Effects of a DVD-delivered randomized controlled physical activity intervention on functional health in cancer survivors

BACKGROUND: Supervised physical activity interventions improve functional health during cancer survivorship, but remain costly and inaccessible for many. We previously reported on the benefits of a DVD-delivered physical activity program (FlexToBa™) in older adults. This is a secondary analysis of the intervention effects among cancer survivors in the original sample. METHODS: Low active, older adults who self-reported a history of cancer (N = 46; M time since diagnosis = 10.7 ± 9.4 years) participated in a 6-month, home-based physical activity intervention. Participants were randomized to either the DVD-delivered physical activity program focused on flexibility, toning, and balance (FlexToBa™; n = 22) or an attentional control condition (n = 24). Physical function was assessed by the Short Physical Performance Battery (SPPB) at baseline, end of intervention, and at 12 and 24 months after baseline. RESULTS: Repeated measures linear mixed models indicated a significant group*time interaction for the SPPB total score (β = - 1.14, p = 0.048), driven by improved function from baseline to six months in the FlexToBa™ group. The intervention group also had improved balance (β = - 0.56, p = 0.041) compared with controls. Similar trends emerged for the SPPB total score during follow-up; the group*time interaction from 0 to 12 months approached significance (β = - 0.97, p = 0.089) and was significant from 0 to 24 months (β = - 1.84, p = 0.012). No significant interactions emerged for other outcomes (ps \u3e 0.11). CONCLUSIONS: A DVD-delivered physical activity intervention designed for cancer-free older adults was capable of eliciting and maintaining clinically meaningful functional improvements in a subgroup of cancer survivors, with similar effects to the original full sample. These findings inform the dissemination of evidence-based physical activity programs during survivorship. TRIAL REGISTRATION: ClinicalTrials.gov NCT01030419 . Registered 11 December 2009

A Laminin G-EGF-Laminin G Module in Neurexin IV Is Essential for the Apico-Lateral Localization of Contactin and Organization of Septate Junctions

Septate junctions (SJs) display a unique ultrastructural morphology with ladder-like electron densities that are conserved through evolution. Genetic and molecular analyses have identified a highly conserved core complex of SJ proteins consisting of three cell adhesion molecules Neurexin IV, Contactin, and Neuroglian, which interact with the cytoskeletal FERM domain protein Coracle. How these individual proteins interact to form the septal arrays that create the paracellular barrier is poorly understood. Here, we show that point mutations that map to specific domains of neurexin IV lead to formation of fewer septae and disorganization of SJs. Consistent with these observations, our in vivo domain deletion analyses identified the first Laminin G-EGF-Laminin G module in the extracellular region of Neurexin IV as necessary for the localization of and association with Contactin. Neurexin IV protein that is devoid of its cytoplasmic region is able to create septae, but fails to form a full complement of SJs. These data provide the first in vivo evidence that specific domains in Neurexin IV are required for protein-protein interactions and organization of SJs. Given the molecular conservation of SJ proteins across species, our studies may provide insights into how vertebrate axo-glial SJs are organized in myelinated axons

White matter plasticity in healthy older adults: The effects of aerobic exercise

White matter deterioration is associated with cognitive impairment in healthy aging and Alzheimer\u27s disease. It is critical to identify interventions that can slow down white matter deterioration. So far, clinical trials have failed to demonstrate the benefits of aerobic exercise on the adult white matter using diffusion Magnetic Resonance Imaging. Here, we report the effects of a 6-month aerobic walking and dance interventions (clinical trial NCT01472744) on white matter integrity in healthy older adults (n = 180, 60-79 years) measured by changes in the ratio of calibrated T1- to T2-weighted images (T1w/T2w). Specifically, the aerobic walking and social dance interventions resulted in positive changes in the T1w/T2w signal in late-myelinating regions, as compared to widespread decreases in the T1w/T2w signal in the active control. Notably, in the aerobic walking group, positive change in the T1w/T2w signal correlated with improved episodic memory performance. Lastly, intervention-induced increases in cardiorespiratory fitness did not correlate with change in the T1w/T2w signal. Together, our findings suggest that white matter regions that are vulnerable to aging retain some degree of plasticity that can be induced by aerobic exercise training. In addition, we provided evidence that the T1w/T2w signal may be a useful and broadly accessible measure for studying short-term within-person plasticity and deterioration in the adult human white matter

Symmetric data-driven fusion of diffusion tensor MRI: Age differences in white matter

In the past 20 years, white matter (WM) microstructure has been studied predominantly using diffusion tensor imaging (DTI). Decreases in fractional anisotropy (FA) and increases in mean (MD) and radial diffusivity (RD) have been consistently reported in healthy aging and neurodegenerative diseases. To date, DTI parameters have been studied individually (e.g., only FA) and separately (i.e., without using the joint information across them). This approach gives limited insights into WM pathology, increases the number of multiple comparisons, and yields inconsistent correlations with cognition. To take full advantage of the information in a DTI dataset, we present the first application of symmetric fusion to study healthy aging WM. This data-driven approach allows simultaneous examination of age differences in all four DTI parameters. We used multiset canonical correlation analysis with joint independent component analysis (mCCA + jICA) in cognitively healthy adults (age 20-33

Designing home-based physical activity programs for rural cancer survivors: A survey of technology access and preferences

BACKGROUND: While technology advances have increased the popularity of remote interventions in underserved and rural cancer communities, less is understood about technology access and preferences for home-based physical activity programs in this cancer survivor population. PURPOSE: To determine access, preferences, and needs, for a home-based physical activity program in rural cancer survivors. METHODS: A Qualtrics Research Panel was recruited to survey adults with cancer across the United States. Participants self-reported demographics, cancer characteristics, technology access and usage, and preferences for a home-based physical activity program. The Godin Leisure Time Exercise Questionnaire (GLTEQ) assessed current levels of physical activity. Descriptive statistics included means and standard deviations for continuous variables, and frequencies for categorical variables. Independent samples t-tests explored differences between rural and non-rural participants. RESULTS: Participants (N=298; mean age=55.2 ± 16.5) had a history of cancer (mean age at diagnosis=46.5), with the most commonly reported cancer type being breast (25.5%), followed by prostate (16.1%). 74.2% resided in rural hometowns. 95% of participants reported accessing the internet daily. On a scale of 0-100, computer/laptop (M=63.4) and mobile phone (M=54.6) were the most preferred delivery modes for a home-based physical activity intervention, and most participants preferred balance/flexibility (72.2%) and aerobic (53.9%) exercises. Desired intervention elements included a frequency of 2-3 times a week (53.5%) for at least 20 minutes (75.7%). While there were notable rural disparities present (e.g., older age at diagnosis, lower levels of education; CONCLUSION: These findings provide insights into the preferred physical activity intervention (e.g., computer delivery, balance/flexibility exercises) in rural cancer survivors, while highlighting the need for personalization. Future efforts should consider these preferences when designing and delivering home-based interventions in this population

Resting state functional connectivity provides mechanistic predictions of future changes in sedentary behavior

Sedentary behaviors are increasing at the cost of millions of dollars spent in health care and productivity losses due to physical inactivity-related deaths worldwide. Understanding the mechanistic predictors of sedentary behaviors will improve future intervention development and precision medicine approaches. It has been posited that humans have an innate attraction towards effort minimization and that inhibitory control is required to overcome this prepotent disposition. Consequently, we hypothesized that individual differences in the functional connectivity of brain regions implicated in inhibitory control and physical effort decision making at the beginning of an exercise intervention in older adults would predict the change in time spent sedentary over the course of that intervention. In 143 healthy, low-active older adults participating in a 6-month aerobic exercise intervention (with three conditions: walking, dance, stretching), we aimed to use baseline neuroimaging (resting state functional connectivity of two a priori defined seed regions), and baseline accelerometer measures of time spent sedentary to predict future pre-post changes in objectively measured time spent sedentary in daily life over the 6-month intervention. Our results demonstrated that functional connectivity between (1) the anterior cingulate cortex and the supplementary motor area and (2) the right anterior insula and the left temporoparietal/temporooccipital junction, predicted changes in time spent sedentary in the walking group. Functional connectivity of these brain regions did not predict changes in time spent sedentary in the dance nor stretch and tone conditions, but baseline time spent sedentary was predictive in these conditions. Our results add important knowledge toward understanding mechanistic associations underlying complex out-of-session sedentary behaviors within a walking intervention setting in older adults

Novel fibronectin mutations and expansion of the phenotype in spondylometaphyseal dysplasia with “corner fractures”

Heterozygous pathogenic variants in the FN1 gene, encoding fibronectin (FN), have recently been shown to be associated with a skeletal disorder in some individuals affected by spondylometaphyseal dysplasia with “corner fractures” (SMD-CF). The most striking feature characterizing SMD-CF is irregularly shaped metaphyses giving the appearance of “corner fractures”. An array of secondary features, including developmental coxa vara, ovoid vertebral bodies and severe scoliosis, may also be present. FN is an important extra cellular matrix component for bone and cartilage development. Here we report five patients affected by this subtype of SMD-CF caused by five novel FN1 missense mutations: p.Cys123Tyr, p.Cys169Tyr, p.Cys213Tyr, p.Cys231Trp and p.Cys258Tyr. All individuals shared a substitution of a cysteine residue, disrupting disulfide bonds in the FN type-I assembly domains located in the N-terminal assembly region. The abnormal metaphyseal ossification and “corner fracture” appearances were the most remarkable clinical feature in these patients. In addition, generalized skeletal fragility with low-trauma bilateral femoral fractures was identified in one patient. Interestingly, the distal femoral changes in this patient healed with skeletal maturation. Our report expands the phenotypic and genetic spectrum of the FN1-related SMD-CF and emphasizes the importance of FN in bone formation and possibly also in the maintenance of bone strength.Peer reviewe

Population genomics of Drosophila suzukii reveal longitudinal population structure and signals of migrations in and out of the continental United States

Drosophila suzukii, or spotted-wing drosophila, is now an established pest in many parts of the world, causing significant damage to numerous fruit crop industries. Native to East Asia, D. suzukii infestations started in the United States (U.S.) a decade ago, occupying a wide range of climates. To better understand invasion ecology of this pest, knowledge of past migration events, population structure, and genetic diversity is needed. In this study, we sequenced whole genomes of 237 individual flies collected across the continental U.S., as well as several sites in Europe, Brazil, and Asia, to identify and analyze hundreds of thousands of genetic markers. We observed strong population structure between Western and Eastern U.S. populations, but no evidence of any population structure between different latitudes within the continental U.S., suggesting there is no broad-scale adaptations occurring in response to differences in winter climates. We detect admixture from Hawaii to the Western U.S. and from the Eastern U.S. to Europe, in agreement with previously identified introduction routes inferred from microsatellite analysis. We also detect potential signals of admixture from the Western U.S. back to Asia, which could have important implications for shipping and quarantine policies for exported agriculture. We anticipate this large genomic dataset will spur future research into the genomic adaptations underlying D. suzukii pest activity and development of novel control methods for this agricultural pes

Symmetric data-driven fusion of diffusion tensor MRI: Age differences in white matter

In the past 20 years, white matter (WM) microstructure has been studied predominantly using diffusion tensor imaging (DTI). Decreases in fractional anisotropy (FA) and increases in mean (MD) and radial diffusivity (RD) have been consistently reported in healthy aging and neurodegenerative diseases. To date, DTI parameters have been studied individually (e.g., only FA) and separately (i.e., without using the joint information across them). This approach gives limited insights into WM pathology, increases the number of multiple comparisons, and yields inconsistent correlations with cognition. To take full advantage of the information in a DTI dataset, we present the first application of symmetric fusion to study healthy aging WM. This data-driven approach allows simultaneous examination of age differences in all four DTI parameters. We used multiset canonical correlation analysis with joint independent component analysis (mCCA + jICA) in cognitively healthy adults (age 20–33, n = 51 and age 60–79, n = 170). Four-way mCCA + jICA yielded one high-stability modality-shared component with co-variant patterns of age differences in RD and AD in the corpus callosum, internal capsule, and prefrontal WM. The mixing coefficients (or loading parameters) showed correlations with processing speed and fluid abilities that were not detected by unimodal analyses. In sum, mCCA + jICA allows data-driven identification of cognitively relevant multimodal components within the WM. The presented method should be further extended to clinical samples and other MR techniques (e.g., myelin water imaging) to test the potential of mCCA+jICA to discriminate between different WM disease etiologies and improve the diagnostic classification of WM diseases

Loss of Guanylyl Cyclase C (GCC) Signaling Leads to Dysfunctional Intestinal Barrier

Guanylyl Cyclase C (GCC) signaling via uroguanylin (UGN) and guanylin activation is a critical mediator of intestinal fluid homeostasis, intestinal cell proliferation/apoptosis, and tumorigenesis. As a mechanism for some of these effects, we hypothesized that GCC signaling mediates regulation of intestinal barrier function.Paracellular permeability of intestinal segments was assessed in wild type (WT) and GCC deficient (GCC-/-) mice with and without lipopolysaccharide (LPS) challenge, as well as in UGN deficient (UGN-/-) mice. IFNγ and myosin light chain kinase (MLCK) levels were determined by real time PCR. Expression of tight junction proteins (TJPs), phosphorylation of myosin II regulatory light chain (MLC), and STAT1 activation were examined in intestinal epithelial cells (IECs) and intestinal mucosa. The permeability of Caco-2 and HT-29 IEC monolayers, grown on Transwell filters was determined in the absence and presence of GCC RNA interference (RNAi). We found that intestinal permeability was increased in GCC-/- and UGN-/- mice compared to WT, accompanied by increased IFNγ levels, MLCK and STAT1 activation in IECs. LPS challenge promotes greater IFNγ and STAT1 activation in IECs of GCC-/- mice compared to WT mice. Claudin-2 and JAM-A expression were reduced in GCC deficient intestine; the level of phosphorylated MLC in IECs was significantly increased in GCC-/- and UGN-/- mice compared to WT. GCC knockdown induced MLC phosphorylation, increased permeability in IEC monolayers under basal conditions, and enhanced TNFα and IFNγ-induced monolayer hyperpermeability.GCC signaling plays a protective role in the integrity of the intestinal mucosal barrier by regulating MLCK activation and TJ disassembly. GCC signaling activation may therefore represent a novel mechanism in maintaining the small bowel barrier in response to injury