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Osteocytes are bone cells that form cellular networks that sense mechanical loads distributed throughout the bone tissue. Interstitial fluid flow in the lacunar canalicular system produces focal strains at localized attachment sites around the osteocyte cell process. These regions of periodic attachment between the osteocyte cell membrane and its canalicular wall are sites where pN-level fluid-flow induced forces are generated in vivo. In this study, we show that focally applied forces of this magnitude using a newly developed Stokesian fluid stimulus probe initiate rapid and transient intercellular electrical signals in vitro. Our experiments demonstrate both direct gap junction coupling and extracellular purinergic P2 receptor signaling between MLO-Y4 cells in a connected bone cell network. Intercellular signaling was initiated by pN-level forces applied at integrin attachment sites along both appositional and distal unapposed cell processes, but not initiated at their cell bodies with equivalent forces. Electrical coupling was evident in 58% of all cell pairs tested with appositional connections; coupling strength increased with the increasing number of junctional connections. Apyrase, a nucleotide-degrading enzyme, suppressed and abolished force-induced effector responses, indicating a contribution from ATP released by the stimulated cell. This work extends the understanding of how osteocytes modulate their microenvironment in response to mechanical signals and highlights mechanisms of intercellular relay of mechanoresponsive signals in the bone network.

Proteoglycans (PGs) are a diverse class of glycoconjugates that serve critical functions in normal mechanobiology and mechanopathology. Both the protein cores and attached glycosaminoglycan (GAG) chains function in mechanically sensitive processes, and loss of either can contribute to development of pathological conditions. PGs function as key components of the extracellular matrix (ECM), where they can serve as mechanosensors in mechanosensitive tissues including bone, cartilage, tendon, blood vessels, and soft organs. The mechanical properties of these tissues depend on the presence and function of PGs, which play important roles in tissue elasticity, osmolarity, and pressure sensing, and response to physical activity. Tissue responses depend on cell surface mechanoreceptors that include integrins, CD44, voltage‐sensitive ion channels, transient receptor potential, and piezo channels. PGs contribute to cell and molecular interplay in wound healing, fibrosis, and cancer, where they transduce the mechanical properties of the ECM and influence the progression of various context‐specific conditions and diseases. The PGs that are most important in mechanobiology vary depending on the tissue and its functions and functional needs. Perlecan, for example, is important in the mechanobiology of basement membranes, cardiac muscle, and skeletal muscle, while aggrecan plays a primary role in the mechanical properties of cartilage and joints. A variety of techniques have been used to study the mechanobiology of PGs, including atomic force microscopy, mouse knockout models, and in vitro cell culture experiments with three‐dimensional organoid models. These studies have helped to elucidate the tissue‐specific roles that PGs play in cell‐level mechanosensing and tissue mechanics. Overall, the study of PGs in mechanobiology is yielding fundamental new concepts in the molecular basis of mechanosensing that can open the door to the development of new treatments for a host of conditions related to mechanopathology.

Extended-duration human spaceflight necessitates a better understanding of the physiological impacts of microgravity. While the ground-based microgravity simulations identified low intensity vibration (LIV) as a possible countermeasure, how cells may respond to LIV under real microgravity remain unexplored. In this way, adaptation of LIV bioreactors for space remains limited, resulting in a significant gap in microgravity research. In this study, we introduce an LIV bioreactor designed specifically for the usage in the International Space Station. Our research covers the bioreactor’s design process and evaluation of the short-term viability of cells encapsulated in hydrogel-laden 3D printed scaffolds under 0.7 g, 90 Hz LIV. An LIV bioreactor compatible with the operation requirements of space missions provides a robust platform to study cellular effects of LIV under real microgravity conditions.

A Stokesian fluid stimulus probe (SFSP), capable of delivering quantifiable pN level hydrodynamic forces, is developed to distinguish the electrophysiological response of the cell process and cell body of osteocyte-like MLO-Y4 cells without touching the cell or its substrate. The hydrodynamic disturbance is a short lived (100ms), constant strength pressure pulse that propagates nearly instantaneously through the medium creating a nearly spherical expanding fluid bolus surrounding a 0.8μm micropipette tip. Laboratory model experiments show that the growth of the bolus and the pressure field can be closely modeled by quasi-steady Stokes flow through a circular orifice provided the tip Reynolds number, Ret<0.03. By measuring the deflection of the dendritic processes between discrete attachment sites, and applying a detailed ultrastructural model for the central actin filament bundle within the process, one is able to calculate the forces produced by the probe using elastic beam theory. One finds that forces between 1 and 2.3pN are sufficient to initiate electrical signaling when applied to the cell process, but not the much softer cell body. Even more significantly, cellular excitation by the process only occurs when the probe is directed at discrete focal attachment sites along the cell process. This suggests that electrical signaling is initiated at discrete focal attachments along the cell process and that these sites are likely integrin-mediated complexes associated with stretch-activated ion channels though their molecular structure is unknown.

A tissue engineering approach can provide replacement salivary gland structures to patients with hyposalivation disorders and xerostomia. Salivary human stem/progenitor cells (hS/PCs) were isolated from healthy regions of parotid glands of head and neck surgery patients, expanded, then encapsulated in biocompatible hyaluronate (HA)-based hydrogels. These bioactive hydrogels provide a surrogate territorial matrix suitable for the dynamic assembly, growth and reorganization of salivary gland components. This study examined the dynamics of salivary microstructure formation, growth, and reorganization using time-lapse imaging over 15 h. Immunofluorescence detection monitored production of individual basement membrane components forming around developing microstructures, and Ki67 assessed proliferation. Dynamic movements in hydrogels were quantified by measuring angular velocity (ω) of rotating salivary microstructures and changes in basement membrane architecture during microstructure growth. Integrin involvement in the dynamic reassembly was assessed using knockdown and inhibitor approaches. Single hS/PCs expanded over 5 days into spherical microstructures typically containing 3–10 cells. In larger macrostructures, proliferation occurred near the peripheral basement membrane that underwent growth-associated cycles of thinning and collapse. De novo secretion of laminin/collagen IV from reorganizing hS/PCs preceded that of perlecan/HSPG2. Microstructures routinely expressed β1 integrin-containing complexes at basement membrane-associated regions and exhibited spontaneous and coordinated rotation during basement membrane maturation. β1 integrin siRNA knockdown at the single-cell state prevented hS/PC microstructure growth. After microstructure formation, β1 integrin knockdown reduced rotation and mean ω by 84%. Blockade of the α1 integrin subunit (CD49a) that associates with β1 reduced mean ω by 66%. Studies presented here show that initial hS/PC structure growth and basement membrane maturation depends on α1β1-integrin mediated signaling. Coordinated cellular motility during neotissue reorganization reminiscent of salivary gland acini was critically dependent both on hS/PC-secretion of laminin,collagen type-IV, and perlecan/HSPG2 and the force-driven interactions of α1β1-integrin activation. We conclude that α1β1-integrin plays a critical role in establishing human salivary gland coordinated structure and function, and that its activation in tissue engineered systems is essential to tissue assembly.

Our understanding of how osteocytes, the principal mechanosensors within bone, sense and perceive force remains unclear. Previous work identified “tethering elements” (TEs) spanning the pericellular space of osteocytes and transmitting mechanical information into biochemical signals. While we identified the heparan sulfate proteoglycan perlecan (PLN) as a component of these TEs, PLN must attach to the cell surface to induce biochemical responses. As voltage-sensitive calcium channels (VSCCs) are critical for bone mechanotransduction, we hypothesized that PLN binds the extracellular α2δ1 subunit of VSCCs to couple the bone matrix to the osteocyte membrane. Here, we showed co-localization of PLN and α2δ1 along osteocyte dendritic processes. Additionally, we quantified the molecular interactions between α2δ1 and PLN domains and demonstrated for the first time that α2δ1 strongly associates with PLN via its domain III. Furthermore, α2δ1 is the binding site for the commonly used pain drug, gabapentin (GBP), which is associated with adverse skeletal effects when used chronically. We found that GBP disrupts PLN::α2δ1 binding in vitro, and GBP treatment in vivo results in impaired bone mechanosensation. Our work identified a novel mechanosensory complex within osteocytes composed of PLN and α2δ1, necessary for bone force transmission and sensitive to the drug GBP.

The incidence of multiple chronic diseases affecting a single individual is high among elderly patients. This incidence is believed to be associated with a decline in many health outcomes, including quality of life, mobility, functional ability, increased frequency of hospitalizations, psychological distress, mortality and the use of health care resources. Health in elderly patients can fluctuate significantly, thus prompting the need for proper integration of comprehensive geriatric care. An increasing amount of data gained from research programs is making it clear that a geriatric assessment identifies many problems in older people with chronic diseases, adds prognostic information, and might improve the outcomes of these patients. This volume reviews research on the value of geriatric programs in different subspecialties of internal medicine. Chapters of this book cover different chronic diseases (coronary artery disease, kidney disease, diabetes, osteoporosis etc.) separately and present new findings in these areas. Readers – both medical students and researchers – will find the book an essential for understanding requirements and nuances of specialized geriatric programs in the healthcare sector.

Abstract Patients with idiopathic pulmonary fibrosis and lung fibrosis secondary to infections such as influenza A and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have limited treatment options outside of supportive therapy and lung transplantation. Multiple lung stem cell populations have been implicated in the pathogenesis of lung fibrosis, and more progenitor cell populations continue to be discovered and characterized. In this review, we summarize the functions and differentiation pathways of various cells that constitute the lung epithelium. We then focus on two subpopulations of KRT5+ or KRT8+ transitional cells that both originate from alveolar type II cells but experience different cell fates and play important roles in lung regeneration and repair. We address these transitional cells’ potential role in fibrosis and bronchiolization of the alveoli, as they are correlated to aggregate near fibrotic foci in both in vivo models and in human fibrotic lung disease. We conclude by discussing recent advances in cell and organoid therapy to replace aberrant transitional cells and treat lung fibrosis. Namely, we focus on strategies to minimize immune clearance of transplanted cells and to optimize engraftment by transplanting cells precultured as three-dimensional organoids.

More than one million Americans are living with human immunodeficiency virus (HIV), and less than half of Americans have ever accepted an HIV test. There are no national HIV testing estimates for Muslim Americans, an underserved and often stigmatized population. Considering the lack of HIV testing estimates for this population, we conducted an exploratory study on HIV testing and potential associates in American Muslim women from across the United States. We applied logistic regression models to examine the Muslim Women's Health Project data, collected in 2015 ( =218). Health care engagement and intimate partner violence were significantly associated with having been tested for HIV. Respondents using contraceptives received an influenza vaccination, and received an abnormal pap test had more than two times higher odds of having been tested for HIV (odds ratio [OR]=2.56, OR=2.43, OR=2.93, respectively; <0.05 all). Having been sexually abused was associated with more than two times higher odds of having been tested for HIV (OR=2.49; <0.05). Respondents reported higher rates of HIV testing as compared with the general public, signaling HIV knowledge, engagement in preventative health care, and possibly HIV risk. Scholars and practitioners should not assume that Muslim patients are at low risk for HIV and do not engage in HIV-risk behaviors. Thus, assumptions about Muslims women's willingness to accept HIV testing should be further examined to elucidate HIV risk among this population.