Multimodal stimuli modulate rapid visual responses during reaching

The reticulospinal tract plays an important role in primate upper limb function, but methods for assessing its activity are limited. One promising approach is to measure rapid visual responses (RVRs) in arm muscle activity during a visually cued reaching task; these may arise from a tecto-reticulospinal pathway. We investigated whether changes in reticulospinal excitability can be assessed noninvasively using RVRs, by pairing the visual stimuli of the reaching task with electrical stimulation of the median nerve, galvanic vestibular stimulation, or loud sounds, all of which are known to activate the reticular formation. Surface electromyogram (EMG) recordings were made from the right deltoid of healthy human subjects as they performed fast reaching movements toward visual targets. Stimuli were delivered up to 200 ms before target appearance, and RVR was quantified as the EMG amplitude in a window 75–125 ms after visual target onset. Median nerve, vestibular, and auditory stimuli all consistently facilitated the RVRs, as well as reducing the latency of responses. We propose that this facilitation reflects modulation of tecto-reticulospinal excitability, which is consistent with the idea that the amplitude of RVRs can be used to assess changes in brain stem excitability noninvasively in humans

Cortical, corticospinal and reticulospinal contributions to strength training

Following a program of resistance training, there are neural and muscular contributions to the gain in strength. Here, we measured changes in important central motor pathways during strength training in two female macaque monkeys. Animals were trained to pull a handle with one arm; weights could be added to increase load. On each day, motor evoked potentials in upper limb muscles were first measured after stimulation of the primary motor cortex (M1), corticospinal tract (CST) and reticulospinal tract (RST). Monkeys then completed 50 trials with weights progressively increased over 8-9 weeks (final weight ∼6kg, close to the animal's body weight). Muscle responses to M1 and RST stimulation increased during strength training; there were no increases in CST responses. Changes persisted during a two-week washout period without weights. After a further three months of strength training, an experiment under anesthesia mapped potential responses to CST and RST stimulation in the cervical enlargement of the spinal cord. We distinguished the early axonal volley and later spinal synaptic field potentials, and used the slope of the relationship between these at different stimulus intensities as a measure of spinal input-output gain. Spinal gain was increased on the trained compared to the untrained side of the cord within the intermediate zone and motor nuclei for RST, but not CST, stimulation. We conclude that neural adaptations to strength training involve adaptations in the RST, as well as intracortical circuits within M1. By contrast, there appears to be little contribution from the CST.Significance StatementWe provide the first report of a strength training intervention in non-human primates. Our results indicate that strength training is associated with neural adaptations in intracortical and reticulospinal circuits, whilst corticospinal and motoneuronal adaptations are not dominant factors

Corticospinal Inputs to Primate Motoneurons Innervatingthe Forelimb from Two Divisions of Primary Motor Cortexand Area 3a

Previous anatomical work in primates has suggested that only corticospinal axons originating in caudal primary motor cortex (“newM1”) and area 3a make monosynaptic cortico-otoneuronal connections with limb motoneurons.By contrast, the more rostral “old M1” is proposed to control motoneurons disynaptically via spinal interneurons. In six macaque monkeys, we examined the effects from focal stimulation within old and new M1 and area 3a on 135 antidromically identified motoneurons projecting to the upper limb. EPSPs withsegmental latency shorter than 1.2 ms were classified as definitively monosynaptic; these were seen only after stimulation within new M1or at the new M1/3a border (incidence 6.6% and 1.3%, respectively; total n=27). However, most responses had longer latencies. Usingmeasures of the response facilitation after a second stimulus compared with the first, and the reduction in response latency after a third stimulus compared with the first, we classified these late responses as likely mediated by either long-latency monosynaptic (n=108) ornon-monosynaptic linkages (n=108). Both old and new M1 generated putative long-latency monosynaptic and non-monosynaptic effects; the majority of responses from area 3a were non-monosynaptic. Both types of responses from new M1 had significantly greateramplitude than those from old M1. We suggest that slowly conducting corticospinal fibers from old M1 generate weak late monosynaptic effects in motoneurons. These may represent a stage in control of primate motoneurons by the cortex intermediate between disynapticoutput via an interposed interneuron seen in nonprimates and the fast direct monosynaptic connections present in new M1.This work was supported by the Wellcome Trust

Slowly-Conducting Pyramidal Tract Neurons in Macaque and Rat

Anatomical studies report a large proportion of fine myelinated fibers in the primate pyramidal tract (PT), while very few PT neurons (PTNs) with slow conduction velocities (CV) (2.6 ms and estimated CV 3-8 m/s, and 67 macaque PTNs (>3.9 ms, CV 6-12 m/s). Spikes of most slow PTNs were small and present on only some recording contacts, while spikes from simultaneously recorded fast-conducting PTNs were large and appeared on all contacts. Antidromic thresholds were similar for fast and slow PTNS, while spike duration was considerably longer in slow PTNs. Most slow PTNs showed no signs of failure to respond antidromically. A number of tests, including intracortical microinjection of bicuculline (GABAA antagonist), failed to provide any evidence that RI prevented antidromic invasion of slow PTNs. Our results suggest that recording bias is the main reason why previous studies were dominated by fast PTNs

EXCITATION CONDITIONS IN THE MULTI-COMPONENT SUBMILLIMETER GALAXY SMM J00266+1708

We present multiline CO observations of the complex submillimeter galaxy SMMJ00266+1708. Using the Zpectrometer on the Green Bank Telescope, we provide the first precise spectroscopic measurement of its redshift (z = 2.742). Based on followup CO(1–0), CO(3–2), and CO(5–4) mapping, SMMJ00266+1708 appears to have two distinct components separated by ∼ 500 kms−1 that are nearly coincident along our line of sight. The two components show hints of different kinematics, with the blue-shifted component dispersion-dominated and the red-shifted component showing a clear velocity gradient. CO line ratios differ slightly between the two components, indicating that the physical conditions in their molecular gas may not be alike. We tentatively infer that SMMJ00266+1708 is an on going merger with a mass ratio of (7.8±4.0)/ sin2(i), with its overall size and surface brightness closely resembling that of other merging systems. We perform large velocity gradient modeling of the CO emission from both components and find that each component’s properties are consistent with a single phase of molecular gas (i.e., a single temperatures and density); additional multi-phase modelling of the red-shifted component, although motivated by a CO(1–0) size larger than the CO(3–2) size, is inconclusive. SMMJ00266+1708 provides evidence of early stage mergers within the submillimeter galaxy population. Continuum observations of J00266 at the ∼ 1′′ resolution of our observations could not have distinguished between the two components due to their separation (0.′′73 ± 0.′′06), illustrating that the additional velocity information provided by spectral line studies is important for addressing the prevalence of unresolved galaxy pairs in low-resolution submillimeter surveys

Excitation Conditions in the Multi-component Submillimeter Galaxy SMM J00266+1708

We present multiline CO observations of the complex submillimeter galaxy SMM J00266+1708. Using the Zpectrometer on the Green Bank Telescope, we provide the first precise spectroscopic measurement of its redshift (z=2.742). Based on followup CO(1-0), CO(3-2), and CO(5-4) mapping, SMM J00266+1708 appears to have two distinct components separated by ~500 km/s that are nearly coincident along our line of sight. The two components show hints of different kinematics, with the blue-shifted component dispersion-dominated and the red-shifted component showing a clear velocity gradient. CO line ratios differ slightly between the two components, indicating that the physical conditions in their molecular gas may not be alike. We tentatively infer that SMM J00266+1708 is an ongoing merger with a mass ratio of (7.8+/-4.0)/sin^2(i), with its overall size and surface brightness closely resembling that of other merging systems. We perform large velocity gradient modeling of the CO emission from both components and find that each component's properties are consistent with a single phase of molecular gas (i.e., a single temperatures and density); additional multi-phase modeling of the red-shifted component, although motivated by a CO(1-0) size larger than the CO(3-2) size, is inconclusive. SMM J00266+1708 provides evidence of early stage mergers within the submillimeter galaxy population. Continuum observations of J00266 at the ~1" resolution of our observations could not have distinguished between the two components due to their separation (0.73" +/- 0.06"), illustrating that the additional velocity information provided by spectral line studies is important for addressing the prevalence of unresolved galaxy pairs in low-resolution submillimeter surveys

In vitro and in vivo evaluation of human adenovirus type 49 as a vector for therapeutic applications

The human adenovirus phylogenetic tree is split across seven species (A–G). Species D adenoviruses offer potential advantages for gene therapy applications, with low rates of pre-exist-ing immunity detected across screened populations. However, many aspects of the basic virology of species D—such as their cellular tropism, receptor usage, and in vivo biodistribution profile— remain unknown. Here, we have characterized human adenovirus type 49 (HAdV-D49)—a rela-tively understudied species D member. We report that HAdV-D49 does not appear to use a single pathway to gain cell entry, but appears able to interact with various surface molecules for entry. As such, HAdV-D49 can transduce a broad range of cell types in vitro, with variable engagement of blood coagulation FX. Interestingly, when comparing in vivo biodistribution to adenovirus type 5, HAdV-D49 vectors show reduced liver targeting, whilst maintaining transduction of lung and spleen. Overall, this presents HAdV-D49 as a robust viral vector platform for ex vivo manipulation of human cells, and for in vivo applications where the therapeutic goal is to target the lung or gain access to immune cells in the spleen, whilst avoiding liver interactions, such as intravascular vaccine applications

Assessment of a novel, capsid-modified adenovirus with an improved vascular gene transfer profile

<p>Background: Cardiovascular disorders, including coronary artery bypass graft failure and in-stent restenosis remain significant opportunities for the advancement of novel therapeutics that target neointimal hyperplasia, a characteristic of both pathologies. Gene therapy may provide a successful approach to improve the clinical outcome of these conditions, but would benefit from the development of more efficient vectors for vascular gene delivery. The aim of this study was to assess whether a novel genetically engineered Adenovirus could be utilised to produce enhanced levels of vascular gene expression.</p> <p>Methods: Vascular transduction capacity was assessed in primary human saphenous vein smooth muscle and endothelial cells using vectors expressing the LacZ reporter gene. The therapeutic capacity of the vectors was compared by measuring smooth muscle cell metabolic activity and migration following infection with vectors that over-express the candidate therapeutic gene tissue inhibitor of matrix metalloproteinase-3 (TIMP-3).</p> <p>Results: Compared to Adenovirus serotype 5 (Ad5), the novel vector Ad5T*F35++ demonstrated improved binding and transduction of human vascular cells. Ad5T*F35++ mediated expression of TIMP-3 reduced smooth muscle cell metabolic activity and migration in vitro. We also demonstrated that in human serum samples pre-existing neutralising antibodies to Ad5T*F35++ were less prevalent than Ad5 neutralising antibodies.</p> <p>Conclusions: We have developed a novel vector with improved vascular transduction and improved resistance to human serum neutralisation. This may provide a novel vector platform for human vascular gene transfer.</p&gt