compared to their hind limbs. Lastly, when housed with a running wheel, affected mice ran for a shorter length of time (p\u3c0.01) but tended to run a greater distance within the time they did run (p\u3c0.01) compared to unaffected mice. When tested just after being given morphine, the affected mice performed more similarly to unaf- fected mice, suggesting there is a pain sensation to this disease process. This highlights the importance of further characterizing inbred mouse mutations, as they may impact research programs or specific study goals

FXR1 splicing is important for muscle development and biomolecular condensates in muscle cells

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Smith, J. A., Curry, E. G., Blue, R. E., Roden, C., Dundon, S. E. R., Rodríguez-Vargas, A., Jordan, D. C., Chen, X., Lyons, S. M., Crutchley, J., Anderson, P., Horb, M. E., Gladfelter, A. S., & Giudice, J. FXR1 splicing is important for muscle development and biomolecular condensates in muscle cells. Journal of Cell Biology, 219(4), (2020): e201911129, doi: 10.1083/jcb.201911129.Fragile-X mental retardation autosomal homologue-1 (FXR1) is a muscle-enriched RNA-binding protein. FXR1 depletion is perinatally lethal in mice, Xenopus, and zebrafish; however, the mechanisms driving these phenotypes remain unclear. The FXR1 gene undergoes alternative splicing, producing multiple protein isoforms and mis-splicing has been implicated in disease. Furthermore, mutations that cause frameshifts in muscle-specific isoforms result in congenital multi-minicore myopathy. We observed that FXR1 alternative splicing is pronounced in the serine- and arginine-rich intrinsically disordered domain; these domains are known to promote biomolecular condensation. Here, we show that tissue-specific splicing of fxr1 is required for Xenopus development and alters the disordered domain of FXR1. FXR1 isoforms vary in the formation of RNA-dependent biomolecular condensates in cells and in vitro. This work shows that regulation of tissue-specific splicing can influence FXR1 condensates in muscle development and how mis-splicing promotes disease.We thank the A.S. Gladfelter and J. Giudice laboratories, Nancy Kedersha, and Silvia Ramos for critical discussions; Eunice Y. Lee for technical help; Dr. Stephanie Gupton (University of North Carolina at Chapel Hill, Chapel Hill, NC) for donation of WT C57BL/6J mouse embryos; and Marcin Wlizla and National Xenopus Resource (RRID:SCR_013731) for their help in maintaining adult frogs and other important technical support. This work has been funded by a University of North Carolina at Chapel Hill Junior Faculty Development Award (to J. Giudice); a Nutrition and Obesity Research Center, University of North Carolina at Chapel Hill, Pilot & Feasibility Research grant (P30DK056350 to J. Giudice); University of North Carolina at Chapel Hill startup funds (to J. Giudice); the March of Dimes Foundation (5-FY18-36, Basil O’Connor Starter Scholar Award to J. Giudice); and NCTraCs Pilot Grant (550KR181805) from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR002489 (to J. Giudice), National Institutes of Health National Institute of General Medical Sciences grants (R01-GM130866 to J. Giudice, R01-GM081506 to A.S. Gladfelter, R35-GM126901 to P. Anderson, K99-GM124458 to S.M. Lyons, R25-GM089569 and 2R25-GM055336-20 to E.G. Curry); Howard Hughes Medical Institute Faculty Scholars program (A.S. Gladfelter), and National Institute of Health grants R01-HD084409 and P40-OD010997 (to M.E. Horb). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.2020-09-1

Influence of young adult cognitive ability and additional education on later-life cognition

How and when education improves cognitive capacity is an issue of profound societal importance. Education and later-life education-related factors, such as occupational complexity and engagement in cognitive-intellectual activities, are frequently considered indices of cognitive reserve, but whether their effects are truly causal remains unclear. In this study, after accounting for general cognitive ability (GCA) at an average age of 20 y, additional education, occupational complexity, or engagement in cognitive-intellectual activities accounted for little variance in late midlife cognitive functioning in men age 56-66 (n = 1009). Age 20 GCA accounted for 40% of variance in the same measure in late midlife and approximately 10% of variance in each of seven cognitive domains. The other factors each accounted for <1% of the variance in cognitive outcomes. The impact of these other factors likely reflects reverse causation-namely, downstream effects of early adult GCA. Supporting that idea, age 20 GCA, but not education, was associated with late midlife cortical surface area (n = 367). In our view, the most parsimonious explanation of our results, a meta-analysis of the impact of education, and epidemiologic studies of the Flynn effect is that intellectual capacity gains due to education plateau in late adolescence/early adulthood. Longitudinal studies with multiple cognitive assessments before completion of education would be needed to confirm this speculation. If cognitive gains reach an asymptote by early adulthood, then strengthening cognitive reserve and reducing later-life cognitive decline and dementia risk may really begin with improving educational quality and access in childhood and adolescence.Peer reviewe

Genetic Influences on Cortical Regionalization in the Human Brain

SummaryAnimal data demonstrate that the development of distinct cortical areas is influenced by genes that exhibit highly regionalized expression patterns. In this paper, we show genetic patterning of cortical surface area derived from MRI data from 406 adult human twins. We mapped genetic correlations of areal expansion between selected seed regions and all other cortical locations, with the selection of seed points based on results from animal studies. “Marching seeds” and a data-driven, hypothesis-free, fuzzy-clustering approach provided convergent validation. The results reveal strong anterior-to-posterior graded, bilaterally symmetric patterns of regionalization, largely consistent with patterns previously reported in nonhuman mammalian models. Broad similarities in genetic patterning between rodents and humans might suggest a conservation of cortical patterning mechanisms, whereas dissimilarities might reflect the functionalities most essential to each species

Optimized Phosphors for Warm White LED Light Engines

The objective of this program is to develop phosphor systems and LED light engines that have steady-state LED efficacies (using LEDs with a 60% wall-plug efficiency) of 105–120 lm/W with correlated color temperatures (CCT) ~3000 K, color rendering indices (CRI) >85, <0.003 distance from the blackbody curve (dbb), and <2% loss in phosphor efficiency under high temperature, high humidity conditions. In order to reach these goals, this involves the composition and processing optimization of phosphors previously developed by GE in combination with light engine package modification