Piezoresistor-Embedded Multifunctional Magnetic Microactuators for Implantable Self-Clearing Catheter

Indwelling catheters are used widely in medicine to treat various chronic medical conditions. However, chronic implantation of catheters often leads to a premature failure due to biofilm accumulation. Previously we reported on the development of a self-clearing catheter by integrating polymer-based microscale magnetic actuators. The microactuator provides an active anti-biofouling mechanism to disrupt and remove adsorbed biofilm on demand using an externally applied stimulus. During an in vivo evaluation of self-clearing catheter, we realized that it is important to periodically monitor the performance of implanted microactuators. Here we integrate gold-based piezoresistive strain-gauge on our magnetic microactuators to directly monitor the device deflection with good sensitivity (0.035%/Deg) and linear range (±30°). With the integrated strain-gauge, we demonstrate the multi-functional capabilities of our magnetic microactuators that enable device alignment, flow-rate measurement, and obstruction detection and removal towards the development of chronically implantable self-clearing smart catheter

A Dynamic View of Trauma/Hemorrhage-Induced Inflammation in Mice: Principal Drivers and Networks

Background: Complex biological processes such as acute inflammation induced by trauma/hemorrhagic shock/ (T/HS) are dynamic and multi-dimensional. We utilized multiplexing cytokine analysis coupled with data-driven modeling to gain a systems perspective into T/HS. Methodology/Principal Findings: Mice were subjected to surgical cannulation trauma (ST) ± hemorrhagic shock (HS; 25 mmHg), and followed for 1, 2, 3, or 4 h in each case. Serum was assayed for 20 cytokines and NO2-/NO3-. These data were analyzed using four data-driven methods (Hierarchical Clustering Analysis [HCA], multivariate analysis [MA], Principal Component Analysis [PCA], and Dynamic Network Analysis [DyNA]). Using HCA, animals subjected to ST vs. ST + HS could be partially segregated based on inflammatory mediator profiles, despite a large overlap. Based on MA, interleukin [IL]-12p40/p70 (IL-12.total), monokine induced by interferon-γ (CXCL-9) [MIG], and IP-10 were the best discriminators between ST and ST/HS. PCA suggested that the inflammatory mediators found in the three main principal components in animals subjected to ST were IL-6, IL-10, and IL-13, while the three principal components in ST + HS included a large number of cytokines including IL-6, IL-10, keratinocyte-derived cytokine (CXCL-1) [KC], and tumor necrosis factor-α [TNF-α]. DyNA suggested that the circulating mediators produced in response to ST were characterized by a high degree of interconnection/complexity at all time points; the response to ST + HS consisted of different central nodes, and exhibited zero network density over the first 2 h with lesser connectivity vs. ST at all time points. DyNA also helped link the conclusions from MA and PCA, in that central nodes consisting of IP-10 and IL-12 were seen in ST, while MIG and IL-6 were central nodes in ST + HS. Conclusions/Significance: These studies help elucidate the dynamics of T/HS-induced inflammation, complementing other forms of dynamic mechanistic modeling. These methods should be applicable to the analysis of other complex biological processes

Immunologic and gene expression profiles of spontaneous canine oligodendrogliomas

Malignant glioma (MG), the most common primary brain tumor in adults, is extremely aggressive and uniformly fatal. Several treatment strategies have shown significant preclinical promise in murine models of glioma; however, none have produced meaningful clinical responses in human patients. We hypothesize that introduction of an additional preclinical animal model better approximating the complexity of human MG, particularly in interactions with host immune responses, will bridge the existing gap between these two stages of testing. Here, we characterize the immunologic landscape and gene expression profiles of spontaneous canine glioma and evaluate its potential for serving as such a translational model. RNA in situ hybridization, flowcytometry, and RNA sequencing were used to evaluate immune cell presence and gene expression in healthy and glioma-bearing canines. Similar to human MGs, canine gliomas demonstrated increased intratumoral immune cell infiltration (CD4+, CD8+ and CD4+Foxp3+ T cells). The peripheral blood of glioma-bearing dogs also contained a relatively greater proportion of CD4+Foxp3+ regulatory T cells and plasmacytoid dendritic cells. Tumors were strongly positive for PD-L1 expression and glioma-bearing animals also possessed a greater proportion of immune cells expressing the immune checkpoint receptors CTLA-4 and PD-1. Analysis of differentially expressed genes in our canine populations revealed several genetic changes paralleling those known to occur in human disease. Naturally occurring canine glioma has many characteristics closely resembling human disease, particularly with respect to genetic dysregulation and host immune responses to tumors, supporting its use as a translational model in the preclinical testing of prospective anti-glioma therapies proven successful in murine studies

Suspected olfactory meningioma and synchronous pituitary microadenoma in a canine patient treated with radiation therapy

AbstractThe authors report on the rare occurrence of dual synchronous primary brain tumors in a canine patient, successful treatment with radiation therapy, and medical therapy with patient stabilization for almost three years. A 12.5-year-old spayed mixed-breed female Labrador was referred to Purdue Veterinary Hospital to treat hyperadrenocorticism of suspected pituitary origin. During MRI imaging, the presence of two possible brain neoplasms was detected: a possible right olfactory bulb meningioma and a microadenoma of the pituitary gland. The patient was treated with a fractionated course of radiation in both tumors, 15 treatments of 3Gy, which limited the tumor growth. Mitotane therapy corrected the hormonal dysregulation. The dog had a normal life for nearly three years and recently passed. Cancer cells were not found at necropsy. No MEN1 germline mutations were identified in constitutional DNA (from blood) via high-coverage whole genome sequencing.</jats:p

Individual-Based Modeling of Amazon Forests Suggests That Climate Controls Productivity While Traits Control Demography

Climate, species composition, and soils are thought to control carbon cycling and forest structure in Amazonian forests. Here, we add a demographics scheme (tree recruitment, growth, and mortality) to a recently developed non-demographic model—the Trait-based Forest Simulator (TFS)—to explore the roles of climate and plant traits in controlling forest productivity and structure. We compared two sites with differing climates (seasonal vs. aseasonal precipitation) and plant traits. Through an initial validation simulation, we assessed whether the model converges on observed forest properties (productivity, demographic and structural variables) using datasets of functional traits, structure, and climate to model the carbon cycle at the two sites. In a second set of simulations, we tested the relative importance of climate and plant traits for forest properties within the TFS framework using the climate from the two sites with hypothetical trait distributions representing two axes of functional variation (“fast” vs. “slow” leaf traits, and high vs. low wood density). The adapted model with demographics reproduced observed variation in gross (GPP) and net (NPP) primary production, and respiration. However, NPP and respiration at the level of plant organs (leaf, stem, and root) were poorly simulated. Mortality and recruitment rates were underestimated. The equilibrium forest structure differed from observations of stem numbers suggesting either that the forests are not currently at equilibrium or that mechanisms are missing from the model. Findings from the second set of simulations demonstrated that differences in productivity were driven by climate, rather than plant traits. Contrary to expectation, varying leaf traits had no influence on GPP. Drivers of simulated forest structure were complex, with a key role for wood density mediated by its link to tree mortality. Modeled mortality and recruitment rates were linked to plant traits alone, drought-related mortality was not accounted for. In future, model development should focus on improving allocation, mortality, organ respiration, simulation of understory trees and adding hydraulic traits. This type of model that incorporates diverse tree strategies, detailed forest structure and realistic physiology is necessary if we are to be able to simulate tropical forest responses to global change scenarios

Cerebrospinal Fluid Drop Metastases of Canine Glioma: Magnetic Resonance Imaging Classification

Dissemination of glioma in humans can occur as leptomeningeal nodules, diffuse leptomeningeal lesions, or ependymal lesions. Cerebrospinal fluid (CSF) drop metastasis of glioma is not well-recognized in dogs. Ten dogs with at least two anatomically distinct and histologically confirmed foci of glioma were included in this study. The 10 dogs underwent 28 magnetic resonance imaging (MRI) examinations, with distant CSF drop metastasis revealed in 13 MRIs. The CSF drop metastases appeared as leptomeningeal nodules in four dogs, diffuse leptomeningeal lesions in six dogs, and ependymal lesions in seven dogs; six dogs had a combination of lesion types. Primary tumors were generally T2-heterogeneous and contrast-enhancing. Many metastases were T2-homogeneous and non-enhancing. Diffuse leptomeningeal lesions were seen as widespread extra-axial contrast-enhancement, again very dissimilar to the intra-axial primary mass. Primary masses were rostrotentorial, whereas metastases generally occurred in the direction of CSF flow, in ventricles, CSF cisterns, and the central canal or leptomeninges of the cervical or thoracolumbar spinal cord. Seven of the dogs had received therapy limited to the primary mass, such as surgery or stereotactic radiation, then developed metastasis in the following months. CSF drop metastasis of glioma may take a very different appearance on MRI to the primary mass, including periventricular lesions that are more homogeneous and less contrast-enhancing, rostral horn signal changes, or leptomeningeal enhancement ventral to the brainstem or encircling the spinal cord

Creation of an NCI comparative brain tumor consortium: informing the translation of new knowledge from canine to human brain tumor patients

On September 14–15, 2015, a meeting of clinicians and investigators in the fields of veterinary and human neuro-oncology, clinical trials, neuropathology, and drug development was convened at the National Institutes of Health campus in Bethesda, Maryland. This meeting served as the inaugural event launching a new consortium focused on improving the knowledge, development of, and access to naturally occurring canine brain cancer, specifically glioma, as a model for human disease. Within the meeting, a SWOT (strengths, weaknesses, opportunities, and threats) assessment was undertaken to critically evaluate the role that naturally occurring canine brain tumors could have in advancing this aspect of comparative oncology aimed at improving outcomes for dogs and human beings. A summary of this meeting and subsequent discussion are provided to inform the scientific and clinical community of the potential for this initiative. Canine and human comparisons represent an unprecedented opportunity to complement conventional brain tumor research paradigms, addressing a devastating disease for which innovative diagnostic and treatment strategies are clearly needed

Anti-biofouling implantable catheter using thin-film magnetic microactuators

Here we report on the development of polyimide-based flexible magnetic actuators for actively combating biofouling that occurs in many chronically implanted devices. The thin-film flexible devices are microfabricated and integrated into a single-pore silicone catheter to demonstrate a proof-of-concept for a self-clearing smart catheter. The static and dynamic mechanical responses of the thin-film magnetic microdevices were quantitatively measured and compared to theoretical values. The mechanical fatigue properties of these polyimide-based microdevices were also characterized up to 300 million cycles. Finally, the biofouling removal capabilities of magnetically powered microdevices were demonstrated using bovine serum albumin and bioconjugated microbeads. Our results indicate that these thin-film microdevices are capable of significantly reducing the amount of biofouling. At the same time, we demonstrated that these microdevices are mechanically robust enough to withstand a large number of actuation cycles during its chronic implantation

A simple method for directional transcriptome sequencing using Illumina technology.

High-throughput sequencing of cDNA has been used to study eukaryotic transcription on a genome-wide scale to single base pair resolution. In order to compensate for the high ribonuclease activity in bacterial cells, we have devised an equivalent technique optimized for studying complete prokaryotic transcriptomes that minimizes the manipulation of the RNA sample. This new approach uses Illumina technology to sequence single-stranded (ss) cDNA, generating information on both the direction and level of transcription throughout the genome. The protocol, and associated data analysis programs, are freely available from http://www.sanger.ac.uk/Projects/Pathogens/Transcriptome/. We have successfully applied this method to the bacterial pathogens Salmonella bongori and Streptococcus pneumoniae and the yeast Schizosaccharomyces pombe. This method enables experimental validation of genetic features predicted in silico and allows the easy identification of novel transcripts throughout the genome. We also show that there is a high correlation between the level of gene expression calculated from ss-cDNA and double-stranded-cDNA sequencing, indicting that ss-cDNA sequencing is both robust and appropriate for use in quantitative studies of transcription. Hence, this simple method should prove a useful tool in aiding genome annotation and gene expression studies in both prokaryotes and eukaryotes

The deglacial history of 79N glacier and the Northeast Greenland Ice Stream

Acknowledgements This work was funded by NERC Standard Grant NE/N011228/1. We thank the Alfred Wegner Institute, and particularly Hicham Rafiq and Daniel Steinhage, for their significant logistic support through the iGRIFF project. Additional support was provided from Station Nord (Jørgen Skafte), Nordland Air, Air Greenland, the Joint Arctic Command and the Department of Geography, Durham University. Naalakkersuisut, Government of Greenland, provided Scientific Survey (VU-00121) and Export (046/2017) licences for this work. We would also like to thank our Field Ranger Isak (Nanu-Travel) and dog Ooni for keeping us safe in the field. TCN Sample preparation was carried out at the National Environmental Isotope Facility, Scottish Universities Environmental Research Centre under grant allocation 9185.0814. Chris Orton in the Cartographic Unit, Geography, Durham University edited several figures. This paper is dedicated to Mr Arnold Jones – a true Quaternarist.Peer reviewe