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1.
Proc Natl Acad Sci U S A ; 121(7): e2305424121, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38315858

RESUMO

Ensuring healthy and sustainable food systems in increasing social, economic, and ecological change is a key global priority to protect human and environmental health. Seafood is an essential component of these food systems and a critical source of nutrients, especially in coastal communities. However, despite rapid transformations in aquatic food systems, and our urgent need to understand them, there is a dearth of data connecting harvested food production to actualized food consumption. Many analyses suggest institutional, legal, or technological innovations to improve food systems, but few have analyzed the pathways through which people already gain access to nutritious food. Here, using a random forest model and cluster analysis of a nationally representative data set from Kiribati, we operationalize access theory to trace the flows of consumptive benefit in a fisheries-based food system. We demonstrate that the market access mechanism is the key mechanism mediating seafood access in Kiribati, but importantly, the highest seafood consumption households showed lower market access, pointing to the importance of non-market acquisition (e.g., home production and gifting). We reveal six distinct household strategies that employ different sets of access mechanisms to ensure high levels of local seafood consumption in different contexts. We demonstrate the impacts of these strategies on the composition of household seafoods consumed, stressing the need to support these existing successful strategies. Finally, we point to key policy and management insights (e.g., improved infrastructure, shifts in species management) that may be more effective in reinforcing these existing pathways than commonly proposed food system interventions.


Assuntos
Pesqueiros , Alimentos Marinhos , Humanos , Alimentos Marinhos/análise , Etnicidade , Abastecimento de Alimentos , Nível de Saúde
2.
J Manuf Sci Eng ; 144(7)2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36578324

RESUMO

Industrial artificial intelligence (IAI) and other analysis tools with obfuscated internal processes are growing in capability and ubiquity within industrial settings. Decision-makers share their concern regarding the objective evaluation of such tools and their impacts at the system level, facility level, and beyond. One application where this style of tool is making a significant impact is in Condition Monitoring Systems (CMSs). This paper addresses the need to evaluate CMSs, a collection of software and devices that alert users to changing conditions within assets or systems of a facility. The presented evaluation procedure uses CMSs as a case study for a broader philosophy evaluating the impacts of IAI tools. CMSs can provide value to a system by forewarning faults, defects, or other unwanted events. However, evaluating CMS value through scenarios that did not occur is rarely easy or intuitive. Further complicating this evaluation are the ongoing investment costs and risks posed by the CMS from imperfect monitoring. To overcome this, an industrial facility needs to regularly and objectively review CMS impacts to justify investments and maintain competitive advantage. This paper's procedure assesses the suitability of a CMS for a system in terms of risk and investment analysis. This risk-based approach uses the changes in the likelihood of good and bad events to quantify CMS value without making any one-time point-wise estimates. Fictional case studies presented in this paper illustrate the procedure and demonstrate its usefulness and validity.

3.
Front Public Health ; 10: 890381, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35719655

RESUMO

The Kiribati 2019 Integrated Household Income and Expenditure Survey (Integrated HIES) embeds novel ecological and human health research into an ongoing social and economic survey infrastructure implemented by the Pacific Community in partnership with national governments. This study seeks to describe the health status of a large, nationally representative sample of a geographically and socially diverse I-Kiribati population through multiple clinical measurements and detailed socio-economic surveys, while also conducting supporting food systems research on ecological, social, and institutional drivers of change. The specific hypotheses within this research relate to access to seafood and the potential nutritional and health benefits of these foods. We conducted this research in 21 of the 23 inhabited islands of Kiribati, excluding the two inhabited islands-Kanton Islands in the Phoenix Islands group with a population of 41 persons (2020 census) and Banaba Island in the Gilbert Islands group with a population of 333 persons (2020 census)-and focusing exclusively on the remaining islands in the Gilbert and Line Islands groups. Within this sample, we focused our intensive human health and ecological research in 10 of the 21 selected islands to examine the relationship between ecological conditions, resource governance, food system dynamics, and dietary patterns. Ultimately, this research has created a baseline for future Integrated HIES assessments to simultaneously monitor change in ecological, social, economic, and human health conditions and how they co-vary over time.


Assuntos
Recifes de Corais , Pesqueiros , Etnicidade , Humanos , Micronésia/epidemiologia
4.
J Gen Intern Med ; 37(13): 3242-3250, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-34993863

RESUMO

BACKGROUND: There are few studies to date of interventions to increase viral hepatitis screening among Asian Americans, who have high rates of chronic hepatitis B (HBV) infection. OBJECTIVE: To develop, implement, and test the efficacy of a mobile application (Hepatitis App) delivered in four languages to increase HBV screening among Asian Americans. DESIGN: Cluster-randomized clinical trial. PARTICIPANTS: Four hundred fifty-two Asian American patients ≥ 18 years of age, who had no prior HBV testing, and received primary care within two healthcare systems in San Francisco, CA. INTERVENTIONS: The intervention group received the Hepatitis App, delivering interactive video education on viral hepatitis in English, Cantonese, Mandarin, or Vietnamese and a provider printout (Provider Alert) and Provider Panel Notification. The comparison group received a mobile application delivering nutrition and physical activity education and Provider Panel Notification. MAIN MEASURES: Primary outcomes were patient-provider discussion about HBV and documentation of a HBV screening test within 3 months post-intervention. Secondary outcome was documentation of an order for a HBV screening test. KEY RESULTS: Participants had a mean age of 57 years and were 64% female, 80% foreign-born, and 44% with limited English fluency. At post-visit, over 80% of intervention participants reported they liked using the Hepatitis App. At 3-month follow-up, the intervention group was more likely than the comparison group (all P < 0.001) to have discussed HBV with their provider (70% vs.16%), have a HBV test ordered (44% vs.10%), and receive a HBV test (38% vs.8%). In multivariable analyses, the intervention odds ratio for HBV test ordering was 7.6 (95% CI: 3.9, 14.8) and test receipt was 7.5 (95% CI: 3.6, 15.5). CONCLUSIONS: A multi-lingual educational intervention using a mobile application in primary care clinics was well received by Asian American patients, enhanced patient-provider communication about HBV, and increased HBV screening. Technology can improve healthcare quality among Asian Americans. TRIAL REGISTRATION: ClinicalTrials.gov NCT02139722 ( https://clinicaltrials.gov/ct2/show/NCT02139722 ).


Assuntos
Asiático , Hepatite B , Feminino , Hepatite B/diagnóstico , Hepatite B/prevenção & controle , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Razão de Chances , Assistência Centrada no Paciente
5.
J Neurosurg ; 136(6): 1760-1772, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34678765

RESUMO

OBJECTIVE: Patients increasingly utilize online physician review websites (PRWs) and social media to inform healthcare-related decisions. This provides neurosurgeons with opportunities for increased patient engagement. And despite the growing use of social media among neurosurgeons, the relationship between social media utilization and online reviews remains unknown. The goal of this study was to characterize the relationship between social media utilization and PRW ratings across academic neurosurgery departments. METHODS: Social media accounts (Twitter, Facebook, YouTube, Instagram) of academic neurosurgery departments were identified. Online reviews for individual faculty were obtained from Healthgrades, Vitals, WebMD, and Google. Reviews were aggregated to identify the total number of reviews per department, to generate a composite departmental rating, and to calculate a summed departmental score. US News & World Report (USNWR) and Doximity rankings were recorded for each department. Social media utilization by individual neurosurgeons and associated ratings were investigated within the departments with the highest social media utilization. RESULTS: Seventy-eight percent of academic neurosurgery departments utilized social media. The most prevalent platform was YouTube (49.1%), followed by Twitter (46.5%), Facebook (38.6%), and Instagram (16.7%). Higher patient ratings on PRWs were associated with the utilization of YouTube (p = 0.048) or Twitter (p = 0.02). The number of social media platforms utilized demonstrated a significant, positive correlation with patient ratings (p = 0.006) and summed patient ratings (p = 0.048). Although USNWR (p = 0.02) and Doximity (p = 0.0008) rankings correlated with patient ratings, only the number of social media platforms utilized remained a significant predictor of patient ratings on multivariate analysis (p = 0.0001). Thirty-one percent of academic neurosurgeons from departments with high social media utilization were active on social media. The most prevalent social media platform among individual neurosurgeons was Twitter (27.4%), followed by Instagram (8.4%), Facebook (4.9%), and YouTube (2.2%). Higher summed patient scores were associated with individual neurosurgeon utilization of YouTube (p = 0.04), Facebook (p < 0.0001), and Instagram (p = 0.01). Increased social media utilization among neurosurgeons was correlated with a greater number of patient reviews (p = 0.006) and higher summed patient scores (p = 0.003). On multivariate analysis, only Facebook use remained a significant predictor of the number of patient reviews received (p = 0.002) and summed patient satisfaction scores (p < 0.001). CONCLUSIONS: An increased social media presence is associated with higher ratings on PRWs. As neurosurgeons continue to expand their online presence, they should be aware of the possible impact of social media on online patient reviews.

6.
Foods ; 10(11)2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34828873

RESUMO

Extensive literature describes the importance of food environments (FEs) as a driver of food choices and nutrition outcomes; yet existing FE frameworks do not adequately capture the diversity of FEs relevant to the Pacific Region. This limits identification of opportunities in food systems to reduce the multiple burden of malnutrition. We present a conceptual typology of FEs including six primary FEs relevant in the Pacific; wild; cultivated; kin and community; informal retail; formal retail; and food aid and services. We then apply this typology to food acquisition data from Solomon Islands 2012/13 Household Income and Expenditure Survey and analyse the relationship between FEs and diet quality. The cultivated FE accounts for 60% of the quantity of food acquired nationally, followed by wild (15%), kin and community (9%), and formal and informal retail FEs (8% each), with wide variation between urban and rural households, provinces and wealth groups. Reliance on different FEs is a significant predictor of diet quality and affirms the importance of subsistence fisheries and agriculture, and community and kinship networks. Integration of a FE typology such as the one presented here in commonly conducted household expenditure surveys offers significant opportunity to advance our understanding of food system leverage points to improve nutrition and health.

7.
Mol Cell ; 81(11): 2278-2289, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33984284

RESUMO

Agents that induce DNA damage can cure some cancers. However, the side effects of chemotherapy are severe because of the indiscriminate action of DNA-damaging agents on both healthy and cancerous cells. DNA repair pathway inhibition provides a less toxic and targeted alternative to chemotherapy. A compelling DNA repair target is the Fanconi anemia (FA) E3 ligase core complex due to its critical-and likely singular-role in the efficient removal of specific DNA lesions. FA pathway inactivation has been demonstrated to specifically kill some types of cancer cells without the addition of exogenous DNA damage, including cells that lack BRCA1, BRCA2, ATM, or functionally related genes. In this perspective, we discuss the genetic and biochemical evidence in support of the FA core complex as a compelling drug target for cancer therapy. In particular, we discuss the genetic, biochemical, and structural data that could rapidly advance our capacity to identify and implement the use of FA core complex inhibitors in the clinic.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Reparo do DNA/efeitos dos fármacos , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Anemia de Fanconi/tratamento farmacológico , Ubiquitina-Proteína Ligases/genética , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/deficiência , Proteína BRCA1/deficiência , Proteína BRCA2/deficiência , Dano ao DNA , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Anemia de Fanconi/genética , Anemia de Fanconi/metabolismo , Anemia de Fanconi/patologia , Proteínas de Grupos de Complementação da Anemia de Fanconi/antagonistas & inibidores , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Terapia de Alvo Molecular/métodos , Morfolinas/uso terapêutico , Pironas/uso terapêutico , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Mutações Sintéticas Letais , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinas/antagonistas & inibidores , Ubiquitinas/genética , Ubiquitinas/metabolismo
8.
Acad Pediatr ; 21(3): 580-582, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33529738

RESUMO

This study examined if preclerkship medical students would find it educational to scribe in a pediatric setting. Scribing promoted students' learning about pediatric clinical encounters enhanced their competency with electronic health record use, and moderately reduced attending physician documentation burden.


Assuntos
Estudantes de Medicina , Criança , Documentação , Registros Eletrônicos de Saúde , Humanos , Aprendizagem , Local de Trabalho
9.
J Pers Soc Psychol ; 120(4): 861-881, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33539153

RESUMO

Terror management theory (TMT) proposes that the awareness of our eventual death is at odds with our evolved desire to live and that humans attempt to resolve this psychological conflict by investing in cultural worldviews that grant symbolic or literal immortality. The present studies examine the interplay between symbolic and literal immortality striving. Three studies show that, following a death reminder, only individuals who did not have a route to literal immortality (belief in an afterlife) increased how long they believe their culture (Canada in Studies 1 and 2, the United States in Study 3), will last by thousands of years. Study 4 demonstrated that this moderation effect cannot be explained by general religiosity; Study 5 conceptually replicated this finding using a different measure of perceived cultural longevity. Finally, Study 6 demonstrates that for those who were highly invested in their nation but did not believe in an afterlife, perceived cultural longevity was associated with decreased death anxiety. These results are consistent with the notion that people possess a primary path to immortality that follows directly from their worldview. The need for increased specificity in study design in TMT and the threat and defense literature more broadly is discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Atitude Frente a Morte , Cultura , Adolescente , Adulto , Canadá , Feminino , Humanos , Masculino , Religião , Identificação Social , Estados Unidos , Adulto Jovem
10.
Mol Immunol ; 131: 155-163, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33423763

RESUMO

BACKGROUND: The IgE- and IgG4-binding patterns of the major fish allergen parvalbumins are not clearly understood. IgE antibody-binding to parvalbumin from Asian seabass, Lat c 1.01, is implicated in up to 90 % of allergic reactions, although the region of IgE or IgG4 epitopes are unknown. In the present study, we characterized the specific IgE- and IgG4-binding regions of Lat c 1.01 using serum from pediatric and adult patients with clinically-confirmed fish allergy. METHODS: A comparative investigation of patient IgE- and IgG4-binding to recombinant Lat c 1.01 was performed by immunoblotting and indirect ELISA using serum from 15 children and eight adults with clinically confirmed IgE-mediated reactions to fish. The IgE- and IgG4-binding regions of Lat c 1.01 were determined by inhibition ELISA using seven overlapping peptides spanning the entire 102 amino acid sequence. Elucidated IgE-binding regions were modelled and compared to known antibody-binding regions of parvalbumins from five other fish species. RESULTS: Ninety five percent (22/23) patients demonstrated IgE-binding to rLat c 1.01, while fewer patients (10/15 children and 7/8 adults) demonstrated robust IgG4 binding when determined by immunoblots. IgE-binding for both cohorts was significantly higher compared to IgG4-binding by ELISA. All patients in this study presented individual IgE and IgG4 epitope-recognition profiles. In addition to these patient-specific antibody binding sites, general IgE epitopes were also identified at the C- and N-terminal regions of this major fish allergen. CONCLUSIONS AND CLINICAL RELEVANCE: Our findings demonstrate two specific IgE epitopes on parvalbumin from Asian seabass, while IgG4 binding is much lower and patient specific. This study highlights the importance of advancement in epitope analysis regardless of the age group for diagnostics and immunotherapies for fish allergy.


Assuntos
Alérgenos/imunologia , Epitopos/imunologia , Peixes/imunologia , Imunoglobulina E/imunologia , Imunoglobulina G/imunologia , Adolescente , Adulto , Sequência de Aminoácidos , Animais , Criança , Pré-Escolar , Mapeamento de Epitopos/métodos , Feminino , Hipersensibilidade Alimentar/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Parvalbuminas/imunologia , Adulto Jovem
11.
Talanta ; 221: 121431, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33076062

RESUMO

Uranium ore is mined and milled to produce uranium ore concentrate (UOC), a regulated product of the nuclear fuel cycle. Diversion of UOC from the fuel cycle into possible weapons production is a key concern in global nonproliferation efforts. As such, the ability to trace the origin of seized nuclear materials is imperative to law enforcement efforts. Although isotopic signatures of UOCs have proven fruitful to pinpoint sample provenance, new isotopic signatures are needed because most existing isotopic signatures are not indicative of the original ore body from which the U is derived. In this work, we developed a new method to separate samarium (Sm) from a U-rich sample matrix and report the first Sm isotope compositions of 32 UOCs derived from a variety of worldwide uranium mines. Relative to terrestrial standards, approximately half the UOCs have resolved and anticorrelated 149Sm-150Sm isotope compositions, consistent with the capture of thermal neutrons by 149Sm in the ore body. The UOCs with anomalous Sm isotope compositions tend to derive from older (~>1.5Ga) and higher-grade ore bodies, although other factors, such as the presence of neutron moderators like water, also play a role. Nonetheless, the Sm isotope compositions of UOCs directly reflects the neutron fluence over the history of the original ore body and can be used to discern different geologic conditions associated with that ore body. As such, this work demonstrates the potential use of Sm isotopes as a novel nuclear forensics signature for origin assessment of UOCs.

12.
Nutrients ; 12(12)2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33266125

RESUMO

National rates of aquatic food consumption in Pacific Island Countries and Territories are among the highest in the world, yet the region is suffering from extensive levels of diet-related ill health. The aim of this paper is to examine the variation in consumption patterns and in nutrient composition of aquatic foods in the Pacific, to help improve understanding of their contribution to food and nutrition security. For this examination we analysed nutrient composition data and trade data from two novel region-specific databases, as well as consumption data from national and village level surveys for two Melanesian case studies, Vanuatu and Solomon Islands. Results demonstrated that consumption depends on availability and the amount and type of aquatic food consumed, and its contribution to nutrition security varies within different geographic and socio-demographic contexts. More data is needed on locally relevant species and consumption patterns, to better inform dietary guidelines and improve public health both now and into the future. Advice on aquatic food consumption must consider the nutrient composition and quantity of products consumed, as well as accessibility through local food systems, to ensure they contribute to diverse and healthy diets.


Assuntos
Estado Nutricional , Valor Nutritivo , Alimentos Marinhos , Animais , Dieta Saudável , Peixes , Desnutrição , Melanesia , Política Nutricional , Ilhas do Pacífico , Saúde Pública
13.
Food Secur ; 12(4): 783-791, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32837656

RESUMO

The unfolding COVID-19 pandemic has exposed the vulnerability of the Pacific food system to externalities and has had far-reaching impacts, despite the small number of COVID-19 cases recorded thus far. Measures adopted to mitigate risk from the pandemic have had severe impacts on tourism, remittances, and international trade, among other aspects of the political economy of the region, and are thus impacting on food systems, food security and livelihoods. Of particular concern will be the interplay between loss of incomes and the availability and affordability of local and imported foods. In this paper, we examine some of the key pathways of impact on food systems, and identify opportunities to strengthen Pacific food systems during these challenging times. The great diversity among Pacific Island Countries and Territories in their economies, societies, and agricultural potential will be an important guide to planning interventions and developing scenarios of alternative futures. Bolstering regional production and intraregional trade in a currently import-dependent region could strengthen the regional economy, and provide the health benefits of consuming locally produced and harvested fresh foods - as well as decreasing reliance on global supply chains. However, significant production, processing, and storage challenges remain and would need to be consistently overcome to influence a move away from shelf-stable foods, particularly during periods when human movement is restricted and during post-disaster recovery.

14.
Sci Rep ; 10(1): 7959, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32409752

RESUMO

DNA inter-strand crosslinks (ICLs) threaten genomic stability by creating a physical barrier to DNA replication and transcription. ICLs can be caused by endogenous reactive metabolites or from chemotherapeutics. ICL repair in humans depends heavily on the Fanconi Anaemia (FA) pathway. A key signalling step of the FA pathway is the mono-ubiquitination of Fanconi Anaemia Complementation Group D2 (FANCD2), which is achieved by the multi-subunit E3 ligase complex. FANCD2 mono-ubiquitination leads to the recruitment of DNA repair proteins to the site of the ICL. The loss of FANCD2 mono-ubiquitination is a common clinical feature of FA patient cells. Therefore, molecules that restore FANCD2 mono-ubiquitination could lead to a potential drug for the management of FA. On the other hand, in some cancers, FANCD2 mono-ubiquitination has been shown to be essential for cell survival. Therefore, inhibition of FANCD2 mono-ubiquitination represents a possible therapeutic strategy for cancer specific killing. We transferred an 11-protein FANCD2 mono-ubiquitination assay to a high-throughput format. We screened 9,067 compounds for both activation and inhibition of the E3 ligase complex. The use of orthogonal assays revealed that candidate compounds acted via non-specific mechanisms. However, our high-throughput biochemical assays demonstrate the feasibility of using sophisticated and robust biochemistry to screen for small molecules that modulate a key step in the FA pathway. The future identification of FA pathway modulators is anticipated to guide future medicinal chemistry projects with drug leads for human disease.


Assuntos
Inibidores Enzimáticos/farmacologia , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Linhagem Celular Tumoral , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Humanos , Ubiquitinação/efeitos dos fármacos
15.
Elife ; 92020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32167469

RESUMO

FANCI:FANCD2 monoubiquitination is a critical event for replication fork stabilization by the Fanconi anemia (FA) DNA repair pathway. It has been proposed that at stalled replication forks, monoubiquitinated-FANCD2 serves to recruit DNA repair proteins that contain ubiquitin-binding motifs. Here, we have reconstituted the FA pathway in vitro to study functional consequences of FANCI:FANCD2 monoubiquitination. We report that monoubiquitination does not promote any specific exogenous protein:protein interactions, but instead stabilizes FANCI:FANCD2 heterodimers on dsDNA. This clamping requires monoubiquitination of only the FANCD2 subunit. We further show using electron microscopy that purified monoubiquitinated FANCI:FANCD2 forms filament-like arrays on long dsDNA. Our results reveal how monoubiquitinated FANCI:FANCD2, defective in many cancer types and all cases of FA, is activated upon DNA binding.


Bone marrow is the spongy tissue inside bones that produces blood cells. Fanconi anemia is the most common form of inherited bone marrow death and affects children and young adults. In this disease, bone marrow cells cannot attach a protein tag called ubiquitin to another protein called FANCD2. When DNA becomes damaged, FANCD2 helps cells to respond and repair the damage but without ubiquitin it cannot do this correctly. Without ubiquitin linked to FANCD2 bone marrow cells die from damaged DNA. Another protein, called FANCI, works in partnership with FANCD2 and also gets linked to ubiquitin. Tan et al. studied purified proteins in the laboratory to understand how linking ubiquitin changes the behavior of FANCD2 and FANCI. When the proteins have ubiquitin attached, they can form stable attachments to DNA. Without ubiquitin, however, the proteins only attach to DNA for short periods of time. Using electron microscopy, Tan et al. discovered that large numbers of the modified proteins become tightly attached to damaged DNA, helping to protect it and triggering DNA repair processes. Understanding the role of FANCD2 in Fanconi anemia could lead to new treatments. FANCD2 and FANCI have similar roles in other cells too. Stopping them from protecting damaged DNA in cancer cells could be used to enhance the success of chemotherapies and radiotherapies.


Assuntos
Dano ao DNA , Reparo do DNA , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Proteínas de Grupos de Complementação da Anemia de Fanconi/metabolismo , Replicação do DNA , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Humanos , Ubiquitinação
16.
PLoS One ; 15(2): e0229000, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32092106

RESUMO

Site-specific conjugation of ubiquitin onto a range of DNA repair proteins regulates their critical functions in the DNA damage response. Biochemical and structural characterization of these functions are limited by an absence of tools for the purification of DNA repair proteins in purely the ubiquitinated form. To overcome this barrier, we designed a ubiquitin fusion protein that is N-terminally biotinylated and can be conjugated by E3 RING ligases onto various substrates. Biotin affinity purification of modified proteins, followed by cleavage of the affinity tag leads to release of natively-mono-ubiquitinated substrates. As proof-of-principle, we applied this method to several substrates of mono-ubiquitination in the Fanconi anemia (FA)-BRCA pathway of DNA interstrand crosslink repair. These include the FANCI:FANCD2 complex, the PCNA trimer and BRCA1 modified nucleosomes. This method provides a simple approach to study the role of mono-ubiquitination in DNA repair or any other mono-ubiquitination signaling pathways.


Assuntos
Avidina/química , Proteína do Grupo de Complementação D2 da Anemia de Fanconi , Proteínas de Grupos de Complementação da Anemia de Fanconi , Antígeno Nuclear de Célula em Proliferação , Ubiquitina-Proteína Ligases , Ubiquitina , Animais , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/química , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/isolamento & purificação , Proteínas de Grupos de Complementação da Anemia de Fanconi/química , Proteínas de Grupos de Complementação da Anemia de Fanconi/isolamento & purificação , Humanos , Antígeno Nuclear de Célula em Proliferação/química , Antígeno Nuclear de Célula em Proliferação/isolamento & purificação , Células Sf9 , Spodoptera , Ubiquitina/química , Ubiquitina/isolamento & purificação , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/isolamento & purificação , Proteínas Ubiquitinadas/química , Proteínas Ubiquitinadas/isolamento & purificação
17.
Artigo em Inglês | MEDLINE | ID: mdl-31555021

RESUMO

Manufacturing environments face many unique challenges in regards to balancing high standards of both product quality and production efficiency. Proper diagnostic health assessment is essential for maximizing uptime and maintaining product and process quality. Information for diagnostic assessments, and reliability information in general, can come from a myriad of sources that can be processed and managed through numerous algorithms that range from simplistic to hyper complex. One area that typifies the assortment of information sources in a modern manufacturing setting is found with the use of industrial robotics and automated manipulators. Although several monitoring methods and technologies have been previously proposed for this and other assets, adoption has been sporadic with returns on investment not always meeting expectations. Practical concerns regarding data limitations, variability of setup, and scarcity of ground truth points of validation from active industrial sites have contributed to this. This paper seeks to provide an overview of barriers and offer a feasible action plan for developing a practical condition monitoring information utilization program, matching available capabilities and assets to maximize knowledge gain. Observations are made on real world case study involving industrial six Degree of Freedom (DOF) robots actively deployed in a manufacturing facility with a variety of operational tasks.

18.
Proc Natl Acad Sci U S A ; 116(5): 1692-1697, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30635425

RESUMO

Immune checkpoint therapy (ICT) has transformed cancer treatment in recent years; however, treatment response is not uniform across tumor types. The tumor immune microenvironment plays a critical role in determining response to ICT; therefore, understanding the differential immune infiltration between ICT-sensitive and ICT-resistant tumor types will help to develop effective treatment strategies. We performed a comprehensive analysis of the immune tumor microenvironment of an ICT-sensitive tumor (melanoma, n = 44) and an ICT-resistant tumor (pancreatic cancer, n = 67). We found that a pancreatic tumor has minimal to moderate infiltration of CD3, CD4, and CD8 T cells; however, the immune infiltrates are predominantly present in the stromal area of the tumor and are excluded from tumoral area compared with melanoma, where the immune infiltrates are primarily present in the tumoral area. Metastatic pancreatic ductal adenocarcinomas (PDACs) had a lower infiltration of total T cells compared with resectable primary PDACs, suggesting that metastatic PDACs have poor immunogenicity. Further, a significantly higher number of CD68+ macrophages and VISTA+ cells (also known as V-domain immunoglobulin suppressor of T cell activation) were found in the pancreatic stromal area compared with melanoma. We identified VISTA as a potent inhibitory checkpoint that is predominantly expressed on CD68+ macrophages on PDACs. These data suggest that VISTA may be a relevant immunotherapy target for effective treatment of patients with pancreatic cancer.


Assuntos
Antígenos B7/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Melanoma/metabolismo , Neoplasias Pancreáticas/metabolismo , Adenocarcinoma/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Humanos , Imunoterapia/métodos , Ativação Linfocitária/fisiologia , Microambiente Tumoral/fisiologia
20.
Artif Organs ; 43(7): 666-676, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30588644

RESUMO

A long-standing goal in the field of biofluid mechanics has been to reliably predict hemolysis across the wide range of flows that can occur in prosthetic cardiovascular devices. A scalar representation of the complex three-dimensional fluid stresses that are exerted on cells is an attractive alternative for the simplicity that it lends to the computations. The appropriateness of the commonly used von-Mises-like scalar stress as a universal hemolysis scaling parameter was previously evaluated, finding that erythrocyte membrane tensions calculated for laminar shear and extensional flows and for three cases of turbulent flow were widely divergent for the same value of scalar stress. The same techniques are applied in this study to laminar and turbulent flows that each have the same energy dissipation rate. Results showed that agreement of membrane tension between laminar shear and turbulent shear inside an eddy was improved relative to the common scalar stress cases, but disagreement between laminar shear and laminar extension remained the same and disagreement between laminar shear and other turbulent flows increased. It is therefore concluded that energy dissipation rate alone is also likely not sufficient to universally scale blood damage across the range of different flows that can be encountered clinically.


Assuntos
Hemólise , Modelos Cardiovasculares , Algoritmos , Fenômenos Biomecânicos , Velocidade do Fluxo Sanguíneo , Próteses Valvulares Cardíacas/efeitos adversos , Coração Artificial/efeitos adversos , Humanos , Fluxo Pulsátil , Estresse Mecânico
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