Differentiation of 3-O-Sulfated Heparin Disaccharide Isomers: Identification of Structural Aspects of the Heparin CCL2 Binding Motif

The presence of 3-O-sulfated glucosamine residues in heparin or heparan sulfate plays a role in binding to antithrombin III and HSV infection. In this study, tandem mass spectrometry was used to differentiate between two heparin disaccharide isomers containing variable sulfate at C6 in a common disaccharide and C3 in a more rare one. The dissociation patterns shown by MS2 and MS3 were clearly distinguishable between the isomers, allowing their differentiation and quantitation. Using this technique, we show that an octasaccharide with 11 sulfate groups with high affinity for inflammatory chemokine CCL2 does not contain 3-O-sulfated disaccharides

Light-dependent grazing can drive formation and deepening of deep chlorophyll maxima

© The Author(s), 2019. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Moeller, H. V., Laufkötter, C., Sweeney, E. M., & Johnson, M. D. Light-dependent grazing can drive formation and deepening of deep chlorophyll maxima. Nature Communications, 10(1), (2019):1978, doi:10.1038/s41467-019-09591-2.Deep Chlorophyll Maxima (DCMs) are subsurface peaks in chlorophyll-a concentration that may coincide with peaks in phytoplankton abundance and primary productivity. Work on the mechanisms underlying DCM formation has historically focused on phytoplankton physiology (e.g., photoacclimation) and behavior (e.g., taxis). While these mechanisms can drive DCM formation, they do not account for top-down controls such as predation by grazers. Here, we propose a new mechanism for DCM formation: Light-dependent grazing by microzooplankton reduces phytoplankton biomass near the surface but allows accumulation at depth. Using mathematical models informed by grazing studies, we demonstrate that light-dependent grazing is sufficient to drive DCM formation. Further, when acting in concert with other mechanisms, light-dependent grazing deepens the DCM, improving the fit of a global model with observational data. Our findings thus reveal another mechanism by which microzooplankton may regulate primary production, and impact our understanding of biogeochemical cycling at and above the DCM.We thank the Sea Education Association and the students and crew of SEA Cruise S272 for collecting and sharing CTD cast data from the South Pacific. We also thank M. Lepori-Bui for assistance in assembling grazing data, A. Mignot for sharing global DCM estimates, J.G. John for providing the COBALT control simulations, E.B. Olson, M.G. Neubert, C.A. Stock, and J.P. Dunne for advice on model formulation, and B.E. Harden for valuable discussion. We thank members of the UCSB EEMB Department for helpful feedback on earlier versions of this manuscript. H.V.M. gratefully acknowledges an NSF Postdoctoral Fellowship (DBI-1401332) and a UBC Biodiversity Center Postdoctoral Fellowship

Inhibitory Control Processes and the Strategies That Support Them during Hand and Eye Movements

Background and Aims: Adaptive behavior depends on the ability to voluntarily suppress context-inappropriate behaviors, a process referred to as response inhibition. Stop Signal tests (SSTs) are the most frequently studied paradigm used to assess response inhibition. Previous studies of SSTs have indicated that inhibitory control behavior can be explained using a common model in which GO and STOP processes are initiated independent from one and another, and the process that is completed first determines whether the behavior is elicited (GO process) or terminated (STOP process). Consistent with this model, studies have indicated that individuals strategically delay their behaviors during SSTs in order to increase their stopping abilities. Despite being controlled by distinct neural systems, prior studies have largely documented similar inhibitory control performance across eye and hand movements. Though, no existing studies have compared the extent to which individuals strategically delay behavior across different effectors is not yet clear. Here, we compared the extent to which inhibitory control processes and the cognitive strategies that support them during oculomotor and manual motor behaviors. Methods: We examined 29 healthy individuals who performed parallel oculomotor and manual motor SSTs. Participants also completed a separate block of GO trials administered prior to the Stop Signal tests to assess baseline reaction times for each effector and reaction time increases during interleaved GO trials of the SST. Results: Our results showed that stopping errors increased for both effectors as the interval between GO and STOP cues was increased (i.e., stop signal delay), but performance deteriorated more rapidly for eye compared to hand movements with increases in stop signal delay. During GO trials, participants delayed the initiation of their responses for each effector, and greater slowing of reaction times on GO trials was associated with increased accuracy on STOP trials for both effectors. However, participants delayed their eye movements to a lesser degree than their hand movements, and strategic reaction time slowing was a stronger determinant of stopping accuracy for hand compared to eye movements. Overall, stopping accuracies for eye and hand movements were only modestly correlated, and the time it took individuals to cancel a response was not related for eye and hand movements. Discussion and Conclusion: Our findings that GO and STOP processes are independent and that individuals strategically delay their behavioral responses to increase stopping accuracy regardless of effector indicate that inhibitory control of Frontiers in Psychology | www.frontiersin.org 1 December 2016 | Volume 7 | Article 1927 Schmitt et al. Inhibitory Control of Hand and Eye Movements oculomotor and manual motor behaviors both follow common guiding principles. Yet, our findings document that eye movements are more difficult to inhibit than hand movements, and the timing, magnitude, and impact of cognitive control strategies used to support voluntary response inhibition are less robust for eye compared to hand movements. This suggests that inhibitory control systems also show unique characteristics that are behavior-dependent. This conclusion is consistent with neurophysiological evidence showing important differences in the architecture and functional properties of the neural systems involved in inhibitory control of eye and hand movements. It also suggests that characterizing inhibitory control processes in health and disease requires effector-specific analysis.NIH Autism Center of Excellence P50HD055751; MH092696, and the Kansas Center for Autism Research and Training Research Investment Council Strategic Initiative Gran

Neurobehavioral Abnormalities in Firest-Degree Relative of Individuals With Autism

CONTEXT: Studying sensorimotor and neurocognitive impairments in unaffected family members of individuals with autism may help identify familial pathophysiological mechanisms associated with the disorder. OBJECTIVE: To determine whether atypical sensorimotor or neurocognitive characteristics associated with autism are present in first-degree relatives of individuals with autism. DESIGN: Case-control comparison of neurobehavioral functions. SETTING: University medical center. PARTICIPANTS: Fifty-seven first-degree relatives of individuals with autism and 40 age-, sex-, and IQ-matched healthy control participants (aged 8-54 years). MAIN OUTCOME MEASURES: Oculomotor tests of sensorimotor responses (saccades and smooth pursuit); procedural learning and response inhibition; neuropsychological tests of motor, memory, and executive functions; and psychological measures of social behavior, communication skills, and obsessive-compulsive behaviors. RESULTS: On eye movement testing, family members demonstrated saccadic hypometria, reduced steady-state pursuit gain, and a higher rate of voluntary response inhibition errors relative to controls. They also showed lateralized deficits in procedural learning and open-loop pursuit gain (initial 100 milliseconds of pursuit) and increased variability in the accuracy of large-amplitude saccades that were confined to rightward movements. In neuropsychological studies, only executive functions were impaired relative to those of controls. Family members reported more communication abnormalities and obsessive-compulsive behaviors than controls. Deficits across oculomotor, neuropsychological, and psychological domains were relatively independent from one another. CONCLUSIONS: Family members of individuals with autism demonstrate oculomotor abnormalities implicating pontocerebellar and frontostriatal circuits and left-lateralized alterations of frontotemporal circuitry and striatum. The left-lateralized alterations have not been identified in other neuropsychiatric disorders and are of interest given atypical brain lateralization and language development associated with the disorder. Similar oculomotor deficits have been reported in individuals with autism, suggesting that they may be familial and useful for studies of neurophysiological and genetic mechanisms in autism

Characterizing the impacts of multi-scale heterogeneity on solute transport in fracture networks

We model flow and transport in three-dimensional fracture networks with varying degrees of fracture-to-fracture aperture/permeability heterogeneity and network density to show how changes in these properties can cause the emergence of anomalous flow and transport behavior. If fracture-to-fracture aperture heterogeneity is increased in sparse networks, velocity fluctuations can inhibit high flow rates and solute transport can be delayed, even in cases where hydraulic aperture is monotonically increased. As the density of the networks is increased, more connected pathways allow for particles to bypass these effects. We discover transition behavior where with relatively few connected pathways in a network from inflow to outflow boundaries, the first arrival times of particles are not heavily affected by fracture-to-fracture aperture heterogeneity, but the scaling behavior of the tails is strongly influenced due to the particles being forced to sample some of the heterogeneity in the velocity field caused by aperture differences. These results reinforce the importance of considering multi-scale effects in fractured systems and can inform flow and transport processes in both natural and engineered fracture systems, especially the latter where high aperture fractures are often stimulated and connect to existing fracture networks with smaller apertures

Fundamentals of Anorectal Technical Skills: A Concise Surgical Skills Course

Introduction Anorectal diseases, among the most common surgical conditions, are underrepresented in medical training. The Fundamentals of Anorectal Technical Skills course was developed to provide cost-effective formal training in diagnosis of common anorectal conditions and in commonly performed anorectal procedures using the theories of deliberative practice and perceptual and adaptive learning. Materials and Methods First- through third-year general surgery and internal medicine residents and third- and fourth-year medical students participated in a course consisting of didactic instruction and hands on skills stations. The course covered common anorectal conditions, including internal and external hemorrhoids, fissures, condylomata, abscesses, fistula-in-ano, rectal prolapse, pilonidal disease, pruritis ani, and anal and rectal cancer, as well as common procedures such as anoscopy, excision of thrombosed external hemorrhoids, banding of internal hemorrhoids, rigid proctoscopy, incision and drainage of an abscess, administration of local anesthesia, and reduction of rectal prolapse. Before the course, participants completed a questionnaire consisting of demographics; previous anorectal experience, as measured by procedural case volume; confidence diagnosing and treating anorectal conditions; and a clinical knowledge multiple-choice quiz. Immediately following the course, participants took an additional survey reassessing their confidence and testing their clinical knowledge. This study was granted an educational exception by the Institutional Review Board at Walter Reed National Military Medical Center. Results Forty-three learners participated in this course. Forty-six percent of participants had not participated in any anorectal cases, 26% had participated in 1 to 5 cases, 17% had participated in 6 to 10 cases, 6% had been involved with 11 to15 cases, and 6% had been involved with more than 15 cases. For learners who had no prior experience, 1 to 5 prior cases, or 6 to 10 cases, there were statistically and educationally significant increases in confidence for all diagnoses and procedures. Additionally, there were statistically and educationally significant increases between pre-course and post-course quiz scores for learners who had no prior experience (7.8 ± 2.0 vs. 11.8 ± 2.5, P < 0.01, Cohen’s d = 1.8) and for those who had only participated in 1 to 5 cases (11.0 ± 3.7 vs. 14.2 ± 2.0, P = 0.04, Cohen’s d = 1.1). The changes in quiz scores for learners who previously had been involved with six or more cases were not statistically significant. Conclusion This course provides a cost-effective training that significantly boosts learners’ confidence in diagnosis of common anorectal procedures and confidence in performance of common anorectal procedures, in addition to improving objectively measured anorectal clinical knowledge

Bayesian Learning of Gas Transport in Three-Dimensional Fracture Networks

Modeling gas flow through fractures of subsurface rock is a particularly challenging problem because of the heterogeneous nature of the material. High-fidelity simulations using discrete fracture network (DFN) models are one methodology for predicting gas particle breakthrough times at the surface, but are computationally demanding. We propose a Bayesian machine learning method that serves as an efficient surrogate model, or emulator, for these three-dimensional DFN simulations. Our model trains on a small quantity of simulation data and, using a graph/path-based decomposition of the fracture network, rapidly predicts quantiles of the breakthrough time distribution. The approach, based on Gaussian Process Regression (GPR), outputs predictions that are within 20-30% of high-fidelity DFN simulation results. Unlike previously proposed methods, it also provides uncertainty quantification, outputting confidence intervals that are essential given the uncertainty inherent in subsurface modeling. Our trained model runs within a fraction of a second, which is considerably faster than other methods with comparable accuracy and multiple orders of magnitude faster than high-fidelity simulations

Blood-Brain Barrier Breakdown in the Aging Human Hippocampus

The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer’s disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment