Publications by authors named "Daniel Gonzalez"

276 Publications

Lactobacillus stress protein GroEL prevents colonic inflammation.

J Gastroenterol 2021 Mar 29. Epub 2021 Mar 29.

INSERM, UMR 1231, Laboratoire d'Excellence LipSTIC and « Equipe labellisée par la Ligue Nationale Contre Le Cancer », 7 boulevard Jeanne d'Arc, 21079, Dijon, France.

Background: We previously showed that supernatants of Lactobacillus biofilms induced an anti-inflammatory response by affecting the secretion of macrophage-derived cytokines, which was abrogated upon immunodepletion of the stress protein GroEL.

Methods: We purified GroEL from L. reuteri and analysed its anti-inflammatory properties in vitro in human macrophages isolated from buffy coats, ex vivo in explants from human biopsies and in vivo in a mouse model of DSS induced intestinal inflammation. As a control, we used GroEL purified (LPS-free) from E. coli.

Results: We found that L. reuteri GroEL (but not E. coli GroEL) inhibited pro-inflammatory M1-like macrophages markers, and favored M2-like markers. Consequently, L. reuteri GroEL inhibited pro-inflammatory cytokines (TNFα, IL-1β, IFNγ) while favouring an anti-inflammatory secretome. In colon tissues from human biopsies, L. reuteri GroEL was also able to decrease markers of inflammation and apoptosis (caspase 3) induced by LPS. In mice, we found that rectal administration of L. reuteri GroEL (but not E. coli GroEL) inhibited all signs of haemorrhagic colitis induced by DSS including intestinal mucosa degradation, rectal bleeding and weight loss. It also decreased intestinal production of inflammatory cytokines (such as IFNγ) while increasing anti-inflammatory IL-10 and IL-13. These effects were suppressed when animals were immunodepleted in macrophages. From a mechanistic point of view, the effect of L. reuteri GroEL seemed to involve TLR4, since it was lost in TRL4 mice, and the activation of a non-canonical TLR4 pathway.

Conclusions: L. reuteri GroEL, by affecting macrophage inflammatory features, deserves to be explored as an alternative to probiotics.
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http://dx.doi.org/10.1007/s00535-021-01774-3DOI Listing
March 2021

Human leukocyte antigen (HLA)-F and -G gene polymorphisms and haplotypes are associated with malaria susceptibility in the Beninese Toffin children.

Infect Genet Evol 2021 Mar 27;92:104828. Epub 2021 Mar 27.

Post-graduate Program in Basic and Applied Immunology, Ribeirão Preto Medical School, University of São Paulo, Avenida Bandeirantes, 3900, Monte Alegre, 14049-900 Ribeirão Preto, SP, Brazil. Electronic address:

Background: Little attention has been devoted to the role of the immunoregulatory HLA-E/-F/-G genes in malaria. We evaluated the entire HLA-E/-F/-G variability in Beninese children highly exposed to Plasmodium falciparum (P.f.) malaria.

Methods: 154 unrelated children were followed-up for six months and evaluated for the presence and number of malaria episodes. HLA-E/-F/-G genes were genotyped using massively parallel sequencing. Anti P.f. antibodies were evaluated using ELISA.

Results: Children carrying the G allele at HLA-F (-1499,rs183540921) showed increased P.f. asymptomatic/symptomatic ratio, suggesting that these children experienced more asymptomatic P.f. episodes than symptomatic one. Children carrying HLA-G-UTR-03 haplotype exhibited increased risk for symptomatic P.f. episodes and showed lower IgG2 response against P.f. GLURP-R2 when compared to the non-carriers. No associations were observed for the HLA-E gene.

Conclusion: HLA-F associations may be related to the differential expression profiles of the encoded immunomodulatory molecules, and the regulatory sites at the HLA-G 3'UTR may be associated to posttranscriptional regulation of HLA-G and to host humoral response against P.f.
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http://dx.doi.org/10.1016/j.meegid.2021.104828DOI Listing
March 2021

Cost-Benefit Analysis of the Upland-Rice Root Architecture in Relation to Phosphate: 3D Simulations Highlight the Importance of S-Type Lateral Roots for Reducing the Pay-Off Time.

Front Plant Sci 2021 12;12:641835. Epub 2021 Mar 12.

Crop, Livestock, and Environment Division, Japan International Research Center for Agricultural Sciences, Tsukuba, Japan.

The rice root system develops a large number of nodal roots from which two types of lateral roots branch out, large L-types and fine S-types, the latter being unique to the species. All roots including S-types are covered by root hairs. To what extent these fine structures contribute to phosphate (P) uptake under P deficiency was investigated using a novel 3-D root growth model that treats root hairs as individual structures with their own Michaelis-Menten uptake kinetics. Model simulations indicated that nodal roots contribute most to P uptake followed by L-type lateral roots and S-type laterals and root hairs. This is due to the much larger root surface area of thicker nodal roots. This thickness, however, also meant that the investment in terms of P needed for producing nodal roots was very large. Simulations relating P costs and time needed to recover that cost through P uptake suggest that producing nodal roots represents a considerable burden to a P-starved plant, with more than 20 times longer pay-off time compared to S-type laterals and root hairs. We estimated that the P cost of these fine root structures is low enough to be recovered within a day of their formation. These results expose a dilemma in terms of optimizing root system architecture to overcome P deficiency: P uptake could be maximized by developing more nodal root tissue, but when P is growth-limiting, adding more nodal root tissue represents an inefficient use of the limiting factor P. In order to improve adaption to P deficiency in rice breeding two complementary strategies seem to exist: (1) decreasing the cost or pay-off time of nodal roots and (2) increase the biomass allocation to S-type roots and root hairs. To what extent genotypic variation exists within the rice gene pool for either strategy should be investigated.
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http://dx.doi.org/10.3389/fpls.2021.641835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996052PMC
March 2021

Selection of Antiobesity Medications Based on Phenotypes Enhances Weight Loss: A Pragmatic Trial in an Obesity Clinic.

Obesity (Silver Spring) 2021 Apr;29(4):662-671

Department of Psychology and Psychiatry, Mayo Clinic, Rochester, Minnesota, USA.

Objective: Little is known about the predictors of response to obesity interventions.

Methods: In 450 participants with obesity, body composition, resting energy expenditure, satiety, satiation, eating behavior, affect, and physical activity were measured by validated studies and questionnaires. These variables were used to classify obesity phenotypes. Subsequently, in a 12-month, pragmatic, real-world trial performed in a weight management center, 312 patients were randomly assigned to phenotype-guided treatment or non-phenotype-guided treatment with antiobesity medications: phentermine, phentermine/topiramate, bupropion/naltrexone, lorcaserin, and liraglutide. The primary outcome was weight loss at 12 months.

Results: Four phenotypes of obesity were identified in 383 of 450 participants (85%): hungry brain (abnormal satiation), emotional hunger (hedonic eating), hungry gut (abnormal satiety), and slow burn (decreased metabolic rate). In 15% of participants, no phenotype was identified. Two or more phenotypes were identified in 27% of patients. In the pragmatic clinical trial, the phenotype-guided approach was associated with 1.75-fold greater weight loss after 12 months with mean weight loss of 15.9% compared with 9.0% in the non-phenotype-guided group (difference -6.9% [95% CI -9.4% to -4.5%], P < 0.001), and the proportion of patients who lost >10% at 12 months was 79% in the phenotype-guided group compared with 34% with non-phenotype-guided treatment group.

Conclusions: Biological and behavioral phenotypes elucidate human obesity heterogeneity and can be targeted pharmacologically to enhance weight loss.
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http://dx.doi.org/10.1002/oby.23120DOI Listing
April 2021

Using molecular genetics in complete androgen insensitivity syndrome: toward a more personalized medicine approach.

Fertil Steril 2021 Mar 18. Epub 2021 Mar 18.

Department of Urology, University of Miami Miller School of Medicine, Miami, Florida.

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http://dx.doi.org/10.1016/j.fertnstert.2021.02.035DOI Listing
March 2021

Androgenization in Klinefelter syndrome: Clinical spectrum from infancy through young adulthood.

J Pediatr Urol 2021 Feb 24. Epub 2021 Feb 24.

Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA.

Klinefelter syndrome (KS) is an uncommon chromosomal disorder in males that has a variable clinical appearance. Classic KS involves an extra X chromosome, (47, XXY), although other variations may exist, including a milder mosaic form as well as multiple extra sex chromosomes with more dramatic phenotypes. KS is underdiagnosed, especially pre-pubertally, owing to a paucity of concrete clinical signs; however, diagnostic rates increase during and after puberty, as the consequences of hypergonadotropic hypogonadism begin to manifest. Testicular failure causing decreased circulating testosterone (T) and germ cell depletion, a hallmark feature in KS, commonly begins shortly after the onset of puberty and leads to the most commonly recognized KS traits: small testes, azoospermia, gynecomastia, decreased facial and pubic hair. While many KS men maintain adequate T levels leading up to young adulthood, some may have lower T levels at an earlier age leading to varied levels of androgenization and clinical KS features. At certain critical time points, absent or decreased T may alter the development of normal male reproductive organs, external genitalia, development of secondary sexual characteristics and spermatogenesis. Testicular failure in utero may lead to ambiguous genitalia, cryptorchidism and/or hypospadias, all of which depend on fetal T production. In the neonatal period and childhood, decreased T levels during the mini-puberty of infancy may negatively impact germ cell differentiation and male neuropsychological development. Finally, decreased T during pubertal and young adulthood can lead to decreased virilization during puberty, eunuchoid skeleton and decreased spermatogenesis. Depending on the timing of the testicular failure, a reproductive window of sperm production may exist to achieve paternity for KS men. The presence or absence of clinical characteristics reflecting decreased androgenization provides an insight to the relative testicular function during these developmental time points for those with KS and contributes to variability within the syndrome.
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http://dx.doi.org/10.1016/j.jpurol.2021.02.021DOI Listing
February 2021

Clinical and Molecular Cytogenetic Characteristics of Five Cases with Isodicentric Y Chromosome.

Sex Dev 2021 Mar 5:1-9. Epub 2021 Mar 5.

Institute of Human Genetics, School of Medicine, Pontificia Universidad Javeriana, Bogotá, Colombia,

Isodicentric Y chromosome [idic(Y)] is one of the most common structural abnormalities of the Y chromosome and has been observed in patients with reproductive disorders and in patients with disorders of sexual development. Most idic(Y) chromosomes are found in mosaic form with a 45,X cell line. These chromosomes are highly unstable during mitosis due to the presence of 2 centromers, which explains their probable loss in early mitosis or mitosis of the embryo and therefore the presence of the 45,X line. It has been hypothesized that the proportion of 45,X cells in various tissues probably influences the phenotypic sex of individuals carrying an idic(Y) chromosome, ranging from infertile men, hypospadias, ambiguous genitalia, and Turner syndrome to sex reversal. In this article we present 5 cases of patients with idic(Y) referred for suspected disorder of sex development (DSD), 3 with a male assignment and 2 with a female assignment. All cases have variable clinical characteristics, which were assessed by the transdisciplinary group of Disorders of Sex Development of the Hospital Universitario San Ignacio, Bogotá, Colombia. Patients were analyzed by conventional and molecular cytogenetics using high-resolution G-band and FISH techniques. Our findings highlight the importance of cytogenetic studies in the diagnosis of DSD patients.
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http://dx.doi.org/10.1159/000512803DOI Listing
March 2021

Cytochrome Deficiency Differentially Affects the Mitochondrial Electron Partitioning and Primary Metabolism Depending on the Photoperiod.

Plants (Basel) 2021 Feb 26;10(3). Epub 2021 Feb 26.

Laboratorio de Fisiología Vegetal, Departamento de Botánica, Facultad de Ciencias Naturales y Oceanográficas, Universidad de Concepción, Concepción 4030000, Chile.

Plant respiration provides metabolic flexibility under changing environmental conditions by modulating the activity of the nonphosphorylating alternative pathways from the mitochondrial electron transport chain, which bypass the main energy-producing components of the cytochrome oxidase pathway (COP). While adjustments in leaf primary metabolism induced by changes in day length are well studied, possible differences in the contribution of the COP and the alternative oxidase pathway (AOP) between different photoperiods remain unknown. In our study, electron partitioning between AOP and COP and expression analysis of respiratory components, photosynthesis, and the levels of primary metabolites were studied in leaves of wild-type (WT) plants and cytochrome c (CYTc) mutants, with reduced levels of COP components, under short- and long-day photoperiods. Our results clearly show that differences in AOP and COP activities between WT and mutants depend on the photoperiod likely due to energy and stress signaling constraints. Parallel responses observed between respiratory activities, TCA cycle intermediates, amino acids, and stress signaling metabolites indicate the coordination of different pathways of primary metabolism to support growth adaptation under different photoperiods.
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http://dx.doi.org/10.3390/plants10030444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996904PMC
February 2021

Clinical Update on Home Testing for Male Fertility.

World J Mens Health 2020 Nov 11. Epub 2020 Nov 11.

Department of Urology, Miller School of Medicine, University of Miami, Miami, FL, USA.

Male factor infertility accounts for about 50% of the incidence of infertility in couples. In current practice, the men must attend a clinic or hospital facility to provide a semen analysis, which is key to the diagnosis of the male reproductive potential. However, many men are often embarrassed with the process and conventional semen analysis requires complex, labor intensive inspection with a microscope. To mitigate these problems, one of the solutions can be at-home semen analysis. In this review we examine the literature of currently available at home semen analysis test kits, describe their limitations, and compare them to the conventional lab-based methods.
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http://dx.doi.org/10.5534/wjmh.200130DOI Listing
November 2020

Cross-talk between mitochondrial function and growth/stress signalling pathways in plants.

J Exp Bot 2020 Dec 28. Epub 2020 Dec 28.

Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Cátedra de Biología Celular y Molecular, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Argentina.

Plant mitochondria harbour complex metabolic routes that are interconnected with those of other cell compartments and changes in mitochondrial function remotely influence processes in different parts of the cell. This implies the existence of signals that convey information about mitochondrial function to the rest of the cell. Increasing evidence indicates that metabolic and redox signals are important for this process, but probably also changes in ion fluxes, protein relocalization and physical contacts with other organelles are involved. Besides possible direct effects of these signalling molecules on cellular functions, changes in mitochondrial physiology also affect the activity of different signalling pathways that modulate plant growth and stress responses. As a consequence, mitochondria influence the responses to internal and external factors that modify the activity of these pathways and associated biological processes. Acting through the activity of hormonal signalling pathways, mitochondria may also exert remote control over distant organs or plant tissues. In addition, an intimate cross-talk of mitochondria with energy signalling pathways, like those represented by Target of Rapamycin and Sucrose non-fermenting1-related protein kinase 1, can be envisaged. This review discusses available evidence on the role of mitochondria in shaping plant growth and stress responses through different signalling pathways.
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http://dx.doi.org/10.1093/jxb/eraa608DOI Listing
December 2020

PRODIGE 59-DURIGAST trial: A randomised phase II study evaluating FOLFIRI + Durvalumab ± Tremelimumab in second-line of patients with advanced gastric cancer.

Dig Liver Dis 2021 Apr 6;53(4):420-426. Epub 2021 Jan 6.

Service d'Oncologie Médicale, CHU de Poitiers, Poitiers, France; Service d'Hépato-gastroentérologie, CHU de Poitiers et Université de Poitiers, 2 rue de la Milétrie, Poitiers 86021, France. Electronic address:

Gastric or gastro-oesophageal junction (GEJ) adenocarcinomas present poor overall survival (OS). First-line chemotherapy regimen for patients with HER2-negative tumours is based on a doublet or triplet of fluoropyrimidine plus platinum salt ± taxane. Second-line chemotherapy (Docetaxel or Irinotecan) improves OS which nonetheless remains poor (around 5 months). The first results of immune checkpoint inhibitors (anti-PD-1) combined with chemotherapy in metastatic gastric and GEJ cancers were discordant in recent phase III trials. Data on dual-blockade (anti-PD-L1 or anti-PD-1 plus anti-CTLA-4) plus chemotherapy are lacking. DURIGAST is a randomised, multicenter, non-comparative, phase II study, evaluating safety and efficacy of FOLFIRI plus Durvalumab (anti-PD-L1) versus FOLFIRI plus Durvalumab and Tremelimumab (anti-CTLA-4) as second-line treatment of advanced gastric and GEJ adenocarcinoma. The primary objective is the rate of patients alive and without progression at 4 months. The main inclusion criteria are: patients with advanced gastric or GEJ adenocarcinoma, pre-treated with fluoropyrimidine + platinum salt ± taxane. Due to a lack of data on FOLFIRI, Durvalumab and Tremelimumab combination, a 2-step safety run-in phase has been performed before the randomised phase II. The safety run-in phase did not show any safety issue and the randomised phase II starts in September 2020.
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http://dx.doi.org/10.1016/j.dld.2020.11.036DOI Listing
April 2021

Therapeutic Effectiveness of Interferon Alpha 2b Treatment for COVID-19 Patient Recovery.

J Interferon Cytokine Res 2020 12;40(12):578-588

Clinical Research Department, Center for Genetic Engineering and Biotechnology, Habana, Cuba.

A previous report on 814 patients who were coronavirus disease 2019 (COVID-19) positive provided preliminary therapeutic efficacy evidence with interferon-α2b (IFN-α2b) in Cuba, from March 11 to April 14, 2020. This study re-evaluates the effectiveness of IFN-α2b during the period from March 11 to June 17, 2020. Patients received a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular or subcutaneous administration of IFN-α2b. The primary endpoint was the proportion of patients discharged from the hospital; the secondary endpoint was the case fatality rate, and several outcomes related to time variables were also evaluated. From March 11 to June 17, 2,295 patients had been confirmed to be severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive in Cuba, 2,165 were treated with Heberon Alpha R, and 130 received the approved protocol without IFN. The proportion of fully recovered patients was higher in the IFN-treated compared with the non-IFN-treated group. Prior IFN treatment decreases the likelihood of intensive care and increases the survival after severe or critical diseases. Benefits of IFN were significantly supported by time variables analyzed. This second report confirmed our preliminary evidence about the therapeutic effectiveness of IFN-α2b in SARS-CoV-2 infection and postulated Heberon Alpha R as the main component within antiviral drugs used in the Cuban protocol COVID-19.
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http://dx.doi.org/10.1089/jir.2020.0188DOI Listing
December 2020

A Systematic Review on the Investigation of SARS-CoV-2 in Semen.

Res Rep Urol 2020 1;12:615-621. Epub 2020 Dec 1.

Department of Urology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a virus that is present in most bodily fluids. However, whether SARS-CoV-2 is present in the semen remains underexplored. Thus, we systematically reviewed the existing studies on the presence of SARS-CoV-2 in semen.

Methods: A literature search of the PubMed, Embase, Cochrane, Web of Science, Google Scholar, and Ovid databases was performed for articles from the dates of their inception to August 2020 using the following keywords: COVID-19, SARS-CoV2, seminal, semen, and sperm. After excluding non-human studies and articles that were not in the English language, we identified 19 relevant studies. The full text of the articles were reviewed and a total of eight articles remained after applying our selection criteria.

Results: After reviewing the presence of SARS-CoV-2 in the eight different studies using semen samples, only one reported the presence of the virus. Six out of 160 total semen samples with SARS-CoV-2 positive demonstrated the presence of viral RNA, of which 2 were from males in the recovery phase and 4 from the acute phase of the infection.

Conclusion: The novel nature of SARS-CoV-2 has limited the number and size of studies on semen. Nevertheless, the current literature, while limited, has confirmed the presence of SARS-CoV-2 in semen in one out of the eight reported studies and totaling 4.3% of the population screened. Taken together, the risk of the presence of SARS-CoV-2 in semen appears to be extremely low and likely negligible in recovered men. Future studies need to focus on whether complete viral particles can be seen in semen and the possibility of sexual transmission.
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http://dx.doi.org/10.2147/RRU.S277679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718981PMC
December 2020

Pro-Resolving Lipid Mediator Resolvin E1 Mitigates the Progress of Diethylnitrosamine-Induced Liver Fibrosis in Sprague-Dawley Rats by Attenuating Fibrogenesis and Restricting Proliferation.

Int J Mol Sci 2020 Nov 22;21(22). Epub 2020 Nov 22.

Departamento de Ciencias Básicas Biomédicas, Facultad de Ciencias de la Salud, Universidad de Talca, Talca 3460000, Chile.

Liver fibrosis is a complex process associated to most types of chronic liver disease, which is characterized by a disturbance of hepatic tissue architecture and the excessive accumulation of extracellular matrix. Resolvin E1 (RvE1) is a representative member of the eicosapentaenoic omega-3 lipid derivatives, and is a drug candidate of the growing family of endogenous resolvins. Considering the aforementioned, the main objective of this study was to analyze the hepatoprotective effect of RvE1 in a rat model of liver fibrosis. Male Sprague-Dawley rats received diethylnitrosamine (DEN, 70 mg/mg body weight intraperitoneally (i.p)) as an inductor of liver fibrosis once weekly and RvE1(100 ng/body weight i.p) twice weekly for four weeks. RvE1 suppressed the alterations induced by DEN, normalizing the levels of alanine aminotransferase (ALT), albumin, and lactate dehydrogenase (LDH), and ameliorated DEN injury by decreasing the architecture distortion, inflammatory infiltration, necrotic areas, and microsteatosis. RvE1 also limited DEN-induced proliferation through a decrease in Ki67-positive cells and cyclin D1 protein expression, which is related to an increase of the levels of cleaved caspase-3. Interestingly, we found that RvE1 promotes higher nuclear translocation of nuclear factor κB (NF-κB)p65 than DEN. RvE1 also increased the levels of nuclear the nuclear factor erythroid 2-related factor 2 (Nrf2), but with no antioxidant effect, measured as an increase in glutathione disulfide (GSSG) and a decrease in the ratio of glutathione (GSH)/GSSG. Taken together, these results suggest that RvE1 modulates the fibrogenesis, steatosis, and cell proliferation in a model of DEN induced fibrosis.
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http://dx.doi.org/10.3390/ijms21228827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700193PMC
November 2020

The sunflower TLDc-containing protein HaOXR2 confers tolerance to oxidative stress and waterlogging when expressed in maize plants.

Plant Sci 2020 Nov 1;300:110626. Epub 2020 Aug 1.

Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Cátedra de Biología Celular y Molecular, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, 3000, Santa Fe, Argentina. Electronic address:

The sunflower (Helianthus annuus L.) genome encodes six proteins containing a TLDc domain, typical of the eukaryotic OXidation Resistance (OXR) protein family. Expression of sunflower HaOXR2 in Arabidopsis generated plants with increased rosette diameter, higher number of leaves and increased seed production. Maize inbred lines expressing HaOXR2 also showed increased total leaf area per plant. In addition, heterologous expression of HaOXR2 induced an increase in the oxidative stress tolerance in Arabidopsis and maize. Maize transgenic plants expressing HaOXR2 experienced less oxidative damage and exhibited increased photosynthetic performance and efficiency than non-transgenic segregant plants after treatment of leaves with the reactive oxygen species generating compound Paraquat. Expression of HaOXR2 in maize also improved tolerance to waterlogging. The number of expanded leaves, aerial biomass, and stem height and cross-section area were less affected by waterlogging in HaOXR2 expressing plants, which also displayed less aerial tissue damage under these conditions. Transgenic plants also showed an increased production of roots, a typical adaptive stress response. The results show the existence of functional conservation of OXR proteins in dicot and monocot plants and indicate that HaOXR2 could be useful to improve plant performance under conditions that increase oxidative stress.
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http://dx.doi.org/10.1016/j.plantsci.2020.110626DOI Listing
November 2020

Supporting Precision Dosing in Drug Labeling.

Clin Pharmacol Ther 2021 Jan 27;109(1):37-41. Epub 2020 Oct 27.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

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http://dx.doi.org/10.1002/cpt.2054DOI Listing
January 2021

Gas-phase kinetics of CHCHO with OH radicals between 11.7 and 177.5 K.

Phys Chem Chem Phys 2020 Sep;22(36):20562-20572

Departamento de Química Física, Facultad de Ciencias y Tecnologías Químicas, Universidad de Castilla-La Mancha, Avda. Camilo José Cela 1B, 13071, Ciudad Real, Spain. and Instituto de Investigación en Combustión y Contaminación Atmosférica (ICCA), Universidad de Castilla-La Mancha, Camino de Moledores s/n, 13071, Ciudad Real, Spain.

Gas-phase reactions in the interstellar medium (ISM) are a source of molecules in this environment. The knowledge of the rate coefficient for neutral-neutral reactions as a function of temperature, k(T), is essential to improve astrochemical models. In this work, we have experimentally measured k(T) for the reaction between the OH radical and acetaldehyde, both present in many sources of the ISM. Laser techniques coupled to a CRESU system were used to perform the kinetic measurements. The obtained modified Arrhenius equation is k(T = 11.7-177.5 K) = (1.2 ± 0.2) × 10-11 (T/300 K)-(1.8±0.1) exp-{(28.7 ± 2.5)/T} cm3 molecule-1 s-1. The k(T) value of the title reaction has been measured for the first time below 60 K. No pressure dependence of k(T) was observed at ca. 21, 50, 64 and 106 K. Finally, a pure gas-phase model indicates that the title reaction could become the main CH3CO formation pathway in dark molecular clouds, assuming that CH3CO is the main reaction product at 10 K.
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http://dx.doi.org/10.1039/d0cp03203dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116299PMC
September 2020

Therapeutic Effectiveness of Interferon-α2b Against COVID-19: The Cuban Experience.

J Interferon Cytokine Res 2020 09;40(9):438-442

Intensive Medicine Department, Octavio de la Concepcion y la Pedraja Military Hospital. Camagüey, Cuba.

A prospective observational study was conducted for assessing the therapeutic efficacy of interferon (IFN)-α2b in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first month after the coronavirus disease 2019 (COVID-19) outbreak began in Cuba. From March 11th to April 14th, 814 patients were confirmed SARS-CoV-2 positive in Cuba. Seven hundred sixty-one (93.4%) were treated with a combination of oral antivirals (lopinavir/ritonavir and chloroquine) with intramuscular administration of IFN-α2b (Heberon Alpha R, Center for Genetic Engineering and Biotechnology, Havana, Cuba), 3 times per week, for 2 weeks. Fifty-three patients received the approved COVID protocol without IFN treatment. The proportion of patients discharged from hospital (without clinical and radiological symptoms and nondetectable virus by real-time polymerase chain reaction) was higher in the IFN-treated compared with the non-IFN treated group (95.4% vs. 26.1%,  < 0.01). The case fatality rate (CFR) for all patients was 2.95%, and for those patients who received IFN-α2b the CFR was reduced to 0.92. Intensive care was required for 82 patients (10.1%), 42 (5.5%) had been treated with IFN. This report provides preliminary evidence for the therapeutic effectiveness of IFN-α2b for COVID-19 and suggests that the use of Heberon Alpha R may contribute to complete recovery of patients.
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http://dx.doi.org/10.1089/jir.2020.0124DOI Listing
September 2020

Class I TCP proteins TCP14 and TCP15 are required for elongation and gene expression responses to auxin.

Plant Mol Biol 2021 Jan 15;105(1-2):147-159. Epub 2020 Sep 15.

Instituto de Agrobiotecnología del Litoral, Cátedra de Biología Celular y Molecular, Facultad de Bioquímica y Ciencias Biológicas, CONICET-Universidad Nacional del Litoral, Centro Científico Tecnológico CONICET Santa Fe. Colectora Ruta Nac. Nº 168 km 0, Paraje el Pozo s/n, 3000, Santa Fe, Argentina.

Key Message: Two class I TCP transcription factors are required for an efficient elongation of hypocotyls in response to auxin and for the correct expression of a subset of auxin-inducible genes In this work, we analyzed the response to auxin of plants with altered function of the class I TEOSINTE BRANCHED 1, CYCLOIDEA, PCF (TCP) transcription factors TCP14 and TCP15. Several SMALL AUXIN UP RNA (SAUR) genes showed decreased expression in mutant plants defective in these TCPs after an increase in ambient temperature to 29 °C, a condition that causes an increase in endogenous auxin levels. Overexpression of SAUR63 caused a more pronounced elongation response in the mutant than in the wild-type at 29 °C, suggesting that the decreased expression of SAUR genes is partly responsible for the defective elongation at warm temperature. Notably, several SAUR genes and the auxin response gene IAA19 also showed reduced expression in the mutant after auxin treatment, while the expression of other SAUR genes and of IAA29 was not affected or was even higher. Expression of the auxin reporter DR5::GUS was also higher in a tcp15 mutant than in a wild-type background after auxin treatment. However, the elongation of hypocotyls in response to auxin was impaired in the mutant. Remarkably, a significant proportion of auxin inducible genes and of targets of the AUXIN RESPONSE FACTOR 6 are regulated by TCP15 and often contain putative TCP recognition motifs in their promoters. Furthermore, we demonstrated that several among them are recognized by TCP15 in vivo. Our results indicate that TCP14 and TCP15 are required for an efficient elongation response to auxin, most likely by regulating a subset of auxin inducible genes related to cell expansion.
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http://dx.doi.org/10.1007/s11103-020-01075-yDOI Listing
January 2021

Associations between stress exposure and new mothers' brain responses to infant cry sounds.

Neuroimage 2020 12 11;223:117360. Epub 2020 Sep 11.

Department of Psychology, University of Denver, Denver, 2155 South Race Street, Denver, CO 80208-3500, United States; Harvard Medical School, Boston, 25 Shattuck St, Boston, MA 02115, United States.

Exposure to severe stress has been linked to negative postpartum outcomes among new mothers including mood disorders and harsh parenting. Non-human animal studies show that stress exposure disrupts the normative adaptation of the maternal brain, thus identifying a neurobiological mechanism by which stress can lead to negative maternal outcomes. However, little is known about the impact of stress exposure on the maternal brain response to infant cues in human mothers. We examined the association of stress exposure with brain response to infant cries and maternal behaviors, in a socioeconomically diverse (low- and middle-income) sample of first-time mothers (N=53). Exposure to stress across socioeconomic, environmental, and psychosocial domains was associated with reduced brain response to infant cry sounds in several regions, including the right insula/inferior frontal gyrus and superior temporal gyrus. Reduced activation in these regions was further associated with lower maternal sensitivity observed during a mother-infant interaction. The findings demonstrate that higher levels of stress exposure may be associated with reduced brain response to an infant's cry in regions that are important for emotional and social information processing, and that reduced brain responses may further be associated with increased difficulties in developing positive mother-infant relationships.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117360DOI Listing
December 2020

Association between Nephrotoxic Drug Combinations and Acute Kidney Injury in the Neonatal Intensive Care Unit.

J Pediatr 2021 01 17;228:213-219. Epub 2020 Aug 17.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC. Electronic address:

Objective: To determine the incidence of acute kidney injury (AKI) in infants exposed to nephrotoxic drug combinations admitted to 268 neonatal intensive care units managed by the Pediatrix Medical Group.

Study Design: We included infants born at 22-36 weeks gestational age, ≤120 days postnatal age, exposed to nephrotoxic drug combinations, with serum creatinine measurements available, and discharged between 2007 and 2016. To identify risk factors associated with a serum creatinine definition of AKI based on the Kidney Disease: Improving Global Outcomes criteria, we performed multivariable logistic and Cox regression adjusting for gestational age, sex, birth weight, postnatal age, race/ethnicity, sepsis, respiratory distress syndrome, baseline serum creatinine, and duration of combination drug exposure. The adjusted odds of AKI were determined relative to gentamicin + indomethacin for the following nephrotoxic drug combinations: chlorothiazide + ibuprofen; chlorothiazide + indomethacin; furosemide + gentamicin; furosemide + ibuprofen; furosemide + tobramycin; ibuprofen + spironolactone; and vancomycin + piperacillin-tazobactam.

Results: Among 8286 included infants, 1384 (17%) experienced AKI. On multivariable analysis, sepsis, lower baseline creatinine, and duration of combination therapy were associated with increased odds of AKI. Furosemide + tobramycin and vancomycin + piperacillin-tazobactam were associated with a decreased risk of AKI relative to gentamicin + indomethacin in both the multivariable and Cox regression models.

Conclusions: In this cohort, infants receiving longer durations of nephrotoxic combination therapy had an increased odds of developing AKI.
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http://dx.doi.org/10.1016/j.jpeds.2020.08.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752849PMC
January 2021

Apocynin Treatment Prevents Cardiac Connexin 43 Hemichannels Hyperactivity by Reducing Nitroso-Redox Stress in Mdx Mice.

Int J Mol Sci 2020 Jul 30;21(15). Epub 2020 Jul 30.

Departamento de Ciencias Básicas Biomédicas, Facultad de Ciencias de la Salud, Universidad de Talca, Talca 3460000, Chile.

Duchenne muscular dystrophy (DMD) is a fatal disease that causes cardiomyopathy and is associated with oxidative stress. In the heart, oxidative stress interferes with the location of connexin 43 (Cx43) to the intercalated discs causing its lateralization to the plasma membrane where Cx43 forms hemichannels. We tested the hypothesis that in DMD cardiomyopathy, increased oxidative stress is associated with the formation and activation of Cx43 hemichannels. For this, we used mdx mice as a DMD model and evaluated cardiac function, nitroso-redox changes and Cx43 hemichannels permeability. Mdx hearts presented increased NADPH oxidase-derived oxidative stress and increased Cx43 S-nitrosylation compared to controls. These redox changes were associated with increased Cx43 lateralization, decreased cardiac contractility and increased arrhythmic events. Pharmacological inhibition of NADPH oxidase using apocynin (one month) reduced systemic oxidative stress and reversed the aforementioned changes towards normal, except Cx43 lateralization. Opening of Cx43 hemichannels was blocked by apocynin treatment and by acute hemichannel blockade with carbenoxolone. NADPH oxidase inhibition also prevented the occurrence of apoptosis in mdx hearts and reversed the ventricular remodeling. These results show that NADPH oxidase activity in DMD is associated with S-nitrosylation and opening of Cx43 hemichannels. These changes lead to apoptosis and cardiac dysfunction and were prevented by NADPH oxidase inhibition.
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http://dx.doi.org/10.3390/ijms21155415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432655PMC
July 2020

A cross-sectional comparison of secondary polycythemia in testosterone-deficient men treated with nasal testosterone gel vs. intramuscular testosterone cypionate.

Can Urol Assoc J 2021 Feb;15(2):E118-E122

Department of Urology, Miller School of Medicine, University of Miami, Miami, FL, United States.

Introduction: Secondary polycythemia is a known adverse effect of testosterone replacement therapy (TRT). Different testosterone formulations are available, with significantly different half-lives, which have varying influences on the development of secondary polycythemia. Herein, we compared the prevalence of secondary polycythemia in testosterone-deficient men treated with intranasal testosterone gel (Natesto) vs. intramuscular testosterone cypionate (TC) therapy.

Methods: We performed a cross-sectional analysis of secondary polycythemia (hematocrit [Hct] ≥54%) in men who received TRT. We included a total of 60 men: 30 men who received Natesto (4.5% testosterone gel [tid, 5.5 mg/nostril, 11 mg/dose, 33 mg/day]), and 30 who received TC (between 0.5 and 1.0 mL or 100-200 mg intramuscularly weekly). A univariable and multiple regression analysis was performed considering last Hct measurement as the main outcome. The analyzed variables included were age, body mass index (BMI), smoking history, treatment group, and testosterone levels on followup.

Results: We identified polycythemia (Hct ≥54%) in 10% (3/30) of men who received TC. Additionally, in men treated with TC, 33.3% (10/30) had a Hct ≥50% during therapy. None of the men who received Natesto had a Hct ≥50% during therapy. On multivariable linear regression analysis, we demonstrated that the use of TC increased Hct by 3.24% (95% confidence interval [CI] 0.74-5.73%, p=0.012) compared to Natesto.

Conclusions: The prevalence of polycythemia in men treated with Natesto was markedly lower compared to the men who received TC therapy.
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http://dx.doi.org/10.5489/cuaj.6651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864697PMC
February 2021

Creatinine-Based Renal Function Assessment in Pediatric Drug Development: An Analysis Using Clinical Data for Renally Eliminated Drugs.

Clin Pharmacol Ther 2021 Jan 29;109(1):263-269. Epub 2020 Aug 29.

Office of Drug Evaluation IV, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

The estimated glomerular filtration rate (eGFR) equations based on serum creatinine (SCR) have been used for pediatric dose adjustment in drug labeling. This study evaluated the performance of those equations in estimating individual clearance of drugs that are predominantly eliminated by glomerular filtration, using clinical data from the renally eliminated drugs gadobutrol, gadoterate, amikacin, and vancomycin. The eGFR was compared with the observed drug clearance (CL) in 352 pediatric patients from birth to 12 years of age. Multiple eGFR equations overestimated the drug CL on average, including the original and bedside Schwartz equations, which showed an average eGFR/CL ratio between 1 and 3. Further analysis with bedside Schwartz equation showed a higher eGFR/CL ratio in the subjects with a lower SCR or CL. Supraphysiological eGFR as high as 380 mL/min/1.73 m was obtained using the bedside Schwartz equation for some of the subjects, most of whom are children < 2 years of age with SCR < 0.2 mg/dL. Excluding the subjects with supraphysiological eGFR from the analysis did not change the overall trend of overestimation. In conclusion, Schwartz equations led to an overestimation of drug clearance for the drugs evaluated. When greater precision is required in predicting eGFR for pediatric patients, such as in drug dosing, revised k constants for the Schwartz equation or new methods of glomerular filtration rate estimation may be necessary.
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http://dx.doi.org/10.1002/cpt.1991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855729PMC
January 2021

Physiologically-Based Pharmacokinetic Modeling Characterizes the CYP3A-Mediated Drug-Drug Interaction Between Fluconazole and Sildenafil in Infants.

Clin Pharmacol Ther 2021 Jan 22;109(1):253-262. Epub 2020 Aug 22.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Physiologically-based pharmacokinetic (PBPK) modeling can potentially predict pediatric drug-drug interactions (DDIs) when clinical DDI data are limited. In infants for whom treatment of pulmonary hypertension and prevention or treatment of invasive candidiasis are indicated, sildenafil with fluconazole may be given concurrently. To account for developmental changes in cytochrome P450 (CYP) 3A, we determined and incorporated fluconazole inhibition constants (K ) for CYP3A4, CYP3A5, and CYP3A7 into a PBPK model developed for sildenafil and its active metabolite, N-desmethylsildenafil. Pharmacokinetic (PK) data in preterm infants receiving sildenafil with and without fluconazole were used for model development and evaluation. The simulated PK parameters were comparable to observed values. Following fluconazole co-administration, differences in the fold change for simulated steady-state area under the plasma concentration vs. time curve from 0 to 24 hours (AUC ) were observed between virtual adults and infants (2.11-fold vs. 2.82-fold change). When given in combination with treatment doses of fluconazole (12 mg/kg i.v. daily), reducing the sildenafil dose by ~ 60% resulted in a geometric mean ratio of 1.01 for simulated AUC relative to virtual infants receiving sildenafil alone. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters.
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http://dx.doi.org/10.1002/cpt.1990DOI Listing
January 2021

Proceedings of a Workshop: Precision Dosing: Defining the Need and Approaches to Deliver Individualized Drug Dosing in the Real-World Setting.

Clin Pharmacol Ther 2021 Jan 14;109(1):25-28. Epub 2020 Jul 14.

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

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http://dx.doi.org/10.1002/cpt.1933DOI Listing
January 2021

Use of 4K3D Video Microscope in Male Infertility Microsurgery.

Urol Video J 2020 Sep 15;7. Epub 2020 Jun 15.

Department of Urology, University of Miami, Miller School of Medicine, Miami, Florida, USA.

Objective: To evaluate a 4K3D video microscope in the operating room of an outpatient surgical center during male infertility microsurgery procedures.

Design: Video presentation.

Setting: University of Miami outpatient surgical center.

Patients: All patients undergoing microsurgical procedures who signed a written, informed consent for video and audio recording.

Interventions: vasovasotomy, vasoepididymostomy, varicocele repair, microsurgical testicular sperm extraction.

Main Outcome Measures: Operating room times and surgeon fatigue.

Results: This video demonstrates the potential advantages of a 4K3D video microscope in the operating room compared to the standard optical operating microscope (SOM), as well as robotic assisted microsurgery. Operating times for all varicocele repair cases performed with the 4k3D video microscope during the 4-week trial period (6), were compared to the 6 most recent varicocelectomies done with a SOM. We observed a decrease in the median operating room times (74.5 minutes vs 96.5 minutes) for those surgeries involving the 4k3D video microscope. Mann Whitney U test was used to compare median operating times, however, because of our small sample size this was not statistically significant (p=0.092) (Figure 1). Additionally, between cases, the transport of microscope from room to room, draping and setup of the 4k3D video microscope required less time and was less strenuous for the OR staff. The 4k3D video microscope allows the surgeon to operate in a more ergonomic position compared to the SOM and comes at a price point which is more reasonable than a surgical robot (DaVinci).

Conclusion: The 4K3D video microscope offers potential ergonomic and logistical advantages over the SOM and robotically assisted surgery. Future studies with larger sample sizes are needed to evaluate these potential advantages and objectively study the ergonomic improvements that the 4k3D video microscope offers over the SOM.
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http://dx.doi.org/10.1016/j.urolvj.2020.100046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357899PMC
September 2020

Simulated Assessment of Pharmacokinetically Guided Dosing for Investigational Treatments of Pediatric Patients With Coronavirus Disease 2019.

JAMA Pediatr 2020 10 5;174(10):e202422. Epub 2020 Oct 5.

Duke Clinical Research Institute, Durham, North Carolina.

Importance: Children of all ages appear susceptible to severe acute respiratory syndrome coronavirus 2 infection. To support pediatric clinical studies for investigational treatments of coronavirus disease 2019 (COVID-19), pediatric-specific dosing is required.

Objective: To define pediatric-specific dosing regimens for hydroxychloroquine and remdesivir for COVID-19 treatment.

Design, Setting, And Participants: Pharmacokinetic modeling and simulation were used to extrapolate investigated adult dosages toward children (March 2020-April 2020). Physiologically based pharmacokinetic modeling was used to inform pediatric dosing for hydroxychloroquine. For remdesivir, pediatric dosages were derived using allometric-scaling with age-dependent exponents. Dosing simulations were conducted using simulated pediatric and adult participants based on the demographics of a white US population.

Interventions: Simulated drug exposures following a 5-day course of hydroxychloroquine (400 mg every 12 hours × 2 doses followed by 200 mg every 12 hours × 8 doses) and a single 200-mg intravenous dose of remdesivir were computed for simulated adult participants. A simulation-based dose-ranging study was conducted in simulated children exploring different absolute and weight-normalized dosing strategies.

Main Outcomes And Measures: The primary outcome for hydroxychloroquine was average unbound plasma concentrations for 5 treatment days. Additionally, unbound interstitial lung concentrations were simulated. For remdesivir, the primary outcome was plasma exposure (area under the curve, 0 to infinity) following single-dose administration.

Results: For hydroxychloroquine, the physiologically based pharmacokinetic model analysis included 500 and 600 simulated white adult and pediatric participants, respectively, and supported weight-normalized dosing for children weighing less than 50 kg. Geometric mean-simulated average unbound plasma concentration values among children within different developmental age groups (32-35 ng/mL) were congruent to adults (32 ng/mL). Simulated unbound hydroxychloroquine concentrations in lung interstitial fluid mirrored those in unbound plasma and were notably lower than in vitro concentrations needed to mediate antiviral activity. For remdesivir, the analysis included 1000 and 6000 simulated adult and pediatric participants, respectively. The proposed pediatric dosing strategy supported weight-normalized dosing for participants weighing less than 60 kg. Geometric mean-simulated plasma area under the time curve 0 to infinity values among children within different developmental age-groups (4315-5027 ng × h/mL) were similar to adults (4398 ng × h/mL).

Conclusions And Relevance: This analysis provides pediatric-specific dosing suggestions for hydroxychloroquine and remdesivir and raises concerns regarding hydroxychloroquine use for COVID-19 treatment because concentrations were less than those needed to mediate an antiviral effect.
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http://dx.doi.org/10.1001/jamapediatrics.2020.2422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275264PMC
October 2020

Class I TCP transcription factors regulate trichome branching and cuticle development in Arabidopsis.

J Exp Bot 2020 09;71(18):5438-5453

Instituto de Agrobiotecnología del Litoral (CONICET-UNL), Cátedra de Biología Celular y Molecular, Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina.

Trichomes and the cuticle are two specialized structures of the aerial epidermis that are important for plant organ development and interaction with the environment. In this study, we report that Arabidopsis thaliana plants affected in the function of the class I TEOSINTE BRANCHED 1, CYCLOIDEA, PCF (TCP) transcription factors TCP14 and TCP15 show overbranched trichomes in leaves and stems and increased cuticle permeability. We found that TCP15 regulates the expression of MYB106, a MIXTA-like transcription factor involved in epidermal cell and cuticle development, and overexpression of MYB106 in a tcp14 tcp15 mutant reduces trichome branch number. TCP14 and TCP15 are also required for the expression of the cuticle biosynthesis genes CYP86A4, GPAT6, and CUS2, and of SHN1 and SHN2, two AP2/EREBP transcription factors required for cutin and wax biosynthesis. SHN1 and CUS2 are also targets of TCP15, indicating that class I TCPs influence cuticle formation acting at different levels, through the regulation of MIXTA-like and SHN transcription factors and of cuticle biosynthesis genes. Our study indicates that class I TCPs are coordinators of the regulatory network involved in trichome and cuticle development.
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http://dx.doi.org/10.1093/jxb/eraa257DOI Listing
September 2020