RESUMEN
Spinal muscular atrophy (SMA) is a motor-neuron disease caused by mutations of the SMN1 gene. The human paralog SMN2, whose exon 7 (E7) is predominantly skipped, cannot compensate for the lack of SMN1. Nusinersen is an antisense oligonucleotide (ASO) that upregulates E7 inclusion and SMN protein levels by displacing the splicing repressors hnRNPA1/A2 from their target site in intron 7. We show that by promoting transcriptional elongation, the histone deacetylase inhibitor VPA cooperates with a nusinersen-like ASO to promote E7 inclusion. Surprisingly, the ASO promotes the deployment of the silencing histone mark H3K9me2 on the SMN2 gene, creating a roadblock to RNA polymerase II elongation that inhibits E7 inclusion. By removing the roadblock, VPA counteracts the chromatin effects of the ASO, resulting in higher E7 inclusion without large pleiotropic effects. Combined administration of the nusinersen-like ASO and VPA in SMA mice strongly synergizes SMN expression, growth, survival, and neuromuscular function.
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Atrofia Muscular Espinal , Oligonucleótidos Antisentido , Animales , Cromatina , Exones , Ratones , Atrofia Muscular Espinal/tratamiento farmacológico , Atrofia Muscular Espinal/genética , Oligonucleótidos Antisentido/farmacología , Oligonucleótidos Antisentido/uso terapéutico , Empalme del ARNRESUMEN
Martinez et al. (2022) uncovered a novel function for the most abundant modified nucleoside in RNA. The study shows that uridines at splice sites and splicing regulatory motifs in the pre-mRNA may be converted to pseudouridine during transcription and impact splicing decisions.
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Seudouridina , Empalme del ARN , Seudouridina/genética , Seudouridina/metabolismo , Precursores del ARN/metabolismo , Procesamiento Postranscripcional del ARN , ARN Mensajero/genéticaRESUMEN
Mammalian chromatin is the site of both RNA polymerase II (Pol II) transcription and coupled RNA processing. However, molecular details of such co-transcriptional mechanisms remain obscure, partly because of technical limitations in purifying authentic nascent transcripts. We present a new approach to characterize nascent RNA, called polymerase intact nascent transcript (POINT) technology. This three-pronged methodology maps nascent RNA 5' ends (POINT-5), establishes the kinetics of co-transcriptional splicing patterns (POINT-nano), and profiles whole transcription units (POINT-seq). In particular, we show by depletion of the nuclear exonuclease Xrn2 that this activity acts selectively on cleaved 5' P-RNA at polyadenylation sites. Furthermore, POINT-nano reveals that co-transcriptional splicing either occurs immediately after splice site transcription or is delayed until Pol II transcribes downstream sequences. Finally, we connect RNA cleavage and splicing with either premature or full-length transcript termination. We anticipate that POINT technology will afford full dissection of the complexity of co-transcriptional RNA processing.
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Nanotecnología , ARN Polimerasa II/metabolismo , Precursores del ARN/biosíntesis , Empalme del ARN , ARN Mensajero/biosíntesis , RNA-Seq , Transcripción Genética , Exorribonucleasas/genética , Exorribonucleasas/metabolismo , Células HCT116 , Células HeLa , Humanos , Cinética , Poliadenilación , Caperuzas de ARN , ARN Polimerasa II/genética , Precursores del ARN/genética , ARN Mensajero/genéticaRESUMEN
Monitoring cell viability is critical in cell biology, pathology, and drug discovery. Most cell viability assays are cell-destructive, time-consuming, expensive, and/or hazardous. Herein, we present a series of newly synthesized 2,4,5-triaminopyrimidine derivatives able to discriminate between live and dead cells. To our knowledge, these compounds are the first fluorescent nucleobase analogues (FNAs) with cell viability monitoring potential. These new fluorescent molecules are synthesized using highly efficient and cost-effective methods and feature unprecedented photophysical properties (longer absorption and emission wavelengths, environment-sensitive emission, and unprecedented brightness within FNAs). Using a live-dead Saccharomyces cerevisiae cell and theoretical assays, the fluorescent 2,4,5-triaminopyrimidine derivatives were found to specifically accumulate inside dead cells by interacting with dsDNA grooves, thus paving the way for the emergence of novel and safe fluorescent cell viability markers emitting in the blue region. As the majority of commercially available viability dyes emit in the green to red region of the visible spectrum, these novel markers might be useful to meet the needs of blue markers for co-staining combinations.
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Colorantes Fluorescentes , Microscopía , Supervivencia CelularRESUMEN
Monitoring the levels of amino acids (AAs) in biological cell cultures provides key information to understand the regulation of cell growth and metabolism. Saccharomyces cerevisiae can naturally excrete AAs, making accurate detection and determination of amino acid levels within the cultivation medium pivotal for gaining insights into this still poorly known process. Given that most AAs lack ultraviolet (UV) chromophores or fluorophores necessary for UV and fluorescence detection, derivatization is commonly utilized to enhance amino acid detectability via UV absorption. Unfortunately, this can lead to drawbacks such as derivative instability, labor intensiveness, and poor reproducibility. Hence, this study aimed to develop an accurate and stable hydrophilic interaction liquid chromatography-tandem mass spectrometry analytical method for the separation of all 20 AAs within a short 17-min run time. The method provides satisfactory linearity and sensitivity for all analytes. The method has been validated for intra- and inter-day precision, accuracy, recovery, matrix effect, and stability. It has been successfully applied to quantify 20 AAs in samples of yeast cultivation medium. This endeavor seeks to enhance our comprehension of amino acid profiles in the context of cell growth and metabolism within yeast cultivation media.
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Aminoácidos , Interacciones Hidrofóbicas e Hidrofílicas , Saccharomyces cerevisiae , Espectrometría de Masas en Tándem , Aminoácidos/metabolismo , Aminoácidos/análisis , Espectrometría de Masas en Tándem/métodos , Saccharomyces cerevisiae/metabolismo , Cromatografía Liquida , Cromatografía Líquida de Alta Presión/métodosRESUMEN
Hoof diseases are a major welfare and economic issue in the global dairy cattle production industry, which can be minimized through improved management and breeding practices. Optimal genetic improvement of hoof health could benefit from a deep understanding of the genetic background and biological underpinning of indicators of hoof health. Therefore, the primary objectives of this study were to perform genome-wide association studies, using imputed high-density genetic markers data from North American Holstein cattle, for 8 hoof-related traits: digital dermatitis, sole ulcer, sole hemorrhage, white line lesion, heel horn erosion, interdigital dermatitis, interdigital hyperplasia, and toe ulcer, and a hoof health index. De-regressed estimated breeding values from 25,580 Holstein animals were used as pseudo-phenotypes for the association analyses. The genomic quality control, genotype phasing, and genotype imputation were performed using the PLINK (version 1.9), Eagle (version 2.4.1), and Minimac4 software, respectively. The functional genomic analyses were performed using the GALLO R package and the DAVID platform. We identified 22, 34, 14, 22, 28, 33, 24, 43, and 15 significant markers for digital dermatitis, heel horn erosion, interdigital dermatitis, interdigital hyperplasia, sole hemorrhage, sole ulcer, toe ulcer, white line lesion disease, and the hoof health index, respectively. The significant markers were located across all autosomes, except BTA10, BTA12, BTA20, BTA26, BTA27, and BTA28. Moreover, the genomic regions identified overlap with various previously reported quantitative trait loci for exterior, health, meat and carcass, milk, production, and reproduction traits. The enrichment analyses identified 44 significant gene ontology terms. These enriched genomic regions harbor various candidate genes previously associated with bone development, metabolism, and infectious and immunological diseases. These findings indicate that hoof health traits are highly polygenic and influenced by a wide range of biological processes.
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Enfermedades de los Bovinos , Dermatitis , Dermatitis Digital , Enfermedades del Pie , Úlcera del Pie , Pezuñas y Garras , Úlcera Cutánea , Bovinos/genética , Animales , Enfermedades del Pie/genética , Enfermedades del Pie/veterinaria , Estudio de Asociación del Genoma Completo/veterinaria , Dermatitis Digital/genética , Úlcera/veterinaria , Hiperplasia/veterinaria , Enfermedades de los Bovinos/genética , Fenotipo , Úlcera del Pie/veterinaria , Genómica , Dermatitis/veterinaria , Hemorragia/veterinaria , América del NorteRESUMEN
BACKGROUND: Cancer patients experience distress as a result of their health condition, which, in turn, contributes to the progression of the disease. Moreover, their daily activities, well-being, and health status are significantly impacted by pain and other symptoms. In this context, empowering these patients with self-care and pain management skills can greatly contribute to effective symptom control. AIM: To develop and implement an educational approach focused on empowering family caregivers and patients with advanced cancer in effectively managing pain at home. METHOD: An educational program, PECP/C-Pain Management, was developed to empower family caregivers and cancer patients to manage pain at home. A quasi-experimental study involving 52 participants with advanced cancer was conducted to test the program. Participants' skills, behaviors, and knowledge related to self-care and pain management were assessed before and after the intervention using an appropriate instrument, the Pain Management Knowledge and Behavior Scale. RESULTS: Pain was reported as the primary symptom, and following the educational program, participants were able to monitor pain and other symptoms and effectively self-manage their treatment. CONCLUSIONS: The findings suggest that the PECP/C-Pain Management intervention was effective in improving participants' knowledge and skills in managing pain, leading to better symptom control. In addition, the Pain Management Knowledge and Behavior Scale is a reliable tool for measuring the outcomes of this intervention.
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Neoplasias , Manejo del Dolor , Autocuidado , Humanos , Femenino , Masculino , Autocuidado/métodos , Manejo del Dolor/métodos , Manejo del Dolor/normas , Persona de Mediana Edad , Neoplasias/complicaciones , Adulto , Anciano , Empoderamiento , Cuidadores/psicología , Cuidadores/educación , Encuestas y Cuestionarios , Educación del Paciente como Asunto/métodos , Educación del Paciente como Asunto/normasRESUMEN
Roads are an important source of human economic progress, but also a threat to wildlife populations and natural habitats. Roads are responsible for the direct mortality of hundreds of millions of animals worldwide, with special negative effects for amphibians. Since the middle of the twentieth century, various types of mitigation measures have been constructed to reduce the negative effects of roads. However, despite the large availability of potential solutions designed for this purpose, there is still a knowledge gap about their effectiveness for amphibians. This study analysed whether permanent concrete drift fences reduced the roadkill risk for amphibians. We applied a before-after-control-impact (BACI) design in two road segments with concrete drift fences for amphibians. We recorded amphibians on these road segments three years before and three years after the fence installation. We further tested whether the presence of these mitigation measures transferred the animals to sites adjacent to the drift fences, creating new potential mortality aggregation sites (fence-end effect). Our results show a significant reduction in the number of amphibians reaching the sites with the drift fences. We were, however, unable to demonstrate the potential movement route transference, as our results were inconclusive. Despite the increase in amphibian numbers at the control sites in the first year after fence installation, the following two years presented similar amphibian numbers as the pre-fence years. We recognise the importance of permanent drift fences in reducing the mortality of amphibian populations; however, we encourage future studies to include tunnel-crossing data as well, to truly unveil the roadkill reduction power of amphibian mitigation measures, while maintaining or increasing connectivity between roadside habitats.
RESUMEN
BACKGROUND: The literature review notes that people in need of care from Rehabilitation Programs do not always see their continuity ensured. OBJECTIVE: This study aim to analyze the perspective of Specialists Nurse in Rehabilitation Nursing in relation to the organization and specialized intervention of transitional care for older people in need of rehabilitation programs. METHODS: This is a qualitative study within the interpretivist paradigm. A focus group with 8 nurses and 13 interviews with Portuguese nurses were carried out between April 2022 and February 2023. Content analysis was carried out. RESULTS: The triangulation of the data made it possible to identify 3 categories: Coordination of a transitional care program; Empowering the person to self-manage the transitional care process and Empowering the Informal Caregiver. CONCLUSIONS: It is imperative to promote the coordination of transitional care, increase the functional capacity of the person and empower the informal caregiver.
RESUMEN
The 2022-2023 mpox outbreak predominantly affected adult men; 1.3% of reported cases were in children and adolescents <18 years of age. Analysis of global surveillance data showed 1 hospital intensive care unit admission and 0 deaths in that age group. Transmission routes and clinical manifestations varied across age subgroups.
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Mpox , Adolescente , Niño , Humanos , Brotes de Enfermedades , Hospitalización , Unidades de Cuidados IntensivosRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a coronavirus belonging to the beta CoV genus, responsible for SARS in humans, which became known as COVID-19. The emergence of variants of this virus is related to the presence of cases of reinfection, reduced vaccine effectiveness and greater transmission of the virus. Objective: In this study, we evaluated the molecular epidemiology of SARS-CoV-2 lineages circulating in the state of Maranhão. This is a cross-sectional and retrospective epidemiological study of genomic surveillance of SARS-CoV-2. The study comprised of 338 genomes sequenced by the Next Generation Sequencing technique on Illumina's Miseq equipment, submitted to Global Initiative on Sharing Avian Influenza Data, 190 (56.2%) are from samples of female and 148 (43.8%) from male patients. Sequencing performed covered samples of patients aged between 1 and 108 years, with emphasis on the age groups from 30 to 39 years with 15.0% of sequenced genomes and 20 to 29 years with 12.4%. As for the distribution of sequenced genomes by health macro-regions, 285 (84.3%) are from cities in the northern macro-region. We evidenced the circulation of 29 lineages and sub-lineages, four of which belonging to the Delta variant (AY.43, AY.99.1, AY.99.2 and AY.101 responsible for 4.5% of the genomes) and the others belonging to the Omicron variant, with emphasis on: BA.1 and sub-lineages (42.8%); BA.4, BA.5 and sub-lineages (5.3% and 41.1%); the sub-lineages DL.1 and BQ.1 (5% and 2%). A strong genomic surveillance system allows the study of the natural history of the disease, when there is a resurgence of SARS-CoV-2 cases.
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COVID-19 , SARS-CoV-2 , Animales , Humanos , Femenino , Masculino , Lactante , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , SARS-CoV-2/genética , Epidemiología Molecular , Brasil/epidemiología , COVID-19/epidemiología , Estudios Transversales , Estudios RetrospectivosRESUMEN
BACKGROUND: Microsporidia are rarely reported to cause outbreaks of diarrhea. We describe a foodborne outbreak of microsporidiosis from a workplace canteen in November 2020 in Denmark. METHODS: A probable case was defined as any person using the canteen between 4 November and 13 December 2020, reporting at least one gastrointestinal symptom, whereas a confirmed case also had an Enterocytozoon bieneusi positive stool sample. A web-based questionnaire was used to collect clinical, epidemiological, and food exposure data. We performed a retrospective cohort study and tested stool samples from affected individuals for bacterial, viral, and parasitic pathogens, including E. bieneusi. RESULTS: Altogether, 195 individuals completed the questionnaire. We identified 52 cases (65% male; median age 45 years [range 25-65]). Diarrhea (90%), fatigue (83%), and abdominal pain (79%) were the most commonly reported symptoms. Eight cases were laboratory-confirmed and had E. bieneusi genotype C. The incubation period was between 5 and 12 days, and polymerase chain reaction (PCR)-detectable spore shedding occurred up to 43 days after symptom onset. Disease was associated with consuming food from the workplace canteen on 4 November 2020 (relative risk [RR[, 2.8 [95% confidence interval [CI]: 1.4 - 5.4]) and lunchboxes containing open sandwiches (RR, 3.2 [95% CI: 1.4 - 7.2]) served that day. CONCLUSIONS: This is the second documented foodborne outbreak of E. bieneusi genotype C-associated diarrhea worldwide. Epidemiological findings advocated an open sandwiches lunchbox from 4 November 2020, as a likely source. E. bieneusi may be an under-reported cause of outbreaks of diarrhea, and testing for it might be useful in foodborne outbreak investigations.
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Enterocytozoon , Adulto , Anciano , Dinamarca/epidemiología , Diarrea/epidemiología , Brotes de Enfermedades , Enterocytozoon/genética , Heces/microbiología , Femenino , Genotipo , Humanos , Periodo de Incubación de Enfermedades Infecciosas , Masculino , Persona de Mediana Edad , Filogenia , Prevalencia , Estudios Retrospectivos , Esporas FúngicasRESUMEN
Insulin-degrading enzyme (IDE) function goes far beyond its known proteolytic role as a regulator of insulin levels. IDE has a wide substrate promiscuity, degrading several proteins such as amyloid-ß peptide, glucagon, islet amyloid polypeptide (IAPP), and insulin-like growth factors, which have diverse physiological and pathophysiological functions. Importantly, IDE plays other non-proteolytic functions such as: a chaperone/dead-end chaperone, an E1-ubiquitin activating enzyme, and a proteasome modulator. It also responds as a heat shock protein, regulating cellular proteostasis. Notably, amyloidogenic proteins such as IAPP, amyloid-ß, and α-synuclein have been reported as substrates for IDE chaperone activity. This is of utmost importance as failure of IDE may result in increased protein aggregation, a key hallmark in the pathogenesis of beta cells in type 2 diabetes mellitus and of neurons in neurodegenerative diseases such as Alzheimer's and Parkinson's disease. In this review, we focus on the biochemical and biophysical properties of IDE and the regulation of its physiological functions. We further raise the hypothesis that IDE plays a central role in the pathological context of dysmetabolic and neurodegenerative diseases and discuss its potential as a therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Insulisina/metabolismo , Enfermedades Metabólicas/enzimología , Enfermedades Neurodegenerativas/enzimología , Animales , HumanosRESUMEN
PURPOSE: Although there have been numerous studies investigating the mental health of individuals during the pandemic, a comparison between countries is still scarce in the literature. To explore this gap, the present study aimed to compare the mental health (i.e., anxiety and depression), quality of life (QoL), and optimism/pessimism among individuals from Brazil and Portugal during the COVID-19 pandemic and the associated factors. METHOD: A cross-sectional population-based study was conducted during the COVID-19 pandemic in Brazil and Portugal. Data collection was carried out between May and June 2020, using an online form which was sent through social networks. A total of 2069 participants (1156 from Brazil and 913 from Portugal) were included. Depressive symptoms (PHQ-9), Anxiety (GAD-7), optimism/pessimism (Revised Life Orientation Test - LOT), QoL (WHOQOL-Bref), and sociodemographic, health, and social distancing variables were assessed. Data was analyzed using univariate and multivariate models. RESULTS: There were remarkable differences between Brazil and Portugal in all outcomes during the COVID-19 pandemic, including higher levels of depressive symptoms, anxiety, and optimism for the Brazilian individuals and higher levels of QoL and pessimism for the Portuguese individuals. The following factors were associated with the mental health and QoL in both Brazilian and Portuguese populations: gender, age, being a healthcare professional, and days in social distancing. CONCLUSION: Despite the fact that Brazilians were more optimistic during the COVID-19 pandemic, they had lower levels of mental health and QoL as compared to the Portuguese individuals.
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COVID-19 , Ansiedad/epidemiología , Ansiedad/psicología , Brasil/epidemiología , COVID-19/epidemiología , Estudios Transversales , Depresión/epidemiología , Depresión/psicología , Humanos , Salud Mental , Pandemias , Portugal/epidemiología , Calidad de Vida/psicología , SARS-CoV-2RESUMEN
Following the report of a non-travel-associated cluster of monkeypox cases by the United Kingdom in May 2022, 41 countries across the WHO European Region have reported 21,098 cases and two deaths by 23 August 2022. Nowcasting suggests a plateauing in case notifications. Most cases (97%) are MSM, with atypical rash-illness presentation. Spread is mainly through close contact during sexual activities. Few cases are reported among women and children. Targeted interventions of at-risk groups are needed to stop further transmission.
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Exantema , Mpox , Animales , Niño , Brotes de Enfermedades , Femenino , Humanos , Mpox/diagnóstico , Mpox/epidemiología , Monkeypox virus , Organización Mundial de la SaludRESUMEN
Human-induced pluripotent stem cells (iPSCs) have great potential for disease modeling. However, generating iPSC-derived models to study brain diseases remains a challenge. In particular, the ability to recapitulate cerebellar development in vitro is still limited. We presented a reproducible and scalable production of cerebellar organoids by using the novel single-use Vertical-Wheel bioreactors, in which functional cerebellar neurons were obtained. Here, we evaluate the global gene expression profiles by RNA sequencing (RNA-seq) across cerebellar differentiation, demonstrating a faster cerebellar commitment in this novel dynamic differentiation protocol. Furthermore, transcriptomic profiles suggest a significant enrichment of extracellular matrix (ECM) in dynamic-derived cerebellar organoids, which can better mimic the neural microenvironment and support a consistent neuronal network. Thus, an efficient generation of organoids with cerebellar identity was achieved for the first time in a continuous process using a dynamic system without the need of organoids encapsulation in ECM-based hydrogels, allowing the possibility of large-scale production and application in high-throughput processes. The presence of factors that favors angiogenesis onset was also detected in dynamic conditions, which can enhance functional maturation of cerebellar organoids. We anticipate that large-scale production of cerebellar organoids may help developing models for drug screening, toxicological tests, and studying pathological pathways involved in cerebellar degeneration.
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Cerebelo/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Organoides/metabolismo , RNA-Seq , Cerebelo/citología , Matriz Extracelular/metabolismo , Humanos , Hidrogeles/química , Células Madre Pluripotentes Inducidas/citología , Organoides/citologíaRESUMEN
Staphylococcus pseudintermedius causes opportunistic infections in dogs. It also has significant zoonotic potential, with the emergence of multidrug resistance leading to difficulty treating both animal and human infections. Manuka honey has previously been reported to inhibit many bacterial pathogens, including methicillin-resistant Staphylococcus aureus, and is successfully utilized in both clinical and veterinary practice. Here, we evaluated the ability of manuka honey to inhibit strains of S. pseudintermedius grown alone and in combination with antibiotics, as well as its capacity to modulate virulence within multiple S. pseudintermedius isolates. All 18 of the genetically diverse S. pseudintermedius strains sequenced and tested were inhibited by ≤12% (wt/vol) medical-grade manuka honey, although tolerance to five clinically relevant antibiotics was observed. The susceptibility of the isolates to four of these antibiotics was significantly increased (P ≤ 0.05) when combined with sublethal concentrations of honey, although sensitivity to oxacillin was decreased. Virulence factor (DNase, protease, and hemolysin) activity was also significantly reduced (P ≤ 0.05) in over half of isolates when cultured with sublethal concentrations of honey (13, 9, and 10 isolates, respectively). These findings highlight the potential for manuka honey to be utilized against S. pseudintermedius infections.IMPORTANCEStaphylococcus pseudintermedius is an important member of the skin microbial community in animals and can cause opportunistic infections in both pets and their owners. The high incidence of antimicrobial resistance in S. pseudintermedius highlights that this opportunistic zoonotic pathogen can cause infections which require prolonged and intensive treatment to resolve. Manuka honey has proven efficacy against many bacterial pathogens and is an accepted topical treatment for infections in both veterinary and clinical practice, and so it is a particularly appropriate antimicrobial for use with zoonotic pathogens such as S. pseudintermedius Here, we demonstrate that not only is manuka honey highly potent against novel multidrug-resistant S. pseudintermedius isolates, it also acts synergistically with clinically relevant antibiotics. In addition, manuka honey modulates S. pseudintermedius virulence activity, even at subinhibitory concentrations. In a clinical setting, these attributes may assist in controlling infection, allowing a more rapid resolution and reducing antibiotic use.
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Antibacterianos/farmacología , Miel/análisis , Staphylococcus/efectos de los fármacos , Antibacterianos/análisis , Staphylococcus/genética , Staphylococcus/patogenicidad , Staphylococcus/fisiología , Virulencia/efectos de los fármacosRESUMEN
Basal protein turnover, which largely relies on the degradation of ubiquitinated substrates, is instrumental for maintenance of muscle mass and function. However, the regulation of ubiquitinated protein degradation in healthy, nonatrophying skeletal muscle is still evolving, and potential tissue-specific modulators remain unknown. Using an unbiased expression analysis of 34 putative autophagy genes across mouse tissues, we identified unc-51 like autophagy activating kinase (Ulk)2, a homolog of the yeast autophagy related protein 1, as particularly enriched in skeletal muscle. Subsequent experiments revealed accumulations of insoluble ubiquitinated protein aggregates associated with the adaptors sequestosome 1 (SQSTM1, also known as p62) and next to breast cancer type 1 susceptibility protein gene 1 protein (NBR1) in adult muscles with ULK2 deficiency. ULK2 deficiency also led to impaired muscle force and caused myofiber atrophy and degeneration. These features were not observed in muscles with deficiency of the ULK2 paralog, ULK1. Furthermore, short-term ULK2 deficiency did not impair autophagy initiation, autophagosome to lysosome fusion, or protease activities of the lysosome and proteasome. Altogether, our results indicate that skeletal muscle ULK2 has a unique role in basal selective protein degradation by stimulating the recognition and proteolytic sequestration of insoluble ubiquitinated protein aggregates associated with p62 and NBR1. These findings have potential implications for conditions of poor protein homeostasis in muscles as observed in several myopathies and aging.-Fuqua, J. D., Mere, C. P., Kronemberger, A., Blomme, J., Bae, D., Turner, K. D., Harris, M. P., Scudese, E., Edwards, M., Ebert, S. M., de Sousa, L. G. O., Bodine, S. C., Yang, L., Adams, C. M., Lira, V. A. ULK2 is essential for degradation of ubiquitinated protein aggregates and homeostasis in skeletal muscle.
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Homeostasis/fisiología , Músculo Esquelético/metabolismo , Agregado de Proteínas/fisiología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Autofagosomas/metabolismo , Autofagia/genética , Lisosomas/metabolismo , Masculino , Ratones Endogámicos C57BL , UbiquitinaciónRESUMEN
A cross-sectional study was conducted with 227 adults, 162 using antiretroviral therapy (ART), both sexes, in Secondary Immunodeficiency Outpatient Clinic of the Department of Dermatology of the Hospital das Clínicas of the Faculty of Medicine of University of São Paulo. The patients were grouped into 92 under ART and self-reported lipodystrophy (G1); 70 under ART and without self-reported lipodystrophy (G2); 65 without ART (G3). We evaluated: (1) self-reported lipodystrophy, self-perception and feeling about body image; (2) Anthropometric and lipemic profile. We included 67% (n = 152) male; 33% (n = 77) female. There was a negative impact of self-reported lipodystrophy on body image, where female was more critical, although it was significant for male (p = 0.014). BMI revealed excess weight in female (p = 0.058). Hip waist ratio was shown to be a better parameter than abdominal perimeter when measuring fat in central region of male and lipohypertrophy was characterized in both sexes. There was lipoatrophy in upper and lower limbs for individuals of the (G1) and the male of this group presented hypertriglyceridemia, (p = 0.012). There was a difference in sex, pattern of self - perceived morphologic alterations and feeling in relation to body image when associated with self - reported lipodystrophy, ART use, anthropometric and lipemic profile.
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Infecciones por VIH , VIH-1 , Síndrome de Lipodistrofia Asociada a VIH , Lipodistrofia , Adulto , Terapia Antirretroviral Altamente Activa/efectos adversos , Imagen Corporal , Estudios Transversales , Femenino , Infecciones por VIH/tratamiento farmacológico , Síndrome de Lipodistrofia Asociada a VIH/inducido químicamente , Humanos , Lipodistrofia/inducido químicamente , Masculino , AutoinformeRESUMEN
BACKGROUND: Straelensia cynotis, a trombidioid larval mite, was identified as a cause of nodular dermatitis in dogs in Southern Europe. It has been suggested that red fox (Vulpes vulpes) is a natural host for S. cynotis. However, no case has been reported in this species. OBJECTIVE: To describe three suspected cases of straelensiosis in red foxes. ANIMALS: Three juvenile wild red foxes from Portugal. RESULTS: Erythematous papules and nodules were found in the head, neck and limbs of these foxes with no associated pruritus. In skin biopsies, well-preserved larval mites were found within dilated hair follicles. These follicular lesions were multifocal and consisted of a degenerative and necrotic area nearby the parasite's mouthparts with marked pseudoepitheliomatous hyperplasia and perifollicular mucinosis. These features are considered pathognomonic in S. cynotis infestations in dogs. Treatment and outcome are outlined. CONCLUSIONS AND CLINICAL IMPORTANCE: To the best of the authors' knowledge, the present case series documents the first known occurrence of nodular dermatitis by Straelensia spp. in red foxes. This new evidence may corroborate participation of the red fox in the life cycle of S. cynotis.