Herbert S. Bresler

Preliminary microRNA analysis in lung tissue to identify potential therapeutic targets against H5N1 infection.

Within the past decade, human infections with the highly pathogenic avian influenza H5N1 have resulted in approximately 60% mortality and increased the need for vaccines and therapeutics. Understanding the molecular events associated with pathology can aid this effort; therefore, this study was conducted to assess microRNA (miRNA) expression in mouse lungs infected with H5N1 A/Vietnam/1203/04. Intranasal administration of 1500 median tissue culture infectious dose of H5N1 promoted differences in the number and expression pattern of miRNA from lung tissue collected at 2, 4, 6, 24, and 96 h post-exposure that mapped to common biological functions. Informatics analysis identified miRNA-specific predicted genes known to be therapeutic drug targets in which Furin was common to all time periods. This study provides insight into the differential miRNA expression with respect to the host-pathogen relationship and identification of potential therapeutic drug targets.

Accumulation of CD11b+Gr-1+ cells in the lung, blood and bone marrow of mice infected with highly pathogenic H5N1 and H1N1 influenza viruses

Infection with pathogenic influenza viruses is associated with intense inflammatory disease. Here, we investigated the innate immune response in mice infected with H5N1 A/Vietnam/1203/04 and with reassortant human H1N1 A/Texas/36/91 viruses containing the virulence genes hemagglutinin (HA), neuraminidase (NA) and NS1 of the 1918 pandemic virus. Inclusion of the 1918 HA and NA glycoproteins rendered a seasonal H1N1 virus capable of inducing an exacerbated host innate immune response similar to that observed for highly pathogenic A/Vietnam/1203/04 virus. Infection with 1918 HA/NA:Tx/91 and A/Vietnam/1203/04 were associated with severe lung pathology, increased cytokine and chemokine production, and significant immune cell changes, including the presence of CD11b+Gr-1+ cells in the blood, lung and bone marrow. Significant differential gene expression in the lung included pathways for cell death, apoptosis, production and response to reactive oxygen radicals, as well as arginine and proline metabolism and chemokines associated with monocyte and neutrophil/granulocyte accumulation and/or activation. Arginase was produced in the lung of animals infected with A/Vietnam/1204. These results demonstrate that the innate immune cell response results in the accumulation of CD11b+Gr-1+ cells and products that have previously been shown to contribute to T cell suppression.

Neuroprosthetic-enabled control of graded arm muscle contraction in a paralyzed human

Neuroprosthetics that combine a brain computer interface (BCI) with functional electrical stimulation (FES) can restore voluntary control of a patients’ own paralyzed limbs. To date, human studies have demonstrated an “all-or-none” type of control for a fixed number of pre-determined states, like hand-open and hand-closed. To be practical for everyday use, a BCI-FES system should enable smooth control of limb movements through a continuum of states and generate situationally appropriate, graded muscle contractions. Crucially, this functionality will allow users of BCI-FES neuroprosthetics to manipulate objects of different sizes and weights without dropping or crushing them. In this study, we present the first evidence that using a BCI-FES system, a human with tetraplegia can regain volitional, graded control of muscle contraction in his paralyzed limb. In addition, we show the critical ability of the system to generalize beyond training states and accurately generate wrist flexion states that are intermediate to training levels. These innovations provide the groundwork for enabling enhanced and more natural fine motor control of paralyzed limbs by BCI-FES neuroprosthetics.

Big data challenges in decoding cortical activity in a human with quadriplegia to inform a brain computer interface

Recent advances in Brain Computer Interfaces (BCIs) have created hope that one day paralyzed patients will be able to regain control of their paralyzed limbs. As part of an ongoing clinical study, we have implanted a 96-electrode Utah array in the motor cortex of a paralyzed human. The array generates almost 3 million data points from the brain every second. This presents several big data challenges towards developing algorithms that should not only process the data in real-time (for the BCI to be responsive) but are also robust to temporal variations and non-stationarities in the sensor data. We demonstrate an algorithmic approach to analyze such data and present a novel method to evaluate such algorithms. We present our methodology with examples of decoding human brain data in real-time to inform a BCI.Recent advances in Brain Computer Interfaces (BCIs) have created hope that one day paralyzed patients will be able to regain control of their paralyzed limbs. As part of an ongoing clinical study, we have implanted a 96-electrode Utah array in the motor cortex of a paralyzed human. The array generates almost 3 million data points from the brain every second. This presents several big data challenges towards developing algorithms that should not only process the data in real-time (for the BCI to be responsive) but are also robust to temporal variations and non-stationarities in the sensor data. We demonstrate an algorithmic approach to analyze such data and present a novel method to evaluate such algorithms. We present our methodology with examples of decoding human brain data in real-time to inform a BCI.

MicroRNA expression in mice infected with seasonal H1N1, swine H1N1 or highly pathogenic H5N1.

Influenza virus infections in humans remain a healthcare concern, and the need for vaccines, therapeutics and prophylactics remains a high priority. Understanding the molecular events associated with influenza-virus-induced pathology may lead to the identification of clinical disease biomarkers and novel antiviral targets. MicroRNAs (miRNAs) are well-conserved endogenous non-coding RNAs known to regulate post-transcriptional gene expression as well as play a major role in many biological processes and pathways. Animal studies have demonstrated that miRNAs are involved in viral disease and controlling inflammation. In this study, we examined the differences in the miRNA expression profiles associated with the lung in mice infected with influenza viruses that varied in virulence and pathogenicity. A statistical model was employed that utilized changes in miRNA expression to identify the virus that was used to infect the mice. This study identified a unique fingerprint of viral pathogenicity associated with seasonal H1N1, swine H1N1 and highly pathogenic H5N1 in the mouse model, and may lead to the identification of novel therapeutic and prophylactic targets.

Dexterous Control of Seven Functional Hand Movements Using Cortically-Controlled Transcutaneous Muscle Stimulation in a Person With Tetraplegia

Individuals with tetraplegia identify restoration of hand function as a critical, unmet need to regain their independence and improve quality of life. Brain-Computer Interface (BCI)-controlled Functional Electrical Stimulation (FES) technology addresses this need by reconnecting the brain with paralyzed limbs to restore function. In this study, we quantified performance of an intuitive, cortically-controlled, transcutaneous FES system on standardized object manipulation tasks from the Grasp and Release Test (GRT). We found that a tetraplegic individual could use the system to control up to seven functional hand movements, each with >95% individual accuracy. He was able to select one movement from the possible seven movements available to him and use it to appropriately manipulate all GRT objects in real-time using naturalistic grasps. With the use of the system, the participant not only improved his GRT performance over his baseline, demonstrating an increase in number of transfers for all objects except the Block, but also significantly improved transfer times for the heaviest objects (videocassette (VHS), Can). Analysis of underlying motor cortex neural representations associated with the hand grasp states revealed an overlap or non-separability in neural activation patterns for similarly shaped objects that affected BCI-FES performance. These results suggest that motor cortex neural representations for functional grips are likely more related to hand shape and force required to hold objects, rather than to the objects themselves. These results, demonstrating multiple, naturalistic functional hand movements with the BCI-FES, constitute a further step toward translating BCI-FES technologies from research devices to clinical neuroprosthetics.