Adipokines as uremic toxins.

The adipose tissue has pleiotropic functions far beyond the mere storage of energy, and it secretes a number of hormones and cytokines, called adipokines, which have biological effects that impact heath and disease. Adipokines are markedly elevated in the plasma of uremic patients, mainly due to decreased renal excretion. They have pluripotent signaling effects on inflammation/oxidative stress (leptin, adiponectin, resistin), protein-energy wasting (leptin, adiponectin), insulin signaling (adiponectin, leptin, visfatin), endothelial dysfunction (visfatin), and vascular damage (adiponectin, leptin, resistin), which are prevalent in uremic patients. Obesity superimposed to uremia may further aggravate hyperadipokinemia, with the exception of adiponectinemia, which is mitigated by adiposity. Among adipokines and until more data become available, only leptin may be considered as a full uremic toxin owing to adverse effects on protein-energy wasting, cardiovascular damage, inflammation, and the immune system, which have been documented both clinically and experimentally. Resistin and visfatin display some features of uremic toxins, but more data are needed to consider these adipokines as true uremic toxins. In contrast, high levels of adiponectin and chemerin seen in uremia appear to be beneficial. Further research is needed to investigate whether selective removal of leptin, resistin, and visfatin and increments of adiponectin and chemerin levels may have clinical relevance in uremic patients.

An Experimental Validation of a Statistical-Based Damage Detection Approach, January 2011

In this work, a previously-developed, statistical-based, damage-detection approach was validated for its ability to autonomously detect damage in bridges. The damage-detection approach uses statistical differences in the actual and predicted behavior of the bridge caused under a subset of ambient trucks. The predicted behavior is derived from a statistics-based model trained with field data from the undamaged bridge (not a finite element model). The differences between actual and predicted responses, called residuals, are then used to construct control charts, which compare undamaged and damaged structure data. Validation of the damage-detection approach was achieved by using sacrificial specimens that were mounted to the bridge and exposed to ambient traffic loads and which simulated actual damage-sensitive locations. Different damage types and levels were introduced to the sacrificial specimens to study the sensitivity and applicability. The damage-detection algorithm was able to identify damage, but it also had a high false-positive rate. An evaluation of the sub-components of the damage-detection methodology and methods was completed for the purpose of improving the approach. Several of the underlying assumptions within the algorithm were being violated, which was the source of the false-positives. Furthermore, the lack of an automatic evaluation process was thought to potentially be an impediment to widespread use. Recommendations for the improvement of the methodology were developed and preliminarily evaluated. These recommendations are believed to improve the efficacy of the damage-detection approach.

Western Iowa Missouri River Flooding -- Geo-Infrastructure Damage Assessment, Repair and Mitigation Strategies, TR-638, 2013

The 2011 Missouri River flooding caused significant damage to many geo-infrastructure systems including levees, bridge abutments/foundations, paved and unpaved roadways, culverts, and embankment slopes in western Iowa. The flooding resulted in closures of several interchanges along Interstate 29 and of more than 100 miles of secondary roads in western Iowa, causing severe inconvenience to residents and losses to local businesses. The main goals of this research project were to assist county and city engineers by deploying and using advanced technologies to rapidly assess the damage to geo-infrastructure and develop effective repair and mitigation strategies and solutions for use during future flood events in Iowa. The research team visited selected sites in western Iowa to conduct field reconnaissance, in situ testing on bridge abutment backfills that were affected by floods, flooded and non-flooded secondary roadways, and culverts. In situ testing was conducted shortly after the flood waters receded, and several months after flooding to evaluate recovery and performance. Tests included falling weight deflectometer, dynamic cone penetrometer, three-dimensional (3D) laser scanning, ground penetrating radar, and hand auger soil sampling. Field results indicated significant differences in roadway support characteristics between flooded and non-flooded areas. Support characteristics in some flooded areas recovered over time, while others did not. Voids were detected in culvert and bridge abutment backfill materials shortly after flooding and several months after flooding. A catalog of field assessment techniques and 20 potential repair/mitigation solutions are provided in this report. A flow chart relating the damages observed, assessment techniques, and potential repair/mitigation solutions is provided. These options are discussed for paved/unpaved roads, culverts, and bridge abutments, and are applicable for both primary and secondary roadways.

Different types of cell death are involved in brain damage of methylmalonic aciduria and glutaric aciduria type I

We previously showed that exposure of 3D organotypic rat brain cell cultures to 1mM 2-methylcitrate (2-MCA) or 3-hydroxyglutarate (3- OHGA) every 12h over three days (DIV11-DIV14) results in ammonium accumulation and cell death. The aim of this study was to define the time course (every 24h) of the observed effects. Ammonium in culture medium already increased at DIV12 staying stable on the following days under 3-OHGA exposure, while it increased consecutively up to much higher levels under 2-MCA exposure. Lactate increase and glucose decrease were observed from DIV13 and DIV14, respectively. We conclude that ammonium accumulation precedes alterations of energy metabolism. As observed by immunohistochemistry glial cells were the predominant dying cells. Immunoblotting and immunohistochemistry with cell death specific markers (caspase-3, alpha-fodrin, LC3) showed that 2-MCA exposure significantly increased apoptosis on DIV14, but did not alter autophagy or necrosis. In contrast, 3-OHGA exposure substantially increased necrosis already from DIV13, while no change was observed for apoptosis and autophagy. In conclusion, ammonium accumulation, secondary disturbance of energy metabolism and glial cell death are involved in the neuropathogenesis ofmethylmalonic aciduria and glutaric aciduria type I. Interestingly, brain cells are dying by necrosis under 3-OHGA exposure and by apoptosis under 2-MCA exposure.

Using spatially distributed parameters and multi-response objective functions to solve parameterization of complex applications of semi-distributed hydrological models

Application of semi-distributed hydrological models to large, heterogeneous watersheds deals with several problems. On one hand, the spatial and temporal variability in catchment features should be adequately represented in the model parameterization, while maintaining the model complexity in an acceptable level to take advantage of state-of-the-art calibration techniques. On the other hand, model complexity enhances uncertainty in adjusted model parameter values, therefore increasing uncertainty in the water routing across the watershed. This is critical for water quality applications, where not only streamflow, but also a reliable estimation of the surface versus subsurface contributions to the runoff is needed. In this study, we show how a regularized inversion procedure combined with a multiobjective function calibration strategy successfully solves the parameterization of a complex application of a water quality-oriented hydrological model. The final value of several optimized parameters showed significant and consistentdifferences across geological and landscape features. Although the number of optimized parameters was significantly increased by the spatial and temporal discretization of adjustable parameters, the uncertainty in water routing results remained at reasonable values. In addition, a stepwise numerical analysis showed that the effects on calibration performance due to inclusion of different data types in the objective function could be inextricably linked. Thus caution should be taken when adding or removing data from an aggregated objective function.

GAP-independent functions of DLC1 in metastasis.

Metastases are responsible for most cancer-related deaths. One of the hallmarks of metastatic cells is increased motility and migration through extracellular matrixes. These processes rely on specific small GTPases, in particular those of the Rho family. Deleted in liver cancer-1 (DLC1) is a tumor suppressor that bears a RhoGAP activity. This protein is lost in most cancers, allowing malignant cells to proliferate and disseminate in a Rho-dependent manner. However, DLC1 is also a scaffold protein involved in alternative pathways leading to tumor and metastasis suppressor activities. Recently, substantial information has been gathered on these mechanisms and this review is aiming at describing the potential and known alternative GAP-independent mechanisms allowing DLC1 to impair migration, invasion, and metastasis formation.

On the spot damage detection methodology for highway bridges (tech transfer summary)

The objective of this work was to develop a low-cost portable damage detection tool to assess and predict damage areas in highway bridges. The proposed tool was based on standard vibration-based damage identification (VBDI) techniques but was extended to a new approach based on operational traffic load. The methodology was tested using numerical simulations, laboratory experiments, and field testing.

IRF4 and BATF are critical for CD8(+) T-cell function following infection with LCMV.

CD8(+) T-cell functions are critical for preventing chronic viral infections by eliminating infected cells. For healthy immune responses, beneficial destruction of infected cells must be balanced against immunopathology resulting from collateral damage to tissues. These processes are regulated by factors controlling CD8(+) T-cell function, which are still incompletely understood. Here, we show that the interferon regulatory factor 4 (IRF4) and its cooperating binding partner B-cell-activating transcription factor (BATF) are necessary for sustained CD8(+) T-cell effector function. Although Irf4(-/-) CD8(+) T cells were initially capable of proliferation, IRF4 deficiency resulted in limited CD8(+) T-cell responses after infection with the lymphocytic choriomeningitis virus. Consequently, Irf4(-/-) mice established chronic infections, but were protected from fatal immunopathology. Absence of BATF also resulted in reduced CD8(+) T-cell function, limited immunopathology, and promotion of viral persistence. These data identify the transcription factors IRF4 and BATF as major regulators of antiviral cytotoxic T-cell immunity.

Web decoration of Micrathena sexpinosa (Araneae: Araneidae): a frame-web-choice experiment with stingless bees

The function of silk web decorations in orb weaving spiders has been debated for decades. The most accepted hypothesized functions are that web decorations I) provide camouflage against predators, 2) are an advertisement for vertebrates to avoid web damage, or 3) increase the attraction of prey to the web. Most studies have focused on only a few genera, Argiope being the most common. In this study, I evaluated the prey attraction hypothesis of silk decorations for a species of a poorly studied genus in this topic, Micrathena sexpinosa Hahn 1822. I used a web-choice experiment in which I presented empty or web-bearing frames at the end of a tunnel to stingless bees (Tetragonisca angustula). This frame-choice experiment consisted of the following comparisons: decorated web vs. empty frame, decorated web vs. undecorated web, and undecorated web vs. empty frame. Webs with decoration intercepted significantly more bees than empty frames and undecorated webs. Therefore, the decorations of Micrathena sexpinosa might play a role in increasing foraging success.

Spatial organization of nucleotide excision repair proteins after UV-induced DNA damage in the human cell nucleus.

Nucleotide excision repair (NER) is an evolutionary conserved DNA repair system that is essential for the removal of UV-induced DNA damage. In this study we investigated how NER is compartmentalized in the interphase nucleus of human cells at the ultrastructural level by using electron microscopy in combination with immunogold labeling. We analyzed the role of two nuclear compartments: condensed chromatin domains and the perichromatin region. The latter contains transcriptionally active and partly decondensed chromatin at the surface of condensed chromatin domains. We studied the distribution of the damage-recognition protein XPC and of XPA, which is a central component of the chromatin-associated NER complex. Both XPC and XPA rapidly accumulate in the perichromatin region after UV irradiation, whereas only XPC is also moderately enriched in condensed chromatin domains. These observations suggest that DNA damage is detected by XPC throughout condensed chromatin domains, whereas DNA-repair complexes seem preferentially assembled in the perichromatin region. We propose that UV-damaged DNA inside condensed chromatin domains is relocated to the perichromatin region, similar to what has been shown for DNA replication. In support of this, we provide evidence that UV-damaged chromatin domains undergo expansion, which might facilitate the translocation process. Our results offer novel insight into the dynamic spatial organization of DNA repair in the human cell nucleus.