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Adeno-associated viral vectors (AAVs) have become popular for gene therapy, given their many advantages, including their reduced inflammatory profile compared with that of other viruses. However, even in areas of immune privilege such as the eye, AAV vectors are capable of eliciting host-cell responses. To investigate the effects of such responses on several ocular cell types, we tested multiple AAV genome structures and capsid types using subretinal injections in mice. Assays of morphology, inflammation, and physiology were performed. Pathological effects on photoreceptors and the retinal pigment epithelium (RPE) were observed. Müller glia and microglia were activated, and the proinflammatory cytokines TNF-α and IL-1β were up-regulated. There was a strong correlation between cisregulatory sequences and toxicity. AAVs with any one of three broadly active promoters, or an RPE-specific promoter, were toxic, while AAVs with four different photoreceptor-specific promoters were not toxic at the highest doses tested. There was little correlation between toxicity and transgene, capsid type, preparation method, or cellular contaminants within a preparation. The toxic effect was dose-dependent, with the RPE being more sensitive than photoreceptors. Our results suggest that ocular AAV toxicity is associated with certain AAV cis-regulatory sequences and/or their activity and that retinal damage occurs due to responses by the RPE and/or microglia. By applying multiple, sensitive assays of toxicity, AAV vectors can be designed so that they can be used safely at high dose, potentially providing greater therapeutic efficacy.

Mammalian cells can generate ATP via glycolysis or mitochondrial respiration. Oncogene activation and hypoxia promote glycolysis and lactate secretion. The significance of these metabolic changes to ATP production remains however ill defined. Here, we integrate LC‐MS‐based isotope tracer studies with oxygen uptake measurements in a quantitative redox‐balanced metabolic flux model of mammalian cellular metabolism. We then apply this approach to assess the impact of Ras and Akt activation and hypoxia on energy metabolism. Both oncogene activation and hypoxia induce roughly a twofold increase in glycolytic flux. Ras activation and hypoxia also strongly decrease glucose oxidation. Oxidative phosphorylation, powered substantially by glutamine‐driven TCA turning, however, persists and accounts for the majority of ATP production. Consistent with this, in all cases, pharmacological inhibition of oxidative phosphorylation markedly reduces energy charge, and glutamine but not glucose removal markedly lowers oxygen uptake. Thus, glutamine‐driven oxidative phosphorylation is a major means of ATP production even in hypoxic cancer cells. The impact of oncogene activation and hypoxia on energy metabolism is analyzed by integrating quantitative measurements into a redox‐balanced metabolic flux model. Glutamine‐driven oxidative phosphorylation is found to be a major ATP source even in oncogene‐expressing or hypoxic cells. Synopsis The impact of oncogene activation and hypoxia on energy metabolism is analyzed by integrating quantitative measurements into a redox‐balanced metabolic flux model. Glutamine‐driven oxidative phosphorylation is found to be a major ATP source even in oncogene‐expressing or hypoxic cells. The integration of oxygen uptake measurements and LC‐MS‐based isotope tracer analyses in a redox‐balanced metabolic flux model enabled quantitative determination of energy generation pathways in cultured cells. In transformed mammalian cells, even in hypoxia (1% oxygen), oxidative phosphorylation produces the majority of ATP. The oncogene Ras simultaneously increases glycolysis and decreases oxidative phosphorylation, thus resulting in no net increase in ATP production. Glutamine is the major source of high‐energy electrons for oxidative phosphorylation, especially upon Ras activation.

This narrative review critically summarizes that microplastics and nanoplastics have been found in many different environments, including water and food, raising concerns on their possible harm to human health. Previous research indicates that microplastics may cause inflammation and tissue damage; however, the full extent of their health risks remains uncertain. Given the long-term use of plastic-based orthodontic appliances such as aligners, retainers, and widespread usage of adhesives, the potential release of microplastics and nanoplastics during routine wear and mechanical stress warrants thorough investigation to ensure patient safety and long-term biocompatibility. The literature search conducted for this review was structured but non-systematic, with no formal risk-of-bias evaluation. This review aimed to critically evaluate the impact of microplastics and nanoplastics on human health, with a focus on their relevance to orthodontics. The review also aimed to identify possible gaps in current research, particularly regarding the quantification of microplastic leakage from orthodontic appliances and their possible long-term effects. Current evidence highlights a clear need for more targeted research to inform and improve safety standards regarding microplastics and plastic usage in orthodontic and dental practice.

Nrf2, a transcription factor that regulates the response to oxidative stress, has been shown to rescue cone photoreceptors and slow vision loss in mouse models of retinal degeneration (rd). The retinal pigment epithelium (RPE) is damaged in these models, but whether it also could be rescued by Nrf2 has not been previously examined. We used an adeno-associated virus (AAV) with an RPE-specific (Best1) promoter to overexpress Nrf2 in the RPE of rd mice. Control rd mice showed disruption of the regular array of the RPE, as well as loss of RPE cells. Cones were lost in circumscribed regions within the cone photoreceptor layer. Overexpression of Nrf2 specifically in the RPE was sufficient to rescue the RPE, as well as the disruptions in the cone photoreceptor layer. Electron microscopy showed compromised apical microvilli in control rd mice but showed preserved microvilli in Best1-Nrf2-treated mice. The rd mice treated with Best1-Nrf2 had slightly better visual acuity. Transcriptome profiling showed that Nrf2 upregulates multiple oxidative defense pathways, reversing declines seen in the glutathione pathway in control rd mice. In summary, Nrf2 overexpression in the RPE preserves RPE morphology and survival in rd mice, and it is a potential therapeutic for diseases involving RPE degeneration, including age-related macular degeneration (AMD).

The oral microbial community (microbiota) plays a critical role in human health and disease. Alterations in the oral microbiota may be associated with disorders such as gingivitis, periodontitis, childhood caries, alveolar osteitis, oral candidiasis and endodontic infections. In the immunosuppressed population, the spectrum of potential oral disease is even broader, encompassing candidiasis, necrotizing gingivitis, parotid gland enlargement, Kaposi's sarcoma, oral warts and other diseases. Here, we used 454 pyrosequencing of bacterial 16S rRNA genes to examine the oral microbiome of saliva, mucosal and tooth samples from HIV-positive and negative children. Patient demographics and clinical characteristics were collected from a cross-section of patients undergoing routine dental care. Multiple specimens from different sampling sites in the mouth were collected for each patient. The goal of the study was to observe the potential diversity of the oral microbiota among individual patients, sample locations, HIV status and various dental characteristics. We found that there were significant differences in the microbiome among the enrolled patients, and between sampling locations. The analysis was complicated by uneven enrollment in the patient cohorts, with only five HIV-negative patients enrolled in the study and by the rapid improvement in the health of HIV-infected children between the time the study was conceived and completed. The generally good oral health of the HIV-negative patients limited the number of dental plaque samples that could be collected. We did not identify significant differences between well-controlled HIV-positive patients and HIV-negative controls, suggesting that well-controlled HIV-positive patients essentially harbor similar oral flora compared to patients without HIV. Nor were significant differences in the oral microbiota identified between different teeth or with different dental characteristics. Additional studies are needed to better characterize the oral microbiome in children and those with poorly-controlled HIV infections.

O estudo das causas do desperdicio alimentar e das potenciais intervençoes para a sua minimizaçâo está entre as preocupaçoes centrais daqueles que trabalham com alimentos. A alimentaçao na educaçao, que inclui os refeitórios das universidades, está entre ossetores que merecem atençao, uma vez que quantidades significativas de alimentos sao desperdiçadas pelos consumidores. Entretanto, ainda há uma escassez de estudos que abordem o problema. Este estudo teve como objetivo geral investigar o desperdicio de alimentos em um refeitório de uma universidade brasileira, bem como a percepçao dos consumidores em relaçao as refeiçoes servidas. Por meio de um questionário, foi possivel investigar quais as principais percepçoes dos consumidores, e o que poderia estar por trás da geraçao do desperdicio. Utilizou-se a correlaçao de Spearman a fim de verificar a correlaçao entre o desperdicio alimentar e a percepçao dos consumidores sobre as razoes por trás da geraçao do desperdicio. Verificou-se um desperdicio médio de 68 g/ consumidor. Além disso, foi observado que os consumidores que colocavam os alimentos em bandejas desperdiçavam mais alimentos do que aqueles que optavam por comer em pratos. As informaçoes coletadas foram utilizadas para proporpotenciais intervençoes voltadas a reduçao do desperdicio de alimentos em refeitórios universitários.

IFN-α is used to suppress the replication of hepatitis C virus (HCV) in chronically infected patients with partial success. Here we present evidence showing that a ligand of Toll-like receptor 7 (TLR7) can induce anti-HCV immunity not only by IFN induction, but also through an IFN-independent mechanism. Human hepatocyte line Huh-7 carrying an HCV replicon expressed TLR7, and activation of the receptor induced several antiviral genes including IFN regulatory factor-7. Inhibitors of the enzyme inosine monophosphate dehydrogenase augmented both IFN-dependent and -independent antiviral effect. Prolonged exposure of Huh-7 cells to a TLR7 ligand [SM360320 (9-benzyl-8-hydroxy-2-(2-methoxyethoxy)adenine)], alone or in combination with an inosine monophosphate dehydrogenase inhibitor, reduced HCV levels dose dependently. Immunohistochemical analysis of livers shows that TLR7 is expressed in hepatocytes of normal or HCV-infected people. Because TLR7 agonists can impede HCV infection both via type I IFN and independently of IFN, they may be considered as an alternative treatment of chronic HCV infection, especially in IFN-a~-resistant patients.

Heart failure (HF) affects 6.2 million Americans and is a leading cause of hospitalization. The mainstay of the management of HF is adherence to pharmacotherapy. Despite the effectiveness of HF pharmacotherapy, effectiveness is closely linked to adherence. Measuring adherence to HF pharmacotherapy is difficult; most clinical measures use indirect strategies such as calculating pharmacy refill data or using self-report. While helpful in guiding treatment adjustments, indirect measures of adherence may miss the detection of suboptimal adherence and co-occurring structural barriers associated with nonadherence. Digital pill systems (DPSs), which use an ingestible radiofrequency emitter to directly measure medication ingestions in real-time, represent a strategy for measuring and responding to nonadherence in the context of HF pharmacotherapy. Previous work has demonstrated the feasibility of using DPSs to measure adherence in other chronic diseases, but this strategy has yet to be leveraged for individuals with HF. We aim to explore through qualitative interviews the facilitators and barriers to using DPS technology to monitor pharmacotherapy adherence among patients with HF. We conducted individual, semistructured qualitative interviews and quantitative assessments between April and August 2022. A total of 20 patients with HF who were admitted to the general medical or cardiology service at an urban quaternary care hospital participated in this study. Participants completed a qualitative interview exploring the overall acceptability of and willingness to use DPS technology for adherence monitoring and perceived barriers to DPS use. Quantitative assessments evaluated HF history, existing medication adherence strategies, and attitudes toward technology. We analyzed qualitative data using applied thematic analysis and NVivo software (QSR International). Most participants (12/20, 60%) in qualitative interviews reported a willingness to use the DPS to measure HF medication adherence. Overall, the DPS was viewed as useful for increasing accountability and reinforcing adherence behaviors. Perceived barriers included technological issues, a lack of need, additional costs, and privacy concerns. Most were open to sharing adherence data with providers to bolster clinical care and decision-making. Reminder messages following detected nonadherence were perceived as a key feature, and customization was desired. Suggested improvements are primarily related to the design and usability of the Reader (a wearable device). Overall, individuals with HF perceived the DPS to be an acceptable and useful tool for measuring medication adherence. Accurate, real-time ingestion data can guide adherence counseling to optimize adherence management and inform tailored behavioral interventions to support adherence among patients with HF.

According to the UN, agriculture can lift more people out of poverty than any other sector. As of 2019, agriculture accounted for only 2.14% of the economy in Panama; however, the agricultural sector serves as one of the primary sources of income for communities living in poverty. Small farmers that own less than 10 hectares account for 82% of the total farmers in Panama and are responsible for the majority of the agricultural production in the country. While only 32% of farmers are below 45 years old, this younger generation is highly interested in adopting new technologies to maximize their production. In particular, the increase in smartphones and Internet-based digital tools results in larger opportunities for improvement in agriculture, such as more precise technologies, better data collection and analysis, and more effective information dissemination.This study utilizes the human-centered design process to explore the informational needs of small-scale producers in Panama, the existing ways they get information, and the tools that can help them improve their decision-making and productivity. Interviews with 30 producers and agricultural experts demonstrated that farmers need reliable, easily accessible, and updated information. Many farmers agreed that previous experience with government sources has proved to be limited and hard to find. AgroInfo is a digital mobile platform that aims to help farmers easily find relevant and updated information while expanding the interaction and knowledge exchange among the agricultural community. This study addresses the difficulties that Panamanian small farmers encounter while searching for information and seeks to explore informational opportunities to increase their efficiency and productivity.

Objective Clinical practice guideline (CPG) quality assessment is important before applying their recommendations. Determining whether recommendation strength is consistent with supporting quality of evidence is also essential. We aimed to determine quality of critical care pharmacotherapy CPGs and to assess whether high quality evidence supports strong pharmacotherapy recommendations. Methods MEDLINE (1966–February 2008), EMBASE (1980–February 2008), National Guideline Clearinghouse (February 2008) and personal files were searched to identify CPGs. Four appraisers evaluated each guideline using the appraisal of guidelines, research and evaluation (AGREE) instrument. AGREE assesses 23 items in six domains that include scope/purpose, stakeholder involvement, rigor of development, clarity, applicability and editorial independence. Standardized domain scores (0–100%) were determined to decide whether to recommend a guideline for use. One appraiser extracted strong pharmacotherapy recommendations and supporting evidence quality. Results Twenty-four CPGs were included. Standardized domain scores were clarity [69% (95% confidence interval (CI) 62–76%)], scope/purpose [62% (95% CI 55–68%)], rigor of development [51% (95% CI 42–60%)], editorial independence [39% (95% CI 26–52%)], stakeholder involvement [32% (95% CI 26–37%)] and applicability [19% (95% CI 12–26%)]. The proportion of guidelines that could be strongly recommended, recommended with alterations and not recommended was 25, 37.5 and 37.5%, respectively. High quality evidence supported 36% of strong pharmacotherapy recommendations. Conclusion Variation in AGREE domain scores explain why one-third of critical care pharmacotherapy CPGs cannot be recommended. Only one-third of strong pharmacotherapy recommendations were supported by high quality evidence. We recommend appraisal of guideline quality and the caliber of supporting evidence prior to applying recommendations.