UVA-degradable Collagenase Nanocapsules as a potential treatment for fibrotic disease.

Peyronie and Dupuytren are pathologies characterized by the appearance of localized fibrotic lesions in an organ. These disorders originate from an excessive production of collagen in the tissue provoking dysfunction and functional limitations to the patients. Local administration of collagenase is the most used treatment for these fibrotic-type diseases, but a high lability of the enzyme limits its therapeutic efficacy. Herein, we present a novel methodology for the preparation of collagenase nanocapsules without affecting its enzymatic activity and capable of releasing the enzyme in response to an ultraviolet A (UVA) light stimulus. Polymeric coating around collagenase was formed by free-radical polymerization of acrylamide-type monomers. Their degradation capacity under UVA irradiation was provided by incorporating a novel photocleavable acrylamide-type crosslinker within the polymeric framework. This property allowed collagenase release to be triggered in a controlled manner by employing an easily focused stimulus. Additionally, UVA irradiation presents considerable benefits by itself due to its capacity to induce collagenase production in situ. An expected synergistic effect of collagenase nanocapsules in conjunction with UVA effect may present a promising treatment for these fibrotic diseases

Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest

In pancreatic ductal adenocarcinoma (PDAC), metabolic rewiring and resistance to standard therapy are closely associated. PDAC cells show enormous requirements for glucose-derived citrate, the first rate-limiting metabolite in the synthesis of new lipids. Both the expression and activity of citrate synthase (CS) are extraordinarily upregulated in PDAC. However, no previous relationship between gemcitabine response and citrate metabolism has been documented in pancreatic cancer. Here, we report for the first time that pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose-derived citrate levels. Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression. Lowered citrate availability was found to be directly associated with diminished proliferation and, remarkably, enhanced gemcitabine response. Moreover, the deregulated citrate-derived lipogenic pathway correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism. Modulation of citric acid metabolism in highly chemoresistant pancreatic adenocarcinoma, through molecules such as vitamin C, could be considered as a future clinical option to improve patient response to standard chemotherapy regimens.Medicin

Mitochondrial function and dysfunction in innate immunity

The mitochondria play an important role in the activation of the innate immune system. This organelle modulates the metabolic reprogramming of the immune cell into proinflammatory or anti-inflammatory subtypes, which typically utilize very different metabolic pathways to fulfill their functions. It also acts as a signaling platform to activate immune routes in both immune and nonimmune cells, as it can generate agonists for inflammatory pathways, including toll-like receptors, inflammasomes, or the cyclic GMP–AMP synthase–stimulator of interferon genes pathway, which lead to the generation of proinflammatory cytokines and antiviral molecules such as type-I interferons. These novel functions of the mitochondria are important in the fight against pathogens, but also contribute to human disease when dysregulated. This review describes recent findings in this field and highlights the role of mitochondrial nucleic acids in the regulation of innate immune signaling pathwaysThis work was supported by the Ministry of Science and Innovation (MICINN) of Spain (grants RYC2018-026050-I and PID2019-105665RAI00 to JT) and by an institutional grant from the Fundación Ramon Areces to the Centro de Biología Molecular Severo Ochoa. CM is the recipient of a Contrato Predoctoral para la Formación de Doctores from MICINN (PRE2020-094403, associated with grant PID2019-105665RA-I00 to JT), and AO is supported by a researcher contract from Comunidad de Madrid (grant PEJ-2020-AI/BMD-17941 to JT

¿Condicionan las características estructurales de la empresa su estrategia de gestión del conocimiento?

Las empresas empiezan a comprender las ventajas de una adecuada gestión del conocimiento (GC); sin embargo, todavía existe cierta confusión en su implantación. A partir de la revisión de la literatura y de un estudio previo de casos, se formula un modelo teórico que plantea la correspondencia entre la estrategia de GC y determinadas características estructurales de la empresa (tamaño, antigüedad, sector y dispersión geográfica). Para la contrastación del modelo teórico se usó una muestra de 310 empresas. Estas compañías presentan diferencias en sus estrategias de GC según el sector al que pertenecen, su tamaño y su dispersión geográfica. También se demuestra que las empresas emplean simultáneamente más de una estrategia para gestionar el conocimiento y el protagonismo de la estrategia de personalización

Growth and Performance: Business Model Innovation in Family Firms

A business model, defined as the underlying logic of a company, is not permanent over time. Instead, companies need to introduce innovations in the business model to be competitive in the market. This is even more critical for family firms which are continuously looking for a way to obtain sustainable growth, together with satisfactory performance. The objective of this research is to analyze the impact that business model innovation activities have in the short/long-term growth and performance of family firms. This study was obtained from panel data made up of 112 valid responses from family firms involved in business model innovation. A composite model approach has been used for data analysis. The significant components of BMI that lead to greater growth and performance are identified, the distinction between long-term and short-term effects of BMI on those outcomes is made, and BMI is proven as an authoritative source of competitive advantage and growth in family firms. Those aspects are valuable insights for researchers and managers with regards to which innovation propositions help sustain growth and performance over time

Intention to use mobile payment by early adopters from mobile phone user data

The data comes from an empirical study conducted to determine the intention to use mobile devices as a means of payment. The data collection was conducted on a total of 463 students at a university, with 425 valid cases. These students were chosen because of their greater affinity with mobile devices, making them digital natives. The questionnaire was developed using scales recognized in the literature on aspects such as intention to use, learning costs or perceived functional value. The reliability and validity of all constructs showed that the questionnaire was proper for measurement. Data analysis was applied l to examine the validity of scales. But, what makes this data really interesting and singular is the collection of data in 2013 (265 respondents) and 2016 (160 respondents). This allows cross-sectional and longitudinal analyses to check the evolution of respondents' perceptions of mobile payments. Results imply that the data is suitable for conducting replication studies

TFAM-deficient mouse skin fibroblasts – an ex vivo model of mitochondrial dysfunction

Mitochondrial dysfunction associates with several pathological processes and contributes to chronic inflammatory and ageing-related diseases. Mitochondrial transcription factor A (TFAM) plays a critical role in maintaining mtDNA integrity and function. Taking advantage of Tfam UBC-Cre/ER mice to investigate mitochondrial dysfunction in the stromal cell component, we describe an inducible in vitro model of mitochondrial dysfunction by stable depletion of TFAM in primary mouse skin fibroblasts (SK-FBs) after 4-hydroxytamoxifen (4-OHT) administration. Tfam gene deletion caused a sustained reduction in Tfam and mtDNA-encoded mRNA in Cre(+) SK-FBs cultured for low (LP) and high (HP) passages that translated into a loss of TFAM protein. TFAM depletion led to a substantial reduction in mitochondrial respiratory chain complexes that was exacerbated in HP SK-FB cultures. The assembly pattern showed that the respiratory complexes fail to reach the respirasome in 4-OHT-treated Cre(+) SK-FBs. Functionally, mito-stress and glycolysis-stress tests showed that mitochondrial dysfunction developed after long-term 4-OHT treatment in HP Cre(+) SK-FBs and was compensated by an increase in the glycolytic capacity. Finally, expression analysis revealed that 4-OHT-treated HP Cre(+) SK-FBs showed a senescent and pro-inflammatory phenotype.Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (FIS16/00032, FIS19/01129 and RETICS RD16/0012), co-financed by the European Regional Development Fund, and the Ministerio de Economı́a y Competitividad Juan de la Cierva Program (IJCI-2016-27666