Publications by authors named "Patricia López"

217 Publications

Fundamentally uncaring: The differential multi-scalar impacts of COVID-19 in the U.S.

Soc Sci Med 2021 03 19;272:113707. Epub 2021 Jan 19.

Dartmouth College, 19 Fayerweather Hill Rd, 6017 Sherman Fairchild, Hanover, NH, 03755, USA. Electronic address:

2020 in the United States was marked by two converging crises-the COVID-19 pandemic and the large-scale uprisings in support of Black lives. These crises were met with both a counterproductive and inadequate response from the federal government. We examine these converging crises at the individual, social, and political scales. The biological realities of COVID-19 impact different populations in widely varied ways-the poor, the elderly, Black, Indigenous, and people of color, and those living with comorbidities get sick and die at the highest rates. Social distancing guidelines shifted millions of people to work-from-home and millions more lost their jobs, even as care laborers, preponderantly women, Black, Indigenous, and people of color, were asked to put their and their loved ones' lives on the line for the continuation of all of our lives. These biological, social, and economic crises have been punctuated by civil unrest, as millions took to the streets for racial justice, noting the unequal impacts of the pandemic. These converging crises have laid bare decades of neoliberal and neoconservative policies and ideologies, undergirded as they have been by racial capitalism, for their fundamental uncaringness. In this paper, we argue that this pandemic not only made a wider population more acutely aware of the necessity and importance of the need to care and for caring labors, but also that we stand at the precipice of potentiality--of producing a more caring society. To frame our argument, we draw on Nancy Scheper-Hughes and Margaret Lock's (1987) framework of three bodies-individual, social, and political-to unpack the multi-scalar entanglements in the differential impacts of COVID-19, questions of care, and their articulation in the current political-economic context.
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http://dx.doi.org/10.1016/j.socscimed.2021.113707DOI Listing
March 2021

Comparative Kinematic Analysis of Hurdle Clearance Technique in Dogs: A Preliminary Report.

Animals (Basel) 2020 Dec 16;10(12). Epub 2020 Dec 16.

Animal Medicine and Surgery Department, Universidad Complutense de Madrid, 28040 Madrid, Spain.

Although the jumping characteristics of agility dogs have been examined in recent years, there is currently a lack of data related to the suspension phase. The purpose of the present study was to investigate the biomechanics of the suspension phase of the agility jump and to analyze the kinematic differences in dogs with different jumping abilities. Two groups of dogs of the same height category (large dogs) competing at different skill levels and assessed as excellent jumpers ( = 4) and less-skilled jumpers ( = 3), respectively, were analyzed and statistically compared. Excellent jumpers showed longer and faster jumps with flatter jump trajectories than less-skilled jumpers. In less-skilled jumpers, the distance in front of the hurdle was notably greater than the distance behind it, while the difference between these two distances was less in excellent jumpers. Length and duration of the jump, maximal height of the jumping trajectory, take-off and landing distances to the hurdle, time of occurrence of maximal jump height, and time of change in back orientation essentially defines the suspension phase of the agility jump. This study presents preliminary evidence that the kinematic characteristics of hurdle clearance are different in excellent jumper dogs and in less-skilled jumper dogs.
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http://dx.doi.org/10.3390/ani10122405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765657PMC
December 2020

Relationship Between T-Cell Exosomes and Cellular Subsets in SLE According to Type I IFN-Signaling.

Front Med (Lausanne) 2020 30;7:604098. Epub 2020 Nov 30.

Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo, Oviedo, Spain.

To quantify the levels of circulating exosomes derived from T-cells and monocytes and their possible associations with leukocyte subpopulations and cytokine milieu in Systemic Lupus Erythematosus (SLE). Total circulating exosomes (CD9-Ex) and those derived from T-cells (CD3-Ex) and monocytes (CD14-Ex) were quantified by flow cytometry in 82 SLE patients and 32 controls. Leukocyte subsets and serum cytokines were analyzed by flow cytometry or by immunoassays. IFN-score was evaluated by real time RT-PCR in whole blood samples from a subgroup of 73 patients and 24 controls. Activation markers (IFNR1 and BLyS) on monocytes, neutrophils and B-cells correlated inversely with circulating exosomes (CD9-Ex, CD3-Ex, and CD14-Ex) in controls but directly with CD3-Ex in patients (all < 0.05). Although CD9-Ex were increased in SLE, no differences were found in CD3-Ex, supporting that exosome content accounts for this opposite role. Interestingly, CD4CD28 cells correlated with CD3-Ex in patients and controls, and displayed similar associations with leukocyte subsets in both groups. Additionally, CD3-Ex correlated in patients with the expression of CD25 in CD4CD28 cells. Furthermore, the activated status of this senescent subset was related to IFNα serum levels in controls and to IFN-score in SLE patients. Finally, patients presenting high IFN-score, in addition to elevated CD25CD28 cells associated with the activation of myeloid cells, displayed higher levels of inflammatory cytokines and chemokines. Our results support a relationship between T-cell exosomes and cellular subsets in SLE according to type I IFN-signaling, which could amplify chronic immune activation and excessive cytokine/chemokine response.
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http://dx.doi.org/10.3389/fmed.2020.604098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734125PMC
November 2020

Regenerated Silk Fibers Obtained by Straining Flow Spinning for Guiding Axonal Elongation in Primary Cortical Neurons.

ACS Biomater Sci Eng 2020 12 27;6(12):6842-6852. Epub 2020 Oct 27.

Center for Biomedical Technology (CTB), Universidad Politécnica de Madrid, Pozuelo de Alarcón, 28223 Madrid, Spain.

The recovery of injured nervous tissue, one of the main goals for regenerative therapeutic approaches, is often hindered by the limited axonal regeneration ability of the central nervous system (CNS). In this regard, the identification of scaffolds that support the reconstruction of functional neuronal tissues and guide the alignment of regenerating neurons is a major challenge in tissue engineering. Ideally, the usage of such scaffolds would promote and guide the axonal growth, a crucial phase for the restoration of neuronal connections and, consequently, the nerve function. Among the materials proposed as scaffolds for CNS regeneration, silk has been used to exploit its outstanding features as a biomaterial to promote axonal regeneration. In this study, we explore, for the first time, the possibility of using high-performance regenerated silk fibers obtained by straining flow spinning (SFS) to serve as scaffolds for inducing and guiding the axonal growth. It is shown that SFS fibers promote the spontaneous organization of dissociated cortical primary cells into highly interconnected cellular spheroid-like tissue formations. Neuronal projections (i.e., axons) from these cellular spheroids span hundreds of microns along the SFS fibers that act as guides and allow the connection of distant spheroids. In addition, it is also shown that SFS fibers serve as scaffolds for neuronal migration covering short and long distances. As a consequence, the usage of high-performance SFS fibers appears as a promising basis for the development of novel therapies, leading to directed axonal regeneration.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00985DOI Listing
December 2020

Profiling of Serum Oxylipins During the Earliest Stages of Rheumatoid Arthritis.

Arthritis Rheumatol 2021 03 29;73(3):401-413. Epub 2021 Jan 29.

Instituto de Investigación Sanitaria del Principado de Asturias and Universidad de Oviedo, Oviedo, Spain.

Objective: Eicosanoids modulate inflammation via complex networks involving different pathways and downstream mediators, including oxylipins. Although altered eicosanoids are linked to rheumatoid arthritis (RA), suggesting that metabolization is enhanced, the role of oxylipins in disease stratification remains unexplored. This study was undertaken to characterize oxylipin networks during the earliest stages of RA and evaluate their associations with clinical features and treatment outcomes.

Methods: In total, 60 patients with early RA (according to the American College of Rheumatology/European League Against Rheumatism 2010 criteria), 11 individuals with clinically suspect arthralgia (CSA), and 28 healthy control subjects were recruited. Serum samples were collected at the time of onset. In the early RA group, 50 patients who had not been exposed to disease-modifying antirheumatic drug (DMARD) or glucocorticoid treatment at the time of recruitment were prospectively followed up at 6 and 12 months after having received conventional synthetic DMARDs. A total of 75 oxylipins, mostly derived from arachidonic, eicosapentanoic, and linoleic acids, were identified in the serum by liquid chromatography tandem mass spectrometry.

Results: Univariate analyses demonstrated differences in expression patterns of 14 oxylipins across the RA, CSA, and healthy control groups, with each exhibiting a different trajectory. Network analyses revealed a strong grouping pattern of oxylipins in RA patients, whereas in individuals with CSA, a fuzzy network of oxylipins with higher degree and closeness was found. Partial least-squares discriminant analyses yielded variable important projection scores of >1 for 22 oxylipins, which allowed the identification of 2 clusters. Cluster usage differed among the groups (P = 0.003), and showed associations with disease severity and low rates of remission at 6 and 12 months in RA patients who were initially treatment-naive. Pathway enrichment analyses revealed different precursors and pathways between the groups, highlighting the relevance of the arachidonic acid pathway in individuals with CSA and the lipooxygenase pathway in patients with early RA. In applying distinct oxylipin signatures, subsets of seropositive and seronegative RA could be identified.

Conclusion: Oxylipin networks differ across stages during the earliest phases of RA. These distinct oxylipin networks could potentially elucidate pathways with clinical relevance for disease progression, clinical heterogeneity, and treatment response.
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http://dx.doi.org/10.1002/art.41537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914204PMC
March 2021

GlycA Levels during the Earliest Stages of Rheumatoid Arthritis: Potential Use as a Biomarker of Subclinical Cardiovascular Disease.

J Clin Med 2020 Aug 1;9(8). Epub 2020 Aug 1.

Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, 33006 Oviedo, Spain.

This study aimed at evaluating the clinical relevance of glycoprotein profiles during the earliest phases of rheumatoid arthritis (RA) as biomarkers of cardiovascular (CV) risk and treatment response. Then, GlycA and GlycB serum levels were measured using 1H-nuclear magnetic resonance in 82 early RA patients, 14 clinically-suspect arthralgia (CSA), and 28 controls. Serum glycosyltransferase activity was assessed by a colorimetric assay. Subclinical CV disease was assessed by Doppler-ultrasound. We found that GlycA and GlycB serum levels were increased in RA (both < 0.001), but not in CSA, independently of cardiometabolic risk factors. Increased serum glycosyltransferase activity paralleled GlycA (r = 0.405, < 0.001) and GlycB levels (r = 0.327, = 0.005) in RA. GlycA, but not GlycB, was associated with atherosclerosis occurrence ( = 0.012) and severity ( = 0.001). Adding GlycA to the mSCORE improved the identification of patients with atherosclerosis over mSCORE alone, increasing sensitivity (29.7 vs. 68.0%) and accuracy (55.8 vs. 76.6%) and allowing reclassification into more appropriate risk categories. GlycA-reclassification identified patients with impaired lipoprotein metabolism. Finally, baseline GlycA levels predicted poor clinical response upon anti-rheumatic treatment at 6 and 12 months in univariate and multivariate analysis. In sum, increased GlycA levels during the earliest stage of RA can be considered a powerful biomarker for CV risk stratification and treatment response.
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http://dx.doi.org/10.3390/jcm9082472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463667PMC
August 2020

Three-year outcomes from the CRADLE study in de novo pediatric kidney transplant recipients receiving everolimus with reduced tacrolimus and early steroid withdrawal.

Am J Transplant 2021 01 27;21(1):123-137. Epub 2020 Jun 27.

Novartis Pharma AG, Basel, Switzerland.

CRADLE was a 36-month multicenter study in pediatric (≥1 to <18 years) kidney transplant recipients randomized at 4 to 6 weeks posttransplant to receive everolimus + reduced-exposure tacrolimus (EVR + rTAC; n = 52) with corticosteroid withdrawal at 6-month posttransplant or continue mycophenolate mofetil + standard-exposure TAC (MMF + sTAC; n = 54) with corticosteroids. The incidence of composite efficacy failure (biopsy-proven acute rejection [BPAR], graft loss, or death) at month 36 was 9.8% vs 9.6% (difference: 0.2%; 80% confidence interval: -7.3 to 7.7) for EVR + rTAC and MMF + sTAC, respectively, which was driven by BPARs. Graft loss was low (2.1% vs 3.8%) with no deaths. Mean estimated glomerular filtration rate at month 36 was comparable between groups (68.1 vs 67.3 mL/min/1.73 m ). Mean changes (z-score) in height (0.72 vs 0.39; P = .158) and weight (0.61 vs 0.82; P = .453) from randomization to month 36 were comparable, whereas growth in prepubertal patients on EVR + rTAC was better (P = .050) vs MMF + sTAC. The overall incidence of adverse events (AEs) and serious AEs was comparable between groups. Rejection was the leading AE for study drug discontinuation in the EVR + rTAC group. In conclusion, though AE-related study drug discontinuation was higher, an EVR + rTAC regimen represents an alternative treatment option that enables withdrawal of steroids as well as reduction of CNIs for pediatric kidney transplant recipients. ClinicalTrials.gov: NCT01544491.
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http://dx.doi.org/10.1111/ajt.16005DOI Listing
January 2021

Structure-Function Relationship of Artificial Spider Silk Fibers Produced by Straining Flow Spinning.

Biomacromolecules 2020 06 10;21(6):2116-2124. Epub 2020 Apr 10.

Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, Centre for Veterinary Medicine and Animal Science, Box 7045, 756 51 Uppsala, Sweden.

The production of large quantities of artificial spider silk fibers that match the mechanical properties of the native material has turned out to be challenging. Recent advancements in the field make biomimetic spinning approaches an attractive way forward since they allow the spider silk proteins to assemble into the secondary, tertiary, and quaternary structures that are characteristic of the native silk fiber. Straining flow spinning (SFS) is a newly developed and versatile method that allows production under a wide range of processing conditions. Here, we use a recombinant spider silk protein that shows unprecedented water solubility and that is capable of native-like assembly, and we spin it into fibers by the SFS technique. We show that fibers may be spun using different hydrodynamical and chemical conditions and conclude that these spinning conditions affect fiber mechanics. In particular, it was found that the addition of acetonitrile and polyethylene glycol to the collection bath results in fibers with increased β-sheet content and improved mechanical properties.
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http://dx.doi.org/10.1021/acs.biomac.0c00100DOI Listing
June 2020

Low-density granulocytes and monocytes as biomarkers of cardiovascular risk in systemic lupus erythematosus.

Rheumatology (Oxford) 2020 07;59(7):1752-1764

Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo.

Objective: The aim was to evaluate the most relevant cell populations involved in vascular homeostasis as potential biomarkers of SLE-related cardiovascular disease (CVD).

Methods: Low-density granulocytes (LDGs), monocyte subsets, endothelial progenitor cells, angiogenic T (Tang) cells, CD4+CD28null and Th1/Th17 lymphocytes and serum cytokine levels were quantified in 109 SLE patients and 33 controls in relationship to the presence of subclinical carotid atheromatosis or cardiovascular disease. A second cohort including 31 recent-onset SLE patients was also included.

Results: Raised monocyte and LDG counts, particularly those LDGs negative for CD16/CD14 expression (nLDGs), in addition to the ratios of monocytes and nLDGs to high-density lipoprotein-cholesterol (HDLc) molecules (MHR and nLHR, respectively), were present in SLE patients with traditional risk factors or subclinical atheromatosis but not in those who were CV-free, thus revealing their value in the identification of patients at risk of CVD, even at the onset of disease. Accordingly, nLDGs were correlated positively with carotid intima-media thickness (cIMT) and with inflammatory markers (CRP and IL-6). A bias towards more differentiated monocyte subsets, related to increased IFN-α and IL-17 serum levels, was also observed in patients. Intermediate monocytes were especially expanded, but independently of their involvement in CVD. Finally, CD4+CD28null, Th17 and Th1 lymphocytes were increased, with CD4+CD28null and Th17 cells being associated with cIMT, whereas endothelial progenitor and Tang cell levels were reduced in all SLE patients.

Conclusion: The present study highlights the potential use of MHR and nLHR as valuable biomarkers of CVD risk in SLE patients, even at diagnosis. The increased amounts of nLDGs, monocytes, Th17 and senescent-CD28null subsets, coupled with reduced pro-angiogenic endothelial progenitor cells and Tang cells, could underlie the development of atheromatosis in SLE.
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http://dx.doi.org/10.1093/rheumatology/keaa016DOI Listing
July 2020

Discovery of a Covalent Inhibitor of KRAS (AMG 510) for the Treatment of Solid Tumors.

J Med Chem 2020 01 24;63(1):52-65. Epub 2019 Dec 24.

KRAS has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRAS inhibitor currently in phase I clinical trials (NCT03600883).
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http://dx.doi.org/10.1021/acs.jmedchem.9b01180DOI Listing
January 2020

In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice.

J Alzheimers Dis 2020 ;73(1):147-161

Oligomerix, Inc., Bronx, NY, USA.

Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer's disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation.
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http://dx.doi.org/10.3233/JAD-190465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957711PMC
April 2021

Silencing of the transcription factors Oct4, Sox2, Klf4, c-Myc or Nanog has different effect on teratoma growth.

Biochem Biophys Res Commun 2019 09 25;517(2):324-329. Epub 2019 Jul 25.

Labsinal, Departamento de Biofísica, Instituto de Biociências, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil; Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. Electronic address:

Induced pluripotent stem cells (iPSC) have a great potential, but their clinical application depends on finding strategies to abolish their tumorigenic potential. The use of Oct4, Sox2, Klf4, c-Myc and Nanog to generate iPSC demonstrated the already known importance of these genes to maintain stemness. Therefore, the presence of these genes is responsible for iPSC-derived teratomas. Similar to iPSC, P19 teratocarcinoma cell line also has characteristics of embryonic carcinoma cells and the ability to differentiate into many cell types. We separately silenced the transcription factors Oct4, Sox2, Klf4, c-Myc and Nanog in P19 cells and measured the impact of this silencing in vivo. All silenced cells generated tumors when injected in immunosuppressed mice, but silencing of Oct4, Sox2 and Klf4 generated mainly teratomas with mesoderm tissue. Our results suggest that downregulation of these transcription factors is not enough to avoid the formation of teratomas, but their silencing affect their differentiation potential.
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http://dx.doi.org/10.1016/j.bbrc.2019.07.064DOI Listing
September 2019

IgM anti-phosphorylcholine antibodies associate with senescent and IL-17+ T cells in SLE patients with a pro-inflammatory lipid profile.

Rheumatology (Oxford) 2020 02;59(2):407-417

Department of Functional Biology, Immunology Area, Faculty of Medicine, University of Oviedo.

Objective: The aim was to evaluate whether T cell subsets and the lipid profile could be linked to the cardioprotective effect of IgM anti-phosphorylcholine (PC) antibodies in SLE.

Methods: Anti-PC antibodies were quantified by ELISA in 197 patients and 99 controls and analysed in relationship to clinical features, treatments and serum lipids. Carotid atheromatosis was evaluated by ultrasonography; Th1, Th17, Treg and CD4+CD28null cells by flow cytometry; and cytokine serum levels by immunoassays, in a subgroup of 120 SLE patients and 33 controls.

Results: IgM anti-PC serum levels were reduced in SLE patients compared with controls (P < 0.001) and were associated with age (β= -0.252; P = 0.002), high-density lipoprotein (HDL; β = 0.271; P = 0.001), low-density lipoprotein (LDL; β= -0.192; P = 0.017) and glucocorticoid treatment (β= -0.201; P = 0.012), whereas the IgG-to-IgM anti-PC ratio was increased (P = 0.007) and associated with age (β = 0.194; P = 0.028) and SLEDAI (β = 0.250; P = 0.005). Also, patients with clinical or subclinical cardiovascular disease exhibited reduced IgM anti-PC levels compared with their cardiovascular disease-free counterparts, regardless of glucocorticoid usage (P = 0.001). CD4+CD28null and Th17 cells were increased in SLE patients compared with controls (P < 0.01) and correlated inversely with IgM anti-PC levels. These associations were observed in patients displaying high triglyceride or low HDL levels, even after adjusting for clinical parameters and treatments (CD4+CD28null: β = -0.455, P = 0.001; Th17: β= -0.280, P = 0.035), but not in those with a normal lipid profile. High triglyceride and low HDL profiles were related to low IgM anti-PC and Treg levels, respectively, whereas both lipid profiles were associated with inflammatory markers and cytokines.

Conclusion: The present study provides evidence for an association of IgM anti-PC antibodies with pro-atherogenic T cell subsets in SLE, with a high triglyceride/low HDL lipid profile playing a facilitating major role.
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http://dx.doi.org/10.1093/rheumatology/kez264DOI Listing
February 2020

Straining Flow Spinning of Artificial Silk Fibers: A Review.

Biomimetics (Basel) 2018 Oct 5;3(4). Epub 2018 Oct 5.

Centro de Tecnología Biomédica, Universidad Politécnica de Madrid, 28223 Pozuelo de Alarcón, Madrid, Spain.

This work summarizes the main principles and some of the most significant results of straining flow spinning (SFS), a technology developed originally by the authors of this work. The principles on which the technology is based, inspired by the natural spinning system of silkworms and spiders, are presented, as well as some of the main achievements of the technique. Among these achievements, spinning under environmentally friendly conditions, obtaining high-performance fibers, and imparting the fibers with emerging properties such as supercontraction are discussed. Consequently, SFS appears as an efficient process that may represent one of the first realizations of a biomimetic technology with a significant impact at the production level.
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http://dx.doi.org/10.3390/biomimetics3040029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6352662PMC
October 2018

Genistein increases the thermogenic program of subcutaneous WAT and increases energy expenditure in mice.

J Nutr Biochem 2019 06 29;68:59-68. Epub 2019 Mar 29.

Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico, D.F. 14080. Electronic address:

White adipose tissue (WAT) can differentiate into beige adipose tissue by the browning process. Some polyphenols, including isoflavones, particularly genistein, are suggested to increase the expression of browning markers. There is evidence that consumption of genistein can attenuate body weight gain and improve glucose tolerance and blood lipid levels. The aim of the present study was to investigate the potential mechanisms of stimulation by which genistein activates the browning of WAT. We studied the stimulation of the expression of browning markers in the following models: mice fed genistein; preadipocytes from 3 T3-L1 cells; and the stromal vascular fraction (SVF) from the inguinal adipose tissue of mice. The results indicated that genistein can stimulate the browning process by at least two mechanisms. An indirect mechanism was involved in the induction of PGC-1α/FNDC5 in skeletal muscle leading to an increase in the myokine irisin. In preadipocytes, irisin was able to increase the expression of Ucp1 and Tmem26, markers of browning, to increase energy expenditure. Interestingly, genistein was also able to activate browning by a direct mechanism. Incubation of preadipocytes with genistein increased UCP1 expression as well as some biomarkers of browning in a concentration-dependent manner, possibly via phosphorylation of AMPK. The effect of genistein was accompanied by an increase in the number of mitochondria as well as in the maximum respiration rate of the adipocytes. In conclusion, this study indicated that genistein can increase energy expenditure by stimulating the browning process directly in preadipocytes and indirectly by increasing the circulating levels of irisin.
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http://dx.doi.org/10.1016/j.jnutbio.2019.03.012DOI Listing
June 2019

Vitamin D Receptor Polymorphism and DHCR7 Contribute to the Abnormal Interplay Between Vitamin D and Lipid Profile in Rheumatoid Arthritis.

Sci Rep 2019 02 22;9(1):2546. Epub 2019 Feb 22.

Area of Immunology, Department of Functional Biology, University of Oviedo, Oviedo, Spain.

Emerging evidence suggests a role for 7-dehydrocholesterol reductase (DHCR7) in the crosstalk between cholesterol and vitamin D. Our aim was to evaluate the impact of vitamin D-related polymorphisms and DHCR7 levels in the association between vitamin D deficiency and altered lipid profile in rheumatoid arthritis (RA). Serum 25(OH)-vitamin D, DHCR7 levels and vitamin D-related polymorphisms (VDR-rs2228570, CYP27A1-rs933994, CYP2R1-rs10741657 and DHCR7-rs12785878) were analyzed in 211 RA patients,94 controls and in a prospective cohort of 13 RA patients undergoing TNFα-blockade. Vitamin D was decreased in RA (p < 0.001), correlated to HDL-cholesterol (r = 0.217, p < 0.001) and total-/HDL-cholesterol ratio (r = -0.227, p = 0.004). These correlations were restricted to the VDR-rs2228570 status. Vitamin D deficiency was associated with lower HDL-cholesterol (p = 0.028), higher tender (p = 0.005) and swollen (p = 0.002) joint counts, higher DAS28 (p = 0.018) and HAQ (p = 0.024) in AG/AA-patients but not in their GG-counterparts. The associations among DHCR7, vitamin D and lipid profile followed a seasonal pattern, decreased DHCR7 (p = 0.008) and vitamin D (p < 0.001) and increased total-cholesterol (p = 0.025) being found in winter/spring. Increasing vitamin D upon TNFα-blockade paralleled RA clinical improvement (r = -0.610, p = 0.027) and DHCR7 elevation (r = 0.766, p = 0.002). In conclusion, vitamin D-related polymorphisms and DHCR7 are pivotal to understand the complex, seasonal associations between vitamin D and lipid profile in RA.
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http://dx.doi.org/10.1038/s41598-019-38756-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385268PMC
February 2019

IRF4 and IRGs Delineate Clinically Relevant Gene Expression Signatures in Systemic Lupus Erythematosus and Rheumatoid Arthritis.

Front Immunol 2018 7;9:3085. Epub 2019 Jan 7.

Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.

Overactivation of the type I interferon (IFN) signature has been observed in several systemic autoimmune conditions, such as Systemic Lupus Erythematosus (SLE) or Rheumatoid Arthritis (RA). Impaired control of Interferon-Responding Genes (IRGs) expression by their regulatory mechanisms, including Interferon Regulatory Factors (IRFs), may underlie these findings and it may explain the heterogeneity observed among these conditions. In the present study we aimed to evaluate the associations between IRF4 gene expression and those of IRGs in SLE and RA patients to gain insight about its links with the IFN signature as well as to explore the potential clinical relevance of these associations. The gene expression of IRF4 and IRGs (IFI44, IFI44L, IFI6, and MX1) in peripheral blood was analyzed in 75 SLE patients, 98 RA patients, and 28 healthy controls. A group of 13 biological-naïve RA patients was prospectively followed upon TNFα-blockade. The associations among IRF4 and IRGs were evaluated by principal component analyses (PCA), correlations and network analyses. Publicly available datasets were used for replication. A broad activation of IRGs was observed in autoimmune patients, although certain heterogeneity can be distinguished, whereas IRF4 was only upregulated in RA. The differential expression of IRF4 in RA was then confirmed in publicly available gene expression datasets. PCA revealed different associations among IRF4 and IRGs in each condition, which was later confirmed by correlation and network analyses. Cluster analysis identified 3 gene expression signatures on the basis of IRF4 and IRGs expression which were differentially used by SLE and RA patients. Cluster III was associated with markers of disease severity in SLE patients. Cluster II, hallmarked by IRF4 upregulation, was linked to clinical stage and mild disease course in RA. TNFα-blockade led to changes in the association between IRF4 and IRGs, whereas increasing IRF4 expression was associated with a good clinical outcome in RA. The differential expression of IRF4 and IRGs observed in SLE and RA can delineate gene expression signatures associated with clinical features and treatment outcomes. These results support a clinically-relevant phenomenon of shaping of the IFN signature by IRF4 in autoimmune patients.
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http://dx.doi.org/10.3389/fimmu.2018.03085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330328PMC
October 2019

Earlier puberty in boys with type 1 diabetes mellitus compared to a simultaneously recruited group of control adolescents.

Pediatr Diabetes 2019 03 8;20(2):197-201. Epub 2019 Jan 8.

Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile.

Background: Recent studies have suggested that there is an earlier age of onset of puberty in healthy boys. However, no study has determined the age of pubertal development in boys with type 1 diabetes (T1D) and compared the results with a simultaneously recruited group of healthy children.

Objective: The aim of this study was to evaluate the age of pubertal events in boys with TD1 and determine whether the duration of diabetes, metabolic control or insulin dose are associated with the age of puberty in boys with T1D.

Methods: Boys aged 7 to 19 years with T1D (n = 148, age 12.9 ± 3.0 years) and healthy boys recruited from schools (n = 388 controls, age 12.8 ± 2.2 years) were studied. A pediatric endocrinologist evaluated pubertal development.

Results: Boys at genital Tanner stage 2 and the final stages of puberty (genital Tanner 4 and 5) were younger than the control group (P = 0.005, P = 0.003, and P = 0.015, respectively). Both groups of boys had a similar age of pubic Tanner stage development. There were no cases of pubertal delay observed in the T1D cohort. There was no association observed between metabolic control with pubertal timing. T1D adolescents had lower height-SDS than the C group at the final stages of puberty.

Conclusions: Boys with T1D who are treated with modern insulin therapy appear to have an earlier age of onset and an earlier age of final pubertal events than a simultaneously studied group of healthy children. These data suggest that pubertal delay is not a frequent problem for male T1D patients.
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http://dx.doi.org/10.1111/pedi.12811DOI Listing
March 2019

Effects of ALAD genotype on the relationship between lead exposure and anthropometry in a Cohort of Mexican children.

Environ Res 2019 03 5;170:65-72. Epub 2018 Dec 5.

Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, State University of New York at Buffalo, Buffalo, NY, USA. Electronic address:

Objectives: Lead exposure is associated with children's growth, but this relationship may depend on the presence of susceptibility factors, including genetic variation. Blood lead levels (BLL) differ by ALAD (aminolevulinic acid dehydratase) genotype. We investigated the association between BLL and growth in Mexican first-graders with different ALAD genotypes.

Methods: Children between the ages of 6-8 years (n = 602) attending first grade in schools within the vicinity of a metal foundry in Torreón, Mexico were enrolled into a randomized controlled trial (RCT) testing the efficacy of iron and/or zinc supplementation on blood lead levels (BLL) and cognition. BLL and anthropometry were assessed at baseline (height, height-for-age z-score (HAZ), knee height, head circumference), after 6 (head circumference) and 12 months (height, HAZ, knee height). Children with ALAD and ALAD were compared. The study sample included 538 and 470 participants who had complete data at baseline and follow-up, respectively. Separate multivariable linear regression models adjusted for covariates were used to test the association between BLL at baseline and each anthropometric measure. Covariates included age, sex, hemoglobin, crowding, and maternal education. BLL x ALAD genotype interaction term was tested.

Results: Median BLL (10.1 μg/dL) did not differ by ALAD genotype. After covariate adjustment, baseline BLL was inversely associated with baseline height, HAZ, and knee height. The association (β [95% CI]) between BLL and baseline height (-0.38[-0.68, -0.09]), HAZ (-0.07[-0.12, -0.02]) and knee height (-0.14[-0.25, -0.02]), was somewhat stronger in children with ALAD than ALAD (-0.09[-0.16, -0.02], -0.02[-0.03, -0.004] and -0.04[-0.06, -0.01], respectively). No associations between BLL and growth at 6 or 12 months were detected irrespective of ALAD genotype.

Conclusions: BLL was adversely associated with anthropometric measures among Mexican children. ALAD genotype may be a susceptibility factor for the effects of lead on child growth.
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http://dx.doi.org/10.1016/j.envres.2018.12.003DOI Listing
March 2019

Ovarian Function in Adolescents Conceived Using Assisted Reproductive Technologies.

J Pediatr Adolesc Gynecol 2019 Apr 28;32(2):117-121. Epub 2018 Nov 28.

Institute of Maternal and Child Research, School of Medicine, University of Chile, Santiago, Chile.

Study Objective: To compare ovarian function between adolescents conceived using assisted reproductive technology (AcART) and adolescents who were conceived spontaneously (AcSP).

Design: Multicenter study of ovarian function in AcART because of male or tubal infertility.

Setting: University Hospital.

Participants: We evaluated 22 AcART and 53 AcSP at 1-2 years after menarche. The participants were born at term (≥37 weeks of gestation) with normal birth weights (≥2500 g) from singleton pregnancies.

Interventions: None.

Main Outcome Measures: Differences in ovulation, reproductive hormones, and ovarian morphology.

Results: AcART had an older age of menarche than that of AcSP, even after adjusting for maternal age at menarche, gestational age, and birth weight (P = .027). AcART had lower incidence of ovulation (P = .021) and higher luteinizing hormone serum levels (P = .01) than those of AcSP. The incidence of oligomenorrhea and the cycle length were similar between AcART and AcSP. AcART had levels of anti-Müllerian hormone, inhibin B, follicle-stimulating hormone, estradiol, and androgens similar to those of AcSP. The ovarian morphology, ovarian volume, and follicle counts were similar in both groups.

Conclusion: AcART had later menarche, lower ovulation rates, and higher luteinizing hormone levels than those of AcSP. Future studies should investigate whether these findings are indicative of a risk of ovarian dysfunction later in life for AcART.
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http://dx.doi.org/10.1016/j.jpag.2018.11.008DOI Listing
April 2019

The Effect of Peer-Group Argumentative Dialogue on Delayed Gains in Scientific Content Knowledge.

New Dir Child Adolesc Dev 2018 Dec 29;2018(162):67-87. Epub 2018 Oct 29.

Universidad Alberto Hurtado.

Experimental evidence has shown the effect of peer-group argumentation on scientific concept development. However, questions regarding how and why it happens remain. The aim of this study is to contribute, with experimental evidence gathered in naturalistic settings (classrooms), to the understanding of the relationship between peer-group argumentation and content knowledge learning, exploring the role that individual argumentative skills play. In total, sixty-one fourth-grade students (aged 9-10 years) participated in the study (thirty-nine female). One teacher was invited to teach a thematic unit (Forces), with lesson plans especially developed to foster argumentation in the classroom. The second teacher taught as usual. Students' conceptual understanding and argumentative skills were evaluated individually, both before and after the lessons. Although there were no differences in the immediate post-test scores between groups (after controlling for pre-test), the intervention group showed significantly higher scores in delayed post-tests. Regression analyses showed that the ratio of argumentative utterances per minute of group work predicted students' scores in delayed post-test disciplinary content knowledge after controlling for initial levels of learning. Argumentation skill gains did not impact learning, but initial levels of argumentation skills predicted delayed scientific content knowledge post-test.
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http://dx.doi.org/10.1002/cad.20263DOI Listing
December 2018

Profiling of B-Cell Factors and Their Decoy Receptors in Rheumatoid Arthritis: Association With Clinical Features and Treatment Outcomes.

Front Immunol 2018 11;9:2351. Epub 2018 Oct 11.

Area of Immunology, Department of Functional Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.

B-cell activation is pivotal in rheumatoid arthritis (RA) pathogenesis and represents a relevant therapeutic target. The main aim of this study was to characterize the profiles of B-cell factors and their decoy receptors in RA and evaluate their clinical relevance. sBLyS, sAPRIL, sBCMA, sTACI, sBLyS-R, and several cytokines' serum levels were measured by immunoassays in 104 RA patients and 33 healthy controls (HC). An additional group of 42 systemic lupus erythematosus (SLE) patients were enrolled as disease controls. Whole blood IFI44, IFI44L, IFI6, and MX1 gene expression was measured and averaged into an IFN-score. BLyS membrane expression (mBLyS) was assessed on blood cell subsets by flow cytometry. increased sAPRIL and sBCMA levels were found in RA, whereas BLyS was elevated in very early RA (VERA). No differences were observed for sTACI and sBLyS-R. An increased sBLyS/sBLyS-R ratio was associated with poor clinical outcome at 6 and 12 months in VERA, whereas a positive association with disease activity was observed in established disease. Increased mBLyS expression was found on monocytes, mDCs, neutrophils and B-cells in RA, to a similar extent that in SLE patients. Cluster analysis identified a specific B-cell factors profile overrepresented in RA and associated with autoantibodies, elevated proinflammatory cytokines (IFNα, MIP1α, TNFα, IL-37, and GM-CSF) and increased type-I IFN signature. Increasing sBCMA and sBLyS serum levels upon treatment and mBLyS expression at baseline on monocytes and mDCs, but not B-cells, were associated with poor clinical outcome upon TNFα-blockade. profound and complex alterations of soluble and membrane-bound B-cell factors are observed in RA associated with clinical outcomes, thus supporting its applicability to guide patient stratification along disease course.
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http://dx.doi.org/10.3389/fimmu.2018.02351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194314PMC
October 2019

Could Fecal Phenylacetic and Phenylpropionic Acids Be Used as Indicators of Health Status?

J Agric Food Chem 2018 Oct 28;66(40):10438-10446. Epub 2018 Sep 28.

Department of Functional Biology , University of Oviedo , C/Julián Clavería s/n Oviedo , 33006 Asturias , Spain.

Although most of the health effects attributed to polyphenols may be linked to their phenolic-derived metabolites, the role of the intestinal derived-phenolics in human health is still far from being well understood. We determined the profile of fecal phenolic-derived metabolites, microbiota, biomarkers of oxidative stress and inflammation, and daily intake of bioactive compounds in 71 elderly volunteers. Phenylacetic and phenylpropionic acids were the main phenolic metabolites present in feces. From them, phenylacetic acid was related with a more pro-oxidant and immune stimulated status, and both were negatively associated with fecal propionate, whereas phenylpropionic acid was directly related with the fecal concentration of acetate. Moreover, phenylacetic acid was negatively associated with the Bacteroides group and Clostridium cluster XIVa and positively with Lactobacillus. These results provide a rationale to explore the potential of fecal microbial phenolic-derived metabolites as possible biomarkers of health status in future studies focused on the elderly population.
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http://dx.doi.org/10.1021/acs.jafc.8b04102DOI Listing
October 2018

The role of gut microbiota in lupus: what we know in 2018?

Expert Rev Clin Immunol 2018 10 8;14(10):787-792. Epub 2018 Sep 8.

a Department of Microbiology and Biochemistry , Instituto de Productos Lácteos de Asturias, Consejo Superior de Investigaciones Científicas , Villaviciosa , Asturias , Spain.

Introduction: The role of the human intestinal microbiota in the maintenance of a healthy physiological condition, as well as its relation to the development of disease, remains to be clarified. Current evidence suggests that intestinal microbes could be involved in the initiation and amplification of autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus (SLE). Despite recent progress in understanding how these microbes influence the pathophysiology of lupus, studies are still limited. Areas covered: In this review, we have tried to summarize the most relevant findings that have contributed to our understanding of the links between the human intestinal microbiota and the development of lupus. We also describe the potential role of individual microbial players in the physiology of lupus, and how they can shape relevant immune responses. Expert commentary: Culture-independent techniques based on massive sequencing represent a powerful tool to unravel the biological activity of gut microbes. Current data demonstrates that, depending on the pattern of intestinal microorganisms or the presence of specific bacteria, different responses related to lupus physiology can be triggered. Fecal microbiota transplantation, live biotherapeutics, or dietary interventions targeting the microbiota will likely become a treatment for SLE.
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http://dx.doi.org/10.1080/1744666X.2018.1519395DOI Listing
October 2018

Early conversion of pediatric kidney transplant patients to everolimus with reduced tacrolimus and steroid elimination: Results of a randomized trial.

Am J Transplant 2019 03 18;19(3):811-822. Epub 2018 Oct 18.

Novartis Pharma AG, Basel, Switzerland.

In a 12-month, multicenter, open-label study, 106 children were randomized at 4 to 6 weeks after kidney transplantation to switch to everolimus with reduced TAC (EVR/rTAC) and steroid elimination from month 5 posttransplant or to continue standard tacrolimus with mycophenolate mofetil (sTAC/MMF) and steroids. The cumulative incidence of a co-primary efficacy end point (biopsy-proven acute rejection [BPAR], graft loss, or death from randomization to month 12) was 10.3% with EVR/rTAC and 5.8% with sTAC/MMF (difference 4.4%; P = .417). BPAR occurred in 9.6% and 5.6% of patients, respectively. Patient and renal allograft survival were 100%. The co-primary end point of mean estimated glomerular filtration rate at month 12 was 76.2 mL/min/1.73 m with EVR/rTAC and 72.5 mL/min/1.73 m for sTAC/MMF (difference 3.8 mL/min/1.73m ; P = .49). One EVR/rTAC patient developed posttransplant lymphoproliferative disease. Longitudinal growth and sexual maturation were equivalent between groups. The randomized drug regimen was discontinued in 34.6% and 13% of patients in the EVR/rTAC and sTAC/MMF groups, respectively (P = .024), and discontinued due to adverse events/infections in 25.0% and 11.1% of patients (P = .062). In conclusion, early conversion of pediatric kidney transplant patients from TAC, MMF, and steroids to EVR/rTAC and steroid withdrawal maintains immunosuppressive efficacy and preserves renal function.
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http://dx.doi.org/10.1111/ajt.15081DOI Listing
March 2019

Long-Term Genistein Consumption Modifies Gut Microbiota, Improving Glucose Metabolism, Metabolic Endotoxemia, and Cognitive Function in Mice Fed a High-Fat Diet.

Mol Nutr Food Res 2018 08 29;62(16):e1800313. Epub 2018 Jul 29.

Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga No. 15, Belisario Dominguez Sección XVI, 14080, Ciudad de México, México.

Scope: The aim of this study is to assess whether the long-term addition of genistein to a high-fat diet can ameliorate the metabolic and the cognitive alterations and whether the changes can be associated with modifications to the gut microbiota.

Methods And Results: C57/BL6 mice were fed either a control (C) diet, a high-fat (HF) diet, or a high-fat diet containing genistein (HFG) for 6 months. During the study, indirect calorimetry, IP glucose tolerance tests, and behavioral analyses were performed. At the end of the study, plasma, liver, brain, and fecal samples were collected. The results showed that mice fed the HFG diet gained less weight, had lower serum triglycerides, and an improvement in glucose tolerance than those fed an HF diet. Mice fed the HFG diet also modified the gut microbiota that was associated with lower circulating levels of lipopolysaccharide (LPS) and reduced expression of pro-inflammatory cytokines in the liver compared to those fed HF diet. The reduction in LPS by the consumption of genistein was accompanied by an improvement of the cognitive function.

Conclusions: Genistein is able to regulate the gut microbiota, reducing metabolic endotoxemia and decreasing the neuroinflammatory response despite the consumption of a HF diet.
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http://dx.doi.org/10.1002/mnfr.201800313DOI Listing
August 2018

Low Cost Photonic Sensor for in-Line Oil Quality Monitoring: Methodological Development Process towards Uncertainty Mitigation.

Sensors (Basel) 2018 Jun 22;18(7). Epub 2018 Jun 22.

Mondragon Unibertsitatea, 20600 Eibar, Spain.

Lubricant and hydraulic fluid ageing impacts the performance of the machines, gears, transmissions or automatisms where they are being used. This manuscript describes the work accomplished for bringing an innovative measurement concept for analysing the physical- chemical properties of these fluids, to a real industrial product ready to be integrated into different industrial equipment. The steps taken to deal with uncertainties and evolving requirements while progressing in the sensor development are described, covering the stages of theoretical formulation of the problem, optical and fluidic simulations, sensor prototype development and tests. The sensor working principle is based on a combination of transmittance and diffuse reflectance photonic inspection of the fluid sample that is collected in a microcavity through a standard hydraulic fitting. Photonics, electronics, micro-mechanics, fluidics, data processing and analysis has been merged with a deep knowledge in the lubricant degradation process to develop a sensor solution that is able to measure the Oil Degradation Index, Oil Oxidation, Acid Number, Ruler and Membrane Patch Colorimetry data from an inservice lubricating oil sample. The photonic micro sensor presented here offers a powerful tool that operates directly immersed in the fluid, at an economic cost and compacted size for inline oil degradation monitoring.
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http://dx.doi.org/10.3390/s18072015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069071PMC
June 2018