Autonomic and Electrophysiological Correlates of Cognitive Control in Aging

This thesis tested a model of neurovisceral integration (Thayer & Lane, 2001) wherein parasympathetic autonomic regulation is considered to play a central role in cognitive control. We asked whether respiratory sinus arrhythmia (RSA), a parasympathetic index, and cardiac workload (rate pressure product, RPP) would influence cognition and whether this would change with age. Cognitive control was measured behaviourally and electrophysiologically through the error-related negativity (ERN) and error positivity (Pe). The ERN and Pe are thought to be generated by the anterior cingulate cortex (ACC), a region involved in regulating cognitive and autonomic control and susceptible to age-related change. In Study 1, older and younger adults completed a working memory Go/NoGo task. Although RSA did not relate to performance, higher pre-task RPP was associated with poorer NoGo performance among older adults. Relations between ERN/Pe and accuracy were indirect and more evident in younger adults. Thus, Study 1 supported the link between cognition and autonomic activity, specifically, cardiac workload in older adults. In Study 2, we included younger adults and manipulated a Stroop task to clarify conditions under which associations between RSA and performance will likely emerge. We varied task parameters to allow for proactive versus reactive strategies, and motivation was increased via financial incentive. Pre-task RSA predicted accuracy when response contingencies required maintenance of a specific item in memory. Thus, RSA was most relevant when performance required proactive control, a metabolically costly strategy that would presumably be more reliant on autonomic flexibility. In Study 3, we included older adults and examined RSA and proactive control in an additive factors framework. We maintained the incentive and measured fitness. Higher pre-task RSA among older adults was associated with greater accuracy when proactive control was needed most. Conversely, performance of young women was consistently associated with fitness. Relations between ERN/Pe and accuracy were modest; however, isolating ACC activity via independent component analysis allowed for more associations with accuracy to emerge in younger adults. Thus, performance in both groups appeared to be differentially dependent on RSA and ACC activation. Altogether, these data are consistent with a neurovisceral integration model in the context of cognitive control

Poly-L-Lactic Acid (PLLA)-Based Biomaterials for Regenerative Medicine: A Review on Processing and Applications

Synthetic biopolymers are effective cues to replace damaged tissue in the tissue engineering(TE) field, both for in vitro and in vivo application. Among them, poly-L-lactic acid (PLLA) has beenhighlighted as a biomaterial with tunable mechanical properties and biodegradability that allowsfor the fabrication of porous scaffolds with different micro/nanostructures via various approaches.In this review, we discuss the structure of PLLA, its main properties, and the most recent advancesin overcoming its hydrophobic, synthetic nature, which limits biological signaling and proteinabsorption. With this aim, PLLA-based scaffolds can be exposed to surface modification or combinedwith other biomaterials, such as natural or synthetic polymers and bioceramics. Further, variousfabrication technologies, such as phase separation, electrospinning, and 3D printing, of PLLA-basedscaffolds are scrutinized along with the in vitro and in vivo applications employed in various tissuerepair strategies. Overall, this review focuses on the properties and applications of PLLA in theTE field, finally affording an insight into future directions and challenges to address an effectiveimprovement of scaffold properties

Assessment of riparian conditions in the Nooksack River Basin with the combination of LiDAR, multi-spectral imagery and GIS

Riparian areas are a complex component of stream ecosystems and provide critical habitat for Pacific salmon (Oncorhynchus spp.). Comprehensive techniques are needed for assessing riparian areas that can be used on small and large regional scales. I examined the application of airborne LiDAR and high resolution multi-spectral imagery from the World View-2 (WV-2) satellite to analyze riparian landcover and riparian forest structure in the Nooksack River Watershed. I employed an object-oriented approach to segment the imagery into meaningful objects consisting of groups of pixels. I examined the advantages of the four additional spectral bands from the 8-Band World View-2 Image compared to the traditional four spectral bands provided from conventional high resolution multi-spectral imagery. Using the Random Forest algorithm, I developed classification and regression models to predict the features of interest across the study area. The classification results from the 8-Band WV-2 image were improved over the traditional 4-Band WV-2 image that is comparable to other high resolution sensors such as IKONOS and Quickbird. Analyzing the combined LiDAR and 8-Band WV-2 spectral data improved the results for landcover classification but did not improve the results for riparian forest structural predictions. However, the results generated from the LiDAR only image was comparable to the 8-Band WV-2 spectral imagery at classifying forest classes and remarkably better at predicting forest structure data. The overall results indicate that classification of forested cover type and structural properties of riparian forest stands can be determined accurately for relatively large study areas with LiDAR-based approaches. From the final LiDAR image output, I applied the models to categorize the riparian forest based on forest class, size, and density to show one application of the results generated in this study. The categorized map provides a tool to prioritize restoration and preservation needs within the riparian forest landscape in the Nooksack River Basin study area

Hemorrhagic risk after intravenous thrombolysis for ischemic stroke in patients with cerebral microbleeds and white matter disease

Objectives: Aim of this study was to evaluate the association between cerebral microbleeds (CMBs) and white matter disease (WMD) with intracerebral hemorrhage (ICH) after intravenous thrombolysis (IVT) with rt-PA. We also evaluated whether CMBs characteristics and WMD burden correlate with symptomatic ICH and outcome. Methods: We included acute ischemic stroke (AIS) patients treated with IVT. The number and location of CMBs as well as severity of WMD were rated analyzing pre- or post-treatment MRI. Multivariable regression analysis was used to determine the impact of CMB and WMD on ICH subgroups and outcome measures. Results: 434 patients were included. CMBs were detected in 23.3% of them. ICH occurred in 34.7% of patients with CMBs. Independent predictors of parenchymal hemorrhage were the presence of CMBs (OR 2.724, 95% CI 1.360–5.464, p = 0.005) as well as cortical-subcortical stroke (OR 3.629, 95% CI 1.841–7.151, p < 0.001) and atherothrombotic stroke subtype (OR 3.381, 95% CI 1.335–8.566, p = 0.010). Either the presence, or number, and location of CMBs, as well as WMD, was not independently associated with the development of SICH. No independent association between the presence, number, or location of CMBs or WMD and outcome measures was observed. Conclusions: The results of our study suggest that the exclusion of eligible candidates to administration of IV rt-PA only on the basis of CMBs presence is not justified. The clinical decision should be weighed with a case-by-case approach. Additional data are needed to evaluate the benefit-risk profile of rt-PA in patients carrying numerous microbleeds

Solution-based processing for scaffold fabrication in tissue engineering applications: A brief review

The fabrication of 3D scaffolds is under wide investigation in tissue engineering (TE) because of its incessant development of new advanced technologies and the improvement of traditional processes. Currently, scientific and clinical research focuses on scaffold characterization to restore the function of missing or damaged tissues. A key for suitable scaffold production is the guarantee of an interconnected porous structure that allows the cells to grow as in native tissue. The fabrication techniques should meet the appropriate requirements, including feasible reproducibility and time-and cost-effective assets. This is necessary for easy processability, which is associated with the large range of biomaterials supporting the use of fabrication technologies. This paper presents a review of scaffold fabrication methods starting from polymer solutions that provide highly porous structures under controlled process parameters. In this review, general information of solution-based technologies, including freeze-drying, thermally or diffusion induced phase separation (TIPS or DIPS), and electrospinning, are presented, along with an overview of their technological strategies and applications. Furthermore, the differences in the fabricated constructs in terms of pore size and distribution, porosity, morphology, and mechanical and biological properties, are clarified and critically reviewed. Then, the combination of these techniques for obtaining scaffolds is described, offering the advantages of mimicking the unique architecture of tissues and organs that are intrinsically difficult to design

Redox-responsive MRI probes to follow-up hypoxia within cell-embedding hydrogels

*Introduction*In regenerative medicine, biocompatible hydrogels are increasingly used to encapsulate therapeutic cells prior to transplantation into the host to enhance their long term survival. Cell embedding within bioengineered hydrogels can shield cells from immune response and provide an optimal life-sustaining microenvironment to therapeutic cells. In addition, cell embedding offers the outstanding opportunity to insert microenvironment-responsive imaging labels within the hydrogel, paving the way for non-invasive monitoring of the extracellular microenvironment within the hydrogel. We have inserted redox-responsive MRI labels within cell-embedding hydrogels to follow-up the microenvironment redox state.*Methods*High molecular weight chitosan polymers were chemically conjugated with a Gd-HPDO3A-chelate through a disulfide bond, and interspersed within alginate-based hydrogel capsules. Human mesenchymal stem cells (hMSCs) as model therapeutic cells were embedded into such imaging labelled hydrogel. Embedded cells were incubated under simulated hypoxiaconditions, while being followed-up by T1-weighted MRI at 7T.*Results*Under reducing conditions, reductive cleavage of the disulfide bond in the Gd-chitosan probe yields a low molecular weight Gd-chelate that eventually diffuses out of the hydrogel capsule. The resulting change of MRI contrast enhancement along time is very sensitive to the oxygenation level within cell capsules. The kinetics of clearance of contrast enhancement is an indirect indicator of the survival of encapsulated cells.*Conclusions*The Gd-chitosan probe we developed is promising to follow-up non-invasively the redox microenvironment within cellembedding hydrogels. This approach will find useful application to monitor whether transplanted cells succeed to restore normal tissue oxygenation levels, especially in regenerative medicine approaches to ischemic diseases

A High-Throughput Mechanical Activator for Cartilage Engineering Enables Rapid Screening of in vitro Response of Tissue Models to Physiological and Supra-Physiological Loads

Articular cartilage is crucially influenced by loading during development, health, and disease. However, our knowledge of the mechanical conditions that promote engineered cartilage maturation or tissue repair is still incomplete. Current in vitro models that allow precise control of the local mechanical environment have been dramatically limited by very low throughput, usually just a few specimens per experiment. To overcome this constraint, we have developed a new device for the high throughput compressive loading of tissue constructs: the High Throughput Mechanical Activator for Cartilage Engineering (HiT-MACE), which allows the mechanoactivation of 6 times more samples than current technologies. With HiT-MACE we were able to apply cyclic loads in the physiological (e.g., equivalent to walking and normal daily activity) and supra-physiological range (e.g., injurious impacts or extensive overloading) to up to 24 samples in one single run. In this report, we compared the early response of cartilage to physiological and supra-physiological mechanical loading to the response to IL-1β exposure, a common but rudimentary in vitro model of cartilage osteoarthritis. Physiological loading rapidly upregulated gene expression of anabolic markers along the TGF-β1 pathway. Notably, TGF-β1 or serum was not included in the medium. Supra-physiological loading caused a mild catabolic response while IL-1β exposure drove a rapid anabolic shift. This aligns well with recent findings suggesting that overloading is a more realistic and biomimetic model of cartilage degeneration. Taken together, these findings showed that the application of HiT-MACE allowed the use of larger number of samples to generate higher volume of data to effectively explore cartilage mechanobiology, which will enable the design of more effective repair and rehabilitation strategies for degenerative cartilage pathologies

Biocompatible Materials labelled with Microenvironment Responsive MRI Probes for the follow-up of Cell Transplants

Introduction: Cell encapsulation by hydrogels is intended to shield transplanted cells from the host hostile environment by preventing the infiltration of host immune cells. Cell scaffolding by solid biocompatible microparticles is intended to provide a structural support to implanted cells and to mimic the extracellular matrix, allowing cells to proliferate and/or differentiate in the desired way. We present strategies to label scaffolding biomaterials with microenvironment responsive MRI probes, for applications in the follow-up of cell transplants. Methods: Microparticles (MPs) based on PLGA/chitosan were incorporated with gadolinium fluoride nanoparticles (GdNPs), as the MRI T1-contrast agent. The system is designed such to release Gd-NPs in the extracellular matrix (ECM), thus activating MRI contrast, unless MPs are attacked by the immune system (Foreign Body Response, FBR). To proof the concept, PLGA-based MPs were seeded with hMSCs and implanted into either immunocompetent or immunocompromised mice, and the transplants were followed-up by MRI for three weeks. Ex-vivo histologic assessment was carried out at the end of the follow-up. Results/Discussion: Immunocompetent mice showed poor activation, if any, of MRI contrast within the cell graft. Immunocompromised mice, on the other hand, showed a progressive activation of MRI contrast. Ex-vivo histology showed extensive FBR directed against microparticles in immunocompetent mice, with some surviving hMSCs in the ECM but not on the scaffold surface. No significant FBR was detected in immunocompromised mice, and hMSCs were still adhering to the scaffolds. Conclusions: The proposed system is able to assess whether or not cell grafts are subjected to innate immune response, an event that is likely correlated to the loss of transplanted cells