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2.  Myocardial Regeneration: Expanding the Repertoire of Thymosin β4 in the Ischaemic Heart 
Efficient cardiac regeneration post-infarction (MI) requires the replacement of lost cardiomyocytes, formation of new coronary vessels and appropriate modulation of the inflammatory response. However, insight into how to stimulate repair of the human heart is currently limited. Utilising the embryonic paradigm of regeneration, we demonstrated that the actin-binding peptide Thymosin β4 (Tβ4), required for epicardium-derived coronary vasculogenesis, can recapitulate its embryonic role and activate quiescent adult epicardial cells (EPDCs). Once stimulated, EPDCs facilitate neovascularisation of the ischaemic adult heart and, moreover, contribute bona fide cardiomyocytes. EPDC-derived cardiomyocytes structurally and functionally integrate with resident muscle, to regenerate functional myocardium, limiting pathological remodelling and effecting an improvement in cardiac function. Alongside pro-survival and anti-inflammatory properties, these regenerative roles, via EPDCs, markedly expand the range of therapeutic benefits of Tβ4 to sustain and repair the myocardium after ischaemic damage.
doi:10.1111/j.1749-6632.2012.06708.x
PMCID: PMC4084412  PMID: 23045976
Thymosin β4; EPDCs; epicardium; Wt1; myocardial regeneration; de novo cardiomyocytes
3.  Resveratrol-based combinatorial strategies for cancer management 
In recent years, combination chemoprevention is being increasingly appreciated and investigated as a viable and effective strategy for cancer management. A plethora of evidence suggests that a combination of agents may afford synergistic (or additive) advantage for cancer management by multiple means, such as by (1) enhancing the bio-availability of chemopreventive agents, (2) modifying different molecular targets, and (3) lowering the effective dose of agents/drug to be used for cancer management. Resveratrol has been shown to afford chemopreventive as well as therapeutic effects against certain cancers. Recent studies are suggesting that resveratrol may be very useful when given in combination with other agent. The two major advantages of using resveratrol in combination with other agents are: (1) synergistically or additively enhancing the efficacy against cancer, and (2) limiting the toxicity and side effects of existing therapies. However, concerted and multidisciplinary efforts are needed to identify the most optimal combinatorial strategies.
doi:10.1111/nyas.12160
PMCID: PMC3713511  PMID: 23855473
resveratrol; cancer; chemoprevention; combination chemoprevention
4.  New paradigms for treatment-resistant depression 
Clinical depression is a serious mental disorder characterized by low mood, anhedonia, loss of interest in daily activities, and other symptoms, and is associated with severe consequences including suicide and increased risk of cardiovascular events. Depression affects nearly 15% of the population. The standard of care for the last 50 years has focused on monoamine neurotransmitters, including such treatments as selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs). However, these treatments have significant limitations: they can take weeks before showing mood-altering effects, and only one to two out of ten patients shows clinical effects beyond those associated with placebo. A major paradigm shift in research into the treatment of depression is underway, based on promising results with the glutamatergic NMDA receptor antagonist ketamine. Further research has demonstrated the significance of glutamatergic pathways in depression and the association of this system with the stress pathway and magnesium homeostasis. Treatment with NMDA receptor antagonists and magnesium have shown the ability to sprout new synaptic connections and reverse stress-induced neural changes, opening up promising new territory for the development of drugs to meet the unmet need in patients with clinical depression.
doi:10.1111/nyas.12223
PMCID: PMC3936783  PMID: 23876043
depression; SSRI; SNRI; ketamine; glutamate antagonist; NMDA; scopolamine; magnesium; glutamine; CP-AMPA
5.  Functional genomics lead to new therapies in follicular lymphoma 
Recent technological advances allow analysis of genomic changes in cancer in unprecedented detail. The next challenge is to prioritize the multitude of genetic aberrations found and identify therapeutic opportunities. We recently completed a study that illustrates the use of unbiased genetic screens and murine cancer models to find therapeutic targets among complex genomic data. We genetically dissected the common deletion of chromosome 6q and identified the ephrin receptor A7 (EPHA7) as a tumor suppressor in lymphoma. Notably, EPHA7 encodes a soluble splice variant that acts as an extrinsic tumor suppressor. Accordingly, we developed an antibody-based strategy to specifically deliver EPHA7 back to tumors that have lost this gene. Recent sequencing studies have implicated EPHA7 in lung cancer and other tumors, suggesting a broader therapeutic potential for antibody-mediated delivery of this tumor suppressor for cancer therapy. Together, our comprehensive approach provides new insights into cancer biology and may directly lead to the development of new cancer therapies.
doi:10.1111/nyas.12120
PMCID: PMC3987118  PMID: 23676193
genomic data; mouse model; therapies
6.  A knockout mouse resource for the biomedical research community 
The Knockout Mouse Project (KOMP) Repository archives and distributes vectors, embryonic stem cell clones, frozen germplasm, and live mutant mice for 8,500 knockout genes. Here, we describe the creation and functions of the KOMP Repository.
doi:10.1111/j.1749-6632.2011.06311.x
PMCID: PMC4070945  PMID: 22211970
genetically altered mice; knockouts; gene targeting; ES cells
7.  Probiotic Therapy in Radiation-Induced Intestinal Injury and Repair 
Intestinal injury from ionizing radiation is a clinically important entity, as enteritis symptoms occur commonly after radiotherapy for pelvic malignancies. Preventative or therapeutic options for radiation enteritis are mostly unsatisfactory; however, available data suggests that probiotic bacteria—those which confer health benefit—may have therapeutic value. Previous reports from both human trials and animal models have evaluated various end points for probiotic usage in limiting radiation-associated intestinal damage. Newer data suggests that particular probiotics and/or their secreted or derived bacterial products may have unique radioprotective properties. We will review the area with a focus on new developments surrounding probiotic therapy in radiation-induced intestinal injury and repair.
doi:10.1111/j.1749-6632.2009.04029.x
PMCID: PMC4063203  PMID: 19538306
probiotics; radiation; enteritis; lactobacillus rhamnosus GG; LGG; COX-2
8.  Enteropathogenic E. coli effectors EspG1/G2 disrupt tight junctions: new roles and mechanisms 
Enteropathogenic E. coli (EPEC) infection is a major cause of infantile diarrhea in the developing world. Using a type-three secretion system, bacterial effector proteins are transferred to the host cell cytosol where they affect multiple physiological functions, ultimately leading to diarrheal disease. Disruption of intestinal epithelial cell tight junctions is a major consequence of EPEC infection and is mediated by multiple effector proteins, among them EspG1 and its homologue EspG2. EspG1/G2 contribute to loss of barrier function via an undefined mechanism that may be linked to their disruption of microtubule networks. Recently new investigations have identified additional roles for EspG. Sequestration of active ADP-ribosylating factor (ARF) proteins and promotion of p21-activated kinase (PAK) activity as well as inhibition of Golgi-mediated protein secretion have all been linked to EspG. In this review, we examine the functions of EspG1/G2 and discuss potential mechanisms of EspG-mediated tight junction disruption.
doi:10.1111/j.1749-6632.2012.06563.x
PMCID: PMC4063556  PMID: 22731728
EPEC; tight junctions; EspG; microtubules; ARF; PAK
9.  Anticipatory eye movements stabilize gaze during self-generated head movements 
Visual acuity and motion perception are degraded during head movements unless the eyes counter-rotate so as to stabilize the line of sight and the retinal image. The vestibulo-ocular reflex (VOR) is assumed to produce this ocular counter-rotation. Consistent with this assumption, oscillopsia is a common complaint of patients with bilateral vestibular weakness.
Shanidze et al. (2010b) described compensatory eye movements in normal guinea pigs that appear to anticipate self-generated head movements. These responses effectively stabilize gaze and occur independently of the vestibular system. These new findings suggest that the VOR stabilizes gaze during passive perturbations of the head in space, but anticipatory responses may supplement or even supplant the VOR during actively generated head movements. This report reviews these findings, potential neurophysiological mechanisms, and their potential application to human clinical treatment of patients with vestibular disease.
doi:10.1111/j.1749-6632.2011.06165.x
PMCID: PMC4049289  PMID: 21950997
vestibulo-ocular reflex (VOR); efference copy; cervico-ocular reflex (COR); vestibular nuclei; oscillopsia; guinea pigs
10.  Measurement of inflammation and oxidative stress following drastic changes in air pollution during the Beijing Olympics: a panel study approach 
Ambient air pollution has been linked to cardiovascular and respiratory morbidity and mortality in epidemiology studies. Frequently, oxidative and nitrosative stress are hypothesized to mediate these pollution effects, however precise mechanisms remain unclear. This paper describes the methodology for a major panel study to examine air pollution effects on these and other mechanistic pathways. The study took place during the drastic air pollution changes accompanying the 2008 Olympics in Beijing, China. After a general description of air pollution health effects, we provide a discussion of panel studies and describe the unique features of this study that make it likely to provide compelling results. This study should lead to a clearer and more precise definition of the role of oxidative and nitrosative stress, as well as other mechanisms, in determining acute morbidity and mortality from air pollution exposure.
doi:10.1111/j.1749-6632.2010.05638.x
PMCID: PMC4049322  PMID: 20716299
panel study; oxidative stress; exhaled breath condensate; 2008 Olympics
11.  Acute effects of motor vehicle traffic-related air pollution exposures on measures of oxidative stress in human airways 
Epidemiological studies have linked exposure to traffic-related air pollutants to increased respiratory and cardiovascular morbidity and mortality. Evidence from human, animal, and in vitro studies supports an important role for oxidative stress in the pathophysiological pathways underlying the adverse health effects of air pollutants. In controlled-exposure studies of animals and humans, emissions from diesel engines, a major source of traffic-related air pollutants, cause pulmonary and systemic inflammation that is mediated by redox-sensitive signaling pathways. Assessment of human responses to traffic-related air pollution under realistic conditions is challenging due to the complex, dynamic nature of near-roadway exposure. Noninvasive measurement of biomarkers in breath and breath condensate may be particularly useful for evaluating the role of oxidative stress in acute responses to exposures that occur in vehicles or during near-roadway activities. Promising biomarkers include nitric oxide in exhaled breath, and nitrite/nitrate, malondialdehyde, and F2-isoprostanes in exhaled breath condensate.
doi:10.1111/j.1749-6632.2010.05604.x
PMCID: PMC4043285  PMID: 20716291
air pollution; traffic; oxidative stress; exhaled breath; airways; biomarkers
12.  Do women stop early? Similarities in fertility decline in humans and chimpanzees 
Two kinds of evidence suggest that female fertility may end at an earlier age in modern people than in ancestral populations or in our closest living relatives, chimpanzees. We investigate both to see whether fertility schedules or ovarian follicle counts falsify the alternative hypothesis that the age of terminal fertility changed little in the human lineage while greater longevity evolved due to grandmother effects. We use 19th century Utah women to represent non-contracepting humans, and compare their fertility by age with published records for wild chimpanzees. Then we revisit published counts of ovarian follicular stocks in both species. Results show wide individual variation in age at last birth and oocyte stocks in both humans and chimpanzees. This heterogeneity, combined with interspecific differences in adult mortality, has large and opposing effects on fertility schedules. Neither realized fertility nor rates of follicular atresia stand as evidence against the hypothesis that ages at last birth changed little while greater longevity evolved in our lineage.
doi:10.1111/j.1749-6632.2010.05527.x
PMCID: PMC4043631  PMID: 20738274
grandmother hypothesis; fertility decline; menopause; heterogeneity; follicular depletion; chimpanzee comparisons
13.  The clinical significance of drug craving 
Although drug craving has received considerable research attention over the past several decades, to date there has been no systematic review of the general clinical significance of craving. This paper presents an overview of measurement issues of particular relevance to a consideration of use of craving in clinical settings. The paper then considers the relevance of craving across a broad array of clinical domains, including diagnosis, prognostic utility, craving as an outcome measure, and the potential value of craving as a direct target of intervention. The paper is both descriptive and prescriptive, informed by the current state of the science on craving with recommendations for the definition of craving, assessment practices, future research, and clinical applications. We conclude that craving has considerable utility for diagnosis and as a clinical outcome, and that findings from future research will likely expand the clinical potential of the craving construct in the domains of prognosis and craving as a treatment target.
doi:10.1111/j.1749-6632.2011.06298.x
PMCID: PMC4041083  PMID: 22172057
craving; clinical significance; diagnosis; prognosis; clinical outcomes
14.  Neuroanatomical asymmetries and handedness in chimpanzees (Pan troglodytes): a case for continuity in the evolution of hemispheric specialization 
Many historical and contemporary theorists have proposed that population-level behavioral and brain asymmetries are unique to humans and evolved as a consequence of human-specific adaptations such as language, tool manufacture and use, and bipedalism. Recent studies in nonhuman animals, notably primates, have begun to challenge this view. Here, I summarize comparative data on neuroanatomical asymmetries in the planum temporale (PT) and inferior frontal gyrus (IFG) of humans and chimpanzees, regions considered the morphological equivalents to Broca’s and Wernicke’s areas. I also review evidence of population-level handedness in captive and wild chimpanzees. When similar methods and landmarks are used to define the PT and IFG, humans and chimpanzees show similar patterns of asymmetry in both cortical regions, though humans show more pronounced directional biases. Similarly, there is good evidence that chimpanzees show population-level handedness, though, again, the expression of handedness is less robust compared to humans. These results stand in contrast to reported claims of significant differences in the distribution of handedness in humans and chimpanzees, and I discuss some possible explanations for the discrepancies in the neuroanatomical and behavioral data.
doi:10.1111/nyas.12109
PMCID: PMC3676728  PMID: 23647534
brain asymmetry; language; handedness
16.  Evaluation of reward from pain relief 
The human experience of pain is multidimensional and comprises sensory, affective, and cognitive dimensions. Preclinical assessment of pain has been largely focused on the sensory features that contribute to nociception. The affective (aversive) qualities of pain are clinically significant but have received relatively less mechanistic investigation in preclinical models. Recently, operant behaviors such as conditioned place preference, avoidance, escape from noxious stimulus, and analgesic drug self-administration have been used in rodents to evaluate affective aspects of pain. An important advance of such operant behaviors is that these approaches may allow the detection and mechanistic investigation of spontaneous neuropathic or ongoing inflammatory/nociceptive (i.e., nonevoked) pain that is otherwise difficult to assess in nonverbal animals. Operant measures may allow the identification of mechanisms that contribute differentially to reflexive hypersensitivity or to pain affect and may inform the decision to progress novel mechanisms to clinical trials for pain therapy. Additionally, operant behaviors may allow investigation of the poorly understood mechanisms and neural circuits underlying motivational aspects of pain and the reward of pain relief.
doi:10.1111/nyas.12095
PMCID: PMC4028681  PMID: 23496247
operant behavior; conditioned place preference; spontaneous pain; pain affect; dopamine; mesolimbic reward circuit
17.  The potential effects of meditation on age-related cognitive decline: a systematic review 
With a rapidly aging society it becomes increasingly important to counter normal age-related decline in cognitive functioning. Growing evidence suggests that cognitive training programs may have the potential to counteract this decline. On the basis of a growing body of research that shows that meditation has positive effects on cognition in younger and middle-aged adults, meditation may be able to offset normal age-related cognitive decline or even enhance cognitive function in older adults. In this paper, we review studies investigating the effects of meditation on age-related cognitive decline. We searched the Web of Science (1900 to present), PsycINFO (1597 to present), MEDLINE (1950 to present), and CABI (1910 to present) to identify original studies investigating the effects of meditation on cognition and cognitive decline in the context of aging. Twelve studies were included in the review, six of which were randomized controlled trials. Studies involved a wide variety of meditation techniques and reported preliminary positive effects on attention, memory, executive function, processing speed, and general cognition. However, most studies had a high risk of bias and small sample sizes. Reported dropout rates were low and compliance rates high. We conclude that meditation interventions for older adults are feasible, and preliminary evidence suggests that meditation can offset age-related cognitive decline.
doi:10.1111/nyas.12348
PMCID: PMC4024457  PMID: 24571182
aging; cognitive decline; meditation; mindfulness
18.  Oxidants and antioxidants in sulfur mustard–induced injury 
Sulfur mustard (SM) is a chemical weapon that targets the skin, eyes, and lung. It was first employed during World War I and it remains a significant military and civilian threat. As a bifunctional alkylating agent, SM reacts with a variety of macromolecules in target tissues including nucleic acids, proteins and lipids, as well as small molecular weight metabolites such as glutathione. By alkylating subcellular components, SM disrupts metabolism, a process that can lead to oxidative stress. Evidence for oxidative stress in tissues exposed to SM or its analogs include increased formation of reactive oxygen species, the presence of lipid peroxidation products and oxidized proteins, and increases in antioxidant enzymes such as superoxide dismutase, catalase, and glutathione-S-transferase. Inhibition of antioxidant enzymes including thioredoxin reductase by SM can also disrupt cellular redox homeostasis. Consistent with these findings, SM-induced toxicity has been shown to be reduced by antioxidants in both in vitro and in vivo models. These data indicate that drugs that target oxidative stress pathways may represent important candidates for reducing SM-induced tissue injury.
doi:10.1111/j.1749-6632.2010.05605.x
PMCID: PMC4023473  PMID: 20716289
oxidative stress; reactive oxygen species; nitric oxide; vesicants; dermatotoxicity
19.  Status of the “East side hypothesis” (transovarial interference) twenty five years later 
Rocky Mountain Spotted Fever cases in the notorious Bitterroot Valley outbreak of the early 20th century were peculiarly distributed, with virtually all reported from the west side of the valley. Such a distribution remained unexplained until Burgdorfer et al (1981) reported that endosymbiotic rickettsiae were prevalent in wood ticks on the east side of the Bitterroot River valley but not on the west side. The “east side agent” was said to prevent the transovarial transmission of Rickettsia rickettsii, thereby severely limiting the prevalence of the latter. This hypothesis has been considered one of the most innovative explanations for an epidemiological conundrum, and indeed, has generally been accepted as a fact in the medical entomology literature. I review the evidence for the interference hypothesis, and suggest that the distribution of the Bitterroot Valley RMSF outbreak might actually have its basis in habitat or microclimate-related factors as opposed to reflecting interspecific competition by closely related rickettsiae.
doi:10.1111/j.1749-6632.2009.04522.x
PMCID: PMC4018725  PMID: 19538274
Rocky Mountain spotted fever; rickettsia; Rickettsia rickettsii; ticks; Dermacentor; Rickettsia peacockii; interference; transovarial transmission; Bitterroot Valley
20.  House calls revisited: Leveraging technology to overcome obstacles to psychiatric care and improve treatment outcomes 
Despite an increasing number of military service members in need of mental health treatment following deployment to Iraq and Afghanistan, numerous psychological and practical barriers limit access to care. Perceived stigma about admitting psychological difficulties as well as frequent long distances to treatment facilities reduce many veterans' willingness and ability to receive care. Telemedicine and virtual human technologies offer a unique potential to expand services to those in greatest need. Telemedicine-based treatment has been used to address multiple psychiatric disorders, including posttraumatic stress disorder, depression, and substance use, as well as to provide suicide risk assessment and intervention. Clinician education and training has also been enhanced and expanded through the use of distance technologies, with trainees practicing clinical skills with virtual patients and supervisors connecting with clinicians via videoconferencing. The use of these innovative and creative vehicles offer a significant and as yet unfulfilled promise to expand delivery of high quality psychological therapies, regardless of clinician and patient location.
doi:10.1111/j.1749-6632.2010.05756.x
PMCID: PMC4018828  PMID: 20955335
telemedicine; virtual reality; videoconferencing; barriers to care; OIF/OEF veterans
21.  Immunotherapy in preneoplastic disease: targeting early procarcinogenic inflammatory changes that lead to immune suppression and tumor tolerance 
Annals of the New York Academy of Sciences  2013;1284:10.1111/nyas.12076.
Recent advances in immunotherapy have demonstrated that single agent vaccines can be effective when given as primary prevention before exposure to the causative agent, and partially effective in some patients with existing cancer. However, as tumors develop and progress, tumor-induced immune suppression and tolerance present the greatest barrier to therapeutic success. Preneoplastic disease represents an important opportunity to intervene with tumor antigen–targeted vaccines before these mechanisms of immune evasion outpace efforts by the immune system to destroy precancerous cells. However, as we discuss in this review, emerging evidence suggests that procarcinogenic inflammatory changes occur early in cancer development, in both patients and mouse models of cancer progression. Defining early inhibitory signals within tumor microenvironments will yield insights that can eventually be used in the clinic to target these events and deliver treatments that can be used in addition to cancer vaccines to prevent premalignant and early invasive cancers.
doi:10.1111/nyas.12076
PMCID: PMC3859134  PMID: 23651188
cancer vaccines; preneoplasia; immunotherapy; pancreatic cancer
22.  Getting away with murder: how do the BCL-2 family of proteins kill with immunity? 
About 1 million per second is the number of white blood cells the adult human body produces. However, only a small fraction of them will survive as the majority is eliminated through a genetically controlled form of cell death referred to as apoptosis. This review places into perspective recent studies pertaining to the BCL-2 family of proteins as critical regulators of the development and function of the immune system, with particular attention on B cell and T cell biology. Here we discuss how elegant murine model systems have revealed the major contributions of the BCL-2 family in establishing an effective immune system. Moreover, we highlight some key regulatory pathways that influence the expression, function, and stability of individual BCL-2 family members, and discuss their role in immunity. From deadly methods to more gentle manners, the final portion of the review discusses the non-apoptotic functions of the BCL-2 family and how they pertain to the control of immunity.
doi:10.1111/nyas.12045
PMCID: PMC3663908  PMID: 23527542
apoptosis; BCL-2 family; immunity; mitochondria
23.  Integration of epidemiology, immunobiology, and translational research for brain tumors 
We recently identified a pivotal role for the host type I interferon (IFN) pathway in immuno-surveillance against de novo mouse glioma development, especially through the regulation of immature myeloid cells (IMCs) in the glioma microenvironment. Using these data, we identified single nucleotide polymorphisms (SNPs) in human IFN genes that dictate altered prognosis of patients with glioma. One of these SNPs (rs12553612) is located in the promoter of IFNA8, whose promoter activity is influenced by rs12553612. Conversely, recent epidemiologic data show that chronic usage of non-steroidal anti-inflammatory drugs lowers the risk of glioma. We translated these findings back to our de novo glioma model and found that cyclooxygenase-2 inhibition enhances anti-glioma immuno-surveillance by reducing glioma-associated IMCs. Taken together, these findings suggest that alterations in myeloid cell function condition the brain for glioma development. Finally, we have begun applying novel immunotherapeutic approaches to patients with low-grade glioma with the aim of preventing malignant transformation. Future research will hopefully better integrate epidemiological, immunobiological, and translational techniques to develop novel preventive approaches for malignant gliomas.
doi:10.1111/nyas.12115
PMCID: PMC3648859  PMID: 23651189
interferon; glioma; non-steroidal anti-inflammatory drugs; single nucleotide polymorphism
24.  Cancer Immunoediting: antigens, mechanisms and implications to cancer immunotherapy 
Accumulated data from animal models and human cancer patients strongly support the concept that the immune system can identify and control nascent tumor cells in a process called cancer immunosurveillance. Additionally, the immune system can also promote tumor progression through chronic inflammation, immunoselection of poorly immunogenic variants and suppressing anti-tumor immunity. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer immunoediting. The current framework of cancer immunoediting is a dynamic process comprised of three distinct phases: elimination, equilibrium, and escape. Recently, we demonstrated that immunoselection by CD8+ T cells of tumor variants lacking strong tumor-specific antigens represents one mechanism by which cancer cells escape tumor immunity and points toward the future of personalized cancer therapy.
doi:10.1111/nyas.12105
PMCID: PMC3648872  PMID: 23651186
cancer immunoediting; immunosurveillance; tumor antigens; immunotherapy; tumor escape; cancer genome
25.  The osteocyte primary cilium and its role in bone mechanotransduction 
Bone is a dynamic tissue that adapts to its local loading environment. Mechanotransduction, the process by which cells convert mechanical forces into biochemical signals, is important for maintaining bone health and homeostasis. It is less clear, however, what the cellular mechanosensor(s) are that sense and initiate these signaling cascades. Primary cilia are solitary, rigid structures that extend from cell body into the extracellular space; as a result, they are prime candidates for mechanosensing in bone. They have been shown to be critical in development, and they have been implicated in mechanosensing in other tissue types including liver and kidney. This review discusses the potential for primary cilia to play an important role in bone mechanotransduction and possible avenues for future study.
doi:10.1111/j.1749-6632.2009.05243.x
PMCID: PMC3999479  PMID: 20392268
bone; osteocyte; primary cilia; mechanosensor; mechanotransduction

Results 1-25 (762)