Publications by authors named "Antonio García"

404 Publications

Beyond words: From jaguar population trends to conservation and public policy in Mexico.

PLoS One 2021 6;16(10):e0255555. Epub 2021 Oct 6.

Laboratorio de Ecología y Conservación de Fauna Silvestre, Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, Ciudad de México, México.

The jaguar (Panthera onca) is one of the most threatened carnivores in the Americas. Despite a long history of research on this charismatic species, to date there have been few systematic efforts to assess its population size and status in most countries across its distribution range. We present here the results of the two National Jaguar Surveys for Mexico, the first national censuses in any country within the species distribution. We estimated jaguar densities from field data collected at 13 localities in 2008-2010 (2010 hereafter) and 11 localities in 2016-2018 (2018 hereafter). We used the 2010 census results as the basis to develop a National Jaguar Conservation Strategy that identified critical issues for jaguar conservation in Mexico. We worked with the Mexican government to implement the conservation strategy and then evaluated its effectivity. To compare the 2010 and 2018 results, we estimated the amount of jaguar-suitable habitat in the entire country based on an ecological niche model for both periods. Suitable jaguar habitat covered ~267,063 km2 (13.9% of the country's territory) in 2010 and ~ 288,890 km2 (~14.8% of the country's territory) in 2018. Using the most conservative density values for each priority region, we estimated jaguar densities for both the high and low suitable habitats. The total jaguar population was estimated in ~4,000 individuals for 2010 census and ~4,800 for the 2018 census. The Yucatan Peninsula was the region with the largest population, around 2000 jaguars, in both censuses. Our promising results indicate that the actions we proposed in the National Jaguar Conservation Strategy, some of which have been implemented working together with the Federal Government, other NGO's, and land owners, are improving jaguar conservation in Mexico. The continuation of surveys and monitoring programs of the jaguar populations in Mexico will provide accurate information to design and implement effective, science-based conservation measures to try to ensure that robust jaguar populations remain a permanent fixture of Mexico's natural heritage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255555PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8494370PMC
October 2021

Intracellular calcium and inflammatory markers, mediated by purinergic stimulation, are differentially regulated in monocytes of patients with major depressive disorder.

Neurosci Lett 2021 Oct 2;765:136275. Epub 2021 Oct 2.

Instituto Teófilo Hernando de I+D del Medicamento, Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain; Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain; Instituto de Investigación Sanitaria del Hospital Universitario de la Princesa, (IIS-IP)., Madrid, Spain. Electronic address:

The P2X7 receptor (P2X7R) is a ligand-gated ion channel that is being recognized as a major player in neuropsychiatric disorders such as Major Depressive Disorder (MDD). P2X7R activation is triggered by high extracellular ATP concentrations, leading to channel opening and inducing an increase in cytosolic calcium concentration ([Ca]), that activates the inflammatory pathway. Those receptors are expressed not only in CNS cells but also in peripheral blood cells, where they are activated in response to inflammatory molecules such as bacterial lipopolysaccharide (LPS). LPS induced-tissue damage promotes an elevation of extracellular ATP, triggering the NRLP3-inflammasome assembly and activation that, sequentially, induces caspase-1 cleavage and IL-1β processing and secretion. In this context, we attempt to understand the role of P2X7R in [Ca] homeostasis regulation, inflammasome expression and its pharmacological modulation in MDD. For this purpose, monocytes were isolated from peripheral blood of MDD patients and [Ca] was monitored with the intracellular probe Fura-2. Our results point out to P2X7R as the responsible of the Ca imbalance, as well as TNF-α-dependent activation of caspase-1 in MDD patients. In addition, P2X7R blockade with its specific antagonist, JNJ-47965567, reduces the Ca entry upon Bz-ATP exposure. Altogether, our results point that MDD patients have both, Ca homeostasis alteration and an inflammatory status, which promote an independent-inflammasome activation of caspase-1. Therefore, we propose the pharmacological modulation of P2X7R as a therapeutic approach against MDD symptoms.
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http://dx.doi.org/10.1016/j.neulet.2021.136275DOI Listing
October 2021

QTL mapping for bioenergy traits in sweet sorghum recombinant inbred lines.

G3 (Bethesda) 2021 Sep 14. Epub 2021 Sep 14.

Embrapa Maize and Sorghum, Sete Lagoas, MG, Brazil.

During the past decade, sweet sorghum (Sorghum bicolor Moench L.) has shown great potential for bioenergy production, especially biofuels. In this study, 223 recombinant inbred lines (RILs) derived from a cross between two sweet sorghum lines (Brandes × Wray) were evaluated in three trials. Single nucleotide polymorphisms (SNPs) derived from genotyping-by-sequencing of 272 RILs were used to build a high-density genetic map comprising 3,767 SNPs spanning 1,368.83 cM. Multi-trait multiple interval mapping (MT-MIM) was carried out to map quantitative trait loci (QTL) for eight bioenergy traits. A total of 33 QTLs were identified for flowering time, plant height, total soluble solids and sucrose (five QTLs each), fibers (four QTLs), and fresh biomass yield, juice extraction yield, and reducing sugars (three QTLs each). QTL hotspots were found on chromosomes 1, 3, 6, 9, and 10, in addition to other QTLs detected on chromosomes 4 and 8. We observed that 14 out of the 33 mapped QTLs were found in all three trials. Upon further development and validation in other crosses, the results provided by the present study have a great potential to be used in marker-assisted selection in sorghum breeding programs for biofuel production.
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http://dx.doi.org/10.1093/g3journal/jkab314DOI Listing
September 2021

The Enhancement of Enargite Dissolution by Sodium Hypochlorite in Ammoniacal Solutions.

Materials (Basel) 2021 Aug 12;14(16). Epub 2021 Aug 12.

Laboratorio de Investigación de Minerales Sulfurados, Departamento de Ingeniería Metalúrgica y Minas, Universidad Católica del Norte, Avenida Angamos 0610, Antofagasta 1270709, Chile.

The dissolution of both copper and arsenic from a copper concentrate was investigated in oxidative ammonia/ammonium solutions at moderate temperatures and atmospheric pressure. The main parameters studied were temperature, pH, concentrations of different ammonia salts, the presence of sodium hypochlorite, pretreatment with sodium chloride, and curing period. In all ammoniacal solutions studied, increasing the temperature enhanced the dissolution of copper, but the dissolution of arsenic remained marginal. Mixing the copper concentrate with sodium chloride and leaving it to rest for 72 h before leaching in ammoniacal solutions significantly increased the dissolution of copper and slightly increased the dissolution of arsenic from the concentrate. A maximum of 35% of Cu and 3.3% of As were extracted when ammonium carbonate was used as the lixiviant. The results show relatively rapid dissolution of the concentrate with the addition of sodium hypochlorite in ammonium carbonate solution, achieving a dissolution of up to 50% and 25% of copper and arsenic, respectively. A copper dissolution with a non-linear regression model was proposed, considering the effect of NaClO and NHCl at 25 °C. These findings highlight the importance of using the correct anionic ligands for the ammonium ions and temperature to obtain a high dissolution of copper or arsenic. The results also showed that the curing time of the packed bed before the commencement of leaching appeared to be an important parameter to enhance the dissolution of copper and leave the arsenic in the residues.
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http://dx.doi.org/10.3390/ma14164529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399718PMC
August 2021

Progressive Mitochondrial SOD1 Accumulation Causes Severe Structural, Metabolic and Functional Aberrations through OPA1 Down-Regulation in a Mouse Model of Amyotrophic Lateral Sclerosis.

Int J Mol Sci 2021 Jul 30;22(15). Epub 2021 Jul 30.

Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain.

In recent years, the "non-autonomous motor neuron death" hypothesis has become more consolidated behind amyotrophic lateral sclerosis (ALS). It postulates that cells other than motor neurons participate in the pathology. In fact, the involvement of the autonomic nervous system is fundamental since patients die of sudden death when they become unable to compensate for cardiorespiratory arrest. Mitochondria are thought to play a fundamental role in the physiopathology of ALS, as they are compromised in multiple ALS models in different cell types, and it also occurs in other neurodegenerative diseases. Our study aimed to uncover mitochondrial alterations in the sympathoadrenal system of a mouse model of ALS, from a structural, bioenergetic and functional perspective during disease instauration. We studied the adrenal chromaffin cell from mutant SOD1 mouse at pre-symptomatic and symptomatic stages. The mitochondrial accumulation of the mutated SOD1 protein and the down-regulation of optic atrophy protein-1 (OPA1) provoke mitochondrial ultrastructure alterations prior to the onset of clinical symptoms. These changes affect mitochondrial fusion dynamics, triggering mitochondrial maturation impairment and cristae swelling, with increased size of cristae junctions. The functional consequences are a loss of mitochondrial membrane potential and changes in the bioenergetics profile, with reduced maximal respiration and spare respiratory capacity of mitochondria, as well as enhanced production of reactive oxygen species. This study identifies mitochondrial dynamics regulator OPA1 as an interesting therapeutic target in ALS. Additionally, our findings in the adrenal medulla gland from presymptomatic stages highlight the relevance of sympathetic impairment in this disease. Specifically, we show new SOD1 toxicity pathways affecting cellular energy metabolism in non-motor neurons, which offer a possible link between cell specific metabolic phenotype and the progression of ALS.
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http://dx.doi.org/10.3390/ijms22158194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8347639PMC
July 2021

Management of asthma in childhood: study protocol of a systematic evidence update by the Paediatric Asthma in Real Life (PeARL) Think Tank.

BMJ Open 2021 07 2;11(7):e048338. Epub 2021 Jul 2.

Department of Paediatrics, University of Turku, Turku, Finland.

Introduction: Clinical recommendations for childhood asthma are often based on data extrapolated from studies conducted in adults, despite significant differences in mechanisms and response to treatments. The Paediatric Asthma in Real Life (PeARL) Think Tank aspires to develop recommendations based on the best available evidence from studies in children. An overview of systematic reviews (SRs) on paediatric asthma maintenance management and an SR of treatments for acute asthma attacks in children, requiring an emergency presentation with/without hospital admission will be conducted.

Methods And Analysis: Standard methodology recommended by Cochrane will be followed. Maintenance pharmacotherapy of childhood asthma will be evaluated in an overview of SRs published after 2005 and including clinical trials or real-life studies. For evaluating pharmacotherapy of acute asthma attacks leading to an emergency presentation with/without hospital admission, we opted to conduct de novo synthesis in the absence of adequate up-to-date published SRs. For the SR of acute asthma pharmacotherapy, we will consider eligible SRs, clinical trials or real-life studies without time restrictions. Our evidence updates will be based on broad searches of Pubmed/Medline and the Cochrane Library. We will use A MeaSurement Tool to Assess systematic Reviews, V.2, Cochrane risk of bias 2 and REal Life EVidence AssessmeNt Tool to evaluate the methodological quality of SRs, controlled clinical trials and real-life studies, respectively.Next, we will further assess interventions for acute severe asthma attacks with positive clinical results in meta-analyses. We will include both controlled clinical trials and observational studies and will assess their quality using the previously mentioned tools. We will employ random effect models for conducting meta-analyses, and Grading of Recommendations Assessment, Development and Evaluation methodology to assess certainty in the body of evidence.

Ethics And Dissemination: Ethics approval is not required for SRs. Our findings will be published in peer reviewed journals and will inform clinical recommendations being developed by the PeARL Think Tank.

Prospero Registration Numbers: CRD42020132990, CRD42020171624.
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http://dx.doi.org/10.1136/bmjopen-2020-048338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8256789PMC
July 2021

Synthetic biology approaches to actinomycete strain improvement.

FEMS Microbiol Lett 2021 06;368(10)

Department of Chemistry, Manchester Institute of Biotechnology, Manchester Synthetic Biology Research Centre SYNBIOCHEM, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK.

Their biochemical versatility and biotechnological importance make actinomycete bacteria attractive targets for ambitious genetic engineering using the toolkit of synthetic biology. But their complex biology also poses unique challenges. This mini review discusses some of the recent advances in synthetic biology approaches from an actinomycete perspective and presents examples of their application to the rational improvement of industrially relevant strains.
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http://dx.doi.org/10.1093/femsle/fnab060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195692PMC
June 2021

One hundred years from Otto Loewi experiment, a dream that revolutionized our view of neurotransmission.

Pflugers Arch 2021 06 27;473(6):977-981. Epub 2021 May 27.

Departamento de Farmacología y Terapéutica, Instituto Fundación Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.

One hundred years ago, a 4-page paper published in the Pflüger's Archiv fűr die Gesamte Physiologie des Menschen und der Tiere dramatically changed our view on synaptic transmission. The paper reported an ingenious, yet straightforward experiment made by Professor Otto Loewi in 1920 and published in 1921, which constitutes the first clear-cut proof for the chemical nature of transmission of the nerve impulse from nerve to muscle. The approach to this experiment was, however, tortuous and long.
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http://dx.doi.org/10.1007/s00424-021-02580-9DOI Listing
June 2021

Ia afferent fibers in peripheral nerve disorders: Evidence for divergent vulnerability.

Clin Neurophysiol Pract 2021 1;6:133-134. Epub 2021 Apr 1.

Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", University of Cantabria, Santander, Spain.

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http://dx.doi.org/10.1016/j.cnp.2021.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091171PMC
April 2021

Angular Leaf Spot Resistance Associated With Different Plant Growth Stages in Common Bean.

Front Plant Sci 2021 13;12:647043. Epub 2021 Apr 13.

Centro de Pesquisa em Recursos Genéticos Vegetais, Instituto Agronômico - IAC, Campinas, Brazil.

Angular leaf spot (ALS) is a disease that causes major yield losses in the common bean crop. Studies based on different isolates and populations have already been carried out to elucidate the genetic mechanisms of resistance to ALS. However, understanding of the interaction of this resistance with the reproductive stages of common bean is lacking. The aim of the present study was to identify ALS resistance at different plant growth stages (PGS) by association and linkage mapping approaches. An BCF inter-gene pool cross population (AND 277 × IAC-Milênio - AM population) profiled with 1,091 SNPs from genotyping by sequencing (GBS) was used for linkage mapping, and a carioca diversity panel (CDP) genotyped by 5,398 SNPs from BeadChip assay technology was used for association mapping. Both populations were evaluated for ALS resistance at the V2 and V3 PGSs (controlled conditions) and R8 PGS (field conditions). Different QTL (quantitative trait ) were detected for the three PGSs and both populations, showing a different quantitative profile of the disease at different plant growth stages. For the three PGS, multiple interval mapping (MIM) identified seven significant QTL, and the Genome-wide association study (GWAS) identified fourteen associate SNPs. Several validated regions of previous studies, and , , and , among the 5 of greatest effects reported in the literature, were detected in the CDP. The AND 277 cultivar contained both the and the QTL, which is reported for the first time in the descendant cultivar CAL143 as ALS10.1. The novel QTL named ALS11.1 was located at the beginning of chromosome Pv11. Gene annotation revealed several putative resistance genes involved in the ALS response at the three PGSs, and with the markers and identified, new specific molecular markers can be developed, representing a powerful tool for common bean crop improvement and for gain in ALS resistance.
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http://dx.doi.org/10.3389/fpls.2021.647043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078856PMC
April 2021

Transition from Pediatric to Adult Care for Transgender Youth: A Qualitative Study of Patient, Parent, and Provider Perspectives.

LGBT Health 2021 May-Jun;8(4):281-289. Epub 2021 Apr 8.

Children's Health System of Texas, Dallas, Texas, USA.

No information exists on the needs of transgender youth transitioning their gender-affirming health care from pediatric to adult settings. We obtained perspectives of transgender youth, their parents, and providers, and aimed to identify barriers and unmet needs during the transition of care. Five online focus groups were conducted between February and March 2019 with separate groups for transgender youth 13-17 and 18-21 years old; parents of transgender youth 13-17 and 18-21 years old; and gender-affirming health care providers. Thematic analysis of transcripts was conducted by two researchers. Pooled Cohen's was 0.83, indicating excellent inter-rater reliability. Sixty-six participants (29 youth, 27 parents, and 10 providers) identified 10 themes. Themes related to barriers to transition included access and insurance challenges, patient readiness and hesitancy to transfer care, and multidisciplinary-system inefficiencies. Themes related to improving transition focused on prioritizing referrals from trusted sources, establishing gradual patient independence, aligning gender transition goals, and setting impetus for transferring care. Successful health care transition for transgender youth must consider the intricacies of a complex medical system and challenges that they pose to adolescents' perceived abilities to independently manage health care and willingness to prepare transfer of care. Given that patients, parents, and providers assume important roles during the process, each can uniquely contribute toward ensuring a smooth transition. Efforts to improve this process should focus on enhancing collaboration between clinics and families through crowdsourcing resources, continued verification of health goals, supporting greater patient autonomy, and delineating an explicit timeline for transition.
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http://dx.doi.org/10.1089/lgbt.2020.0487DOI Listing
August 2021

Construction of a High-Density Genetic Map of (Berg.) Burret, an Outcrossing Species, Based on Two Connected Mapping Populations.

Front Plant Sci 2021 23;12:626811. Epub 2021 Feb 23.

Laboratório de Genética Estatística, Departamento de Genética, Escola Superior de Agricultura "Luiz de Queiroz", Universidade de São Paulo, Piracicaba, Brazil.

, known as feijoa or pineapple guava, is a diploid, (2 = 2 = 22) outcrossing fruit tree species native to Uruguay and Brazil. The species stands out for its highly aromatic fruits, with nutraceutical and therapeutic value. Despite its promising agronomical value, genetic studies on this species are limited. Linkage genetic maps are valuable tools for genetic and genomic studies, and constitute essential tools in breeding programs to support the development of molecular breeding strategies. A high-density composite genetic linkage map of was constructed using two genetically connected populations: H5 (TCO × BR, = 160) and H6 (TCO × DP, = 184). Genotyping by sequencing (GBS) approach was successfully applied for developing single nucleotide polymorphism (SNP) markers. A total of 4,921 SNP markers were identified using the reference genome of the closely related species , whereas other 4,656 SNPs were discovered using a pipeline. The individual H5 and H6 maps comprised 1,236 and 1,302 markers distributed over the expected 11 linkage groups, respectively. These two maps spanned a map length of 1,593 and 1,572 cM, with an average inter-marker distance of 1.29 and 1.21 cM, respectively. A large proportion of markers were common to both maps and showed a high degree of collinearity. The composite map consisted of 1,897 SNPs markers with a total map length of 1,314 cM and an average inter-marker distance of 0.69. A novel approach for the construction of composite maps where the meiosis information of individuals of two connected populations is captured in a single estimator is described. A high-density, accurate composite map based on a consensus ordering of markers provides a valuable contribution for future genetic research and breeding efforts in . A novel mapping approach based on an estimation of multipopulation recombination fraction described here may be applied in the construction of dense composite genetic maps for any other outcrossing diploid species.
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http://dx.doi.org/10.3389/fpls.2021.626811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940835PMC
February 2021

OpenADR and Agreement Audit Architecture for a Complete Cycle of a Flexibility Solution.

Sensors (Basel) 2021 Feb 9;21(4). Epub 2021 Feb 9.

Department of Electronic Technology, Escuela Politécnica Superior, Universidad de Sevilla, 41011 Sevilla, Spain.

Nowadays, the presence of renewable generation systems and mobile loads (i.e., electric vehicle) spread throughout the distribution network is increasing. The problem is that this type of system introduces an added difficulty since they present a strong dependence on the meteorology and the mobility needs of the users. This problem forces the distribution system operators to seek tools that make it possible to balance the relationship between consumption and generation. In this sense, automated demand response systems are an appropriate solution that allow the operator to request specific reductions in customers' consumption, offering a discount to the customer and avoiding network congestion. This paper analyzes the implementation and architecture of a demand response solution based on OpenADR standard and its possible integration with a building management system through a use case. As will be analyzed, a key part of the architecture is the measurement system based on smart meters acting as sensors. This is the base of the auditing system which makes it possible to verify compliance with the consumption reduction agreements. Additionally, this study is completed with a parallel auditing system which makes it possible to verify compliance with the consumption reduction agreements. All of the proposed demand response cycle is implemented as a proof of concept in a classroom in the at the University of Seville, which makes it possible to identify the advantages of this architecture in the ambit of connection between distribution network and buildings.
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http://dx.doi.org/10.3390/s21041204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916020PMC
February 2021

Synthesis and Pharmacological Evaluation of Novel Non-nucleotide Purine Derivatives as P2X7 Antagonists for the Treatment of Neuroinflammation.

J Med Chem 2021 02 9;64(4):2272-2290. Epub 2021 Feb 9.

Instituto-Fundación Teófilo Hernando and Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo 4, 28029 Madrid, Spain.

The ATP-gated P2X7 purinergic receptor (P2X7) is involved in the pathogenesis of many neurodegenerative diseases (NDDs). Several P2X7 antagonists have been developed, though none of them reached clinical trials for this indication. In this work, we designed and synthesized novel blood-brain barrier (BBB)-permeable derivatives as potential P2X7 antagonists. They comprise purine or xanthine cores linked to an aryl group through different short spacers. Compounds were tested in YO-PRO-1 uptake assays and intracellular calcium dynamics in a human P2X7-expressing HEK293 cell line, two-electrode voltage-clamp recordings in oocytes, and in interleukin 1β release assays in mouse peritoneal macrophages. BBB permeability was assessed by parallel artificial membrane permeability assays and P-glycoprotein ATPase activity. Dichloroarylpurinylethanones featured a certain P2X7 blockade, being compound (2-(6-chloro-9-purin-9-yl)-1-(2,4-dichlorophenyl)ethan-1-one), named ITH15004, the most potent, selective, and BBB-permeable antagonist. Compound can be considered as a first non-nucleotide purine hit for future drug optimizations.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02145DOI Listing
February 2021

Developing a Curriculum on Transgender Health Care for Physician Assistant Students.

J Physician Assist Educ 2021 Mar;32(1):48-53

Bethany G. Hart, MPAS, PA-C, is a recent graduate of the UT Southwestern Physician Assistant Studies Program in Dallas, Texas.

Purpose: Our goal was to (1) evaluate physician assistant (PA) students' knowledge, skills, and attitudes toward transgender patients, (2) develop and deliver a lecture on transgender health care, and (3) determine changes in knowledge, skills, and attitudes postlecture.

Methods: A 32-item survey was developed and emailed to PA students. Students were then invited to a 2-hour lecture on transgender-specific psychosocial topics and clinical skills plus medical treatment for gender dysphoria. Lecture attendees retook the survey after 2 weeks.

Results: Initial mean self-assessment scores regarding clinical knowledge and skills were below 3 on a 7-point Likert scale. All measures improved following the lecture (p < .001 for all). Overall, 86.7% of students were interested in the addition of transgender health into their didactic curriculum.

Conclusions: Our results illustrate insufficient student competence in transgender medicine. Our proposed transgender curriculum may be a useful guide for educators wanting to integrate this topic into their instruction.
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http://dx.doi.org/10.1097/JPA.0000000000000339DOI Listing
March 2021

Chronic administration of P2X7 receptor antagonist JNJ-47965567 delays disease onset and progression, and improves motor performance in ALS SOD1 female mice.

Dis Model Mech 2020 10 30;13(10). Epub 2020 Oct 30.

Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid 28029, Spain

Neuroinflammation is one of the main physiopathological mechanisms of amyotrophic lateral sclerosis (ALS), produced by the chronic activation of microglia in the CNS. This process is triggered by the persistent activation of the ATP-gated P2X7 receptor (P2RX7, hereafter referred to as P2X7R). The present study aimed to evaluate the effects of the chronic treatment with the P2X7R antagonist JNJ-47965567 in the development and progression of ALS in the SOD1 murine model. SOD1 mice were intraperitoneally (i.p.) injected with either 30 mg/kg of JNJ-47965567 or vehicle 4 times per week, from pre-onset age (here, postnatal day 60; P60) until study endpoint. Body weight, motor coordination, phenotypic score, disease onset and survival were measured throughout the study, and compared between vehicle- and drug-injected groups. Treatment with the P2X7R antagonist JNJ-47965567 delayed disease onset, reduced body weight loss and improved motor coordination and phenotypic score in female SOD1 mice, although it did not increase lifespan. Interestingly, neither beneficial nor detrimental effects were observed in males in any of the analyzed parameters. Treatment did not affect motor neuron survival or ChAT, Iba-1 and P2X7R protein expression in endpoint individuals of mixed sexes. Overall, chronic administration of JNJ-47965567 for 4 times per week to SOD1 mice from pre-onset stage altered disease progression in female individuals while it did not have any effect in males. Our results suggest a partial, yet important, effect of P2X7R in the development and progression of ALS.
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http://dx.doi.org/10.1242/dmm.045732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648608PMC
October 2020

The Adrenal Medulla Modulates Mechanical Allodynia in a Rat Model of Neuropathic Pain.

Int J Mol Sci 2020 Nov 6;21(21). Epub 2020 Nov 6.

Department of Pharmacology and Toxicology, Veterinary Faculty and Instituto Universitario de Investigación en Neuroquímica, Universidad Complutense de Madrid, 28040 Madrid, Spain.

We have investigated whether the stress response mediated by the adrenal medulla in rats subjected to chronic constriction injury of the sciatic nerve (CCI) modulates their nocifensive behavior. Treatment with SK29661 (300 mg/kg; intraperitoneal (I.P.)), a selective inhibitor of phenylethanolamine N-methyltransferase (PNMT) that converts noradrenaline (NA) into adrenaline (A), fully reverted mechanical allodynia in the injured hind paw without affecting mechanical sensitivity in the contralateral paw. The effect was fast and reversible and was associated with a decrease in the A to NA ratio (A/NA) in the adrenal gland and circulating blood, an A/NA that was elevated by CCI. 1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (SKF29661) did not affect exocytosis evoked by Ca entry as well as major ionic conductances (voltage-gated Na, Ca, and K channels, nicotinic acetylcholine receptors) involved in stimulus-secretion coupling in chromaffin cells, suggesting that it acted by changing the relative content of the two adrenal catecholamines. Denervation of the adrenal medulla by surgical splanchnectomy attenuated mechanical allodynia in neuropathic animals, hence confirming the involvement of the adrenal medulla in the pathophysiology of the CCI model. Inhibition of PNMT appears to be an effective and probably safe way to modulate adrenal medulla activity and, in turn, to alleviate pain secondary to the injury of a peripheral nerve.
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http://dx.doi.org/10.3390/ijms21218325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664230PMC
November 2020

Flexibility Services Based on OpenADR Protocol for DSO Level.

Sensors (Basel) 2020 Nov 3;20(21). Epub 2020 Nov 3.

Department of Electronic Technology, EPS, Universidad de Sevilla, 41011 Sevilla, Spain.

Nowadays, Distribution System Operators are increasing the digitalization of their smart grids, making it possible to measure and manage their state at any time. However, with the massive eruption of change-distributed generation (e.g., renewable resources, electric vehicles), the grid operation have become more complex, requiring specific technologies to balance it. In this sense, the demand-side management is one of its techniques; the demand response is a promising approach for providing Flexibility Services (FSs) and complying with the regulatory directives of the energy market. As a solution, this paper proposes the use of the OpenADR (Open Automated Demand Response) standard protocol in combination with a Decentralized Permissioned Market Place (DPMP) based on Blockchain. On one hand, OpenADR hierarchical architecture based on distributed nodes provides communication between stakeholders, adding monitoring and management services. Further, this architecture is compatible with an aggregator schema that guarantees the compliance with the strictest regulatory framework (i.e., European market). On the other hand, DPMP is included at different levels of this architecture, providing a global solution to Flexibility Service Providers (FSP) that can be adapted depending on the regulation of a specific country. As a proof of concept, this paper shows the result of a real experimental case, which implements a Capacity Bidding Program where the OpenADR protocol is used as a communication method to control and monitor energy consumption. In parallel, the proposed DPMP based on Blockchain makes it possible to manage the incentives of FSs, enabling the integration of local and global markets.
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http://dx.doi.org/10.3390/s20216266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662250PMC
November 2020

Acute reversible SERCA blockade facilitates or blocks exocytosis, respectively in mouse or bovine chromaffin cells.

Pflugers Arch 2021 02 27;473(2):273-286. Epub 2020 Oct 27.

Instituto Teófilo Hernando, Universidad Autónoma de Madrid, Madrid, Spain.

Pre-blockade of the sarco-endoplasmic reticulum (ER) calcium ATPase (SERCA) with irreversible thapsigargin depresses exocytosis in adrenal bovine chromaffin cells (BCCs). Distinct expression of voltage-dependent Ca-channel subtypes and of the Ca-induced Ca release (CICR) mechanism in BCCs versus mouse chromaffin cells (MCCs) has been described. We present a parallel study on the effects of the acute SERCA blockade with reversible cyclopizonic acid (CPA), to repeated pulsing with acetylcholine (ACh) at short (15 s) and long intervals (60 s) at 37 °C, allowing the monitoring of the initial size of a ready-release vesicle pool (RRP) and its depletion and recovery in subsequent stimuli. We found (i) strong depression of exocytosis upon ACh pulsing at 15-s intervals and slower depression at 60-s intervals in both cell types; (ii) facilitation of exocytosis upon acute SERCA inhibition, with back to depression upon CPA washout in MCCs; (iii) blockade of exocytosis upon acute SERCA inhibition and pronounced rebound of exocytosis upon CPA washout in BCCs; (iv) basal [Ca] elevation upon stimulation with ACh at short intervals (but not at long intervals) in both cell types; and (v) augmentation of basal [Ca] and inhibition of peak [Ca] amplitude upon CPA treatment in both cell types, with milder effects upon stimulation at 60-s intervals. These results are compatible with the view that while in MCCs the uptake of Ca via SERCA contributes to the mitigation of physiological ACh triggered secretion, in BCCs the uptake of Ca into the ER facilitates such responses likely potentiating a Ca-induced Ca release mechanism. These drastic differences in the regulation of ACh-triggered secretion at 37 °C may help to understand different patterns of the regulation of exocytosis by the circulation of Ca at a functional ER Ca store.
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http://dx.doi.org/10.1007/s00424-020-02483-1DOI Listing
February 2021

The effect of antibiotic prophylaxis on infection rates in mohs micrographic surgery: a single-institution retrospective study.

Arch Dermatol Res 2021 Oct 24;313(8):663-667. Epub 2020 Oct 24.

Department of Dermatology, University of Texas Southwestern Medical Center, 5939 Harry Hines Blvd, 4th Floor, Suite 100, Dallas, 75390, USA.

As data and recommendations regarding antibiotic prophylaxis in dermatologic surgery vary, we tried to describe the effect of antibiotic prophylaxis (AP) in Mohs micrographic surgery (MMS) on infective endocarditis, prosthetic joint infection, and surgical site infection using a single-institution retrospective cohort study of antibiotic use (pre-/intra-operative, post-operative or none) among 2,364 patient encouters treated with MMS. Bivariate logistic regression was evaluated for associations between patient and operative characteristics, antibiotic use, and infectious complications. 85.8% of patients received no AP, 10.0% received post-operative AP, and 4.1% received pre-/intra-operative AP. The overall surgical site infection (SSI) rate was 1.3%. SSI did not differ between patients who received pre-/intra-operative prophylaxis, post-operative prophylaxis or no antibiotics. One patient receiving pre-/intra-operative prophylaxis developed SSI. Repairs involving porcine xenografts and interpolation/pedicle flaps were associated with increased SSI. In addition, there were no patients who post-operatively experienced an infected joint or infective endocarditis. Limitations include selection bias, use of observational retrospective data, low infection rates, single institution analysis, and possible omission of explanatory variables or confounders. There was no difference in rates of SSI when comparing MMS patients who received pre-/intra-operative, post-operative or no AP. There were no cases of infective endocarditis or infected prosthetic joint.
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http://dx.doi.org/10.1007/s00403-020-02153-3DOI Listing
October 2021

Does Selectivity of Molecular Catalysts Change with Time? Polymerization Imaged by Single-Molecule Spectroscopy.

Angew Chem Int Ed Engl 2021 Jan 13;60(3):1550-1555. Epub 2020 Nov 13.

Department of Chemistry, University of California, Irvine, Irvine, CA, 92697-2025, USA.

The chemoselectivity of molecular catalysts underpins much of modern synthetic organic chemistry. However, little is known about the selectivity of individual catalysts because this single-catalyst-level behavior is hidden by the bulk catalytic behavior. Here, for the first time, the selectivity of individual molecular catalysts for two different reactions is imaged in real time at the single-catalyst level. This imaging is achieved through fluorescence microscopy paired with spectral probes that produce a snapshot of the instantaneous chemoselectivity of a single catalyst for either a single-chain-elongation or a single-chain-termination event during ruthenium-catalyzed polymerization. Superresolution imaging of multiple selectivity events, each at a different single-molecular ruthenium catalyst, indicates that catalyst selectivity may be unexpectedly spatially and time-variable.
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http://dx.doi.org/10.1002/anie.202010101DOI Listing
January 2021

Chronic resveratrol consumption prevents hypertension development altering electrophysiological currents and Ca signaling in chromaffin cells from SHR rats.

Cell Signal 2020 12 17;76:109811. Epub 2020 Oct 17.

Departamento de Farmacología y Terapéutica, Facultad de Medicina, Instituto Teófilo Hernando, Universidad Autónoma de Madrid (ITH/UAM), Madrid, Spain; Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, Universidad Autónoma de Madrid (UAM), Madrid, Spain.

Resveratrol (RESV) is one of the most abundant polyphenol-stilbene compounds found in red wine with well-established cardioprotective and antihypertensive effects. Hyperactivity of the sympathoadrenal axis seems to be one of the major contributing factors in the pathogenesis of human essential hypertension. Alterations in outward voltage-dependent potassium currents (I) and inward voltage-dependent sodium (I), calcium (I) and nicotinic (I) currents, CCs excitability, Ca homeostasis, and catecholamine exocytosis were previously related to the hypertensive state. This raised the issue of whether in vivo long-term RESV treatment can directly act as a modulator of Ca influx or a regulator of ion channel permeability in CCs. We monitored outward and inward currents, and cytosolic Ca concentrations ([Ca]) using different pharmacological approaches in CCs from normotensive (WKY) and hypertensive (SHR) animals chronically exposed to trans-RESV (50 mg/L/v.o, 28 days). The long-term RESV treatment prevented the increase of the systolic blood pressure (SBP) in SHR, without reversion of cardiac hypertrophy. We also found an increase of the outward I, reduction in inward II, and I, and the mitigation of [Ca] overload in CCs from SHR at the end of RESV treatment. Our data revealed that electrophysiological alterations of the CCs and in its Ca homeostasis are potential new targets related to the antihypertensive effects of long-term RESV treatment.
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http://dx.doi.org/10.1016/j.cellsig.2020.109811DOI Listing
December 2020

Trichoptera and Plecoptera of the Seybouse River, northeast Algeria: Distribution, phenology and new records.

Zootaxa 2020 Sep 4;4845(4):zootaxa.4845.4.5. Epub 2020 Sep 4.

Laboratoire de Conservation des Zones Humides, Université 8 mai 1945 Guelma, Guelma, Algeria Department of Biology, University Badji Mokhtar Annaba, Annaba, Algeria.

The stoneflies and caddisflies of North Africa are still poorly known as vast areas of Algeria have yet to be investigated. A survey of the macroinvertebrates of the Seybouse River, northeast Algeria, was carried out from July 2014 to December 2016. Three species of stoneflies (Capnopsis schilleri, Capnioneura petitpierreae, and Tyrrhenoleuctra tangerina) and five taxa of caddisflies (Mesophylax aspersus, Hydropsyche maroccana, H. resmineda, H. artax/lobata, and H. gr. pellucidula) were identified. All taxa are new records to the Seybouse River and seven of them are new to northeastern Algeria. A multivariate analysis indicated that the Hydropsychidae exhibited a clear longitudinal gradient along the Seybouse River while Mesophylax aspersus seemed adapted to species-poor, intermittent streams. Further investigations of the stoneflies and caddisflies may inform conservation efforts and will prove useful to monitor the Seybouse River and similarly threatened North African rivers and streams.
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http://dx.doi.org/10.11646/zootaxa.4845.4.5DOI Listing
September 2020

Estimation of Molecular Pairwise Relatedness in Autopolyploid Crops.

G3 (Bethesda) 2020 12 3;10(12):4579-4589. Epub 2020 Dec 3.

Department of Genetics, Luiz de Queiroz College of Agriculture, University of São Paulo, Brazil

A suitable pairwise relatedness estimation is key to genetic studies. Several methods are proposed to compute relatedness in autopolyploids based on molecular data. However, unlike diploids, autopolyploids still need further studies considering scenarios with many linked molecular markers with known dosage. In this study, we provide guidelines for plant geneticists and breeders to access trustworthy pairwise relatedness estimates. To this end, we simulated populations considering different ploidy levels, meiotic pairings patterns, number of loci and alleles, and inbreeding levels. Analysis were performed to access the accuracy of distinct methods and to demonstrate the usefulness of molecular marker in practical situations. Overall, our results suggest that at least 100 effective biallelic molecular markers are required to have good pairwise relatedness estimation if methods based on correlation is used. For this number of loci, current methods based on multiallelic markers show lower performance than biallelic ones. To estimate relatedness in cases of inbreeding or close relationships (as parent-offspring, full-sibs, or half-sibs) is more challenging. Methods to estimate pairwise relatedness based on molecular markers, for different ploidy levels or pedigrees were implemented in the AGHmatrix R package.
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http://dx.doi.org/10.1534/g3.120.401669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718764PMC
December 2020

Estimation of Molecular Pairwise Relatedness in Autopolyploid Crops.

G3 (Bethesda) 2020 12 3;10(12):4579-4589. Epub 2020 Dec 3.

Department of Genetics, Luiz de Queiroz College of Agriculture, University of São Paulo, Brazil

A suitable pairwise relatedness estimation is key to genetic studies. Several methods are proposed to compute relatedness in autopolyploids based on molecular data. However, unlike diploids, autopolyploids still need further studies considering scenarios with many linked molecular markers with known dosage. In this study, we provide guidelines for plant geneticists and breeders to access trustworthy pairwise relatedness estimates. To this end, we simulated populations considering different ploidy levels, meiotic pairings patterns, number of loci and alleles, and inbreeding levels. Analysis were performed to access the accuracy of distinct methods and to demonstrate the usefulness of molecular marker in practical situations. Overall, our results suggest that at least 100 effective biallelic molecular markers are required to have good pairwise relatedness estimation if methods based on correlation is used. For this number of loci, current methods based on multiallelic markers show lower performance than biallelic ones. To estimate relatedness in cases of inbreeding or close relationships (as parent-offspring, full-sibs, or half-sibs) is more challenging. Methods to estimate pairwise relatedness based on molecular markers, for different ploidy levels or pedigrees were implemented in the AGHmatrix R package.
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http://dx.doi.org/10.1534/g3.120.401669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718764PMC
December 2020

Macitentan in the treatment of pulmonary arterial hypertension.

Future Cardiol 2021 01 17;17(1):49-58. Epub 2020 Jul 17.

Cardiopulmonary Department, National Heart Institute, Mexico City, Mexico.

Pulmonary arterial hypertension (PAH) is an uncommon but lethal and progressive disease in which prostacyclin, nitric oxide and endothelin-1 pathways are disturbed and contribute to the pathophysiology of this disease. Endothelin receptor antagonists are a class of drugs that have been approved as PAH therapy. Macitentan is a lipophilic, tissue specific, dual receptor antagonist with a higher potency than bosentan and a reduced risk of hepatic injury. Macitentan has shown a reduction in morbidity and mortality due to PAH at long-term follow-up and improvements in hemodynamics, exercise capacity and functional class at the short term. Its main adverse events are nasopharyngitis, bronchitis and an increased risk of anemia. We review the clinical data of macitentan and its use in PAH.
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http://dx.doi.org/10.2217/fca-2020-0012DOI Listing
January 2021

The purinergic P2X7 receptor as a potential drug target to combat neuroinflammation in neurodegenerative diseases.

Med Res Rev 2020 11 16;40(6):2427-2465. Epub 2020 Jul 16.

Departamento de Farmacología, Instituto-Fundación Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.

Neurodegenerative diseases (NDDs) represent a huge social burden, particularly in Alzheimer's disease (AD) in which all proposed treatments investigated in murine models have failed during clinical trials (CTs). Thus, novel therapeutic strategies remain crucial. Neuroinflammation is a common pathogenic feature of NDDs. As purinergic P2X7 receptors (P2X7Rs) are gatekeepers of inflammation, they could be developed as drug targets for NDDs. Herein, we review this challenging hypothesis and comment on the numerous studies that have investigated P2X7Rs, emphasizing their molecular structure and functions, as well as their role in inflammation. Then, we elaborate on research undertaken in the field of medicinal chemistry to determine potential P2X7R antagonists. Subsequently, we review the state of neuroinflammation and P2X7R expression in the brain, in animal models and patients suffering from AD, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, and retinal degeneration. Next, we summarize the in vivo studies testing the hypothesis that by mitigating neuroinflammation, P2X7R blockers afford neuroprotection, increasing neuroplasticity and neuronal repair in animal models of NDDs. Finally, we reviewed previous and ongoing CTs investigating compounds directed toward targets associated with NDDs; we propose that CTs with P2X7R antagonists should be initiated. Despite the high expectations for putative P2X7Rs antagonists in various central nervous system diseases, the field is moving forward at a relatively slow pace, presumably due to the complexity of P2X7Rs. A better pharmacological approach to combat NDDs would be a dual strategy, combining P2X7R antagonism with drugs targeting a selective pathway in a given NDD.
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http://dx.doi.org/10.1002/med.21710DOI Listing
November 2020

P2X7 Receptor Antagonism as a Potential Therapy in Amyotrophic Lateral Sclerosis.

Front Mol Neurosci 2020 12;13:93. Epub 2020 Jun 12.

Instituto Teófilo Hernando and Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.

This review focuses on the purinergic ionotropic receptor P2X7 (P2X7R) as a potential target for developing drugs that delay the onset and/or disease progression in patients with amyotrophic lateral sclerosis (ALS). Description of clinical and genetic ALS features is followed by an analysis of advantages and drawbacks of transgenic mouse models of disease based on mutations in a bunch of proteins, particularly Cu/Zn superoxide dismutase (SOD1), TAR-DNA binding protein-43 (TDP-43), Fused in Sarcoma/Translocated in Sarcoma (FUS), and Chromosome 9 open reading frame 72 (C9orf72). Though of limited value, these models are however critical to study the proof of concept of new compounds, before reaching clinical trials. The authors also provide a description of ALS pathogenesis including protein aggregation, calcium-dependent excitotoxicity, dysfunction of calcium-binding proteins, ultrastructural mitochondrial alterations, disruption of mitochondrial calcium handling, and overproduction of reactive oxygen species (ROS). Understanding disease pathogenic pathways may ease the identification of new drug targets. Subsequently, neuroinflammation linked with P2X7Rs in ALS pathogenesis is described in order to understand the rationale of placing the use of P2X7R antagonists as a new therapeutic pharmacological approach to ALS. This is the basis for the hypothesis that a P2X7R blocker could mitigate the neuroinflammatory state, indirectly leading to neuroprotection and higher motoneuron survival in ALS patients.
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http://dx.doi.org/10.3389/fnmol.2020.00093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303288PMC
June 2020

Impact of COVID-19 on Pediatric Asthma: Practice Adjustments and Disease Burden.

J Allergy Clin Immunol Pract 2020 09 17;8(8):2592-2599.e3. Epub 2020 Jun 17.

Charité Universitätsmedizin Berlin, Pediatric Pulmonology, Immunology and Intensive Care Medicine, Berlin, Germany.

Background: It is unclear whether asthma may affect susceptibility or severity of coronavirus disease 2019 (COVID-19) in children and how pediatric asthma services worldwide have responded to the pandemic.

Objective: To describe the impact of the COVID-19 pandemic on pediatric asthma services and on disease burden in their patients.

Methods: An online survey was sent to members of the Pediatric Asthma in Real Life think tank and the World Allergy Organization Pediatric Asthma Committee. It included questions on service provision, disease burden, and the clinical course of confirmed cases of COVID-19 infection among children with asthma.

Results: Ninety-one respondents, caring for an estimated population of more than 133,000 children with asthma, completed the survey. COVID-19 significantly impacted pediatric asthma services: 39% ceased physical appointments, 47% stopped accepting new patients, and 75% limited patients' visits. Consultations were almost halved to a median of 20 (interquartile range, 10-25) patients per week. Virtual clinics and helplines were launched in most centers. Better than expected disease control was reported in 20% (10%-40%) of patients, whereas control was negatively affected in only 10% (7.5%-12.5%). Adherence also appeared to increase. Only 15 confirmed cases of COVID-19 were reported among the population; the estimated incidence is not apparently different from the reports of general pediatric cohorts.

Conclusions: Children with asthma do not appear to be disproportionately affected by COVID-19. Outcomes may even have improved, possibly through increased adherence and/or reduced exposures. Clinical services have rapidly responded to the pandemic by limiting and replacing physical appointments with virtual encounters.
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http://dx.doi.org/10.1016/j.jaip.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297686PMC
September 2020

Postoperative bleeding complications associated with blood thinning agents during Mohs micrographic surgery: A retrospective cohort study.

J Am Acad Dermatol 2021 01 8;84(1):225-227. Epub 2020 Jun 8.

Department of Dermatology, University of Texas Southwestern Medical School, Dallas, Texas. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2020.06.011DOI Listing
January 2021
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