Animal-to-animal variability in the phasing of the crustacean cardiac motor pattern: An experimental and computational analysis

The cardiac ganglion (CG) of Homarus americanus is a central pattern generator that consists of two oscillatory groups of neurons: small cells (SCs) and large cells (LCs). We have shown that SCs and LCs begin their bursts nearly simultaneously but end their bursts at variable phases. This variability contrasts with many other central pattern generator systems in which phase is well maintained. To determine both the consequences of this variability and how CG phasing is controlled, we modeled the CG as a pair of Morris-Lecar oscillators coupled by electrical and excitatory synapses and constructed a database of 15,000 simulated networks using random parameter sets. These simulations, like our experimental results, displayed variable phase relationships, with the bursts beginning together but ending at variable phases. The model suggests that the variable phasing of the pattern has important implications for the functional role of the excitatory synapses. In networks in which the two oscillators had similar duty cycles, the excitatory coupling functioned to increase cycle frequency. In networks with disparate duty cycles, it functioned to decrease network frequency. Overall, we suggest that the phasing of the CG may vary without compromising appropriate motor output and that this variability may critically determine how the network behaves in response to manipulations. © 2013 the American Physiological Society

Distinct or shared actions of peptide family isoforms: II. Multiple pyrokinins exert similar effects in the lobster stomatogastric nervous system

Many neuropeptides are members of peptide families, with multiple structurally similar isoforms frequently found even within a single species. This raises the question of whether the individual peptides serve common or distinct functions. In the accompanying paper, we found high isoform specificity in the responses of the lobster (Homarus americanus) cardiac neuromuscular system to members of the pyrokinin peptide family: only one of five crustacean isoforms showed any bioactivity in the cardiac system. Because previous studies in other species had found little isoform specificity in pyrokinin actions, we examined the effects of the same five crustacean pyrokinins on the lobster stomatogastric nervous system (STNS). In contrast to our findings in the cardiac system, the effects of the five pyrokinin isoforms on the STNS were indistinguishable: they all activated or enhanced the gastric mill motor pattern, but did not alter the pyloric pattern. These results, in combination with those from the cardiac ganglion, suggest that members of a peptide family in the same species can be both isoform specific and highly promiscuous in their modulatory capacity. The mechanisms that underlie these differences in specificity have not yet been elucidated; one possible explanation, which has yet to be tested, is the presence and differential distribution of multiple receptors for members of this peptide family

Predicting forefoot-orthosis interactions in rheumatoid arthritis using computational modelling

Foot orthoses are prescribed to reduce forefoot plantar pressures and pain in people with rheumatoid arthritis. Computational modelling can assess how the orthoses affect internal tissue stresses, but previous studies have focused on a single healthy individual. This study aimed to ascertain whether simplified forefoot models would produce differing biomechanical predictions at the orthotic interface between people with rheumatoid arthritis of varying severity, and in comparison to a healthy control. The forefoot models were developed from magnetic resonance data of 13 participants with rheumatoid arthritis and one healthy individual. Measurements of bony morphology and soft tissue thickness were taken to assess deformity. These were compared to model predictions (99th% shear strain and plantar pressure, max. pressure gradient, volume of soft tissue over 10% shear strain), alongside clinical data including body mass index and Leeds Foot Impact Scale–Impairment/Footwear score (LFIS-IF). The predicted pressure and shear strain for the healthy participant fell at the lower end of the rheumatoid models’ range. Medial first metatarsal head curvature moderately correlated to all model predicted outcomes (0.529 < r < 0.574, 0.040 < p < 0.063). BMI strongly correlated to all model predictions except pressure gradients (0.600 < r < 0.652, p < 0.05). There were no apparent relationships between model predictions and instances of bursae, erosion and synovial hypertrophy or LFIS-IF score. The forefoot models produced differing biomechanical predictions between a healthy individual and participants with rheumatoid arthritis, and between individuals with rheumatoid arthritis. Models capable of predicting subject specific biomechanical orthotic interactions could be used in the future to inform more personalised devices to protect skin and soft tissue health. While the model results did not clearly correlate with all clinical measures, there was a wide range in model predictions and morphological measures across the participants. Thus, the need for assessment of foot orthoses across a population, rather than for one individual, is clear

Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism

Limiting dysfunctional neutrophilic inflammation while preserving effective immunity requires a better understanding of the processes that dictate neutrophil function in the tissues. Quantitative mass-spectrometry identified how inflammatory murine neutrophils regulated expression of cell surface receptors, signal transduction networks, and metabolic machinery to shape neutrophil phenotypes in response to hypoxia. Through the tracing of labeled amino acids into metabolic enzymes, proinflammatory mediators, and granule proteins, we demonstrated that ongoing protein synthesis shapes the neutrophil proteome. To maintain energy supplies in the tissues, neutrophils consumed extracellular proteins to fuel central carbon metabolism. The physiological stresses of hypoxia and hypoglycemia, characteristic of inflamed tissues, promoted this extracellular protein scavenging with activation of the lysosomal compartment, further driving exploitation of the protein-rich inflammatory milieu. This study provides a comprehensive map of neutrophil proteomes, analysis of which has led to the identification of active catabolic and anabolic pathways that enable neutrophils to sustain synthetic and effector functions in the tissues

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

Steroid-refractory ulcerative colitis treated with corticosteroids, metronidazole and vancomycin: a case report

BACKGROUND: Increasing evidence elucidating the pathogenic mechanisms of ulcerative colitis (UC) has accumulated and the disease is widely assumed to be the consequence of genetic susceptibility and an abnormal immune response to commensal bacteria. However evidence regarding an infectious etiology in UC remains elusive. CASE PRESENTATION: We report a provocative case of UC with profound rheumatologic involvement directly preceded by Clostridium difficile infection and accompanying fever, vomiting, bloody diarrhea, and arthritis. Colonic biopsy revealed a histopathology suggestive of UC. Antibiotic treatment eliminated detectable levels of enteric pathogens but did not abate symptoms. Resolution of symptoms was procurable with oral prednisone, but tapering of corticosteroids was only achievable in combination therapy with vancomycin and metronidazole. CONCLUSIONS: An infectious pathogen may have both precipitated and exacerbated autoimmune disease attributes in UC, symptoms of which could be resolved only with a combination of corticosteroids, vancomycin and metronidazole. This may warrant the need for more perceptive scrutiny of C. difficile and the like in patients with UC

A propofol binding site on mammalian GABAA receptors identified by photolabeling

Propofol is the most important intravenous general anesthetic in current clinical use. It acts by potentiating GABA(A) receptors, but where it binds to this receptor is not known and has been a matter of some controversy. We have synthesized a novel propofol analogue photolabeling reagent that has a biological activity very similar to that of propofol. We confirmed that this reagent labeled known propofol binding sites in human serum albumin which have been identified using X-ray crystallography. Using a combination of the protiated label and a deuterated version, and mammalian receptors labeled in intact membranes, we have identified a novel binding site for propofol in GABA(A) receptors consisting of both β(3) homopentamers and α(1)β(3) heteropentamers. The binding site is located within the β subunit, at the interface between the transmembrane domains and the extracellular domain, and lies close to known determinants of anesthetic sensitivity in transmembrane segments TM1 and TM2

A scoping review of digital fabrication techniques applied to prosthetics and orthotics: Part 1 of 2—Prosthetics

Background: Traditionally, the manufacture of prostheses is time-consuming and labor-intensive. One possible route to improving access and quality of these devices is the digitalizing of the fabrication process, which may reduce the burden of manual labor and bring the potential for automation that could help unblock access to assistive technologies globally. Objectives: To identify where there are gaps in the literature that are creating barriers to decision-making on either appropriate uptake by clinical teams or on the needed next steps in research that mean these technologies can continue on a pathway to maturity. Study design: Scoping literature review. Methods: A comprehensive search was completed in the following databases: Allied and Complementary Medicine Database, MEDLINE, Embase, Global Health Archive, CINAHL Plus, Cochrane Library, Web of Science, Association for Computing Machinery, Institute of Electrical and Electronics Engineers, and Engineering Village, resulting in 3487 articles to be screened. Results: After screening, 130 lower limb prosthetic articles and 117 upper limb prosthetic articles were included in this review. Multiple limitations in the literature were identified, particularly a lack of long-term, larger-scale studies; research into the training requirements for these technologies and the necessary rectification processes; and a high range of variance of production workflows and materials which makes drawing conclusions difficult. Conclusions: These limitations create a barrier to adequate evidence-based decision-making for clinicians, technology developers, and wider policymakers. Increased collaboration between academia, industry, and clinical teams across more of the pathway to market for new technologies could be a route to addressing these gaps

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

In Silico Reconstitution of Actin-Based Symmetry Breaking and Motility

Computational modeling and experimentation in a model system for actin-based force generation explain how actin networks initiate and maintain directional movement