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1.
Radiat Res ; 201(2): 93-103, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38171489

RESUMO

The pervasiveness of deep space radiation remains a confounding factor for the transit of humans through our solar system. Spacecraft shielding both protects astronauts but also contributes to absorbed dose through galactic cosmic ray interactions that produce secondary particles. The resultant biological effects drop to a minimum for aluminum shielding around 20 g/cm2 but increase with additional shielding. The present work evaluates for the first time, the impact of secondary pions on central nervous system functionality. The fractional pion dose emanating from thicker shielded spacecraft regions could contribute up to 10% of the total absorbed radiation dose. New results from the Paul Scherrer Institute have revealed that low dose exposures to 150 MeV positive and negative pions, akin to a Mars mission, result in significant, long-lasting cognitive impairments. These surprising findings emphasize the need to carefully evaluate shielding configurations to optimize safe exposure limits for astronauts during deep space travel.


Assuntos
Radiação Cósmica , Mésons , Proteção Radiológica , Voo Espacial , Humanos , Astronave , Radiação Cósmica/efeitos adversos , Proteção Radiológica/métodos , Astronautas , Cognição , Doses de Radiação
2.
Front Public Health ; 11: 1149667, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37965513

RESUMO

Introduction: Patient safety is a global challenge of preventing and mitigating medical errors which might harm patients during their course of treatment and care. This study was employed to contribute to the existing literature aimed to assess patient safety culture among health staff and to determine predictors of health staff perceptions of patient safety in hospitals in Vietnam. Methods: A cross-sectional study was conducted in three hospitals of Vietnam with a total of 763 participants. This study used the Hospital Patient Safety Scale developed by the American Health and Quality Research Organization. Results: In general, 8 of 12 patient safety dimensions in two hospital; and 10 of 12 dimensions in a third hospital had average scores of 60% and above positive responses. The communication openness and organizational learning dimensions were found to be significant different when comparing hospitals. Regarding sample characteristics, department (subclinical department) and health staff positions (nurses/technicians, pharmacists) were significant predictors in the total model including three hospitals (R2 = 0.07). Conclusion: This study reported that communication openness and organization learning are two aspects that need to be improved they are strongly related to patient safety culture and to knowledge exchange among health staff. It has been suggested that hospitals should deliver patient safety training courses and establish a supportive learning environment to improve these challenges.


Assuntos
Cultura Organizacional , Segurança do Paciente , Humanos , Estados Unidos , Estudos Transversais , Vietnã , Inquéritos e Questionários , Hospitais
3.
Cancer Res Commun ; 3(4): 725-737, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37377749

RESUMO

Implementation of ultra-high dose-rate FLASH radiotherapy (FLASH-RT) is rapidly gaining traction as a unique cancer treatment modality able to dramatically minimize normal tissue toxicity while maintaining antitumor efficacy compared with standard-of-care radiotherapy at conventional dose rate (CONV-RT). The resultant improvements in the therapeutic index have sparked intense investigations in pursuit of the underlying mechanisms. As a preamble to clinical translation, we exposed non-tumor-bearing male and female mice to hypofractionated (3 × 10 Gy) whole brain FLASH- and CONV-RT to evaluate differential neurologic responses using a comprehensive panel of functional and molecular outcomes over a 6-month follow-up. In each instance, extensive and rigorous behavioral testing showed FLASH-RT to preserve cognitive indices of learning and memory that corresponded to a similar protection of synaptic plasticity as measured by long-term potentiation (LTP). These beneficial functional outcomes were not found after CONV-RT and were linked to a preservation of synaptic integrity at the molecular (synaptophysin) level and to reductions in neuroinflammation (CD68+ microglia) throughout specific brain regions known to be engaged by our selected cognitive tasks (hippocampus, medial prefrontal cortex). Ultrastructural changes in presynaptic/postsynaptic bouton (Bassoon/Homer-1 puncta) within these same regions of the brain were not found to differ in response to dose rate. With this clinically relevant dosing regimen, we provide a mechanistic blueprint from synapse to cognition detailing how FLASH-RT reduces normal tissue complications in the irradiated brain. Significance: Functional preservation of cognition and LTP after hypofractionated FLASH-RT are linked to a protection of synaptic integrity and a reduction in neuroinflammation over protracted after irradiation times.


Assuntos
Potenciação de Longa Duração , Doenças Neuroinflamatórias , Masculino , Camundongos , Feminino , Animais , Plasticidade Neuronal , Hipofracionamento da Dose de Radiação
4.
Psychol Res Behav Manag ; 16: 1663-1675, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37169002

RESUMO

Objective: To evaluate the prevalence of post-traumatic stress disorder (PTSD) and other psychological disturbances in the Vietnamese healthcare workers (HCWs) at COVID-19 field hospitals. Methods: A cross-sectional study was conducted using the Impact of Event Scale-Revised (IES-R) to measure PTSD and the Depression Anxiety Stress scale (DASS) to measure other psychological disturbances. The anxiety about COVID-19 was evaluated by the fear of COVID-19 (FOC) scale. A self-developed questionnaire was used to assess work conditions and HCW's major concerns and preparedness. Ordinal logistic regression was used to identify factors associated with the severity of PTSD. A structural modeling equation (SEM) model was fitted to examine the correlation between PTSD and other psychological disturbances. Results: A total of 542 HCWs participated in this study. The prevalence of PTSD was 21.2%, most cases were mild. In the ordinal logistic regression analysis, a history of mental illness, poor preparedness, working in a condition with poor resources, a greater number of concerns, and greater fear of COVID-19 were independently associated with higher severity of PTSD. The prevalence of depression, anxiety, and stress was 46.8%, 38.3%, and 60.2, respectively. In the SEM model, PTSD and psychological disturbances had a strong correlation (standardized covariance 0.86). Conclusion: The prevalence of PTSD and other psychological disturbances was alarmingly high among HCWs who worked at COVID-19 field hospitals. The reported associated factors can be useful for policymakers and health authorities in the preparation for future pandemics.

5.
PLoS One ; 18(4): e0284603, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37104504

RESUMO

OBJECTIVES: To evaluate the practice of TB care among physicians at private facilities. METHODS: A cross-sectional study was conducted using questionnaires on knowledge, attitude, and practice related to TB care. The responses to these scales were used to explore latent constructs and calculate the standardized continuous scores for these domains. We described the percentages of participant's responses and explored their associated factors using multiple linear regression. RESULTS: A total of 232 physicians were recruited. The most important gaps in practice included requesting chest imaging to confirm TB diagnosis (~80%), not testing HIV for confirmed active TB cases (~50%), only requesting sputum testing for MDR-TB cases (65%), only requesting follow-up examination at the end of the treatment course (64%), and not requesting sputum testing at follow-up (54%). Surgical mask was preferred to N95 respirator when examining TB patients. Prior TB training was associated with better knowledge and less stigmatizing attitude, which were associated with better practice in both TB management and precautions. CONCLUSION: There were important gaps in knowledge, attitude, and practice of TB care among private providers. Better knowledge was associated with positive attitude towards TB and better practice. Tailored training may help to address these gaps and improve the quality of TB care in the private sector.


Assuntos
Médicos , Tuberculose , Humanos , Estudos Transversais , Vietnã , Instalações Privadas , Tuberculose/diagnóstico , Tuberculose/terapia , Prática Privada
6.
Cell Mol Life Sci ; 80(1): 29, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36607431

RESUMO

Technological advancements have facilitated the implementation of realistic, terrestrial-based complex 33-beam galactic cosmic radiation simulations (GCR Sim) to now probe central nervous system functionality. This work expands considerably on prior, simplified GCR simulations, yielding new insights into responses of male and female mice exposed to 40-50 cGy acute or chronic radiations relevant to deep space travel. Results of the object in updated location task suggested that exposure to acute or chronic GCR Sim induced persistent impairments in hippocampus-dependent memory formation and reconsolidation in female mice that did not manifest robustly in irradiated male mice. Interestingly, irradiated male mice, but not females, were impaired in novel object recognition and chronically irradiated males exhibited increased aggressive behavior on the tube dominance test. Electrophysiology studies used to evaluate synaptic plasticity in the hippocampal CA1 region revealed significant reductions in long-term potentiation after each irradiation paradigm in both sexes. Interestingly, network-level disruptions did not translate to altered intrinsic electrophysiological properties of CA1 pyramidal cells, whereas acute exposures caused modest drops in excitatory synaptic signaling in males. Ultrastructural analyses of CA1 synapses found smaller postsynaptic densities in larger spines of chronically exposed mice compared to controls and acutely exposed mice. Myelination was also affected by GCR Sim with acutely exposed mice exhibiting an increase in the percent of myelinated axons; however, the myelin sheathes on small calibur (< 0.3 mm) and larger (> 0.5 mm) axons were thinner when compared to controls. Present findings might have been predicted based on previous studies using single and mixed beam exposures and provide further evidence that space-relevant radiation exposures disrupt critical cognitive processes and underlying neuronal network-level plasticity, albeit not to the extent that might have been previously predicted.


Assuntos
Hipocampo , Exposição à Radiação , Feminino , Camundongos , Masculino , Animais , Sinapses , Potenciação de Longa Duração , Plasticidade Neuronal
7.
Neuro Oncol ; 25(5): 927-939, 2023 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-36334265

RESUMO

BACKGROUND: Ultrahigh dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising antitumor efficacy compared to conventional dose-rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to a human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes. METHODS: Cohorts of 3-week-old male and female C57Bl/6 mice exposed to hypofractionated (2 × 10 Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months posttreatment. Animals were sacrificed 6 months post-irradiation and tissues were analyzed for neurological and cerebrovascular decrements. RESULTS: The neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin), and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and the preservation of the cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels. CONCLUSIONS: Hypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlights its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature.


Assuntos
Neoplasias Encefálicas , Humanos , Criança , Masculino , Feminino , Animais , Camundongos , Modelos Animais de Doenças , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/etiologia , Dosagem Radioterapêutica , Radioterapia/efeitos adversos
8.
PLoS Negl Trop Dis ; 16(12): e0010942, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36538536

RESUMO

Anthrax is a serious zoonosis caused by Bacillus anthracis, which primarily affects wild herbivorous animals with spillover into humans. The disease occurs nearly worldwide but is poorly reported in Southeast Asian countries. In Vietnam, anthrax is underreported, and little is known about its temporal and spatial distributions. This paper examines the spatio-temporal distribution and epidemiological characteristics of human and livestock anthrax from Dien Bien province, Vietnam from 2010 to 2019. We also aim to define the role of livestock vaccination in reducing human cases. Historical anthrax data were collected by local human and animal health sectors in the province. Spatial rate smoothing and spatial clustering analysis, using Local Moran's I in GeoDa and space-time scan statistic in SaTScan, were employed to address these objectives. We found temporal and spatial overlap of anthrax incidence in humans and livestock with hotspots of human anthrax in the east. We identified three significant space-time clusters of human anthrax persisting from 2010 to 2014 in the east and southeast, each with high relative risk. Most of the human cases were male (69%), aged 15-59 years (80%), involved in processing, slaughtering, or eating meat of sick or dead livestock (96.9%) but environmental and unknown exposure were reported. Animal reports were limited compared to humans and at coarser spatial scale, but in areas with human case clusters. In years when livestock vaccination was high (>~25%), human incidence was reduced, with the opposite effect when vaccine rates dropped. This indicates livestock vaccination campaigns reduce anthrax burden in both humans and livestock in Vietnam, though livestock surveillance needs immediate improvement. These findings suggest further investigation and measures to strengthen the surveillance of human and animal anthrax for other provinces of Vietnam, as well as in other countries with similar disease context.


Assuntos
Antraz , Bacillus anthracis , Animais , Humanos , Masculino , Feminino , Antraz/epidemiologia , Antraz/prevenção & controle , Antraz/veterinária , Gado , Vietnã/epidemiologia , Animais Selvagens , Análise Espacial , Vacinação/veterinária , Surtos de Doenças/prevenção & controle , Surtos de Doenças/veterinária
9.
Environ Monit Assess ; 194(Suppl 2): 765, 2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36255568

RESUMO

Can Tho city in the Mekong Delta is in the top ten areas affected by climate change. Therefore, assessing climate change impacts, social and economic activities require proposed solutions to respond to climate change. This study aims to (i) apply the MIKE 11 model (Hydrodynamic module and Advection-Dispersion module) to simulate the impacts of climate change scenarios on water resources in Can Tho city; (ii) calculate water balance in Can Tho city; and (iii) suggest climate change adaptation plan for sustainable social-economic activities of the city. The results show that when the rainfall changes due to climate change, the flow rate tends to decrease at high tide and increase at low tide. When the sea level rises due to climate change, the flow rate tends to increase at high tide and decrease at low tide. For 2030, the flow will decrease up to 15.6% and 14.3% at the low tide period for RCP 2.6 and RCP 8.5 compared to the present, respectively. The flow will increase up to 63.5% and 58.9% at the high tide period for RCP 2.6 and RCP 8.5 compared to the present, respectively. The water demand evaluation shows that the water resource reserve in Can Tho city meets water demands in current and future scenarios under climate change. While rainwater and groundwater can provide enough water in the rainy season, the city has to use surface water during the dry season due to a lack of rainwater. Of these, agriculture contributes the most water demands (85%). Eight adaptation measures to climate change for Can Tho city are developed from 2021 to 2050.


Assuntos
Mudança Climática , Recursos Hídricos , Vietnã , Monitoramento Ambiental , Água
10.
J Am Soc Nephrol ; 33(12): 2211-2231, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36280286

RESUMO

BACKGROUND: The mechanisms regulating CD8+ T cell migration to nonlymphoid tissue during inflammation have not been fully elucidated, and the migratory properties of effector memory CD8+ T cells that re-express CD45RA (TEMRA CD8+ T cells) remain unclear, despite their roles in autoimmune diseases and allotransplant rejection. METHODS: We used single-cell proteomic profiling and functional testing of CD8+ T cell subsets to characterize their effector functions and migratory properties in healthy volunteers and kidney transplant recipients with stable or humoral rejection. RESULTS: We showed that humoral rejection of a kidney allograft is associated with an accumulation of cytolytic TEMRA CD8+ T cells in blood and kidney graft biopsies. TEMRA CD8+ T cells from kidney transplant recipients exhibited enhanced migratory properties compared with effector memory (EM) CD8+ T cells, with enhanced adhesion to activated endothelium and transmigration in response to the chemokine CXCL12. CXCL12 directly triggers a purinergic P2×4 receptor-dependent proinflammatory response of TEMRA CD8+ T cells from transplant recipients. The stimulation with IL-15 promotes the CXCL12-induced migration of TEMRA and EM CD8+ T cells and promotes the generation of functional PSGL1, which interacts with the cell adhesion molecule P-selectin and adhesion of these cells to activated endothelium. Although disruption of the interaction between functional PSGL1 and P-selectin prevents the adhesion and transmigration of both TEMRA and EM CD8+ T cells, targeting VLA-4 or LFA-1 (integrins involved in T cell migration) specifically inhibited the migration of TEMRA CD8+ T cells from kidney transplant recipients. CONCLUSIONS: Our findings highlight the active role of TEMRA CD8+ T cells in humoral transplant rejection and suggest that kidney transplant recipients may benefit from therapeutics targeting these cells.


Assuntos
Linfócitos T CD8-Positivos , Transplante de Rim , Humanos , Transplantados , Selectina-P/metabolismo , Receptores Purinérgicos P2X4/metabolismo , Rejeição de Enxerto , Memória Imunológica , Proteômica , Antígenos Comuns de Leucócito/metabolismo , Subpopulações de Linfócitos T/metabolismo
11.
Polymers (Basel) ; 14(14)2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35890642

RESUMO

Cationic polyacrylamide (CPAM) emulsifier is widely applied in the wastewater treatment industry, mining industry, paper industry, cosmetic chemistry, etc. However, optimization of input parameters in the synthesis of CPAM by using the traditional approach (i.e., changing one factor while leaving the others fixed at a particular set of conditions) would require a long time and a high cost of input materials. Onsite mass production of CPAM requires fast optimization of input parameters (i.e., stirring speed, reaction temperature and time, the amount of initiator, etc.) to minimize the production cost of specific-molecular-weight CPAM. Therefore, in this study, we synthesized CPAM using reverse emulsion copolymerization, and proposed response surface models for predicting the average molecular weight and reaction yield based on those input parameters. This study offers a time-saving tool for onsite mass production of specific-molecular-weight CPAM. Based on our response surface models, we obtained the optimal conditions for the synthesis of CPAM emulsions, which yielded medium-molecular-weight polymers and high conversion, with a reaction temperature of 60-62 °C, stirring speed of 2500-2600 rpm, and reaction time of 7 h. Quadratic models showed a good fit for predicting molecular weight (Adj.R2 = 0.9888, coefficient of variation = 2.08%) and reaction yield (Adj.R2 = 0.9982, coefficient of variation = 0.50%). The models suggested by our study would benefit the cost-minimization of CPAM mass production, where one could find optimal conditions for synthesizing different molecular weights of CPAM more quickly than via the traditional approach.

12.
SN Bus Econ ; 2(7): 62, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35702484

RESUMO

Reputation is a crucial intangible asset of any business. The model of corporate reputation determinants, including both cognitive and emotional dimensions and their interactions, may vary in different contexts and industries. The purpose of this paper is to examine the determinants of bank reputation in the context of the Vietnam banking sector during the Covid-19 crisis. The conceptual framework was developed from both exploratory research with in-depth interviews and the literature. A structural equation model linking both emotional and cognitive antecedents to each other and bank reputation is tested using data from a sample of 318 Vietnamese individual bank customers. The research results indicate that apart from customers' perceptions about their banks' products and services, social responsibility, vision and leadership, financial capacity, customer satisfaction and trust which are suggested from the literature, banks' ability to provide risk management solutions to customers also has a positive impact on bank reputation. In addition, customer trust totally mediates the effects of customers' perceptions about their banks' offerings and social responsibility on bank reputation. The findings imply multiple ways in which both cognitive and emotional variables should be considered to build bank reputation, in which, building customer trust and providing risk management solutions to customers are the keys. The study is noteworthy that given a special research context, it finds the invalidity of some bank characteristics in signalling bank reputation though they have been repeatedly mentioned as determinants of corporate reputation from the relevant classical postulates.

13.
Int J Mol Sci ; 22(16)2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34445726

RESUMO

A recognized risk of long-duration space travel arises from the elevated exposure astronauts face from galactic cosmic radiation (GCR), which is composed of a diverse array of energetic particles. There is now abundant evidence that exposures to many different charged particle GCR components within acute time frames are sufficient to induce central nervous system deficits that span from the molecular to the whole animal behavioral scale. Enhanced spacecraft shielding can lessen exposures to charged particle GCR components, but may conversely elevate neutron radiation levels. We previously observed that space-relevant neutron radiation doses, chronically delivered at dose-rates expected during planned human exploratory missions, can disrupt hippocampal neuronal excitability, perturb network long-term potentiation and negatively impact cognitive behavior. We have now determined that acute exposures to similar low doses (18 cGy) of neutron radiation can also lead to suppressed hippocampal synaptic signaling, as well as decreased learning and memory performance in male mice. Our results demonstrate that similar nervous system hazards arise from neutron irradiation regardless of the exposure time course. While not always in an identical manner, neutron irradiation disrupts many of the same central nervous system elements as acute charged particle GCR exposures. The risks arising from neutron irradiation are therefore important to consider when determining the overall hazards astronauts will face from the space radiation environment.


Assuntos
Radiação Cósmica/efeitos adversos , Hipocampo/efeitos da radiação , Nêutrons/efeitos adversos , Animais , Comportamento Animal/efeitos da radiação , Masculino , Memória/efeitos da radiação , Camundongos , Plasticidade Neuronal/efeitos da radiação
14.
Biomed Res Int ; 2021: 5597867, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34327230

RESUMO

Lead poisoning in children is a major public health concern worldwide, especially in developing countries. We conducted a cross-sectional study on 403 children aged from 3 to 14 years living nearly zinc-lead mining areas in two provinces in Vietnam (Bac Kan and Thai Nguyen) from 06/2016 to 10/2016 to identify risk factors for lead contamination. Results. The proportion of children with blood lead levels (BLLs) ≥ 10 µg/dL was 80.51% in Bac Kan and 50% in Thai Nguyen; the mean blood lead level for children was 14.41 ± 9.42 µg/dL. In linear regression analyses, the body mass index was negatively associated with elevated BLLs with r = -0.404, p < 0.05 (95% CI: -0.801, -0.006). In multivariable regression analysis, several risk factors were associated with lead contamination including male sex (aOR = 2.44, 95% CI: 1.13-5.24, p = 0.02), play areas in Bac Kan (aOR = 2.3 (1.02-5.17), p = 0.04), proximity of children's home of less than 2 kilometers from the mine (aOR = 2.90 (1.54-5.44), p = 0.001), and inattentive symptoms in Thai Nguyen (aOR = 7.85, 95% CI 3.49-17.69, p = 0.001). Environmental factors, including lead concentrations in the soil and ambient air samples in both locations, are many times higher than Vietnamese standards.


Assuntos
Chumbo/sangue , Mineração , Fatores Socioeconômicos , Zinco/sangue , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , Água Potável/análise , Feminino , Geografia , Hemoglobinas/metabolismo , Humanos , Modelos Logísticos , Masculino , Fatores de Risco , Solo/química , Vietnã
15.
Cancers (Basel) ; 12(6)2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32599789

RESUMO

Major advances in high precision treatment delivery and imaging have greatly improved the tolerance of radiotherapy (RT); however, the selective sparing of normal tissue and the reduction of neurocognitive side effects from radiation-induced toxicities remain significant problems for pediatric patients with brain tumors. While the overall survival of pediatric patients afflicted with medulloblastoma (MB), the most common type primary brain cancer in children, remains high (≥80%), lifelong neurotoxic side-effects are commonplace and adversely impact patients' quality of life. To circumvent these clinical complications, we have investigated the capability of ultra-high dose rate FLASH-radiotherapy (FLASH-RT) to protect the radiosensitive juvenile mouse brain from normal tissue toxicities. Compared to conventional dose rate (CONV) irradiation, FLASH-RT was found to ameliorate radiation-induced cognitive dysfunction in multiple independent behavioral paradigms, preserve developing and mature neurons, minimize microgliosis and limit the reduction of the plasmatic level of growth hormone. The protective "FLASH effect" was pronounced, especially since a similar whole brain dose of 8 Gy delivered with CONV-RT caused marked reductions in multiple indices of behavioral performance (objects in updated location, novel object recognition, fear extinction, light-dark box, social interaction), reductions in the number of immature (doublecortin+) and mature (NeuN+) neurons and increased neuroinflammation, adverse effects that were not found with FLASH-RT. Our data point to a potentially innovative treatment modality that is able to spare, if not prevent, many of the side effects associated with long-term treatment that disrupt the long-term cognitive and emotional well-being of medulloblastoma survivors.

16.
J Biol Chem ; 295(29): 9959-9973, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32482890

RESUMO

Intracellular collagen assembly begins with the oxidative folding of ∼30-kDa C-terminal propeptide (C-Pro) domains. Folded C-Pro domains then template the formation of triple helices between appropriate partner strands. Numerous C-Pro missense variants that disrupt or delay triple-helix formation are known to cause disease, but our understanding of the specific proteostasis defects introduced by these variants remains immature. Moreover, it is unclear whether or not recognition and quality control of misfolded C-Pro domains is mediated by recognizing stalled assembly of triple-helical domains or by direct engagement of the C-Pro itself. Here, we integrate biochemical and cellular approaches to illuminate the proteostasis defects associated with osteogenesis imperfecta-causing mutations within the collagen-α2(I) C-Pro domain. We first show that "C-Pro-only" constructs recapitulate key aspects of the behavior of full-length Colα2(I) constructs. Of the variants studied, perhaps the most severe assembly defects are associated with C1163R C-Proα2(I), which is incapable of forming stable trimers and is retained within cells. We find that the presence or absence of an unassembled triple-helical domain is not the key feature driving cellular retention versus secretion. Rather, the proteostasis network directly engages the misfolded C-Pro domain itself to prevent secretion and initiate clearance. Using MS-based proteomics, we elucidate how the endoplasmic reticulum (ER) proteostasis network differentially engages misfolded C1163R C-Proα2(I) and targets it for ER-associated degradation. These results provide insights into collagen folding and quality control with the potential to inform the design of proteostasis network-targeted strategies for managing collagenopathies.


Assuntos
Colágeno Tipo I/metabolismo , Retículo Endoplasmático/metabolismo , Mutação , Osteogênese Imperfeita/metabolismo , Proteostase , Colágeno Tipo I/genética , Retículo Endoplasmático/genética , Células HEK293 , Humanos , Osteogênese Imperfeita/genética , Domínios Proteicos
17.
J Am Soc Nephrol ; 31(4): 876-891, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32165419

RESUMO

BACKGROUND: Identifying biomarkers to predict kidney transplant failure and to define new therapeutic targets requires more comprehensive understanding of the immune response to chronic allogeneic stimulation. METHODS: We investigated the frequency and function of CD8+ T cell subsets-including effector memory (EM) and terminally differentiated EM (TEMRA) CD8+ T cells-in blood samples from 284 kidney transplant recipients recruited 1 year post-transplant and followed for a median of 8.3 years. We also analyzed CD8+ T cell reactivity to donor-specific PBMCs in 24 patients who had received living-donor kidney transplants. RESULTS: Increased frequency of circulating TEMRA CD8+ T cells at 1 year post-transplant associated with increased risk of graft failure during follow-up. This association remained after adjustment for a previously reported composite of eight clinical variables, the Kidney Transplant Failure Score. In contrast, increased frequency of EM CD8+ T cells associated with reduced risk of graft failure. A distinct TEMRA CD8+ T cell subpopulation was identified that was characterized by expression of FcγRIIIA (CD16) and by high levels of proinflammatory cytokine secretion and cytotoxic activity. Although donor-specific stimulation induced a similar rapid, early response in EM and TEMRA CD8+ T cells, CD16 engagement resulted in selective activation of TEMRA CD8+ T cells, which mediated antibody-dependent cytotoxicity. CONCLUSIONS: At 1 year post-transplant, the composition of memory CD8+ T cell subsets in blood improved prediction of 8-year kidney transplant failure compared with a clinical-variables score alone. A subpopulation of TEMRA CD8+ T cells displays a novel dual mechanism of activation mediated by engagement of the T-cell receptor or of CD16. These findings suggest that TEMRA CD8+ T cells play a pivotal role in humoral and cellular rejection and reveal the potential value of memory CD8+ T cell monitoring for predicting risk of kidney transplant failure.


Assuntos
Linfócitos T CD8-Positivos , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Falência Renal Crônica/sangue , Falência Renal Crônica/cirurgia , Transplante de Rim , Adulto , Idoso , Biomarcadores/sangue , Estudos de Coortes , Feminino , Rejeição de Enxerto/sangue , Rejeição de Enxerto/diagnóstico , Humanos , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Medição de Risco , Resultado do Tratamento
18.
BMC Bioinformatics ; 20(Suppl 23): 634, 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31881828

RESUMO

BACKGROUND: Since protein-DNA interactions are highly essential to diverse biological events, accurately positioning the location of the DNA-binding residues is necessary. This biological issue, however, is currently a challenging task in the age of post-genomic where data on protein sequences have expanded very fast. In this study, we propose iProDNA-CapsNet - a new prediction model identifying protein-DNA binding residues using an ensemble of capsule neural networks (CapsNets) on position specific scoring matrix (PSMM) profiles. The use of CapsNets promises an innovative approach to determine the location of DNA-binding residues. In this study, the benchmark datasets introduced by Hu et al. (2017), i.e., PDNA-543 and PDNA-TEST, were used to train and evaluate the model, respectively. To fairly assess the model performance, comparative analysis between iProDNA-CapsNet and existing state-of-the-art methods was done. RESULTS: Under the decision threshold corresponding to false positive rate (FPR) ≈ 5%, the accuracy, sensitivity, precision, and Matthews's correlation coefficient (MCC) of our model is increased by about 2.0%, 2.0%, 14.0%, and 5.0% with respect to TargetDNA (Hu et al., 2017) and 1.0%, 75.0%, 45.0%, and 77.0% with respect to BindN+ (Wang et al., 2010), respectively. With regards to other methods not reporting their threshold settings, iProDNA-CapsNet also shows a significant improvement in performance based on most of the evaluation metrics. Even with different patterns of change among the models, iProDNA-CapsNets remains to be the best model having top performance in most of the metrics, especially MCC which is boosted from about 8.0% to 220.0%. CONCLUSIONS: According to all evaluation metrics under various decision thresholds, iProDNA-CapsNet shows better performance compared to the two current best models (BindN and TargetDNA). Our proposed approach also shows that CapsNet can potentially be used and adopted in other biological applications.


Assuntos
Aminoácidos/química , Proteínas de Ligação a DNA/metabolismo , Redes Neurais de Computação , Software , Algoritmos , Sequência de Aminoácidos , DNA/química , Humanos , Matrizes de Pontuação de Posição Específica , Curva ROC , Reprodutibilidade dos Testes
20.
Environ Health ; 18(1): 51, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31174534

RESUMO

BACKGROUND: Growing evidence indicates that in utero arsenic exposures in humans may increase the risk of adverse health effects and development of diseases later in life. This study aimed to evaluate potential health risks of in utero arsenic exposure on genetic damage in newborns in relation to maternal arsenic exposure. METHODS: A total of 205 pregnant women residing in arsenic-contaminated areas in Hanam province, Vietnam, were recruited. Prenatal arsenic exposure was determined by arsenic concentration in mother's toenails and urine during pregnancy and in umbilical cord blood collected at delivery. Genetic damage in newborns was assessed by various biomarkers of early genetic effects including oxidative/nitrative DNA damage (8-hydroxydeoxyguanosine, 8-OHdG, and 8-nitroguanine), DNA strand breaks and micronuclei (MN) in cord blood. RESULTS: Maternal arsenic exposure, measured by arsenic levels in toenails and urine, was significantly increased (p <  0.05) in subjects residing in areas with high levels of arsenic contamination in drinking water. Cord blood arsenic level was significantly increased in accordance with maternal arsenic exposure (p <  0.001). Arsenic exposure in utero is associated with genotoxic effects in newborns indicated as increased levels of 8-OHdG, 8-nitroguanine, DNA strand breaks and MN frequency in cord blood with increasing levels of maternal arsenic exposure. Maternal toenail arsenic level was significantly associated with all biomarkers of early genetic effects, while cord blood arsenic levels associated with DNA strand breaks and MN frequency. CONCLUSIONS: In utero arsenic exposure is associated with various types of genetic damage in newborns potentially contributing to the development of diseases, including cancer, later in life.


Assuntos
Arsênio/toxicidade , Dano ao DNA/efeitos dos fármacos , Sangue Fetal/química , Exposição Materna/efeitos adversos , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Adulto , Biomarcadores/sangue , Feminino , Humanos , Recém-Nascido , Unhas/química , Gravidez , Vietnã , Adulto Jovem
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