PurUUpurU: An Oligonucleotide Virulence Factor in RNA Viruses.

Background The copy number of the oligonucleotide 5'-purine-uridine-uridine-purine-uridine-3' (purUUpurU) motif in a viral genome was previously shown to correlate with the severity of acute illness. This study aimed to determine whether purUUpurU content correlates with virulence in other single-strand RNA (ssRNA) viruses that vary in clinical severity. Methodology We determined the copy number of purUUpurU in the genomes of two subtypes of human respiratory syncytial virus (RSV), respiratory syncytial virus A (RSV-A), and respiratory syncytial virus B (RSV-B), which vary in clinical severity. In addition, we determined the purUUpurU content of the four ebolaviruses that cause human disease, dengue virus, rabies virus, human rhinovirus-A, poliovirus type 1, astrovirus, rubella, yellow fever virus, and measles virus. Viral nucleotide sequence files were downloaded from the National Center for Biotechnology Information (NCBI)/National Institutes of Health website. In addition, we determined the cumulative case fatality rate of 20 epidemics of the Ebola virus and compared it with that of the other human ebolaviruses. Results The genomic purUUpurU content correlated with the severity of acute illness caused by both subtypes of RSV and human ebolaviruses. The lowest purUUpurU content was in the genome of the rubella virus, which causes mild disease. Conclusions The quantity of genomic purUUpurU is a virulence factor in ssRNA viruses. Blood hyperviscosity is one mechanism by which purUUpurU causes pathology. Comparative quantitative genomic analysis for purUUpurU will be helpful in estimating the risk posed by emergent ssRNA viruses.

Constraint-induced intervention as an emergent phenomenon from synaptic competition in biological systems.

The principle of constraint-induced therapy is widely practiced in rehabilitation. In hemiplegic cerebral palsy (CP) with impaired contralateral corticospinal projection due to unilateral injury, function improves after imposing a temporary constraint on limbs from the less affected hemisphere. This type of partially-reversible impairment in motor control by early brain injury bears a resemblance to the experience-dependent plastic acquisition and modification of neuronal response selectivity in the visual cortex. Previously, such mechanism was modeled within the framework of BCM (Bienenstock-Cooper-Munro) theory, a rate-based synaptic modification theory. Here, we demonstrate a minimally complex yet sufficient neural network model which provides a fundamental explanation for inter-hemispheric competition using a simplified spike-based model of information transmission and plasticity. We emulate the restoration of function in hemiplegic CP by simulating the competition between cells of the ipsilateral and contralateral corticospinal tracts. We use a high-speed hardware neural simulation to provide realistic numbers of spikes and realistic magnitudes of synaptic modification. We demonstrate that the phenomenon of constraint-induced partial reversal of hemiplegia can be modeled by simplified neural descending tracts with 2 layers of spiking neurons and synapses with spike-timing-dependent plasticity (STDP). We further demonstrate that persistent hemiplegia following unilateral cortical inactivation or deprivation is predicted by the STDP-based model but is inconsistent with BCM model. Although our model is a highly simplified and limited representation of the corticospinal system, it offers an explanation of how constraint as an intervention can help the system to escape from a suboptimal solution. This is a display of an emergent phenomenon from the synaptic competition.

A Prototype of a Fully-Implantable Charge-Balanced Artificial Sensory Stimulator for Bi-directional Brain-Computer-Interface (BD-BCI).

Bi-directional brain-computer interfaces (BD-BCI) to restore movement and sensation must achieve concurrent operation of recording and decoding of motor commands from the brain and stimulating the brain with somatosensory feedback. Previously we developed and validated a benchtop prototype of a fully implantable BCI system for motor decoding. Here, a prototype artificial sensory stimulator was integrated into the benchtop system to develop a prototype of a fully-implantable BD-BCI. The artificial sensory stimulator incorporates an active charge balancing mechanism based on pulse-width modulation to ensure safe stimulation for chronically interfaced electrodes to prevent damage to brain tissue and electrodes. The feasibility of the BD-BCI system's active charge balancing was tested in phantom brain tissue. With the charge-balancing, the removal of the residual charges on an electrode was evident. This is a critical milestone toward fully-implantable BD-BCI systems.

Increased long-latency reflex activity as a sufficient explanation for childhood hypertonic dystonia: a neuromorphic emulation study.

OBJECTIVE: Childhood dystonia is a movement disorder that interferes with daily movements and can have a devastating effect on quality of life for children and their families. Although injury to basal ganglia is associated with dystonia, the neurophysiological mechanisms leading to the clinical manifestations of dystonia are not understood. Previous work suggested that long-latency stretch reflex (LLSR) is hyperactive in children with hypertonia due to secondary dystonia. We hypothesize that abnormal activity in motor cortices may cause an increase in the LLSR leading to hypertonia. APPROACH: We modeled two possibilities of hyperactive LLSR by either creating a tonic involuntary drive to cortex, or increasing the synaptic gain in cortical neurons. Both models are emulated using programmable very-large-scale-integrated-circuit hardware to test their sufficiency for producing dystonic symptoms. The emulation includes a joint with two Hill-type muscles, realistic muscle spindles, and 2,304 Izhikevich-type spiking neurons. The muscles are regulated by a monosynaptic spinal pathway with 32 ms delay and a long-latency pathway with 64 ms loop-delay representing transcortical/supra-spinal connections. MAIN RESULTS: When the limb is passively stretched, both models produce involuntary resistance with increased antagonist EMG responses similar to human data; also the muscle relaxation is delayed similar to human data. Both models predict reduced range of motion in voluntary movements. SIGNIFICANCE: Although our model is a highly simplified and limited representation of reflex pathways, it shows that increased activity of the LLSR is by itself sufficient to cause many of the features of hypertonic dystonia.