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Hyaluronidases are enzymes that degrade hyaluronan an important constituent of the extracellular matrix. They have been used as a spreading agent, improving the absorption of drugs and facilitating the subcutaneous infusion of fluids. Here, we investigated the influence of bovine testes hyaluronidase (HYAL) during cutaneous wound healing in in vitro and in vivo assays. We demonstrated in the wound scratch assay that HYAL increased the migration and proliferation of fibroblasts in vitro at low concentration, e.g. 0.1 U HYAL enhanced the cell number by 20%. HYAL presented faster and higher reepithelialization in in vivo full-thickness excisional wounds generated on adult Wistar rats back skin already in the early phase at 2nd day post operatory compared to vehicle-control group. Wound closured area observed in the 16 U and 32 U HYAL treated rats reached 38% and 46% compared to 19% in the controls, respectively. Histological and biochemical analyses supported the clinical observations and showed that HYAL treated wounds exhibited increased granulation tissue, diminished edema formation and regulated the inflammatory response by modulating the release of pro and anti-inflammatory cytokines, growth factor and eicosanoids mediators. Moreover, HYAL increased gene expression of peroxisome proliferator-activated receptors (PPAR) γ and PPAR β/δ, the collagen content in the early stages of healing processes as well as angiogenesis. Altogether these data revealed that HYAL accelerates wound healing processes and might be beneficial for treating wound disorders.

Insufficient oxygen delivery to organs leads to tissue dysfunction and cell death. Reperfusion, although vital to organ survival, initiates an inflammatory response that may both aggravate local tissue injury and elicit remote organ damage. Polymorphonuclear neutrophil (PMN) trafficking to remote organs following ischaemia/reperfusion (I/R) is associated with the release of lipid mediators, including leucotriene (LT) B4, cysteinyl‐LTs (CysLTs) and platelet‐activating factor (PAF). Yet, their potentially cooperative role in regulating I/R‐mediated inflammation has not been thoroughly assessed. The present study aimed to determine the cooperative role of lipid mediators in regulating PMN migration, tissue oedema and injury using selective receptor antagonists in selected models of I/R and dermal inflammation. Our results show that rabbits, pre‐treated orally with BIIL 284 and/or WEB 2086 and MK‐0571, were protected from remote tissue injury following I/R or dermal inflammation in an additive or synergistic manner when the animals were pre‐treated with two drugs concomitantly. The functional selectivity of the antagonists towards their respective agonists was assessed in vitro, showing that neither BIIL 284 nor WEB 2086 prevented the inflammatory response to IL‐8, C5a and zymosan‐activated plasma stimulation. However, these agonists elicited LTB4 biosynthesis in isolated rabbit PMNs. Similarly, a cardioprotective effect of PAF and LTB4 receptor antagonists was shown following myocardial I/R in mice. Taken together, these results underscore the intricate involvement of LTB4 and PAF in each other's responses and provide further evidence that targeting both LTs and PAF receptors provides a much stronger anti‐inflammatory effect, regulating PMN migration and oedema formation.

Objective and designInvestigate survival outcomes, and immunological and metabolomic effects of hyaluronidase (Hz) treatment during mouse models of acute inflammation and sepsis.MethodsSurvival of C57Bl/6 mice was monitored after lethal challenge with lipopolysaccharide (LPS) or cecal and ligation puncture (CLP)-induced sepsis and treated with Hz or saline. Mice were also challenged with LPS and treated with Hz for leukocyte counting, cytokine quantification and determination of metabolomic profiles in the peritoneal fluid.ResultsHz treatment improved survival outcomes after lethal challenge with LPS or CLP-induced sepsis. LPS challenge promoted acute neutrophil accumulation and production of interleukin-1β (IL-1β) and IL-6 in the peritoneum, whereas Hz treatment suppressed neutrophil infiltration and cytokine production. We further characterized the metabolomic alterations caused by LPS challenge, which predicted activity of metabolic pathways related to fatty acids and eicosanoids. Hz treatment had a profound effect over the metabolic response, reflected by reductions of the relative levels of fatty acids.ConclusionCollectively, these data demonstrate that Hz treatment is associated with metabolic reprogramming of pathways that sustain the inflammatory response.

Hyaluronidases (HYALs) comprise a group of enzymes that degrade hyaluronic acid (HA). In this report, we reveal that a single intranasal inoculation of HYAL induces an increase in mononuclear cells within the bronchoalveolar space demonstrating a mesenchymal-like phenotype, expressing stem cell antigen-1 (SCA-1), CD44 and CD73 but not CD34, CD45, CD3, CD4, CD8 or CD19. This influx of mesenchymal stem cell (MSC)-like cells was dependent on leukotriene production within the lung parenchyma. These findings prompted experiments demonstrating that HYAL treatment potently blocked bleomycin-induced lung injury and fibrosis while decreasing transforming growth factor (TGF)-β production and collagen deposition. These data suggest that HYAL is a novel and promising tool to use autologous MSC-like cells in the treatment of pulmonary fibrosis.

Schistosomiasis is one of the most important neglected diseases found in developing countries and affects 249 million people worldwide. The development of an efficient vaccination strategy is essential for the control of this disease. Previous work showed partial protection induced by DNA-Sm14 against Schistosoma mansoni infection, whereas DNA-Hsp65 showed immunostimulatory properties against infectious diseases, autoimmune diseases, cancer and antifibrotic properties in an egg-induced granuloma model. C57BL/6 mice received 4 doses of DNA-Sm14 (100 μg/dose) and DNA-Hsp65 (100 μg/dose), simultaneously administrated, or DNA-Sm14 alone, once a week, during four weeks. Three groups were included: 1- Control (no immunization); 2- DNA-Sm14; 3- DNA-Sm14/DNA-Hsp65. Two weeks following last immunization, animals were challenged subcutaneously with 30 cercariae. Fifteen, 48 and 69 days after infection splenocytes were collected to evaluate the number of CD8+ memory T cells (CD44(high)CD62(low)) using flow cytometry. Forty-eight days after challenge adult worms were collected by portal veins perfusion and intestines were collected to analyze the intestinal egg viability. Histological, immunohistochemical and soluble quantification of collagen and α-SMA accumulation were performed on the liver. In the current work, we tested a new vaccination strategy using DNA-Sm14 with DNA-Hsp65 to potentiate the protection against schistosomiasis. Combined vaccination increased the number of CD8+ memory T cells and decreased egg viability on the intestinal wall of infected mice. In addition, simultaneous vaccination with DNA-Sm14/DNA-Hsp65 reduced collagen and α-SMA accumulation during the chronic phase of granuloma formation. Simultaneous vaccination with DNA-Sm14/DNA-Hsp65 showed an immunostimulatory potential and antifibrotic property that is associated with the reduction of tissue damage on Schistosoma mansoni experimental infection.

Insects have established mutualistic symbiotic interactions with microorganisms that are beneficial to both host and symbiont. Many insects have exploited these symbioses to diversify and expand their ecological ranges. In the Hemiptera (i.e., aphids, cicadas, and true bugs), symbioses have established and evolved with obligatory essential microorganisms (primary symbionts) and with facultative beneficial symbionts (secondary symbionts). Primary symbionts are usually intracellular microorganisms found in insects with specialized diets such as obligate hematophagy or phytophagy. Most Heteroptera (true bugs), however, have gastrointestinal (GI) tract extracellular symbionts with functions analogous to primary endosymbionts. The triatomines, are vectors of the human parasite, Trypanosoma cruzi. A description of their small GI tract microbiota richness was based on a few culturable microorganisms first described almost a century ago. A growing literature describes more complex interactions between triatomines and bacteria with properties characteristic of both primary and secondary symbionts. In this review, we provide an evolutionary perspective of beneficial symbioses in the Hemiptera, illustrating the context that may drive the evolution of symbioses in triatomines. We highlight the diversity of the triatomine microbiota, bacterial taxa with potential to be beneficial symbionts, the unique characteristics of triatomine-bacteria symbioses, and the interactions among trypanosomes, microbiota, and triatomines.

Objective: social innovation plays a crucial role in addressing social challenges, but innovation initiatives can be remote and short-term. Scalability is essential for expanding the impact of these solutions, thus making it critical to investigate the factors that may contribute to this process. A promising approach to enhancing the scalability of social innovations lies in the use of digital technology. The objective of this study was to understand how digital technologies contribute to scale social innovations. Methods: we conducted a qualitative multiple case study that analyzed three social innovation initiatives. Results: our key contributions include: (1) identifying different types of digital technology that can be applied in the social context; (2) providing evidence that scaling out, scaling up, and scaling deep can occur simultaneously and reinforce one another; (3) understanding the role of technology in scaling social innovations by facilitating operationalization, strengthening trust, and building relationships and network engagement. Conclusions: it is expected that the results and contributions will foster reffections on the importance of establishing a digital infrastructure that favors initiatives aimed at solving societal challenges. Keywords: social innovation; scalability; digital technologies JEL Code: O35

Purpose The purpose of this study is to identify dynamic capabilities in joint R&D projects, that enable them to successfully achieve knowledge creation and discover how they behave throughout the life cycle of a collaborative project, although this understanding could enhance the interorganizational knowledge creation process. Design/methodology/approach The authors conducted 65 semi-structured interviews and utilized secondary data from a joint R&D project. The authors analyzed all data using the Gioia method. Findings The authors confirm that specific dynamic capabilities are needed to create interorganizational knowledge and discovered 11 knowledge-based dynamic capabilities (KBDCs) for successful innovation results in joint R&D projects. Gioia method allowed to discover that different KBDCs are necessary for the different phases of the project lifecycle. Additionally, the authors identify two microprocesses in which KBDCs are engaged in joint R&D projects, knowing that is a part of the sensing and seizing processes and synthetizing that is a part of the seizing process, and establish several KBDC microfoundations. Research limitations/implications We used retrospective interviews. This kind of interviews are impacted by the experiences of the respondents lived after they have participated in the joint R&D project. Practical implications Dynamic capabilities for collaborative knowledge creation and their specific microfoundations can help managers delineate their strategic practices and actions to achieve more sustainable, long-lasting results from joint R&D projects. Originality/value The authors improve Teece’s model and propose two microprocesses in which dynamic capabilities are engaged, that emerged in the context of a joint R&D project, knowing that is a part of the sensing and seizing processes and synthetizing that is a part of the seizing process, which supplement those already known: sensing, seizing and transforming. The authors tested the Gioia method, which is important for detecting dynamic capabilities; therefore, the authors propose a methodological advance that can contribute to future studies. The authors provide an interorganizational perspective on KBDC and a methodological view of the changes in KBDCs required for joint R&D projects.

This paper aims to map out how the field of dynamic capabilities has developed since the seminal studies by Teece et al. (1997) and Eisenhardt and Martin (2000). We identified 10,838 papers and used the Latent Dirichlet Allocation algorithm for topic modeling. We conducted two analyses: the first was based on the temporality and characteristics of the studies; the second was interpretative and based on the network of theoretical concepts. Results indicate an approximation between the ideas of the two seminal studies, which were initially viewed as opposite. We observe a movement to value relational issues, following a collective construction path, and paying less attention to the firm itself. Overall, we were able to understand the consolidation of the dynamic capabilities field; understand the core elements involved in the development of dynamic capabilities; set out the original and current concepts of dynamic capabilities; and indicate tendencies and a possible future research agenda. Keywords: dynamic capabilities, topic modeling, innovation, uncertainty, performance. Este artigo visa mapear como o campo das capacidades dinamicas se desenvolveu desde os artigos seminais de Teece et al. (1997) e Eisenhardt e Martin (2000). Identificamos 10.838 artigos e usamos o algoritmo de alocagao latente de Dirichlet para modelagem de topicos. Realizamos dois tipos distintos de analise: a primeira foi haseada na temporalidade e caracteristicas dos estados, enquanto a segunda foi interpretativa e baseada na rede de conceitos teoricos estabelecidos. Os resultados indicam que ha urna aproximagao entre as ideias dos dois artigos seminais, que inicialmente eram vistas como opostas. Observamos um movimento de valorizagao das questoes relacionais, seguindo um caminho de construgao coletiva e de menor atengno a empresa isoladamente. A contribuigao do artigo esta em afrontar a consolidagao do campo das capacidades dinamicas e saos tendencias, ampliar a compreensao dos principais elementos envolvidos no desenvolvimento dessas capacidades e definir seus conceitos originais e atuais, bem como oferecer urna possivel agenda para futuras pesquisas. Palavras-chave: capacidades dinamicas, modelagem de topicos, inovagao, incerteza, desempenho. Este articulo pretende mapear como se ha desarrollado el campo de las capacidades dinamicas desde los articulos de Teece et al. (1997) y Eisenhardt y Martin (2000). Identificamos 10.838 articulos y utilizamos el algoritmo de asignacion latente de Dirichlet para el modelado de temas. Realizamos dos tipos de analisis: el primero, basado en la temporalidad y caracteristicas de los estudios; y el segundo, en la red de conceptos teoricos establecidos. Los resultados indican que existe aproximacion entre las ideas de dos articulos seminales que inicialmente se veian como opuestas. Observamos un movimiento hacia la valoracion de las cuestiones relacionales, siguiendo un camino de construccion colectiva y prestando menos atencion a la empresa de forma aislada. El articulo contribuye a: senalar la consolidacion del campo de las capacidades dinamicas; comprender los principales elementos involucrados en el desarrollo de las capacidades dinamicas; definir sus conceptos originales y actuales; e indicar las tendencias en el campo y una posible agenda para futuras investigaciones. Palabras clave: capacidades dinamicas, modelado de temas, innovacion, incertidumbre, desempeno.

Scorpion sting-induced human envenomation provokes an intense inflammatory reaction. However, the mechanisms behind the recognition of scorpion venom and the induction of mediator release in mammalian cells are unknown. We demonstrated that TLR2, TLR4 and CD14 receptors sense Tityus serrulatus venom (TsV) and its major component, toxin 1 (Ts1), to mediate cytokine and lipid mediator production. Additionally, we demonstrated that TsV induces TLR2- and TLR4/MyD88-dependent NF-κB activation and TLR4-dependent and TLR2/MyD88-independent c-Jun activation. Similar to TsV, Ts1 induces MyD88-dependent NF-κB phosphorylation via TLR2 and TLR4 receptors, while c-Jun activation is dependent on neither TLR2 nor TLR4/MyD88. Therefore, we propose the term venom-associated molecular pattern (VAMP) to refer to molecules that are introduced into the host by stings and are recognized by PRRs, resulting in inflammation.