Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 913
Filtrar
1.
J Sci Med Sport ; 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38839539

RESUMO

We quantified and compared the mechanical force demands relative to the maximum dynamic force (MDF) of 11 cyclists when pedaling at different intensities (ventilatory threshold, maximum lactate steady state, respiratory compensation point, and maximal aerobic power), cadences (free, 40, 60 and 80 rpm), and all-out resisted sprints. Relative force demands (expressed as %MDF) progressively increased with higher intensities (p < 0.001) and lower cadences (p < 0.001). Notwithstanding, relative force demands were low (<54 % MDF) for all conditions, even during the so-called 'torque training'. These results might be useful when programming on-bike resistance training to improve torque production capacity.

2.
Phys Rev E ; 109(4-1): 044313, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38755908

RESUMO

We present a multiscale stochastic analysis of foreign exchange rates using the H-theory formalism, which provides a hierarchical intermittency model for the information cascade in the currency market. We examine the distributions of returns and volatilities for the three most traded currency pairs: euro-U.S. dollar, U.S. dollar-Japanese yen, and British pound-U.S. dollar. We find that these markets have a hierarchy of timescales, with larger markets exhibiting more hierarchy levels. We provide a theoretical framework for understanding why the number of levels in the information cascade increases with market size, in analogy with similar behavior for the energy cascade in turbulence as a function of Reynolds number. We briefly argue that using turbulence-like models for financial markets can also provide valuable insights for developing efficient algorithmic trading strategies.

3.
Int J Radiat Oncol Biol Phys ; 119(2): 338-353, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38760115

RESUMO

At its very core, radiation oncology involves a trade-off between the benefits and risks of exposing tumors and normal tissue to relatively high doses of ionizing radiation. This trade-off is particularly critical in childhood cancer survivors (CCS), in whom both benefits and risks can be hugely consequential due to the long life expectancy if the primary cancer is controlled. Estimating the normal tissue-related risks of a specific radiation therapy plan in an individual patient relies on predictive mathematical modeling of empirical data on adverse events. The Pediatric Normal-Tissue Effects in the Clinic (PENTEC) collaborative network was formed to summarize and, when possible, to synthesize dose-volume-response relationships for a range of adverse events incident in CCS based on the literature. Normal-tissue clinical radiation biology in children is particularly challenging for many reasons: (1) Childhood malignancies are relatively uncommon-constituting approximately 1% of new incident cancers in the United States-and biologically heterogeneous, leading to many small series in the literature and large variability within and between series. This creates challenges in synthesizing data across series. (2) CCS are at an elevated risk for a range of adverse health events that are not specific to radiation therapy. Thus, excess relative or absolute risk compared with a reference population becomes the appropriate metric. (3) Various study designs and quantities to express risk are found in the literature, and these are summarized. (4) Adverse effects in CCS often occur 30, 50, or more years after therapy. This limits the information content of series with even very extended follow-up, and lifetime risk estimates are typically extrapolations that become dependent on the mathematical model used. (5) The long latent period means that retrospective dosimetry is required, as individual computed tomography-based radiation therapy plans gradually became available after 1980. (6) Many individual patient-level factors affect outcomes, including age at exposure, attained age, lifestyle exposures, health behaviors, other treatment modalities, dose, fractionation, and dose distribution. (7) Prospective databases with individual patient-level data and radiation dosimetry are being built and will facilitate advances in dose-volume-response modeling. We discuss these challenges and attempts to overcome them in the setting of PENTEC.


Assuntos
Sobreviventes de Câncer , Relação Dose-Resposta à Radiação , Humanos , Sobreviventes de Câncer/estatística & dados numéricos , Criança , Lesões por Radiação , Órgãos em Risco/efeitos da radiação , Neoplasias/radioterapia , Medição de Risco , Neoplasias Induzidas por Radiação/etiologia , Dosagem Radioterapêutica
4.
Vet Ophthalmol ; 2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38768284

RESUMO

OBJECTIVE: Identify microorganisms present in canine eyes affected by ulcerative keratitis and assess its resistance profile to available antimicrobial drugs. METHODS: Samples were collected from 88 canine eyes that exhibited ulcerative keratitis. They were identified using MALDI-TOF and subjected to antimicrobial susceptibility testing by disk diffusion. RESULTS: Among the assessed subjects, brachycephalic dogs accounted for 74.48% (50/83) of the evaluated canines. Among the 88 evaluated eyes, 90.9% (80/88) showed positive cultures, with 11.33% (10/88) of the samples isolating more than one species of bacteria. Of all bacterial isolates identified (90), Gram-positive bacteria accounted for 63.33% (57/90), while Gram-negative bacteria constituted 36.66% (33/90), with predominance of Staphylococcus spp. at 35.55% (32/90) being, Staphylococcus pseudintermedius at 68.75% (22/32), and Pseudomonas aeruginosa at 15.55% (14/90), respectively. Staphylococcus spp. exhibited resistance to penicillin (89.29%), sulfadiazine and trimethoprim (60.71%), and tetracycline (67.86%), while doxycycline (88.89%), cefotaxime (85.71%), chloramphenicol (82.14%), gentamicin, and moxifloxacin (78.57%) showed the highest sensitivity rates. Pseudomonas aeruginosa displayed sensitivity (100%) to gentamicin and imipenem, and resistance (8.33%) to norfloxacin, ciprofloxacin, and cefepime. Similarly, the Enterobacteriaceae family showed higher sensitivity to amikacin and gentamicin (88.89%), imipenem (88.24%), and levofloxacin (87.5%), with pronounced resistance to amoxicillin-clavulanate (50%) and cefazolin (47.06%). This highlights multiresistance in 23.33% (21/90) of the isolates. CONCLUSIONS: The most isolated species in canine ulcerative keratitis are S. pseudintermedius and P. aeruginosa. However, other species were also isolated, demonstrating diversity in ocular microbiota infection. There is a high-rate multidrug resistance associated with canine ulcerative keratitis. Nevertheless, these strains exhibited sensitivity to antimicrobials commonly used in veterinary ophthalmology.

5.
Biomacromolecules ; 25(5): 2823-2837, 2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38602228

RESUMO

Self-assembled nanostructures such as those formed by peptide amphiphiles (PAs) are of great interest in biological and pharmacological applications. Herein, a simple and widely applicable chemical modification, a urea motif, was included in the PA's molecular structure to stabilize the nanostructures by virtue of intermolecular hydrogen bonds. Since the amino acid residue nearest to the lipid tail is the most relevant for stability, we decided to include the urea modification at that position. We prepared four groups of molecules (13 PAs in all), with varying levels of intermolecular cohesion, using amino acids with distinct ß-sheet promoting potential and/or containing hydrophobic tails of distinct lengths. Each subset contained one urea-modified PA and nonmodified PAs, all with the same peptide sequence. The varied responses of these PAs to variations in pH, temperature, counterions, and biologically related proteins were examined using microscopic, X-ray, spectrometric techniques, and molecular simulations. We found that the urea group contributes to the stabilization of the morphology and internal arrangement of the assemblies against environmental stimuli for all peptide sequences. In addition, microbiological and biological studies were performed with the cationic PAs. These assays reveal that the addition of urea linkages affects the PA-cell membrane interaction, showing the potential to increase the selectivity toward bacteria. Our data indicate that the urea motif can be used to tune the stability of a wide range of PA nanostructures, allowing flexibility on the biomaterial's design and opening a myriad of options for clinical therapies.


Assuntos
Ligação de Hidrogênio , Ureia , Ureia/química , Interações Hidrofóbicas e Hidrofílicas , Peptídeos/química , Peptídeos/farmacologia , Nanoestruturas/química , Tensoativos/química
7.
Protein Sci ; 33(5): e4971, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38591647

RESUMO

As protein crystals are increasingly finding diverse applications as scaffolds, controlled crystal polymorphism presents a facile strategy to form crystalline assemblies with controllable porosity with minimal to no protein engineering. Polymorphs of consensus tetratricopeptide repeat proteins with varying porosity were obtained through co-crystallization with metal salts, exploiting the innate metal ion geometric requirements. A single structurally exposed negative amino acid cluster was responsible for metal coordination, despite the abundance of negatively charged residues. Density functional theory calculations showed that while most of the crystals were the most thermodynamically stable assemblies, some were kinetically trapped states. Thus, crystalline porosity diversity is achieved and controlled with metal coordination, opening a new scope in the application of proteins as biocompatible protein-metal-organic frameworks (POFs). In addition, metal-dependent polymorphic crystals allow direct comparison of metal coordination preferences.


Assuntos
Estruturas Metalorgânicas , Proteínas , Proteínas/genética , Proteínas/química , Metais/química , Cristalização
8.
Sensors (Basel) ; 24(6)2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38544265

RESUMO

We aimed to determine the feasibility, test-retest reliability and long-term stability of a novel method for assessing the force (torque)-velocity (cadence) profile and maximal dynamic force (MDF) during leg-pedaling using a friction-loaded isoinertial cycle ergometer and a high-precision power-meter device. Fifty-two trained male cyclists completed a progressive loading test up to the one-repetition maximum (1RM) on a cycle ergometer. The MDF was defined as the force attained at the cycle performed with the 1RM-load. To examine the test-retest reliability and long-term stability of torque-cadence values, the progressive test was repeated after 72 h and also after 10 weeks of aerobic and strength training. The participants' MDF averaged 13.4 ± 1.3 N·kg-1, which was attained with an average pedal cadence of 21 ± 3 rpm. Participants' highest power output value was attained with a cadence of 110 ± 16 rpm (52 ± 5% MDF). The relationship between the MDF and cadence proved to be very strong (R2 = 0.978) and independent of the cyclists' MDF (p = 0.66). Cadence values derived from this relationship revealed a very high test-retest repeatability (mean SEM = 4 rpm, 3.3%) and long-term stability (SEM = 3 rpm, 2.3%); despite increases in the MDF following the 10-week period. Our findings support the validity, reliability and long-term stability of this method for the assessment of the torque-cadence profile and MDF in cyclists.


Assuntos
Ciclismo , Ergometria , Humanos , Masculino , Torque , Reprodutibilidade dos Testes , , Teste de Esforço/métodos
9.
J Surg Case Rep ; 2024(3): rjae126, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38524673

RESUMO

This study presented a pioneering investigation of the changes in the magnetic resonance imaging images of pectoralis major muscle (PMM) tendon rupture. In all, 26 men were evaluated with acute total PMM rupture (<3 months since injury) with a mean age of 37.3 years (SD = 9.7 years) and 10 control patients with a mean age of 32.6 years (SD = 4.2 years). The evaluation of the tendon PMM injuries was based on the magnetic resonance imaging exam and the histological analysis. The magnetic resonance imaging of the surgically showed two (7.1%) contralateral sides were normal, 16 (57.1%) showed superior tendinopathy, and 10 (35.7%) had total tendinopathy. Inferior tendinopathy was not observed. The tendon histology revealed degenerative changes in 16 (66.7%) fragments, with 12 (50.0%) considered as mild (<25%), and four considered as (16.7%) high (>50.0%) tendinopathy. Total acute rupture of the PMM tendon among weightlifters might be associated with tendinous degeneration prior to injury.

10.
J Surg Case Rep ; 2024(3): rjae093, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38495048

RESUMO

To compare outcomes between autologous fascia lata and autologous hamstring grafts for chronic pectoralis major muscle (PMM) rupture repair, and perform histological, and imaging analyses. Forty male patients with chronic PMM ruptures (time since injury ranging from >3 months to 5 years) and a mean age of 37.3 years (SD = 9.7 years) were evaluated. One group (20 patients) received an autologous semitendinosus graft, and another group (20 patients) received an autologous fascia lata graft for PMM reconstruction. These patients with fascia lata grafts by Bak 2criterium 60% of the patients presented excellent results, 20% presented good results, 15% presented fair results, and 5% presented poor results. In the hamstring group 65% of the patients presented excellent results, 30% presented good results, and 5% presented fair results. In this comparative study, no difference was observed regarding the functional result, image, and histology between groups.

11.
Int J Radiat Oncol Biol Phys ; 119(2): 681-696, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38430101

RESUMO

PURPOSE: In this Pediatric Normal Tissue Effects in the Clinic (PENTEC) vision paper, challenges and opportunities in the assessment of subsequent neoplasms (SNs) from radiation therapy (RT) are presented and discussed in the context of technology advancement. METHODS AND MATERIALS: The paper discusses the current knowledge of SN risks associated with historic, contemporary, and future RT technologies. Opportunities for research and SN mitigation strategies in pediatric patients with cancer are reviewed. RESULTS: Present experience with radiation carcinogenesis is from populations exposed during widely different scenarios. Knowledge gaps exist within clinical cohorts and follow-up; dose-response and volume effects; dose-rate and fractionation effects; radiation quality and proton/particle therapy; age considerations; susceptibility of specific tissues; and risks related to genetic predisposition. The biological mechanisms associated with local and patient-level risks are largely unknown. CONCLUSIONS: Future cancer care is expected to involve several available RT technologies, necessitating evidence and strategies to assess the performance of competing treatments. It is essential to maximize the utilization of existing follow-up while planning for prospective data collection, including standardized registration of individual treatment information with linkage across patient databases.


Assuntos
Sobreviventes de Câncer , Neoplasias Induzidas por Radiação , Órgãos em Risco , Humanos , Criança , Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias Induzidas por Radiação/prevenção & controle , Neoplasias Induzidas por Radiação/etiologia , Órgãos em Risco/efeitos da radiação , Terapia com Prótons/efeitos adversos , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/prevenção & controle , Relação Dose-Resposta à Radiação , Fracionamento da Dose de Radiação , Fatores Etários , Adolescente , Radioterapia/efeitos adversos , Predisposição Genética para Doença , Neoplasias/radioterapia
12.
Biochem Soc Trans ; 52(2): 947-959, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38526159

RESUMO

Caveolin-1 (Cav1) is a 22 kDa intracellular protein that is the main protein constituent of bulb-shaped membrane invaginations known as caveolae. Cav1 can be also found in functional non-caveolar structures at the plasma membrane called scaffolds. Scaffolds were originally described as SDS-resistant oligomers composed of 10-15 Cav1 monomers observable as 8S complexes by sucrose velocity gradient centrifugation. Recently, cryoelectron microscopy (cryoEM) and super-resolution microscopy have shown that 8S complexes are interlocking structures composed of 11 Cav1 monomers each, which further assemble modularly to form higher-order scaffolds and caveolae. In addition, Cav1 can act as a critical signaling regulator capable of direct interactions with multiple client proteins, in particular, the endothelial nitric oxide (NO) synthase (eNOS), a role believed by many to be attributable to the highly conserved and versatile scaffolding domain (CSD). However, as the CSD is a hydrophobic domain located by cryoEM to the periphery of the 8S complex, it is predicted to be enmeshed in membrane lipids. This has led some to challenge its ability to interact directly with client proteins and argue that it impacts signaling only indirectly via local alteration of membrane lipids. Here, based on recent advances in our understanding of higher-order Cav1 structure formation, we discuss how the Cav1 CSD may function through both lipid and protein interaction and propose an alternate view in which structural modifications to Cav1 oligomers may impact exposure of the CSD to cytoplasmic client proteins, such as eNOS.


Assuntos
Caveolina 1 , Transdução de Sinais , Caveolina 1/metabolismo , Caveolina 1/química , Humanos , Animais , Óxido Nítrico Sintase Tipo III/metabolismo , Cavéolas/metabolismo , Microscopia Crioeletrônica , Domínios Proteicos , Membrana Celular/metabolismo
13.
Sci Rep ; 14(1): 5023, 2024 02 29.
Artigo em Inglês | MEDLINE | ID: mdl-38424101

RESUMO

Understanding temperature-sensitivity of R gene-mediated resistance against apoplastic pathogens is important for sustainable food production in the face of global warming. Here, we show that resistance of Brassica napus cotyledons against Leptosphaeria maculans was temperature-sensitive in introgression line Topas-Rlm7 but temperature-resilient in Topas-Rlm4. A set of 1,646 host genes was differentially expressed in Topas-Rlm4 and Topas-Rlm7 in response to temperature. Amongst these were three WAKL10 genes, including BnaA07g20220D, representing the temperature-sensitive Rlm7-1 allele and Rlm4. Network analysis identified a WAKL10 protein interaction cluster specifically for Topas-Rlm7 at 25 °C. Diffusion analysis of the Topas-Rlm4 network identified WRKY22 as a putative regulatory target of the ESCRT-III complex-associated protein VPS60.1, which belongs to the WAKL10 protein interaction community. Combined enrichment analysis of gene ontology terms considering gene expression and network data linked vesicle-mediated transport to defence. Thus, dysregulation of effector-triggered defence in Topas-Rlm7 disrupts vesicle-associated resistance against the apoplastic pathogen L. maculans.


Assuntos
Brassica napus , Mapas de Interação de Proteínas , Temperatura , Genes vpr , Proteínas/metabolismo , Brassica napus/genética , Brassica napus/metabolismo , Perfilação da Expressão Gênica , Doenças das Plantas/genética
14.
Mol Cell ; 84(5): 854-866.e7, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38402612

RESUMO

Deaminases have important uses in modification detection and genome editing. However, the range of applications is limited by the small number of characterized enzymes. To expand the toolkit of deaminases, we developed an in vitro approach that bypasses a major hurdle with their toxicity in cells. We assayed 175 putative cytosine deaminases on a variety of substrates and found a broad range of activity on double- and single-stranded DNA in various sequence contexts, including CpG-specific deaminases and enzymes without sequence preference. We also characterized enzyme selectivity across six DNA modifications and reported enzymes that do not deaminate modified cytosines. The detailed analysis of diverse deaminases opens new avenues for biotechnological and medical applications. As a demonstration, we developed SEM-seq, a non-destructive single-enzyme methylation sequencing method using a modification-sensitive double-stranded DNA deaminase. The streamlined protocol enables accurate, base-resolution methylome mapping of scarce biological material, including cell-free DNA and 10 pg input DNA.


Assuntos
Citosina Desaminase , Epigenoma , DNA/genética , Citosina , DNA de Cadeia Simples/genética , Citidina Desaminase/genética
15.
ACS Nano ; 18(3): 2446-2454, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38207242

RESUMO

Two-dimensional (2D) nanomaterials have numerous interesting chemical and physical properties that make them desirable building blocks for the manufacture of macroscopic materials. Liquid-phase processing is a common method for forming macroscopic materials from these building blocks including wet-spinning and vacuum filtration. As such, assembling 2D nanomaterials into ordered functional materials requires an understanding of their solution dynamics. Yet, there are few experimental studies investigating the hydrodynamics of disk-like materials. Herein, we report the lateral diffusion of hexagonal boron nitride nanosheets (h-BN and graphene) in aqueous solution when confined in 2-dimensions. This was done by imaging fluorescent surfactant-tagged nanosheets and visualizing them by using fluorescence microscopy. Spectroscopic studies were conducted to characterize the interactions between h-BN and the fluorescent surfactant, and atomic force microscopy (AFM) was conducted to characterize the quality of the dispersion. The diffusion data under different gap sizes and viscosities displayed a good correlation with Kramers' theory. We propose that the yielded activation energies by Kramers' equation express the magnitude of the interaction between fluorescent surfactant tagged h-BN and glass because the energies remain constant with changing viscosity and decrease with increasing confinement size. The diffusion of graphene presented a similar trend with similar activation energy as the h-BN. This relationship suggests that Kramers' theory can also be applied to simulate the diffusion of other 2D nanomaterials.

16.
Minerva Cardiol Angiol ; 72(2): 102-110, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38231079

RESUMO

BACKGROUND: The potential influence of renin-angiotensin inhibitors on the severity of SARS-CoV-2 infection has been considered in preclinical and observational studies with contradictory results. Therefore, we investigated the effect of telmisartan in reducing lung injury among hospitalized COVID-19 patients. METHODS: The STAR-COVID trial was conducted as a prospective, parallel-group, randomized, open-label study involving hospitalized adult patients with severe COVID-19 (NCT04510662). Sixty-six patients were enrolled: 33 were assigned to the telmisartan group and 33 to the control group. The mean age of participants was 48.8 years, with 62.5% being male. Participants were randomly assigned in a 1:1 ratio to receive either telmisartan (40 mg daily for 14 days or until discharge) plus standard of care or standard of care alone. The primary outcome assessed was the initiation of mechanical ventilation within 14 days. Secondary outcomes included 30-day mortality, the need for vasopressors, hemodialysis requirements, and length of hospital stay. RESULTS: Comparison between the telmisartan group and the control group revealed no significant difference in the occurrence of mechanical ventilation at 14 days (25% with telmisartan vs. 18.7% with control, P=0.579). Additionally, there were no significant differences observed in terms of mortality (25% vs. 21.9%, P=0.768), the need for vasopressors (18.8% in both groups, P=1.000), hemodialysis requirements (6.3% vs. 3.1%, P=0.500), and length of hospital stay (median of 7 days in both groups, P=0.962). CONCLUSIONS: Compared with the standard of care, telmisartan therapy demonstrated no significant impact on respiratory failure in hospitalized patients with severe COVID-19.


Assuntos
COVID-19 , Insuficiência Respiratória , Adulto , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , COVID-19/complicações , Telmisartan/uso terapêutico , SARS-CoV-2 , Estudos Prospectivos , Padrão de Cuidado , Insuficiência Respiratória/tratamento farmacológico
17.
Radiother Oncol ; 192: 110090, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38224916

RESUMO

BACKGROUND AND PURPOSE: The SOFT trial is a prospective, multicenter, phase 2 trial investigating magnetic resonance (MR)-guided stereotactic ablative radiotherapy (SABR) for abdominal, soft tissue metastases in patients with oligometastatic disease (OMD) (clinicaltrials.gov ID NCT04407897). We present the primary endpoint analysis of 1-year treatment-related toxicity (TRAE). MATERIALS AND METHODS: Patients with up to five oligometastases from non-hematological cancers were eligible for inclusion. A risk-adapted strategy prioritized fixed organs at risk (OAR) constraints over target coverage. Fractionation schemes were 45-67.5 Gy in 3-8 fractions. The primary endpoint was grade ≥ 4 TRAE within 12 months post-SABR. The association between the risk of gastrointestinal (GI) toxicity and clinical and dosimetric parameters was tested using a normal tissue complication probability model. RESULTS: We included 121 patients with 147 oligometastatic targets, mainly located in the liver (41 %), lymph nodes (35 %), or adrenal glands (14 %). Nearly half of all targets (48 %, n = 71) were within 10 mm of a radiosensitive OAR. No grade 4 or 5 TRAEs, 3.5 % grade 3 TRAEs, and 43.7 % grade 2 TRAEs were reported within the first year of follow-up. We found a significant association between grade ≥ 2 GI toxicity and the parameters GI OAR D0.1cc, D1cc, and D20cc. CONCLUSION: In this phase II study of MR-guided SABR of oligometastases in the infra-diaphragmatic region, we found a low incidence of toxicity despite half of the lesions being within 10 mm of a radiosensitive OAR. GI OAR D0.1cc, D1cc, and D20cc were associated with grade ≥ 2 GI toxicity.


Assuntos
Neoplasias , Radiocirurgia , Humanos , Estudos Prospectivos , Fracionamento da Dose de Radiação , Radiocirurgia/efeitos adversos
18.
Biochim Biophys Acta Proteins Proteom ; 1872(2): 140974, 2024 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-38065227

RESUMO

NEIL glycosylases, including NEIL1, NEIL2, and NEIL3, play a crucial role in the base excision DNA repair pathway (BER). The classical importin pathway mediated by importin α/ß and cargo proteins containing nuclear localization sequences (NLS) is the most common transport mechanism of DNA repair proteins to the nucleus. Previous studies have identified putative NLSs located at the C-terminus of NEIL3 and NEIL1. Crystallographic, bioinformatics, calorimetric (ITC), and fluorescence assays were used to investigate the interaction between NEIL1 and NEIL3 putative NLSs and importin-α (Impα). Our findings showed that NEIL3 contains a typical cNLS, with medium affinity for the major binding site of Impα. In contrast, crystallographic analysis of NEIL1 NLS revealed its binding to Impα, but with high B-factors and a lack of electron density at the linker region. ITC and fluorescence assays indicated no detectable affinity between NEIL1 NLS and Impα. These data suggest that NEIL1 NLS is a non-classical NLS with low affinity to Impα. Additionally, we compared the binding mode of NEIL3 and NEIL1 with Mus musculus Impα to human isoforms HsImpα1 and HsImpα3, which revealed interesting binding differences for HsImpα3 variant. NEIL3 is a classical medium affinity monopartite NLS, while NEIL1 is likely to be an unclassical low-affinity bipartite NLS. The base excision repair pathway is one of the primary systems involved in repairing DNA. Thus, understanding the mechanisms of nuclear transport of NEIL proteins is crucial for comprehending the role of these proteins in DNA repair and disease development.


Assuntos
DNA Glicosilases , alfa Carioferinas , Animais , Camundongos , Humanos , alfa Carioferinas/genética , alfa Carioferinas/metabolismo , Transporte Ativo do Núcleo Celular , Sequência de Aminoácidos , Núcleo Celular/metabolismo , Sinais de Localização Nuclear/genética , DNA Glicosilases/metabolismo
19.
Expert Opin Drug Saf ; 23(1): 67-78, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38062555

RESUMO

BACKGROUND: Recently, case reports of priapism associated with the use of some anti-seizure medications began to emerge in the literature. We aimed to investigate if there is a potential safety signal of priapism among individual anti-seizure medications and to search the literature for relevant published cases. RESEARCH DESIGN AND METHODS: We conducted a disproportionality analysis using OpenVigil 2.1 to query the United States Food and Drug Administration's Adverse Event Reporting System (FAERS) database. Literature search was conducted in PubMed/MEDLINE, Scopus and Web of Science up to 12 July 2023. RESULTS: We identified positive signal of priapism for valproic acid and its derivatives (n = 23, chi-squared = 59.943, PRR = 4.566), gabapentin (n = 20, chi-squared = 9.790, PRR = 2.060), lamotrigine (n = 16, chi-squared = 8.318, PRR = 2.120), levetiracetam (n = 16, chi-squared = 10.766, PRR = 2.329), topiramate (n = 14, chi-squared = 28.067, PRR = 3.972) and carbamazepine (n = 8, chi-squared = 6.147, PRR = 2.568), as well as published cases of priapism associated with these drugs. We also found published cases of priapism for pregabalin and phenytoin in the literature and FAERS, and at least one reported adverse event of priapism in FAERS for clonazepam, lacosamide, ethosuximide, oxcarbazepine, and vigabatrin in which they were considered primary suspect. CONCLUSIONS: Our study identified signals for priapism for several anti-seizure medications, but these results need to be confirmed in well-designed pharmacoepidemiological studies.


Assuntos
Farmacovigilância , Priapismo , Masculino , Humanos , Estados Unidos , Priapismo/induzido quimicamente , Anticonvulsivantes/efeitos adversos , Gabapentina/efeitos adversos , Levetiracetam , Sistemas de Notificação de Reações Adversas a Medicamentos , United States Food and Drug Administration
20.
Fitoterapia ; 172: 105754, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37992781

RESUMO

Canthium Lam. is a genus of flowering plants of the Rubiaceae family with about 80-102 species mainly distributed in Asia, tropical and subtropical Africa. The genus is closely related to Keetia E. Phillips and Psydrax Gaertn. and plants of this genus are used in folk medicine for the treatment of diarrhea, worms, leucorrhoea, constipation, snake bites, diabetes, hypertension, venereal diseases, and malaria. The present review covers a period of 52 years of biological and chemical investigations into the genus Canthium and has resulted in the isolation of about 96 secondary metabolites and several reported biological properties. For the Rubiaceae family, iridoids were reported as being the chemotaxonomic markers of this genus (∼25%). Other reported classes of compounds include alkaloids, flavonoids, phenolic compounds, cyanogenic glycosides, coumarins, sugar alcohols, lignans, triterpenoids, and benzoquinones. The main reported pharmacological properties of most species of this genus include antioxidant, antiplasmodial, antipyretic, anti-inflammatory, antidiabetic, neuroprotective and antimicrobial activities with the latter being the most prominent. Considering the diversity of compounds reported from plants of this genus and their wide range of biological activities, it is considered to be worthy to further investigate them for the discovery of potentially new and cost effective drugs.


Assuntos
Fitoterapia , Rubiaceae , Etnofarmacologia , Extratos Vegetais/química , Estrutura Molecular , Compostos Fitoquímicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...