Ultradian Rhythms Underlying the Dynamics of the Circadian Pacemaker

Non

Synchronization, Oscillator Death, and Frequency Modulation in a Class of Biologically Inspired Coupled Oscillators

The general purpose of this paper is to build up on our understanding of the basic mathematical principles that underlie the emergence of synchronous biological rhythms, in particular, the circadian clock. To do so, we study the role that the coupling strength, coupling type, and noise play in the synchronization of a system of coupled, non-linear oscillators. First, we study a deterministic model based on Van der Pol coupled oscillators, modeling a population of diffusively coupled cells, to find regions in the parameter space for which synchronous oscillations emerge and to provide conditions under which diffusive coupling kills the synchronous oscillation. Second, we study how noise and coupling interact and lead to synchronous oscillations in linearly coupled oscillators, modeling the interaction between various pacemaker populations, each having an endogenous circadian clock. To do so, we use the Fokker-Planck equation associated to the system. We show how coupling can tune the frequency of the emergent synchronous oscillation, which provides a general mechanism to make fast (ultradian) pacemakers slow (circadian) and synchronous via coupling. The basic mechanisms behind the generation of oscillations and the emergence of synchrony that we describe here can be used to guide further studies of coupled oscillations in biophysical non-linear models

Monitoring of miR-181a-5p and miR-155-5p Plasmatic Expression as Prognostic Biomarkers for Acute and Subclinical Rejection in de novo Adult Liver Transplant Recipients.

Background and Aims: News strategies for the accurate assessment of the state of immunosuppression (IS) in liver transplant recipients are needed to prevent rejection and minimize drug-related side effects. miRNAs can potentially be used as diagnostic or prognostic biomarkers in transplant patients. This study evaluated the capacity of a plasmatic miRNA panel (miR-155-5p, miR-122-5p, miR-181a-5p, and miR148-3p) as an early non-invasive prognostic and diagnostic biomarker for T cell-mediated acute rejection (TCMAR) and subclinical rejection (SCR) in adult liver recipients. Methods: A total of 145 liver recipients were included. All patients received a calcineurin inhibitor with or without mycophenolate mofetil and methylprednisolone. Plasmatic miRNA expression was assessed by qPCR before and at different time-points after liver transplantation. Results: Seventeen patients experienced TCMAR, and eight were diagnosed with SCR during the protocol biopsy at the 3rd month post-transplantation. Pre-transplantation, miR-155-5p expression was significantly higher in TCMAR patients and in SCR patients than in non-rejectors, and miR-181a-5p expression was also significantly higher in SCR patients than in non-rejectors. Post-transplantation, before transaminase-level modification, significantly increased miR-181a-5p, miR-155-5p, and miR-122-5p expression was observed in TCMAR and SCR patients. Binary logistic regression analyses showed, post-transplantation, that TCMAR risk was better predicted by individual expression of miR-181a-5p (LOGIT = -6.35 + 3.87*miR-181a-5p), and SCR risk was better predicted by the combination of miR-181a-5p and miR-155-5p expression (LOGIT = -5.18 + 2.27*miR-181a-5p+1.74*miR-155-5p). Conclusions: Pre-transplantation plasmatic miR-155-5p expression may be useful for stratifying low-immunologic-risk patients, and post-transplantation miR-181a-5p and miR-155-5p may be candidates for inclusion in early, non-invasive prognostic biomarker panels to prevent TCMAR or SCR and better identify patient candidates for IS minimization. Large prospective randomized multicenter trials are needed to refine the cut-off values and algorithms and validate the clinical usefulness of these biomarkers

Uso de isótopos ambientales del agua y geoquímica para determinar fuentes de nitrato en el sur del acuífero Cuernavaca

El acuífero Cuernavaca es la principal fuente de agua dulce permanente que sustenta el desarrollo económico y el suministro a la población de la capital del estado de Morelos. En los últimos 30 años, los nitratos en el sur del acuífero Cuernavaca se han incrementado, degradando la calidad del agua subterránea. La identificación del origen del nitrato es fundamental para implementar políticas públicas que controlen y reviertan dicha contaminación. Con base en las características propias de la región, como son tipo de suelo y geología, incremento acelerado de la población, y actividades industriales, agrícolas y recreativas, entre ellas la práctica del golf, se plantean cuatro posibles fuentes de nitrato en la zona de estudio: 1) nitrato del suelo, 2) infiltración de aguas residuales, 3) fertilizantes provenientes de zonas agrícolas, y 4) fertilizantes provenientes de campos de golf. En la porción sur del acuífero Cuernavaca, los datos geoquímicos y los isótopos ambientales del agua (δ18O, δ2H, δ3H) indican que la contaminación por nitrato proviene principalmente de aguas residuales. Asimismo, indican que el flujo profundo aporta arsénico a algunos aprovechamientos subterráneos. Los resultados también muestran correlación entre las concentraciones del nitrato y del uranio en el acuífero. El registro periódico de los datos isotópicos permitió también determinar la línea de agua meteórica de la zona del acuífero Cuernavaca

Long-term follow-up of certolizumab pegol in uveitis due to immune-mediated inflammatory diseases: multicentre study of 80 patients

Objectives: To evaluate effectiveness and safety of certolizumab pegol (CZP) in uveitis due to immune-mediated inflammatory diseases (IMID). Methods: Multicentre study of CZP-treated patients with IMID uveitis refractory to conventional immunosuppressant. Effectiveness was assessed through the following ocular parameters: best-corrected visual acuity, anterior chamber cells, vitritis, macular thickness and retinal vasculitis. These variables were compared between the baseline, and first week, first, third, sixth months, first and second year. Results: We studied 80 (33 men/47 women) patients (111 affected eyes) with a mean age of 41.6±11.7 years. The IMID included were: spondyloarthritis (n=43), Behçet's disease (n=10), psoriatic arthritis (n=8), Crohn's disease (n=4), sarcoidosis (n=2), juvenile idiopathic arthritis (n=1), reactive arthritis (n=1), rheumatoid arthritis (n=1), relapsing polychondritis (n=1), CONCLUSIONS: CZP seems to be effective and safe in uveitis related to different IMID, even in patients refractory to previous biological drugs.Funding: This work was also partially supported by RETICS Programmes, RD08/0075 (RIER) and RD12/0009/0013 from 'Instituto de Salud Carlos III' (ISCIII) (Spain)

Parvimonas micra can translocate from the subgingival sulcus of the human oral cavity to colorectal adenocarcinoma

[Abstract] Oral and intestinal samples from a cohort of 93 colorectal cancer (CRC) patients and 30 healthy controls (non-CRC) were collected for microbiome analysis. Saliva (28 non-CRC and 94 CRC), feces (30 non-CRC and 97 CRC), subgingival fluid (20 CRC), and tumor tissue samples (20 CRC) were used for 16S metabarcoding and/or RNA sequencing (RNAseq) approaches. A differential analysis of the abundance, performed with the ANCOM-BC package, adjusting the P-values by the Holm-Bonferroni method, revealed that Parvimonas was significantly over-represented in feces from CRC patients (P-value < 0.001) compared to healthy controls. A total of 11 Parvimonas micra isolates were obtained from the oral cavity and adenocarcinoma of CRC patients. Genome analysis identified a pair of isolates from the same patient that shared 99.2% identity, demonstrating that P. micra can translocate from the subgingival cavity to the gut. The data suggest that P. micra could migrate in a synergistic consortium with other periodontal bacteria. Metatranscriptomics confirmed that oral bacteria were more active in tumor than in non-neoplastic tissues. We suggest that P. micra could be considered as a CRC biomarker detected in non-invasive samples such as feces.The present authors want to thank all the cancer patients of the University Hospital of A Coruña for participating in this study, collaborating with us despite their health problems. We warmly want to thank Gema Carro Díaz and Montserrat Ingelmo Sánchez (surgical service nurses of HUAC) for their support during patient's recruitment time and also with sample collection. Moreover, we want to appreciate the valuable assistance received in anaerobic culturing by David Velasco Fernández (microbiologist) and Ana María Fernández Liñares (technician), and in FFPE samples processing by the pathology service technicians: Diego Barco Díaz, Cristina Vázquez Costa and Ana María Mejuto Rial. This work would not be possible without all the professionals of the Microbiology, Surgery, Pathology and Oncology services and Biobank from CHUAC who support this microbiome and cancer research project. This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project PI20/00413 and co-funded by the European Union to MP. The work has been also supported by the project RTI2018-102032-B-I00 from the Spanish Ministry of Science and Innovation to AM and by the CIBER INF ISCIII (CB21/13/00055) to GB and MP. Biobank of University Hospital Complex of A Coruña was supported by Instituto de Salud Carlos III – Fondos FEDER (EU) by grant PT20/00128. K. Conde-Pérez was financially supported with a predoctoral fellowship by the Asociación Española Contra el Cáncer (AECC). E. Buetas is supported by a grant from the Spanish Ministry of Science and Innovation with the reference PRE2019-088126. S. Ladra, E. Martin-De Arribas and Iago Iglesias-Corrás are supported by grants from GAIN (Xunta de Galicia, Spain) with references ED431C 2021/53 and ED431GXunta de Galicia; ED431C 2021/53Xunta de Galicia; ED431

The multispecies microbial cluster of Fusobacterium, Parvimonas, Bacteroides and Faecalibacterium as a precision biomarker for colorectal cancer diagnosis

[Abstract] The incidence of colorectal cancer (CRC) has increased worldwide, and early diagnosis is crucial to reduce mortality rates. Therefore, new noninvasive biomarkers for CRC are required. Recent studies have revealed an imbalance in the oral and gut microbiomes of patients with CRC, as well as impaired gut vascular barrier function. In the present study, the microbiomes of saliva, crevicular fluid, feces, and non-neoplastic and tumor intestinal tissue samples of 93 CRC patients and 30 healthy individuals without digestive disorders (non-CRC) were analyzed by 16S rRNA metabarcoding procedures. The data revealed that Parvimonas, Fusobacterium, and Bacteroides fragilis were significantly over-represented in stool samples of CRC patients, whereas Faecalibacterium and Blautia were significantly over-abundant in the non-CRC group. Moreover, the tumor samples were enriched in well-known periodontal anaerobes, including Fusobacterium, Parvimonas, Peptostreptococcus, Porphyromonas, and Prevotella. Co-occurrence patterns of these oral microorganisms were observed in the subgingival pocket and in the tumor tissues of CRC patients, where they also correlated with other gut microbes, such as Hungatella. This study provides new evidence that oral pathobionts, normally located in subgingival pockets, can migrate to the colon and probably aggregate with aerobic bacteria, forming synergistic consortia. Furthermore, we suggest that the group composed of Fusobacterium, Parvimonas, Bacteroides, and Faecalibacterium could be used to design an excellent noninvasive fecal test for the early diagnosis of CRC. The combination of these four genera would significantly improve the reliability of a discriminatory test with respect to others that use a single species as a unique CRC biomarker.The authors want to appreciate the good disposition of all the CRC patients for collaborating with us. We would like to thank Gema Carro Díaz and Montserrat Ingelmo Sánchez for their assistance during patients' recruitment time and also during tissue sample collection. This work would not be possible without the support of professionals from the Microbiology, Surgery, Pathology and Oncology Services and Biobank of CHUAC (Spain). The present study received funding from the Instituto de Salud Carlos III (ISCIII), Spain, through the project PI20/00413, cofunded by the European Union (EU) to MP. The whole work has been also supported by the project RTI2018-102032-B-I00 from the Spanish Ministry of Science and Innovation to AM and by CIBER INFEC ISCIII (CB21/13/00055) to GB and MP Biobank of A Coruña was supported by ISCIII-Fondos FEDER (EU) by grant PT20/00128. KC-P was financially supported by the Spanish Association against Cancer (AECC). EB was supported by a grant from the Spanish Ministry of Science and Innovation PRE2019-088126. SL and EM-DA were supported by grants from GAIN (Xunta de Galicia, Spain) with references ED431C 2021/53 and ED431G 2019/01.Xunta de Galicia; ED431C 2021/53Xunta de Galicia; ED431G 2019/0

Anti-IL-6 Receptor Tocilizumab in Refractory Graves? Orbitopathy: National Multicenter Observational Study of 48 Patients

Graves’ orbitopathy (GO) is the most common extrathyroidal manifestation of Graves’ disease (GD). Our aim was to assess the e cacy and safety of Tocilizumab (TCZ) in GO refractory to conventional therapy. This was an open-label multicenter study of glucocorticoid-resistant GO treated with TCZ. The main outcomes were the best-corrected visual acuity (BVCA), Clinical Activity Score (CAS) and intraocular pressure (IOP). These outcome variables were assessed at baseline, 1st, 3rd, 6th and 12th month after TCZ therapy onset. The severity of GO was assessed according to the European Group on Graves’ Orbitopathy (EUGOGO). We studied 48 (38 women and 10 men) patients (95 eyes); mean age standard deviation 51 11.8 years. Before TCZ and besides oral glucocorticoids, they had received IV methylprednisolone (n = 43), or selenium (n = 11). GO disease was moderate (n =29) or severe (n = 19) and dysthyroid optic neuropathy (DON) (n = 7). TCZ was used in monotherapy (n = 45) or combined (n = 3) at a dose of 8 mg/kg IV every four weeks (n = 43) or 162 mg/s.c. every week (n = 5). TCZ yielded a significant improvement in all of the main outcomes at the 1st month that was maintained at one year. Comparing the baseline with data at 1 year all of the variables improved; BCVA (0.78 0.25 vs. 0.9 0.16; p = 0.0001), CAS (4.64 1.5 vs. 1.05 1.27; p = 0.0001) and intraocular pressure (IOP) (19.05 4.1 vs. 16.73 3.4 mmHg; p = 0.007). After a mean follow-up of 16.1 2.1 months, low disease activity (CAS 3), was achieved in 88 eyes (92.6%) and TCZ was withdrawn in 29 cases due to low disease activity (n = 25) or ine cacy (n = 4). No serious adverse events were observed. In conclusion, TCZ is a useful and safe therapeutic option in refractory GO treatment.This work was also partially supported by RETICS Programs, RD08/0075 (RIER) and RD12/0009/0013 from “Instituto de Salud Carlos III” (ISCIII) (Spain)

Long-term follow-up of certolizumab pegol in uveitis due to immune-mediated inflammatory diseases : multicentre study of 80 patients

Objectives To evaluate effectiveness and safety of certolizumab pegol (CZP) in uveitis due to immune-mediated inflammatory diseases (IMID). Methods Multicentre study of CZP-treated patients with IMID uveitis refractory to conventional immunosuppressant. Effectiveness was assessed through the following ocular parameters: best-corrected visual acuity, anterior chamber cells, vitritis, macular thickness and retinal vasculitis. These variables were compared between the baseline, and first week, first, third, sixth months, first and second year. Results We studied 80 (33 men/47 women) patients (111 affected eyes) with a mean age of 41.6±11.7 years. The IMID included were: spondyloarthritis (n=43), Behçet's disease (n=10), psoriatic arthritis (n=8), Crohn's disease (n=4), sarcoidosis (n=2), juvenile idiopathic arthritis (n=1), reactive arthritis (n=1), rheumatoid arthritis (n=1), relapsing polychondritis (n=1), Conclusions CZP seems to be effective and safe in uveitis related to different IMID, even in patients refractory to previous biological drugs

Clínica jurídica de acción social

Memoria ID-025. Ayudas de la Universidad de Salamanca para la innovación docente, curso 2018-2019