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In this research, the dimensional catalysts of pure g-C3N4 photocatalysts (1D, 2D, and 3D) were investigated for the reduction of the highly toxic/carcinogenic Cr(VI) under visible light irradiation. The catalysts underwent explanation through various surface analysis techniques. According to the BET data, the specific surface area of the 3D catalyst was 1.3 and 7 times higher than those of the 2D and 1D CN catalysts, respectively. The 3D catalyst demonstrated superior performance, achieving an efficiency greater than 99% within 60 min under visible light irradiation in the presence of EDTA due to the abundance of active sites. The study also delved into the influence of factors such as the amount of EDTA-hole scavenger, pH, catalyst dosage, and temperature on the photocatalytic reduction of Cr(VI). Moreover, the 3D catalyst showed excellent reusability, maintaining an efficiency of more than 80% even after 10 cycles, and performed effectively in real water samples. The 3D CN catalyst, with its facile synthesis process, excellent visible light harvesting properties, high reduction efficiency that sustains over multiple cycles, and outstanding performance in real water samples, presents a significant advancement for practical applications in environmental remediation. This research contributes to a new understanding of developing efficient degradation methods for heavy metals in polluted water, highlighting the potential of 3D g-C3N4 catalysts in environmental cleanup efforts.
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Cromo , Luz , Poluentes Químicos da Água , Cromo/química , Catálise , Poluentes Químicos da Água/química , Oxirredução , Recuperação e Remediação Ambiental/métodos , Processos Fotoquímicos , Nitrilas/química , Compostos de Nitrogênio/química , GrafiteRESUMO
In the immunocompromised setting, there are distinct radiologic findings of primary central nervous system lymphoma (PCNSL), including necrotic ring-enhancing lesions, increased propensity for intralesional haemorrhage, and multiplicity. In this clinical context, advanced imaging with MR perfusion, spectroscopy, and diffusion-weighted imaging can be used to increase accuracy in the diagnosis of lymphoma over mimics such as high-grade glioma, metastases, or infection. This review summarizes the histology and pathophysiology of PCNSL in immunodeficient hosts, which provide a basis for its imaging appearances, prognosis, and treatment. This discussion is important for the general radiologist as the incidence of immunodeficiency-related PCNSL may be increasing.
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Countries that are high burden for TB must reverse the COVID-19 pandemic's devastating effects to accelerate progress toward ending TB. Vietnam's Double X (2X) strategy uses chest radiography (CXR) and GeneXpert (Xpert) rapid diagnostic testing to improve early detection of TB disease. Household contacts and vulnerable populations (e.g., individuals aged 60 years and older, smokers, diabetics, those with alcohol use disorders, and those previously treated for TB) with and without TB symptoms were screened in community campaigns using CXRs, followed by Xpert for those with a positive screen. In public non-TB district facilities, diabetics, respiratory outpatients, inpatients with lung disease, and other vulnerable populations underwent 2X evaluation. During COVID-19 restrictions in Vietnam, the 2X strategy improved access to TB services by decentralization to commune health stations, the lowest level of the health system, and enabling self-screening using a quick response mobile application. The number needed to screen (NNS) with CXRs to diagnose 1 person with TB disease was calculated for all 2X models and showed the highest yield among self-screeners (11 NNS with CXR), high yield for vulnerable populations in communities (60 NNS) and facilities (19 NNS), and moderately high yield for household contacts in community campaigns (154 NNS). Computer-aided diagnosis for CXRs was incorporated into community and facility implementation and improved physicians' CXR interpretations and Xpert referral decisions. Integration of TB infection and TB disease evaluation increased eligibility for TB preventive treatment among household contacts, a major challenge during implementation. The 2X strategy increased the rational use of Xpert, employing a health system-wide approach that reached vulnerable populations with and without TB symptoms in communities and facilities for early detection of TB disease. This strategy was effectively adapted to different levels of the health system during COVID-19 restrictions and contributed to post-pandemic TB recovery in Vietnam.
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COVID-19 , Humanos , Vietnã/epidemiologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/prevenção & controle , Tuberculose Pulmonar/epidemiologia , Programas de Rastreamento/organização & administração , Programas de Rastreamento/métodos , SARS-CoV-2 , Pessoa de Meia-Idade , Radiografia Torácica , Tuberculose/diagnóstico , Tuberculose/prevenção & controle , Tuberculose/epidemiologia , Feminino , Pandemias , Masculino , Populações VulneráveisRESUMO
This article documents the work conducted in implementing the IAEA non-agreement TC regional RAS6088 project "Strengthening Education and Training Programmes for Medical Physics". Necessary information on the project was collected from the project counterparts via emails for a period of one month, starting from 21st September 2023, and verified at the Final Regional Coordination Meeting in Bangkok, Thailand from 30th October 2023 to 3rd November 2023. Sixty-three participants were trained in 5 Regional Training Courses (RTCs), with 48%, 32% and 20% in radiation therapy, diagnostic radiology, and nuclear medicine, respectively. One RTC was successfully organised to introduce molecular biology as an academic module to participants. Three participating Member States, namely United Arab Emirates (UAE), Nepal and Afghanistan have initiated processes to start the postgraduate master medical physics education programmes by coursework, adopting the IAEA TCS56 Guidelines. UAE has succeeded in completing the process while Nepal and Afghanistan have yet to initiate the programme. The postgraduate master medical physics programmes by coursework were strengthened in Indonesia, Jordan, Malaysia, Pakistan, Syria, and Thailand, along with the national registration of medical physicists. In particular, Thailand has revised 6 postgraduate master medical physics programmes by coursework during the tenure of this project. Home Based Assignment and RTCs have resulted in two publications. In conclusion, the RAS6088 project was found to have achieved its planned outcomes despite challenges faced due to the COVID-19 pandemic. It is proposed that a follow up project be implemented to increase the number of Member States who are better prepared to improve medical physics education and training in the region.
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The ubiquitin-proteasome system is essential to all eukaryotes and has been shown to be critical to parasite survival as well, including Plasmodium falciparum, the causative agent of the deadliest form of malarial disease. Despite the central role of the ubiquitin-proteasome pathway to parasite viability across its entire life-cycle, specific inhibitors targeting the individual enzymes mediating ubiquitin attachment and removal do not currently exist. The ability to disrupt P. falciparum growth at multiple developmental stages is particularly attractive as this could potentially prevent both disease pathology, caused by asexually dividing parasites, as well as transmission which is mediated by sexually differentiated parasites. The deubiquitinating enzyme PfUCHL3 is an essential protein, transcribed across both human and mosquito developmental stages. PfUCHL3 is considered hard to drug by conventional methods given the high level of homology of its active site to human UCHL3 as well as to other UCH domain enzymes. Here, we apply the RaPID mRNA display technology and identify constrained peptides capable of binding to PfUCHL3 with nanomolar affinities. The two lead peptides were found to selectively inhibit the deubiquitinase activity of PfUCHL3 versus HsUCHL3. NMR spectroscopy revealed that the peptides do not act by binding to the active site but instead block binding of the ubiquitin substrate. We demonstrate that this approach can be used to target essential protein-protein interactions within the Plasmodium ubiquitin pathway, enabling the application of chemically constrained peptides as a novel class of antimalarial therapeutics.
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Peptídeos , Plasmodium falciparum , Proteínas de Protozoários , Ubiquitina Tiolesterase , Plasmodium falciparum/enzimologia , Plasmodium falciparum/metabolismo , Plasmodium falciparum/efeitos dos fármacos , Ubiquitina Tiolesterase/metabolismo , Ubiquitina Tiolesterase/antagonistas & inibidores , Ubiquitina Tiolesterase/genética , Humanos , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacologia , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/química , Proteínas de Protozoários/genética , Proteínas de Protozoários/antagonistas & inibidores , Antimaláricos/farmacologia , Antimaláricos/química , Ubiquitina/metabolismo , Malária Falciparum/parasitologia , Malária Falciparum/tratamento farmacológicoRESUMO
The present study introduces Fe3O4-coated lapatinib-labeled 153Sm nanoparticles (denoted as Fe3O4@lapatinib-153Sm) as a promising avenue for advancing breast cancer treatment. The radiolabeled nanoparticles combine various attributes, offering enhanced therapeutic precision. The integration of lapatinib confers therapeutic effects and targeted delivery. The inherent magnetic characteristics of Fe3O4 nanoparticles contribute to improved imaging contrast and targeted localization. Incorporating the gamma-emitting 153Sm isotope permits single-photon emission computed tomography imaging and radiation dose evaluation, while its beta-emitting nature ensures targeted cancer cell eradication. The synthesis of Fe3O4@lapatinib-153Sm was meticulously optimized by investigating the effects of parameters on radiolabeling efficiency. Physicochemical attributes were scrutinized using several analytical techniques. In-depth in vivo assessment evaluated the biocompatibility, toxicity, and biodistribution in a murine model, illuminating clinical utility. Optimal conditions (153SmCl3 concentration of 10 mCi mL-1, pH 7.4, a reaction time of 30 min, and a temperature of 25 °C) achieved >99% labeling efficiency and radiochemical purity. The TEM analysis indicated that the diameter of Fe3O4@lapatinib-153Sm nanoparticles ranged from 10 to 40 nm. Vibrating-sample magnetometry verified their superparamagnetic behaviour with a saturation magnetization of 41.4 emu g-1. The synthesized radiopharmaceutical exhibited high sterility and in vitro stability. Acute toxicity studies showed the mild effects of Fe3O4@lapatinib-153Sm at a dose of 20 mCi kg-1, with no observed mortality. Notably, lesions from Fe3O4@lapatinib-153Sm use recovered naturally over time. Radiation doses below 20 mCi kg-1 were recommended for clinical trials. The biodistribution study in BT474 xenograft mice revealed rapid clearance of Fe3O4@lapatinib-153Sm within 48 h. Significant accumulation occurred in the liver, spleen, and tumor tissue, while minimal accumulation was found in other tissues. Future steps involve studying biocorona formation and therapeutic efficacy on tumour models, refining its clinical potential.
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Neoplasias da Mama , Nanopartículas , Humanos , Animais , Camundongos , Feminino , Lapatinib , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Distribuição Tecidual , Controle de QualidadeRESUMO
This study aims to provide in vitro and in vivo data to support the utilization of antinuclear antibodies (ANAs) as novel tools for the diagnosis and treatment of prostate cancers. The hematological, biochemical, and histological toxicities of ANAs were assessed at the doses of 5 and 50 µg per mouse. Radiolabeling study was then conducted with ANA and 131I using the chloramine T method, and the biodistribution and treatment efficacy were subsequently investigated in a PC3 xenograft model. No changes in clinical behavior or signs of intoxication, necrosis, or malignancy were observed in ANA-treated mice. 131I-ANA was obtained in very high yield and radiochemical purity, at 94.97 ± 0.98% and 98.56 ± 0.29%, respectively. They achieved immunoreactivity fraction of 0.841 ± 0.17% with PC-3 cells. Levels of radiolabeled ANAs were 1.15-10.14 times higher in tumor tissues than in other examined organs at 24 h post-injection. The tumor growth inhibition rates were 28.33 ± 5.01% in PC3 xenografts mice treated with 131I-ANAs compared with controls and a nearly twofold improvement in median survival was observed. These results demonstrate that radioimmunotherapy of radiolabeled natural ANAs may be an effective treatment for prostate tumors.
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Radioisótopos do Iodo , Neoplasias da Próstata , Masculino , Humanos , Animais , Camundongos , Radioisótopos do Iodo/uso terapêutico , Anticorpos Antinucleares , Xenoenxertos , Distribuição Tecidual , Neoplasias da Próstata/tratamento farmacológico , Linhagem Celular TumoralRESUMO
Dysfunctions caused by missense mutations in the tumour suppressor p53 have been extensively shown to be a leading driver of many cancers. Unfortunately, it is time-consuming and labour-intensive to experimentally elucidate the effects of all possible missense variants. Recent works presented a comprehensive dataset and machine learning model to predict the functional outcome of mutations in p53. Despite the well-established dataset and precise predictions, this tool was trained on a complicated model with limited predictions on p53 mutations. In this work, we first used computational biophysical tools to investigate the functional consequences of missense mutations in p53, informing a bias of deleterious mutations with destabilizing effects. Combining these insights with experimental assays, we present two interpretable machine learning models leveraging both experimental assays and in silico biophysical measurements to accurately predict the functional consequences on p53 and validate their robustness on clinical data. Our final model based on nine features obtained comparable predictive performance with the state-of-the-art p53 specific method and outperformed other generalized, widely used predictors. Interpreting our models revealed that information on residue p53 activity, polar atom distances and changes in p53 stability were instrumental in the decisions, consistent with a bias of the properties of deleterious mutations. Our predictions have been computed for all possible missense mutations in p53, offering clinical diagnostic utility, which is crucial for patient monitoring and the development of personalized cancer treatment.
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Mutação de Sentido Incorreto , Neoplasias , Humanos , Proteína Supressora de Tumor p53/genética , Mutação , Neoplasias/genética , Aprendizado de MáquinaRESUMO
Background: Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI) disorder that results from defects in the respiratory burst activity in phagocytes, leading to the inability to kill bacterial and fungal microorganisms. CGD patients usually have a high incidence of morbidity such as infections and autoinflammatory diseases and a high mortality rate. Allogeneic bone marrow transplantation (BMT) is the only definitive cure for patients who suffer from CGD. Case presentation: We report the first transplant case of chronic granulomatous disease in Vietnam. A 25-month-old boy with X-linked CGD underwent bone marrow transplantation from his 5-year-old, full-matched human leukocyte antigen (HLA)-carrier sibling after myeloablative conditioning regimen with busulfan 5.1 mg/kg/day for 4 days, fludarabine 30 mg/m2/day for 5 days, and rATG (Grafalon-Fresenius) 10 mg/kg/day for 4 days. Neutrophil was engrafted on day 13 posttransplant, donor chimerism was 100% on day 30 with the dihydrorhodamine-1,2,3 (DHR 123) flow cytometric assay test that reached 38% of the normal 45 days posttransplant. Five months after transplant, the patient was free of infection with stable DHR 123 assay at 37%, and donor chimerism remained 100%. No sign of a graft-versus-host disease had been observed posttransplant. Conclusion: We suggest that bone marrow transplantation is a safe and effectual cure for CGD patients, especially for patients with HLA-identical siblings.
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Doença Granulomatosa Crônica , Transplante de Células-Tronco Hematopoéticas , Masculino , Humanos , Pré-Escolar , Transplante de Medula Óssea , Doença Granulomatosa Crônica/terapia , Vietnã , População do Sudeste Asiático , Transplante de Células-Tronco Hematopoéticas/métodosRESUMO
Purpose: The centrally restricted diffusion sign of diffusion-weighted imaging (DWI) is associated with radiation necrosis (RN) in treated gliomas. Our goal was to evaluate its diagnostic accuracy to distinguish RN from tumor recurrence (TR) in treated brain metastases. Methods: Retrospective study of consecutive patients with brain metastases who developed a newly centrally necrotic lesion after radiotherapy (RT). One reader placed regions of interest (ROI) in the enhancing solid lesion and the non-enhancing central necrosis on the apparent diffusion coefficient (ADC) map. Two readers qualitatively assessed the presence of the centrally restricted diffusion sign. The final diagnosis was made by histopathology (n = 39) or imaging follow-up (n = 2). Differences between groups were assessed by Fisher's exact or Mann-Whitney U tests. Diagnostic accuracy and inter-reader agreement were evaluated using receiver operating characteristic (ROC) curve analysis and kappa scores. Results: Forty-one lesions (32 predominant RN; 9 predominant TR) were analyzed. An ADC value ≤ 1220 × 10-6 mm2/s (sensitivity 74%, specificity 89%, area under the curve [AUC] .85 [95% confidence interval {CI}, .70-.94] P < .0001) from the necrosis and an ADC necrosis/enhancement ratio ≤1.37 (sensitivity 74%, specificity 89%, AUC .82 [95% CI, .67-.93] P < .0001) provided the highest performance for RN diagnosis. The qualitative centrally restricted diffusion sign had a sensitivity of 69% (95% CI, .50-.83), specificity of 77% (95% CI, .40-.96), and a moderate (k = .49) inter-reader agreement for RN diagnosis. Conclusions: Radiation necrosis is associated with lower ADC values in the central necrosis than TR. A moderate interobserver agreement might limit the qualitative assessment of the centrally restricted diffusion sign.
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Neoplasias Encefálicas , Recidiva Local de Neoplasia , Humanos , Estudos Retrospectivos , Recidiva Local de Neoplasia/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/radioterapia , Imagem de Difusão por Ressonância Magnética/métodos , Necrose/diagnóstico por imagem , Sensibilidade e Especificidade , Diagnóstico DiferencialRESUMO
Protein phosphorylation acts as an essential on/off switch in many cellular signaling pathways. This has led to ongoing interest in targeting kinases for therapeutic intervention. Computer-aided drug discovery has been proven a useful and cost-effective approach for facilitating prioritization and enrichment of screening libraries, but limited effort has been devoted providing insights on what makes a potent kinase inhibitor. To fill this gap, here we developed kinCSM, an integrative computational tool capable of accurately identifying potent cyclin-dependent kinase 2 (CDK2) inhibitors, quantitatively predicting CDK2 ligand-kinase inhibition constants (pKi ) and classifying different types of inhibitors based on their favorable binding modes. kinCSM predictive models were built using supervised learning and leveraged the concept of graph-based signatures to capture both physicochemical properties and geometry properties of small molecules. CDK2 inhibitors were accurately identified with Matthew's Correlation Coefficients (MCC) of up to 0.74, and inhibition constants predicted with Pearson's correlation of up to 0.76, both with consistent performances of 0.66 and 0.68 on a nonredundant blind test, respectively. kinCSM was also able to identify the potential type of inhibition for a given molecule, achieving MCC of up to 0.80 on cross-validation and 0.73 on the blind test. Analyzing the molecular composition of revealed enriched chemical fragments in CDK2 inhibitors and different types of inhibitors, which provides insights into the molecular mechanisms behind ligand-kinase interactions. kinCSM will be an invaluable tool to guide future kinase drug discovery. To aid the fast and accurate screening of CDK2 inhibitors, kinCSM is freely available at https://biosig.lab.uq.edu.au/kin_csm/.
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Antineoplásicos , Inibidores de Proteínas Quinases , Quinase 2 Dependente de Ciclina/química , Ligantes , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Descoberta de Drogas , Antineoplásicos/químicaRESUMO
Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.
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Proteína 7 com Repetições F-Box-WD , Transtornos do Neurodesenvolvimento , Ubiquitinação , Proteína 7 com Repetições F-Box-WD/química , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/metabolismo , Células Germinativas , Mutação em Linhagem Germinativa , Humanos , Transtornos do Neurodesenvolvimento/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Kinases play crucial roles in cellular signalling and biological processes with their dysregulation associated with diseases, including cancers. Kinase inhibitors, most notably those targeting ABeLson 1 (ABL1) kinase in chronic myeloid leukemia, have had a significant impact on cancer survival, yet emergence of resistance mutations can reduce their effectiveness, leading to therapeutic failure. Limited effort, however, has been devoted to developing tools to accurately identify ABL1 resistance mutations, as well as providing insights into their molecular mechanisms. Here we investigated the structural basis of ABL1 mutations modulating binding affinity of eight FDA-approved drugs. We found mutations impair affinity of type I and type II inhibitors differently and used this insight to developed a novel web-based diagnostic tool, SUSPECT-ABL, to pre-emptively predict resistance profiles and binding free-energy changes (ΔΔG) of all possible ABL1 mutations against inhibitors with different binding modes. Resistance mutations in ABL1 were successfully identified, achieving a Matthew's Correlation Coefficient of up to 0.73 and the resulting change in ligand binding affinity with a Pearson's correlation of up to 0.77, with performances consistent across non-redundant blind tests. Through an in silico saturation mutagenesis, our tool has identified possibly emerging resistance mutations, which offers opportunities for in vivo experimental validation. We believe SUSPECT-ABL will be an important tool not just for improving precision medicine efforts, but for facilitating the development of next-generation inhibitors that are less prone to resistance. We have made our tool freely available at http://biosig.unimelb.edu.au/suspect_abl/.
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Proteins of the major histocompatibility complex (MHC) class I, or human leukocyte antigen (HLA) in humans interact with endogenous peptides and present them to T cell receptors (TCR), which in turn tune the immune system to recognize and discriminate between self and foreign (non-self) peptides. Of especial importance are peptides derived from tumor-associated antigens. T cells recognizing these peptides are found in cancer patients, but not in cancer-free individuals. What stimulates this recognition, which is vital for the success of checkpoint based therapy? A peptide derived from the protein p53 (residues 161-169 or p161) was reported to show this behavior. T cells recognizing this unmodified peptide could be further stimulated in vitro to create effective cancer killing CTLs (cytotoxic T lymphocytes). We hypothesize that the underlying difference may arise from post-translational glycosylation of p161 in normal individuals, likely masking it against recognition by TCR. Defects in glycosylation in cancer cells may allow the presentation of the native peptide. We investigate the structural consequences of such peptide glycosylation by investigating the associated structural dynamics.
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Antígeno HLA-A24/química , Antígeno HLA-A24/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Acetilglucosamina/metabolismo , Glicosilação , Proteínas do Vírus da Imunodeficiência Humana/química , Proteínas do Vírus da Imunodeficiência Humana/metabolismo , Humanos , Ligação de Hidrogênio , Modelos Moleculares , Simulação de Dinâmica Molecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Conformação Proteica , Receptores de Antígenos de Linfócitos T/química , Proteína Supressora de Tumor p53/químicaRESUMO
Rabies virus phosphoprotein (P protein) is a multifunctional protein that plays key roles in replication as the polymerase cofactor that binds to the complex of viral genomic RNA and the nucleoprotein (N protein), and in evading the innate immune response by binding to STAT transcription factors. These interactions are mediated by the C-terminal domain of P (PCTD). The colocation of these binding sites in the small globular PCTD raises the question of how these interactions underlying replication and immune evasion, central to viral infection, are coordinated and, potentially, coregulated. While direct data on the binding interface of the PCTD for STAT1 is available, the lack of direct structural data on the sites that bind N protein limits our understanding of this interaction hub. The PCTD was proposed to bind via two sites to a flexible loop of N protein (Npep) that is not visible in crystal structures, but no direct analysis of this interaction has been reported. Here we use Nuclear Magnetic Resonance, and molecular modelling to show N protein residues, Leu381, Asp383, Asp384 and phosphor-Ser389, are likely to bind to a 'positive patch' of the PCTD formed by Lys211, Lys214 and Arg260. Furthermore, in contrast to previous predictions we identify a single site of interaction on the PCTD by this Npep. Intriguingly, this site is proximal to the defined STAT1 binding site that includes Ile201 to Phe209. However, cell-based assays indicate that STAT1 and N protein do not compete for P protein. Thus, it appears that interactions critical to replication and immune evasion can occur simultaneously with the same molecules of P protein so that the binding of P protein to activated STAT1 can potentially occur without interrupting interactions involved in replication. These data suggest that replication complexes might be directly involved in STAT1 antagonism.
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Evasão da Resposta Imune/fisiologia , Chaperonas Moleculares/metabolismo , Vírus da Raiva/metabolismo , Raiva/virologia , Proteínas Estruturais Virais/metabolismo , Replicação Viral/fisiologia , Animais , Células COS , Chlorocebus aethiops , Células HEK293 , Humanos , Proteínas do Nucleocapsídeo/metabolismo , Raiva/metabolismo , Fator de Transcrição STAT1/metabolismoRESUMO
In this work, we proposed a facile approach to fabricate a superhydrophobic surface for anti-icing performance in terms of adhesive strength and freezing time. A hierarchical structure was generated on as-received Al plates using a wet etching method and followed with a low energy chemical compound coating. Surfaces after treatment exhibited the great water repellent properties with a high contact angle and extremely low sliding angle. An anti-icing investigation was carried out by using a custom-built apparatus and demonstrated the expected low adhesion and freezing time for icephobic applications. In addition, we proposed a model for calculating the freezing time. The experimented results were compared with theoretical calculation and demonstrated the good agreement, illustrating the importance of theoretical contribution in design icephobic surfaces. Therefore, this study provides a guideline for the understanding of icing phenomena and designing of icephobic surfaces.
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S100B(ßß) proteins are a family of multifunctional proteins that are present in several tissues and regulate a wide variety of cellular processes. Their altered expression levels have been associated with several human diseases, such as cancer, inflammatory disorders and neurodegenerative conditions, and hence are of interest as a therapeutic target and a biomarker. Small molecule inhibitors of S100B(ßß) have achieved limited success. Guided by the wealth of available experimental structures of S100B(ßß) in complex with diverse peptides from various protein interacting partners, we combine comparative structural analysis and molecular dynamics simulations to design a series of peptides and their analogues (stapled) as S100B(ßß) binders. The stapled peptides were subject to in silico mutagenesis experiments, resulting in optimized analogues that are predicted to bind to S100B(ßß) with high affinity, and were also modified with imaging agents to serve as diagnostic tools. These stapled peptides can serve as theranostics, which can be used to not only diagnose the levels of S100B(ßß) but also to disrupt the interactions of S100B(ßß) with partner proteins which drive disease progression, thus serving as novel therapeutics.
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Inflamação/genética , Fragmentos de Peptídeos/genética , Mapas de Interação de Proteínas/genética , Subunidade beta da Proteína Ligante de Cálcio S100/genética , Simulação por Computador , Humanos , Inflamação/terapia , Modelos Moleculares , Simulação de Dinâmica Molecular , Neoplasias/genética , Neoplasias/terapia , Fragmentos de Peptídeos/química , Medicina de Precisão , Ligação Proteica/genética , Subunidade beta da Proteína Ligante de Cálcio S100/química , Subunidade beta da Proteína Ligante de Cálcio S100/ultraestruturaRESUMO
PURPOSE: The humanized monoclonal antibody hR3, both alone and in combination with other chemotherapeutic agents and radiotherapy, can be used to treat head and neck cancers. Substantial progress has been made in the development of targeted radioimmunotherapy using iodine-131 (131I) and yttrium-90 (90Y) radioisotopes in recent years. In the present study, we examined the efficacy of hR3 conjugated with 131I or 90Y to inhibit tumor growth in a laryngeal carcinoma xenograft tumor model. METHODS: hR3 was labeled with 131I or 90Y to generate the conjugates 131I-hR3 or 90Y-hR3. The conjugates were incubated with HEp-2 laryngeal carcinoma cells to evaluate binding capacity. The efficacy of the labeled hR3 conjugates to treat laryngeal cancer was also evaluated in nude mice inoculated with HEp-2 tumors. RESULTS: The purified radioimmunoconjugates with specific activities of 187-191 MBq/mg had radiochemical purity >98% and >80% immunoreactivity with HEp-2 cells. Mice with HEp-2 xenografts treated with 131I-hR3 or 90Y-hR3 showed reduced tumor volume and improved survival rates compared to the untreated control group and the group treated with unlabeled hR3. At equivalent doses, radioimmunotherapeutic hR3 labeled with 90Y had increased tumor inhibition activity compared to hR3 labeled with 131I. CONCLUSIONS: 131I-hR3 and 90Y-hR3 are promising targeted radiopharmaceuticals for treatment of head and neck cancers, especially laryngeal cancers.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Transformação Celular Neoplásica , Radioisótopos do Iodo/uso terapêutico , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/radioterapia , Radioimunoterapia/métodos , Radioisótopos de Ítrio/uso terapêutico , Animais , Humanos , Camundongos , Camundongos NusRESUMO
The occurrence of arsenic (As) in groundwater (drilled well water) that were used for drinking, cooking, and personal hygiene and its risks to human health in Long An and Tien Giang provinces (Mekong delta, Vietnam) were evaluated in this study. The average As concentrations were 15.92 ± 11.4 µg/L (n = 24, Long An) and 4.95 ± 4.7 µg/L (n = 24, Tien Giang). The average concentrations of As in Long An had not reached the WHO and QCVN 01: 2009/BYT healthy drinking water standard (10 µg/L). When used as a source of water for drinking and daily activities, arsenic-contaminated groundwater may have a direct impact on human health. The risk assessment from groundwater established by the US Environmental Protection Agency (USEPA) was conducted. The risk assessment showed that the average cancer risk (CR) values were 8.68 × 10-4 (adults) and 2.39 × 10-3 (children) for Long An, and 2.70 × 10-4 (adults) and 7.43 × 10-4 (children) for Tien Giang. These results were significantly higher than the CR (1 × 10-4) proposed by the USEPA. The adverse health effect was therefore specifically warned by the use of arsenic-contaminated groundwater. This research offers valuable knowledge for efficient water management approaches to guarantee local communities' health protection.