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Synthetic stigmastanes with dual antiherpetic and immunomodulating activities inhibit ERK and Akt signaling pathways without binding to glucocorticoid receptors

Publication date: January 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 1, Part A

Author(s): Flavia M. Michelini, Carlos A. Bueno, Alejandro M. Molinari, Mario D. Galigniana, Lydia R. Galagovsky, Laura E. Alché, Javier A. Ramírez

Background We have previously shown that some synthetic hydroxylated stigmastanes derived from plant sterols inhibit in vitro HSV-1 replication in ocular cell lines and decrease cytokine production in stimulated macrophages, suggesting that these steroids might combine antiviral and immunomodulating properties. In this paper we report the synthesis of some analogs fluorinated at C-6 in order to study the effect of this modification on bioactivity. Methods The following methods were used: organic synthesis of fluorinated analogs, cytotoxicity determination with MTT assays, cytokine production quantification with ELISAs, glucocorticoid activity determination by displacement assays, immunofluorescence and transcriptional activity assays, studies of the activation of signaling pathways by Western blot, antiviral activity evaluation through virus yield reduction assays. Results We report the chemical synthesis of new fluorinated stigmastanes and show that this family of steroidal compounds exerts its immunomodulating activity by inhibiting ERK and Akt signaling pathways, but do not act as glucocorticoids. We also demonstrate that fluorination enhances the antiviral activity. Conclusions Fluorination on C-6 did not enhance the anti-inflammatory effect, however, an increase in the in vitro antiviral activity was observed. Thus, our results suggest that it is possible to introduce chemical modifications on the parent steroids in order to selectively modulate one of the effects. General significance This family of steroids could allow the development of an alternative treatment for ocular immunopathologies triggered by HSV-1, without the undesirable side effects of the currently used drugs.





Role of crystallins in diabetic complications

Publication date: January 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 1, Part B

Author(s): Vadde Sudhakar Reddy, G. Bhanuprakash Reddy

Background Crystallins are the major structural proteins of vertebrate eye lens responsible for maintaining the refractive index of the lens. However, recent studies suggest that they also have a functional significance in non-lenticular tissues. Prolonged uncontrolled diabetes results in the development of macro and microvascular complications that are the leading causes of morbidity and mortality in diabetic patients all over the world. Scope of review Recent studies have shown that crystallins play an instrumental role in diabetes and its complications. Therefore, this review highlights the current data on the impact of chronic hyperglycemia on expression, distribution, glycation, phosphorylation, chaperone-like function and, anti-apoptotic activity of crystallins. Furthermore, we discussed the insights for developing therapeutic strategies for diabetic complications including natural agents, peptides, and pharmacological chaperones that modulate or mimic chaperone activity of α-crystallins. Major conclusions Upregulation of crystallins appears to be a common feature of chronic diabetes. Further, chronic hyperglycemia induces the glycation and phosphorylation of crystallins, mainly α-crystallins and thereby alters their properties. The disturbed interaction of αB-crystallin with various apoptotic mediators including Bax and caspases is also an important factor for increased cell death in diabetes. Numerous dietary agents, peptides, and chemical chaperones prevent apoptosis and the loss of chaperone activity in diabetes. General significance Understanding the role of crystallins will aid in developing therapeutic strategies for alleviating pathophysiological conditions such as protein aggregation, inflammation, oxidative stress and apoptosis associated with chronic complications of diabetes including cataract, retinopathy, and cardiomyopathy. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.





Ab initio electron propagator calculations of transverse conduction through DNA nucleotide bases in 1-nm nanopore corroborate third generation sequencing

Publication date: January 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 1, Part A

Author(s): Aleksey A. Kletsov, Evgeny G. Glukhovskoy, Aleksey S. Chumakov, Joseph V. Ortiz

Background The conduction properties of DNA molecule, particularly its transverse conductance (electron transfer through nucleotide bridges), represent a point of interest for DNA chemistry community, especially for DNA sequencing. However, there is no fully developed first-principles theory for molecular conductance and current that allows one to analyze the transverse flow of electrical charge through a nucleotide base. Methods We theoretically investigate the transverse electron transport through all four DNA nucleotide bases by implementing an unbiased ab initio theoretical approach, namely, the electron propagator theory. Results The electrical conductance and current through DNA nucleobases (guanine [G], cytosine [C], adenine [A] and thymine [T]) inserted into a model 1-nm Ag–Ag nanogap are calculated. The magnitudes of the calculated conductance and current are ordered in the following hierarchies: g A > g G > g C > g T and I G > I A > I T > I C correspondingly. The new distinguishing parameter for the nucleobase identification is proposed, namely, the onset bias magnitude. Nucleobases exhibit the following hierarchy with respect to this parameter: V onset (A)< V onset (T)< V onset (G)< V onset (C). Conclusions The difference in current magnitudes and onset voltages implies the possibility of nucleobases electrical identification by virtue of DNA translocation through an electrode-equipped nanopore. General significance The results represent interest for the theorists and practitioners in the field of third generation sequencing techniques as well as in the field of DNA chemistry.





Crystallins and neuroinflammation: The glial side of the story

Publication date: January 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 1, Part B

Author(s): Jennifer E. Dulle, Patrice E. Fort

Background There is an abundance of evidence to support the association of damaging neuroinflammation and neurodegeneration across a multitude of diseases. One of the links between these pathological phenomena is the role of chaperone proteins as both neuroprotective and immune-regulatory agents. Scope of review Chaperone proteins are highly expressed at sites of neuroinflammation both in glial cells and in the injured neurons that initiate the immune response. For this reason, the use of chaperones as treatment for various diseases associated with neuroinflammation is a highly active area of investigation. This review explores the various ways that the small heat shock protein chaperones, α-crystallins, can affect glial cell function with a specific focus on their implication in the inflammatory response associated with neurodegenerative disorders, and their potential as therapeutic treatment. Major conclusions Although the mechanisms are still under investigation, a clear link has now been established between alpha-crystallins and neuroinflammation, especially through their roles in microglial and macroglial cells. Interestingly, similar to inflammation in itself, crystallins can have a beneficial or detrimental impact on the CNS based on the context and duration of the condition. General significance Overall this review points out the novel roles that chaperones such as alpha-crystallins can play outside of the classical protein folding pathways, and their potential in the development of new therapies for the treatment of neuroinflammatory/neurodegenerative diseases. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.





βA3/A1-crystallin and persistent fetal vasculature (PFV) disease of the eye

Publication date: January 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 1, Part B

Author(s): J. Samuel Zigler, Mallika Valapala, Peng Shang, Stacey Hose, Morton F. Goldberg, Debasish Sinha

Background Persistent fetal vasculature (PFV) is a human disease in which the fetal vasculature of the eye fails to regress normally. The fetal, or hyaloid, vasculature nourishes the lens and retina during ocular development, subsequently regressing after formation of the retinal vessels. PFV causes serious congenital pathologies and is responsible for as much as 5% of blindness in the United States. Scope of review The causes of PFV are poorly understood, however there are a number of animal models in which aspects of the disease are present. One such model results from mutation or elimination of the gene (Cryba1) encoding βA3/A1-crystallin. In this review we focus on the possible mechanisms whereby loss of functional βA3/A1-crystallin might lead to PFV. Major conclusions Cryba1 is abundantly expressed in the lens, but is also expressed in certain other ocular cells, including astrocytes. In animal models lacking βA3/A1-crystallin, astrocyte numbers are increased and they migrate abnormally from the retina to ensheath the persistent hyaloid artery. Evidence is presented that the absence of functional βA3/A1-crystallin causes failure of the normal acidification of endolysosomal compartments in the astrocytes, leading to impairment of certain critical signaling pathways, including mTOR and Notch/STAT3. General significance The findings suggest that impaired endolysosomal signaling in ocular astrocytes can cause PFV disease, by adversely affecting the vascular remodeling processes essential to ocular development, including regression of the fetal vasculature. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.





Ca2+ and βγ-crystallins: An affair that did not last?

Publication date: January 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 1, Part B

Author(s): Amita Mishra, Bal Krishnan, Rajeev Raman, Yogendra Sharma

Background During the last three decades, lens β- and γ-crystallins have found a huge number of kin from numerous taxonomical sources. Most of these proteins from invertebrates and microbes have been demonstrated or predicted to bind Ca2+ involving a distinct double-clamp motif, which is largely degenerated in lens homologues. Scope of review The various aspects of transformation of βγ-crystallins from a quintessential Ca2+-binding protein into a primarily structural molecule have been reviewed. Major conclusions In lens members of βγ-crystallins, the residues involved in Ca2+ binding have diverged considerably from the classical consensus with consequent reduction in their Ca2+-binding properties. This evolutionary change is congenial to their new role as robust constituents of lens. The exact functions of the residual affinity for Ca2+ are yet to be established. General significance This review highlights the significance of reduction in Ca2+-binding ability of the βγ-crystallins for lens physiology and why this residual affinity may be functionally important. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.





Differences in solution dynamics between lens β-crystallin homodimers and heterodimers probed by hydrogen–deuterium exchange and deamidation

Publication date: January 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 1, Part B

Author(s): Kirsten J. Lampi, Matthew R. Murray, Matthew P. Peterson, Bryce S. Eng, Eileen Yue, Alice R. Clark, Elisar Barbar, Larry L. David

Background Lens transparency is due to the ordered arrangement of the major structural proteins, called crystallins. βB2 crystallin in the lens of the eye readily forms dimers with other β-crystallin subunits, but the resulting heterodimer structures are not known and were investigated in this study. Methods Structures of βA3 and βB2 crystallin homodimers and the βA3/βB2 crystallin heterodimers were probed by measuring changes in solvent accessibility using hydrogen–deuterium exchange with mass spectrometry. We further mimicked deamidation in βB2 and probed the effect on the βA3/βB2 heterodimer. Results were confirmed with chemical crosslinking and NMR. Results Both βA3 and βB2 had significantly decreased deuterium levels in the heterodimer compared to their respective homodimers, suggesting that they had less solvent accessibility and were more compact in the heterodimer. The compact structure of βB2 was supported by the identification of chemical crosslinks between lysines in βB2 within the heterodimer that were inconsistent with βB2's extended homodimeric structure. The compact structure of βA3 was supported by an overall decrease in mobility of βA3 in the heterodimer detected by NMR. In βB2, peptides 70–84 and 121–134 were exposed in the homodimer, but buried in the heterodimer with ≥50% decreases in deuterium levels. Homologous peptides in βA3, 97–109 and 134–149, had 25–50% decreases in deuterium levels in the heterodimer. These peptides are probable sites of interaction between βB2 and βA3 and are located at the predicted interface between subunits with bent linkers. Deamidation at Q184 in βB2 at this predicted interface led to a less compact βB2 in the heterodimer. The more compact structure of the βA3/βB2 heterodimer was also more heat stable than either of the homodimers. Conclusions The major structural proteins in the lens, the β-crystallins, are not static, but dynamic in solution, with differences in accessibility between the homo-and hetero-dimers. This structural flexibility, particularly of βB2, may facilitate formation of different size higher-ordered structures found in the transparent lens. General significance Understanding complex hetero-oligomer interactions between β-crystallins in normal lens and how these interactions change during aging is fundamental to understanding the cause of cataracts. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.
Graphical abstract




Deamidation of N76 in human γS-crystallin promotes dimer formation

Publication date: January 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 1, Part B

Author(s): Nicholas J. Ray, Damien Hall, John A. Carver

Background Cataract formation is often attributed to the build-up of post-translational modifications in the crystallin proteins of the eye lens. One such modification, the deamidation of N76 in human γS-crystallin to D76, is highly correlated with age-related cataract (Hooi et al. Invest. Ophthalmol. Vis. Sci. 53 (2012) 3554–3561). In the current work, this modification has been extensively characterised in vitro. Methods Biophysical characterisation was performed on wild type and N76D γS-crystallins using turbidity measurements to monitor aggregation, intrinsic fluorescence and circular dichroism spectroscopy to determine the folded state and NMR spectroscopy for identifying local changes in structure. Protein mass was determined using SEC–MALLS and analytical ultracentrifugation methods. Results Relative to the wild type protein, deamidation at N76 in γS-crystallin causes an increase in the thermal stability and resistance to thermally induced aggregation alongside a decrease in stability to denaturants, a propensity to aggregate rapidly once destabilised and a tendency to form a dimer. We ascribe the apparent increase in thermal stability upon deamidation to the formation of dimer which prevents the unfolding of the inherently less stable monomer. Conclusions Deamidation causes a decrease in stability of γS-crystallin but this is offset by an increased tendency for dimer formation. General significance Deamidation at N76 in human γS-crystallin likely has a combinatorial effect with other post-translational crystallin modifications to induce age-related cataract. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.





Increased hydrophobic surface exposure in the cataract-related G18V variant of human γS-crystallin

Publication date: January 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 1, Part B

Author(s): Domarin Khago, Eric K. Wong, Carolyn N. Kingsley, J. Alfredo Freites, Douglas J. Tobias, Rachel W. Martin

Background The objective of this study was to determine whether the cataract-related G18V variant of human γS-crystallin has increased exposure of hydrophobic residues that could explain its aggregation propensity and/or recognition by αB-crystallin. Methods We used an ANS fluorescence assay and NMR chemical shift perturbation to experimentally probe exposed hydrophobic surfaces. These results were compared to flexible docking simulations of ANS molecules to the proteins, starting with the solution-state NMR structures of γS-WT and γS-G18V. Results γS-G18V exhibits increased ANS fluorescence, suggesting increased exposed hydrophobic surface area. The specific residues involved in ANS binding were mapped by NMR chemical shift perturbation assays, revealing ANS binding sites in γS-G18V that are not present in γS-WT. Molecular docking predicts three binding sites that are specific to γS-G18V corresponding to the exposure of a hydrophobic cavity located at the interdomain interface, as well as two hydrophobic patches near a disordered loop containing solvent-exposed cysteines, all but one of which is buried in γS-WT. Conclusions Although both proteins display non-specific binding, more residues are involved in ANS binding to γS-G18V, and the affected residues are localized in the N-terminal domain and the nearby interdomain interface, proximal to the mutation site. General significance Characterization of changes in exposed hydrophobic surface area between wild-type and variant proteins can help elucidate the mechanisms of aggregation propensity and chaperone recognition, presented here in the context of cataract formation. Experimental data and simulations provide complementary views of the interactions between proteins and the small molecule probes commonly used to study aggregation. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.
Graphical abstract




Gamma crystallins of the human eye lens

Publication date: January 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1860, Issue 1, Part B

Author(s): Venkata Pulla Rao Vendra, Ismail Khan, Sushil Chandani, Anbukkarasi Muniyandi, Dorairajan Balasubramanian

Background Protein crystallins co me in three types (α, β and γ) and are found predominantly in the eye, and particularly in the lens, where they are packed into a compact, plastic, elastic, and transparent globule of proper refractive power range that aids in focusing incoming light on to the retina. Of these, the γ-crystallins are found largely in the nuclear region of the lens at very high concentrations (>400mg/ml). The connection between their structure and inter-molecular interactions and lens transparency is an issue of particular interest. Scope of review We review the origin and phylogeny of the gamma crystallins, their special structure involving the use of Greek key supersecondary structural motif, and how they aid in offering the appropriate refractive index gradient, intermolecular short range attractive interactions (aiding in packing them into a transparent ball), the role that several of the constituent amino acid residues play in this process, the thermodynamic and kinetic stability and how even single point mutations can upset this delicate balance and lead to intermolecular aggregation, forming light-scattering particles which compromise transparency. We cite several examples of this, and illustrate this by cloning, expressing, isolating and comparing the properties of the mutant protein S39C of human γS-crystallin (associated with congenital cataract-microcornea), with those of the wild type molecule. In addition, we note that human γ-crystallins are also present in other parts of the eye (e.g., retina), where their functions are yet to be understood. Major conclusions There are several ‘crucial’ residues in and around the Greek key motifs which are essential to maintain the compact architecture of the crystallin molecules. We find that a mutation that replaces even one of these residues can lead to reduction in solubility, formation of light-scattering particles and loss of transparency in the molecular assembly. General significance Such a molecular understanding of the process helps us construct the continuum of genotype–molecular structural phenotype–clinical (pathological) phenotype. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease.





Editorial Board

Publication date: December 2015
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1850, Issue 12









Beyond water homeostasis: Diverse functional roles of mammalian aquaporins

Publication date: December 2015
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1850, Issue 12

Author(s): Philip Kitchen, Rebecca E. Day, Mootaz M. Salman, Matthew T. Conner, Roslyn M. Bill, Alex C. Conner

Background Aquaporin (AQP) water channels are best known as passive transporters of water that are vital for water homeostasis. Scope of review AQP knockout studies in whole animals and cultured cells, along with naturally occurring human mutations suggest that the transport of neutral solutes through AQPs has important physiological roles. Emerging biophysical evidence suggests that AQPs may also facilitate gas (CO2) and cation transport. AQPs may be involved in cell signalling for volume regulation and controlling the subcellular localization of other proteins by forming macromolecular complexes. This review examines the evidence for these diverse functions of AQPs as well their physiological relevance. Major conclusions As well as being crucial for water homeostasis, AQPs are involved in physiologically important transport of molecules other than water, regulation of surface expression of other membrane proteins, cell adhesion, and signalling in cell volume regulation. General significance Elucidating the full range of functional roles of AQPs beyond the passive conduction of water will improve our understanding of mammalian physiology in health and disease. The functional variety of AQPs makes them an exciting drug target and could provide routes to a range of novel therapies.





Endostatin's emerging roles in angiogenesis, lymphangiogenesis, disease, and clinical applications

Publication date: December 2015
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1850, Issue 12

Author(s): Amit Walia, Jessica F. Yang, Yu-hui Huang, Mark I. Rosenblatt, Jin-Hong Chang, Dimitri T. Azar

Background Angiogenesis is the process of neovascularization from pre-existing vasculature and is involved in various physiological and pathological processes. Inhibitors of angiogenesis, administered either as individual drugs or in combination with other chemotherapy, have been shown to benefit patients with various cancers. Endostatin, a 20-kDa C-terminal fragment of type XVIII collagen, is one of the most potent inhibitors of angiogenesis. Scope of review We discuss the biology behind endostatin in the context of its endogenous production, the various receptors to which it binds, and the mechanisms by which it acts. We focus on its inhibitory role in angiogenesis, lymphangiogenesis, and cancer metastasis. We also present emerging clinical applications for endostatin and its potential as a therapeutic agent in the form a short peptide. Major conclusions The delicate balance between pro- and anti-angiogenic factors can be modulated to result in physiological wound healing or pathological tumor metastasis. Research in the last decade has emphasized an emerging clinical potential for endostatin as a biomarker and as a therapeutic short peptide. Moreover, elevated or depressed endostatin levels in diseased states may help explain the pathophysiological mechanisms of the particular disease. General significance Endostatin was once sought after as the ‘be all and end all’ for cancer treatment; however, research throughout the last decade has made it apparent that endostatin's effects are complex and involve multiple mechanisms. A better understanding of newly discovered mechanisms and clinical applications still has the potential to lead to future advances in the use of endostatin in the clinic.





Nitric oxide and the thioredoxin system: a complex interplay in redox regulation

Publication date: December 2015
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1850, Issue 12

Author(s): Moran Benhar

Background The free radical nitric oxide (NO) and the thiol oxidoreductase thioredoxin (Trx) play essential roles in cellular redox regulation. Recent biochemical and cellular studies have revealed a complex thiol-dependent crosstalk between NO and Trx that modulates multiple redox-dependent pathways. Scope of review This review aims to discuss recent progress, as well as the remaining questions, regarding the interaction and cross regulation between NO and Trx in cellular function and dysfunction. Major conclusions The importance and ubiquity of NO-mediated S-nitrosylation of protein thiols as a signaling mechanism is increasingly recognized as is the central role of Trx in regulating S-nitrosylation processes. By denitrosylating diverse protein substrates, Trx plays an active role in attenuating NO signaling as well as in ameliorating nitrosative stress. Yet, at the same time, Trx can also support the activity of NO synthases, thus promoting NO production and its downstream effects. Finally, NO can reciprocally modulate the redox activity of Trx and Trx reductase. General significance Further elucidation of the crosstalk between NO and Trx will be important for an improved understanding of the effects of reactive oxygen and nitrogen species on cellular signaling and function.
Graphical abstract




The S100 proteins in epidermis: Topology and function

Publication date: December 2015
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1850, Issue 12

Author(s): Wiesława Leśniak, Agnieszka Graczyk-Jarzynka







Lupeol derivative mitigates Echis carinatus venom-induced tissue destruction by neutralizing venom toxins and protecting collagen and angiogenic receptors on inflammatory cells

Publication date: December 2015
Source:Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1850, Issue 12

Author(s): G.D. Katkar, Rachana D. Sharma, G.J. Vishalakshi, S.K. Naveenkumar, Gaurav Madhur, R.M. Thushara, T. Narender, K.S. Girish, K. Kemparaju

Background Echis carinatus bite is a serious threat in South-Asian countries including India, as it causes highest number of deaths and terrifying long-term tissue destruction at the bitten site. Although venom metalloproteinases and hyaluronidases are the suggested key players, studies on the effect of venom on polymorphonuclear cells, peripheral blood mononuclear cells and platelets, and their role in long-term tissue destruction are still in infancy. While, the effect of venom on collagen receptors, integrin α2β1/GP VI/DDR1 and CX3CR1 chemokine receptor present on these cells is an untouched area. Methods Lupeol, lupeol acetate, its synthetic derivatives 2–8 were screened for inhibition of E. carinatus venom induced-hemorrhage in mouse model where compound 8 was found to be the most potent. Further, compound 8 efficiently neutralized venom induced hemorrhage, edema, dermonecrosis, myonecrosis, myotoxicity, pro-coagulant, oxidative stress, inflammatory cytokines and cleavage of collagen and CX3CR1 receptors on inflammatory cells in in vivo, in silico, ex vivo and in vitro studies. Conclusions This study for the first time demonstrated the cleavage of collagen receptors and the receptor for angiogenesis and wound healing by the venom and its inhibition by compound 8, as these are important for firm adhesion of inflammatory cells at the damaged site to resolve inflammation and promote tissue repair. General significance This study provides a lead in venom pharmacology, wherein, compound 8 could be a therapeutic agent for the better management of viper venom-induced long-term tissue destruction.





C3-OH of Amphotericin B Plays an Important Role in Ion Conductance

Journal of American Chemical Society - Mon, 11/30/2015 - 00:14

Journal of the American Chemical SocietyDOI: 10.1021/jacs.5b05766
Categories: Journal Articles

Effects of a discoloration-resistant calcium aluminosilicate cement on the viability and proliferation of undifferentiated human dental pulp stem cells

Nature Scientific Reports - Mon, 11/30/2015 - 00:00

Effects of a discoloration-resistant calcium aluminosilicate cement on the viability and proliferation of undifferentiated human dental pulp stem cells

Scientific Reports, Published online: 30 November 2015; doi:10.1038/srep17177

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