Immune-Mediated Inflammation May Contribute to the Pathogenesis of Cardiovascular Disease in Mucopolysaccharidosis Type I.

BackgroundCardiovascular disease, a progressive manifestation of α-L-iduronidase deficiency or mucopolysaccharidosis type I, continues in patients both untreated and treated with hematopoietic stem cell transplantation or intravenous enzyme replacement. Few studies have examined the effects of α-L-iduronidase deficiency and subsequent glycosaminoglycan storage upon arterial gene expression to understand the pathogenesis of cardiovascular disease.MethodsGene expression in carotid artery, ascending, and descending aortas from four non-tolerized, non-enzyme treated 19 month-old mucopolysaccharidosis type I dogs was compared with expression in corresponding vascular segments from three normal, age-matched dogs. Data were analyzed using R and whole genome network correlation analysis, a bias-free method of categorizing expression level and significance into discrete modules. Genes were further categorized based on module-trait relationships. Expression of clusterin, a protein implicated in other etiologies of cardiovascular disease, was assessed in canine and murine mucopolysaccharidosis type I aortas via Western blot and in situ immunohistochemistry.ResultsGene families with more than two-fold, significant increased expression involved lysosomal function, proteasome function, and immune regulation. Significantly downregulated genes were related to cellular adhesion, cytoskeletal elements, and calcium regulation. Clusterin gene overexpression (9-fold) and protein overexpression (1.3 to 1.62-fold) was confirmed and located specifically in arterial plaques of mucopolysaccharidosis-affected dogs and mice.ConclusionsOverexpression of lysosomal and proteasomal-related genes are expected responses to cellular stress induced by lysosomal storage in mucopolysaccharidosis type I. Upregulation of immunity-related genes implicates the potential involvement of glycosaminoglycan-induced inflammation in the pathogenesis of mucopolysaccharidosis-related arterial disease, for which clusterin represents a potential biomarker

Autonomy Infused Teleoperation with Application to BCI Manipulation

Robot teleoperation systems face a common set of challenges including latency, low-dimensional user commands, and asymmetric control inputs. User control with Brain-Computer Interfaces (BCIs) exacerbates these problems through especially noisy and erratic low-dimensional motion commands due to the difficulty in decoding neural activity. We introduce a general framework to address these challenges through a combination of computer vision, user intent inference, and arbitration between the human input and autonomous control schemes. Adjustable levels of assistance allow the system to balance the operator's capabilities and feelings of comfort and control while compensating for a task's difficulty. We present experimental results demonstrating significant performance improvement using the shared-control assistance framework on adapted rehabilitation benchmarks with two subjects implanted with intracortical brain-computer interfaces controlling a seven degree-of-freedom robotic manipulator as a prosthetic. Our results further indicate that shared assistance mitigates perceived user difficulty and even enables successful performance on previously infeasible tasks. We showcase the extensibility of our architecture with applications to quality-of-life tasks such as opening a door, pouring liquids from containers, and manipulation with novel objects in densely cluttered environments

Understanding Unauthorized Access using Fine-Grained Human-Computer Interaction Data

Unauthorized Data Access (UDA) by an internal employee is a major threat to an organization. Regardless of whether the individuals engaged in UDA with malicious intent or not, real-time identification of UDA events and anomalous behaviors is extremely difficult. For example, various artificial intelligence methods for detecting insider threat UDA have become readily available; while useful, such methods rely on post hoc analysis of the past (e.g., unsupervised learning algorithms on access logs). This research-in-progress note reports on if the analysis of Human-Computer Interaction (HCI) behaviors, which have been empirically validated in various studies to reveal hidden cognitive state, can be utilized as a method to detect UDAs. To examine this, an experimental design was required that would grant the subjects an opportunity to engage in UDA events while tracking the HCI behaviors in an unobtrusive manner. Background, experimental design, study execution, preliminary results, and future research plans are presented

Building on the past, shaping the future: The environmental mutagenesis and genomics society

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97167/1/em21765.pd

Wolverine Gene Flow Across a Narrow Climatic Niche

Wolverines (Guio guio) are one of the rarest carnivores in the contiguous United States. Effective population sizes in Montana, Idaho, and Wyoming, where most of the wolverines in the contiguous United States exist, were calculated to be 35 (credible limits, 28 52) suggesting low abundance. Landscape features that influence wolverine population substructure and gene flow are largely unknown. Recent work has identified strong associations between areas with persistent spring snow and wolverine presence and range. We tested whether a dispersal model in which wolverines prefer to disperse through areas characterized by persistent spring snow cover produced least-cost paths among all individuals that correlated with genetic distance among individuals. Models simulating large preferences for dispersing within areas characterized by persistent spring snow explained the data better than a model based on Euclidean distance. Partial Mantel tests separating Euclidean distance from spring snow-cover-based effects indicated that Euclidean distance was not significant in describing patterns of genetic distance. Because these models indicated that successful dispersal paths followed areas characterized by spring snow cover, we used these understandings to derive empirically based least-cost corridor maps in the U.S. Rocky Mountains. These corridor maps largely explain previously published population subdivision patterns based on mitochondrial DNA and indicate that natural colonization of the southern Rocky Mountains by wolverines will be difficult but not impossible

Thermocapillary actuation of liquid flow on chemically patterned surfaces

We have investigated the thermocapillary flow of a Newtonian liquid on hydrophilic microstripes which are lithographically defined on a hydrophobic surface. The speed of the microstreams is studied as a function of the stripe width w, the applied thermal gradient |dT/dx| and the liquid volume V deposited on a connecting reservoir pad. Numerical solutions of the flow speed as a function of downstream position show excellent agreement with experiment. The only adjustable parameter is the inlet film height, which is controlled by the ratio of the reservoir pressure to the shear stress applied to the liquid stream. In the limiting cases where this ratio is either much smaller or much larger than unity, the rivulet speed shows a power law dependency on w, |dT/dx| and V. In this study we demonstrate that thermocapillary driven flow on chemically patterned surfaces can provide an elegant and tunable method for the transport of ultrasmall liquid volumes in emerging microfluidic technologies

Extremely Large Area (88 mm X 88 mm) Superconducting Integrated Circuit (ELASIC)

Superconducting integrated circuit (SIC) is a promising "beyond-CMOS" device technology enables speed-of-light, nearly lossless communications to advance cryogenic (4 K or lower) computing. However, the lack of large-area superconducting IC has hindered the development of scalable practical systems. Herein, we describe a novel approach to interconnect 16 high-resolution deep UV (DUV EX4, 248 nm lithography) full reticle circuits to fabricate an extremely large (88mm X 88 mm) area superconducting integrated circuit (ELASIC). The fabrication process starts by interconnecting four high-resolution DUV EX4 (22 mm X 22 mm) full reticles using a single large-field (44 mm X 44 mm) I-line (365 nm lithography) reticle, followed by I-line reticle stitching at the boundaries of 44 mm X 44 mm fields to fabricate the complete ELASIC field (88 mm X 88 mm). The ELASIC demonstrated a 2X-12X reduction in circuit features and maintained high-stitched line superconducting critical currents. We examined quantum flux parametron (QFP) circuits to demonstrate the viability of common active components used for data buffering and transmission. Considering that no stitching requirement for high-resolution EX4 DUV reticles is employed, the present fabrication process has the potential to advance the scaling of superconducting quantum devices

The Persistence of Cool Galactic Winds in High Stellar Mass Galaxies Between z~1.4 and ~1

We present an analysis of the MgII 2796, 2803 and FeII 2586, 2600 absorption line profiles in coadded spectra of 468 galaxies at 0.7 < z < 1.5. The galaxy sample, drawn from the Team Keck Treasury Redshift Survey of the GOODS-N field, has a range in stellar mass (M_*) comparable to that of the sample at z~1.4 analyzed in a similar manner by Weiner et al. (2009; W09), but extends to lower redshifts and has specific star formation rates which are lower by ~0.6 dex. We identify outflows of cool gas from the Doppler shift of the MgII absorption lines and find that the equivalent width (EW) of absorption due to outflowing gas increases on average with M_* and star formation rate (SFR). We attribute the large EWs measured in spectra of the more massive, higher-SFR galaxies to optically thick absorbing clouds having large velocity widths. The outflows have hydrogen column densities N(H) > 10^19.3 cm^-2, and extend to velocities of ~500 km/s. While galaxies with SFR > 10 Msun/yr host strong outflows in both this and the W09 sample, we do not detect outflows in lower-SFR (i.e., log M_*/Msun < 10.5) galaxies at lower redshifts. Using a simple galaxy evolution model which assumes exponentially declining SFRs, we infer that strong outflows persist in galaxies with log M_*/Msun > 10.5 as they age between z=1.4 and z~1, presumably because of their high absolute SFRs. Finally, using high resolution HST/ACS imaging in tandem with our spectral analysis, we find evidence for a weak trend (at 1 sigma significance) of increasing outflow absorption strength with increasing galaxy SFR surface density.Comment: Submitted to ApJ. 25 pages, 19 figures, Figure 2 reduced in resolution. Uses emulateapj forma

Recovery of Wolverines in the Western United States: Recent Extirpation and Recolonization or Range Retraction and Expansion?

Wolverines were greatly reduced in number and possibly extirpated from the contiguous United States (U.S.) by the early 1900s. Wolverines currently occupy much of their historical range in Washington, Idaho, Montana, and Wyoming, but are absent from Utah and only single individuals are known to occur in California and Colorado. In response, the translocation of wolverines to California and Colorado is being considered. If wolverines are to be reintroduced, managers must identify appropriate source populations based on the genetic affinities of historical and modern wolverine populations. We amplified the mitochondrial control region of 13 museum specimens dating from the late 1800s to early 1900s and 209 wolverines from modern populations in the contiguous U.S. and Canada and combined results with previously published haplotypes. Collectively, these data indicated that historical wolverine populations in the contiguous U.S. were extirpated by the early 20th century, and that modern populations in the contiguous U.S. are likely the descendants of recent immigrants from the north. The Cali1 haplotype previously identified in California museum specimens was also common in historical samples from the southern Rocky Mountains, and likely evolved in isolation in the southern ice-free refugium that encompassed most of the contiguous U.S. during the last glaciation. However, when southern populations were extirpated, these matrilines were eliminated. Several of the other haplotypes found in historical specimens from the contiguous U.S. also occur in modern North American populations, and belong to a group of haplotypes that are associated with the rapid expansion of northern wolverine populations after the last glacial retreat. Modern wolverines in the contiguous U.S. are primarily haplotype A, which is the most common and widespread haplotype in Canada and Alaska. For the translocation of wolverines to California, Colorado, and other areas in the western U.S., potential source populations in the Canadian Rocky Mountains may provide the best mix of genetic diversity and appropriate learned behavior

Severe Sepsis: Variation in Resource and Therapeutic Modality use Among Academic Centers

Background: Treatment of severe sepsis is expensive, often encompassing a number of discretionary modalities. The objective of the present study was to assess intercenter variation in resource and therapeutic modality use in patients with severe sepsis. Methods: We conducted a prospective cohort study of 1028 adult admissions with severe sepsis from a stratified random sample of patients admitted to eight academic tertiary care centers. The main outcome measures were length of stay (LOS; total LOS and LOS after onset of severe sepsis) and total hospital charges. Results: The adjusted mean total hospital charges varied from $69 429 to US$237 898 across centers, whereas the adjusted LOS after onset varied from 15.9 days to 24.2 days per admission. Treatments used frequently after the first onset of sepsis among patients with severe sepsis were pulmonary artery catheters (19.4%), ventilator support (21.8%), pressor support (45.8%) and albumin infusion (14.4%). Pulmonary artery catheter use, ventilator support and albumin infusion had moderate variation profiles, varying 3.2-fold to 4.9-fold, whereas the rate of pressor support varied only 1.92-fold across centers. Even after adjusting for age, sex, Charlson comorbidity score, discharge diagnosis-relative group weight, organ dysfunction and service at onset, the odds for using these therapeutic modalities still varied significantly across centers. Failure to start antibiotics within 24 hours was strongly correlated with a higher probability of 28-day mortality (r2 = 0.72). Conclusion: These data demonstrate moderate but significant variation in resource use and use of technologies in treatment of severe sepsis among academic centers. Delay in antibiotic therapy was associated with worse outcome at the center level