RESUMO
The phytohormone abscisic acid (ABA) promotes plant tolerance to major stresses such as drought, partly by modulating growth through poorly understood mechanisms. Here, we show that ABA-triggered repression of cell proliferation in the Arabidopsis thaliana root meristem relies on the swift subcellular relocalization of SNF1-RELATED KINASE 1 (SnRK1). Under favorable conditions, the SnRK1 catalytic subunit, SnRK1α1, is enriched in the nuclei of root cells, and this is accompanied by normal cell proliferation and meristem size. Depletion of two key drivers of ABA signaling, SnRK2.2 and SnRK2.3, causes constitutive cytoplasmic localization of SnRK1α1 and reduced meristem size, suggesting that, under nonstress conditions, SnRK2s promote growth by retaining SnRK1α1 in the nucleus. In response to ABA, SnRK1α1 translocates to the cytoplasm, and this is accompanied by inhibition of target of rapamycin (TOR), decreased cell proliferation, and reduced meristem size. Blocking nuclear export with leptomycin B abrogates ABA-driven SnRK1α1 relocalization to the cytoplasm and ABA-elicited inhibition of TOR. Furthermore, fusing SnRK1α1 to an SV40 nuclear localization signal leads to defective ABA-dependent TOR repression. Altogether, we demonstrate that SnRK2-dependent changes in SnRK1α1 subcellular localization are crucial for inhibiting TOR and root growth in response to ABA. Rapid relocalization of central regulators such as SnRK1 may represent a general strategy of eukaryotic organisms to respond to environmental changes.
Assuntos
Proteínas de Arabidopsis , Arabidopsis/metabolismo , Raízes de Plantas/metabolismo , Proteínas Serina-Treonina Quinases , Ácido Abscísico/metabolismo , Proteínas de Arabidopsis/metabolismo , Meristema/metabolismo , Fosfatidilinositol 3-Quinases , Fosforilação , Raízes de Plantas/citologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de SinaisRESUMO
Turritopsis dohrnii is the only metazoan able to rejuvenate repeatedly after its medusae reproduce, hinting at biological immortality and challenging our understanding of aging. We present and compare whole-genome assemblies of T. dohrnii and the nonimmortal Turritopsis rubra using automatic and manual annotations, together with the transcriptome of life cycle reversal (LCR) process of T. dohrnii. We have identified variants and expansions of genes associated with replication, DNA repair, telomere maintenance, redox environment, stem cell population, and intercellular communication. Moreover, we have found silencing of polycomb repressive complex 2 targets and activation of pluripotency targets during LCR, which points to these transcription factors as pluripotency inducers in T. dohrnii. Accordingly, we propose these factors as key elements in the ability of T. dohrnii to undergo rejuvenation.
Assuntos
Hidrozoários , Rejuvenescimento , Animais , Genômica , Hidrozoários/genética , Hidrozoários/crescimento & desenvolvimento , Estágios do Ciclo de Vida/genética , TranscriptomaRESUMO
Plants need to integrate internal and environmental signals to mount adequate stress responses. The NUCLEAR PORE COMPLEX (NPC) component HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES 1 (HOS1) is emerging as such an integrator, affecting responses to cold, heat, light, and salinity. Stress conditions often converge in a low-energy signal that activates SUCROSE NON-FERMENTING 1-RELATED KINASE 1 (SnRK1) to promote stress tolerance and survival. Here, we explored the role of HOS1 in the SnRK1-dependent response to low-energy stress in Arabidopsis thaliana, using darkness as a treatment and a combination of genetic, biochemical, and phenotypic assays. We show that the induction of starvation genes and plant tolerance to prolonged darkness are defective in the hos1 mutant. HOS1 interacts physically with the SnRK1α1 catalytic subunit in yeast two-hybrid assays and in planta, and the nuclear accumulation of SnRK1α1 is reduced in the hos1 mutant. Likewise, another NPC mutant, nup160, exhibits lower activation of starvation genes and decreased tolerance to prolonged darkness. Importantly, defects in low-energy responses in the hos1 background are rescued by fusing SnRK1α1 to a potent nuclear localization signal or by sugar supplementation during the dark treatment. Altogether, this work demonstrates the importance of HOS1 for the nuclear accumulation of SnRK1α1, which is key for plant tolerance to low-energy conditions.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Proteínas Quinases/genética , Proteínas Nucleares/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Cardioembolic stroke is one of the most devastating complications of nonischemic dilated cardiomyopathy (NIDCM). However, in clinical trials of primary prevention, the benefits of anticoagulation are hampered by the risk of bleeding. Indices of cardiac blood stasis may account for the risk of stroke and be useful to individualize primary prevention treatments. We performed a cross-sectional study in patients with NIDCM and no history of atrial fibrillation (AF) from two sources: 1) a prospective enrollment of unselected patients with left ventricular (LV) ejection fraction <45% and 2) a retrospective identification of patients with a history of previous cardioembolic neurological event. The primary end point integrated a history of ischemic stroke or the presence intraventricular thrombus, or a silent brain infarction (SBI) by imaging. From echocardiography, we calculated blood flow inside the LV, its residence time (TR) maps, and its derived stasis indices. Of the 89 recruited patients, 18 showed a positive end point, 9 had a history of stroke or transient ischemic attack (TIA) and 9 were diagnosed with SBIs in the brain imaging. Averaged TR, [Formula: see text] performed well to identify the primary end point [AUC (95% CI) = 0.75 (0.61-0.89), P = 0.001]. When accounting only for identifying a history of stroke or TIA, AUC for [Formula: see text] was 0.92 (0.85-1.00) with odds ratio = 7.2 (2.3-22.3) per cycle, P < 0.001. These results suggest that in patients with NIDCM in sinus rhythm, stasis imaging derived from echocardiography may account for the burden of stroke.NEW & NOTEWORTHY Patients with nonischemic dilated cardiomyopathy (NIDCM) are at higher risk of stroke than their age-matched population. However, the risk of bleeding neutralizes the benefit of preventive oral anticoagulation. In this work, we show that in patients in sinus rhythm, the burden of stroke is related to intraventricular stasis metrics derived from echocardiography. Therefore, stasis metrics may be useful to personalize primary prevention anticoagulation in these patients.
Assuntos
Cardiomiopatia Dilatada , Humanos , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Dilatada/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Transversais , Estudos Retrospectivos , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/etiologia , Infarto Encefálico/fisiopatologia , Ecocardiografia , Função Ventricular Esquerda , Fatores de Risco , Estudos Prospectivos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/prevenção & controle , AVC Embólico/etiologia , AVC Embólico/prevenção & controle , AVC Embólico/diagnóstico por imagem , Doenças Assintomáticas , Volume SistólicoRESUMO
ABSTRA: Osteological collections are an important resource for the development of methods to assist in the study of skeletal remains in archeological and/or forensic contexts. The aim is to describe the current characteristics of the Identified Skeletal Collection of the School of Legal Medicine and its historical context. The Identified Skeletal Collection of the School of Legal Medicine of the Complutense University of Madrid consists of 138 male and 95 female individuals, born between 1880 and 1980 and deceased between 1970 and 2009. The minimum age of the sample is perinatal and the maximum age is 97 years. The collection is an essential tool for forensic research, given that its population characteristics can be extrapolated to those of present-day Spain. Access to this collection offers unique teaching opportunities as well as provides the information necessary to develop various lines of research.
Assuntos
Antropologia Forense , Medicina Legal , Humanos , Masculino , Feminino , Idoso de 80 Anos ou mais , Espanha , Universidades , Restos MortaisRESUMO
BACKGROUND: The clinical use of colistin methanesulphonate (CMS) is limited by potential nephrotoxicity. The selection of an efficient and safe CMS dose for individual patients is complicated by the narrow therapeutic window and high interpatient pharmacokinetic variability. In this study, a simple predictive equation for estimating the plasma concentration of formed colistin in patients with multidrug and extremely drug-resistant gram-negative bacterial infections was developed. METHODS: The equation was derived from the largest clinical cohort of patients undergoing therapeutic drug monitoring (TDM) of colistin for over 8 years in a tertiary Spanish hospital. All variables associated with Css,avg were selected in a multiple linear regression model that was validated in a second cohort of 40 patients. Measured Css,avg values were compared with those predicted by our model and a previous published algorithm for critically ill patients. RESULTS: In total, 276 patients were enrolled [the mean age was 67.2 (13.7) years, 203 (73.6%)] were male, and the mean (SD) Css,avg was 1.12 (0.98) mg/L. Age, gender, estimated glomerular filtration rate, CMS dose and frequency, and concomitant drugs were included in the model. In the external validation, the previous algorithm appeared to yield more optimized colistin plasma concentrations when all types of Css,avg values (high and low) were considered, while our equation yielded a more optimized prediction in the subgroup of patients with low colistin plasma concentrations (Css,avg <1.5 mg/L). CONCLUSIONS: The proposed equation may help clinicians to better use CMS among a wide variety of patients, to maximize efficacy and prevent nephrotoxicity. A further prospective PK study is warranted to externally validate this algorithm.
RESUMO
OBJECTIVE: The aim of this study was to compare surgical complexity, post-operative complications, and survival outcomes between patients with minimal residual disease (completeness of cytoreduction (CC) score) CC-1 at the time of primary debulking surgery and those with complete cytoreduction (CC-0) at the time of interval debulking surgery. METHODS: A retrospective multicenter study was conducted of patients with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage IIIC-IV) who underwent cytoreductive surgery achieving either minimal or no residual disease between January 2008 and December 2015. Patients underwent either primary or interval debulking surgery after receiving ≥3 cycles of neoadjuvant chemotherapy. The sub-group of patients with primary debulking surgery/CC-1 was compared with those with interval debulking surgery/CC-0. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. RESULTS: A total of 549 patients were included, with upfront surgery performed in 175 patients (31.9%) and 374 patients (68.1%) undergoing interval debulking surgery. After primary debulking surgery, 157/175 (89.7%) had complete cytoreduction and 18/175 (10.3%) had minimal residual disease (primary debulking surgery/CC-1 group), while after interval debulking surgery, 324/374 (86.6%) had complete cytoreduction (interval debulking surgery/CC-0 group) and 50/374 (13.4%) had minimal residual disease. The rate of patients with peritoneal cancer index >10 was 14/17 (82.4%) for the primary debulking surgery/CC-1 group and 129/322 (40.1%) for the interval debulking surgery/CC-0 (p<0.001). The rate of patients with an Aletti score of ≥8 was 11/18 (61.1%) and 132/324 (40.7%), respectively (p=0.09) and the rate of major post-operative complications was 5/18 (27.8%) and 64/324 (19.8%), respectively (p=0.38). Overall median disease-free and overall survival were 19.4 months (95% CI 18.0 to 20.6) and 56.7 months (95%CI 50.2 to 65.8), respectively. Median disease-free survival for the primary debulking surgery/CC-1 group was 16.7 months (95% CI 13.6 to 20.0) versus 18.2 months (95% CI 16.4 to 20.0) for the interval debulking surgery/CC-0 group (p=0.56). Median overall survival for the primary debulking surgery/CC-1 group was 44.7 months (95% CI 34.3 to not reached) and 49.4 months (95% CI 46.2 to 57.3) for the interval debulking surgery/CC-0 group (p=0.97). CONCLUSIONS: Patients with primary debulking surgery with minimal residual disease and those with interval debulking surgery with no residual disease had similar survival outcomes. Interval surgery should be considered when achieving absence of residual disease is challenging at upfront surgery, given the lower tumor burden found during surgery.
RESUMO
PURPOSE: Fifty percent of cranial CT scans performed achieve no benefit and entail risks. Our aim is to determine the yield of non-traumatic urgent cranial-CT and develop a pretest clinical probability scale approach. METHODS: Adult patients seen in our emergency department between 2017-2021 and referred for urgent cranial-CT for non-traumatic reasons were retrospectively recruited and randomly selected. Presenting complaint (PC), demographic variables, Relevant radiological findings (RRF) on the urgent cranial-CT and Relevant clinical-radiological findings (RCRF: admission need or RRF detection on the urgent cranial-CT or cranial CT/MRI in the following three months) were recruited. RESULTS: We recruited 702 patients, with median age 62 [47-76] years, 363 (51.7%) females. RCRF were observed in 404 (57.55%); of these, 352 (50.1%) required admission. RRF were detected in 190 (27.06%): 36 acute ischemic and 27 acute hemorrhagic lesions, 115 masses, 9 edema, and 27 hydrocephalus. Predictive PC for urgent cranial-CT were motor, speech, sensory deficits, sudden alteration of mental status, epileptic seizure, cognitive impairment, neurological symptoms in cancer patients, acute headache without a prior history and with meningeal signs; nausea, vomiting, or hypertensive crisis; visual deficits, and dizziness. This algorithm provided sensitivity, specificity, positive predictive value, and negative predictive value (NPV, 95%CI in brackets) of 92.1% (89-94.5%), 27.5% (22.5-33.0%), 63.3% (59.2-67.2%), and 71.9% (62.7-80.0%), to diagnose RCRF, and 97.4% (93.4-99.1%), 21.3% (17.8-25.1%), 31.5% (27.7-35.4%), and 95.6% (90.1-98.6%), to diagnose RRF. In patients not requiring admission (n = 350), the NPV for RRF was 98.8% (93.6-100%); the negative likelihood ratio 0.08 (0.01-0.57), and sensitivity remained at 97.8% (82.2-99.9%). Applying it would have avoided performing 85/350 urgent cranial-CT (24.29%). To find one RRF, we would have gone from performing 7.8 (350/45) to 5.9 (265/45) CTs, failing to diagnose 1/45 (2.2%) RRF. CONCLUSIONS: This proposed clinical scale could potentially decrease 24% of urgent cranial-CT.
RESUMO
BACKGROUND: The response to inhaled corticosteroids (ICS) in asthma is affected by the interplay of several factors. Among these, the role of the upper-airway microbiome has been scarcely investigated. We aimed to evaluate the association between the salivary, pharyngeal, and nasal microbiome with asthma exacerbations despite receipt of ICS. METHODS: Samples from 250 asthma patients from the Genomics and Metagenomics of Asthma Severity (GEMAS) study treated with ICS were analyzed. Control/case subjects were defined by the absence/presence of asthma exacerbations in the past 6 months despite being treated with ICS. The bacterial microbiota was profiled by sequencing the V3-V4 region of the 16S rRNA gene. Differences between groups were assessed by PERMANOVA and regression models adjusted for potential confounders. A false discovery rate (FDR) of 5% was used to correct for multiple comparisons. Classification models of asthma exacerbations despite ICS treatment were built with machine learning approaches based on clinical, genetic, and microbiome data. RESULTS: In nasal and saliva samples, case subjects had lower bacterial diversity (Richness, Shannon, and Faith indices) than control subjects (.007 ≤ P ≤ .037). Asthma exacerbations accounted for 8% to 9% of the interindividual variation of the salivary and nasal microbiomes (.003 ≤ P ≤ .046). Three, 4, and 11 bacterial genera from the salivary, pharyngeal, and nasal microbiomes were differentially abundant between groups (4.09 × 10-12 ≤ FDR ≤ 0.047). Integrating clinical, genetic, and microbiome data showed good discrimination for the development of asthma exacerbations despite receipt of ICS (AUCtraining: 0.82 and AUCvalidation: 0.77). CONCLUSION: The diversity and composition of the upper-airway microbiome are associated with asthma exacerbations despite ICS treatment. The salivary microbiome has a potential application as a biomarker of asthma exacerbations despite receipt of ICS.
Assuntos
Antiasmáticos , Asma , Microbiota , Humanos , Antiasmáticos/uso terapêutico , RNA Ribossômico 16S , Administração por Inalação , Asma/tratamento farmacológico , Corticosteroides/uso terapêutico , BiomarcadoresRESUMO
BACKGROUND: The upper-airway microbiome is involved in asthma exacerbations despite inhaled corticosteroid (ICS) treatment. Although human genetics regulates microbiome composition, its influence on asthma-related airway bacteria remains unknown. OBJECTIVE: We sought to identify genes and biological pathways regulating airway-microbiome traits involved in asthma exacerbations and ICS response. METHODS: Saliva, nasal, and pharyngeal samples from 257 European patients with asthma were analyzed. The association of 6,296,951 genetic variants with exacerbation-related microbiome traits despite ICS treatment was tested through microbiome genome-wide association studies. Variants with 1 × 10-4
Assuntos
Antiasmáticos , Asma , Humanos , Antiasmáticos/uso terapêutico , Estudo de Associação Genômica Ampla , NF-kappa B/genética , Administração por Inalação , Asma/tratamento farmacológico , Asma/genética , Corticosteroides/uso terapêutico , Genética Humana , Citidina Desaminase , Antígenos de Histocompatibilidade Menor , Proteínas de Transporte/genéticaRESUMO
Posttranslational modifications (PTMs), particularly phosphorylation, play a pivotal role in expanding the complexity of the proteome and regulating diverse cellular processes. In this study, we present an efficient Escherichia coli phosphorylation system designed to streamline the evaluation of potential substrates for Arabidopsis thaliana plant kinases, although the technology is amenable to any. The methodology involves the use of IPTG-inducible vectors for co-expressing kinases and substrates, eliminating the need for radioactive isotopes and prior protein purification. We validated the system's efficacy by assessing the phosphorylation of well-established substrates of the plant kinase SnRK1, including the rat ACETYL-COA CARBOXYLASE 1 (ACC1) and FYVE1/FREE1 proteins. The results demonstrated the specificity and reliability of the system in studying kinase-substrate interactions. Furthermore, we applied the system to investigate the phosphorylation cascade involving the A. thaliana MKK3-MPK2 kinase module. The activation of MPK2 by MKK3 was demonstrated to phosphorylate the Myelin Basic Protein (MBP), confirming the system's ability to unravel sequential enzymatic steps in phosphorylation cascades. Overall, this E. coli phosphorylation system offers a rapid, cost-effective, and reliable approach for screening potential kinase substrates, presenting a valuable tool to complement the current portfolio of molecular techniques for advancing our understanding of kinase functions and their roles in cellular signaling pathways.
Assuntos
Proteínas de Arabidopsis , Arabidopsis , Animais , Ratos , Fosforilação , Escherichia coli/genética , Reprodutibilidade dos Testes , Processamento de Proteína Pós-Traducional , Proteínas Serina-Treonina Quinases , Proteínas de Transporte VesicularRESUMO
Papillary thyroid carcinoma (PTC) is the most common histological category of thyroid cancer. In recent years, there has been an increasing number of studies on lncRNAs in PTC. Long intergenic non-protein coding RNA 887 (LINC00887) is a critical oncogene in developing other cancers. LINC00887 is upregulated in PTC samples but its role in PTC is currently unclear. This study aimed to investigate the impact the disruption of LINC00887 expression has on PTC progression. We performed a CRISPR/Cas9 strategy for the truncation of LINC00887 in BCPAP and TPC1 cell lines. Functional assays showed that LINC00887 knockdown in both TPC1 and BCPAP cells reduced cell proliferation, colony formation and migration, delayed the cell cycle, and increased apoptosis. These results strengthened the role of LINC00887 in cancer and showed for the first time that this lncRNA could be a potential oncogene in PTC, acting as a tumor promoter. Modulation of the immune system may be one of the etiopathogenic mechanisms of LINC00887 in PTC, as shown by the observed influence of this lncRNA on PD-L1 expression. In addition, the biological pathways of LINC00887 identified to date, such as EMT, the Wnt/ß-catenin signaling pathway or the FRMD6-Hippo signaling pathway may also be relevant regulatory mechanisms operating in PTC.
Assuntos
Carcinoma Papilar , RNA Longo não Codificante , Câncer Papilífero da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , RNA Longo não Codificante/genética , Câncer Papilífero da Tireoide/genética , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Regulação para Cima/genéticaRESUMO
OBJECTIVE: The recommendations of the Spanish Ministry of Health on vaccination in risk groups include mesalazine among the treatments with a possible negative effect on its effectiveness. However, this is not the recommendation of most experts. Our objective was to evaluate the effect of mesalazine on the humoral response to the SARS-CoV-2 vaccine in patients with inflammatory bowel disease (IBD). METHODS: VACOVEII is a Spanish, prospective, multicenter study promoted by GETECCU, which evaluates the effectiveness of the SARS-CoV-2 vaccine in patients with IBD. This study includes IBD patients who have recieved the full vaccination schedule and without previous COVID-19 infection. Seroconversion was set at 260BAU/mL (centralized determination) and was assessed 6 months after full vaccination. In this subanalysis of the study, we compare the effectiveness of the vaccine between patients treated with mesalazine and patients without treatment. RESULTS: A total of 124 patients without immunosuppressive therapy were included, of which 32 did not receive any treatment and 92 received only mesalazine. Six months after full vaccination, no significant differences are observed in the mean concentrations of IgG anti-S between both groups. In the multivariate analysis, antibody titers were independently associated with the use of mRNA vaccines and with SARS-CoV-2 infection. CONCLUSION: Mesalazine does not have a negative effect on the response to SARS-CoV-2 vaccines in IBD patients.
Assuntos
Anti-Inflamatórios não Esteroides , Vacinas contra COVID-19 , COVID-19 , Doenças Inflamatórias Intestinais , Mesalamina , Humanos , Mesalamina/uso terapêutico , Feminino , Estudos Prospectivos , Masculino , Vacinas contra COVID-19/imunologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Pessoa de Meia-Idade , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , COVID-19/prevenção & controle , COVID-19/imunologia , Anticorpos Antivirais/sangue , Vacinação , Idoso , Soroconversão , Eficácia de Vacinas , SARS-CoV-2/imunologiaRESUMO
INTRODUCTION: Biological therapies used for the treatment of inflammatory bowel disease (IBD) have shown to be effective and safe, although these results were obtained from studies involving mostly a young population, who are generally included in clinical trials. The aim of our study was to determine the efficacy and safety of the different biological treatments in the elderly population. METHODS: Multicenter study was carried out in the GETECCU group. Patients diagnosed with IBD and aged over 65 years at the time of initiating biological therapy (infliximab, adalimumab, golimumab, ustekinumab or vedolizumab) were retrospectively included. Among the patients included, clinical response was assessed after drug induction (12 weeks of treatment) and at 52 weeks. Patients' colonoscopy data in week 52 were assessment, where available. Regarding complications, development of oncological events during follow-up and infectious processes occurring during biological treatment were collected (excluding bowel infection by cytomegalovirus). RESULTS: A total of 1090 patients were included. After induction, at approximately 12-14 weeks of treatment, 419 patients (39.6%) were in clinical remission, 502 patients (47.4%) had responded without remission and 137 patients (12.9%) had no response. At 52 weeks of treatment 442 patients (57.1%) had achieved clinical remission, 249 patients had responded without remission (32.2%) and 53 patients had no response to the treatment (6.8%). Before 52 weeks, 129 patients (14.8%) had discontinued treatment due to inefficacy, this being significantly higher (p<0.0001) for Golimumab - 9 patients (37.5%) - compared to the other biological treatments analyzed. With respect to tumor development, an oncological event was observed in 74 patients (6.9%): 30 patients (8%) on infliximab, 23 (7.14%) on adalimumab, 3 (11.1%) on golimumab, 10 (6.4%) on ustekinumab, and 8 (3.8%) on vedolizumab. The incidence was significantly lower (p=0.04) for the vedolizumab group compared to other treatments. As regards infections, these occurred in 160 patients during treatment (14.9%), with no differences between the different biologicals used (p=0.61): 61 patients (19.4%) on infliximab, 39 (12.5%) on adalimumab, 5 (17.8%) on golimumab, 22 (14.1%) on ustekinumab, and 34 (16.5%) on vedolizumab. CONCLUSIONS: Biological drug therapies have response rates in elderly patients similar to those described in the general population, Golimumab was the drug that was discontinued most frequently due to inefficacy. In our experience, tumor development was more frequent in patients who used anti-TNF therapies compared to other targets, although its incidence was generally low and that this is in line with younger patients based on previous literature.
RESUMO
BACKGROUND: In the USA, genetically admixed populations have the highest asthma prevalence and severe asthma exacerbations rates. This could be explained not only by environmental factors but also by genetic variants that exert ethnic-specific effects. However, no admixture mapping has been performed for severe asthma exacerbations. OBJECTIVE: We sought to identify genetic variants associated with severe asthma exacerbations in Hispanic/Latino subgroups by means of admixture mapping analyses and fine mapping, and to assess their transferability to other populations and potential functional roles. METHODS: We performed an admixture mapping in 1124 Puerto Rican and 625 Mexican American children with asthma. Fine-mapping of the significant peaks was performed via allelic testing of common and rare variants. We performed replication across Hispanic/Latino subgroups, and the transferability to non-Hispanic/Latino populations was assessed in 1001 African Americans, 1250 Singaporeans and 941 Europeans with asthma. The effects of the variants on gene expression and DNA methylation from whole blood were also evaluated in participants with asthma and in silico with data obtained through public databases. RESULTS: Genomewide significant associations of Indigenous American ancestry with severe asthma exacerbations were found at 5q32 in Mexican Americans as well as at 13q13-q13.2 and 3p13 in Puerto Ricans. The single nucleotide polymorphism (SNP) rs1144986 (C5orf46) showed consistent effects for severe asthma exacerbations across Hispanic/Latino subgroups, but it was not validated in non-Hispanics/Latinos. This SNP was associated with DPYSL3 DNA methylation and SCGB3A2 gene expression levels. CONCLUSIONS: Admixture mapping study of asthma exacerbations revealed a novel locus that exhibited Hispanic/Latino-specific effects and regulated DPYSL3 and SCGB3A2.
Assuntos
Asma , Hispânico ou Latino , Adolescente , Humanos , Asma/genética , Estudo de Associação Genômica Ampla , Hispânico ou Latino/genética , Polimorfismo de Nucleotídeo Único , Estados Unidos/epidemiologia , Criança , Americanos MexicanosRESUMO
Compulsivity is considered a transdiagnostic dimension in obsessive-compulsive and related disorders, characterized by heterogeneous cognitive and behavioral phenotypes associated with abnormalities in cortico-striatal-thalamic-cortical circuitry. The present study investigated the structural morphology of white and gray matter in rats selected for low- (LD) and high- (HD) compulsive drinking behavior on a schedule-induced polydipsia (SIP) task. Regional brain morphology was assessed using ex-vivo high-resolution magnetic resonance imaging (MRI). Voxel-based morphometry of segmented MRI images revealed larger white matter volumes in anterior commissure and corpus callosum of HD rats compared with LD rats. HD rats also showed significantly larger regional volumes of dorsolateral orbitofrontal cortex, striatum, amygdala, hippocampus, midbrain, sub-thalamic nucleus, and cerebellum. By contrast, the medial prefrontal cortex was significantly smaller in HD rats compared with LD rats with no significant group differences in whole brain, ventricular, or cerebrospinal fluid volumes. These findings show that limbic cortico-basal ganglia structures implicated in impulse control disorders are distinct in rats that are vulnerable to develop compulsive behavior. Such abnormalities may be relevant to the etiology of compulsive disorders in humans.
Assuntos
Encéfalo , Comportamento Compulsivo , Humanos , Ratos , Masculino , Animais , Encéfalo/patologia , Comportamento Compulsivo/psicologia , Tonsila do Cerebelo/patologia , Gânglios da Base , Fenótipo , Imageamento por Ressonância Magnética , Mapeamento EncefálicoRESUMO
Replication stress, a major cause of genome instability in cycling cells, is mainly prevented by the ATR-dependent replication stress response pathway in somatic cells. However, the replication stress response pathway in embryonic stem cells (ESCs) may be different due to alterations in cell cycle phase length. The transcription factor MYBL2, which is implicated in cell cycle regulation, is expressed a hundred to a thousand-fold more in ESCs compared with somatic cells. Here we show that MYBL2 activates ATM and suppresses replication stress in ESCs. Consequently, loss of MYBL2 or inhibition of ATM or Mre11 in ESCs results in replication fork slowing, increased fork stalling and elevated origin firing. Additionally, we demonstrate that inhibition of CDC7 activity rescues replication stress induced by MYBL2 loss and ATM inhibition, suggesting that uncontrolled new origin firing may underlie the replication stress phenotype resulting from loss/inhibition of MYBL2 and ATM. Overall, our study proposes that in addition to ATR, a MYBL2-MRN-ATM replication stress response pathway functions in ESCs to control DNA replication initiation and prevent genome instability.
Assuntos
Proteínas de Ciclo Celular , Células-Tronco Pluripotentes , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Dano ao DNA , Replicação do DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células-Tronco Pluripotentes/metabolismoRESUMO
The lifestyle of intracellular pathogens, such as malaria parasites, is intimately connected to that of their host, primarily for nutrient supply. Nutrients act not only as primary sources of energy but also as regulators of gene expression, metabolism and growth, through various signalling networks that enable cells to sense and adapt to varying environmental conditions. Canonical nutrient-sensing pathways are presumed to be absent from the causative agent of malaria, Plasmodium, thus raising the question of whether these parasites can sense and cope with fluctuations in host nutrient levels. Here we show that Plasmodium blood-stage parasites actively respond to host dietary calorie alterations through rearrangement of their transcriptome accompanied by substantial adjustment of their multiplication rate. A kinome analysis combined with chemical and genetic approaches identified KIN as a critical regulator that mediates sensing of nutrients and controls a transcriptional response to the host nutritional status. KIN shares homology with SNF1/AMPKα, and yeast complementation studies suggest that it is part of a functionally conserved cellular energy-sensing pathway. Overall, these findings reveal a key parasite nutrient-sensing mechanism that is critical for modulating parasite replication and virulence.
Assuntos
Regulação da Expressão Gênica , Malária/parasitologia , Parasitos/metabolismo , Parasitos/patogenicidade , Fosfotransferases/metabolismo , Plasmodium/metabolismo , Plasmodium/patogenicidade , Animais , Restrição Calórica , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Teste de Complementação Genética , Glucose/metabolismo , Glucose/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Parasitemia/sangue , Parasitemia/genética , Parasitemia/metabolismo , Parasitemia/parasitologia , Parasitos/genética , Parasitos/crescimento & desenvolvimento , Fosfotransferases/deficiência , Fosfotransferases/genética , Plasmodium/genética , Plasmodium/crescimento & desenvolvimento , Ratos , Transcriptoma/efeitos dos fármacos , Virulência/efeitos dos fármacosRESUMO
OBJECTIVES: Little is known about how to perform the endoscopic ultrasound (EUS)-directed transgastric endoscopic retrograde cholangiopancreatography (ERCP; EDGE) in patients with gastric bypass using lumen-apposing metal stents (LAMS). The aim was to assess the risk factors of anastomosis-related difficult ERCP. METHODS: Observational single-center study. All patients who underwent an EDGE procedure in 2020-2022 following a standardized protocol were included. Risk factors for difficult ERCP, defined as the need of >5 min LAMS dilation or failure to pass a duodenoscope in the second duodenum, were assessed. RESULTS: Forty-five ERCPs were performed in 31 patients (57.4 ± 8.2 years old, 38.7% male). The EUS procedure was done using a wire-guided technique (n = 28, 90.3%) for biliary stones (n = 22, 71%) in most cases. The location of the anastomosis was gastro-gastric (n = 24, 77.4%) and mainly in the middle-excluded stomach (n = 21, 67.7%) with an oblique axis (n = 22, 71%). The ERCP technical success was 96.8%. There were 10 difficult ERCPs (32.3%) due to timing (n = 8), anastomotic dilation (n = 8), or failure to pass (n = 3). By multivariable analysis adjusted by two-stage procedures, the risk factors for a difficult ERCP were the jejuno-gastric route (85.7% vs. 16.7%; odds ratio [ORa ] 31.875; 95% confidence interval [CI] 1.649-616.155; P = 0.022), and the anastomosis to the proximal/distal excluded stomach (70% vs. 14.3%; ORa 22.667; 95% CI 1.676-306.570; P = 0.019). There was only one complication (3.2%) and one persistent gastro-gastric fistula (3.2%) in a median follow-up of 4 months (2-18 months), with no weight regain (P = 0.465). CONCLUSIONS: The jejunogastric route and the anastomosis with the proximal/distal excluded stomach during the EDGE procedure increase the difficulty of ERCP.
Assuntos
Colangiopancreatografia Retrógrada Endoscópica , Derivação Gástrica , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Colangiopancreatografia Retrógrada Endoscópica/métodos , Endossonografia/métodos , Derivação Gástrica/métodos , Gastrostomia/efeitos adversos , Estudos Observacionais como Assunto , Estudos Retrospectivos , Fatores de Risco , Stents , Ultrassonografia de IntervençãoRESUMO
This study focuses on the assessment of the mechanical effect produced by Morton's extension as an orthopedic intervention in patients with bilateral foot pronation posture, through a variation in hindfoot and forefoot prone-supinator forces during the stance phase of gait. A quasi-experimental and transversal research was designed comparing three conditions: barefoot (A); wearing footwear with a 3 mm EVA flat insole (B); and wearing a 3 mm EVA flat insole with a 3 mm thick Morton's extension (C), with respect to the force or time relational to the maximum time of supination or pronation of the subtalar joint (STJ) using a Bertec force plate. Morton's extension did not show significant differences in the moment during the gait phase in which the maximum pronation force of the STJ is produced, nor in the magnitude of the force, although it decreased. The maximum force of supination increased significantly and was advanced in time. The use of Morton's extension seems to decrease the maximum force of pronation and increase supination of the subtalar joint. As such, it could be used to improve the biomechanical effects of foot orthoses to control excessive pronation.