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Biomedical subjects

Charles L Howe

Publications and source records attributed to Charles L Howe.

At least 19 recordsLinked to original sources
PubMed2026

Instrumented Walkway Gait Analysis Predicts Fallers in Neurological Disorders: Identifying Digital Biomarkers for Balance Monitoring.

Assessing balance is crucial in neurological rehabilitation, yet while wearable sensors enable real-world monitoring, identifying reliable digital biomarkers remains challenging. This study utilized a high-fidelity instrumented walkway to determine which gait parameters best predict balance impairment, providing robust targets for future wearable applications. We analyzed 49 steady-state gait metrics from 140 individuals with diverse neurological conditions. Using statistical analysis and machine learning, we evaluated these parameters against objective force plate sway scores and clinical fall-history labels. Group analysis identified 16 parameters significantly distinguishing fallers from non-fallers, and a neural network classified fallers with an area under the curve of 0.75. Across all analytical approaches, overall gait variability, e.g., Stride Width S.D. and the Gait Variability Index, emerged as a universal predictor of balance impairment and fall risk. Furthermore, while traditional linear models emphasized spatial postural control, machine learning classification uniquely identified inter-limb asymmetry as a premier driver of fall prediction. These findings indicate that instrumented gait analysis effectively identifies digital biomarkers for balance deficits. Isolating these specific metrics provides a clear blueprint for meaningful metrics required for continuous objective monitoring and future development of personalized, adaptive rehabilitation strategies.

Humans↗
PubMed2026

Integration of biological avatars and digital twins for "ex vivo clinical trials".

Drug development is slow, costly, and prone to late-stage failure, in part because animal models poorly predict human responses. Two human-relevant technologies are maturing in parallel: biological avatars, defined as patient- or stem-cell-derived models such as organoids and organ-on-a-chip systems, and digital twins, defined as computational models that integrate a patient's molecular and clinical data to forecast treatment responses. We propose the ex vivo clinical trial concept, in which an avatar and a digital twin are coupled in an iterative loop so that laboratory measurements refine the computational prediction and the prediction guides the next experiment, allowing candidate therapies to be tested and prioritised before a patient is exposed. We review the platforms, their predictive performance in cancer, cystic fibrosis, and liver toxicity, the conditions under which they fail, and the qualification, turnaround, and standardisation requirements that must be met before such trials can inform drug development or clinical care.

Biological avatars↗
PubMed2025

Genomewide association study of a homogeneous multiple sclerosis cohort: Tumefactive demyelination.

BACKGROUND: Tumefactive demyelination (TD) is a rare variant of multiple sclerosis (MS) characterized by tumor-like lesions that often require aggressive management. Genome-wide association studies (GWAS) identified variants associated with MS; similar analyses in TD are lacking. OBJECTIVE: A GWAS was performed to identify variants associated with TD. METHODS: The case-control study included 142 TD cases and 293 controls. TD patients were required to have a demyelinating event and magnetic resonance imaging (MRI) showing one or more lesions. Controls were patients without a neurologic or systemic inflammatory disease or cancer. Logistic regression was used to compare cases versus controls for each variant; age, sex, and principal components were included as covariates. A p-value threshold of 5 × 10-8 was GWAS significant and 5 × 10-6 nominally significant. A polygenic risk score (PRS) was compared across TD and controls. RESULTS: Variants on chromosome 14 (rs117797734, p = 2.06 × 10-11, odds ratio (OR) = 13.14) and chromosome 6 (most significant rs6936540, p = 5.5 × 10-7, OR = 2.61) near DCBLD1 were significant. Seven non-MHC and two MHC variants associated with MS were associated with TD. The PRS was significantly higher in TD versus controls. CONCLUSION: We identified novel regions associated with TD, demonstrating the importance of performing GWAS in homogeneous subtypes of MS. Further validation and functional experiments are necessary.

Humans↗
PubMed2007

A high-throughput 3-parameter flow cytometry-based cell death assay.

Apoptosis plays a role in many disease states, and the evaluation of novel therapeutics that alters the apoptotic cascade is an area of intense investigation. However, many generally available methods to evaluate cell death are either time consuming, imprecise, or both. We report a system that permits simultaneous evaluation of three apoptotic markers (cell membrane integrity, mitochondrial membrane potential, and cell cycle progression) with minimal technical manipulation. This system is particularly well-suited for toxicologic evaluation of novel compounds and profiling of new apoptosis-inducing agents.

Apoptosis↗
PubMed2006

Absence of perforin expression confers axonal protection despite demyelination.

Current evidence suggests that demyelination may be a necessary but not a sufficient condition for neurologic deficits associated with multiple sclerosis. Axon injury that occurs within the permissive environment of the demyelinated lesion is better correlated with functional deficits, but the mechanisms and cellular effectors of this injury are largely unknown. In an effort to identify potential axon injury mediators, we examined demyelination, motor function, and the number of spinal axons in perforin-deficient mice. Perforin is a critical molecular mediator of cytotoxic immunological injury and we hypothesized that genetic deletion of perforin expression would protect demyelinated axons. Indeed, we found that while perforin-deficient mice had considerable spinal cord demyelination 180 days after infection with Theiler's murine encephalomyelitis virus, such mice exhibited functional and axonal preservation comparable to non-demyelinated perforin-competent controls. We conclude that perforin-dependent effector cells such as cytotoxic T cells, gammadelta T cells, and natural killer cells may play a role in axon damage that is dependent upon but separable from demyelination.

Animals↗
PubMed2006

Induction of a gene expression program in dendritic cells with a cross-linking IgM antibody to the co-stimulatory molecule B7-DC.

While bivalent antibodies can block ligand-receptor interactions, IgM pentamers efficiently cross-link cell surface targets and evoke physiological responses. We have described one such interaction between an IgM antibody (Ab) and the B7-DC costimulatory molecule expressed by dendritic cells that induces strong antitumor immunity and modulates pathogenic responses associated with allergic asthma. Progressive changes in gene expression in dendritic cells activated by an IgM B7-DC cross-linking Ab resulted in the increased expression in 350 genes and decreased expression of more than 200 genes over the course of 24 h following Ab treatment. In particular, up-regulation of the caspase inhibitor FLIP and the chemokine receptor CCR7, and the down-regulation of the CXCR4 receptor provide a mechanistic basis of Ab-induced survival and enhanced migration into draining lymph nodes. Increased expression of both cell surface and secreted molecules known to be mediators of the immunomodulatory properties of dendritic cells was detected at both the levels of RNA and protein expression. This analysis documents the ability of IgM Ab to activate a gene expression cascade leading to important biological changes in cellular function and provides mechanistic insight into the potent immunomodulatory properties attributed to this Ab.

Animals↗
PubMed2006

Disrupted spatial memory is a consequence of picornavirus infection.

Picornaviruses are a socioeconomically important family of viruses that includes the rhinoviruses and enteroviruses. Many of these viruses, including the "common cold" Coxsackie virus A21, maintain neurovirulent potential and may induce hippocampal injury. The behavioral implications of this injury have not been adequately explored. Using C57BL/6J mice infected with Theiler's murine encephalomyelitis virus, we examined the formation of spatial memories using the Morris water maze test. Virus-infected mice had greater search error compared to sham-infected animals during the location of a hidden platform and were unable to discriminate the location of the training quadrant during the final probe trial. Furthermore, sham-infected mice were place responders whereas virus-infected mice were cue responders, indicating a lack of spatial memory formation in infected animals. Importantly, the degree of memory impairment was correlated to the extent of hippocampal injury. This suggests that picornavirus infection of the human CNS may also result in at least some degree of neurologic deficit. An important implication of such subclinical virus-induced neurologic deficit is that the injury may accumulate over the lifetime of the individual, eventually leading to the manifestation of clinical cognitive or memory deficits.

Animals↗
PubMed2006

Activated microglia stimulate transcriptional changes in primary oligodendrocytes via IL-1beta.

No therapy currently exists to repair demyelinated lesions in multiple sclerosis. However, the use of IgM antibodies may provide a valuable therapeutic avenue for evoking such repair. Unfortunately, the mechanism of immunoglobulin action in CNS repair is currently unknown but may depend upon complex interactions between multiple cell types rather than upon direct activation of a single cell type. Using rat mixed glial cultures containing oligodendrocytes, microglia, and astrocytes, we found that the Fc portion of human IgM shifts microglia to an activated phenotype, reduces glial proliferation, upregulates a variety of immediate early genes, including JunB, Egr-1, and c-Fos, and stimulates microglial production and release of IL-1beta. Microglia-derived IL-1beta consequently triggers transcriptional upregulation of immediate early genes such as c-Jun, Egr-1, and c-Fos in the mixed glial cultures, and stimulates the upregulation of late response genes such as lipocalin in purified oligodendrocytes. Treatment with an IL-1beta receptor antagonist abrogates the effects of Fcmu on glial proliferation and prevents the upregulation of lipocalin in response to Fcmu, but does not prevent Fcmu-mediated upregulation of IL-1beta, suggesting that IL-1beta mediates at least some of the downstream effects of Fcmu in mixed glial cultures. We hypothesize that Fcmu-stimulated IL-1beta-induced upregulation of immediate early and late response genes in oligodendrocytes may promote CNS repair.

Animals↗
PubMed2006

Coated glass and vicryl microfibers as artificial axons.

The complex interactions that occur between oligodendrocytes and axons during the process of central nervous system myelination and remyelination remain unclear. Elucidation of the cell-biological and -biochemical mechanisms supporting myelin production and elaboration requires a robust in vitro system that recapitulates the relationship between axons and oligodendrocytes in a manner that is open to molecular dissection. We provide evidence for an artificial axon culture system in which we observed oligodendrocytes extending large plasma membrane projections that frequently completely ensheathed fibers coated with a variety of extracellular matrix molecules. These membrane projections varied in extent and thickness depending upon the substrate and upon the diameter of the coated fiber. Matrigel-coated glass microfibers were found to support the development of thick membrane sheaths that extended for hundreds of microns and exhibited many features suggestive of the potential for true myelin deposition. Likewise, Matrigel-coated Vicryl fibers supported plasma membrane extensions that covered extremely large surface areas and occasionally wrapped the coated Vicryl fibers in more than one membrane layer. Our findings suggest that the deposition of molecular cues onto glass or polymer fibers either via adsorption or chemical modification may be a useful tool for the discovery or validation of axonal factors critical for myelination and remyelination. Herein, we provide evidence that polyglactin 910 and glass microfibers coated with adhesion factors may provide a reasonable system for the in vitro analysis of myelination, and may eventually serve a role in engineering artificial systems for neural repair.

Animals↗
PubMed2005

Picornaviruses and cell death.

Members of the picornavirus family, including poliovirus and foot-and-mouth disease virus, are widespread pathogens of humans and domestic animals. Recent global developments in the resurgence of poliovirus infection and in the control of foot-and-mouth disease infection highlight the problems caused by the ability of picornaviruses to alter the apoptotic machinery of host cells and establish persistent infections. Despite the medical, economic and social impact of this family of viruses, little information exists that integrates the mechanisms of cell death and damage induced by related family members. Fortunately, examination of the reported roles and functions of individual viral proteins from multiple picornaviruses makes it possible to surmise canonical functions for these proteins. This review analyzes the canonical function of picornavirus proteins involved in the alteration of apoptotic homeostasis in infected host cells.

Animals↗
PubMed2005

Modeling the signaling endosome hypothesis: why a drive to the nucleus is better than a (random) walk.

BACKGROUND: Information transfer from the plasma membrane to the nucleus is a universal cell biological property. Such information is generally encoded in the form of post-translationally modified protein messengers. Textbook signaling models typically depend upon the diffusion of molecular signals from the site of initiation at the plasma membrane to the site of effector function within the nucleus. However, such models fail to consider several critical constraints placed upon diffusion by the cellular milieu, including the likelihood of signal termination by dephosphorylation. In contrast, signaling associated with retrogradely transported membrane-bounded organelles such as endosomes provides a dephosphorylation-resistant mechanism for the vectorial transmission of molecular signals. We explore the relative efficiencies of signal diffusion versus retrograde transport of signaling endosomes. RESULTS: Using large-scale Monte Carlo simulations of diffusing STAT-3 molecules coupled with probabilistic modeling of dephosphorylation kinetics we found that predicted theoretical measures of STAT-3 diffusion likely overestimate the effective range of this signal. Compared to the inherently nucleus-directed movement of retrogradely transported signaling endosomes, diffusion of STAT-3 becomes less efficient at information transfer in spatial domains greater than 200 nanometers from the plasma membrane. CONCLUSION: Our model suggests that cells might utilize two distinct information transmission paradigms: 1) fast local signaling via diffusion over spatial domains on the order of less than 200 nanometers; 2) long-distance signaling via information packets associated with the cytoskeletal transport apparatus. Our model supports previous observations suggesting that the signaling endosome hypothesis is a subset of a more general hypothesis that the most efficient mechanism for intracellular signaling-at-a-distance involves the association of signaling molecules with molecular motors that move along the cytoskeleton. Importantly, however, cytoskeletal association of membrane-bounded complexes containing ligand-occupied transmembrane receptors and downstream effector molecules provides the ability to regenerate signals at any point along the transmission path. We conclude that signaling endosomes provide unique information transmission properties relevant to all cell architectures, and we propose that the majority of relevant information transmitted from the plasma membrane to the nucleus will be found in association with organelles of endocytic origin.

Animals↗
PubMed2005

Long-distance retrograde neurotrophic signaling.

The retrograde communication of neurotrophic signals from axon terminals to neuron cell bodies is crucial for neuron survival and plasticity. Several mechanisms have been proposed in the past, but recent evidence strongly supports the hypothesis that the retrograde propagation of self-regenerating signaling organelles, derived from the endocytosis of activated neurotrophin-bound receptor tyrosine kinases, is the primary mechanism responsible for this long-distance communication.

Animals↗
PubMed2005

Differential endocytic sorting of p75NTR and TrkA in response to NGF: a role for late endosomes in TrkA trafficking.

NGF binds to two receptors, p75NTR and TrkA. The endosomal trafficking of receptors is of emerging importance for the understanding of their signaling. We compared the endocytic trafficking of the two NGF receptors in PC12 cells. Both p75NTR and TrkA were internalized in response to NGF and colocalized with early endosomes. However, surprisingly, the subsequent endosomal trafficking paths of both NGF receptors diverged: whereas p75NTR recycled back to the surface, TrkA moved to late endosomes and underwent lysosomal degradation. By performing subcellular fractionations of NGF stimulated PC12 cells, tyrosine-phosphorylated TrkA was recovered in fractions corresponding to late endosomes. This implicates these organelles as novel endosomal NGF signaling platforms. Furthermore, the trafficking of NGF receptors could be manipulated by pharmacological means. Disrupting p75NTR recycling diminished TrkA activation in response to low concentrations of NGF, demonstrating a functional role for the recycling of p75NTR.

Animals↗
PubMed2004

Signaling endosome hypothesis: A cellular mechanism for long distance communication.

The kinetics of signaling endosome retrograde transport along axons is analyzed and offered as evidence that such transport is more efficient than diffusion or calcium wave-based signaling systems over even relatively small distances. Evidence is provided to support the signaling endosome hypothesis and to expand the hypothesis to include signaling in many cell types and many cellular dimensions. Finally, a saltatory, regenerating inositol 1,4,5-trisphosphate wave model is offered to reconcile current discrepancies in the literature regarding endosomal-based retrograde signaling.

Animals↗
PubMed2004

Differences in the surface binding and endocytosis of neurotrophins by p75NTR.

Neurotrophins transmit signals retrogradely from synapses to cell bodies by two different types of surface receptors, p75NTR and Trks. Compared to TrkA, the function of p75NTR in nerve growth factor (NGF) endocytosis is less clear, and it is unknown whether p75NTR by itself may internalize other neurotrophins besides NGF. We directly compared TrkA and p75NTR for their ability to internalize NGF, and we also examined the endocytosis of iodinated brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) by p75NTR. Cells expressing solely TrkA internalized NGF more efficiently than cells expressing p75NTR. Surprisingly, cells expressing only p75NTR internalized far more BDNF or NT3 than NGF. Moreover, p75NTR was more important for surface binding than for intracellular accumulation of each neurotrophin. Finally, we established a mechanistic role for the clathrin pathway in p75NTR endocytosis. Our results suggest that p75NTR may have multiple roles in different subcellular locations, functioning both at the cell surface and also within endocytic compartments.

Animals↗
PubMed2004

Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody.

Stabilizing the survival of oligodendrocytes and oligodendrocyte precursors within and near lesions in patients suffering from multiple sclerosis (MS) and other demyelinating diseases is an important therapeutic goal. Previous studies have identified a human-derived monoclonal IgM antibody designated rHIgM22 that induces remyelination in a mouse model of MS. We provide evidence that this antibody, directed against myelin, induces antiapoptotic signaling in premyelinating oligodendrocytes and reduces caspase-3 activation and caspase gene expression in mice undergoing antibody-induced remyelination. This effect was dependent on calcium entry via CNQX-sensitive channels and on lipid raft integrity, and was correlated with suppression of JNK signaling. We conclude that rHIgM22 may induce remyelination via rescue of oligodendrocytes, and suggest that such autoantibody-mediated signaling may have important therapeutic implications for a variety of neurological diseases, including stroke and Alzheimer's disease.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2004

Trafficking the NGF signal: implications for normal and degenerating neurons.

Nerve growth factor (NGF) activates TrkA to trigger signaling events that promote the survival, differentiation and maintenance of neurons. The mechanism(s) that controls the retrograde transport of the NGF signal from axon terminals to neuron cell bodies is not known. The 'signaling endosome' hypothesis stipulates that NGF, TrkA and signaling proteins are retrogradely transported on endocytic vesicles. Here, we provide evidence for the existence of signaling endosomes. Following NGF treatment, clathrin-coated vesicles (CCVs) contain NGF bound to TrkA together with activated signaling proteins of the Ras/pErk1/2 pathway. NGF signals from isolated CCVs through the Erk1/2 pathway. Early endosomes appear to represent a second type of signaling endosomes. We found that NGF induced a sustained activation of Rap1, a small monomeric GTP-binding protein of the Ras family, and that this activation occurred in early endosomes that contain key elements of Rap1/pErk1/2 pathway. We discuss the possibility that the failure of retrograde NGF signaling in a mouse model of Down syndrome (Ts65Dn) may be due to the failure to retrograde transport signaling endosomes. It is important to define further the significance of signaling endosomes in the biology of both normal and degenerating neurons.

Adaptor Protein Complex 2↗