Miracle-dz/UniFAR-FTUs huggingface dataset:
Behavioral Battery for Testing Candidate Analgesics in Mice. II. Effects of Endocannabinoid Catabolic Enzyme Inhibitors and ∆9-Tetrahydrocannabinol

Enhanced signaling of the endocannabinoid (eCB) system through inhibition of the catabolic enzymes monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) has received increasing interest for development of candidate analgesics. This study compared effects of MAGL and FAAH inhibitors with effects of ∆9-tetrahydrocannabinol (THC) using a battery of pain-stimulated, pain-depressed, and pain-independent behaviors in male and female mice. Intraperitoneal injection of dilute lactic acid (IP acid) served as an acute visceral noxious stimulus to stimulate two behaviors (stretching, facial grimace) and depress two behaviors (rearing, nesting). Nesting and locomotion were also assessed in the absence of IP acid as pain-independent behaviors. THC and a spectrum of six eCB catabolic enzyme inhibitors ranging from MAGL- to FAAH-selective were assessed for effectiveness to alleviate pain-related behaviors at doses that did not alter pain-independent behaviors. The MAGL-selective inhibitor MJN110 produced the most effective antinociceptive profile, with 1.0 mg/kg alleviating IP acid effects on stretching, grimace, and nesting without altering pain-independent behaviors. MJN110 effects on IP acid–depressed nesting had a slow onset and long duration (40 minutes to 6 hours), were blocked by rimonabant, and tended to be greater in females. As inhibitors increased in FAAH selectivity, antinociceptive effectiveness decreased. PF3845, the most FAAH-selective inhibitor, produced no antinociception up to doses that disrupted locomotion. THC decreased IP acid–stimulated stretching and grimace at doses that did not alter pain-independent behaviors; however, it did not alleviate IP acid–induced depression of rearing or nesting. These results support further consideration of MAGL-selective inhibitors as candidate analgesics for acute inflammatory pain. SIGNIFICANCE STATEMENT This study characterized a spectrum of endocannabinoid catabolic enzyme inhibitors ranging in selectivity from monoacylglycerol lipase–selective to fatty acid amide hydrolase–selective in a battery of pain-stimulated, pain-depressed, and pain-independent behaviors previously pharmacologically characterized in a companion paper. This battery provides a method for prioritizing candidate analgesics by effectiveness to alleviate pain-related behaviors at doses that do not alter pain-independent behaviors, with inclusion of pain-depressed behaviors increasing translational validity and decreasing susceptibility to motor-depressant false positives.
Ozone responses in Arabidopsis: beyond stomatal conductance

Abstract Tropospheric ozone (O3) is a major air pollutant that decreases yield of important crops worldwide. Despite long-lasting research of its negative effects on plants, there are many gaps in our knowledge on how plants respond to O3. In this study, we used natural variation in the model plant Arabidopsis (Arabidopsis thaliana) to characterize molecular and physiological mechanisms underlying O3 sensitivity. A key parameter in models for O3 damage is stomatal uptake. Here we show that the extent of O3 damage in the sensitive Arabidopsis accession Shahdara (Sha) does not correspond with O3 uptake, pointing toward stomata-independent mechanisms for the development of O3 damage. We compared tolerant (Col-0) versus sensitive accessions (Sha, Cvi-0) in assays related to photosynthesis, cell death, antioxidants, and transcriptional regulation. Acute O3 exposure increased cell death, development of lesions in the leaves, and decreased photosynthesis in sensitive accessions. In both Sha and Cvi-0, O3-induced lesions were associated with decreased maximal chlorophyll fluorescence and low quantum yield of electron transfer from Photosystem II to plastoquinone. However, O3-induced repression of photosynthesis in these two O3-sensitive accessions developed in different ways. We demonstrate that O3 sensitivity in Arabidopsis is influenced by genetic diversity given that Sha and Cvi-0 developed accession-specific transcriptional responses to O3. Our findings advance the understanding of plant responses to O3 and set a framework for future studies to characterize molecular and physiological mechanisms allowing plants to respond to high O3 levels in the atmosphere as a result of high air pollution and climate change.
Theoretical Characterization of the Reduction Potentials of Nucleic Acids in Solution

Here, we present the theoretical–computational modeling of the oxidation properties of four DNA nucleosides and nucleotides and a set of dinucleotides in solutions. Our estimates of the vertical ionization energies and reduction potentials, close to the corresponding experimental data, show that an accurate calculation of the molecular electronic properties in solutions requires a proper treatment of the effect of the environment. In particular, we found that the effect of the environment is to stabilize the oxidized state of the nucleobases resulting in a remarkable reduction—up to 6.6 eV—of the energy with respect to the gas phase. Our estimates of the aqueous and gas-phase vertical ionization energies, in good agreement with photoelectron spectroscopy experiments, also show that the effect on the reduction potential of the phosphate group and of the additional nucleotide in dinucleotides is rather limited.
Patulin and Trichothecene: characteristics, occurrence, toxic effects and detection capabilities via clinical, analytical and nanostructured electrochemical sensing/biosensing assays in foodstuffs

Abstract Patulin and Trichothecene as the main groups of mycotoxins in significant quantities can cause health risks from allergic reactions to death on both humans and animals. Accordingly, rapid and highly sensitive determination of these toxics agents is of great importance. This review starts with a comprehensive outlook regarding the characteristics, occurrence and toxic effects of Patulin and Trichothecene. In the following, numerous clinical and analytical approaches have been extensively discussed. The main emphasis of this review is placed on the utilization of novel nanomaterial based electrochemical sensing/biosensing tools for highly sensitive determination of Patulin and Trichothecene. Furthermore, a detailed and comprehensive comparison has been performed between clinical, analytical and sensing methods. Subsequently, the nanomaterial based electrochemical sensing platforms have been approved as reliable tools for on-site analysis of Patulin and Trichothecene in food processing and manufacturing industries. Different nanomaterials in improving the performance of detecting assays were investigated and have various benefits toward clinical and analytical methods. This paper would address the limitations in the current developments as well as the future challenges involved in the successful construction of sensing approaches with the functionalized nanomaterials and also allow exploring into core-research works regarding this area.
ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma

PURPOSE Patients with the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) historically showed inferior survival with standard rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Phase II studies demonstrated that adding the immunomodulatory agent lenalidomide to R-CHOP improved outcomes in ABC-type DLBCL. The goal of the global, phase III ROBUST study was to compare lenalidomide plus R-CHOP (R2-CHOP) with placebo/R-CHOP in previously untreated, ABC-type DLBCL. METHODS Histology and cell-of-origin type were prospectively analyzed by central pathology prior to random assignment and study treatment. Patients with ABC-DLBCL received lenalidomide oral 15 mg/d, days 1-14/21 plus standard R-CHOP21 versus placebo/R-CHOP21 for six cycles. The primary end point was progression-free survival (PFS) per independent central radiology review. RESULTS A total of 570 patients with ABC-DLBCL (n = 285 per arm) were stratified by International Prognostic Index score, age, and bulky disease, and randomly assigned to R2-CHOP or placebo/R-CHOP. Baseline demographics were similar between arms. Most patients completed six cycles of treatment: 74% R2-CHOP and 84% placebo/R-CHOP. The most common grade 3/4 adverse events for R2-CHOP versus placebo/R-CHOP were neutropenia (60% v 48%), anemia (22% v 14%), thrombocytopenia (17% v 11%), and leukopenia (14% v 15%). The primary end point of PFS was not met, with a hazard ratio of 0.85 (95% CI, 0.63 to 1.14) and P = . 29; median PFS has not been reached for either arm. PFS trends favoring R2-CHOP over placebo/R-CHOP were seen in patients with higher-risk disease. CONCLUSION ROBUST is the first DLBCL phase III study to integrate biomarker-driven identification of eligible ABC patients. Although the ROBUST trial did not meet the primary end point of PFS in all patients, the safety profile of R2-CHOP was consistent with individual treatments with no new safety signals.
Searching for Genes of Lactococcus lactis subsp lactis Encoding the Bacteriocin Nisin using DNA/DNA Hybridisation

In this work, PCR primers P8 and P9 were used for amplification of a 320 bp long PCR product specific to the nisin gene. The PCR product was labelled with digoxigenine during amplification and used as a DNA probe for the screening of homologous DNA sequences in 7 Lactococcus lactis subsp. lactis strains from the Culture Collection of Dairy Microorganisms (CCDM). Dot blot hybridisation and hybridisation of colonies were used for DNA/DNA hybridisation. It was shown that 6 tested strains of Lactococcus lactis subsp. lactis have genes encoding nisin. One
Breast cancer differential diagnosis using diffuse optical spectroscopic imaging and regression with z-score normalized data

Abstract. Significance: Current imaging paradigms for differential diagnosis of suspicious breast lesions suffer from high false positive rates that force patients to undergo unnecessary biopsies. Diffuse optical spectroscopic imaging (DOSI) noninvasively probes functional hemodynamic and compositional parameters in deep tissue and has been shown to be sensitive to contrast between normal and malignant tissues. Aim: DOSI methods are under investigation as an adjunct to mammography and ultrasound that could reduce false positive rates and unnecessary biopsies, particularly in radiographically dense breasts. Methods: We performed a retrospective analysis of 212 subjects with suspicious breast lesions who underwent DOSI imaging. Physiological tissue parameters were z-score normalized to the patient’s contralateral breast tissue and input to univariate logistic regression models to discriminate between malignant tumors and the surrounding normal tissue. The models were then used to differentiate malignant lesions from benign lesions. Results: Models incorporating several individual hemodynamic parameters were able to accurately distinguish malignant tumors from both the surrounding background tissue and benign lesions with area under the curve (AUC) ≥0.85. Z-score normalization improved the discriminatory ability and calibration of these predictive models relative to unnormalized or ratio-normalized data. Conclusions: Findings from a large subject population study show how DOSI data normalization that accounts for normal tissue heterogeneity and quantitative statistical regression approaches can be combined to improve the ability of DOSI to diagnose malignant lesions. This improved diagnostic accuracy, combined with the modality’s inherent logistical advantages of portability, low cost, and nonionizing radiation, could position DOSI as an effective adjunct modality that could be used to reduce the number of unnecessary invasive biopsies.
Using the police cell as intervention in mental health crises: Qualitative approach to an interdisciplinary practice and its possible consequences

Abstract Purpose The aim of this study was to analyze the views of patients, police‐officers and emergency mental health workers on the use of the police cell as intervention in a mental health crisis. Design and Methods We analyzed interviews with individuals involved in police cell interventions, found first labels and categorized them in concordance with the four principles of biomedical ethics and compared them to relevant scientific literature. Findings and Practical Implications Professionals should know that emergency mental healthcare aimed at controlling the situation is not enough to provide good care. It probably generates better outcomes for patients in the short and long term when patient experiences are taken into consideration.
Keratoconus Features on Corneal Higher-Order Aberration Ablation Maps: Proof-of-Concept of a New Diagnostic Modality

Purpose To assess the potential application of corneal higher-order aberration (HOA) excimer ablation map imaging in identifying reproducible keratoconus (KC) features and to explore if newly derived map metrics correlate to Pentacam KC indices. Methods Case series of 12 eyes with KC ≥ grade 2. Topolyzer Vario corneal imaging with its resultant HOA ablation map islands were analyzed for their centroid, distance from center, angular position, orientation, sphericity, diameter, area, and maximal ablation depth. Correlations to Pentacam indices were studied. Results All eyes showed recurrent features with an arrangement of two elliptical paracentral ablation islands, one deep inferotemporal and one shallow superonasal, in direct mirror-like opposition to each other. These were always accompanied by superior peripheral ablation crescents. The two paracentral islands had highly reproducible distance from center (1.2 ± 0.1 mm and 1.3 ± 0. 2 mm) and angular positions (246.8 ± 15.9° and 76.7 ± 7.7°), with greater variation in ablation depth (68.3 ± 33.2 µm and 17.6 ± 12.1 µm). Distance from center of the peripheral superior crescents was highly reproducible (3.3 ± 0.1 mm), with a larger range of depth (74.5 ± 37.2 µm). The deep paracentral inferotemporal island “hot spot” was coincident with the topographical apical cone. Strong correlations were found between the depth of the inferotemporal island and Pentacam indices of posterior radius curvature (PRC: R = −0.74) and Belin/Ambrosio enhanced ectasia total deviation (BAD-D: R = 0.71). Conclusion The corneal HOA ablation map revealed a recurring, distinct, easily recognizable pattern in KC eyes. There was a strong correlation between the depth of novel HOA ablation map metrics and validated Pentacam KC indices. Novel information can be extracted from the corneal HOA ablation map giving it the potential to be a new modality to diagnose and grade KC.
ELF3 activated by a superenhancer and an autoregulatory feedback loop is required for high-level HLA-C expression on extravillous trophoblasts

Significance Several techniques have identified ELF3 as particularly important in regulating trophoblast-specific HLA-C expression. This results from a single-nucleotide difference in the promotor of the HLA-C gene at the RFX5 binding site that creates an ELF3 binding site not found in the HLA-A or HLA-B promoters. We discovered a superenhancer and a positive autoregulatory feedback loop that promotes expression of the ELF3 gene in trophoblasts. Disruption of either the superenhancer by (+)-JQ1 or interference with the positive-feedback loop by wrenchnolol decreased ELF3 levels, and thus HLA-C expression. Aberrations of this complex regulatory system could be involved in control of infection, miscarriage, preterm birth, preeclampsia, as well as parturition in normal pregnancy and in development of choriocarcinoma. HLA-C arose during evolution of pregnancy in the great apes 10 to 15 million years ago. It has a dual function on placental extravillous trophoblasts (EVTs) as it contributes to both tolerance and immunity at the maternal–fetal interface. The mode of its regulation is of considerable interest in connection with the biology of pregnancy and pregnancy abnormalities. First-trimester primary EVTs in which HLA-C is highly expressed, as well as JEG3, an EVT model cell line, were employed. Single-cell RNA-seq data and quantitative PCR identified high expression of the transcription factor ELF3 in those cells. Chromatin immunoprecipitation (ChIP)-PCR confirmed that both ELF3 and MED1 bound to the proximal HLA-C promoter region. However, binding of RFX5 to this region was absent or severely reduced, and the adjacent HLA-B locus remained closed. Expression of HLA-C was inhibited by ELF3 small interfering RNAs (siRNAs) and by wrenchnolol treatment. Wrenchnolol is a cell-permeable synthetic organic molecule that mimics ELF3 and is relatively specific for binding to ELF3’s coactivator, MED23, as our data also showed in JEG3. Moreover, the ELF3 gene is regulated by a superenhancer that spans more than 5 Mb, identified by assay for transposase-accessible chromatin using sequencing (ATAC-seq), as well as by its sensitivity to (+)-JQ1 (inhibitor of BRD4). ELF3 bound to its own promoter, thus creating an autoregulatory feedback loop that establishes expression of ELF3 and HLA-C in trophoblasts. Wrenchnolol blocked binding of MED23 to ELF3, thus disrupting the positive-feedback loop that drives ELF3 expression, with down-regulation of HLA-C expression as a consequence.
WeChat-based education and rehabilitation program in unprotected left main coronary artery disease patients after coronary artery bypass grafting: an effective approach in reducing anxiety, depression, loss to follow-up, and improving quality of life

This study aimed to investigate the effect of WeChat-based education and rehabilitation program (WERP) on anxiety, depression, health-related quality of life (HRQoL), major adverse cardiac/cerebrovascular events (MACCE)-free survival, and loss to follow-up rate in unprotected left main coronary artery disease (ULMCAD) patients after coronary artery bypass grafting (CABG). In this randomized controlled study, 140 ULMCAD patients who underwent CABG were randomly assigned to WERP group (n=70) or control care (CC) group (n=70). During the 12-month intervention period, anxiety and depression (using hospital anxiety and depression scale (HADS)) and HRQoL (using 12-Item Short-Form Health Survey (SF-12)) were assessed longitudinally. During the total 36-month follow-up period (12-month intervention and 24-month non-intervention periods), MACCE and loss to follow-up were recorded. During the intervention period, HADS-anxiety score at month 9 (M9) (P=0.047) and month 12 (M12) (P=0.034), anxiety rate at M12 (P=0.028), and HADS-D score at M12 (P=0.048) were all reduced in WERP group compared with CC group. As for HRQoL, SF-12 physical component summary score at M9 (P=0.020) and M12 (P=0.010) and SF-12 mental component summary score at M9 (P=0.040) and M12 (P=0.028) were all increased in WERP group compared with CC group. During the total follow-up period, WERP group displayed a trend of longer MACCE-free survival than that in CC group but without statistical significance (P=0.195). Additionally, loss to follow-up rate was attenuated in WERP group compared with CC group (P=0.033). WERP serves as an effective approach in optimizing mental health care and promoting life quality in ULMCAD patients after CABG.
Elderly people's experiences in emergencies through access to other levels of health care.

OBJECTIVE to understand elderly people's experiences in emergencies through access to other levels of health care. METHODS a phenomenological study in the light of Heidegger, conducted with 19 elderly patients admitted to an Emergency Care Unit of the city of Salvador, between April and October 2019. RESULTS ontic primacy: Disposition of the experience of elderly people waiting for regulation; Constitutional anguish and fear in the willingness to be an elderly person waiting for regulation in an Emergency Care Unit; Inappropriate elderly being suppressed while waiting for regulation; Being an elderly person unveiled in the existential modality of being for death. Ontological primacy: Heal how to be the presence of elderly people waiting for regulation. FINAL CONSIDERATIONS elderly people being anguished and afraid, feelings that allow the questioning of their own being, who want a healing and seeks ways that allows an active and proper participation in care.
Morphology and Thermomechanical Properties of Melt‐Mixed Polyoxymethylene/Polyhedral Oligomeric Silsesquioxane Nanocomposites

The influence of the functionalization of fully condensed POSS cages on the properties of POMbased nanocomposites is studied. POSS with different organic substituents [glycidylethyl, aminopropylisobutyl, and poly(ethylene glycol)] are taken into account and melt mixed with POM. Good dispersion was achieved upon the addition of amino functionalized POSS, leading to an increase on the thermal decomposition temperature under nitrogen atmosphere up to 50 8C. However, mm-size aggregates were observed for other nanocomposites. There is no significant change in other thermal properties of the nanocomposites. The relationships among these effects and the morphological characteristics of the systems were analyzed.
Can the banana weevil Cosmopolites sordidus be a vector of Fusarium oxysporum f.sp. cubense race 1? Unravelling the internal and external acquisition of effective inoculum.

BACKGROUND With the undergoing world outbreak of Fusarium wilt of bananas, it is essential to unravel all the possible process of dissemination of this disease. The host-pest interactions of the banana weevil with banana plants make this insect an important potential vector. This study, carried in controlled conditions, explores the interaction between the banana weevil and Fusarium oxysporum f.sp. cubense Race 1 (FOC), with a focus on the external and internal transport of viable fungal propagules. RESULTS Viable inoculum of FOC was detected very rapidly on external teguments and in the digestive tract of the insect, i.e. at the lowest time studied of 5 min after contact with infected pseudostems. Maximal inoculum acquisition occurred after 1 h contact with an inoculum source. External inoculum was higher than the inoculum present in the digestive tract, but external and internal inoculum had the same dynamics. After a contact of an infected source, external and internal inoculum decreased exponentially within 50 h, but weevils remained infested for a long time, as long as 2 or 3 days that would be enough for inoculum dispersal. Viable inoculum was also detected in feces. Foc strains isolated were pathogenic when inoculated to banana plants of the Gros Michel variety but did not provoke any symptom on Cavendish banana plants CONCLUSION: These results demonstrate that the infective structures of Foc remain externally viable in the digestive system and the excreta of the banana weevil. Such excreta are capable of making healthy banana plants of Gros Michel. This article is protected by copyright. All rights reserved.