Search

In this work, different occurrences of the connective "and" in some Basque proverbs gathered in the 16th and 19th centuries are studied. "And" appears in grammatically definable types of constructions beyond pragmatic ambiguity; the environments where "and" occurs show a fixed pattern linked to a conceptual structure. This work focuses on the less fixed pattern of the typology "A and B is Y", where the first term mentioned "A" is defined in terms of the second "B" demonstrating the important role played by analogy. There is also a complex variety of coordinated proverbs, which link two seemingly independent proverbs; in these proverbs "and" provokes a shift in point of view of the fictional utterer. The evaluative string (Y) poses the question of the directionality of the proverb, when there are variants of the same proverb, one of them lacking the string, what the presupposition range of the given cultural milieu is, from Honeck's (1997) "Generic Ideals" to Kay's (1996) "context proposition". The methodology is based on Turner and Fauconnier's Blending Theory (1998) and Conceptual Integration Networks (Turner & Fauconnier 2001), and on contemporary Rhetoric of Argument (Perelman & Olbrechts-Tyteca), The simple type of proverbs falls either under the category of "one-sided shared organizing topology" or under the category of "unfilled shared topology network". In the complex type of proverbs, two asymmetric spaces are linked, but analogously to the simple type, the second part of the proverb constraints the meaning of the first part. Two alternative space configurations for proverb understanding are provided.

Copyright of International Journal of Engineering & Management Sciences (2498-700X) / Műszaki és Menedzsment Tudományi Közlemények is the property of University of Debrecen and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Despite the availability of curative penicillin treatment for syphilis during pregnancy, congenital syphilis (CS) cases have surged in the United States, including in Oregon., Methods: We conducted a retrospective analysis of individual- and county-level predictors of CS among pregnant people with syphilis in Oregon from 2013-2021. Data were collated from surveillance reports, County Health Rankings, and other sources with upstream county-level data. We used multi-level Poisson regression models to assess associations between CS and individual- and county-level factors., Results: Among 343 people with syphilis during pregnancy, 95 (27.6%) were associated with a case of CS. At the individual-level, a history of injection drug use and a history of corrections involvement were associated with an increased risk of CS, while a recent gonorrhea diagnosis was associated with a decreased risk of CS. County-level violent crime rate, unemployment, income inequality, and adverse childhood experiences increased the risk of CS. Higher county-level socioenvironmental challenges exacerbated CS risk, particularly among people with corrections involvement., Conclusions: Injection drug use, corrections involvement, and county-level socioenvironmental challenges increased CS risk among pregnant people with syphilis in Oregon. Urgent interventions are needed, including innovative care models, policy reforms targeting systemic issues, and enhanced collaboration with community services to address the escalating CS crisis., Competing Interests: Conflicts of Interest: The authors declare that they have NO affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript., (Copyright © 2024 American Sexually Transmitted Diseases Association. All rights reserved.)

Aims: This study aimed to investigate the association between glucose metrics and diabetic retinopathy in type 1 diabetes (T1D) patients using flash continuous glucose monitoring (FGM) systems, including those maintaining glycated hemoglobin (HbA1c) within the target range., Methods: We conducted a cross-sectional study involving 1070 T1D patients utilizing FGM systems. Data on clinical, anthropometric, and socioeconomic characteristics were collected and retinopathy was classified based on international standards., Results: Patients' mean age was 47.6 ± 15.0 years, with 49.4% of them being females. Within the cohort, 24.8% of patients presented some form of retinopathy. In the analysis involving the entire sample of subjects, male gender (OR = 1.51, p = 0.027), Time Above Range (TAR) > 250 mg/dL (OR = 1.07, p = 0.025), duration of diabetes (OR = 1.09, p < 0.001), smoking (OR = 2.30, p < 0.001), and history of ischemic stroke (OR = 5.59, p = 0.025) were associated with diabetic retinopathy. No association was observed between the coefficient of variation and diabetic retinopathy (p = 0.934). In patients with HbA1c < 7%, the highest quartile of TAR > 250 was independently linked to diabetic retinopathy (OR = 8.32, p = 0.040), in addition to smoking (OR = 2.90, p = 0.031), duration of diabetes (OR = 1.09, p < 0.001), and hypertension (OR = 2.35, p = 0.040)., Conclusion: TAR > 250 mg/dL significantly emerges as a modifiable factor associated with diabetic retinopathy, even among those patients maintaining recommended HbA1c levels. Understanding glucose metrics is crucial for tailoring treatment strategies for T1D patients., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

The COVID-19 pandemic reminded us of the urgent need for new antivirals to control emerging infectious diseases and potential future pandemics. Immunotherapy has revolutionized oncology and could complement the use of antivirals, but its application to infectious diseases remains largely unexplored. Nucleoside analogs are a class of agents widely used as antiviral and anti-neoplastic drugs. Their antiviral activity is generally based on interference with viral nucleic acid replication or transcription. Based on our previous work and computer modeling, we hypothesize that antiviral adenosine analogs, like remdesivir, have previously unrecognized immunomodulatory properties which contribute to their therapeutic activity. In the case of remdesivir, we here show that these properties are due to its metabolite, GS-441524, acting as an Adenosine A2A Receptor antagonist. Our findings support a new rationale for the design of next-generation antiviral agents with dual - immunomodulatory and intrinsic - antiviral properties. These compounds could represent game-changing therapies to control emerging viral diseases and future pandemics., (© 2024. The Author(s).)

Background: African ancestry is a known factor associated with the presentation and aggressiveness of prostate cancer (PC). Hispanic/Latino populations exhibit varying degrees of genetic admixture across Latin American countries, leading to diverse levels of African ancestry. However, it remains unclear whether genetic ancestry plays a role in the aggressiveness of PC in Hispanic/Latino patients. We explored the associations between genetic ancestry and the clinicopathological data in Hispanic/Latino PC patients from Colombia., Patients and Methods: We estimated the European, Indigenous and African genetic ancestry, of 230 Colombian patients with localized/regionally advanced PC through a validated panel for genotypification of 106 Ancestry Informative Markers. We examined the associations of the genetic ancestry components with the Gleason Grade Groups (GG) and the clinicopathological characteristics., Results: No association was observed between the genetic ancestry with the biochemical recurrence or Gleason GG; however, in a two groups comparison, there were statistically significant differences between GG3 and GG4/GG5 for European ancestry, with a higher mean ancestry proportion in GG4/GG5. A lower risk of being diagnosed at an advanced age was observed for patients with high African ancestry than those with low African ancestry patients (OR: 0.96, CI: 0.92-0.99, p=0.03)., Conclusion: Our findings revealed an increased risk of presentation of PC at an earlier age in patients with higher African ancestry compared to patients with lower African ancestry in our Hispanic/Latino patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Acosta-Vega, Varela, Mesa, Garai, Gómez-Gutiérrez, Serrano-Gómez, Zabaleta, Sanabria-Salas and Combita.)

Objective: Christmas holidays can impact weight and glycemic control in type 2 diabetes, but their effect on type 1 diabetes (T1D) remains understudied. This study assessed how Christmas holidays affect individuals with T1D who use flash continuous glucose monitoring systems., Methods: This retrospective study involved 812 adults diagnosed with T1D recruited from 3 hospitals. Clinical, anthropometric, and socioeconomic data were collected. Glucose metrics from 14 days before January 1st, and before December 1st and February 1st as control periods, were recorded. Analyses adjusted for multiple variables were conducted to assess the holiday season's impact on glycemic control., Results: The average time in range during the holidays (60.0 ± 17.2%) was lower compared to December (61.9 ± 17.2%, P < .001) and February (61.7 ± 17.7%, P < .001). Time above range (TAR > 180 mg/dL) was higher during Christmas (35.8 ± 18.2%) compared to December (34.1 ± 18.3%, P < .001) and February (34.2 ± 18.4%, P < .001). Differences were also observed in TAR >250 mg/dL, coefficient of variation, and average glucose (P < .05). No differences were found in time below range or other metrics. Linear regression models showed that the holidays reduced time in range by 1.9% (β = -1.92, P = .005) and increased TAR >180 mg/dL by 1.8% (β = 1.75, P = .016)., Conclusion: Christmas holidays are associated with a mild and reversible deterioration in glucose metrics among individuals with T1D using flash continuous glucose monitoring, irrespective of additional influencing factors. These discoveries can be useful to advise individuals with diabetes during the festive season and to recognize potential biases within studies conducted during this timeframe., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Objective: Maternal exposure during pregnancy is a strong determinant of offspring health outcomes. Such exposure induces changes in the offspring epigenome resulting in gene expression and functional changes. In this study, we investigated the effect of maternal Western hypercaloric diet (HCD) programming during the perinatal period on neuronal plasticity and cardiometabolic health in adult offspring., Methods: C57BL/6J dams were fed HCD for 1 month prior to mating with regular diet (RD) sires and kept on the same diet throughout pregnancy and lactation. At weaning, offspring were maintained on either HCD or RD for 3 months resulting in 4 treatment groups that underwent cardiometabolic assessments. DNA and RNA were extracted from the hypothalamus to perform whole genome methylation, mRNA, and miRNA sequencing followed by bioinformatic analyses., Results: Maternal programming resulted in male-specific hypertension and hyperglycemia, with both males and females showing increased sympathetic tone to the vasculature. Surprisingly, programmed male offspring fed HCD in adulthood exhibited lower glucose levels, less insulin resistance, and leptin levels compared to non-programmed HCD-fed male mice. Hypothalamic genes involved in inflammation and type 2 diabetes were targeted by differentially expressed miRNA, while genes involved in glial and astrocytic differentiation were differentially methylated in programmed male offspring. These data were supported by our findings of astrogliosis, microgliosis and increased microglial activation in programmed males in the paraventricular nucleus (PVN). Programming induced a protective effect in male mice fed HCD in adulthood, resulting in lower protein levels of hypothalamic TGFβ2, NF-κB2, NF-κBp65, Ser-pIRS1, and GLP1R compared to non-programmed HCD-fed males. Although TGFβ2 was upregulated in male mice exposed to HCD pre- or post-natally, only blockade of the brain TGFβ receptor in RD-HCD mice improved glucose tolerance and a trend to weight loss., Conclusions: Our study shows that maternal HCD programs neuronal plasticity in the offspring and results in male-specific hypertension and hyperglycemia associated with hypothalamic inflammation in mechanisms and pathways distinct from post-natal HCD exposure. Together, our data unmask a compensatory role of HCD programming, likely via priming of metabolic pathways to handle excess nutrients in a more efficient way., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eric Lazartigues reports financial support was provided by American Diabetes Association. Franck Mauvais-Jarvis reports financial support was provided by National Institute of Health. Franck Mauvais-Jarvis reports financial support was provided by USDepartment of Veterans Affairs., (Published by Elsevier GmbH.)

Background: This study investigates the association between socioeconomic status (SES) and glycemic control in individuals with type 1 diabetes (T1D) using flash glucose monitoring (FGM) devices within a public health system where these technologies are freely available and utilized according to recommended guidelines., Methods: A follow-up study of 1060 adults (mean age 47.4 ± 15.0 years, 49.0% women) with T1D, receiving care at three Spanish university hospitals that regularly employ the FGM system. SES was assessed using the Spanish Deprivation Index and the average annual net income per person. Glycemic data were collected over a 14-day follow-up period, including baseline glycated hemoglobin (HbA1c) levels prior to sensor placement, the last available HbA1c levels, and FGM-derived glucose metrics. Individuals with sensor usage time < 70% were excluded. Chronic micro and macrovascular complications related to diabetes were documented. Regression models, adjusted for clinical variables, were employed to determine the impact of SES on optimal sensor control (defined as time in range (TIR) ≥ 70% with time below range < 4%) and disease complications., Results: The average follow-up was of 2 years. The mean TIR and the percentage of individuals with optimal control were higher in individuals in the highest SES quartile (64.9% ± 17.8% and 27.9%, respectively) compared to those in the lowest SES quartile (57.8 ± 17.4% and 12.1%) (p < 0.001). Regression models showed a higher risk of suboptimal control (OR 2.27, p < 0.001) and ischemic heart disease and/or stroke (OR 3.59, p = 0.005) in the lowest SES quartile. No association was observed between SES and the risk of diabetic nephropathy and retinopathy. FGM system improved HbA1c levels across all SES quartiles. Although individuals in the highest SES quartile still achieved a significantly lower value at the end of the follow-up 55 mmol/mol (7.2%) compared to those in the lowest SES quartile 60 mmol/mol (7.6%) (p < 0.001), the significant disparities in this parameter between the various SES groups were significantly reduced after FGM technology use., Conclusions: Socioeconomic status plays a significant role in glycemic control and complications in individuals with T1D, extending beyond access to technology and its proper utilization. The free utilization of FGM technology helps alleviate the impact of social inequalities on glycemic control., (© 2024. The Author(s).)

Background: The COVID-19 pandemic has disrupted HIV and sexually transmitted infection (STI) testing accessibility. We sought to assess the longer-term impacts of COVID-19 on HIV and STI testing and diagnosis in Oregon., Methods: First, we examined HIV, Neisseria gonorrhoeae / Chlamydia trachomatis (CT), and syphilis tests conducted at the Oregon State Public Health Laboratory (public sector) and a large commercial laboratory (private sector) and HIV, N. gonorrhoeae , CT, and primary and secondary (P&S) syphilis diagnoses in Oregon from January 1, 2019, to December 31, 2021. We compared monthly testing and diagnosis rates in 5 prespecified periods: pre-COVID-19 (January 2019-February 2020), stay-at-home order (March 2020-May 2020), reopening (June 2020-December 2020), vaccine availability (January 2021-June 2021), and Delta/early Omicron spread (July 2021-December 2021). Second, we calculated the number of HIV and STI diagnoses per test in the public and private sectors. Finally, we used seasonal autoregressive integrated moving average models to predict expected HIV and STI diagnoses for comparison to those observed., Results: Both public and private sector HIV and bacterial STI testing fell to nadirs in April 2020 with incomplete recovery to 2019 levels by the close of 2021. Compared with pre-COVID-19, public sector and private sector testing was significantly lower in all subsequent periods. Compared with pre-COVID-19, P&S syphilis cases were 52%, 75%, and 124% greater in the reopening, vaccine availability, and Delta/early Omicron periods, respectively. From March 2020 to December 2021, we observed an excess of P&S syphilis cases (+37.1%; 95% confidence interval, 22.2% to 52.1%) and a deficit in CT cases (-10.7%; 95% confidence interval, -15.4% to -6.0%)., Conclusions: By December 2021, HIV/STI testing had not recovered to pre-COVID-19 levels, and HIV/STI continues to be underdiagnosed. Despite decreased testing, P&S syphilis cases have increased substantially., Competing Interests: Conflict of Interest and Sources of Funding: The authors declare that they have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this article., (Copyright © 2023 American Sexually Transmitted Diseases Association. All rights reserved.)

Biomarkers to identify women at risk of cervical cancer among those with high-risk HPV infection (hrHPV+) are needed. Deregulated expression of microRNAs (miRNAs) contributes to hrHPV-induced cervical carcinogenesis. We aimed at identifying miRNAs with the capacity to distinguish high (CIN2+) and low (≤ CIN1) grade cervical lesions. We sequenced miRNA libraries from Formalin-Fixed Paraffin-Embedded (FFPE) tissues from women with CIN2+ (n = 10) and age-matched women with ≤ CIN1 (n = 10), randomly and retrospectively selected from a trial that followed women for 24 months after a hrHPV+ test at the screening visit. Five miRNAs differentially expressed were validated by RT-qPCR in an independent set of FFPE tissues with a reviewed diagnosis of CIN2+ (n = 105) and ≤ CIN1 (n = 105). The Ingenuity Pathway Analysis (IPA) was conducted to identify mRNAs inversely correlated with the top 25 differentially expressed miRNAs. Inverse correlations with 401 unique mRNA targets were identified for fourteen of the top 25 differentially expressed miRNAs. Eleven of these miRNAs targeted 26 proteins of pathways deregulated by HPV E6 and E7 oncoproteins and two of them, miR-143-5p and miR-29a-3p, predicted CIN2+ and CIN3+ in the independent validation by RT-qPCR of FFPE tissues from hrHPV-positive women., (© 2023. The Author(s).)

The COVID-19 pandemic has brought unprecedented suffering to the lives and livelihoods of indigenous people across the country, especially in the south-eastern parts of Bangladesh, but the situation has rarely reported by the mass media and academic literature. This study was an attempt to find out the impacts and vulnerabilities of COVID-19 on the indigenous Chakma community at Rangamati sadar (sub-district) of Rangamati (district) in the Chattogram Hill Tracts (CHT) area, Bangladesh. It also aimed to investigate how indigenous people respond to the pandemic and how they can develop resilience to adapt to the adverse situation. For conducting this study, a critical ethnographic approach was adopted, along with participant observation, in-depth interview, and focus group (FGs) for collecting data in the study area. The findings of the study indicate that the COVID-19 pandemic severely affects the traditional way of life, mythology, culture, food security, economic activities, and educational activities, along with increasing health risks for the people of the indigenous community. However, indigenous people respond to this pandemic in their own ways, involving their ancestors' works, avoiding dependence on market systems, keeping faith in traditional medicines, building close relation to nature, along with following some health guidelines announced by government. This work refutes the existing mainstream discourse that indigenous people are unwittingly vulnerable and docile in their waiting for outside assistance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Elsevier Ltd. All rights reserved.)

Rhizomatous growth and associated physiological integration can allow a clonal dune species to potentially compensate for the selective removal of leaves associated with herbivory. Hydrocotyle bonariensis is a rhizomatous clonal plant species that is abundant in the coastal dune environments of the southeastern United States that are inhabited by large feral horse populations. H. bonariensis has been shown to integrate resources among ramets within extensive clones as an adaptation to resource heterogeneity in sandy soils. In this study, we hypothesized that clonal integration is a mechanism that promotes H. bonariensis persistence in these communities, despite high levels of herbivory by feral horses. In a field experiment, we used exclosures to test for herbivory in H. bonariensis over a four-month period. We found that feral horses utilized H. bonariensis as a food species, and that while grazing will suppress clonal biomass, H. bonariensis is able to maintain populations in a high grazing regime with and without competition present. We then conducted an experiment in which portions of H. bonariensis clones were clipped to simulate different levels of grazing. Half of the clones were severed to eliminate the possibility of integration. We found that after 12 weeks, the mean number of leaves and ramets increased as the grazing level increased, for integrated clones. Integrated clones had significantly increased biomass production compared to the severed equivalents. Our research suggests that rhizomatous growth and physiological integration are traits that allow clonal plant species to maintain populations and to tolerate grazing in coastal dune environments.

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with enzymatic activities. Anti-inflammatory effects of MIF enzyme inhibitors indicate a link between its cytokine- and catalytic activities. Herein the synthesis, docking, and bioactivity of substituted benzylidene-1-indanone and -1-tetralone derivatives as MIF-tautomerase inhibitors is reported. Many of these substituted benzylidene-1-tetralones and -indan-1-ones were potent MIF-tautomerase inhibitors (IC 50  < 10 μmol/L), and the most potent inhibitors were the 1-indanone derivatives 16 and 20. Some of these compounds acted as selective enolase or ketonase inhibitors. In addition, compounds 16, 20, 26, 37 and 61 efficiently inhibited NO, TNFα and IL-6 production in lipopolysaccharide-induced macrophages. Compound 20, 37 and 61 also inhibited ROS generation, and compound 26 and 37 abolished activation of NF-κB. Compound 37 significantly augmented hypothermia induced by high dose of lipopolysaccharide in mice. The possible mechanisms of action were explored using molecular modelling and docking, as well as molecular dynamics simulations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The role of ERG-status molecular subtyping in prognosis of prostate cancer (PCa) is still under debate. In this study, we identified differentially expressed genes (DEGs) according to ERG-status to explore their enriched pathways and implications in prognosis in Hispanic/Latino PCa patients., Methods: RNA from 78 Hispanic PCa tissues from radical prostatectomies (RP) were used for RNA-sequencing. ERG high /ERG low tumor groups were determined based on the 1.5-fold change median expression in non-tumor samples. DEGs with a False Discovery Rate (FDR) < 0.01 and a fold change >2 were identified between ERG high and ERG low tumors and submitted to enrichment analysis in MetaCore. Survival and association analyses were performed to evaluate biochemical recurrence (BCR)-free survival., Results: The identification of 150 DEGs between ERG high and ERG low tumors revealed clustering of most of the non-BCR cases (60%) into de ERG high group and most of the BCR cases (60.8%) in ERG low group. Kaplan-Meier survival curves showed a worst BCR-free survival for ERG low patients, and a significant reduced risk of BCR was observed for ERG high cases (OR = 0.29 (95%CI, 0.10-0.8)). Enrichment pathway analysis identified metabolic-related pathways, such as the renin-angiotensin system and angiotensin maturation system, the linoleic acid metabolism, and polyamines metabolism in these ERG groups., Conclusions: ERG low tumor cases were associated with poor BCR-free survival in our Hispanic/Latino patients, with metabolism-related pathways altered in the BCR progression., Impact: Our findings suggest the need to dissect the role of diet, metabolism, and lifestyle as risk factors for more aggressive PCa subtypes., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Macrophage migration inhibitory factor (MIF) has been considered as a biomarker in sepsis, however the predictive value of the pattern of its kinetics in the serum and in the urine has remained unclarified. It is also unclear whether the kinetics of MIF are different between males and females. We conducted a single-center prospective, observational study with repeated measurements of MIF in serum and urine on days 0, 2, and 4 from admission to the intensive care unit (ICU) in 50 adult septic patients. We found that in patients who died within 90 days, there was an increase in serum MIF level from day 0 to 4, whereas in the survivors there was rather a decrease (p = 0.018). The kinetics were sex-dependent as the same difference in the pattern was present in males (p = 0.014), but not in females (p = 0.418). We also found that urine MIF was markedly lower in patients who died than in survivors of sepsis (p < 0.050). Urine MIF levels did not show temporal changes: there was no meaningful difference between day 0 and 4. These results suggest that kinetics of serum MIF during the initial days from ICU admission can predict death, especially in male patients. Additionally, lower urine MIF levels can also indicate death without showing meaningful temporal kinetics., (© 2023. The Author(s).)

Background: In the U.S., African Americans (AAs) present with the highest incidence and mortality rates for Colorectal Cancer (CRC). When compared to Caucasian American (CA) patients, AAs also have reduced response to the first line standard of care chemotherapeutic agent 5-Fluorouracil (5-FU). Previously, we observed differential gene expression between the two populations, suggesting that colon tumors from AA patients display a decreased antitumor immune response and an increased expression of genes encoding proteins involved in inflammatory processes, such as Interleukin-1β (IL-1β). Here, we investigate the role of IL-1β in modifying chemotherapeutic response and altering expression of proteins in novel AA and well-established CA colon cancer cell lines., Methods: RNA sequencing analysis was performed to detect expression of genes involved in inflammation in AA and CA colon cancer cells. The effects of IL-1β on 5-FU response was evaluated by assessing cell viability (MTS assay) and apoptosis (flow cytometry analysis) following treatment with 5-FU alone or in combination with the cytokine. Further, we used an IL-1 receptor antagonist (IL-1Ra) to inhibit IL-1β-induced effects on 5-FU sensitivity and NF-kB pathway activation., Results: AA colon cancer cell lines present significant increase in expression of genes IL1R2 (373-fold change (FC), IRAK1 ( 3.24 FC), IKBKB , (5.33 FC) NF-KB IA (5.95 FC), MYD88 , (3.72 FC), IRAK3 (161 FC), TRAF5 (4.1 FC). A significant decrease in the response to 5-FU treatment, as well as a significant increase in phosphorylation of IκBα and secretion of IL-8, was seen following IL-1β treatment, in both AA and CA cell lines. Finally, treatment with IL-1Ra was able to reverse the effects induced by IL-1β, by increasing the cells sensitivity to 5-FU. IL-1Ra also inhibited phosphorylation of IκBα and IL-8 secretion., Conclusions: Our results suggest a differential expression of inflammatory genes and proteins that might regulate the different response to IL-1β between AA and CA colon cancer cell lines. Our data also demonstrates that IL-1β is involved in modulating 5-FU response in both AA and CA colon cancer cell lines. Further investigation of these mechanisms might help elucidate the differences seen in incidence, mortality and response to therapy in AA colon cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Spagnardi, Paredes, Zabaleta, Garai, Reyes, Martello and Williams.)

Infectious Bronchitis (IB) is a respiratory disease caused by a highly variable Gammacoronavirus , which generates a negative impact on poultry health worldwide. GI-11 and GI-16 lineages have been identified in South America based on Infectious Bronchitis virus (IBV) partial S1 sequences. However, full genome sequence information is limited. In this study we report, for the first time, the whole-genome sequence of IBV from Colombia. Seven IBV isolates obtained during 2012 and 2013 from farms with respiratory disease compatible with IB were selected and the complete genome sequence was obtained by NGS. According to S1 sequence phylogenetic analysis, six isolates belong to lineage GI-1 and one to lineage GVI-1. When whole genome was analyzed, five isolates were related to the vaccine strain Ma5 2016 and two showed mosaic genomes. Results from complete S1 sequence analysis provides further support for the hypothesis that GVI-1, considered a geographically confined lineage in Asia, could have originated in Colombia. Complete genome information reported in this research allow a deeper understanding of the phylogenetic evolution of variants and the recombination events between strains that are circulating worldwide, contributing to the knowledge of coronavirus in Latin America and the world.

Treatment of patients with triple-negative breast cancer (TNBC) has been challenging due to the absence of well-defined molecular targets and the highly invasive and proliferative nature of TNBC cells. Current treatments against TNBC have shown little promise due to high recurrence rate in patients. Consequently, there is a pressing need for novel and efficacious therapies against TNBC. Here, we report the discovery of a novel small molecule inhibitor (NSC33353) with potent anti-tumor activity against TNBC cells. The anti-proliferative effects of this small molecule inhibitor were determined using 2D and 3D cell proliferation assays. We found that NSC33353 significantly reduces the proliferation of TNBC cells in these assays. Using proteomics, next generation sequencing (NGS), and gene enrichment analysis, we investigated global regulatory pathways affected by this compound in TNBC cells. Proteomics data indicate a significant metabolic reprograming affecting both glycolytic enzymes and energy generation through oxidative phosphorylation. Subsequently, using metabolic (Seahorse) and enzymatic assays, we validated our proteomics and NGS analysis findings. Finally, we showed the inhibitory and anti-tumor effects of this small molecule in vitro and confirmed its inhibitory activity in vivo. Doxorubicin is one of the most effective agents in the treatment of TNBC and resistance to this drug has been a major problem. We show that the combination of NSC33353 and doxorubicin suppresses the growth of TNBC cells synergistically, suggesting that NSC33353 enhances TNBC sensitivity to doxorubicin. In summary, our data indicate that the small molecule inhibitor, NSC33353, exhibits anti-tumor activity in TNBC cells, and works in a synergistic fashion with a well-known chemotherapeutic agent., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Dyadic self-care in chronic heart failure (CHF) is key to ensure treatment continuity, reduce complications and readmissions, and minimise caregiver burden, but it requires specific strategies. The aim of the study was to identify dyadic self-management interventions in CHF in hospital settings by means of a systematic literature review conducted in the Pubmed, CINAHL and PsycInfo databases. Methodological quality was assessed according to CASPe and Joanna Briggs Institute tools. The main components of the interventions were identified: delivery format; dimensions and strategies used (cognitive-attitudinal, affective-emotional and behavioural); providers and recipients; measurement instruments used; and effectiveness. Most of the studies demonstrated improved outcomes, especially in depression and/or anxiety symptoms, adherence to treatment, diet and weight control. Innovative interventions that include components of the three dimensions identified and the use of valid, reliable and specific scales to measure outcomes are recommended.

Background: Low-density neutrophils (LDN) are increased in several inflammatory diseases and may also play a role in the low-grade chronic inflammation associated with obesity. Here we explored their role in obesity, determined their gene signatures, and assessed the effect of bariatric surgery., Methods: We compared the number, function, and gene expression profiles of circulating LDN in morbidly obese patients (MOP, n=27; body mass index (BMI) > 40 Kg/m 2 ) and normal-weight controls (NWC, n=20; BMI < 25 Kg/m 2 ) in a case-control study. Additionally, in a prospective longitudinal study, we measured changes in the frequency of LDN after bariatric surgery (n=36) and tested for associations with metabolic and inflammatory parameters., Findings: LDN and inflammatory markers were significantly increased in MOP compared to NWC. Transcriptome analysis showed increased neutrophil-related gene expression signatures associated with inflammation, neutrophil activation, and immunosuppressive function. However, LDN did not suppress T cells proliferation and produced low levels of reactive oxygen species (ROS). Circulating LDN in MOP significantly decreased after bariatric surgery in parallel with BMI, metabolic syndrome, and inflammatory markers., Interpretation: Obesity increases LDN displaying an inflammatory gene signature. Our results suggest that LDN may represent a neutrophil subset associated with chronic inflammation, a feature of obesity that has been previously associated with the appearance and progression of co-morbidities. Furthermore, bariatric surgery, as an efficient therapy for severe obesity, reduces LDN in circulation and improves several components of the metabolic syndrome supporting its recognized anti-inflammatory and beneficial metabolic effects., Funding: This work was supported in part by grants from the National Institutes of Health (NIH; 5P30GM114732-02, P20CA233374 - A. Ochoa and L. Miele), Pennington Biomedical NORC (P30DK072476 - E. Ravussin & LSU-NO Stanley S. Scott Cancer Center and Louisiana Clinical and Translational Science Center (LACaTS; U54-GM104940 - J. Kirwan)., Competing Interests: Declaration of interests Augusto Ochoa, and Lucio Miele were funded by grants from the National Cancer Institute and the National Institutes of Health. The remaining authors have declared that no conflict of interest exists., (Published by Elsevier B.V.)

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine playing crucial role in immunity. MIF exerts a unique tautomerase enzymatic activity that has relevance concerning its multiple functions and its small molecule inhibitors have been proven to block its pro-inflammatory effects. Here we demonstrate that some of the E -2-arylmethylene-1-tetralones and their heteroanalogues efficiently bind to MIF's active site and inhibit MIF tautomeric (enolase, ketolase activity) functions. A small set of the synthesised derivatives, namely compounds ( 4 ), ( 23 ), ( 24 ), ( 26 ) and ( 32 ), reduced inflammatory macrophage activation. Two of the selected compounds ( 24 ) and ( 26 ), however, markedly inhibited ROS and nitrite production, NF-κB activation, TNF-α, IL-6 and CCL-2 cytokine expression. Pre-treatment of mice with compound ( 24 ) exaggerated the hypothermic response to high dose of bacterial endotoxin. Our experiments suggest that tetralones and their derivatives inhibit MIF's tautomeric functions and regulate macrophage activation and thermal changes in severe forms of systemic inflammation.

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1 + G-MDSC (Arg + G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg + G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dean, Ochoa, Sanchez-Pino, Zabaleta, Garai, Del Valle, Wyczechowska, Baiamonte, Philbrook, Majumder, Vander Heide, Dunkenberger, Thylur, Nossaman, Roberts, Chapple, Wu, Hicks, Collins, Luke, Johnson, Koul, Rees, Morris, Garcia-Diaz and Ochoa.)

Abstract: Human immunodeficiency virus, Neisseria gonorrhoeae/Chlamydia trachomatis, and syphilis testing decreased with the implementation of mitigation measures for SARS-CoV-2 and did not return to 2019 levels by September 2020. However, primary and secondary syphilis diagnoses increased during mitigation measures. Sexual health services are essential during the SARS-CoV-2 pandemic., Competing Interests: Conflict of Interest and Sources of Funding: None declared., (Copyright © 2021 American Sexually Transmitted Diseases Association. All rights reserved.)

This study aims to identify pathway involvement in the development of cisplatin (cis-diamminedichloroplatinum (II); CDDP) resistance in A549 lung cancer (LC) cells by utilizing advanced bioinformatics software. We developed CDDP-resistant A549 (A549/DDP) cells through prolonged incubation with the drug and performed RNA-seq on RNA extracts to determine differential mRNA and miRNA expression between A549/DDP and A549 cells. We analyzed the gene dysregulation with Ingenuity Pathway Analysis (IPA; QIAGEN) software. In contrast to prior research, which relied on the clustering of dysregulated genes to pathways as an indication of pathway activity, we utilized the IPA software for the dynamic evaluation of pathway activity depending on the gene dysregulation levels. We predicted 15 pathways significantly contributing to the chemoresistance, with several of them to have not been previously reported or analyzed in detail. Among them, the PKR signaling, cholesterol biosynthesis, and TEC signaling pathways are included, as well as genes, such as PIK3R3, miR-34c-5p, and MDM2, among others. We also provide a preliminary analysis of SNPs and indels, present exclusively in A549/DDP cells. This study's results provide novel potential mechanisms and molecular targets that can be explored in future studies and assist in improving the understanding of the chemoresistance phenotype.

We implemented a pilot home HIV self-testing program one week after a stay-home order for SARS-CoV2 was enacted in Oregon. We advertised the program on a geospatial networking app and community partner websites targeting men who have sex with men; nine percent of web visits resulted in an order. Over 70% of the kits initially allotted to the program were ordered in the first 24 h of launch. One-third of participants had never tested for HIV. We found enthusiasm for discreet, free, home-based testing and uncovered an unmet need for HIV testing as clinical and outreach programs shuttered in Oregon.

Private well water systems in rural areas that are improperly maintained will result in poor drinking water quality, loss of water supply, and pose human health risk. The purpose of this study was to investigate the occurrence of fecal indicator bacteria (FIB) and opportunistic pathogens in private well water in rural areas surrounding New Orleans, Louisiana. Our results confirmed the ubiquitous nature of Legionella (86.7%) and mycobacteria (68.1%) in private well water in the study area, with gene concentration ranged from 0.60 to 5.53 and 0.67 to 5.95 Log 10 of GC/100 mL, respectively. Naegleria fowleri target sequence was detected in 16.8% and Escherichia coli was detected in 43.4% of the water samples. Total coliform, as well as Legionella and mycobacteria genetic markers' concentrations were significantly reduced by 3-minute flushing. Next-generation sequencing (NGS) data indicated that the abundance of bacterial species was significantly increased in water collected in kitchens compared with samples from wells directly. This study provided integrated knowledge on the persistence of pathogenic organisms in private well water. Further study is needed to explore the presence of clinical species of those opportunistic pathogens in private well water systems to elucidate the health risk.

Background: Colorectal cancer is the third most deadly cancer among African Americans (AA). When compared to Caucasian Americans (CA), AA present with more advanced disease and lower survival rates. Here, we investigated if differences in tumor immunology could be contributive to disparities observed between these populations. Methods: We examined gene expression of tumor and non-tumor adjacent tissues from AA and CA by whole transcriptome sequencing, and generated scores for immune cell populations by NanoString. In addition, we utilized "The Cancer Genome Atlas" (TCGA) database from AA and CA as a validation cohort. Finally, we measured the secretion of cytokines characteristic of effector T helper cell (T h ) subsets by ELISA using plasma from each AA and CA participant. Results: Colon tumors from AA patients showed significant fold-change increase in gene expression when compared to CA for FOXP3 (6.22 vs. 3.22), IL1B (103 vs. 11.4) and IL8 (220 vs. 28.9) ( p < 0.05). In contrast, among CA we observed statistically higher gene expression of markers associated with antitumor activity such as GZMB (Granzyme B), IFNG and the immunotherapy targets PDL1 ( CD274 ) and CTLA4 ( p < 0.05). TCGA data validated our observed higher gene expression of GZMB and PDL1 in CA patients when compared to AA. Notably, our observations on immune cell populations show that AA tumors have significantly higher number of exhausted CD8+ cells ( p < 0.01), mast cells ( p < 0.02) and increased T regulatory cells when compared to CA. AA colon cancer patients differed from CA in cytokine production patterns in plasma (i.e., reduced IL-12). Conclusions: Our study demonstrates significant differences of the immunological profiles of colon tumors from AA compared to CA that suggest a deficiency of appropriate immune defense mechanisms in terms of gene expression, recruitment of immune cells and systemic secretion of cytokines. As such, these immune differences could be mitigated through population-specific therapeutic approaches., (Copyright © 2020 Paredes, Zabaleta, Garai, Ji, Imtiaz, Spagnardi, Alvarado, Li, Akadri, Barrera, Munoz-Sagastibelza, Gupta, Alshal, Agaronov, Talus, Wang, Carethers, Williams and Martello.)

Introduction: Gas-based cryotherapy is the conventional ablative treatment for cervical pre-cancer in low-income settings, but the use of gas poses significant challenges. We compared the depth of necrosis induced by gas-based cryotherapy with two gas-free alternatives: cryotherapy using CryoPen,and thermoablation., Methods: We conducted a five-arm randomized non-inferiority trial: double-freeze carbon dioxide (CO 2 ) cryotherapy (referent), single-freeze CO 2 cryotherapy, double-freeze CryoPen, single-freeze CryoPen, and thermoablation. Subjects were 130 women scheduled for hysterectomy for indications other than cervical pathology, and thus with healthy cervical tissue available for histological evaluation of depth of necrosis post-surgery. The null hypothesis was rejected (ie, conclude non-inferiority) if the upper bound of the 90% confidence interval (90% CI) for the difference in mean depth of necrosis (referent minus each experimental method) was <1.14 mm. Patient pain during treatment was reported on a scale of 0 (no pain) to 10 (worst pain)., Results: A total of 133 patients were enrolled in the study. The slides from three women were deemed unreadable. One patient was excluded because her hysterectomy was postponed for reasons unrelated to the study, and two patients were excluded because treatment application did not follow the established protocol. For the remaining 127 women, mean depth of necrosis for double-freeze CO 2 (referent) was 6.0±1.6 mm. Differences between this and other methods were: single-freeze CO 2 = 0.4 mm (90% CI -0.4 to 1.2 mm), double-freeze CryoPen= 0.7 mm (90% CI 0.04 to 1.4 mm), single-freeze CryoPen= 0.5 mm (90% CI -0.2 to 1.2 mm), and thermoablation = 2.6 mm (90% CI 2.0 to 3.1 mm). Mean pain levels were 2.2±1.0 (double-freeze CO 2 cryotherapy), 1.8±0.8 (single-freeze CO 2 cryotherapy), 2.5±1.4 (double-freeze CryoPen), 2.6±1.4 (single-freeze CryoPen), and 4.1±2.3 (thermoablation)., Discussion: Compared with the referent, non-inferiority could not be concluded for other methods. Mean pain scores were low for all treatments. Depth of necrosis is a surrogate for treatment efficacy, but a randomized clinical trial is necessary to establish true cure rates., Competing Interests: Competing interests: MC is president/founder of Basic Health International, a trainer for Nexplanon, and a speaker for Merck. PEC has received cervical screening tests and diagnostics at a reduced or no cost for research from Roche, BD, Cepheid, and Arbor Vita Corporation. JCG declares that the National Cancer Institute has received cervical cytology and HPV testing results for independent NCI-directed studies at reduced or no cost from Roche and Becton Dickinson. MS is a former employee of Basic Health International., (© IGCS and ESGO 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Hereditary hemorrhagic telangiectasia is an autosomal dominant vascular disorder caused by heterozygous, loss-of-function mutations in 4 transforming growth factor beta (TGFβ) pathway members, including the central transcriptional mediator of the TGFβ pathway, Smad4. Loss of Smad4 causes the formation of inappropriate, fragile connections between arteries and veins called arteriovenous malformations (AVMs), which can hemorrhage leading to stroke, aneurysm, or death. Unfortunately, the molecular mechanisms underlying AVM pathogenesis remain poorly understood, and the TGFβ downstream effectors responsible for hereditary hemorrhagic telangiectasia-associated AVM formation are currently unknown., Methods: To identify potential biological targets of the TGFβ pathway involved in AVM formation, we performed RNA- and chromatin immunoprecipitation-sequencing experiments on BMP9 (bone morphogenetic protein 9)-stimulated endothelial cells (ECs) and isolated ECs from a Smad4-inducible, EC-specific knockout ( Smad4-iECKO) mouse model that develops retinal AVMs. These sequencing studies identified the angiopoietin-Tek signaling pathway as a downstream target of SMAD4. We used monoclonal blocking antibodies to target a specific component in this pathway and assess its effects on AVM development., Results: Sequencing studies uncovered 212 potential biological targets involved in AVM formation, including the EC surface receptor, TEK (TEK receptor tyrosine kinase) and its antagonistic ligand, ANGPT2 (angiopoietin-2). In Smad4-iECKO mice, Angpt2 expression is robustly increased, whereas Tek levels are decreased, resulting in an overall reduction in angiopoietin-Tek signaling. We provide evidence that SMAD4 directly represses Angpt2 transcription in ECs. Inhibition of ANGPT2 function in Smad4-deficient mice, either before or after AVMs form, prevents and alleviates AVM formation and normalizes vessel diameters. These rescue effects are attributed to a reversion in EC morphological changes, such as cell size and shape that are altered in the absence of Smad4., Conclusions: Our studies provide a novel mechanism whereby the loss of Smad4 causes increased Angpt2 transcription in ECs leading to AVM formation, increased blood vessel calibers, and changes in EC morphology in the retina. Blockade of ANGPT2 function in an in vivo Smad4 model of hereditary hemorrhagic telangiectasia alleviated these vascular phenotypes, further implicating ANGPT2 as an important TGFβ downstream mediator of AVM formation. Therefore, alternative approaches that target ANGPT2 function may have therapeutic value for the alleviation of hereditary hemorrhagic telangiectasia symptoms, such as AVMs.