Printable microscale interfaces for long-term peripheral nerve mapping and precision control

The nascent field of bioelectronic medicine seeks to decode and modulate peripheral nervous system signals to obtain therapeutic control of targeted end organs and effectors. Current approaches rely heavily on electrode-based devices, but size scalability, material and microfabrication challenges, limited surgical accessibility, and the biomechanically dynamic implantation environment are significant impediments to developing and deploying advanced peripheral interfacing technologies. Here, we present a microscale implantable device – the nanoclip – for chronic interfacing with fine peripheral nerves in small animal models that begins to meet these constraints. We demonstrate the capability to make stable, high-resolution recordings of behaviorally-linked nerve activity over multi-week timescales. In addition, we show that multi-channel, current-steering-based stimulation can achieve a high degree of functionally-relevant modulatory specificity within the small scale of the device. These results highlight the potential of new microscale design and fabrication techniques for the realization of viable implantable devices for long-term peripheral interfacing.https://www.biorxiv.org/node/801468.fullFirst author draf

Retinal glia promote dorsal root ganglion axon regeneration.

Axon regeneration in the adult central nervous system (CNS) is limited by several factors including a lack of neurotrophic support. Recent studies have shown that glia from the adult rat CNS, specifically retinal astrocytes and Müller glia, can promote regeneration of retinal ganglion cell axons. In the present study we investigated whether retinal glia also exert a growth promoting effect outside the visual system. We found that retinal glial conditioned medium significantly enhanced neurite growth and branching of adult rat dorsal root ganglion neurons (DRG) in culture. Furthermore, transplantation of retinal glia significantly enhanced regeneration of DRG axons past the dorsal root entry zone after root crush in adult rats. To identify the factors that mediate the growth promoting effects of retinal glia, mass spectrometric analysis of retinal glial conditioned medium was performed. Apolipoprotein E and secreted protein acidic and rich in cysteine (SPARC) were found to be present in high abundance, a finding further confirmed by western blotting. Inhibition of Apolipoprotein E and SPARC significantly reduced the neuritogenic effects of retinal glial conditioned medium on DRG in culture, suggesting that Apolipoprotein E and SPARC are the major mediators of this regenerative response.This work was supported by a van Geest Fight for Sight Early Career Investigator Award, grant number 1868 [BL].This is the final version of the article. It first appeared at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.011599

Expression of an Activated Integrin Promotes Long-Distance Sensory Axon Regeneration in the Spinal Cord.

UNLABELLED: After CNS injury, axon regeneration is blocked by an inhibitory environment consisting of the highly upregulated tenascin-C and chondroitin sulfate proteoglycans (CSPGs). Tenascin-C promotes growth of axons if they express a tenascin-binding integrin, particularly α9β1. Additionally, integrins can be inactivated by CSPGs, and this inhibition can be overcome by the presence of a β1-binding integrin activator, kindlin-1. We examined the synergistic effect of α9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia. After 12 weeks, axons from C6-C7 dorsal root ganglia regenerated through the tenascin-C-rich dorsal root entry zone into the dorsal column up to C1 level and above (>25 mm axon length) through a normal pathway. Animals also showed anatomical and electrophysiological evidence of reconnection to the dorsal horn and behavioral recovery in mechanical pressure, thermal pain, and ladder-walking tasks. Expression of α9 integrin or kindlin-1 alone promoted much less regeneration and recovery. SIGNIFICANCE STATEMENT: The study demonstrates that long-distance sensory axon regeneration over a normal pathway and with sensory and sensory-motor recovery can be achieved. This was achieved by expressing an integrin that recognizes tenascin-C, one of the components of glial scar tissue, and an integrin activator. This enabled extensive long-distance (>25 mm) regeneration of both myelinated and unmyelinated sensory axons with topographically correct connections in the spinal cord. The extent of growth and recovery we have seen would probably be clinically significant. Restoration of sensation to hands, perineum, and genitalia would be a significant improvement for a spinal cord-injured patient

Indicators of relative completeness of the glacial record of the Port Askaig Formation, Garvellach Islands, Scotland

The Port Askaig Formation (PAF) is a diamictite-bearing succession in the Dalradian Supergroup of Scotland that provides an excellent archive of a Cryogenian glaciation in the Garvellach Islands and Islay, Argyll. The formation is ∼1100 m thick, comprises 5 members and includes 47 diamictite beds, interbedded with siltstones, dolostones and sandstones. Here we document seven features of the PAF that indicate its relative stratigraphic completeness. There are gradual, progressive changes up-section in the lithologies of the diamictites, their interbeds, and clast lithologies. The sharp basal surfaces of the diamictites each show the same, repeated pattern of environmental change, from non-glacial to glacial. Many of the top surfaces of the diamictites show evidence of periglacial conditions. The succession in the PAF records a total of 76 climatically-related stratigraphic episodes: 28 glacial episodes, 25 periglacial episodes and 23 non-glacial episodes. Parts of Member 1 (Diamictites 1–12 and Diamictites 16–18) and Member 2 (Diamictite 31 to the base of Member 3) are most compete on the east coast of Garbh Eileach. The PAF in the Garvellach Islands occurs within a succession that is several kilometres thick, as newly revealed by sea-floor mapping. Compared with other Cryogenian and Phanerozoic glacial successions, the PAF is exceptional in its combination of formation thickness, the number of climatically-related stratigraphic episodes, and the considerable thickness of its host supergroup. Furthermore, these indicators of relative stratigraphic completeness provide evidence that the base of the PAF on the east coast of Garbh Eileach is a succession without a major break in deposition, supporting the account of the strata at and below the base of the PAF in the companion article by Fairchild et al. (2018)

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) U-Pb carbonate geochronology: strategies, progress, and limitations

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) U–Pb geochronology of carbonate minerals, calcite in particular, is rapidly gaining popularity as an absolute dating method. The high spatial resolution of LA-ICP-MS U–Pb carbonate geochronology has benefits over traditional isotope dilution methods, particularly for diagenetic and hydrothermal calcite, because uranium and lead are heterogeneously distributed on the sub-millimetre scale. At the same time, this can provide limitations to the method, as locating zones of radiogenic lead can be time-consuming and “hit or miss”. Here, we present strategies for dating carbonates with in situ techniques, through imaging and petrographic techniques to data interpretation; our examples are drawn from the dating of fracture-filling calcite, but our discussion is relevant to all carbonate applications. We review several limitations to the method, including open-system behaviour, variable initial-lead compositions, and U–daughter disequilibrium. We also discuss two approaches to data collection: traditional spot analyses guided by petrographic and elemental imaging and image-based dating that utilises LA-ICP-MS elemental and isotopic map data

Establishing the Scope and Methodological Approach to Out-of-hospital Outcomes and Effectiveness Research

: Outcomes research offers out-of-hospital medicine a valuable methodology for studying the effectiveness of services provided in the out-of hospital setting. A clear understanding of the history and constructs of outcomes research is necessary for its integration into emergency medical services research. This report describes the conceptual framework of outcomes research and key methodological considerations for the successful implementation of out-of-hospital outcomes research. Illustrations of the specific applications of outcomes research and implications to existing methodologies are given, as well as suggestions for improved interdisciplinary research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75033/1/j.aem.2004.04.014.pd

Risk Adjustment and Outcome Measures for Out-of-hospital Respiratory Distress

: The purpose of the Emergency Medical Services Outcomes Project (EMSOP) is to develop a foundation and framework for out-of-hospital outcomes research. In prior work, this group delineated the priority conditions, described conceptual models, suggested core and risk adjustment measures potentially useful to emergency medical services research, and summarized out-of-hospital pain measurement. In this fifth article in the EMSOP series, the authors recommend specific risk-adjustment measures and outcome measures for use in out-of-hospital research on patients presenting with respiratory distress. The methodology included systematic literature searches and a structured review by an expert panel. The EMSOP group recommends use of pulse oximetry, peak expiratory flow rate, and the visual analog dyspnea scale as potential risk-adjustment measures and outcome measures for out-of-hospital research in patients with respiratory distress. Furthermore, using mortality as an outcome measure is also recommended. Future research is needed to alleviate the paucity of validated tools for out-of-hospital outcomes research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73779/1/j.aem.2004.03.010.pd

The Arabidopsis Framework Model version 2 predicts the organism-level effects of circadian clock gene mis-regulation

Predicting a multicellular organism’s phenotype quantitatively from its genotype is challenging, as genetic effects must propagate across scales. Circadian clocks are intracellular regulators that control temporal gene expression patterns and hence metabolism, physiology and behaviour. Here we explain and predict canonical phenotypes of circadian timing in a multicellular, model organism. We used diverse metabolic and physiological data to combine and extend mathematical models of rhythmic gene expression, photoperiod-dependent flowering, elongation growth and starch metabolism within a Framework Model for the vegetative growth of Arabidopsis thaliana, sharing the model and data files in a structured, public resource. The calibrated model predicted the effect of altered circadian timing upon each particular phenotype in clock-mutant plants under standard laboratory conditions. Altered night-time metabolism of stored starch accounted for most of the decrease in whole-plant biomass, as previously proposed. Mobilisation of a secondary store of malate and fumarate was also mis-regulated, accounting for any remaining biomass defect. The three candidate mechanisms tested did not explain this organic acid accumulation. Our results link genotype through specific processes to higher-level phenotypes, formalising our understanding of a subtle, pleiotropic syndrome at the whole-organism level, and validating the systems approach to understand complex traits starting from intracellular circuits

The quality of energy- and macronutrient-balanced diets regulates host susceptibility to influenza in mice

Modulation of individual macronutrients or caloric density is known to regulate host resistance to infection in mice. However, the impact of diet composition, independent of macronutrient and energy content, on infection susceptibility is unclear. We show that two laboratory rodent diets, widely used as standard animal feeds and experimental controls, display distinct abilities in supporting mice during influenza infection. Mice placed on the highly processed AIN93G showed increased mortality to infection compared with those on a grain-based chow diet, suggesting a detrimental role for highly processed food in host defense. We further demonstrate that the heightened susceptibility of AIN93G-fed mice was associated with the failure in homeostasis restoration mediated by the cytokine interferon (IFN)-γ. Our findings show that diet composition calibrates host survival threshold by regulating adaptive homeostasis and highlights a pivotal role for extrinsic signals in host phenotype and outcome of host-pathogen interaction