Publications by authors named "Jessica L Allen"

38 Publications

Copy number alterations identify a smoking-associated expression signature predictive of poor outcome in head and neck squamous cell carcinoma.

Cancer Genet 2021 Aug 28;256-257:136-148. Epub 2021 May 28.

Department of Biochemistry, Program in Cancer Cell Biology USA. Electronic address:

Cigarette smoking is a risk factor for the development of head and neck squamous cell carcinoma (HNSCC), partially due to tobacco-induced large-scale chromosomal copy-number alterations (CNAs). Identifying CNAs caused by smoking is essential in determining how gene expression from such regions impact tumor progression and patient outcome. We utilized The Cancer Genome Atlas (TCGA) whole genome sequencing data for HNSCC to directly identify amplified or deleted genes correlating with smoking pack-year based on linear modeling. Internal cross-validation identified 35 CNAs that significantly correlated with patient smoking, independent of human papillomavirus (HPV) status. The most abundant CNAs were chromosome 11q13.3-q14.4 amplification and 9p23.1/9p24.1 deletion. Evaluation of patient amplicons reveals four different patterns of 11q13 gene amplification in HNSCC resulting from breakage-fusion-bridge (BFB) events. . Predictive modeling identified 16 genes from these regions that denote poorer overall and disease-free survival with increased pack-year use, constituting a smoking-associated expression signature (SAES). Patients with altered expression of signature genes have increased risk of death and enhanced cervical lymph node involvement. The identified SAES can be utilized as a novel predictor of increased disease aggressiveness and poor outcome in smoking-associated HNSCC.
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http://dx.doi.org/10.1016/j.cancergen.2021.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273756PMC
August 2021

A BAFF/APRIL axis regulates obesogenic diet-driven weight gain.

Nat Commun 2021 05 18;12(1):2911. Epub 2021 May 18.

Department of Pediatrics, The University of Cincinnati College of Medicine, Cincinnati, OH, USA.

The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with protection from weight gain, approximating a log-linear dose response relation to BAFF concentrations. Gene expression analysis of BAFF-stimulated subcutaneous white adipocytes unveils upregulation of lipid metabolism pathways, with BAFF inducing white adipose tissue (WAT) lipolysis. Brown adipose tissue (BAT) from BAFF-overexpressing mice exhibits increased Ucp1 expression and BAFF promotes brown adipocyte respiration and in vivo energy expenditure. A proliferation-inducing ligand (APRIL), a BAFF homolog, similarly modulates WAT and BAT lipid handling. Genetic deletion of both BAFF and APRIL augments diet-induced obesity. Lastly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with greater BMI decrease after bariatric surgery. Together, the BAFF/APRIL axis is a multifaceted immune regulator of weight gain and adipose tissue function.
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http://dx.doi.org/10.1038/s41467-021-23084-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131685PMC
May 2021

Generalization of motor module recruitment across standing reactive balance and walking is associated with beam walking performance in young adults.

Gait Posture 2020 10 16;82:242-247. Epub 2020 Sep 16.

Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, USA.

Background: Recent studies provide compelling evidence that recruiting a common pool of motor modules across behaviors (i.e., motor module generalization) may facilitate motor performance. In particular, motor module generalization across standing reactive balance and walking is associated with both walking speed and endurance in neurologically impaired populations (e.g., stroke survivors and individual's with Parkinson's disease). To test whether this phenomenon is a general neuromuscular strategy associated with well-coordinated walking and not limited to motor impairment, this relationship must be confirmed in neurologically intact adults.

Research Question: Is motor module generalization across standing reactive balance and walking related to walking performance in neurologically intact young adults?

Methods: Two populations of young adults were recruited to capture a wide range of walking performance: professionally-trained ballet dancers (i.e., experts, n = 12) and novices (n = 8). Motor modules (a.k.a. muscle synergies) were extracted from muscles spanning the trunk, hip, knee and ankle during walking and multidirectional perturbations to standing. Motor module generalization was calculated as the number of modules common to these behaviors. Walking performance was assessed using self-selected walking speed and beam-walking proficiency (i.e., distance walked on a narrow beam). Motor module generalization between experts and novices was compared using rank-sum tests and the association between generalization and walking performance was assessed using correlation analyses.

Results: Experts generalized more motor modules across standing reactive balance and walking than novices (p = 0.009). Across all subjects, motor module generalization was moderately associated with increased beam walking proficiency (r = 0.456, p = 0.022) but not walking speed (r = 0.092, p = 0.349).

Significance: Similar relationships between walking performance and motor module generalization exist in neurologically intact and impaired populations, suggesting that motor module generalization across standing reactive balance and walking may be a general neuromuscular mechanism contributing to the successful control of walking.
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http://dx.doi.org/10.1016/j.gaitpost.2020.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718426PMC
October 2020

Reorganization of motor modules for standing reactive balance recovery following pyridoxine-induced large-fiber peripheral sensory neuropathy in cats.

J Neurophysiol 2020 09 12;124(3):868-882. Epub 2020 Aug 12.

The Wallace H. Coulter Department of Biomedical Engineering, Georgia Tech and Emory University, Atlanta, Georgia.

Task-level goals such as maintaining standing balance are achieved through coordinated muscle activity. Consistent and individualized groupings of synchronously activated muscles can be estimated from muscle recordings in terms of motor modules or muscle synergies, independent of their temporal activation. The structure of motor modules can change with motor training, neurological disorders, and rehabilitation, but the central and peripheral mechanisms underlying motor module structure remain unclear. To assess the role of peripheral somatosensory input on motor module structure, we evaluated changes in the structure of motor modules for reactive balance recovery following pyridoxine-induced large-fiber peripheral somatosensory neuropathy in previously collected data in four adult cats. Somatosensory fiber loss, quantified by postmortem histology, varied from mild to severe across cats. Reactive balance recovery was assessed using multidirectional translational support-surface perturbations over days to weeks throughout initial impairment and subsequent recovery of balance ability. Motor modules within each cat were quantified by non-negative matrix factorization and compared in structure over time. All cats exhibited changes in the structure of motor modules for reactive balance recovery after somatosensory loss, providing evidence that somatosensory inputs influence motor module structure. The impact of the somatosensory disturbance on the structure of motor modules in well-trained adult cats indicates that somatosensory mechanisms contribute to motor module structure, and therefore may contribute to some of the pathological changes in motor module structure in neurological disorders. These results further suggest that somatosensory nerves could be targeted during rehabilitation to influence pathological motor modules for rehabilitation. Stable motor modules for reactive balance recovery in well-trained adult cats were disrupted following pyridoxine-induced peripheral somatosensory neuropathy, suggesting somatosensory inputs contribute to motor module structure. Furthermore, the motor module structure continued to change as the animals regained the ability to maintain standing balance, but the modules generally did not recover pre-pyridoxine patterns. These results suggest changes in somatosensory input and subsequent learning may contribute to changes in motor module structure in pathological conditions.
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http://dx.doi.org/10.1152/jn.00739.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509294PMC
September 2020

Disparate survival of late-stage male oropharyngeal cancer in Appalachia.

Sci Rep 2020 07 15;10(1):11612. Epub 2020 Jul 15.

Department of Biochemistry, Program in Cancer Cell Biology, West Virginia University Cancer Institute, West Virginia University, P.O. Box 9300, Morgantown, WV, 26506, USA.

The United States Appalachian region harbors a higher cancer burden than the rest of the nation, with disparate incidence of head and neck squamous cell carcinomas (HNSCC), including oral cavity and pharynx (OC/P) cancers. Whether elevated HNSCC incidence generates survival disparities within Appalachia is unknown. To address this, HNSCC survival data for 259,737 tumors from the North American Association for Central Cancer Registries 2007-2013 cohort were evaluated, with age-adjusted relative survival (RS) calculated based on staging, race, sex, and Appalachian residence. Tobacco use, a primary HNSCC risk factor, was evaluated through the Behavioral Risk Factor Surveillance System from Appalachian states. Decreased OC/P RS was found in stage IV Appalachian white males within a subset of states. The survival disparity was confined to human papillomavirus (HPV)-associated oropharyngeal cancers, specifically the oropharynx subsite. This correlated with significantly higher smoking and male smokeless tobacco use in most Appalachian disparity states. Lower survival of Appalachian males with advanced-stage HPV-associated oropharyngeal cancers suggests pervasive tobacco consumption likely generates more aggressive tumors at HPV-associated oropharynx subsites than national averages. Comprehensive tobacco and HPV status should therefore be evaluated prior to considering treatment de-intensification regimens for HPV-associated oropharyngeal cancers in populations with high tobacco consumption.
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http://dx.doi.org/10.1038/s41598-020-68380-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363863PMC
July 2020

Complete, high-quality genomes from long-read metagenomic sequencing of two wolf lichen thalli reveals enigmatic genome architecture.

Genomics 2020 09 3;112(5):3150-3156. Epub 2020 Jun 3.

Department of Biology, Eastern Washington University, Cheney, WA, USA.

Fungal genomes display incredible levels of complexity and diversity, and are exceptional study systems for genome evolution. Here we used the Oxford Nanopore MinION sequencing platform to generate high-quality fungal genomes from complex metagenomic samples of lichen thalli. We sequenced two wolf lichens using one flow cell per sample, generating 17.1 Gbps for Letharia lupina and 14.3 Gbps for Letharia columbiana. The resulting L. lupina genome is one of the most contiguous lichen genomes available to date, with 49.2 Mbp contained on 31 contigs. The L. columbiana genome, while less contiguous, is still relatively high quality, with 52.3 Mbp on a total of 161 contigs. Each thallus for both species contained multiple distinct haplotypes, a phenomenon that has rarely been empirically demonstrated. The Oxford Nanopore sequencing technologies are robust and effective when applied to complex symbioses, and have the potential to fundamentally transform our understanding of fungal genetics.
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http://dx.doi.org/10.1016/j.ygeno.2020.06.006DOI Listing
September 2020

Computational Design of FastFES Treatment to Improve Propulsive Force Symmetry During Post-stroke Gait: A Feasibility Study.

Front Neurorobot 2019 1;13:80. Epub 2019 Oct 1.

Rice Computational Neuromechanics Laboratory, Department of Mechanical Engineering, Rice University, Houston, TX, United States.

Stroke is a leading cause of long-term disability worldwide and often impairs walking ability. To improve recovery of walking function post-stroke, researchers have investigated the use of treatments such as fast functional electrical stimulation (FastFES). During FastFES treatments, individuals post-stroke walk on a treadmill at their fastest comfortable speed while electrical stimulation is delivered to two muscles of the paretic ankle, ideally to improve paretic leg propulsion and toe clearance. However, muscle selection and stimulation timing are currently standardized based on clinical intuition and a one-size-fits-all approach, which may explain in part why some patients respond to FastFES training while others do not. This study explores how personalized neuromusculoskeletal models could potentially be used to enable individual-specific selection of target muscles and stimulation timing to address unique functional limitations of individual patients post-stroke. Treadmill gait data, including EMG, surface marker positions, and ground reactions, were collected from an individual post-stroke who was a non-responder to FastFES treatment. The patient's gait data were used to personalize key aspects of a full-body neuromusculoskeletal walking model, including lower-body joint functional axes, lower-body muscle force generating properties, deformable foot-ground contact properties, and paretic and non-paretic leg neural control properties. The personalized model was utilized within a direct collocation optimal control framework to reproduce the patient's unstimulated treadmill gait data (verification problem) and to generate three stimulated walking predictions that sought to minimize inter-limb propulsive force asymmetry (prediction problems). The three predictions used: (1) Standard muscle selection (gastrocnemius and tibialis anterior) with standard stimulation timing, (2) Standard muscle selection with optimized stimulation timing, and (3) Optimized muscle selection (soleus and semimembranosus) with optimized stimulation timing. Relative to unstimulated walking, the optimal control problems predicted a 41% reduction in propulsive force asymmetry for scenario (1), a 45% reduction for scenario (2), and a 64% reduction for scenario (3), suggesting that non-standard muscle selection may be superior for this patient. Despite these predicted improvements, kinematic symmetry was not noticeably improved for any of the walking predictions. These results suggest that personalized neuromusculoskeletal models may be able to predict personalized FastFES training prescriptions that could improve propulsive force symmetry, though inclusion of kinematic requirements would be necessary to improve kinematic symmetry as well.
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http://dx.doi.org/10.3389/fnbot.2019.00080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779709PMC
October 2019

Machine-learning to stratify diabetic patients using novel cardiac biomarkers and integrative genomics.

Cardiovasc Diabetol 2019 06 11;18(1):78. Epub 2019 Jun 11.

Division of Exercise Physiology, West Virginia University School of Medicine, PO Box 9227, 1 Medical Center Drive, Morgantown, WV, 26505, USA.

Background: Diabetes mellitus is a chronic disease that impacts an increasing percentage of people each year. Among its comorbidities, diabetics are two to four times more likely to develop cardiovascular diseases. While HbA1c remains the primary diagnostic for diabetics, its ability to predict long-term, health outcomes across diverse demographics, ethnic groups, and at a personalized level are limited. The purpose of this study was to provide a model for precision medicine through the implementation of machine-learning algorithms using multiple cardiac biomarkers as a means for predicting diabetes mellitus development.

Methods: Right atrial appendages from 50 patients, 30 non-diabetic and 20 type 2 diabetic, were procured from the WVU Ruby Memorial Hospital. Machine-learning was applied to physiological, biochemical, and sequencing data for each patient. Supervised learning implementing SHapley Additive exPlanations (SHAP) allowed binary (no diabetes or type 2 diabetes) and multiple classification (no diabetes, prediabetes, and type 2 diabetes) of the patient cohort with and without the inclusion of HbA1c levels. Findings were validated through Logistic Regression (LR), Linear Discriminant Analysis (LDA), Gaussian Naïve Bayes (NB), Support Vector Machine (SVM), and Classification and Regression Tree (CART) models with tenfold cross validation.

Results: Total nuclear methylation and hydroxymethylation were highly correlated to diabetic status, with nuclear methylation and mitochondrial electron transport chain (ETC) activities achieving superior testing accuracies in the predictive model (~ 84% testing, binary). Mitochondrial DNA SNPs found in the D-Loop region (SNP-73G, -16126C, and -16362C) were highly associated with diabetes mellitus. The CpG island of transcription factor A, mitochondrial (TFAM) revealed CpG24 (chr10:58385262, P = 0.003) and CpG29 (chr10:58385324, P = 0.001) as markers correlating with diabetic progression. When combining the most predictive factors from each set, total nuclear methylation and CpG24 methylation were the best diagnostic measures in both binary and multiple classification sets.

Conclusions: Using machine-learning, we were able to identify novel as well as the most relevant biomarkers associated with type 2 diabetes mellitus by integrating physiological, biochemical, and sequencing datasets. Ultimately, this approach may be used as a guideline for future investigations into disease pathogenesis and novel biomarker discovery.
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http://dx.doi.org/10.1186/s12933-019-0879-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560734PMC
June 2019

Adaptation of the group A Streptococcus adhesin Scl1 to bind fibronectin type III repeats within wound-associated extracellular matrix: implications for cancer therapy.

Mol Microbiol 2019 09 12;112(3):800-819. Epub 2019 Jun 12.

Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV, USA.

The human-adapted pathogen group A Streptococcus (GAS) utilizes wounds as portals of entry into host tissue, wherein surface adhesins interact with the extracellular matrix, enabling bacterial colonization. The streptococcal collagen-like protein 1 (Scl1) is a major adhesin of GAS that selectively binds to two fibronectin type III (FnIII) repeats within cellular fibronectin, specifically the alternatively spliced extra domains A and B, and the FnIII repeats within tenascin-C. Binding to FnIII repeats was mediated through conserved structural determinants present within the Scl1 globular domain and facilitated GAS adherence and biofilm formation. Isoforms of cellular fibronectin that contain extra domains A and B, as well as tenascin-C, are present for several days in the wound extracellular matrix. Scl1-FnIII binding is therefore an example of GAS adaptation to the host's wound environment. Similarly, cellular fibronectin isoforms and tenascin-C are present in the tumor microenvironment. Consistent with this, FnIII repeats mediate GAS attachment to and enhancement of biofilm formation on matrices deposited by cancer-associated fibroblasts and osteosarcoma cells. These data collectively support the premise for utilization of the Scl1-FnIII interaction as a novel method of anti-neoplastic targeting in the tumor microenvironment.
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http://dx.doi.org/10.1111/mmi.14317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736723PMC
September 2019

Motor module generalization across balance and walking is impaired after stroke.

J Neurophysiol 2019 07 8;122(1):277-289. Epub 2019 May 8.

Department of Rehabilitation Medicine, Division of Physical Therapy, Emory University School of Medicine , Atlanta, Georgia.

Muscle coordination is often impaired after stroke, leading to deficits in the control of walking and balance. In this study, we examined features of muscle coordination associated with reduced walking performance in chronic stroke survivors using motor module (a.k.a. muscle synergy) analysis. We identified differences between stroke survivors and age-similar neurotypical controls in the modular control of both overground walking and standing reactive balance. In contrast to previous studies that demonstrated reduced motor module number poststroke, our cohort of stroke survivors did not exhibit a reduction in motor module number compared with controls during either walking or reactive balance. Instead, the pool of motor modules common to walking and reactive balance was smaller, suggesting reduced generalizability of motor module function across behaviors. The motor modules common to walking and reactive balance tended to be less variable and more distinct, suggesting more reliable output compared with motor modules specific to either behavior. Greater motor module generalization in stroke survivors was associated with faster walking speed, more normal step length asymmetry, and narrower step widths. Our work is the first to show that motor module generalization across walking and balance may help to distinguish important and clinically relevant differences in walking performance across stroke survivors that would have been overlooked by examining only a single behavior. Finally, because similar relationships between motor module generalization and walking performance have been demonstrated in healthy young adults and individuals with Parkinson's disease, this suggests that motor module generalization across walking and balance may be important for well-coordinated walking. This is the first work to simultaneously examine neuromuscular control of walking and standing reactive balance in stroke survivors. We show that motor module generalization across these behaviors (i.e., recruiting common motor modules) is reduced compared with controls and is associated with slower walking speeds, asymmetric step lengths, and larger step widths. This is true despite no between-group differences in module number, suggesting that motor module generalization across walking and balance is important for well-coordinated walking.
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http://dx.doi.org/10.1152/jn.00561.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689783PMC
July 2019

Pain-Reducing Effects of Physical Therapist-Delivered Interventions: A Systematic Review of Randomized Trials Among Older Adults With Dementia.

J Geriatr Phys Ther 2020 Jul/Sep;43(3):159-169

Department of Physical Therapy, The University of Texas Medical Branch, Galveston.

Background And Purpose: Pain is common among older adults with dementia. There are nonpharmacological options for managing pain in this population. However, the effects of physical therapist-delivered interventions have not been summarized. The purpose of this systematic review was to summarize the literature on physical therapist-delivered interventions in randomized trials for reducing pain among older adults with dementia.

Methods: A systematic search of MEDLINE/PubMed, CINAHL, PsycINFO, and Web of Science was conducted for randomized trials of pain management in individuals 60 years or older with medically diagnosed dementia of any severity. Included studies addressed the effects of nonpharmacological physical therapist-delivered interventions on pain outcomes. Pain outcomes included patient or caregiver self-report, observational or interactive measures. Independent reviewers extracted relevant data and assessed methodological quality using the PEDro scale.

Results And Discussion: Three studies (total = 222 participants; mean age range = 82.2-84.0 years; 178 [80.2%] females) met inclusion criteria. PEDro scores ranged from 4 to 8/10. Interventions included passive movement and massage. Pain outcomes included the observational measures Pain Assessment Checklist for Seniors with Limited Ability to Communicate (PACSLAC), Pain in Advanced Dementia (PAINAD), and Doloplus-2 Scale. Passive movement did not show better results when compared with no treatment, while massage showed pain-reducing effects in 1 study compared with no treatment.

Conclusions: The evidence supporting pain-reducing physical therapy interventions for patients with dementia is limited. There is a clear gap in knowledge related to evidence-based physical therapy for managing pain in this population. Future studies should examine active physical therapist-delivered interventions and utilize interactive pain measures.
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http://dx.doi.org/10.1519/JPT.0000000000000235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800767PMC
January 2021

Gait Rehabilitation Using Functional Electrical Stimulation Induces Changes in Ankle Muscle Coordination in Stroke Survivors: A Preliminary Study.

Front Neurol 2018 20;9:1127. Epub 2018 Dec 20.

Division of Physical Therapy, Department of Rehabilitation Medicine, Emory University School of Medicine, Atlanta, GA, United States.

Previous studies have demonstrated that post-stroke gait rehabilitation combining functional electrical stimulation (FES) applied to the ankle muscles during fast treadmill walking (FastFES) improves gait biomechanics and clinical walking function. However, there is considerable inter-individual variability in response to FastFES. Although FastFES aims to sculpt ankle muscle coordination, whether changes in ankle muscle activity underlie observed gait improvements is unknown. The aim of this study was to investigate three cases illustrating how FastFES modulates ankle muscle recruitment during walking. We conducted a preliminary case series study on three individuals (53-70 y; 2 M; 35-60 months post-stroke; 19-22 lower extremity Fugl-Meyer) who participated in 18 sessions of FastFES (3 sessions/week; ClinicalTrials.gov: NCT01668602). Clinical walking function (speed, 6-min walk test, and Timed-Up-and-Go test), gait biomechanics (paretic propulsion and ankle angle at initial-contact), and plantarflexor (soleus)/dorsiflexor (tibialis anterior) muscle recruitment were assessed pre- and post-FastFES while walking without stimulation. Two participants (R1, R2) were categorized as responders based on improvements in clinical walking function. Consistent with heterogeneity of clinical and biomechanical changes commonly observed following gait rehabilitation, how muscle activity was altered with FastFES differed between responders. R1 exhibited improved plantarflexor recruitment during stance accompanied by increased paretic propulsion. R2 exhibited improved dorsiflexor recruitment during swing accompanied by improved paretic ankle angle at initial-contact. In contrast, the third participant (NR1), classified as a non-responder, demonstrated increased ankle muscle activity during inappropriate phases of the gait cycle. Across all participants, there was a positive relationship between increased walking speeds after FastFES and reduced SOL/TA muscle coactivation. Our preliminary case series study is the first to demonstrate that improvements in ankle plantarflexor and dorsiflexor muscle recruitment (muscles targeted by FastFES) accompanied improvements in gait biomechanics and walking function following FastFES in individuals post-stroke. Our results also suggest that inducing more appropriate (i.e., reduced) ankle plantar/dorsi-flexor muscle coactivation may be an important neuromuscular mechanism underlying improvements in gait function after FastFES training, suggesting that pre-treatment ankle muscle status could be used for inclusion into FastFES. The findings of this case-series study, albeit preliminary, provide the rationale and foundations for larger-sample studies using similar methodology.
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http://dx.doi.org/10.3389/fneur.2018.01127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306420PMC
December 2018

Cortactin Phosphorylation by Casein Kinase 2 Regulates Actin-Related Protein 2/3 Complex Activity, Invadopodia Function, and Tumor Cell Invasion.

Mol Cancer Res 2019 04 4;17(4):987-1001. Epub 2019 Jan 4.

Program in Cancer Cell Biology, Department of Biochemistry, West Virginia University, Morgantown, West Virginia.

Malregulation of the actin cytoskeleton enhances tumor cell motility and invasion. The actin-binding protein cortactin facilitates branched actin network formation through activation of the actin-related protein (Arp) 2/3 complex. Increased cortactin expression due to gene amplification is observed in head and neck squamous cell carcinoma (HNSCC) and other cancers, corresponding with elevated tumor progression and poor patient outcome. Arp2/3 complex activation is responsible for driving increased migration and extracellular matrix (ECM) degradation by governing invadopodia formation and activity. Although cortactin-mediated activation of Arp2/3 complex and invadopodia regulation has been well established, signaling pathways responsible for governing cortactin binding to Arp2/3 are unknown and potentially present a new avenue for anti-invasive therapeutic targeting. Here we identify casein kinase (CK) 2α phosphorylation of cortactin as a negative regulator of Arp2/3 binding. CK2α directly phosphorylates cortactin at a conserved threonine (T24) adjacent to the canonical Arp2/3 binding motif. Phosphorylation of cortactin T24 by CK2α impairs the ability of cortactin to bind Arp2/3 and activate actin nucleation. Decreased invadopodia activity is observed in HNSCC cells with expression of CK2α phosphorylation-null cortactin mutants, shRNA-mediated CK2α knockdown, and with the CK2α inhibitor Silmitasertib. Silmitasertib inhibits HNSCC collective invasion in tumor spheroids and orthotopic tongue tumors in mice. Collectively these data suggest that CK2α-mediated cortactin phosphorylation at T24 is critical in regulating cortactin binding to Arp2/3 complex and pro-invasive activity, identifying a potential targetable mechanism for impairing HNSCC invasion. IMPLICATIONS: This study identifies a new signaling pathway that contributes to enhancing cancer cell invasion. http://mcr.aacrjournals.org/content/molcanres/17/4/987/F1.large.jpg.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6445698PMC
April 2019

First genome-wide analysis of the endangered, endemic lichen Cetradonia linearis reveals isolation by distance and strong population structure.

Am J Bot 2018 09 29;105(9):1556-1567. Epub 2018 Aug 29.

The Graduate Center, City University of New York, 365 5th Avenue, New York, New York, 10016, USA.

Premise Of The Study: Lichenized fungi are evolutionarily diverse and ecologically important, but little is known about the processes that drive their diversification and genetic differentiation. Distributions are often assumed to be wholly shaped by ecological requirements rather than dispersal limitations. Furthermore, although asexual and sexual reproductive structures are observable, the lack of information about recombination rates makes inferences about reproductive strategies difficult. We investigated the population genomics of Cetradonia linearis, a federally endangered lichen in the southern Appalachians of eastern North America, to test the relative contributions of environmental and geographic distance in shaping genetic structure, and to characterize the mating system and genome-wide recombination.

Methods: Whole-genome shotgun sequencing was conducted to generate data for 32 individuals of C. linearis. A reference genome was assembled, and reads from all samples were aligned to generate a set of single-nucleotide polymorphisms for further analyses.

Key Results: We found evidence for low rates of recombination and for isolation by distance, but not for isolation by environment. The species is putatively unisexual, given that only one mating-type locus was found. Hindcast species distribution models and the distribution of genetic diversity support C. linearis having a larger range during the Last Glacial Maximum in the southern portion of its current extent.

Conclusions: Our findings contribute to the understanding of factors that shape genetic diversity in C. linearis and in fungi more broadly. Because all populations are highly genetically differentiated, the extirpation of any population would mean the loss of unique genetic diversity; therefore, our results support the continued conservation of this species.
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http://dx.doi.org/10.1002/ajb2.1150DOI Listing
September 2018

The motor repertoire of older adult fallers may constrain their response to balance perturbations.

J Neurophysiol 2018 11 22;120(5):2368-2378. Epub 2018 Aug 22.

Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University , Chapel Hill, North Carolina.

Older adults are at a high risk of falls, and most falls occur during locomotor activities like walking. This study aimed to improve our understanding of changes in neuromuscular control associated with increased risk of falls in older adults in the presence of dynamic balance challenges during walking. Motor module (also known as muscle synergy) analyses identified changes in the neuromuscular recruitment of leg muscles during walking with and without perturbations designed to elicit the visual perception of lateral instability. During normal walking we found that a history of falls (but not age) was associated with reduced motor module complexity and that age (but not a history of falls) was associated with increased step-to-step variability of module recruitment timing. Furthermore, motor module complexity was unaltered in the presence of optical flow perturbations. The specific effects of a history of falls on leg muscle recruitment included an absence and/or inability to independently recruit motor modules normally recruited to perform biomechanical functions important for walking balance control. These results suggest that fallers do not recruit the appropriate motor modules necessary for well-coordinated walking balance control even in the presence of perturbations. The identified changes in the modular control of walking balance in older fallers may either represent a neural deficit that leads to poor balance control or a prior history of falls that results in a compensatory motor adaptation. In either case, our study provides initial evidence that a reduced motor repertoire in older adult fallers may be a constraint on their ability to appropriately respond to balance challenges during walking. NEW & NOTEWORTHY This is the first study to demonstrate a reduced motor repertoire during walking in older adults with a history of falls but without any overt neurological deficits. Furthermore, using virtual reality during walking to elicit the visual perception of lateral instability, we provide initial evidence that a reduced motor repertoire in older adult fallers may be a constraint on their ability to appropriately respond to balance challenges during walking.
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http://dx.doi.org/10.1152/jn.00302.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295530PMC
November 2018

Nanoporous Immunoprotective Device for Stem-Cell-Derived β-Cell Replacement Therapy.

ACS Nano 2017 08 7;11(8):7747-7757. Epub 2017 Aug 7.

UCSF-UC Berkeley Joint PhD Program in Bioengineering , San Francisco, California 94143, United States.

Encapsulation of human embryonic stem-cell-differentiated beta cell clusters (hES-βC) holds great promise for cell replacement therapy for the treatment of diabetics without the need for chronic systemic immune suppression. Here, we demonstrate a nanoporous immunoprotective polymer thin film cell encapsulation device that can exclude immune molecules while allowing exchange of oxygen and nutrients necessary for in vitro and in vivo stem cell viability and function. Biocompatibility studies show the device promotes neovascular formation with limited foreign body response in vivo. The device also successfully prevented teratoma escape into the peritoneal cavity of mice. Long-term animal studies demonstrate evidence of engraftment, viability, and function of cells encapsulated in the device after 6 months. Finally, in vivo study confirms that the device was able to effectively immuno-isolate cells from the host immune system.
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http://dx.doi.org/10.1021/acsnano.7b01239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667644PMC
August 2017

Increased neuromuscular consistency in gait and balance after partnered, dance-based rehabilitation in Parkinson's disease.

J Neurophysiol 2017 07 5;118(1):363-373. Epub 2017 Apr 5.

Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia;

Here we examined changes in muscle coordination associated with improved motor performance after partnered, dance-based rehabilitation in individuals with mild to moderate idiopathic Parkinson's disease. Using motor module (a.k.a. muscle synergy) analysis, we identified changes in the modular control of overground walking and standing reactive balance that accompanied clinically meaningful improvements in behavioral measures of balance, gait, and disease symptoms after 3 wk of daily Adapted Tango classes. In contrast to previous studies that revealed a positive association between motor module number and motor performance, none of the six participants in this pilot study increased motor module number despite improvements in behavioral measures of balance and gait performance. Instead, motor modules were more consistently recruited and distinctly organized immediately after rehabilitation, suggesting more reliable motor output. Furthermore, the pool of motor modules shared between walking and reactive balance increased after rehabilitation, suggesting greater generalizability of motor module function across tasks. Our work is the first to show that motor module distinctness, consistency, and generalizability are more sensitive to improvements in gait and balance function after short-term rehabilitation than motor module number. Moreover, as similar differences in motor module distinctness, consistency, and generalizability have been demonstrated previously in healthy young adults with and without long-term motor training, our work suggests commonalities in the structure of muscle coordination associated with differences in motor performance across the spectrum from motor impairment to expertise. We demonstrate changes in neuromuscular control of gait and balance in individuals with Parkinson's disease after short-term, dance-based rehabilitation. Our work is the first to show that motor module distinctness, consistency, and generalizability across gait and balance are more sensitive than motor module number to improvements in motor performance following short-term rehabilitation. Our results indicate commonalities in muscle coordination improvements associated with motor skill reacquisition due to rehabilitation and motor skill acquisition in healthy individuals.
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http://dx.doi.org/10.1152/jn.00813.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501921PMC
July 2017

Contribution of muscle short-range stiffness to initial changes in joint kinetics and kinematics during perturbations to standing balance: A simulation study.

J Biomech 2017 04 21;55:71-77. Epub 2017 Feb 21.

W.H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA; Department of Rehabilitation Medicine, Division of Physical Therapy, Emory University, Atlanta, GA, USA.

Simulating realistic musculoskeletal dynamics is critical to understanding neural control of muscle activity evoked in sensorimotor feedback responses that have inherent neural transmission delays. Thus, the initial mechanical response of muscles to perturbations in the absence of any change in muscle activity determines which corrective neural responses are required to stabilize body posture. Muscle short-range stiffness, a history-dependent property of muscle that causes a rapid and transient rise in muscle force upon stretch, likely affects musculoskeletal dynamics in the initial mechanical response to perturbations. Here we identified the contributions of short-range stiffness to joint torques and angles in the initial mechanical response to support surface translations using dynamic simulation. We developed a dynamic model of muscle short-range stiffness to augment a Hill-type muscle model. Our simulations show that short-range stiffness can provide stability against external perturbations during the neuromechanical response delay. Assuming constant muscle activation during the initial mechanical response, including muscle short-range stiffness was necessary to account for the rapid rise in experimental sagittal plane knee and hip joint torques that occurs simultaneously with very small changes in joint angles and reduced root mean square errors between simulated and experimental torques by 56% and 47%, respectively. Moreover, forward simulations lacking short-range stiffness produced unreasonably large joint angle changes during the initial response. Using muscle models accounting for short-range stiffness along with other aspects of history-dependent muscle dynamics may be important to advance our ability to simulate inherently unstable human movements based on principles of neural control and biomechanics.
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http://dx.doi.org/10.1016/j.jbiomech.2017.02.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436583PMC
April 2017

Interactions between rates of temperature change and acclimation affect latitudinal patterns of warming tolerance.

Conserv Physiol 2016 9;4(1):cow053. Epub 2016 Nov 9.

Centre for Invasion Biology, Department of Botany and Zoology , Stellenbosch University , Private Bag X1, Matieland 7602 , South Africa.

Critical thermal limits form an increasing component of the estimation of impacts of global change on ectotherms. Whether any consistent patterns exist in the interactive effects of rates of temperature change (or experimental ramping rates) and acclimation on critical thermal limits and warming tolerance (one way of assessing sensitivity to climate change) is, however, far from clear. Here, we examine the interacting effects of ramping rate and acclimation on the critical thermal maxima (CTmax) and minima (CTmin) and warming tolerance of six species of springtails from sub-tropical, temperate and polar regions. We also provide microhabitat temperatures from 26 sites spanning 5 years in order to benchmark environmentally relevant rates of temperature change. Ramping rate has larger effects than acclimation on CTmax, but the converse is true for CTmin. Responses to rate and acclimation effects are more consistent among species for CTmax than for CTmin. In the latter case, interactions among ramping rate and acclimation are typical of polar species, less marked for temperate ones, and reduced in species from the sub-tropics. Ramping rate and acclimation have substantial effects on estimates of warming tolerance, with the former being more marked. At the fastest ramping rates (>1.0°C/min), tropical species have estimated warming tolerances similar to their temperate counterparts, whereas at slow ramping rates (<0.4°C/min) the warming tolerance is much reduced in tropical species. Rates of temperate change in microhabitats relevant to the springtails are typically <0.05°C/min, with rare maxima of 0.3-0.5°C/min depending on the site. These findings emphasize the need to consider the environmental setting and experimental conditions when assessing species' vulnerability to climate change using a warming tolerance approach.
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http://dx.doi.org/10.1093/conphys/cow053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142048PMC
November 2016

Hip and ankle responses for reactive balance emerge from varying priorities to reduce effort and kinematic excursion: A simulation study.

J Biomech 2016 10 8;49(14):3230-3237. Epub 2016 Aug 8.

The Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA, USA. Electronic address:

Although standing balance is important in many daily activities, there has been little effort in developing detailed musculoskeletal models and simulations of balance control compared to other whole-body motor activities. Our objective was to develop a musculoskeletal model of human balance that can be used to predict movement patterns in reactive balance control. Similar to prior studies using torque-driven models, we investigated how movement patterns during a reactive balance response are affected by high-level task goals (e.g., reducing center-of-mass movement, maintaining vertical trunk orientation, and minimizing effort). We generated 23 forward dynamics simulations where optimal muscle excitations were found using cost functions with different weights on minimizing these high-level goals. Variations in hip and ankle angles observed experimentally (peak hip flexion=7.9-53.1°, peak dorsiflexion=0.5-4.7°) could be predicted by varying the priority of these high-level goals. More specifically, minimizing center-of-mass motion produced a hip strategy (peak hip flexion and ankle dorsiflexion angles of 45.5° and 2.3°, respectively) and the response shifted towards an ankle strategy as the priority to keep the trunk vertical was increased (peak hip and ankle angles of 13.7° and 8.5°, respectively). We also found that increasing the priority to minimize muscle stress always favors a hip strategy. These results are similar to those from sagittal-plane torque-driven models. Our muscle-actuated model facilitates the investigation of neuromechanical interactions governing reactive balance control to predict muscle activity and movement patterns based on interactions between neuromechanical elements such as spinal reflexes, muscle short-range stiffness, and task-level sensorimotor feedback.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5074864PMC
http://dx.doi.org/10.1016/j.jbiomech.2016.08.007DOI Listing
October 2016

Nanotopography applications in drug delivery.

Expert Opin Drug Deliv 2015 29;12(12):1823-7. Epub 2015 Oct 29.

b Department of Bioengineering and Therapeutic Sciences , University of California , San Francisco , CA 94158 , USA.

Refinement of micro- and nanofabrication in the semiconductor field has led to innovations in biomedical technologies. Nanotopography, in particular, shows great potential in facilitating drug delivery. The flexibility of fabrication techniques has created a diverse array of topographies that have been developed for drug delivery applications. Nanowires and nanostraws deliver drug cytosolically for in vitro and ex vivo applications. In vivo drug delivery is limited by the barrier function of the epithelium. Nanowires on microspheres increase adhesion and residence time for oral drug delivery, while also increasing permeability of the epithelium. Low aspect ratio nanocolumns increase paracellular permeability, and in conjunction with microneedles increase transdermal drug delivery of biologics in vivo. In summary, nanotopography is a versatile tool for drug delivery. It can deliver directly to cells or be used for in vivo delivery across epithelial barriers. This editorial highlights the application of nanotopography in the field of drug delivery.
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http://dx.doi.org/10.1517/17425247.2015.1103734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839586PMC
May 2016

Long-term training modifies the modular structure and organization of walking balance control.

J Neurophysiol 2015 Dec 14;114(6):3359-73. Epub 2015 Oct 14.

Wallace H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, Georgia

How does long-term training affect the neural control of movements? Here we tested the hypothesis that long-term training leading to skilled motor performance alters muscle coordination during challenging, as well as nominal everyday motor behaviors. Using motor module (a.k.a., muscle synergy) analyses, we identified differences in muscle coordination patterns between professionally trained ballet dancers (experts) and untrained novices that accompanied differences in walking balance proficiency assessed using a challenging beam-walking test. During beam walking, we found that experts recruited more motor modules than novices, suggesting an increase in motor repertoire size. Motor modules in experts had less muscle coactivity and were more consistent than in novices, reflecting greater efficiency in muscle output. Moreover, the pool of motor modules shared between beam and overground walking was larger in experts compared with novices, suggesting greater generalization of motor module function across multiple behaviors. These differences in motor output between experts and novices could not be explained by differences in kinematics, suggesting that they likely reflect differences in the neural control of movement following years of training rather than biomechanical constraints imposed by the activity or musculoskeletal structure and function. Our results suggest that to learn challenging new behaviors, we may take advantage of existing motor modules used for related behaviors and sculpt them to meet the demands of a new behavior.
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http://dx.doi.org/10.1152/jn.00758.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868379PMC
December 2015

The Parmotrema acid test: a look at species delineation in the P. perforatum group 40 y later.

Mycologia 2015 Nov-Dec;107(6):1120-9. Epub 2015 Sep 9.

Institute of Systematic Botany, New York Botanical Garden, Bronx, New York 10458-5126.

Parmotrema perforatum and its relatives form a morphologically distinctive group of species, most of which are common and endemic to eastern North America. Species delimitation in this ecologically important group was the subject of extensive inquiry before the advent of molecular systematics and computationally intensive niche modeling. As part of a large-scale lichen biodiversity inventory of the Mid-Atlantic Coastal Plain, we used ITS sequence data to examine the utility of characters (morphological, chemical, reproductive, ecological) in circumscribing four species in this group (P. hypoleucinum, P. hypotropum, P. perforatum, P. subrigidum). We found that P. hypoleucinum and P. subrigidum as currently circumscribed are monophyletic and the latter comprises two chemotypes differing in the presence or absence of norstictic acid in addition to alectoronic acid. The sequences of P. hypotropum and P. perforatum, which are chemically identical species and differ only in reproductive mode, were intermixed in a single, well-supported clade. The two chemotypes of P. subrigidum are partially allopatric and their sequences are >99% identical. Nonetheless, niche modeling suggests they occupy significantly different ecological niches. These results provide a new perspective on much-debated questions on species circumscription in lichens and suggest new avenues for genetic, ecological and systematic research.
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http://dx.doi.org/10.3852/14-263DOI Listing
March 2016

Feasible muscle activation ranges based on inverse dynamics analyses of human walking.

J Biomech 2015 Sep 11;48(12):2990-7. Epub 2015 Aug 11.

George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, GA, United States; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, GA, United States. Electronic address:

Although it is possible to produce the same movement using an infinite number of different muscle activation patterns owing to musculoskeletal redundancy, the degree to which observed variations in muscle activity can deviate from optimal solutions computed from biomechanical models is not known. Here, we examined the range of biomechanically permitted activation levels in individual muscles during human walking using a detailed musculoskeletal model and experimentally-measured kinetics and kinematics. Feasible muscle activation ranges define the minimum and maximum possible level of each muscle's activation that satisfy inverse dynamics joint torques assuming that all other muscles can vary their activation as needed. During walking, 73% of the muscles had feasible muscle activation ranges that were greater than 95% of the total muscle activation range over more than 95% of the gait cycle, indicating that, individually, most muscles could be fully active or fully inactive while still satisfying inverse dynamics joint torques. Moreover, the shapes of the feasible muscle activation ranges did not resemble previously-reported muscle activation patterns nor optimal solutions, i.e. static optimization and computed muscle control, that are based on the same biomechanical constraints. Our results demonstrate that joint torque requirements from standard inverse dynamics calculations are insufficient to define the activation of individual muscles during walking in healthy individuals. Identifying feasible muscle activation ranges may be an effective way to evaluate the impact of additional biomechanical and/or neural constraints on possible versus actual muscle activity in both normal and impaired movements.
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http://dx.doi.org/10.1016/j.jbiomech.2015.07.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592831PMC
September 2015

Neuromechanical principles underlying movement modularity and their implications for rehabilitation.

Neuron 2015 Apr;86(1):38-54

W.H. Coulter Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA 30332, USA; Department of Rehabilitation Medicine, Division of Physical Therapy, Emory University, Atlanta, GA 30322, USA.

Neuromechanical principles define the properties and problems that shape neural solutions for movement. Although the theoretical and experimental evidence is debated, we present arguments for consistent structures in motor patterns, i.e., motor modules, that are neuromechanical solutions for movement particular to an individual and shaped by evolutionary, developmental, and learning processes. As a consequence, motor modules may be useful in assessing sensorimotor deficits specific to an individual and define targets for the rational development of novel rehabilitation therapies that enhance neural plasticity and sculpt motor recovery. We propose that motor module organization is disrupted and may be improved by therapy in spinal cord injury, stroke, and Parkinson's disease. Recent studies provide insights into the yet-unknown underlying neural mechanisms of motor modules, motor impairment, and motor learning and may lead to better understanding of the causal nature of modularity and its underlying neural substrates.
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http://dx.doi.org/10.1016/j.neuron.2015.02.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4392340PMC
April 2015

Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease.

Blood 2015 Jun 7;125(26):4085-94. Epub 2015 Apr 7.

Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN;

Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B-cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multiorgan system, nonsclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells, but not T cells, for disease progression. Bone marrow-specific Syk deletion in vivo was effective in treating established cGVHD, as was a small-molecule inhibitor of Syk, fostamatinib, which normalized GC formation and decreased activated CD80/86(+) dendritic cells. In multiple distinct models of sclerodermatous cGVHD, clinical and pathological disease manifestations were not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these scleroderma models. We further demonstrated that Syk inhibition was effective at inducing apoptosis of human cGVHD B cells. Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD.
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http://dx.doi.org/10.1182/blood-2014-08-595470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481596PMC
June 2015

Forward propulsion asymmetry is indicative of changes in plantarflexor coordination during walking in individuals with post-stroke hemiparesis.

Clin Biomech (Bristol, Avon) 2014 Aug 8;29(7):780-6. Epub 2014 Jun 8.

Department of Mechanical Engineering, The University of Texas at Austin, Austin, TX, USA. Electronic address:

Background: A common measure of rehabilitation effectiveness post-stroke is self-selected walking speed, yet individuals may achieve the same speed using different coordination strategies. Asymmetry in the propulsion generated by each leg can provide insight into paretic leg coordination due to its relatively strong correlation with hemiparetic severity. Subjects walking at the same speed can exhibit different propulsion asymmetries, with some subjects relying more on the paretic leg and others on the nonparetic leg. The goal of this study was to assess whether analyzing propulsion asymmetry can help distinguish between improved paretic leg coordination versus nonparetic leg compensation.

Methods: Three-dimensional forward dynamics simulations were developed for two post-stroke hemiparetic subjects walking at identical speeds before/after rehabilitation with opposite changes in propulsion asymmetry. Changes in the individual muscle contributions to forward propulsion were examined.

Findings: The major source of increased forward propulsion in both subjects was from the ankle plantarflexors. How they were utilized differed and appears related to changes in propulsion asymmetry. Subject A increased propulsion generated from the paretic plantarflexors, while Subject B increased propulsion generated from the nonparetic plantarflexors. Each subject's strategy to increase speed also included differences in other muscle groups (e.g., hamstrings) that did not appear to be related to propulsion asymmetry.

Interpretation: The results of this study highlight how speed cannot be used to elucidate underlying muscle coordination changes following rehabilitation. In contrast, propulsion asymmetry appears to provide insight into changes in plantarflexor output affecting propulsion generation and may be useful in monitoring rehabilitation outcomes.
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http://dx.doi.org/10.1016/j.clinbiomech.2014.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157942PMC
August 2014

Increased BCR responsiveness in B cells from patients with chronic GVHD.

Blood 2014 Mar 14;123(13):2108-15. Epub 2014 Feb 14.

Division of Hematological Malignancies and Cellular Therapy, Duke University Department of Medicine and Duke Cancer Institute, Durham, NC;

Although B cells have emerged as important contributors to chronic graft-versus-host-disease (cGVHD) pathogenesis, the mechanisms responsible for their sustained activation remain unknown. We previously showed that patients with cGVHD have significantly increased B cell-activating factor (BAFF) levels and that their B cells are activated and resistant to apoptosis. Exogenous BAFF confers a state of immediate responsiveness to antigen stimulation in normal murine B cells. To address this in cGVHD, we studied B-cell receptor (BCR) responsiveness in 48 patients who were >1 year out from allogeneic hematopoietic stem cell transplantation (HSCT). We found that B cells from cGVHD patients had significantly increased proliferative responses to BCR stimulation along with elevated basal levels of the proximal BCR signaling components B cell linker protein (BLNK) and Syk. After initiation of BCR signaling, cGVHD B cells exhibited increased BLNK and Syk phosphorylation compared with B cells from patients without cGVHD. Blocking Syk kinase activity prevented relative post-HSCT BCR hyper-responsiveness of cGVHD B cells. These data suggest that a lowered BCR signaling threshold in cGVHD associates with increased B-cell proliferation and activation in response to antigen. We reveal a mechanism underpinning aberrant B-cell activation in cGVHD and suggest that therapeutic inhibition of the involved kinases may benefit these patients.
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http://dx.doi.org/10.1182/blood-2013-10-533562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968393PMC
March 2014

The influence of merged muscle excitation modules on post-stroke hemiparetic walking performance.

Clin Biomech (Bristol, Avon) 2013 Jul 2;28(6):697-704. Epub 2013 Jul 2.

Department of Mechanical Engineering, The University of Texas at Austin, TX 78712-1591, USA.

Background: Post-stroke subjects with hemiparesis typically utilize a reduced number of modules or co-excited muscles compared to non-impaired controls, with at least one module resembling the merging of two or more non-impaired modules. In non-impaired walking, each module has distinct contributions to important biomechanical functions, and thus different merged module combinations post-stroke may result in different functional consequences.

Methods: Three-dimensional forward dynamics simulations were developed for non-impaired controls and two groups of post-stroke hemiparetic subjects with different merged module combinations to analyze how paretic leg muscle contributions to body support, forward propulsion, mediolateral control and leg swing are altered.

Findings: The potential of the plantarflexors to generate propulsion was impaired in both hemiparetic groups while the remaining functional consequences differed depending on which modules were merged. Paretic leg swing was impaired during pre-swing when Modules 1 (hip abductors and knee extensors during early stance), and 2 (plantarflexors during late stance) were merged and during late swing when Modules 1 and 4 (hamstrings during late swing into early stance) were merged. When Modules 1 and 4 were merged, body support during early stance was also impaired.

Interpretation: These results suggest that improving plantarflexor ability to generate propulsion is critical during rehabilitation regardless of module composition. If Modules 1 and 2 are merged, then rehabilitation should also focus on improving paretic leg pre-swing whereas if Modules 1 and 4 are merged, then rehabilitation should also focus on improving early stance body support and late paretic leg swing.
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http://dx.doi.org/10.1016/j.clinbiomech.2013.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3732538PMC
July 2013

A review of chest compression interruptions during out-of-hospital cardiac arrest and strategies for the future.

J Emerg Med 2013 Sep 18;45(3):458-66. Epub 2013 Apr 18.

Richmond Ambulance Authority, Richmond, Virginia, USA.

Background: It has been known for many years that interrupting chest compressions during cardiopulmonary resuscitation (CPR) from out-of-hospital cardiac arrest (OHCA) leads directly to negative outcomes. Interruptions in chest compressions occur for a variety of reasons, including provider fatigue and switching of compressors, performance of ventilations, placement of invasive airways, application of CPR devices, pulse and rhythm determinations, vascular access placement, and patient transfer to the ambulance. Despite significant resuscitation guideline changes in the last decade, several studies have shown that chest compressions are still frequently interrupted or poorly executed during OHCA resuscitations. Indeed, the American Heart Association has made great strides to improve outcomes by placing a greater emphasis on uninterrupted chest compressions. As highly trained health care providers, why do we still interrupt chest compressions? And are any of these interruptions truly necessary?

Objectives: This article aims to review the clinical effects of both high-quality chest compressions and the effects that interruptions during chest compressions have clinically on patient outcomes.

Discussion: The causes of chest compression interruptions are explored from both provider and team perspectives. Current and future methods are introduced that may prompt the provider to reduce unnecessary interruptions during chest compressions.

Conclusions: New and future technologies may provide promising results, but the greatest benefit will always be a well-directed, organized, and proactive team of providers performing excellent-quality and continuous chest compressions during CPR.
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http://dx.doi.org/10.1016/j.jemermed.2013.01.023DOI Listing
September 2013
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