Wharton’s jelly-derived mesenchymal stromal cells as a promising cellular therapeutic strategy for the management of graft-versus-host disease

Citation: McGuirk, J. P., Robert Smith, J., Divine, C. L., Zuniga, M., & Weiss, M. L. (2015). Wharton’s jelly-derived mesenchymal stromal cells as a promising cellular therapeutic strategy for the management of graft-versus-host disease. Pharmaceuticals, 8(2), 196-220. doi:10.3390/ph8020196Allogeneic hematopoietic cell transplantation (allo-HCT), a treatment option in hematologic malignancies and bone marrow failure syndromes, is frequently complicated by Graft-versus-host disease (GVHD). The primary treatment for GVHD involves immune suppression by glucocorticoids. However, patients are often refractory to the steroid therapy, and this results in a poor prognosis. Therefore alternative therapies are needed to treat GVHD. Here, we review data supporting the clinical investigation of a novel cellular therapy using Wharton’s jelly (WJ)-derived mesenchymal stromal cells (MSCs) as a potentially safe and effective therapeutic strategy in the management of GVHD. Adult-derived sources of MSCs have demonstrated signals of efficacy in the management of GVHD. However, there are limitations, including: limited proliferation capacity; heterogeneity of cell sources; lengthy expansion time to clinical dose; expansion failure in vitro; and a painful, invasive, isolation procedure for the donor. Therefore, alternative MSC sources for cellular therapy are sought. The reviewed data suggests MSCs derived from WJ may be a safe and effective cellular therapy for GVHD. Laboratories investigated and defined the immune properties of WJ-MSCs for potential use in cellular therapy. These cells represent a more uniform cell population than bone marrow-derived MSCs, displaying robust immunosuppressive properties and lacking significant immunogenicity. They can be collected safely and painlessly from individuals at birth, rapidly expanded and stored cryogenically for later clinical use. Additionally, data we reviewed suggested licensing MSCs (activating MSCs by exposure to cytokines) to enhance effectiveness in treating GVHD. Therefore, WJCs should be tested as a second generation, relatively homogeneous allogeneic cell therapy for the treatment of GVHD. © 2015 by the authors; licensee MDPI, Basel, Switzerland

Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB’s role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors

Systemic Inhibition of Tissue-Nonspecific Alkaline Phosphatase Alters the Brain-Immune Axis in Experimental Sepsis

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitous enzyme present in many cells and tissues, including the central nervous system. Yet its functions at the brain-immune axis remain unclear. The goal of this study was to use a novel small molecular inhibitor of TNAP, SBI-425, to interrogate the function of TNAP in neuroimmune disorders. Following intraperitoneal (IP) administration of SBI-425, mass spectrometry analysis revealed that the SBI-425 does not cross the blood-brain barrier (BBB) in healthy mice. To elucidate the role of TNAP at the brain-immune axis, mice were subjected to experimental sepsis and received either vehicle or SBI-425 (25 mg/kg, IP) daily for 7 days. While SBI-425 administration did not affect clinical severity outcomes, we found that SBI-425 administration suppressed CD4 + Foxp3+ CD25− and CD8 + Foxp3+ CD25− splenocyte T-cell populations compared to controls. Further evaluation of SBI-425’s effects in the brain revealed that TNAP activity was suppressed in the brain parenchyma of SBI-425-treated mice compared to controls. When primary brain endothelial cells were treated with a proinflammatory stimulus the addition of SBI-425 treatment potentiated the loss of barrier function in BBB endothelial cells. To further demonstrate a protective role for TNAP at endothelial barriers within this axis, transgenic mice with a conditional overexpression of TNAP were subjected to experimental sepsis and found to have increased survival and decreased clinical severity scores compared to controls. Taken together, these results demonstrate a novel role for TNAP activity in shaping the dynamic interactions within the brain-immune axis

Overview of the New Horizons Science Payload

The New Horizons mission was launched on 2006 January 19, and the spacecraft is heading for a flyby encounter with the Pluto system in the summer of 2015. The challenges associated with sending a spacecraft to Pluto in less than 10 years and performing an ambitious suite of scientific investigations at such large heliocentric distances (> 32 AU) are formidable and required the development of lightweight, low power, and highly sensitive instruments. This paper provides an overview of the New Horizons science payload, which is comprised of seven instruments. Alice provides spatially resolved ultraviolet spectroscopy. The Ralph instrument has two components: the Multicolor Visible Imaging Camera (MVIC), which performs panchromatic and color imaging, and the Linear Etalon Imaging Spectral Array (LEISA), which provides near-infrared spectroscopic mapping capabilities. The Radio Experiment (REX) is a component of the New Horizons telecommunications system that provides both occultation and radiometry capabilities. The Long Range Reconnaissance Imager (LORRI) provides high sensitivity, high spatial resolution optical imaging capabilities. The Solar Wind at Pluto (SWAP) instrument measures the density and speed of solar wind particles. The Pluto Energetic Particle Spectrometer Science Investigation (PEPSSI) measures energetic protons and CNO ions. The Venetia Burney Student Dust Counter (VB-SDC) is used to record dust particle impacts during the cruise phases of the mission.Comment: 17 pages, 4 figures, 1 table; To appear in a special volume of Space Science Reviews on the New Horizons missio

Dynamic contrast enhanced (DCE) MRI estimation of vascular parameters using knowledge-based adaptive models

We introduce and validate four adaptive models (AMs) to perform a physiologically based Nested-Model-Selection (NMS) estimation of such microvascular parameters as forward volumetric transfer constant, K(trans), plasma volume fraction, v(p), and extravascular, extracellular space, v(e), directly from Dynamic Contrast-Enhanced (DCE) MRI raw information without the need for an Arterial-Input Function (AIF). In sixty-six immune-compromised-RNU rats implanted with human U-251 cancer cells, DCE-MRI studies estimated pharmacokinetic (PK) parameters using a group-averaged radiological AIF and an extended Patlak-based NMS paradigm. One-hundred-ninety features extracted from raw DCE-MRI information were used to construct and validate (nested-cross-validation, NCV) four AMs for estimation of model-based regions and their three PK parameters. An NMS-based a priori knowledge was used to fine-tune the AMs to improve their performance. Compared to the conventional analysis, AMs produced stable maps of vascular parameters and nested-model regions less impacted by AIF-dispersion. The performance (Correlation coefficient and Adjusted R-squared for NCV test cohorts) of the AMs were: 0.914/0.834, 0.825/0.720, 0.938/0.880, and 0.890/0.792 for predictions of nested model regions, v(p), K(trans), and v(e), respectively. This study demonstrates an application of AMs that quickens and improves DCE-MRI based quantification of microvasculature properties of tumors and normal tissues relative to conventional approaches

Implications of surface flooding on airborne estimates of snow depth on sea ice

Snow depth observations from airborne snow radars, such as the NASA's Operation IceBridge (OIB) mission, have recently been used in altimeter-derived sea ice thickness estimates, as well as for model parameterization. A number of validation studies comparing airborne and in situ snow depth measurements have been conducted in the western Arctic Ocean, demonstrating the utility of the airborne data. However, there have been no validation studies in the Atlantic sector of the Arctic. Recent observations in this region suggest a significant and predominant shift towards a snow-ice regime caused by deep snow on thin sea ice. During the Norwegian young sea Ice, Climate and Ecosystems (ICE) expedition (N-ICE2015) in the area north of Svalbard, a validation study was conducted on 19 March 2015. This study collected ground truth data during an OIB overflight. Snow and ice thickness measurements were obtained across a two-dimensional (2-D) 400 m × 60 m grid. Additional snow and ice thickness measurements collected in situ from adjacent ice floes helped to place the measurements obtained at the gridded survey field site into a more regional context. Widespread negative freeboards and flooding of the snowpack were observed during the N-ICE2015 expedition due to the general situation of thick snow on relatively thin sea ice. These conditions caused brine wicking into and saturation of the basal snow layers. This causes the airborne radar signal to undergo more diffuse scattering, resulting in the location of the radar main scattering horizon being detected well above the snow–ice interface. This leads to a subsequent underestimation of snow depth; if only radar-based information is used, the average airborne snow depth was 0.16 m thinner than that measured in situ at the 2-D survey field. Regional data within 10 km of the 2-D survey field suggested however a smaller deviation between average airborne and in situ snow depth, a 0.06 m underestimate in snow depth by the airborne radar, which is close to the resolution limit of the OIB snow radar system. Our results also show a broad snow depth distribution, indicating a large spatial variability in snow across the region. Differences between the airborne snow radar and in situ measurements fell within the standard deviation of the in situ data (0.15–0.18 m). Our results suggest that seawater flooding of the snow–ice interface leads to underestimations of snow depth or overestimations of sea ice freeboard measured from radar altimetry, in turn impacting the accuracy of sea ice thickness estimates.</p

Tracking animal movements using biomarkers in tail hairs: a novel approach for animal geolocating from sulfur isoscapes.

This research article published by Movement Ecology, 2020Background Current animal tracking studies are most often based on the application of external geolocators such as GPS and radio transmitters. While these technologies provide detailed movement data, they are costly to acquire and maintain, which often restricts sample sizes. Furthermore, deploying external geolocators requires physically capturing and recapturing of animals, which poses an additional welfare concern. Natural biomarkers provide an alternative, non-invasive approach for addressing a range of geolocation questions and can, because of relatively low cost, be collected from many individuals thereby broadening the scope for population-wide inference. Methods We developed a low-cost, minimally invasive method for distinguishing between local versus non-local movements of cattle using sulfur isotope ratios (δ34S) in cattle tail hair collected in the Greater Serengeti Ecosystem, Tanzania. Results We used a Generalized Additive Model to generate a predicted δ34S isoscape across the study area. This isoscape was constructed using spatial smoothers and underpinned by the positive relationship between δ34S values and lithology. We then established a strong relationship between δ34S from recent sections of cattle tail hair and the δ34S from grasses sampled in the immediate vicinity of an individual’s location, suggesting δ34S in the hair reflects the δ34S in the environment. By combining uncertainty in estimation of the isoscape, with predictions of tail hair δ34S given an animal’s position in the isoscape we estimated the anisotropic distribution of travel distances across the Serengeti ecosystem sufficient to detect movement using sulfur stable isotopes. Conclusions While the focus of our study was on cattle, this approach can be modified to understand movements in other mobile organisms where the sulfur isoscape is sufficiently heterogeneous relative to the spatial scale of animal movements and where tracking with traditional methods is difficult

Ethnic Speech and Ethnic Action as Ethnic Behavior: Part 1. Construction of the Brunel Ethnic Behavior Inventory

© 2016 Taylor & Francis.This article reports the construction of a new survey—specifically, the Brunel Ethnic Behavior Inventory (BEBI)—designed to measure ethnic speech and ethnic action as separate, yet related, aspects of individuals’ ethnic behavior. Using Tajfel’s social identity theory as a conceptual frame of reference, this study sought an answer to the research question of how many factors actually are measured by the BEBI, and tested the hypothesis that a two-factor model (i.e., Ethnic Speech and Ethnic Action as two correlated factors) would provide significantly better goodness of fit to the correlational data than would a one-factor model (i.e., Ethnic Behavior as one undifferentiated factor). Across one pilot sample (n = 101) and two main samples (n = 120 for Sample 1, n = 148 for Sample 2), the study found that not only did the BEBI measure two factors at most (i.e., Ethnic Speech and Ethnic Action) but, consistent with the hypothesis, the two-factor model yielded better goodness of fit than did the one-factor model. Implications for the conceptualization and measurement of Verkuyten’s “ways of ethnicity” are discussed

US hegemony and the origins of Japanese nuclear power : the politics of consent

This paper deploys the Gramscian concepts of hegemony and consent in order to explore the process whereby nuclear power was brought to Japan. The core argument is that nuclear power was brought to Japan as a consequence of US hegemony. Rather than a simple manifestation of one state exerting material ‘power over' another, bringing nuclear power to Japan involved a series of compromises worked out within and between state and civil society in both Japan and the USA. Ideologies of nationalism, imperialism and modernity underpinned the process, coalescing in post-war debates about the future trajectory of Japanese society, Japan's Cold War alliance with the USA and the role of nuclear power in both. Consent to nuclear power was secured through the generation of a psychological state in the public mind combining the fear of nuclear attack and the hope of unlimited consumption in a nuclear-fuelled post-modern world