Effects Of Destabilization Research Articles

Kierkegaard, Social Media, and Despair

ABSTRACTThis essay offers a Kierkegaardian analysis of and response to the harmful effects of destabilization that can be caused by engaging with certain technological media. It argues that the intellectual technological ethic that is at work in social media platforms reflects two types of despair discussed in Søren Kierkegaard's Sickness Unto Death. It advises using a Kierkegaard‐inspired Socratic rhetorical strategy of communication that ironically employs technology for depicting this despair and awakening individuals to its presence in their lives. Moreover, this essay suggests that the edifying themes of “misery” and “guilt” can be communicated indirectly and thereby offer one intervention that could possibly help the current technological age move from the immediate aesthetic sphere of existence to the religious sphere. Considering the important role of upbuilding in Kierkegaard's oeuvre, the final portion explores how even someone who does not identify with a religious tradition or community may encounter what Kierkegaard terms the paradox of the eternal in time in ways that foster the development of authentic selfhood.

Dual Regulation of Nicotine on NLRP3 Inflammasome in Macrophages with the Involvement of Lysosomal Destabilization, ROS and α7nAChR.

Nicotine, the primary alkaloid in tobacco products, has been shown to have immunoregulatory function in at least 20 diseases. The biological mechanism of action of nicotine immunoregulation is complex, resulting in an improvement of some disease states and exacerbation of others. Given the central role of the NLRP3 inflammasome in macrophages among multiple inflammatory diseases, this study examined how nicotine alters NLRP3 inflammasome activation in macrophages. NLRP3 inflammasome activation was examined mechanistically in the context of different nicotine dosages. We show NLRP3 inflammasome activation, apoptosis-associated speck-like protein (ASC) expression, caspase-1 activity and subsequent IL-1β secretion were positively correlated with nicotine in a dose-dependent relationship, and destabilization of lysosomes and ROS production were also involved. At high concentrations of nicotine surpassing 0.25mM, NLRP3 inflammasome activity declined, along with increased expression of the anti-inflammatory Alpha7 nicotinic acetylcholine receptor (α7nAChR) and the inhibition of TLR4/NF-κB signaling. Consequently, high doses of nicotine also reduced ASC expression, caspase-1 activity and IL-1β secretion in macrophages. Collectively, these results suggest a dual regulatory function of nicotine on NLRP3 inflammasome activation in macrophages, that is involved with the pro-inflammatory effects of lysosomal destabilization and ROS production. We also show nicotine mediates anti-inflammatory effects by activating α7nAChR at high doses.

Structural effects of charge destabilization and amino acid substitutions in amyloid fragments of CsgA

The most studied functional amyloid is the CsgA, major curli subunit protein, which is produced by numerous strains of Enterobacteriaceae. Although CsgA sequences are highly conserved, they exhibit species diversity, which reflects the specific evolutionary and functional adaptability of the major curli subunit. Herein, we performed bioinformatics analyses to uncover the differences in the amyloidogenic properties of the R4 fragments in Escherichia coli and Salmonella enterica and proposed four mutants for more detailed studies: M1, M2, M3, and M4. The mutated sequences were characterized by various experimental techniques, such as circular dichroism, ATR-FTIR, FT-Raman, thioflavin T, transmission electron microscopy and confocal microscopy. Additionally, molecular dynamics simulations were performed to determine the role of buffer ions in the aggregation process. Our results demonstrated that the aggregation kinetics, fibril morphology, and overall structure of the peptide were significantly affected by the positions of charged amino acids within the repeat sequences of CsgA. Notably, substituting glycine with lysine resulted in the formation of distinctive spherically packed globular aggregates. The differences in morphology observed are attributed to the influence of phosphate ions, which disrupt the local electrostatic interaction network of the polypeptide chains. This study provides knowledge on the preferential formation of amyloid fibrils based on charge states within the polypeptide chain.

Economic crisis and crime: Money under the mattress during financial destabilization

The paper investigates the effect of a (semi-) deposit run during a debt crisis on crime rates. The study focuses on Greece’s protracted debt crisis (2009–2018) and analyzes the response of crime to deposit outflows. It shows that deposit outflows corresponded to a significant increase in property crimes (thefts and burglaries), but not other types of offenses. The study provides useful policy insights for regulatory authorities tasked with monitoring and decreasing the criminogenic effects of financial destabilization

Computational Study of Ground-State Destabilization Effects and Dipole-Dipole Interaction Energies in Amphidynamic Crystals.

Ground-state destabilization is a promising strategy to modulate rotational barriers in amphidynamic crystals. Density functional theory studies of polar phenylenes installed as rotators in pillared paddle-wheel metal organic frameworks were performed to investigate the effects of ground-state destabilization on their rotational dynamics. We found that as the steric size of phenylene substituents increases, the ground-state destabilization effect is also increased. Specifically, a significant destabilization of the ground-state energy occurred as the size of the substituents increased, with values ranging from 2 to 11.7 kcal/mol. An evaluation of the effects of substituents on dipole-dipole interaction energies and rotational barriers suggests that it should be possible to engineer amphidynamic crystals where the dipole-dipole interaction energy becomes comparable to the rotational barriers. Notably, while pure dipole-dipole interaction energies reached values ranging from 0.6 to 2.4 kcal/mol, the inclusion of electronic and steric effects can alter dipolar orientations to significantly greater values. We propose that careful selection of polar substituents with different sizes may help create temperature-responsive materials with switchable collective polarization.

Identification of and Mechanistic Insights into SARS-CoV-2 Main Protease Non-Covalent Inhibitors: An In-Silico Study.

The indispensable role of the SARS-CoV-2 main protease (Mpro) in the viral replication cycle and its dissimilarity to human proteases make Mpro a promising drug target. In order to identify the non-covalent Mpro inhibitors, we performed a comprehensive study using a combined computational strategy. We first screened the ZINC purchasable compound database using the pharmacophore model generated from the reference crystal structure of Mpro complexed with the inhibitor ML188. The hit compounds were then filtered by molecular docking and predicted parameters of drug-likeness and pharmacokinetics. The final molecular dynamics (MD) simulations identified three effective candidate inhibitors (ECIs) capable of maintaining binding within the substrate-binding cavity of Mpro. We further performed comparative analyses of the reference and effective complexes in terms of dynamics, thermodynamics, binding free energy (BFE), and interaction energies and modes. The results reveal that, when compared to the inter-molecular electrostatic forces/interactions, the inter-molecular van der Waals (vdW) forces/interactions are far more important in maintaining the association and determining the high affinity. Given the un-favorable effects of the inter-molecular electrostatic interactions-association destabilization by the competitive hydrogen bond (HB) interactions and the reduced binding affinity arising from the un-compensable increase in the electrostatic desolvation penalty-we suggest that enhancing the inter-molecular vdW interactions while avoiding introducing the deeply buried HBs may be a promising strategy in future inhibitor optimization.

Effects of destabilization and tempering on microstructure and mechanical properties of a hypereutectic high-chromium cast iron

Effects of destabilization and tempering on microstructure and mechanical properties of a hypereutectic high-chromium cast iron

Глобальні рекомендації щодо звітності про стійкість підприємств у транзитивних країнах: умови воєнного стану та відновлення в Україні

Introduction. The most important task of the sovereign state of Ukraine nowadays is the victory in the war with the Russian aggressor, as well as ensuring sustainable innovation development in close cooperation with the international community. Problem Statement. In countries with economies in transition in the preparation of non-financial reporting we can notice the following : lack of institutional levers of impact and motivation for the disclosure of environmental, social and other indicators; lack of standard approaches to the content of non-financial reporting and procedures for its administration, etc Purpose. The aim of the study is: to substantiate the improvement to Ukraine’s public policy in Ukraine on non-financial reporting on sustainable development; to study contradictions of the new reality and directions to overcome them for the countries with transition economies while preparing non-financial reporting and applying indicators of sustainable development; to develop proposals on the content of such reporting in emergency situations, in particular during hostilities, as well as post-war reconstruction. Materials and methods. The following methods: institutional, systemic, empirical, structural and functional and others have been applied while using UNCTAD guidelines and factual data., Results. The authors suggest ways to overcome these obstacles and to supplement the “Guidance on core indicators for entity reporting on contribution to the implementation of SDGs” (GCI) with a block of indicators on crisis management trends in conditions of uncertainty and post-war overcoming of the effects of destabilization. Conclusions. The martial law in the country, the consequences of hostilities have a profound impact on the activities of companies and should be shown in the reports. On the basis of regulatory initiatives of the European Union on non-financial reporting in the electronic format in Ukraine it is necessary: to regulate the Taxonomy of non-financial reporting (EU Regulation 2020/852); to show in the management report the disclosure of basic performance indicators of enterprises in various fields (economic, environmental, social, institutional); to implement the concept of sustainable development in the national non-financial reporting infrastructure.

Euro-emerytura jako koncepcja dodatkowego zabezpieczenia emerytalnego dla obywateli państw członkowskich Unii Europejskiej

Przedmiot badań: Przedmiotem prowadzonych badań jest zainicjowanie dyskusji nad utworze­niem projektu dotyczącego bazowego systemu emerytalnego, obejmującego wszystkie państwa członkowskie Unii Europejskiej.
 Cel badawczy: Celem prowadzonych przez autorów badań, których jednym ze składowych jest przedmiotowy artykuł, jest zainicjowanie dyskusji nad utworzeniem projektu dotyczącego bazo­wego systemu emerytalnego, obejmującego wszystkie państwa członkowskie Unii Europejskiej, a co za tym idzie umożliwieniem otrzymania świadczenia łagodzącego skutki wieku starości przez każdego euro-obywatela. Projekt jest wzorowany na schematach I filaru systemów emerytalnych, które obowiązują w pań­stwach członkowskich Wspólnoty Europejskiej, lecz bez części kapitałowej. Utworzenie ogól­nodostępnego, dobrowolnego programu emerytalnego, niezależnego od poszczególnych państw członkowskich, obejmującego obszar wspólnoty, umiejscowionego w strukturach UE, z gwaran­cjami EBC wypłaty środków i dofinansowaniu ze środków finansowych UE, niezwiązanego z bu­dżetami członkowskimi, prywatnego, uzupełniającego krajowe systemy zabezpieczenia emerytal­nego, zwiększy poczucie powszechnie pożądanej stabilności i pewności życia w okresie starości wszystkim mieszkańcom euro-społeczności. Tak zorganizowana struktura złagodzi problemy demograficzne, z którymi poszczególne państwa UE w sposób autonomiczny nie będą w stanie sobie poradzić. Narastający kryzys demograficzny niweczy, a w niedalekiej przyszłości będzie paraliżował wszelkie poczynania gospodarcze wszystkich członków Unii. Zarówno konflikty we­wnętrzne poszczególnych państw członkowskich, jak i spory zewnętrzne można powstrzymać, organizując wspólne, powszechnie akceptowalne programy społecznie użyteczne. Jednym z nich jest Euro-emerytura, czyli europejski system emerytalny stanowiący uzupełnienie programów zabezpieczenia emerytalnego obowiązujących w poszczególnych państwach członkowskich.
 Metoda badawcza: W opracowaniu zastosowano metodę analizy aktów prawnych, piśmiennic­twa w powiązaniu z metodą dedukcji.
 Wyniki: Odpowiednio zorganizowany, umiejscowiony i zarządzany przez struktury Unii Euro­pejskiej nowy bazowy system emerytalny może zapewnić poczucie stabilizacji. Należy stwo­rzyć i zastosować niekonwencjonalne rozwiązania, dać coś od siebie, wziąć sprawy (emeryturę) w swoje ręce bowiem na cud w czasach kryzysu demograficznego i ekonomicznego liczyć nie możemy. Tym mocniej, że skutki destabilizacji w gospodarce światowej wywołanej COVID-19 w chwili obecnej nie są znane.

Dysmetabolic mechanisms of preeclampsia development

Background: An in-depth study of dismetabolic mechanisms in the genesis of pre-eclampsia (PE) has been updated because pregnancy is considered as a natural model of metabolic syndrome (MS), as well as the metabolic disorders are important in development of essential hypertension.Aims: to reveal clinical and laboratory parallels in pregnancy complicated by PE without MS and pregnancy proceeding on the background of MS to assess the role of metabolic disturbances in the development of PE.Materials and methods: 82 women with MS were examined in the dynamics of pregnancy and were divided into 2 groups depending on the implementation of PE: group I consisted of 50 women with PE on the background of MS, group II 32 women with MS without PE. We formed group III consisting of 44 pregnant women with PE without accompanying diseases to assess the pathogenetic value of metabolic disorders in the development of PE. The IV (control) group consisted of 30 healthy women with physiological pregnancy. Metabolic, hematological parameters, hormones, markers of the proinflammatory state, endothelial hemostasiological dysfunction, decidualization and placental angiogenesis, accumulation dynamics and distribution loci of adipose tissue were determined in all pregnant women.Results: In the groups of pregnant women with PE, changes similar to MS were revealed: pronounced diabetic and atherogenic disorders with the development of pathological insulin resistance, hyperinsulinemia and leptinemia, endothelial-platelet link hyperactivation, thrombotic and inflammatory status, visceral type of fat deposition, hyperuricemia, hypersympathicotonia. It is proved that in the hierarchy of mechanisms of PE formation, placental dysfunction is a secondary alteration factor, which additionally potentiates the insulin resistance increase and the effects of structural and functional destabilization of the vascular endothelium.Conclusions: The direction of metabolic changes during pregnancy, the common development of PE and MS indicate the important role of dismetabolic mechanisms in the formation of PE.

Ninety-five years of observed disturbance-based tree mortality modeled with climate-sensitive accelerated failure time models

Modeling disturbance-based tree mortality is becoming increasingly important in the discussion of how to adapt forests to climate change and to preserve their ecosystem services and mitigate the risk of economic losses. In this study, we fitted species-specific interval-censored Accelerated Failure Time models for five major tree species to derive the influence of climate, soil, silvicultural measures, stand and tree characteristics on survival times. We coded all disturbance-based mortality causes as events and analyzed 473,501 individual trees distributed across 2248 long-term (1929–2014) forest growth and yield plots in southwestern Germany. We observed different survival probabilities among tree species with Douglas-fir having the lowest survival probability at age 100 years, followed by Norway spruce and Silver fir. Contrastingly, beech and oak had survival probabilities above 0.98 at age 100 years. Most important factor influencing these survival times was climate. Higher summer temperature shortens the survival time of beech, Silver fir and oak, while Norway spruce suffers more from warmer and wetter winters. Beside climatic factors, base saturation showed a significant positive relationship to survival time for all investigated tree species, except for Norway spruce, which had shorter survival times with increasing cation exchange capacity of the soil. Additionally, short-term effects of destabilization after thinning were found. In conclusion, favoring broadleaved tree species, avoiding heavy thinning in older stands and limiting tree age reduce the probability of disturbance-based tree mortality. However, some of the effects found that cause-unspecific mortality modeling has limited potential to describe the mortality–climate change relation.

Small molecule-induced simultaneous destabilization of \u03b2-catenin and RAS is an effective molecular strategy to suppress stemness of colorectal cancer cells

BackgroundCancer stem cells (CSCs), the major driver of tumorigenesis, is a sub-population of tumor cells responsible for poor clinical outcomes. However, molecular mechanism to identify targets for controlling CSCs is poorly understood.MethodsGene Set Enrichment Analyses (GSEA) of Wnt/β-catenin and RAS signaling pathways in stem-like subtype of colorectal cancer (CRC) patients were performed using two gene expression data set. The therapeutic effects of destabilization of β-catenin and RAS were tested by treatment of small molecule KYA1797K using CRC patient derived cells.ResultsTreatment with KYA1797K, a small molecule that destabilizes both β-catenin and RAS via Axin binding, effectively suppresses the stemness of CSCs as shown in CRC spheroids and small intestinal tumors of ApcMin/+/K-RasG12DLA2 mice. Moreover, KYA1797K also suppresses the stemness of cells in CRC patient avatar model systems, such as patient-derived tumor organoids (PDTOs) and patient-derived tumor xenograft (PDTX).ConclusionOur results suggest that destabilization of both β-catenin and RAS is a potential therapeutic strategy for controlling stemness of CRC cells.EL4qu77E_Vg6o-DHLyPXBuVideo abstract

Representing Ecological Crises in Children’s Media: An Analysis of The Lorax and Wall-E

ABSTRACT This article examines representation of ecological crises in children’s media. Children’s media constitutes an important area of ecocinema critique due to the particular vulnerability of children to persuasive messaging. Using themes from ecocinema studies, we conduct a textual analysis of two animated motion pictures: Universal Pictures’ The Lorax [(2012). The Lorax. Directed by Chris Renaud. Universal City, CA: Author)] and Pixar’s Wall-E [(2008). Wall-E. Directed by Andrew Stanton. 2008. Emeryville, CA: Author]. We analyze these films in terms of: (1) anthropomorphic representations; (2) displacement of collective aspects of ecological crisis to the level of interpersonal conflict; (3) greenwashing; and (4) narratives of pastoralism and replenishment. We consider how these films discursively constitute ecological conditions, processes, and crises. We examine these representations as indicators of an underlying crisis in capitalism, of a struggle to come to terms with ecological destabilization. Ultimately, we conclude that a more speculative reimagining of the relationship between humans and the natural world is required to stave off the worst effects of global ecological destabilization.

Boosting low-temperature de/re-hydrogenation performances of MgH2 with Pd-Ni bimetallic nanoparticles supported by mesoporous carbon

Bimetallic Pd-Ni nano-particles supported by a mesoporous carbon material CMK-3 (denoted as Pd30Ni70/CMK-3) were synthesized through solution impregnation and hydrogen reduction methods. Among those hierarchical Ni-Pd nano-particles, majorly large ones (>10 nm) are dispersed over the surface of CMK-3, while a litter small ones (<10 nm) are embedded into the pores. It significantly improves the de/re-hydrogenation performances of MgH2 at low temperature. The onset desorption temperature of MgH2-Pd30Ni70/CMK-3 is lowered by 150 K from that of pristine MgH2 (above 593 K). About 6 wt% hydrogen could be released during its decomposition below 561 K. Noticeably, MgH2-Pd30Ni70/CMK-3 is capable of releasing 1.3 wt% H2 even at 373 K. 4 wt% hydrogen can be absorbed at 343 K under a hydrogen pressure of 3 MPa within 18000 s. Activation energy values of both hydrogen decomposition (65.9 kJ mol−1) and absorption (78.9 kJ mol−1) for MgH2-Pd30Ni70/CMK-3 are greatly improved from those of as-milled MgH2. Thermal stability of the composite system is remarkably destabilized by 4.3 kJ mol H2−1 from pristine MgH2 according to pressure-composition isotherm curves and van't Hoff plots. The enhanced performances can be ascribed to the synergistic effects of both destabilization and catalysis from nano-dispersed Pd and Ni particles, respectively.

Characteristics of Stress Transfer and Progressive Fracture in Overlying Strata due to Mining-Induced Disturbances

In this study, based on the mining of the 13210 working face in the Yima coal mine of the Gengcun village, China, a simplified mechanical model for the analysis of dynamic destabilization of the overlying strata during underground mining was constructed. The numerical simulation was used to analyze the stress patterns in the advanced abutments of the tunnel face and the characteristics of dynamic failures in the overlying strata. Furthermore, similitude experiments were conducted to study the process of stress release and deformation in the overlying strata, and to analyze the effects of overburden destabilization on the ground surface settlement. The theoretical analysis indicated that if the geometric parameters of a working face are fully determined, a stiffness ratio no greater than 1 is required for dynamic destabilization to occur. The numerical simulation results show that the stress in the overlying strata decreases with a decrease in distance from the tunnel face. The stresses in the advanced abutments initially increase with an increase in distance from the tunnel face, followed by a decrease in stress, and an eventual stabilization of the stress levels; this corresponds to the existence of a “stress build-up zone,” “stress reduction zone,” and “native rock stress zone.” In similitude experiments, it was observed that a “pseudoplastic beam” state arises after the local stresses of the overlying strata have been completely released, and the “trapezoidal” fractures begin to form at stress concentrations. If the excavation of the working face continues to progress, the area of collapse expands upward, thereby increasing the areas of the fracture and densification zones. Owing to the nonuniform settlement of the overlying strata and the continuous development of bed-separating cracks, secondary fractures will be generated on both sides of the working face, which increase the severity of the ground surface settlement.

Enhancing hydrogen storage performances of MgH2 by Ni nano-particles over mesoporous carbon CMK-3

Nano-dispersed Ni particles over mesoporous carbon material CMK-3 (Ni/CMK-3) was fabricated by means of impregnation-reduction strategy using precursor NiCl2 · 6H2O, which is beneficial to improving the de/rehydrogenation performances of MgH2. The dehydrogenation onset temperature of MgH2–Ni/CMK-3 is significantly lowered by 170 K from that of pristine MgH2 (around 603 K). Totally 5.9 wt% of hydrogen absorption capacity is liberated within 1 h at a temperature of 423 K under a pressure of 3 MPa. This composite can absorb 3.9 wt% hydrogen even at a temperature of 328 K under 3 MPa H2. Activation energy values of both dehydrogenation (43.4 kJ mol−1) and rehydrogenation (37.4 kJ mol−1) for MgH2–Ni/CMK-3 are greatly enhanced from those of as-milled MgH2. Ni/CMK-3 also slightly destabilizes the dehydrogenation of MgH2 by 1.5 kJ mol The enhanced performances can be attributed to the synergistic effects of both destabilization and activation from nano-dispersed Ni particles.

Improved exogenous DNA uptake in bovine spermatozoa and gene expression in embryos using membrane destabilizing agents in ICSI-SMGT.

Sperm-mediated gene transfer (SMGT) is a simple, fast, and economical biotechnological tool for producing transgenic animals. However, transgene expression with this technique in bovine embryos is still inefficient due to low uptake and binding of exogenous DNA in spermatozoa. The present study evaluated the effects of sperm membrane destabilization on the binding capacity, location and quantity of bound exogenous DNA in cryopreserved bovine spermatozoa using Triton X-100 (TX-100), lysolecithin (LL) and sodium hydroxide (NaOH). Effects of these treatments were also evaluated by intracytoplasmic sperm injection (ICSI)-SMGT. Results showed that all treatments bound exogenous DNA to spermatozoa including the control. Spermatozoa treated with different membrane destabilizing agents bound the exogenous DNA throughout the head and tail of spermatozoa, compared with the control, in which binding occurred mainly in the post-acrosomal region and tail. The amount of exogenous DNA bound to spermatozoa was much higher for the different sperm treatments than the control (P < 0.05), most likely due to the damage induced by these treatments to the plasma and acrosomal membranes. Exogenous gene expression in embryos was also improved by these treatments. These results demonstrated that sperm membrane destabilization could be a novel strategy in bovine SMGT protocols for the generation of transgenic embryos by ICSI.

TRENDS OF RESEARCH OF STRATEGIC PARTNERSHIP (ASPECT OF MODERN HISTORY)

The article analyzes the multidimensionality of world politics, which requires global actors to search for conceptual forms of interaction to solve complex international processes, which contributes to deeper cooperation and creating special partnerships. The growing political, economic and military instability at the global level has led to the need for theoretical and practical renewal of foreign policy strategies, as well as for the development of effective mechanisms for collective cooperation. A comprehensive study of the conceptual and applied dimensions of strategic partnership, which is a special tool for aligning the foreign policy of global actors and at the same time serves as one of the effective types of international partnership, allows to take into account the growing political risks and identify ways to mitigate the effects of global destabilization on global actors, identify points of coordination for their strategic engagement and to offer programs of cooperation at the international, transregional and global level of forming partnerships. The strategic partnership of global actors at this stage is marked by the impact of global trends in international development, so the topic is examined through the transition from general to specific, taking into account the problems and processes of globalization that affect all participants in international relations, who are forced to seek optimal solutions for foreign policy issues.

The Influence of Oblique Angle Forced Exercise in Surgically Destabilized Stifle Joints Is Synergistic with Bone, but Antagonistic with Cartilage in an Ovine Model of Osteoarthritis.

Large animal models of osteoarthritis are a necessary testing ground for FDA approval of human medicine applications. Sheep models have advantages over other available large animals, but development and progression of osteoarthritis in sheep is exceedingly slow, which handicaps progress in development of potential treatments. We combined oblique angle forced exercise to increase stress on the stifle, with surgical destabilization to hasten the development of osteoarthritis in ewes. Methods for early detection of clinical signs included radiography, urine, and serum biomarker assays and gait analysis and ex vivo we used microcomputed tomography and macroscopic joint analysis. Our model was able to produce clinically detectable signs of osteoarthritis in a relatively short period (14 weeks). Changes in bone were highly correlated between microcomputed tomography and radiographic analysis and changes in cartilage correlated well between urinary glycosaminoglycan levels and serum aggrecanase analyses. Exercise improved the negative effects of destabilization in bone but exacerbated the negative effects of destabilization in cartilage. These observations suggest that we may need to consider treatments for bone and cartilage separately. These results represent an improved large animal model of osteoarthritis with rapid onset of disease and superior detection of bone and soft tissue changes.

Wnt10b and Dkk-1 gene therapy differentially influenced trabecular bone architecture, soft tissue integrity, and osteophytosis in a skeletally mature rat model of osteoarthritis

ABSTRACTAims: Our goals in the current experiments were to determine if (a) upregulation of Wnt signaling would induce osteoarthritis changes in stable stifle joints and (b) if downregulation of Wnt signaling in destabilized joints would influence the progression of OA. Methods: At 37 weeks of age, rats were injected in the stifle joint with a recombinant adeno-associated viral vector containing the Wnt-inhibitor Dkk-1 or a Wnt10b transgene. At 40 weeks of age, rats underwent surgical destabilization of the joint. At 50 weeks of age, stifle joints were submitted for micro-computed tomography and histopathological analysis. Results: Injection of either Wnt10b or Dkk-1 transgenes in stable joints improved bone architectural parameters, but worsened soft tissue integrity. Osteophytosis was decreased by Dkk-1, but unchanged by Wnt10b. Destabilization negatively influenced bone architecture, increased osteophytosis, and decreased soft tissue integrity. Dkk-1 exacerbated the negative effects of destabilization, whereas Wnt10b had little effect on these parameters. Osteophytosis was improved, whereas soft tissue integrity was worsened by both transgenes in destabilized joints. Conclusions: The Wnt-inhibitor Dkk-1 does not appear to completely inhibit the effects of Wnt signaling on bone remodeling. In vivo upregulation of Wnt10b and its inhibitor, Dkk-1, can produce both parallel or contrasting phenotypic responses depending on the specific parameter measured and the fidelity of the examined joint. These observations elucidate different roles for Wnt signaling in stable versus destabilized joints and may help to explain the conflicting results previously reported for the role of Dkk-1 in joint disease.