Search

Abstract Metabolic dysfunction in chondrocytes drives the pro-catabolic phenotype associated with osteoarthritic cartilage. In this study, substitution of galactose for glucose in culture media was used to promote a renewed dependence on mitochondrial respiration and oxidative phosphorylation. Galactose replacement alone blocked enhanced usage of the glycolysis pathway by IL1β-activated chondrocytes as detected by real-time changes in the rates of proton acidification of the medium and changes in oxygen consumption. The change in mitochondrial activity due to galactose was visualized as a rescue of mitochondrial membrane potential but not an alteration in the number of mitochondria. Galactose-replacement reversed other markers of dysfunctional mitochondrial metabolism, including blocking the production of reactive oxygen species, nitric oxide, and the synthesis of inducible nitric oxide synthase. Of more clinical relevance, galactose-substitution blocked downstream functional features associated with osteoarthritis, including enhanced levels of MMP13 mRNA, MMP13 protein, and the degradative loss of proteoglycan from intact cartilage explants. Blocking baseline and IL1β-enhanced MMP13 by galactose-replacement in human osteoarthritic chondrocyte cultures inversely paralleled increases in markers associated with mitochondrial recovery, phospho-AMPK, and PGC1α. Comparisons were made between galactose replacement and the glycolysis inhibitor 2-deoxyglucose. Targeting intermediary metabolism may provide a novel approach to osteoarthritis care.

BackgroundSarcoidosis is a chronic inflammatory disease of unknown cause characterized by granuloma formation. Mechanisms for chronic persistence of granulomas are unknown. Matrix Metalloproteinase-12 (MMP12) degrades extracellular matrix elastin and enables infiltration of immune cells responsible for inflammation and granuloma formation. Previous studies report increased MMP12 in sarcoidosis patients and association between MMP12 expression and disease severity. We also observed elevated MMP12 in our multiwall carbon nanotube (MWCNT) murine model of granulomatous inflammation. Here we hypothesized that MMP12 is important to acute and late phases of granuloma pathogenesis. To test this hypothesis, we analyzed granulomatous and inflammatory responses of Mmp12 knock-out (KO) mice at 10 (acute) and 60 days (late) after MWCNT instillation.MethodsC57BL/6 (wildtype) and Mmp12 KO mice underwent oropharyngeal instillation of MWCNT. Lungs were harvested at 3, 10, 20, and 60 days post instillation for evaluation of MMP12 expression and granulomatous changes. Bronchoalveolar lavage (BAL) cells were analyzed 60 days after MWCNT instillation for expression of mediators thought to play a role in sarcoid granulomatosis: peroxisome proliferator-activated receptor-gamma (PPARγ), interferon-gamma (IFN-γ), and CCL2 (MCP-1).ResultsPulmonary granuloma appearance at 10 days after MWCNT instillation showed no differences between wildtype and Mmp12 KO mice. In contrast, by 60 days after MWCNT instillation, Mmp12 KO mice revealed markedly attenuated granuloma formation together with elevated PPARγ and reduced IFNγ expression in BAL cells compared to wildtype. Unexpectedly, Mmp12 KO mice further demonstrated increased alveolar macrophages with increased CCL2 at 60 days.ConclusionsThe striking reduction of granuloma formation at day 60 in Mmp12 KO mice suggests that MMP12 is required to maintain chronic granuloma pathophysiology. The increased PPARγ and decreased IFNγ findings suggest that these mediators also may be involved since previous studies have shown that PPARγ suppresses IFNγ and PPARγ deficiency amplifies granuloma formation. Interestingly, a role of MMP12 in granuloma resolution is also suggested by increases in both macrophage influx and CCL2. Overall, our results strongly implicate MMP12 as a key factor in granuloma persistence and as a possible therapeutic target in chronic pulmonary sarcoidosis.

Successful episodic memory involves dynamic increases in activity across distributed hippocampal networks, including the posterior-medial (PMN) and the anterior-temporal (ATN) networks. We tested whether this up-regulation of functional connectivity during memory processing can be enhanced within hippocampal networks by noninvasive stimulation, and whether such task-dependent connectivity enhancement predicts memory improvement. Participants received stimulation targeting the PMN or an out-of-network control location. We compared the effects of stimulation on fMRI connectivity during an autobiographical retrieval task versus during rest within the PMN and the ATN. PMN-targeted stimulation significantly increased connectivity during autobiographical retrieval versus rest within the PMN. This effect was not observed in the ATN, or in either network following control stimulation. Task-dependent increases in connectivity within the medial temporal lobe predicted improved performance of a separate episodic memory test. It is therefore possible to enhance the task-dependent regulation of hippocampal network connectivity that supports memory processing using noninvasive stimulation., Competing Interests: KW, MH, AN, JV No competing interests declared, (© 2019, Warren et al.)

Despite advances in the development of biomarkers for Alzheimer's disease (AD), accurate ante-mortem diagnosis remains challenging because a variety of neuropathologic disease states can coexist and contribute to the AD dementia syndrome. Here, we report a neuroimaging study correlating hippocampal deformity with regional AD and transactive response DNA-binding protein of 43 kDA pathology burden. We used hippocampal shape analysis of ante-mortem T1-weighted structural magnetic resonance imaging images of 42 participants from two longitudinal cohort studies conducted by the Rush Alzheimer's Disease Center. Surfaces were generated for the whole hippocampus and zones approximating the underlying subfields using a previously developed automated image-segmentation pipeline. Multiple linear regression models were constructed to correlate the shape with pathology measures while accounting for covariates, with relationships mapped out onto hippocampal surface locations. A significant relationship existed between higher paired helical filaments-tau burden and inward hippocampal shape deformity in zones approximating CA1 and subiculum which persisted after accounting for coexisting pathologies. No significant patterns of inward surface deformity were associated with amyloid-beta or transactive response DNA-binding protein of 43 kDA after including covariates. Our findings indicate that hippocampal shape deformity measures in surface zones approximating CA1 may represent a biomarker for postmortem AD pathology., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Autobiographical memory retrieval is associated with activity of a distributed network that is similar to the default-mode network (DMN) identified via activity correlations measured during rest. We tested whether activity correlations could be used to identify the autobiographical network during extended bouts of retrieval. Global-correlativity analysis identified regions with activity correlation differences between autobiographical-retrieval and resting states. Increased correlations were identified for retrieval versus resting states within a distributed network that included regions prototypical for autobiographical memory. This network segregated into two subnetworks comprised of regions related to memory versus cognitive control, suggesting greater functional segregation during autobiographical retrieval than rest. DMN regions were important drivers of these effects, with increased correlations between DMN and non-DMN regions and segregation of the DMN into distinct subnetworks during retrieval. Thus, the autobiographical network can be robustly identified via activity correlations and retrieval is associated with network functional organization distinct from rest., (© 2018 Wiley Periodicals, Inc.)

While collective movement is ecologically widespread and conveys numerous benefits on individuals, it also poses a coordination problem: who controls the group's movements? The role that animal 'personalities' play in this question has recently become a focus of research interest. Although many animal groups have distributed leadership (i.e. multiple individuals influence collective decisions), studies linking personality and leadership have focused predominantly on the group's single most influential individual. In this study, we investigate the relationship between personality and the influence of multiple leaders on collective movement using homing pigeons, Columba livia , a species known to display complex multilevel leadership hierarchies during flock flights. Our results show that more exploratory (i.e. 'bold') birds are more likely to occupy higher ranks in the leadership hierarchy and thus have more influence on the direction of collective movement than less exploratory (i.e. 'shy') birds during both free flights around their lofts and homing flights from a distant site. Our data also show that bold pigeons fly faster than shy birds during solo flights. We discuss our results in light of theories about the evolution of personality, with specific reference to the adaptive value of heterogeneity in animal groups.This article is part of the theme issue 'Collective movement ecology'., (© 2018 The Author(s).)

Background: Chronic inflammation has been linked to memory and other cognitive impairments, as well as Alzheimer's disease. Here, we investigate the association between inflammatory markers and changes in brain activity measured by regional cerebral blood flow (rCBF) to assess the relationship between inflammation and brain function in older individuals., Methods: Annual 15O water resting-state positron emission tomography (PET) scans collected over a 5-year period were assessed in 138 cognitively normal older participants (77 males; mean age at baseline = 71.3; mean scans per participant = 3.5) in the Baltimore Longitudinal Study of Aging. Voxel-wise linear mixed models were used to investigate associations between rCBF and C-reactive protein (CRP) and interleukin-6 (IL-6) at the time of scanning. We examined relationships between baseline CRP and IL-6 levels and baseline rCBF, and relationships between baseline and mean inflammatory levels over time and longitudinal rCBF changes., Results: Higher baseline CRP and IL-6 were each associated with lower baseline rCBF primarily in frontal and occipital regions, with only the lingual gyrus surviving atrophy correction. Higher baseline and mean CRP were also associated with greater rCBF declines over time in anterior cingulate and hippocampal regions, whereas higher baseline and mean IL-6 levels were associated with greater rCBF declines in orbitofrontal and hippocampal regions., Conclusions: Higher levels of inflammation are associated with longitudinal changes in brain function in regions important for cognition. These results, along with previous studies, suggest that chronic inflammation in older adults may contribute to age-associated declines in cognitive function.

The use of common data elements (CDEs) is growing in medical research; CDEs have demonstrated benefit in maximizing the impact of existing research infrastructure and funding. However, the field of burn care does not have a standard set of CDEs. The objective of this study is to examine the extent of common data collected in current burn databases.This study examines the data dictionaries of six U.S. burn databases to ascertain the extent of common data. This was assessed from a quantitative and qualitative perspective. Thirty-two demographic and clinical data elements were examined. The number of databases that collect each data element was calculated. The data values for each data element were compared across the six databases for common terminology. Finally, the data prompts of the data elements were examined for common language and structure.Five (16%) of the 32 data elements are collected by all six burn databases; additionally, five data elements (16%) are present in only one database. Furthermore, there are considerable variations in data values and prompts used among the burn databases. Only one of the 32 data elements (age) contains the same data values across all databases.The burn databases examined show minimal evidence of common data. There is a need to develop CDEs and standardized coding to enhance interoperability of burn databases.