Borax induces osteogenesis by stimulating NaBC1 transporter via activation of BMP pathway

[EN] The intrinsic properties of mesenchymal stem cells (MSCs) make them ideal candidates for tissue engineering applications. Efforts have been made to control MSC behavior by using material systems to engineer synthetic extracellular matrices and/or include soluble factors in the media. This work proposes a simple approach based on ion transporter stimulation to determine stem cell fate that avoids the use of growth factors. Addition of borax alone, transported by the NaBC1-transporter, enhanced MSC adhesion and contractility, promoted osteogenesis and inhibited adipogenesis. Stimulated-NaBC1 promoted osteogenesis via the BMP canonical pathway (comprising Smad1/YAP nucleus translocation and osteopontin expression) through a mechanism that involves simultaneous NaBC1/BMPR1A and NaBC1/alpha (5)beta (1)/alpha (v)beta (3) co-localization. We describe an original function for NaBC1 transporter, besides controlling borate homeostasis, capable of stimulating growth factor receptors and fibronectin-binding integrins. Our results open up new biomaterial engineering approaches for biomedical applications by a cost-effective strategy that avoids the use of soluble growth factors. Rico et al. propose a simple approach based on borax stimulation of NaBC1 transporter, which enhances FN-binding integrin-dependent mesenchymal stem cell adhesion and contractility, promotes osteogenesis and inhibits adipogenesis. Osteogenic differentiation depends on activation of the BMP pathway through a mechanism that involves simultaneous co-localization of NaBC1 with FN-binding integrins and BMPR1A.P.R. acknowledges support from the Spanish Ministry of Science, Innovation and Universities (RTI2018-096794), and Fondo Europeo de Desarrollo Regional (FEDER). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. M.S.S. acknowledges support from the UK Engineering and Physical Sciences Research Council (EPSRC-EP/P001114/1).Rico Tortosa, PM.; Rodrigo Navarro, A.; Sánchez-Pérez, L.; Salmerón Sánchez, M. (2020). Borax induces osteogenesis by stimulating NaBC1 transporter via activation of BMP pathway. Communications Biology. 3(1):1-15. https://doi.org/10.1038/s42003-020-01449-4S11531Akhurst, R. J. & Hata, A. Targeting the TGFbeta signalling pathway in disease. Nat. Rev. Drug Discov. 11, 790–811 (2012).Brizzi, M. F., Tarone, G. & Defilippi, P. Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. Curr. Opin. Cell Biol. 24, 645–651 (2012).Watt, F. M. & Huck, W. T. S. Role of extracellular matrix regulating stem cell fate. 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Programa de mentoría en la Facultad de Ciencias de la Universidad de Alicante

Un programa de mentoría es un proceso a través del cual, una persona con mayores conocimientos y experiencia en un determinado campo (el mentor) enseña, aconseja, guía y ayuda a otra (el mentorizado) en el aprendizaje, desarrollo de habilidades y mejora de actitudes relacionadas con dicho campo. El programa de mentoría que desarrollan la mayoría de universidades españolas es un programa educativo que trata de favorecer a los estudiantes de nuevo ingreso (mentorizados) su adaptación al entorno universitario, facilitando su integración social, académica y administrativa. Dicha labor es realizada por estudiantes de últimos cursos (mentores). Dado que la Universidad de Alicante ofrece el Programa de Acción Tutorial que cubre el aspecto de integración de los alumnos en la vida universitaria así como en el contexto curricular de los estudios que comienzan, el programa de mentoría que por segundo año ha llevado a cabo la Facultad de Ciencias de la Universidad de Alicante de manera global se ha dirigido exclusivamente a mejorar el rendimiento en las asignaturas de Matemáticas en las titulaciones de Biología, Ciencias del Mar, Geología, Química y Óptica y Optometría, donde los mentores han sido alumnos del último curso de la Licenciatura en Matemáticas. Con él se pretendía proporcionar una ayuda a los estudiantes de nuevo ingreso de las titulaciones mencionadas para que alcanzaran conceptos y niveles básicos necesarios para afrontar con éxito dichas asignaturas y disminuir los niveles de abandono actuales. En el presente trabajo se relata esta experiencia

Effects of rapid gravity load changes on immunophenotyping and leukocyte function of human peripheral blood after parabolic flight

One of the biological systems that suffers a physiological de-conditioning in space is the immune system. It is in charge of defending the body against pathogens and other aggressions. The aim of this work is to assess if there are any relevant changes in the aggregation of erythrocytes, cell count, immunophenotyping and functionality after parabolic flight. This effect has been assessed ex vivo using human peripheral blood, which was drawn from the radial vein (n=6 healthy volunteers) and anticoagulated with heparin and EDTA. Blood samples were split into two aliquots and maintained in two identical thermally isolated boxes; one stayed on the ground whereas the other one was subjected to parabolic flight. The parabolic flight consisted of 15 parabolas performed with a Mudry CAP-10B acrobatic aircraft. Each parabola consists of 8 seconds of hypogravity preceded and followed by 2 seconds of hypergravity. Any of the biological parameters measured showed no statistically significant differences. Altered gravity could increase aggregation of red blood cells, as demonstrated by a decrease in the number of single cells after parabolic flight exposure. No counting changes in haemoglobin concentration were observed when comparing the two different groups. Furthermore, potential functional alterations of monocytes and neutrophils cannot be rejected. Although these possible changes could be associated with hypogravity, other factors such as hypergravity and acceleration or deceleration cannot be ruled out. Our findings indicate that, under this specific experimental setup, there was no significant alteration in leukocyte immunophenotyping and functional capacity when using ex vivo blood samples and short exposure to altered gravity.Peer ReviewedObjectius de Desenvolupament Sostenible::3 - Salut i BenestarPostprint (published version

Comparison of Visual Performance and Patient Satisfaction Outcomes with Two Trifocal IOLs with Similar Optical Design but Different Materials

Purpose: To compare clinical outcomes in a prospective trial of cataract surgery patients bilaterally implanted with two different trifocal intraocular lenses (IOLs) with very similar optical designs but consisting of different IOL materials (hydrophobic and hydrophilic). Patients and Methods: Fifty-one patients (102 eyes) were randomized to receive trifocal IOLs bilaterally – FineVision POD F (hydrophilic) or FineVision POD F GF (hydrophobic) (both PhysIOL, Liége, Belgium). The follow-up period was 3 months. Outcome measurements included uncorrected distance (UDVA), corrected distance (CDVA), distance-corrected intermediate (DCIVA), and distance-corrected near visual acuity (DCNVA), refraction, negative dysphotopsia, optical quality of vision, contrast sensitivity under photopic and mesopic conditions, halometry (discrimination index), and patient-reported outcomes. Results: At the final study visit, mean (SD) values for binocular UDVA, CDVA, DCIVA (80 cm), and DCNVA (40 cm) were − 0.01 (0.06), − 0.04 (0.04), 0.09 (0.10), and 0.10 (0.09) logMAR, respectively, for POD F, and 0.01 (0.08), − 0.03 (0.03), 0.08 (0.1), and 0.13 (0.11) respectively, for POD F GF. Defocus assessments showed a continuous curve with a functional range of visual acuity (≤ 0.15 logMAR) from ∼ 30 cm to infinity in both groups. The discrimination index was > 0.85 for all patients, and both groups showed similar contrast sensitivity under photopic and mesopic conditions. At 3 months, no patient reported negative dysphotopsia, and high satisfaction rates were observed. Conclusion: Clinical outcomes showed no significant difference between each lens when measured at 1 month and 3 months after implantation. This equally good clinical performance of hydrophilic and hydrophobic trifocal lenses allows the surgeon to choose the IOL material based on personal preferences or patients’ needs

Visual and optical quality of enhanced intermediate monofocal versus standard monofocal intraocular lens

Purpose: Intraocular lens designs are constantly evolving, trying to obtain more spectacle independence after cataract surgery. This advantage can be linked to some disadvantages, such as optical quality decrease. For that reason, it is important to assess, not only the amount of vision provided but also the quality of vision once they are implanted. The purpose of the present work was to compare the visual performance between two monofocal intraocular models: a standard model and a monofocal with enhanced intermediate vision lens. Methods: Prospective, randomized, comparative study. Sixty adult subjects scheduled to undergo bilateral cataract surgery and IOL implantation were randomized to receive one of the two IOLs in both eyes at Miranza IOA, Madrid, Spain (group A: monofocal with enhanced intermediate vision lens and group B: standard monofocal lens). Monocular outcomes (right eyes) determined 1 and 3 months postoperatively were photopic corrected distance visual acuity (CDVA), uncorrected distance visual acuity (UDVA), perceived halo, corrected intermediate-distance contrast sensitivity, and higher-order aberrations. The impact of the new IOL in the postoperative management with autorefraction devices was also evaluated. Results: No differences were found in CDVA between the two groups. Significant differences were detected between the two lenses evaluated in both total HOA (p = 0.028) and internal HOA (p = 0.037). Contrast sensitivity and halometry results obtained at 1 month were similar across the two IOL groups. Conclusion: In patients undergoing cataract surgery, monofocal with enhanced intermediate vision IOL offered similar distance performance and contrast sensitivity along with perceived HOA and halos compared with the standard monofocal IOLs tested

A novel group of avian astroviruses from Neotropical passerine birds broaden the diversity and host range of Astroviridae

Metagenomics is helping to expand the known diversity of viruses, especially of those with poorly studied hosts in remote areas. The Neotropical region harbors a considerable diversity of avian species that may play a role as both host and short-distance vectors of unknown viruses. Viral metagenomics of cloacal swabs from 50 Neotropical birds collected in French Guiana revealed the presence of four complete astrovirus genomes. They constitute an early diverging novel monophyletic clade within the Avastrovirus phylogeny, representing a putative new astrovirus species (provisionally designated as Avastrovirus 5) according to the International Committee on Taxonomy of Viruses (ICTV) classifcation criteria. Their genomic organization shares some characteristics with Avastrovirus but also with Mamastrovirus. The pan-astrovirus RT-PCR analysis of the cloacal samples of 406 wild Neotropical birds showed a community-level prevalence of 4.9% (5.1% in passerines, the highest described so far in this order of birds). By screening birds of a remote region, we expanded the known host range of astroviruses to the avian families Cardinalidae, Conopophagidae, Furnariidae, Thamnophilidae, Turdidae and Tyrannidae. Our results provide important frst insights into the unexplored viral communities, the ecology, epidemiology and features of host-pathogen interactions that shape the evolution of avastroviruses in a remote Neotropical rainforest

Positive correlation between the nuclear expression of GPER and pGLI3 in prostate cancer tissues from patients with different Gleason scores

Prostate cancer (PCa) is the most prevalent cause of death in the male population worldwide. The G Protein-Coupled Estrogen Receptor (GPER) has been gaining relevance in the development of PCa. Hedgehog (Hh) pathway activation is associated with aggressiveness, metastasis, and relapse in PCa patients. To date, no studies have evaluated the crosstalk between the GPER and the Hh pathway along different group grades in PCa. We conducted an analysis of paraffin-embedded tissues derived from patients with different prognostic grade of PCa using immunohistochemistry. Expression and correlation between GPER and glioma associated oncogene homologue (GLI) transcriptional factors in the parenchyma and stroma of PCa tumors were evaluated. Our results indicate that GPER is highly expressed in the nucleus and increases with higher grade groups. Additionally, GPER’s expression correlates with pGLI3 nuclear expression across different grade groups in PCa tissues; however, whether the receptor induces the activation of GLI transcriptional factors, or the latter modulate the expression of GPER is yet to be discovered, as well as the functional consequence of this correlation

Alu retrotransposons promote differentiation of human carcinoma cells through the aryl hydrocarbon receptor

Cell differentiation is a central process in development and in cancer growth and dissemination. OCT4 (POU5F1) and NANOG are essential for cell stemness and pluripotency; yet, the mechanisms that regulate their expression remain largely unknown. Repetitive elements account for almost half of the Human Genome; still, their role in gene regulation is poorly understood. Here, we show that the dioxin receptor (AHR) leads to differentiation of human carcinoma cells through the transcriptional upregulation of Alu retrotransposons, whose RNA transcripts can repress pluripotency genes. Despite the genome-wide presence of Alu elements, we provide evidences that those located at the NANOG and OCT4 promoters bind AHR, are transcribed by RNA polymerase-III and repress NANOG and OCT4 in differentiated cells. OCT4 and NANOG repression likely involves processing of Alu-derived transcripts through the miRNA machinery involving the Microprocessor and RISC. Consistently, stable AHR knockdown led to basal undifferentiation, impaired Alus transcription and blockade of OCT4 and NANOG repression. We suggest that transcripts produced from AHR-regulated Alu retrotransposons may control the expression of stemness genes OCT4 and NANOG during differentiation of carcinoma cells. The control of discrete Alu elements by specific transcription factors may have a dynamic role in genome regulation under physiological and diseased conditions.Trabajo financiado por: Ministerio de Economía y Competitividad. Proyectos BFU2011-22678, SAF2014-51813-R (I+D+i) para Pedro María Fernández Salguero Ministerio de Economía y Competitividad, Instituto Carlos III, Red Temática de Investigación Cooperativa en Cáncer Junta de Extremadura. Ayudas GR10008, GR15008 CICE-FEDER-P09-CTS-4980, CICE-FEDERP12-CTS-2256, Plan Nacional de I+D+I 2008–2011 y 2013–2016 (FIS-FEDER-PI11/01489, FIS-FEDERPI14/02152), PCIN-2014-115-ERA-NET NEURON II, para José Luis García Pérez European Research Council ERC-Consolidator ERC-STG-2012-233764 International Early Career Scientist Beca de la Howard Hughes Medical Institute IECS-55007420 Programa Unión Europea de Fondos FEDERpeerReviewe

Shifts in plant foliar and floral metabolomes in response to the suppression of the associated microbiota

The phyllospheric microbiota is assumed to play a key role in the metabolism of host plants. Its role in determining the epiphytic and internal plant metabolome, however, remains to be investigated. We analyzed the Liquid Chromatography-Mass Spectrometry (LC-MS) profiles of the epiphytic and internal metabolomes of the leaves and flowers of Sambucus nigra with and without external antibiotic treatment application. The epiphytic metabolism showed a degree of complexity similar to that of the plant organs. The suppression of microbial communities by topical applications of antibiotics had a greater impact on the epiphytic metabolome than on the internal metabolomes of the plant organs, although even the latter changed significantly both in leaves and flowers. The application of antibiotics decreased the concentration of lactate in both epiphytic and organ metabolomes, and the concentrations of citraconic acid, acetyl-CoA, isoleucine, and several secondary compounds such as terpenes and phenols in the epiphytic extracts. The metabolite pyrogallol appeared in the floral epiphytic community only after the treatment. The concentrations of the amino acid precursors of the ketoglutarate-synthesis pathway tended to decrease in the leaves and to increase in the foliar epiphytic extracts. These results suggest that anaerobic and/or facultative anaerobic bacteria were present in high numbers in the phyllosphere and in the apoplasts of S. nigra. The results also show that microbial communities play a significant role in the metabolomes of plant organs and could have more complex and frequent mutualistic, saprophytic, and/or parasitic relationships with internal plant metabolism than currently assumed. The online version of this article (doi:10.1186/s12870-016-0767-7) contains supplementary material, which is available to authorized users

Efficacy and safety clinical trial with efavirenz in patients diagnosed with adult Niemann-pick type C with cognitive impairment

Background:Niemann-Pick disease Type C (NPC) is a genetic, incurable, neurodegenerative disorder. This orphan disease is most frequently caused by mutations in the NPC1 protein, resulting in intralysossomal cholesterol accumulation. NPC1 is found in neuronal cell bodies, axon terminals and synaptosomes, suggesting it plays a role in lysosomal degradation pathway and in synaptic transmission. Neuronal function is especially vulnerable to NPC1 deficiency and synaptic changes seem a key element in disease development. Currently, Miglustat (Zavesca (R)) is the only approved treatment for NPC. However, preclinical evidence showed that low-dose Efavirenz reverted synaptic defects through pharmacological activation of the enzyme CYP46. Methods:This is a single-center, phase II clinical trial to evaluate the efficacy and safety of Efavirenz in addition to standard of care in patients diagnosed with adult or late juvenile-onset NPC with cognitive impairment. All enrolled patients will be treated orally with 25 mg/d of Efavirenz for 52 weeks (1 year). Secondary objectives include evaluating clinical (neurological and neuropsychological questionnaires) and biological (imaging and biochemical biomarkers) parameters. Discussion:NPC is still an unmet medical need. Although different therapeutic approaches are under study, this is the first clinical trial (to the best of our knowledge) studying the effects of Efavirenz in adult- and late-juvenile-onset NPC. Despite the small sample size and the single-arm design, we expect the results to show Efavirenz's capacity of activating the CYP46 enzyme to compensate for NPC1 deficiency and correct synaptic changes, therefore compensating cognitive and psychiatric changes in these patients. This study may provide direct benefit to enrolled patients in terms of slowing down the disease progression