An intra-neural microstimulation system for ultra-high field magnetic resonance imaging and magnetoencephalography.

BACKGROUND: Intra-neural microstimulation (INMS) is a technique that allows the precise delivery of low-current electrical pulses into human peripheral nerves. Single unit INMS can be used to stimulate individual afferent nerve fibres during microneurography. Combining this with neuroimaging allows the unique monitoring of central nervous system activation in response to unitary, controlled tactile input, with functional magnetic resonance imaging (fMRI) providing exquisite spatial localisation of brain activity and magnetoencephalography (MEG) high temporal resolution. NEW METHOD: INMS systems suitable for use within electrophysiology laboratories have been available for many years. We describe an INMS system specifically designed to provide compatibility with both ultra-high field (7T) fMRI and MEG. Numerous technical and safety issues are addressed. The system is fully analogue, allowing for arbitrary frequency and amplitude INMS stimulation. RESULTS: Unitary recordings obtained within both the MRI and MEG screened-room environments are comparable with those obtained in 'clean' electrophysiology recording environments. Single unit INMS (current <7μA, 200μs pulses) of individual mechanoreceptive afferents produces appropriate and robust responses during fMRI and MEG. COMPARISON WITH EXISTING METHOD(S): This custom-built MRI- and MEG-compatible stimulator overcomes issues with existing INMS approaches; it allows well-controlled switching between recording and stimulus mode, prevents electrical shocks because of long cable lengths, permits unlimited patterns of stimulation, and provides a system with improved work-flow and participant comfort. CONCLUSIONS: We demonstrate that the requirements for an INMS-integrated system, which can be used with both fMRI and MEG imaging systems, have been fully met

C-tactile afferent stimulating touch carries a positive affective value

The rewarding sensation of touch in affiliative interactions is hypothesized to be underpinned by a specialized system of nerve fibers called C-Tactile afferents (CTs), which respond optimally to slowly moving, gentle touch, typical of a caress. However, empirical evidence to support the theory that CTs encode socially relevant, rewarding tactile information in humans is currently limited. While in healthy participants, touch applied at CT optimal velocities (1-10cm/sec) is reliably rated as subjectively pleasant, neuronopathy patients lacking large myelinated afferents, but with intact C-fibres, report that the conscious sensation elicited by stimulation of CTs is rather vague. Given this weak perceptual impact the value of self-report measures for assessing the specific affective value of CT activating touch appears limited. Therefore, we combined subjective ratings of touch pleasantness with implicit measures of affective state (facial electromyography) and autonomic arousal (heart rate) to determine whether CT activation carries a positive affective value. We recorded the activity of two key emotion-relevant facial muscle sites (zygomaticus major—smile muscle, positive affect & corrugator supercilii—frown muscle, negative affect) while participants evaluated the pleasantness of experimenter administered stroking touch, delivered using a soft brush, at two velocities (CT optimal 3cm/sec & CT non-optimal 30cm/sec), on two skin sites (CT innervated forearm & non-CT innervated palm). On both sites, 3cm/sec stroking touch was rated as more pleasant and produced greater heart rate deceleration than 30cm/sec stimulation. However, neither self-report ratings nor heart rate responses discriminated stimulation on the CT innervated arm from stroking of the non-CT innervated palm. In contrast, significantly greater activation of the zygomaticus major (smiling muscle) was seen specifically to CT optimal, 3cm/sec, stroking on the forearm in comparison to all other stimuli. These results offer the first empirical evidence in humans that tactile stimulation that optimally activates CTs carries a positive affective valence that can be measured implicitly

Organized crime and preventive justice

By comparison with the prevention of terrorism, the prevention of acts of organizedcrime might be thought easier to conceptualize precisely and less controversial to legislate against and police. This impression is correct up to a point, because it is possible to arrive at some general characteristics of organized crime, and because legislation against it is not obviously bedevilled by the risk of violating civil or political rights, as in the case of terrorism. But there is a significant residue of legal, moral and political difficulty: legislation against organized crime is hard to make effective; the harm of organized crime is not uniform, and so some preventive legislation seems too sweeping and potentially unjust. More fundamentally, the scale and rewards of organized crime are often dependent on mass public participation in markets for proscribed goods, which may point to a hidden public consensus in favour of some of what is criminalized. Preventive policing and legislation in both areas, then, are less easily justified than first appears

Dominant role of greenhouse-gas forcing in the recovery of Sahel rainfall

Sahelian summer rainfall, controlled by the West African monsoon, exhibited large-amplitude multidecadal variability during the twentieth century. Particularly important was the severe drought of the 1970s and 1980s, which had widespread impacts1–6. Research into the causes of this drought has identified anthropogenic aerosol forcing3,4,7 and changes in sea surface temperatures (SSTs; refs 1,2,6,8–11) as the most important drivers. Since the 1980s, there has been some recovery of Sahel rainfall amounts2–6,11–14, although not to the pre-drought levels of the 1940s and 1950s. Here we report on experiments with the atmospheric component of a state-of-the-art global climate model to identify the causes of this recovery. Our results suggest that the direct influence of higher levels of greenhouse gases in the atmosphere was the main cause, with an additional role for changes in anthropogenic aerosol precursor emissions. We find that recent changes in SSTs, although substantial, did not have a significant impact on the recovery. The simulated response to anthropogenic greenhouse-gas and aerosol forcing is consistent with a multivariate fingerprint of the observed recovery, raising confidence in our findings. Although robust predictions are not yet possible, our results suggest that the recent recovery in Sahel rainfall amounts is most likely to be sustained or amplified in the near term

An ensemble of AMIP simulations with prescribed land surface temperatures

General circulation models (GCMs) are routinely run under Atmospheric Modelling Intercomparison Project (AMIP) conditions with prescribed sea surface temperatures (SSTs) and sea ice concentrations (SICs) from observations. These AMIP simulations are often used to evaluate the role of the land and/or atmosphere in causing the development of systematic errors in such GCMs. Extensions to the original AMIP experiment have also been developed to evaluate the response of the global climate to increased SSTs (prescribed) and carbon dioxide (CO2) as part of the Cloud Feedback Model Intercomparison Project (CFMIP). None of these international modelling initiatives has undertaken a set of experiments where the land conditions are also prescribed, which is the focus of the work presented in this paper. Experiments are performed initially with freely varying land conditions (surface temperature, and soil temperature and moisture) under five different configurations (AMIP, AMIP with uniform 4&thinsp;K added to SSTs, AMIP SST with quadrupled CO2, AMIP SST and quadrupled CO2 without the plant stomata response, and increasing the solar constant by 3.3&thinsp;%). Then, the land surface temperatures from the free land experiments are used to perform a set of AMIP prescribed land (PL) simulations, which are evaluated against their free land counterparts. The PL simulations agree well with the free land experiments, which indicates that the land surface is prescribed in a way that is consistent with the original free land configuration. Further experiments are also performed with different combinations of SSTs, CO2 concentrations, solar constant and land conditions. For example, SST and land conditions are used from the AMIP simulation with quadrupled CO2 in order to simulate the atmospheric response to increased CO2 concentrations without the surface temperature changing. The results of all these experiments have been made publicly available for further analysis. The main aims of this paper are to provide a description of the method used and an initial validation of these AMIP prescribed land experiments.</p

Inhomogeneous Point-Processes to Instantaneously Assess Affective Haptic Perception through Heartbeat Dynamics Information

This study proposes the application of a comprehensive signal processing framework, based on inhomogeneous point-process models of heartbeat dynamics, to instantaneously assess affective haptic perception using electrocardiogram-derived information exclusively. The framework relies on inverse-Gaussian point-processes with Laguerre expansion of the nonlinear Wiener-Volterra kernels, accounting for the long-term information given by the past heartbeat events. Up to cubic-order nonlinearities allow for an instantaneous estimation of the dynamic spectrum and bispectrum of the considered cardiovascular dynamics, as well as for instantaneous measures of complexity, through Lyapunov exponents and entropy. Short-term caress-like stimuli were administered for 4.3?25?seconds on the forearms of 32 healthy volunteers (16 females) through a wearable haptic device, by selectively superimposing two levels of force, 2?N and 6?N, and two levels of velocity, 9.4?mm/s and 65?mm/s. Results demonstrated that our instantaneous linear and nonlinear features were able to finely characterize the affective haptic perception, with a recognition accuracy of 69.79% along the force dimension, and 81.25% along the velocity dimension

The Use of Silver Nitrate Staining and Backscattered Electron Imaging to Visualize Nematode Sensory Structures

Parasitic nematodes of the species Cosmocercoides variabilis were stained with silver nitrate and examined with backscattered electron imaging (BEI). Sensory papillae were selectively highlighted in backscatter images. Silver stain deposited on papillae was located on the papillary surface as well as on the underlying dendritic process. Portions of the body cuticle were also stained. Some cuticular staining was attributed to non-specific deposition of silver but, consistent patterns of cuticular staining were noted in the anterior and posterior regions. This observation suggests that some staining of the cuticle was specific. Results of this preliminary work suggest that BEI is a technique useful to the study of nematode form

Aerosols implicated as a prime driver of twentieth-century North Atlantic climate variability

Systematic climate shifts have been linked to multidecadal variability in observed sea surface temperatures in the North Atlantic Ocean1. These links are extensive, influencing a range of climate processes such as hurricane activity2 and African Sahel3, 4, 5 and Amazonian5 droughts. The variability is distinct from historical global-mean temperature changes and is commonly attributed to natural ocean oscillations6, 7, 8, 9, 10. A number of studies have provided evidence that aerosols can influence long-term changes in sea surface temperatures11, 12, but climate models have so far failed to reproduce these interactions6, 9 and the role of aerosols in decadal variability remains unclear. Here we use a state-of-the-art Earth system climate model to show that aerosol emissions and periods of volcanic activity explain 76 per cent of the simulated multidecadal variance in detrended 1860–2005 North Atlantic sea surface temperatures. After 1950, simulated variability is within observational estimates; our estimates for 1910–1940 capture twice the warming of previous generation models but do not explain the entire observed trend. Other processes, such as ocean circulation, may also have contributed to variability in the early twentieth century. Mechanistically, we find that inclusion of aerosol–cloud microphysical effects, which were included in few previous multimodel ensembles, dominates the magnitude (80 per cent) and the spatial pattern of the total surface aerosol forcing in the North Atlantic. Our findings suggest that anthropogenic aerosol emissions influenced a range of societally important historical climate events such as peaks in hurricane activity and Sahel drought. Decadal-scale model predictions of regional Atlantic climate will probably be improved by incorporating aerosol–cloud microphysical interactions and estimates of future concentrations of aerosols, emissions of which are directly addressable by policy actions

Using E. coli NfsA as a model to improve our understanding of enzyme engineering

There is a substantial gap between the levels of enzyme activity that nature can achieve and those that scientists can evolve in the lab. This suggests that conventional directed evolution techniques involving incremental improvements in enzyme activity may frequently fail to ascend even local fitness maxima. This is most likely due to the difficulty for step-wise evolutionary approaches in effectively retaining mutations that are beneficial in combination with one another, but on an individual basis are neutral or deleterious (i.e., exhibit positive epistasis). We sought to determine whether a superior enzyme identified using a simultaneous mass site directed mutagenesis approach could have been identified using a step-wise approach. We conducted simultaneous mass randomisation of eight key active site residues in Escherichia coli NfsA, a nitroreductase enzyme that has diverse applications in biotechnology. Using degenerate codons, we generated a diverse library containing 394 million unique variants. We then applied a powerful positive selection using chloramphenicol which is toxic to E. coli but can be detoxified via nitro-reduction. This has enabled us to recover a diverse range of highly active nitroreductase variants. For two of the most active variants, we have created all possible combinations of single mutations. This allowed us to examine whether a step-wise mutagenesis pathway could have also yielded these enzymes. As anticipated, we identified complex epistatic interactions between residues in these enzyme variants. We have also investigated the “black-box” effect of enzyme engineering, examining the consequences that evolving NfsA towards one specialist activity had on the other promiscuous activities of NfsA. Variants generated in this study have also had practical applications, in particular for targeted cell ablation in zebrafish. We have identified NfsA variants that are highly active with nil-bystander prodrugs that can selectively ablate nitroreductase expressing cells without harm to adjacent cells. In ongoing work, our lead variants are being evaluated for their utility in transgenic zebrafish models of degenerative disease

Genome-Wide Association Analysis Identifies a Mutation in the Thiamine Transporter 2 (SLC19A3) Gene Associated with Alaskan Husky Encephalopathy

Alaskan Husky Encephalopathy (AHE) has been previously proposed as a mitochondrial encephalopathy based on neuropathological similarities with human Leigh Syndrome (LS). We studied 11 Alaskan Husky dogs with AHE, but found no abnormalities in respiratory chain enzyme activities in muscle and liver, or mutations in mitochondrial or nuclear genes that cause LS in people. A genome wide association study was performed using eight of the affected dogs and 20 related but unaffected control AHs using the Illumina canine HD array. SLC19A3 was identified as a positional candidate gene. This gene controls the uptake of thiamine in the CNS via expression of the thiamine transporter protein THTR2. Dogs have two copies of this gene located within the candidate interval (SLC19A3.2 – 43.36–43.38 Mb and SLC19A3.1 – 43.411–43.419 Mb) on chromosome 25. Expression analysis in a normal dog revealed that one of the paralogs, SLC19A3.1, was expressed in the brain and spinal cord while the other was not. Subsequent exon sequencing of SLC19A3.1 revealed a 4bp insertion and SNP in the second exon that is predicted to result in a functional protein truncation of 279 amino acids (c.624 insTTGC, c.625 C>A). All dogs with AHE were homozygous for this mutation, 15/41 healthy AH control dogs were heterozygous carriers while 26/41 normal healthy AH dogs were wild type. Furthermore, this mutation was not detected in another 187 dogs of different breeds. These results suggest that this mutation in SLC19A3.1, encoding a thiamine transporter protein, plays a critical role in the pathogenesis of AHE.University of California, Davis. School of Veterinary Medicine. Center for Companion Animal Healt