O objetivo deste estudo foi analisar como se dá a integração da tecnologia, ou melhor, CALL – Computer Assisted Language Learning – na sala de aula dos cursos de licenciatura em Letras do estado do Paraná. A Teoria da Difusão de Inovações e o Modelo Esférico de Integração de CALL foram os modelos teórico e analítico que respectivamente nortearam a pesquisa. Este estudo é uma pesquisa de métodos mistos e foi adotado um delineamento explanatório sequencial composto de duas fases distintas: uma primeira fase com abordagem quantitativa e uma segunda fase com abordagem qualitativa. As inferências finais foram feitas a partir dos resultados de ambas as fases do estudo. Analiticamente, o uso da tecnologia na sala de aula não foi considerado um construto unitário, mas sim multifacetado. Com relação ao contexto foram estudadas diferentes instituições de ensino superior, e não apenas uma ou duas universidades. Buscou-se evitar, assim, as limitações metodológicas, analíticas e contextuais comumente encontradas em estudos sobre a integração de CALL. Para a primeira fase quantitativa foi desenvolvido um questionário para coleta de dados. O instrumento foi validado por um painel de especialistas, testado em um estudo-piloto e, por fim, administrado a uma amostra constituída de 152 professores de 33 cursos de Letras de instituições públicas e privadas de todo o estado do Paraná. Análises estatísticas foram feitas para examinar a relação entre os três conjuntos de fatores do Modelo Esférico de Integração de CALL e os usos multifacetados da tecnologia pelos professores dos cursos de licenciatura em línguas do estado do Paraná. Os resultados identificaram quatro usos diferentes e também a influência sobre eles dos fatores individuais, contextuais e da formação prévia em CALL/TICs, mostrando que os fatores individuais e os fatores contextuais são importantes preditores da integração de CALL/TICs. Com base nos resultados da fase quantitativa e fazendo uso da Teoria da Inovação Individual foram selecionados os participantes para a segunda fase. Foram conduzidas 16 entrevistas individuais semiestruturadas. A fase qualitativa aprofundou os resultados quantitativos e explicou os resultados inesperados e sem resposta da fase quantitativa. A integração dos resultados mostrou que além dos fatores individuais e contextuais, aparentemente a formação prévia dos professores em CALL/TICs não deve ser descartada como preditor da integração de CALL/TICs. Foi possível também traçar o panorama atual de CALL nos cursos de Letras do estado do Paraná. CALL ainda está distante da normalização. Descobertas adicionais foram obtidas nas duas fases do estudo. No contexto internacional, assim como no contexto brasileiro, apesar das inúmeras pesquisas sobre CALL, ainda existem lacunas significativas em algumas áreas e percebe-se a necessidade de mais estudos que aprofundem o tema da integração e ajudem a elucidar a relação entre os fatores que levam ou não a integração de CALL. Esta pesquisa sobre a integração de CALL no contexto brasileiro buscou contribuir para que se tenha uma compreensão mais ampla de como lidar com CALL e mostrar caminhos para que a integração ocorra em outros contextos. / The objective of this study was to analyze the integration of technology, or rather CALL – Computer Assisted Language Learning – in the classroom of Modern Languages courses in the state of Paraná. The Diffusion of Innovations Theory and the Spherical Model of L2 Teachers’ Integration of CALL Technology into the Classroom were the theoretical and analytical models that respectively guided the research. This is a mixed methods study that adopted a sequential explanatory design that consisted of two distinct phases: a first phase with a quantitative approach and a second phase with a qualitative approach. The final inferences were made from the results of both phases of the study. Analytically, the use of technology in the classroom was not considered a unitary construct, but rather multifaceted. Contextually, different higher educational institutions, not just one or two universities were investigated. The purpose was to avoid methodological, analytical and contextual constraints commonly found in studies on the integration of CALL. For the first quantitative phase a questionnaire was developed to collect data. The instrument was validated by a panel of experts, tested in a pilot study and, finally, applied to a sample of 152 teachers from 33 Modern Languages courses from public and private institutions throughout the state of Paraná. Statistical analyzes were performed to examine the relationship between the three sets of factors from the Spherical Model and the multifaceted uses of technology by the teachers of undergraduate language courses in the state of Paraná. The results identified four different uses and also the influences of individual factors, contextual factors and prior CALL/ICTs education on the uses of technology, showing that individual factors and contextual factors are important predictors of CALL/ICTs integration. Participants were selected for the qualitative phase according to the results of the quantitative phase and to Rogers’ Individual Innovativeness Theory. Sixteen semi-structured individual interviews were conducted. The qualitative phase deepened the quantitative results and explained the unexpected results and the results that could not be answered in the quantitative phase. The integration of the results showed that in addition to individual and contextual factors, apparently prior CALL/ICTs education should not be dismissed as a predictor of CALL/ICTs integration. It was also possible to provide a clearer picture of CALL in the Modern Languages courses in the state of Paraná. CALL is far from normalization. Additional findings were obtained in the two phases of the study. In international and Brazilian contexts, despite extensive research on CALL, there are still significant gaps in some areas. There is the need for more studies to further investigate the issue of integration and help elucidate the relationship between the factors that lead to CALL integration or not. This research on the integration of CALL in the Brazilian context sought to contribute to a broader understanding of CALL and to show ways for integration to take place in other contexts.

O objetivo deste estudo foi analisar como se dá a integração da tecnologia, ou melhor, CALL – Computer Assisted Language Learning – na sala de aula dos cursos de licenciatura em Letras do estado do Paraná. A Teoria da Difusão de Inovações e o Modelo Esférico de Integração de CALL foram os modelos teórico e analítico que respectivamente nortearam a pesquisa. Este estudo é uma pesquisa de métodos mistos e foi adotado um delineamento explanatório sequencial composto de duas fases distintas: uma primeira fase com abordagem quantitativa e uma segunda fase com abordagem qualitativa. As inferências finais foram feitas a partir dos resultados de ambas as fases do estudo. Analiticamente, o uso da tecnologia na sala de aula não foi considerado um construto unitário, mas sim multifacetado. Com relação ao contexto foram estudadas diferentes instituições de ensino superior, e não apenas uma ou duas universidades. Buscou-se evitar, assim, as limitações metodológicas, analíticas e contextuais comumente encontradas em estudos sobre a integração de CALL. Para a primeira fase quantitativa foi desenvolvido um questionário para coleta de dados. O instrumento foi validado por um painel de especialistas, testado em um estudo-piloto e, por fim, administrado a uma amostra constituída de 152 professores de 33 cursos de Letras de instituições públicas e privadas de todo o estado do Paraná. Análises estatísticas foram feitas para examinar a relação entre os três conjuntos de fatores do Modelo Esférico de Integração de CALL e os usos multifacetados da tecnologia pelos professores dos cursos de licenciatura em línguas do estado do Paraná. Os resultados identificaram quatro usos diferentes e também a influência sobre eles dos fatores individuais, contextuais e da formação prévia em CALL/TICs, mostrando que os fatores individuais e os fatores contextuais são importantes preditores da integração de CALL/TICs. Com base nos resultados da fase quantitativa e fazendo uso da Teoria da Inovação Individual foram selecionados os participantes para a segunda fase. Foram conduzidas 16 entrevistas individuais semiestruturadas. A fase qualitativa aprofundou os resultados quantitativos e explicou os resultados inesperados e sem resposta da fase quantitativa. A integração dos resultados mostrou que além dos fatores individuais e contextuais, aparentemente a formação prévia dos professores em CALL/TICs não deve ser descartada como preditor da integração de CALL/TICs. Foi possível também traçar o panorama atual de CALL nos cursos de Letras do estado do Paraná. CALL ainda está distante da normalização. Descobertas adicionais foram obtidas nas duas fases do estudo. No contexto internacional, assim como no contexto brasileiro, apesar das inúmeras pesquisas sobre CALL, ainda existem lacunas significativas em algumas áreas e percebe-se a necessidade de mais estudos que aprofundem o tema da integração e ajudem a elucidar a relação entre os fatores que levam ou não a integração de CALL. Esta pesquisa sobre a integração de CALL no contexto brasileiro buscou contribuir para que se tenha uma compreensão mais ampla de como lidar com CALL e mostrar caminhos para que a integração ocorra em outros contextos. / The objective of this study was to analyze the integration of technology, or rather CALL – Computer Assisted Language Learning – in the classroom of Modern Languages courses in the state of Paraná. The Diffusion of Innovations Theory and the Spherical Model of L2 Teachers’ Integration of CALL Technology into the Classroom were the theoretical and analytical models that respectively guided the research. This is a mixed methods study that adopted a sequential explanatory design that consisted of two distinct phases: a first phase with a quantitative approach and a second phase with a qualitative approach. The final inferences were made from the results of both phases of the study. Analytically, the use of technology in the classroom was not considered a unitary construct, but rather multifaceted. Contextually, different higher educational institutions, not just one or two universities were investigated. The purpose was to avoid methodological, analytical and contextual constraints commonly found in studies on the integration of CALL. For the first quantitative phase a questionnaire was developed to collect data. The instrument was validated by a panel of experts, tested in a pilot study and, finally, applied to a sample of 152 teachers from 33 Modern Languages courses from public and private institutions throughout the state of Paraná. Statistical analyzes were performed to examine the relationship between the three sets of factors from the Spherical Model and the multifaceted uses of technology by the teachers of undergraduate language courses in the state of Paraná. The results identified four different uses and also the influences of individual factors, contextual factors and prior CALL/ICTs education on the uses of technology, showing that individual factors and contextual factors are important predictors of CALL/ICTs integration. Participants were selected for the qualitative phase according to the results of the quantitative phase and to Rogers’ Individual Innovativeness Theory. Sixteen semi-structured individual interviews were conducted. The qualitative phase deepened the quantitative results and explained the unexpected results and the results that could not be answered in the quantitative phase. The integration of the results showed that in addition to individual and contextual factors, apparently prior CALL/ICTs education should not be dismissed as a predictor of CALL/ICTs integration. It was also possible to provide a clearer picture of CALL in the Modern Languages courses in the state of Paraná. CALL is far from normalization. Additional findings were obtained in the two phases of the study. In international and Brazilian contexts, despite extensive research on CALL, there are still significant gaps in some areas. There is the need for more studies to further investigate the issue of integration and help elucidate the relationship between the factors that lead to CALL integration or not. This research on the integration of CALL in the Brazilian context sought to contribute to a broader understanding of CALL and to show ways for integration to take place in other contexts.

O presente estudo procura discutir a validade, para um determinado caso, da principal tese da bibliografia dos anos 90 sobre os movimentos sociais brasileiros: a de que eles introduzem e ampliam direitos. O caso abordado é o da mudança da política habitacional da Prefeitura de São Paulo para as favelas (1979-1989): de uma política centrada na remoção para uma caracterizada pela urbanização. A pesquisa foi feita com base em um modelo desenvolvido no campo de estudo das políticas públicas (MSM3). Especificamente, a partir das proposições de Kingdon (1984). Desta forma, o estudo intenta verificar se, mesmo quando se parte de outra bibliografia, aquela tese se sustenta. Ou seja, se as conclusões a que se chega são similares, quanto ao lugar do movimento social na explicação dessa mudança da política pública. / This study discusses the validity, for a particular case, the main thesis of the literature of the 90s on Brazilian social movements: that they introduce and expand rights. The case discussed is the change of the Municipality of São Paulo favelas to housing policy (1979-1989): a policy focused on removal for a characterized by urbanization. The research was based on a model developed in the field of study of public policy (MSM3). Specifically, from the propositions of Kingdon (1984). Thus, the study intends to verify whether, even when another part of the bibliography, that argument holds up. That is, if the conclusions now reached are similar to previous ones, about the place of social movements in explaining this change in public policy

Indiana University-Purdue University Indianapolis (IUPUI) / The immune system initiates tissue repair following injury. In response to sterile tissue injury, neutrophils infiltrate the tissue to remove tissue debris and subsequently undergo apoptosis. Proper clearance of apoptotic neutrophils in the tissue by recruited macrophages, in a process termed efferocytosis, is critical to facilitate the resolution of inflammation and tissue repair. However, the events leading to suppression of sterile inflammation following efferocytosis, and the contribution of other innate cell types are not clearly defined in an in vivo setting. Using a sterile mouse peritonitis model, we identified IL-4 production from efferocytosing macrophages in the peritoneum that activate invariant NKT cells to produce cytokines including IL-4 and IL-13. Importantly, IL-4 from macrophages functions in autocrine and paracrine circuits to promote alternative activation of peritoneal exudate macrophages and augment type-2 cytokine production from NKT cells to suppress inflammation. The increased peritonitis in mice deficient in IL-4, NKT cells, or IL-4Ra expression on myeloid cells suggested that each is a key component for resolution of sterile inflammation. The phagocyte NADPH oxidase, a multi-subunit enzyme complex we demonstrated to require a physical interaction between the Rac GTPase and the oxidase subunit gp91phox for generation of reactive oxygen species (ROS), is required for production of ROS within macrophage phagosomes containing ingested apoptotic cells. In mice with X-linked chronic granulomatous disease (X-CGD) that lack gp91phox, efferocytosing macrophages were unable to produce ROS and were defective in activating iNKT during sterile peritonitis, resulting in enhanced and prolonged inflammation. Thus, efferocytosis-induced IL-4 production and activation of IL-4-producing iNKT cells by macrophages are immunomodulatory events in an innate immune circuit required to resolve sterile inflammation and promote tissue repair.

Indiana University-Purdue University Indianapolis (IUPUI) / Skeletal manifestations including short stature, osteoporosis, kyphoscoliosis, and tibial dysplasia cumulatively affect approximately 70% of patients with neurofibromatosis type 1 (NF1). Tibial pseudarthrosis, the chronic non-union of a spontaneous fracture, is a debilitating skeletal malady affecting young children with NF1. These non-healing fractures respond poorly to treatment and often require amputation of the affected limb due to limited understanding of the causative mechanisms. To better understand the cellular and molecular pathogenesis of these osseous defects, we have established a new mouse model which recapitulates a spectrum of skeletal pathologies frequently observed in patients with NF1. Nf1flox/-;Col2.3Cre mice, harboring Nf1 nullizygous osteoblasts on a Nf1+/- background, exhibit multiple osseous defects which are closely reminiscent of those found in NF1 patients, including runting (short stature), bone mass deficits, spinal deformities, and tibial fracture non-union. Through adoptive bone marrow transfer studies, we have demonstrated that the Nf1 haploinsufficient hematopoietic system pivotally mediates the pathogenesis of bone loss and fracture non-union in Nf1flox/-;Col2.3Cre mice. By genetic ablation of a single Nf1 allele in early myeloid development, under the control of LysMCre, we have further delineated that Nf1 haploinsufficient myeloid progenitors and osteoclasts are the culprit lineages mediating accelerated bone loss. Interestingly, conditional Nf1 haploinsufficiency in mature osteoclasts, induced by CtskCre, was insufficient to trigger enhanced lytic activity. These data provide direct genetic evidence for Nf1’s temporal significance as a gatekeeper of the osteoclast progenitor pool in primitive myelopoiesis. On the molecular level, we found that transforming growth factor-beta1 (TGF-β1), a primary mediator in the spatiotemporal coupling of bone remodeling, is pathologically overexpressed by five- to six- fold in both NF1 patients and in mice. Nf1 deficient osteoblasts, the principal source of TGF-β1 in the bone matrix, overexpress TGF-β1 in a gene dosage dependent fashion. Moreover, p21Ras dependent hyperactivation of the Smad pathway accentuates responses to pathological TGF-β1 signals in Nf1 deficient bone cells. As a proof of concept, we demonstrate that pharmacologic TβRI kinase inhibition can rescue bone mass defects and prevent tibial fracture non-union in Nf1flox/-;Col2.3Cre mice, suggesting that targeting TGF-β1 signaling in myeloid lineages may provide therapeutic benefit for treating NF1 skeletal defects.

Indiana University-Purdue University Indianapolis (IUPUI) / Type I diabetes is an autoimmune disorder characterized by the loss of insulin producing islet cell mass. While daily insulin injection provides an easy means of glycemic control, it does not prevent long-term complications associated with diabetes. Islet transplantation has been suggested as a permanent cure for type 1 diabetes. However, the recurrence of host immunity and shortage of donor islets hinder the prevalence of islet transplantation. Biomaterial strategies provide an alternative route to solving the problems associated with host immune response and shortage of donor islets. One highly recognized platform for achieving these goals are hydrogels, which are hydrophilic crosslinked polymers with tissue-like elasticity and high permeability. Hydrogels prepared from poly(ethylene glycol) (PEG) derivatives are increasingly used for a variety of tissue engineering applications, including encapsulation of pancreatic islets and serving as a material platform for pseudo-islet differentiation. PEG hydrogels formed by mild and rapid thiol-ene photo-click reactions are particularly useful for studying cell behaviors in three-dimension (3D). Thiol-ene PEG-based hydrogels can be rendered biodegradable if appropriate macromer and cross-linker chemistry is employed. However, the influence of hydrogel matrix properties on the survival, growth, and morphogenesis of cells in 3D has not been fully evaluated. This thesis aims at using norbornene-functionalized PEG macromers to prepare thiol-ene hydrogels with various stiffness and degradability, from which to study the influence of hydrogel properties on pancreatic cell fate processes in 3D. Toward establishing an adaptable hydrogel platform for pancreatic tissue engineering, this thesis systematically studies the influence of hydrogel properties on encapsulated endocrine cells (e.g., MIN6 beta-cells) and exocrine cells (PANC-1 cells), as well as human mesenchymal stem cells (hMSC). It was found that thiol-ene photo-click hydrogels provide a cytocompatible environment for 3D culture of these cells. However, cell viability was negatively affected in hydrogels with higher cross-linking density. In contrast to a monolayer when cultured on a 2D surface, cells with epithelial characteristic formed clusters and cells with mesenchymal features retained single cell morphology in 3D. Although cells survived in all hydrogel formulations studied, the degree of proliferation, and the size and morphology of cell clusters formed in 3D were significantly influenced by hydrogel matrix compositions. For example: encapsulating cells in hydrogels formed by hydrolytically degradable macromer positively influenced cell survival indicated by increased proliferation. In addition, when cells were encapsulated in thiol-ene gels lacking cell-adhesive motifs, hydrolytic gel degradation promoted their survival and proliferation. Further, adjusting peptide crosslinker type and immobilized ECM-mimetic bioactive cues provide control over cell fate by determining whether observed cellular morphogenesis is cell-mediated or matrix-controlled. These fundamental studies have established PEG-peptide hydrogels formed by thiol-ene photo-click reaction as a suitable platform for pancreatic tissue engineering

Indiana University-Purdue University Indianapolis (IUPUI) / Proteins are the building blocks in a biological system. They interact with other proteins to make unique biological phenomenon. Protein-protein interactions play a valuable role in understanding the molecular mechanisms occurring in any biological system. Protein interaction databases are a rich source on protein interaction related information. They gather large amounts of information from published literature to enrich their data. Expert curators put in most of these efforts manually. The amount of accessible and publicly available literature is growing very rapidly. Manual annotation is a time consuming process. And with the rate at which available information is growing, it cannot be dealt with only manual curation. There need to be tools to process this huge amounts of data to bring out valuable gist than can help curators proceed faster. In case of extracting protein-protein interaction evidences from literature, just a mere mention of a certain protein by look-up approaches cannot help validate the interaction. Supporting protein interaction information with experimental evidence can help this cause. In this study, we are applying machine learning based classification techniques to classify and given protein interaction related document into an interaction detection method. We use biological attributes and experimental factors, different combination of which define any particular interaction detection method. Then using predicted detection methods, proteins identified using named entity recognition techniques and decomposing the parts-of-speech composition we search for sentences with experimental evidence for a protein-protein interaction. We report an accuracy of 75.1% with a F-score of 47.6% on a dataset containing 2035 training documents and 300 test documents.

Indiana University-Purdue University Indianapolis (IUPUI) / Hydrogels prepared from photopolymerization have been used for a variety of tissue engineering and controlled release applications. Polymeric biomaterials with high cytocompatibility, versatile degradation behaviors, and diverse material properties are particularly useful in studying cell fate processes. In recent years, step-growth thiol-ene photochemistry has been utilized to form cytocompatible hydrogels for tissue engineering applications. This radical-mediated gelation scheme utilizes norbornene functionalized multi-arm poly(ethylene glycol) (PEGNB) as the macromer and di-thiol containing molecules as the crosslinkers to form chemically crosslinked hydrogels. While the gelation mechanism was well-described in the literature, the network properties and degradation behaviors of these hydrogels have not been fully characterized. In addition, existing thiol-ene photopolymerizations often used type I photoinitiators in conjunction with an ultraviolet (UV) light source to initiate gelation. The use of cleavage type initiators and UV light often raises biosafety concerns. The first objective of this thesis was to understand the gelation and degradation properties of thiol-ene hydrogels. In this regard, two types of step-growth hydrogels were compared, namely thiol-ene hydrogels and Michael-type addition hydrogels. Between these two step-growth gel systems, it was found that thiol-ene click reactions formed hydrogels with higher crosslinking efficiency. However, thiol-ene hydrogels still contained significant network non-ideality, demonstrated by a high dependency of hydrogel swelling on macromer contents. In addition, the presence of ester bonds within the PEGNB macromer rendered thiol-ene hydrogels hydrolytically degradable. Through validating model predictions with experimental results, it was found that the hydrolytic degradation of thiol-ene hydrogels was not only governed by ester bond hydrolysis, but also affected by the degree of network crosslinking. In an attempt to manipulate network crosslinking and degradation rate of thiol-ene hydrogels, different macromer contents and peptide crosslinkers with different amino acid sequences were used. A chymotrypsin-sensitive peptide was also used as part of the hydrogel crosslinkers to render thiol-ene hydrogels enzymatically degradable. The second objective of this thesis was to develop a visible light-mediated thiol-ene hydrogelation scheme using a type II photoinitiator, eosin-Y, as the only photoinitiator. This approach eliminates the incorporation of potentially cytotoxic co-initiator and co-monomer that are typically used with a type II initiator. In addition to investigating the gelation kinetics and properties of thiol-ene hydrogels formed by this new gelation scheme, it was found that the visible light-mediated thiol-ene hydrogels were highly cytocompatible for human mesenchymal stem cells (hMSCs) and pancreatic MIN6 beta-cells. It was also found that eosin-Y could be repeatedly excited for preparing step-growth hydrogels with multilayer structures. This new gelation chemistry may have great utilities in controlled release of multiple sensitive growth factors and encapsulation of multiple cell types for tissue regeneration.

Indiana University-Purdue University Indianapolis (IUPUI) / Immunostimulatory cytokines can enhance anti-tumor immunity and are part of the therapeutic armamentarium for cancer treatment. We previously reported that chemotherapy-treated lymphoma patients acquire a deficiency of Signal Transducer and Activator of Transcription 4 (STAT4), which results in defective IFNy production during clinical immunotherapy. With the goal of further improvement in cytokine-based immunotherapy, we examined the effects of a soybean peptide called lunasin that exhibits immunostimulatory effects on natural killer cells (NKCs). Peripheral blood mononucleated cells (PBMCs) from healthy donors and chemotherapy-treated lymphoma patients were stimulated with or without lunasin in the presence of IL-12 or IL-2. NK activation was evaluated, and its tumoricidal activity was assessed using in vitro and in vivo tumor models. Chromatin immunoprecipitation (ChIP) assay was performed to evaluate the histone modification of gene loci that are regulated by lunasin and cytokine. Adding lunasin to IL-12- or IL-2-cultuted NK cells demonstrated synergistic effects in the induction of IFNG and genes involved in cytotoxicity. The combination of lunasin and cytokines (IL-12 plus IL-2) was capable of restoring IFNy production by NK cells from post-transplant lymphoma patients. In addition, NK cells stimulated with lunasin plus cytokines have higher tumoricidal activity than those stimulated with cytokines alone using in vitro tumor models. The underlying mechanism responsible for the effects of lunasin on NK cells is likely due to epigenetic modulation at target gene loci. Lunasin represents a different class of immune modulating agent that may augment the therapeutic responses mediated by cytokine-based immunotherapy.

Indiana University-Purdue University Indianapolis (IUPUI) / Signal Transducer and Activator of Transcription 3 (STAT3) is known to be related to bone metabolism. Mutation of STAT3 causes a rare disorder in which serum levels of IgE are elevated. This causes various skeletal problems similar to osteoporosis. To examine the effect of STAT3 in the osteoclast, we obtained two osteoclast specific STAT3 knockout mouse models: one using the CTSK promoter to drive Cre recombinase and another using a TRAP promoter. Examination of these mice at 8 weeks of age revealed a decreased trabecular bone volume in CTSK specific STAT3 knockout mice along with a slight decrease in osteoclast number in both CTSK and TRAP specific STAT3 knockout females. We also noticed changes in bone mineral density and bone mechanical strength in females. These data suggest that STAT3 plays a part in the function of the osteoclast.