Search Results (10)

Combined therapies with Heat Shock Protein 90 (HSP90) inhibitors and Heat Shock Protein 70 (HSP70) inducers are gaining significant interest in cancer and cardiovascular research. Here, we tested the hypothesis that HSP90 inhibitors and HSP70 inducers, together, can block the development of pulmonary fibrosis. We exposed New Zealand White Rabbits to hydrochloric acid (HCl, 0.1 N, 1.5 mL/kg), one of the top five chemicals most commonly involved in accidental exposures and inhalation injuries worldwide, and treated animals with either the orally available HSP90 inhibitor TAS-116 (1.7 mg/kg 5x/week) or TAS-116 combined with the HSP70 inducer, geranylgeranyl acetone (GGA, 50 mg/kg, 3x/week). At 60 days post-HCl instillation, TAS and GGA treatment markedly reduced the degree of pulmonary fibrosis, lung dysfunction, and activation of profibrotic pathways. The use of HSP70 inducers may be a helpful tool to improve the profile of HSP90 inhibitors and reduce their minimal effective dose and side effects. Further investigation is required to explore the exact synergistic mechanism behind the antifibrotic profile of HSP90 inhibitors and HSP70 inducers. Full article

Breast cancer (BC) is a complex disease affecting one in eight women in the USA. Advances in population genomics have led to the development of polygenic risk scores (PRSs) with the potential to augment current risk models, but replication is often limited. We evaluated 2 robust PRSs with 313 and 3820 SNPs and the effects of multiple genotype imputation replications in BC cases and control populations. Biological samples from BC cases and cancer-free controls were drawn from three European ancestry cohorts. Genotyping on the Illumina Global Screening Array was followed by stringent quality control measures and 20 genotype imputation replications. A total of 468 unrelated cases and 4337 controls were scored, revealing significant differences in mean PRS percentiles between cases and controls (p < 0.001) for both SNP sets (313-SNP PRS: 52.81 and 48.07; 3820-SNP PRS: 55.45 and 49.81), with receiver operating characteristic curve analysis showing area under the curve values of 0.596 and 0.603 for the 313-SNP and 3820-SNP PRS, respectively. PRS fluctuations (from ~2–3% up to 9%) emerged across imputation iterations. Our study robustly reaffirms the predictive capacity of PRSs for BC by replicating their performance in an independent BC population and showcases the need to average imputed scores for reliable outcomes. Full article

The act of believing implies an inner assent, but it is neither limited to a blind acceptance of certain arguments nor to an empty repetition, without practical consequences, of a set of concepts that one claims to defend. This article, allied with the philosophy of language (Austin) and the philosophy of science (Lakatos) will aim, on the one hand, to present a philosophical–theological reading of believing and, on the other hand, an understanding of the implications of the assent of faith regarding the Nicean Creed for Christian identity. The research briefly presented here will refer to the firm core of Christianity, as well as the arguments that aid its defence and understanding vis-à-vis believers and non-believers. Full article

Background and objectives: Chronic obstructive pulmonary disease (COPD) is usually comorbid with other chronic diseases. We aimed to assess the multimorbidity medication patterns and explore if the patterns are similar for phase 1 (P1) and 5-year follow-up phase 2 (P2) in the COPDGene cohort. Materials and Methods: A total of 5564 out of 10,198 smokers from the COPDGene cohort who completed 2 visits, P1 and P2 visits, with complete medication use history were included in the study. We conducted latent class analysis (LCA) among the 27 categories of chronic disease medications, excluding COPD treatments and cancer medications at P1 and P2 separately. The best number of LCA classes was determined through both statistical fit and interpretation of the patterns. Results: We found four classes of medication patterns at both phases. LCA showed that both phases shared similar characteristics in their medication patterns: LC0: low medication; LC1: hypertension (HTN) or cardiovascular disease (CVD)+high cholesterol (Hychol) medication predominant; LC2: HTN/CVD+type 2 diabetes (T2D) +Hychol medication predominant; LC3: Hychol medication predominant. Conclusions: We found similar multimorbidity medication patterns among smokers at P1 and P2 in the COPDGene cohort, which provides an understanding of how multimorbidity medication clustered and how different chronic diseases combine in smokers. Full article

Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial isozyme in the PDK family (PDK1-4) partially responsible for phosphorylation of pyruvate dehydrogenase (PDH). Phosphorylation of PDH is thought to result in a pro-proliferative shift in metabolism that sustains growth of cancer cells. Previous data from our lab indicate the pan-PDK inhibitor dichloroacetate (DCA) or acute genetic knockdown of PDK4 blocks proliferation of bladder cancer (BCa) cells. The goal of this study was to determine the role of PDK4 in an in vivo BCa model, with the hypothesis that genetic depletion of PDK4 would impair formation of BCa. PDK4^−/− or WT animals were exposed to N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) for 16 weeks, and tumors were allowed to develop for up to 7 additional weeks. PDK4^−/− mice had significantly larger tumors at later time points. When animals were treated with cisplatin, PDK4^−/− animals still had larger tumors than WT mice. PDK4 expression was assessed in human tissue and in mice. WT mice lost expression of PDK4 as tumors became muscle-invasive. Similar results were observed in human samples, wherein tumors had less expression of PDK4 than benign tissue. In summary, PDK4 has a complex, multifunctional role in BCa and may represent an underrecognized tumor suppressor. Full article

We characterize the overall incidence and risk factors for breakthrough infection among fully vaccinated participants in the North Carolina COVID-19 Community Research Partnership cohort. Among 15,808 eligible participants, 638 reported a positive SARS-CoV-2 test after vaccination. Factors associated with a lower risk of breakthrough in the time-to-event analysis included older age, prior SARS-CovV-2 infection, higher rates of face mask use, and receipt of a booster vaccination. Higher rates of breakthrough were reported by participants vaccinated with BNT162b2 or Ad26.COV2.S compared to mRNA-1273, in suburban or rural counties compared to urban counties, and during circulation of the Delta and Omicron variants. Full article

With limited research supporting local nutrient management decisions in North Carolina grape (Vitis vinifera) production, field studies (2015–17) were conducted to evaluate late season foliar nitrogen (N) application on leaf and petiole N concentration and yeast assimilable N (YAN) in the fruit. Foliar urea (1% v/v) was applied at different rates and application times beginning pre-and post-veraison. Compared to soil applied N, late season foliar N substantially enhanced petiole N and grape YAN. Smaller split N applications were generally more effective in increasing YAN than single larger N rates. These data demonstrate the value of assessing plant N content at full bloom with petiole N analysis or remote sensing to guide foliar N management decisions. Additional field studies (2008–11) were conducted to evaluate pre-bud soil applied phosphorus (P) and potassium (K) effects on petiole P and K nutrient status. Fertilizer P and K were initially broadcast applied (0–896 kg P₂O₅ ha⁻¹; 0–672 kg K₂O ha⁻¹) prior to bud-break in 2008–09 and petiole P and K at full bloom soil test P and K were monitored for three to four years after application. Soil test and petiole P and K were significantly increased with increasing P and K rates, which subsequently declined to near unfertilized levels over the sampling time depending on site and P and K rate applied. These data demonstrate the value of annually monitoring petiole P and K levels to accurately assess plant P and K status to better inform nutrient management decisions. Full article

Field studies were conducted in 2016 and 2017 to determine if multispectral imagery collected from an unmanned aerial vehicle (UAV) equipped with a five-band sensor could successfully identify Palmer amaranth (Amaranthus palmeri) infestations of various densities growing among soybeans (Glycine max [L.] Merr.). The multispectral sensor captures imagery from five wavebands: 475 (blue), 560 (green), 668 (red), 840 (near infrared [NIR]), and 717 nm (red-edge). Image analysis was performed to examine the spectral properties of discrete Palmer amaranth and soybean plants at various weed densities using these wavebands. Additionally, imagery was subjected to supervised classification to evaluate the usefulness of classification as a tool to differentiate the two species in a field setting. Date was a significant factor influencing the spectral reflectance values of the Palmer amaranth densities. The effects of altitude on reflectance were less clear and were dependent on band and density being evaluated. The near infrared (NIR) waveband offered the best resolution in separating Palmer amaranth densities. Spectral separability in the other wavebands was less defined, although low weed densities were consistently able to be discriminated from high densities. Palmer amaranth and soybean were found to be spectrally distinct regardless of imaging date, weed density, or waveband. Soybean exhibited overall lower reflectance intensity than Palmer amaranth across all wavebands. The reflectance of both species within blue, green, red, and red-edge wavebands declined as the season progressed, while reflectance in NIR increased. Near infrared and red-edge wavebands were shown to be the most useful for species discrimination and maintained their utility at most weed densities. Palmer amaranth weed densities were found to be spectrally distinct from one another in all wavebands, with greatest distinction when using the red, NIR and red-edge wavebands. Supervised classification in a two-class system was consistently able to discriminate between Palmer amaranth and soybean with at least 80% overall accuracy. The incorporation of a weed density component into these classifications introduced an error of 65% or greater into these classifications. Reducing the number of classes in a supervised classification system could improve the accuracy of discriminating between Palmer amaranth and soybean. Full article

Coronavirus Disease-2019 (COVID-19) vaccine acceptance is variable. We surveyed participants in the COVID-19 Community Research Partnership from 17 December 2020 to 13 January 2021 to assess vaccine receptiveness. Vaccine uptake was then monitored until 15 May 2021; 20,232 participants responded to the receptiveness survey with vaccination status accessed in 18,874 participants via daily follow-up surveys (participants not completing daily surveys ≥30 days to 15 May 2021, were excluded). In the initial survey, 4802 (23.8%) were vaccine hesitant. Hesitancy was most apparent in women (Adjusted RR 0.93, p < 0.001), Black Americans (Adjusted RR 1.39, 1.41, 1.31 to non-Hispanic Whites, Other, and Hispanic or Latino, respectively p < 0.001), healthcare workers (Adjusted RR 0.93, p < 0.001), suburbanites (ref. Urban Adjusted RR 0.85, 0.90 to urban and rural dwellers, respectively, p < 0.01), and those previously diagnosed with COVID-19 (RR 1.20, p < 0.01). Those <50 years were also less accepting of vaccination. Subsequent vaccine uptake was 99% in non-hesitant participants. For those who were unsure, preferred not to answer, or answered “no”, vaccination rates were 80% (Adjusted RR 0.86, p < 0.0001), 78% (Adjusted RR 0.83, p < 0.0001), and 52.7% (Adjusted RR 0.65, p < 0.0001), respectively. These findings suggest that initial intent did not correlate with vaccine uptake in our cohort. Full article

Future scenarios provide challenging, plausible and relevant stories about how the future could unfold. Urban Futures (UF) research has identified a substantial set (>450) of seemingly disparate scenarios published over the period 1997–2011 and within this research, a sub-set of >160 scenarios has been identified (and categorized) based on their narratives according to the structure first proposed by the Global Scenario Group (GSG) in 1997; three world types (Business as Usual, Barbarization, and Great Transitions) and six scenarios, two for each world type (Policy Reform—PR, Market Forces—MF, Breakdown—B, Fortress World—FW, Eco-Communalism—EC and New Sustainability Paradigm—NSP). It is suggested that four of these scenario archetypes (MF, PR, NSP and FW) are sufficiently distinct to facilitate active stakeholder engagement in futures thinking. Moreover they are accompanied by a well-established, internally consistent set of narratives that provide a deeper understanding of the key fundamental drivers (e.g., STEEP—Social, Technological, Economic, Environmental and Political) that could bring about realistic world changes through a push or a pull effect. This is testament to the original concept of the GSG scenarios and their development and refinement over a 16 year period. Full article