Synergic effect of ozonation and electrochemical methods on oxidation and toxicity reduction: Phenol degradation

The degradation of phenol was studied under three chemical environments, ozonation (O3), electrooxidation (EO) and ozonation-electro-oxidation (O3-EO) coupled process. The parent compound concentration was established by UV–Vis spectrophotometry while the by-products were identified by HPLC. This allowed proposing a mechanism of phenol oxidation during the coupled process. This coupled process was found to practically mineralize all phenol (TOC removal = 99.8%) under pH 7.0 ± 0.5 and at a current density of 60 mA cm 2, 0.05 L min 1 flowrate, ozone concentration of 5 ± 0.5 mg L 1. Furthermore, it was found that the coupled process is practically twice faster than the EO process alone to achieve a high degree of mineralization. In this sense, it was concluded that ozone alone only partially mineralizes the phenol molecule and mainly leads to the formation of aliphatic compounds. In addition, the toxicities of phenol and its degradation products were established by using a bioassay with lettuce seeds. It was concluded that, unlike ozonation, the coupled oxidation process not only mineralizes the organic molecule but also completely eliminates the toxicity of the treated phenolic solution

Expression of Musashi-1 Increases in Bone Healing

The authors of this manuscript were partially supported by Research Groups #CTS-138 and #CTS-1028 (Junta de Andalucía, Spain). This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.All experiments were performed after the approval of the Committee on Animal Research of the University of Granada (CEEA 2014/357) and under the European Union and Spanish regulations for ethics in animal research (EU Directive 63/2010 and Spanish RD 53/2013) and reported following the ARRIVE guidelines.The data that support the findings of this study are available from the corresponding author upon reasonable request.The authors would especially like to acknowledge the contribution to the histochemical and immunohistochemical studies of Serafin Vélez García and Carmen Ruíz Guzmán, technicians in the Department of Surgery, and María Dolores Rodriguez, in the Department of Pathology and IBIMER of the University of Granada and Justin G. Davis for assistance with the writing style.Musashi-1 (MSI1) is an RNA-binding protein that regulates progenitor cells in adult and developing organisms to maintain self-renewal capacities. The role of musashi-1 in the bone healing environment and its relation with other osteogenic factors is unknown. In the current study, we analyze the expression of MSI1 in an experimental model of rat femoral bone fractures. We also analyze the relation between MSI1 expression and the expression of two osteogenic markers: periostin (POSTN) and runt-related transcription factor 2 (RUNX2). We use histological, immunohistochemical, and qPCR techniques to evaluate bone healing and the expression of MSI1, POSTN, and RUNX2 over time (4, 7, and 14 days). We compare our findings with non-fractured controls. We find that in bone calluses, the number of cells expressing MSI1 and RUNX2 increase over time and the intensity of POSTN expression decreases over time. Within bone calluses, we find the presence of MSI1 expression in mesenchymal stromal cells, osteoblasts, and osteocytes but not in hypertrophic chondrocytes. After 14 days, the expression of MSI1, POSTN, and RUNX2 was significantly correlated. Thus, we conclude that musashi-1 potentially serves in the osteogenic differentiation of mesenchymal stromal cells and bone healing. Therefore, further studies are needed to determine the possibility of musashi-1 ' s role as a clinical biomarker of bone healing and therapeutic agent for bone regeneration.Junta de Andalucia European Commission CTS-138 CTS-102

Inflammasomes NLRP3 and AIM2 in peri-implantitis: A cross-sectional study

Background: Inflammasome components NLRP3 and AIM2 contribute to inflammation development by the activation of caspase-1 and IL-1β. They have not been yet evaluated in samples from patients with active peri-implantitis. Thus, the aim of the present study is to analyze the expression of inflammasomes NLRP3 and AIM2 and subsequent caspase 1 and IL-1β assessing the microenvironment of leukocyte subsets in samples from patients with active peri-implantitis. Methods: Biopsies were collected from 33 implants in 21 patients being treated for peri-implantitis. Biopsies from gingival tissues from 15 patients with healthy periodontium were also collected for control. These tissues were evaluated through conventional histological stainings. Then, immunohistochemical detection was performed to analyze NLRP3, AIM2, caspase-1, and IL-1β and markers of different leukocyte subsets. PCR for inflammasomes and related genes was also done. Results: This manuscript reveals a high immunohistochemical and mRNA expression of NLRP3 and AIM2 inflammasomes, caspase-1, and IL-1β in biopsies collected from human peri-implantitis. The expression of the tested markers was significantly correlated with the increase in inflammatory infiltrate, probing depth, presence of biofilm, and bleeding on probing. In these peri-implantitis lesions, the area of biopsy tissue occupied by inflammatory infiltrate was intense while the area occupied by collagen was significantly lower. In comparison with periodontal healthy tissues, the inflammatory infiltrate was statistically significantly higher in the peri-implantitis biopsies and was mainly composed of plasma cells, followed by T and B lymphocytes. Conclusion: In human peri-implantitis, chronic inflammation can be explained in part by the action of IL-1β/ caspase 1 induced through NLRP3 and AIM2 inflammasome activation.Junta de Andalucía, Grant/Award Number: CTS-138CTS-1028; Universidad de Granada, Grant/Award Number: B-CTS- 504- UGR18Universidad de Granada/CBU

Maxillary sinus floor augmentation comparing bovine versus porcine bone xenografts mixed with autogenous bone graft. A split-mouth randomized controlled trial

This investigation was conducted under an Investigator--Initiated Study partially funded by Dentsply Sirona Implants (Molndal, Sweden) through a research transfer agreement with the Technology Transfer Office of the University of Granada (number I--BI--17--026) and the Research Cathedra "Dentsply Sirona-UGR" agreed between Dentsply Sirona Iberia S.A.U. and the University of Granada. The authors are also supported by funding from Research Groups #CTS-138 and #CTS--1028 (Junta de Andalucia, Spain) The authors are grateful to Justin G. Davis for assistance with the English translation and to Emilio Couso-Queiruga for assistance with the volumetric radiographic analyses.Aim: To compare the effectiveness of two xenografts for maxillary sinus floor augmentation in terms of clinical, radiographical, histologic, and molecular outcomes. Materials and methods: A split-mouth randomized clinical trial was conducted at the University of Granada. Ten consecutive patients in need of bilateral two-staged maxillary sinus floor augmentation were included. Each patient received both biomaterials (porcine bone mineral and anorganic bovine bone), which were randomly assigned for bilateral sinus augmentation. The maxillary autogenous bone scraped from the sinus access window was mixed with each xenograft at a 20:80 ratio. After a healing period of 6 months, bone biopsies were collected with a trephine during the implant placement in the regenerated area. Histologic, histomorphometrical, immunohistochemical, and molecular outcomes were analyzed. Clinical and radiographical data throughout the treatment phases were also evaluated. Results: The resulting anatomic features were similar between both groups. After six months of graft consolidation, the graft resorption rates were similar between both biomaterials. The histologic, histomorphometrical, and immunohistochemical results showed no statistical differences between groups. Conclusion: Anorganic bovine bone and porcine bone mineral combined with maxillary autogenous cortical bone show similar biologic and radiologic features in terms of biomaterial resorption, osteoconduction, and osteogenesis when used for maxillary sinus floor augmentation.Dentsply Sirona Implants (Molndal, Sweden)Technology Transfer Office of the University of Granada I-BI-17-026Dentsply Sirona Iberia S.A.U.University of GranadaJunta de AndaluciaEuropean Commission CTS-138 CTS-102

Mineralocorticoid receptor blockade improved gut microbiota dysbiosis by reducing gut sympathetic tone in spontaneously hypertensive rats.

Microbiota has a crucial role in the host blood pressure (BP) regulation. The present study analyzes whether the mineralocorticoid receptor antagonist spironolactone ameliorates the dysbiosic state in a genetic model of neurogenic hypertension. Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were randomly allocated into three groups: untreated WKY, untreated SHR, and SHR treated with spironolactone for 5 weeks. Spironolactone restored the Firmicutes/Bacteroidetes proportion, and acetate-producing bacteria populations to WKY levels. Spironolactone reduced the percentage of intestinal aerobic bacteria. The amelioration of gut dysbiosis was linked to a reduction in the gut pathology, an enhanced colonic integrity, a reduced gut permeability and an attenuated sympathetic drive in the gut. Spironolactone was unable to reduce neuroinflammation and oxidative stress in the paraventricular nuclei in the hypothalamus. Spironolactone reduced the higher Th17 cells proportion in mesenteric lymph nodes and Th17 infiltration in aorta, improved aortic endothelial function and reduced systolic BP. This study demonstrates for the first time that spironolactone reduces gut dysbiosis in SHR. This effect could be related to its capability to improve gut integrity and pathology due to reduced sympathetic drive in the gut.This work was supported by Grants from Comision ´ Interministerial de Ciencia y Tecnología, Ministerio de Economía y competitividad (PID2020-116347RB-I00), and Junta de Andalucía (CTS 164, P20_00193, A-CTS-318-UGR20) with funds from the European Union, and by the Ministerio de Economia y Competitividad, Instituto de Salud Carlos III (CIBER-CV), Spain. M.T. and I.R.-V. are postdoctoral fellow of Instituto de Salud Carlos III (Juan de la Cierva Incorporacion ´ Program, and Juan de la Cierva Formacion ´ Program, respectively). J.M. is a predoctoral fellow of MINECO, and C.G.-C. and S.M. are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).S

Targeting the gut microbiota with dietary fibers: a novel approach to prevent the development cardiovascular complications linked to systemic lupus erythematosus in a preclinical study.

This study is to investigate whether dietary fiber intake prevents vascular and renal damage in a genetic mouse model of systemic lupus erythematosus (SLE), and the contribution of gut microbiota in the protective effects. Female NZBWF1 (SLE) mice were treated with resistant-starch (RS) or inulin-type fructans (ITF). In addition, inoculation of fecal microbiota from these experimental groups to recipient normotensive female C57Bl/6J germ-free (GF) mice was performed. Both fiber treatments, especially RS, prevented the development of hypertension, renal injury, improved the aortic relaxation induced by acetylcholine, and the vascular oxidative stress. RS and ITF treatments increased the proportion of acetate- and butyrate-producing bacteria, respectively, improved colonic inflammation and integrity, endotoxemia, and decreased helper T (Th)17 proportion in mesenteric lymph nodes (MLNs), blood, and aorta in SLE mice. However, disease activity (splenomegaly and anti-ds-DNA) was unaffected by both fibers. T cell priming and Th17 differentiation in MLNs and increased Th17 infiltration was linked to aortic endothelial dysfunction and hypertension after inoculation of fecal microbiota from SLE mice to GF mice, without changes in proteinuria and autoimmunity. All these effects were lower in GF mice after fecal inoculation from fiber-treated SLE mice. In conclusion, these findings support that fiber consumption prevented the development of hypertension by rebalancing of dysfunctional gut-immune system-vascular wall axis in SLE.This work was supported by Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RBI00 funded by MCIN/AEI/10.13039/501100011033, PID2021- 122490NB-I00 funded by MCIN/AEI/10.13039/ 501100011033) co-funded by the European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193) with funds from the European Union, and by the Instituto de Salud Carlos III (CIBER-CV). IR-V is postdoctoral funded by MINECO (FJC2021-048099-I). JM is a predoctoral fellow of MINECO (FPU18/02561), and CG-C and SM are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).S

Targeting the gut microbiota with dietary fibers: a novel approach to prevent the development cardiovascular complications linked to systemic lupus erythematosus in a preclinical study

This work was supported by Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RB- I00 funded by MCIN/AEI/10.13039/501100011033, PID2021- 122490NB-I00 funded by MCIN/AEI/10.13039/ 501100011033) co-funded by the European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193) with funds from the European Union, and by the Instituto de Salud Carlos III (CIBER-CV). IR-V is postdoctoral funded by MINECO (FJC2021-048099-I). JM is a predoctoral fellow of MINECO (FPU18/02561), and CG-C and SM are predoctoral fellow of Junta de Andalucía. The cost of this publication was paid in part with funds from the European Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”).This study is to investigate whether dietary fiber intake prevents vascular and renal damage in a genetic mouse model of systemic lupus erythematosus (SLE), and the contribution of gut microbiota in the protective effects. Female NZBWF1 (SLE) mice were treated with resistantstarch (RS) or inulin-type fructans (ITF). In addition, inoculation of fecal microbiota from these experimental groups to recipient normotensive female C57Bl/6J germ-free (GF) mice was performed. Both fiber treatments, especially RS, prevented the development of hypertension, renal injury, improved the aortic relaxation induced by acetylcholine, and the vascular oxidative stress. RS and ITF treatments increased the proportion of acetate- and butyrate-producing bacteria, respectively, improved colonic inflammation and integrity, endotoxemia, and decreased helper T (Th)17 proportion in mesenteric lymph nodes (MLNs), blood, and aorta in SLE mice. However, disease activity (splenomegaly and anti-ds-DNA) was unaffected by both fibers. T cell priming and Th17 differentiation in MLNs and increased Th17 infiltration was linked to aortic endothelial dysfunction and hypertension after inoculation of fecal microbiota from SLE mice to GF mice, without changes in proteinuria and autoimmunity. All these effects were lower in GF mice after fecal inoculation from fiber-treated SLE mice. In conclusion, these findings support that fiber consumption prevented the development of hypertension by rebalancing of dysfunctional gutimmune system-vascular wall axis in SLE.Grants from Ministry of Science and Innovation of Spain (MCIN) (Ref. PID2020-116347RB- I00 funded by MCIN/AEI/10.13039/501100011033, PID2021- 122490NB-I00 funded by MCIN/AEI/10.13039/ 501100011033)European Regional Development Fund FEDER, Consejería de Universidad, Investigación e Innovación de la Junta de Andalucía (Ref. CTS 164, P20_00193) with funds from the European Union, and by the Instituto de Salud Carlos III (CIBER-CV)MINECO (FJC2021-048099-I)MINECO (FPU18/02561)Junta de AndalucíaEuropean Union (Fondo Europeo de Desarrollo Regional, FEDER, “FEDER una manera de hacer Europa”

Role of age and comorbidities in mortality of patients with infective endocarditis

[Purpose]: The aim of this study was to analyse the characteristics of patients with IE in three groups of age and to assess the ability of age and the Charlson Comorbidity Index (CCI) to predict mortality. [Methods]: Prospective cohort study of all patients with IE included in the GAMES Spanish database between 2008 and 2015.Patients were stratified into three age groups:<65 years,65 to 80 years,and ≥ 80 years.The area under the receiver-operating characteristic (AUROC) curve was calculated to quantify the diagnostic accuracy of the CCI to predict mortality risk. [Results]: A total of 3120 patients with IE (1327 < 65 years;1291 65-80 years;502 ≥ 80 years) were enrolled.Fever and heart failure were the most common presentations of IE, with no differences among age groups.Patients ≥80 years who underwent surgery were significantly lower compared with other age groups (14.3%,65 years; 20.5%,65-79 years; 31.3%,≥80 years). In-hospital mortality was lower in the <65-year group (20.3%,<65 years;30.1%,65-79 years;34.7%,≥80 years;p < 0.001) as well as 1-year mortality (3.2%, <65 years; 5.5%, 65-80 years;7.6%,≥80 years; p = 0.003).Independent predictors of mortality were age ≥ 80 years (hazard ratio [HR]:2.78;95% confidence interval [CI]:2.32–3.34), CCI ≥ 3 (HR:1.62; 95% CI:1.39–1.88),and non-performed surgery (HR:1.64;95% CI:11.16–1.58).When the three age groups were compared,the AUROC curve for CCI was significantly larger for patients aged <65 years(p < 0.001) for both in-hospital and 1-year mortality. [Conclusion]: There were no differences in the clinical presentation of IE between the groups. Age ≥ 80 years, high comorbidity (measured by CCI),and non-performance of surgery were independent predictors of mortality in patients with IE.CCI could help to identify those patients with IE and surgical indication who present a lower risk of in-hospital and 1-year mortality after surgery, especially in the <65-year group

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation