Bone marrow stroma influences metastatic prostate cancer (PCa) progression, latency, and recurrence. At sites of PCa bone metastasis, cancer-associated fibroblasts and tumor-associated macrophages ...interact to establish a perlecan-rich desmoplastic stroma. As a heparan sulfate proteoglycan, perlecan (HSPG2) stores and stabilizes growth factors, including heparin-binding Wnt3A, a positive regulator of PCa cell growth. Because PCa cells alone do not induce CAF production of perlecan in the desmoplastic stroma, we sought to discover the sources of perlecan and its growth factor-releasing modifiers SULF1, SULF2, and heparanase in PCa cells and xenografts, bone marrow fibroblasts, and macrophages. SULF1, produced primarily by bone marrow fibroblasts, was the main glycosaminoglycanase present, a finding validated with primary tissue specimens of PCa metastases with desmoplastic bone stroma. Expression of both HSPG2 and SULF1 was concentrated in αSMA-rich stroma near PCa tumor nests, where infiltrating pro-tumor TAMs also were present. To decipher SULF1's role in the reactive bone stroma, we created a bone marrow biomimetic hydrogel incorporating perlecan, PCa cells, macrophages, and fibroblastic bone marrow stromal cells. Finding that M2-like macrophages increased levels of SULF1 and HSPG2 produced by fibroblasts, we examined SULF1 function in Wnt3A-mediated PCa tumoroid growth in tricultures. Comparing control or SULF1 knockout fibroblastic cells, we showed that SULF1 reduces Wnt3A-driven growth, cellularity, and cluster number of PCa cells in our 3D model. We conclude that SULF1 can suppress Wnt3A-driven growth signals in the desmoplastic stroma of PCa bone metastases, and SULF1 loss favors PCa progression, even in the presence of pro-tumorigenic TAMs.
To determine the relationship between the amount and intensity of physical activity performed by older adults in North America (United States and Canada) and their depression and anxiety symptoms ...while currently under social distancing guidelines (SDG) for the COVID-19 pandemic.
Descriptive cross-sectional study.
Online survey conducted between April 9 and April 30, 2020, during the COVD-19 pandemic.
About 1,046 older adults over the age of 50 who live in North America.
Participants were asked about their basic demographic information, current health status, and the impact of the current SDG on their subjective state of mental health. Participants completed the Physical Activity Scale for the Elderly, to determine the amount and intensity of physical activity performed, as well as both the Geriatric Depression Scale and Geriatric Anxiety Scale, to ascertain the extent of their depression and anxiety-like symptoms.
Ninety-seven percent of participants indicated that they adhered to current SDG "Most of the time" or "Strictly." Participants who performed greater levels of physical activity experienced lower levels of depression-like symptoms when age, sex, and education were accounted for; however, no relationship between physical activity and anxiety-like symptoms was found. A hierarchical regression analysis that incorporated the intensity of physical activity performed (light, moderate, and vigorous) in the model indicated that greater light and strenuous activity, but not moderate, predicted lower depression-like symptoms.
These results suggest that performing even light physical activity during the COVID-19 pandemic may help alleviate some of the negative mental health impacts that older adults may be experiencing while isolated and adhering to SDG during the COVID-19 pandemic.
The extracellular matrix proteoglycan (ECM) perlecan, also known as heparan sulfate proteoglycan 2 or HSPG2, is one of the largest (>200nm) and oldest (>550Myears) extracellular matrix molecules. In ...vertebrates, perlecan's five-domain structure contains numerous independently folding modules with sequence similarities to other ECM proteins, all connected like cars into one long, diverse complex train following a unique N-terminal domain I decorated with three long glycosaminoglycan chains, and an additional glycosaminoglycan attachment site in the C-terminal domain V. In lower invertebrates, perlecan is not typically a proteoglycan, possessing the majority of the core protein modules, but lacking domain I where the attachment sites for glycosaminoglycan chains are located. This suggests that uniting the heparan sulfate binding growth factor functions of domain I and the core protein functions of the rest of the molecule in domains II–V occurred later in evolution for a new functional purpose. In this review, we surveyed several decades of pertinent literature to ask a fundamental question: Why did nature design this protein uniquely as an extraordinarily long multifunctional proteoglycan with a single promoter regulating expression, rather than separating these functions into individual proteins that could be independently regulated? We arrived at the conclusion that the concentration of perlecan at functional borders separating tissues and tissue layers is an ancient key function of the core protein. The addition of the heparan sulfate chains in domain I likely occurred as an additional means of binding the core protein to other ECM proteins in territorial matrices and basement membranes, and as a means to reserve growth factors in an on-site depot to assist with rapid repair of those borders when compromised, such as would occur during wounding. We propose a function for perlecan that extends its role from that of an extracellular scaffold, as we previously suggested, to that of a critical agent for establishing and patrolling tissue borders in complex tissues in metazoans. We also propose that understanding these unique functions of the individual portions of the perlecan molecule can provide new insights and tools for engineering of complex multi-layered tissues including providing the necessary cues for establishing neotissue borders.
•Perlecan's function in maintaining tissue borders is examined.•Perlecan's functions during degradation and as an intact proteoglycan are compared.•Perlecan's use and potential in tissue engineering is assessed.•Evolution of the perlecan gene is considered.•The HSPG2 gene's structure and perlecan's protein domain functions are described.
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Growth factor gradients orchestrate many biological processes including organogenesis, wound healing, cancer invasion, and metastasis. Heparin-binding growth factor (HBGF) gradients ...are established in living systems by proteoglycans including the extracellular matrix heparan sulfate proteoglycan, perlecan/HSPG2. Three potential HBGF-binding glycosaminoglycan attachment sites occur in N-terminal domain I of perlecan’s five domains. Our overarching goal was to form stable, biomimetic non-covalently bound HBGF gradients surrounding cells encapsulated in hyaluronate-based hydrogels by first establishing perlecan domain I (PlnD1) gradients. A versatile multichannel gradient maker device (MGMD) was designed and 3D printed, then used to create desired gradients of microparticles in hydrogels. Next, we used the device to covalently incorporate gradients of PEGylated PlnD1 in hydrogels with high-low-high or high-medium-low concentrations across the hydrogel width. Fluorescently-labeled fibroblast growth factor-2 was delivered to hydrogels in phosphate-buffered saline and allowed to electrostatically bind to the covalently pre-incorporated PlnD1, producing stable non-covalent HBGF gradients. To test cell viability after flow through the MGMD, delicate primary human salivary stem/progenitor cells were encapsulated in gradient hydrogels where they showed high viability and continued to grow. Next, to test migratory behavior in response to HBGF gradients, two cell types, preosteoblastic MC3T3-E1 cell line and breast cancer cell line MDA-MB-231 were encapsulated in or adjacent to PlnD1-modified hydrogels. Both cell lines migrated toward HBGFs bound to PlnD1. We conclude that establishing covalently-bound PlnD1 gradients in hydrogels provides a new means to establish physiologically-relevant gradients of HBGFs that are useful for a variety of applications in tissue engineering and cancer biology.
Gradients of heparin binding growth factors (HBGFs) direct cell behavior in living systems. HBGFs bind electrostatically to gradients of HS proteoglycans in the extracellular matrix creating HBGF gradients. We recreated HBGF gradients in physiological hyaluronate-based hydrogels using a 3D-printed multichannel gradient maker device (MGMD) that created gradients of HS proteoglycan-derived perlecan/HSPG2 domain I. We demonstrated the ability of a variety of cells, including primary salivary stem/progenitor cells, pre-osteoblastic cells and an invasive breast cancer cell line, to be co-encapsulated in gradient hydrogels by flowing them together through the MGMD. The versatile device and the ability to create HBGF gradients in hydrogels for a variety of applications is innovative and of broad utility in both cancer biology and tissue engineering applications.
Inadequate levels of exercise is one of the most potent modifiable risk factors for preventing cognitive decline and dementia as we age. Meanwhile, network science-based measures of structural brain ...network global and local efficiency show promise as robust biomarkers of aging, cognitive decline, and pathological disease progression. Despite this, little to no work has established how maintaining physical activity (PA) and physical fitness might relate to cognition and network efficiency measures across the lifespan. Therefore the purpose of this study was to determine the relationship between (1) PA and fitness and cognition, (2) fitness and network efficiency, and (3) how network efficiency measures relate to cognition. To accomplish this, we analyzed a large cross-sectional data set (n = 720; 36–100 years) from the aging human connectome project, which included the Trail Making Task (TMT) A and B, a measure of fitness (2-min walk test), physical activity (International Physical Activity Questionnaire), and high-resolution diffusion imaging data. Our analysis consisted of employing multiple linear regression while controlling for age, sex, and education. Age was associated with lower global and local brain network efficiency and poorer Trail A & B performance. Meanwhile, fitness, but not physical activity, was related to better Trail A and B performance and fitness, and was positively associated with local and global brain efficiency. Finally, local efficiency was related to better TMT B performance and partially mediated the relationship between fitness and TMT B performance. These results indicate aging may be associated with a shift towards less efficient local and global neural networks and that maintaining physical fitness might protect against age-related cognitive performance deterioration by bolstering structural network efficiency.
•Age was negatively related to network efficiency measures and Trail Making Task performance.•Physical fitness but not physical activity was associated with better Trail Making Task performance.•Physical fitness was positively associated with global and local efficiency measures.•Local efficiency measures partially mediated the relationship between physical fitness and Trail Making Task B performance.
Heparan sulfate proteoglycans are a remarkably diverse family of glycosaminoglycan-bearing protein cores that include the syndecans, the glypicans, perlecan, agrin, and collagen XVIII. Members of ...this protein class play key roles during normal processes that occur during development, tissue morphogenesis, and wound healing. As key components of basement membranes in organs and tissues, they also participate in selective filtration of biological fluids, in establishing cellular barriers, and in modulation of angiogenesis. The ability to perform these functions is provided both by the features of the protein cores as well as by the unique properties of heparan sulfate, which is assembled as a polymer of N-acetylglucosamine and glucuronic acid and modified by specific enzymes to generate specialized biologically active structures. This article discusses the structures and functions of this amazing family of proteoglycans and provides a platform for further study of the individual members.
The role of mucin 1 (MUC1) in protecting epithelia from microbial infection, enzymatic digestion, and other irritants has been appreciated for some time. In addition, MUC1 serves as a barrier to ...embryo implantation. MUC1 is highly abundant in many tumors in which its role in barrier function may serve to protect cells from the host immune system, whereas MUC1 is less abundant in certain other cells-for example, in trophoblasts and hematopoietic cells. Most of the functions of MUC1 depend upon its large, extracellular ectodomain. Nonetheless, a series of studies have demonstrated a surprisingly diverse role for the small, highly conserved cytoplasmic domain of MUC1 in intracellular signaling. These intracellular activities have potential roles in the physiology of both malignant and nonmalignant cells.
The relationship between gait speed and working memory is well-understood in older adults. However, it remains to be determined whether this relationship also exists in younger adults; and there is ...little known regarding the possible neural mechanism underlying the association between gait speed and working memory. The aims of this study are to determine if there is: (1) an association between gait speed and working memory performance; and (2) a mediating role of cerebellar subregion volume in the correlation between gait speed and working memory in healthy younger adults. 1054 younger adults (28.7 ± 3.6 years) from the Human Connectome Project were included in the analyses. A four-meter gait test was used to assess gait speed. The 2-back task was used to measure working memory performance accuracy and response time (RT). T1-weighted structural MRI data (obtained using Siemens 3 T MRI scanner) was used to assess cerebellar subregion volumes. Linear regression and mediation analysis were used to examine the relationships between the variables after controlling for age, sex, and education. There was no association between gait speed and 2-back working memory performance in younger adults. Greater Crus I and whole cerebellar volumes were associated with better 2-back working memory accuracy. Greater VIIIa volume was associated with faster gait speed. Greater Crus 1 and VIIIa volumes were also associated with higher fluid cognition. The present study suggests that specific subregions of the cerebellar volumes are distinctively associated with gait speed and working memory performance in healthy younger adults.
Aging is associated with deterioration in dentate gyrus (DG) and CA3, both crucial hippocampal subfields for age susceptible memory processes such as mnemonic discrimination (MD). Meanwhile, a single ...aerobic exercise session alters DG/CA3 function and neural activity in both rats and younger adults and can elicit short‐term microstructural alterations in the hippocampus of older adults. However, our understanding of the effects of acute exercise on hippocampal subfield integrity via function and microstructure in older adults is limited. Thus, a within subject‐design was employed to determine if 20‐min of moderate to vigorous aerobic exercise alters bilateral hippocampal subfield function and microstructure using high‐resolution functional magnetic resonance imaging (fMRI) during an MD task (n = 35) and high angular resolution multi‐shell diffusion imaging (n = 31), in healthy older adults, compared to seated rest. Following the exercise condition, participants exhibited poorer MD performance, particularly when their perception of effort was higher. Exercise was also related to lower MD‐related activity within the DG/CA3 but not CA1 subfield. Finally, after controlling for whole brain gray matter diffusion, exercise was associated with lower neurite density index (NDI) within the DG/CA3. However, exercise‐related differences in DG/CA3 activity and NDI were not associated with differences in MD performance. Our results suggest moderate to vigorous aerobic exercise may temporarily inhibit MD performance, and suppress DG/CA3 MD‐related activity and NDI, potentially through neuroinflammatory/glial processes. However, additional studies are needed to confirm whether these short‐term changes in behavior and hippocampal subfield neurophysiology are beneficial and how they might relate to long‐term exercise habits.
Growing evidence suggests physical activity and cardiorespiratory fitness are associated with better cognition across the lifespan. However, the neurobiological underpinnings relating fitness and ...cognition remain unclear, particularly in healthy younger adults. Using a well-established and popular multi-compartment diffusion modeling approach, called Neurite Orientation and Dispersion and Density Imaging (NODDI), we investigated the relationship between physical fitness (measured via a 2-min walk test), cognition (fluid and crystallized), and gray and white matter microstructure, in a large sample (n = 816) of healthy younger adults (ages 22–35 years) from the human connectome project (HCP). Concurrent with previous literature, we found that fitness was positively associated with both fluid and crystallized cognition. Furthermore, we found that physical fitness was negatively associated with white matter orientation dispersion index (ODIWM) around the cerebellar peduncle and was negatively associated with widespread cortical and subcortical gray matter neurite density index (NDIGM). Lower ODIWM of the cerebral peduncle was associated with better fluid cognitive performance, while lower NDIGM was associated with better crystallized cognition. Finally, we found that while ODIWM partially mediated the relationship between fitness and fluid cognition, NDIGM partially mediated the relationship between fitness and crystallized cognition. This study is the first to explore the relationship between physical fitness and white and gray matter microstructure measures using NODDI. Our findings suggest that in addition to improved cognitive performance, higher physical fitness may be associated with lower white matter tract dispersion and lower neurite density in the cortical and subcortical gray matter of healthy younger adults.
•Two minute walk distance is associated with better fluid and crystallized cognition in healthy younger adults.•Walk distance is associated with lower white matter neurite dispersion and lower gray matter neurite density.•White matter neurite dispersionand gray matter density were associated with better fluid and crystallized cognition.•White matter neurite dispersion partially mediates relationship between 2 min walk distance and fluid cognition.•Gray matter neurite density partially mediates relationship between walk distance and crystallized cognition.
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