Miracle-dz/UniFAR-FTUs huggingface dataset:
Effects of Cardiac Resynchronization Therapy on Cardio-Respiratory Coupling

In this study, the effect of cardiac resynchronization therapy (CRT) on the relationship between the cardiovascular and respiratory systems in heart failure subjects was examined for the first time. We hypothesized that alterations in cardio-respiratory interactions, after CRT implantation, quantified by signal complexity, could be a marker of a favorable CRT response. Sample entropy and scaling exponents were calculated from synchronously recorded cardiac and respiratory signals 20 min in duration, collected in 47 heart failure patients at rest, before and 9 months after CRT implantation. Further, cross-sample entropy between these signals was calculated. After CRT, all patients had lower heart rate and CRT responders had reduced breathing frequency. Results revealed that higher cardiac rhythm complexity in CRT non-responders was associated with weak correlations of cardiac rhythm at baseline measurement over long scales and over short scales at follow-up recording. Unlike CRT responders, in non-responders, a significant difference in respiratory rhythm complexity between measurements could be consequence of divergent changes in correlation properties of the respiratory signal over short and long scales. Asynchrony between cardiac and respiratory rhythm increased significantly in CRT non-responders during follow-up. Quantification of complexity and synchrony between cardiac and respiratory signals shows significant associations between CRT success and stability of cardio-respiratory coupling.
NMR investigation of a thermotropic liquid crystal showing isotropic-isotropic'-(columnar)-cubic phase transitions

ABSTRACT In this work, we report a first detailed study of the mesophasic behaviour of the calamitic liquid crystal, a (4,4′-bis(4″-carboxybelzyloxy)biphenyl derivate, labelled 9/2 RS/RS, showing an isotropic-isotropic-(columnar)-cubic phase behaviour on cooling. 1H NMR diffusometry allowed to distinguish between the two isotropic phases in terms of diffusion characterized by different Arrhenius activation energy, while 13C NMR static measurements and 2H NMR investigations were of help in understanding the orientational ordering properties of the metastable columnar phase and confirmed the isotropic state of the sample in the cubic phase.
Standard Tone Stability as a Manipulation of Precision in the Oddball Paradigm: Modulation of Prediction Error Responses to Fixed-Probability Deviants

Electrophysiological sensory deviance detection signals, such as the mismatch negativity (MMN), have been interpreted from the predictive coding framework as manifestations of prediction error (PE). From a frequentist perspective of the classic oddball paradigm, deviant stimuli are unexpected because of their low probability. However, the amount of PE elicited by a stimulus can be dissociated from its probability of occurrence: when the observer cannot make confident predictions, any event holds little surprise value, no matter how improbable. Here we tested the hypothesis that the magnitude of the neural response elicited to an improbable sound (D) would scale with the precision of the prediction derived from the repetition of another sound (S), by manipulating repetition stability. We recorded the Electroencephalogram (EEG) from 20 participants while passively listening to 4 types of isochronous pure tone sequences differing in the probability of the S tone (880 Hz) while holding constant the probability of the D tone [1,046 Hz; p(D) = 1/11]: Oddball [p(S) = 10/11]; High confidence (7/11); Low confidence (4/11); and Random (1/11). Tones of 9 different frequencies were equiprobably presented as fillers [p(S) + p(D) + p(F) = 1]. Using a mass-univariate non-parametric, cluster-based correlation analysis controlling for multiple comparisons, we found that the amplitude of the deviant-elicited ERP became more negative with increasing S probability, in a time-electrode window consistent with the MMN (ca. 120–200 ms; frontal), suggesting that the strength of a PE elicited to an improbable event indeed increases with the precision of the predictive model.
Case Report: Recurrent Variant c.298 TA in CCN6 Gene Found in Progressive Pseudorheumatoid Dysplasia Patients From Patni Community of Gujarat: A Report of Three Cases

Biallelic mutations in the CCN6 gene are known to cause a rare genetic disorder—progressive pseudorheumatoid dysplasia (PPD). PPD is characterized by distinct joint deformities of interphalangeal joints, stiffness, gait disturbance, abnormal posture, and absence of inflammation, resulting in significant morbidity. The largest case series of PPD from India suggests c.233G>A and c.1010G>A to be the most common mutations in the CCN6 gene, although the distribution of these variants among endogamous communities in India has not been carried out. We here report three cases of PPD from three independent families belonging to the Patni community of Gujarat, a community known to practice endogamy. All three cases had short stature, gait disturbance, scoliosis, and interphalangeal joint deformities. Analysis by whole-exome sequencing in the first case showed the presence of a previously known, homozygous, missense variant c.298T>A (p.Cys100Ser) in exon 3 of the CCN6 gene in all cases. Due to all three families belonging to the same community, analysis by Sanger sequencing in the remaining two cases for the variant mentioned earlier showed both cases to be of homozygous mutant genotype. Unaffected family members, i.e., parents and siblings, were either heterozygous carriers or wildtype for the said variant. The present case series is the first report of a recurrent variant occurring across multiple PPD-affected individuals from unrelated families belonging to the same community from India.
Serum CD203c+ Extracellular Vesicle Serves as a Novel Diagnostic and Prognostic Biomarker for Succinylated Gelatin Induced Perioperative Hypersensitive Reaction

Background Perioperative hypersensitivity reaction (HR) is an IgE-FcϵRI-mediated hypersensitivity reaction with degranulation and activation of mast cells and basophils. Several studies have focused on assessing the degranulation and activation of mast cells and basophils to diagnose and predict the prognosis of drug induced HR. However, it is challenging to isolate sufficiently pure mast cells and basophils from human sources to investigate. Effective biomarkers to assess mast cells and basophils activation in vivo could potentially have high diagnostic and prognostic values. In the present study, we investigated EVs pelleted from serum in patients with succinylated gelatin induced HR. Methods Extracellular vesicles (EVs) were isolated using a total exosome isolation kit and ultracentrifugation, characterized by Western blot, transmission electron microscopy, and nanoparticle tracking analysis. Basophils were isolated from fresh peripheral blood by negative selection using Basophil Isolation Kit II. Human mast cell line was stimulated with IL4. The expression levels of proteins related to the hypersensitive response were evaluated by Western blotting and flow Cytometer. Histamine and tryptase levels were tested using a commercial ELISA kit, and gene expression of inflammatory mediators was evaluated by qRT-PCR. The receiver operating characteristic (ROC) curve was used to evaluate the specificity and sensitivity of biomarker in predicting HR. Results The concentration of EVs and protein expression level of CD63, FcϵRI, CD203c and tryptase were significantly (p< 0.05) increased in HR samples. The expression level of mast cell/basophil specific CD203c were significantly increased in EVs derived from serum and basophils of HR patients, and the CD203c+-EVs production in mast cells is dramatically increased in the presence of IL4, which positively correlated with histamine, tryptase and inflammatory mediators. Moreover, the ROC curve of EVs concentration and CD203c expression indicated that CD203c+-EVs had a strong diagnostic ability for HR. Conclusion Serum CD203c+-EVs serves as a novel diagnostic and prognostic biomarker for HR.
The Effect of Smoking on the Immune Microenvironment and Immunogenicity and Its Relationship With the Prognosis of Immune Checkpoint Inhibitors in Non-small Cell Lung Cancer

Background: The emergence of immune checkpoint inhibitors (ICIs) has opened a new chapter for the treatment of non-small cell lung cancer (NSCLC), and the best beneficiaries of ICI treatment are still being explored. Smoking status has been repeatedly confirmed to affect the efficacy of ICIs in NSCLC patients, but the specific mechanism is still unclear. Methods: We performed analysis on the Memorial Sloan Kettering Cancer Center (MSKCC) clinical NSCLC cohort receiving ICI treatment, The Cancer Genome Atlas (TCGA) Pan-Lung Cancer cohort, and Gene Expression Omnibus (GEO) database GSE41271 lung cancer cohort that did not receive ICI treatment, including survival prognosis, gene mutation, copy number variation, immunogenicity, and immune microenvironment, and explored the impact of smoking status on the prognosis of NSCLC patients treated with ICIs and possible mechanism. In addition, 8 fresh NSCLC surgical tissue samples were collected for mass cytometry (CyTOF) experiments to further characterize the immune characteristics and verify the mechanism. Result: Through the analysis of the clinical data of the NSCLC cohort treated with ICIs in MSKCC, it was found that the smokers in NSCLC receiving ICI treatment had a longer progression-free survival (HR: 0.69, 95% CI: 0.49–0.97, p = 0.031) than those who never smoked. Further analysis of the TCGA and GEO validation cohorts found that the differences in prognosis between different groups may be related to the smoking group’s higher immunogenicity, higher gene mutations, and stronger immune microenvironment. The results of the CyTOF experiment further found that the immune microenvironment of smoking group was characterized by higher expression of immune positive regulatory chemokine, and higher abundance of immune activated cells, including follicular helper CD4+ T cells, gamma delta CD4+ T cells, activated DC, and activated CD8+ T cells. In contrast, the immune microenvironment of non-smoking group was significantly enriched for immunosuppressive related cells, including regulatory T cells and M2 macrophages. Finally, we also found highly enriched CD45RAhighCD4+ T cells and CD45RAhighCD8+ T cells in the non-smoking group. Conclusion: Our research results suggest that among NSCLC patients receiving ICI treatment, the stronger immunogenicity and activated immune microenvironment of the smoking group make their prognosis better.
Molecular and Cellular Mediators of the Gut-Liver Axis in the Progression of Liver Diseases

The gut-liver axis covers the bidirectional communication between the gut and the liver, and thus includes signals from liver-to-gut (e.g., bile acids, immunoglobulins) and from gut-to-liver (e.g., nutrients, microbiota-derived products, and recirculating bile acids). In a healthy individual, liver homeostasis is tightly controlled by the mostly tolerogenic liver resident macrophages, the Kupffer cells, capturing the gut-derived antigens from the blood circulation. However, disturbances of the gut-liver axis have been associated to the progression of varying chronic liver diseases, such as non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and primary sclerosing cholangitis. Notably, changes of the gut microbiome, or intestinal dysbiosis, combined with increased intestinal permeability, leads to the translocation of gut-derived bacteria or their metabolites into the portal vein. In the context of concomitant or subsequent liver inflammation, the liver is then infiltrated by responsive immune cells (e.g., monocytes, neutrophils, lymphoid, or dendritic cells), and microbiota-derived products may provoke or exacerbate innate immune responses, hence perpetuating liver inflammation and fibrosis, and potentiating the risks of developing cirrhosis. Similarly, food derived antigens, bile acids, danger-, and pathogen-associated molecular patterns are able to reshape the liver immune microenvironment. Immune cell intracellular signaling components, such as inflammasome activation, toll-like receptor or nucleotide-binding oligomerization domain-like receptors signaling, are potent targets of interest for the modulation of the immune response. This review describes the current understanding of the cellular landscape and molecular pathways involved in the gut-liver axis and implicated in chronic liver disease progression. We also provide an overview of innovative therapeutic approaches and current clinical trials aiming at targeting the gut-liver axis for the treatment of patients with chronic liver and/or intestinal diseases.
The Role of Temperature in Moral Decision-Making: Limited Reproducibility

Temperature is one of the major environmental factors that people are exposed to on a daily basis, often in conditions that do not afford control. It is known that heat and cold can influence a person’s productivity and performance in simple tasks. With respect to social cognition, it has also been suggested that temperature impacts on relatively high-level forms of decision-making. For instance, previous research demonstrated that cold temperature promotes utilitarian judgment in a moral dilemma task. This effect could be due to psychological processing, when a cool temperature primes a set of internal representations (associated with “coldness”). Alternatively, the promotion of utilitarian judgment in cold conditions could be due to physiological interference from temperature, impeding on social cognition. Refuting both explanations of psychological or physiological processing, however, it has been suggested that there may be problems of reproducibility in the literature on temperature modulating complex or abstract information processing. To examine the role of temperature in moral decision-making, we conducted a series of experiments using ambient and haptic temperature with careful manipulation checks and modified task methodology. Experiment 1 manipulated room temperature with cool (21°C), control (24°C) and hot (27°C) conditions and found only a cool temperature effect, promoting utilitarian judgment as in the previous study. Experiment 2 manipulated the intensity of haptic temperature but failed to obtain the cool temperature effect. Experiments 3 and 4 examined the generalizability of the cool ambient temperature effect with another moral judgment task and with manipulation of exposure duration. However, again there were no cool temperature effects, suggesting a lack of reproducibility. Despite successful manipulations of temperature in all four experiments, as measured in body temperature and the participants’ self-reported perception, we found no systematic influence of temperature on moral decision-making. A Bayesian meta-analysis of the four experiments showed that the overall data tended to provide strong support in favor of the null hypothesis. We propose that, at least in the range of temperatures from 21 to 27°C, the cool temperature effect in moral decision-making is not a robust phenomenon.
Information Optimized Multilayer Network Representation of High Density Electroencephalogram Recordings

High-density electroencephalography (hd-EEG) provides an accessible indirect method to record spatio-temporal brain activity with potential for disease diagnosis and monitoring. Due to their highly multidimensional nature, extracting useful information from hd-EEG recordings is a complex task. Network representations have been shown to provide an intuitive picture of the spatial connectivity underlying an electroencephalogram recording, although some information is lost in the projection. Here, we propose a method to construct multilayer network representations of hd-EEG recordings that maximize their information content and test it on sleep data recorded in individuals with mental health issues. We perform a series of statistical measurements on the multilayer networks obtained from patients and control subjects and detect significant differences between the groups in clustering coefficient, betwenness centrality, average shortest path length and parieto occipital edge presence. In particular, patients with a mood disorder display a increased edge presence in the parieto-occipital region with respect to healthy control subjects, indicating a highly correlated electrical activity in that region of the brain. We also show that multilayer networks at constant edge density perform better, since most network properties are correlated with the edge density itself which can act as a confounding factor. Our results show that it is possible to stratify patients through statistical measurements on a multilayer network representation of hd-EEG recordings. The analysis reveals that individuals with mental health issues display strongly correlated signals in the parieto-occipital region. Our methodology could be useful as a visualization and analysis tool for hd-EEG recordings in a variety of pathological conditions.
The Combination of Gefitinib With ATRA and ATO Induces Myeloid Differentiation in Acute Promyelocytic Leukemia Resistant Cells

In approximately 15% of patients with acute myeloid leukemia (AML), total and phosphorylated EGFR proteins have been reported to be increased compared to healthy CD34+ samples. However, it is unclear if this subset of patients would benefit from EGFR signaling pharmacological inhibition. Pre-clinical studies on AML cells provided evidence on the pro-differentiation benefits of EGFR inhibitors when combined with ATRA or ATO in vitro. Despite the success of ATRA and ATO in the treatment of patients with acute promyelocytic leukemia (APL), therapy-associated resistance is observed in 5-10% of the cases, pointing to a clear need for new therapeutic strategies for those patients. In this context, the functional role of EGFR tyrosine-kinase inhibitors has never been evaluated in APL. Here, we investigated the EGFR pathway in primary samples along with functional in vitro and in vivo studies using several APL models. We observed that total and phosphorylated EGFR (Tyr992) was expressed in 28% and 19% of blast cells from APL patients, respectively, but not in healthy CD34+ samples. Interestingly, the expression of the EGF was lower in APL plasma samples than in healthy controls. The EGFR ligand AREG was detected in 29% of APL patients at diagnosis, but not in control samples. In vitro, treatment with the EGFR inhibitor gefitinib (ZD1839) reduced cell proliferation and survival of NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Moreover, the combination of gefitinib with ATRA and ATO promoted myeloid cell differentiation in ATRA- and ATO-resistant APL cells. In vivo, the combination of gefitinib and ATRA prolonged survival compared to gefitinib- or vehicle-treated leukemic mice in a syngeneic transplantation model, while the gain in survival did not reach statistical difference compared to treatment with ATRA alone. Our results suggest that gefitinib is a potential adjuvant agent that can mitigate ATRA and ATO resistance in APL cells. Therefore, our data indicate that repurposing FDA-approved tyrosine-kinase inhibitors could provide new perspectives into combination therapy to overcome drug resistance in APL patients.
Complete Genome Sequence of Weissella confusa LM1 and Comparative Genomic Analysis

The genus Weissella is attracting an increasing amount of attention because of its multiple functions and probiotic potential. In particular, the species Weissella confusa is known to have great potential in industrial applications and exhibits numerous biological functions. However, the knowledge on this bacterium in insects is not investigated. Here, we isolated and identified W. confusa as the dominant lactic acid bacteria in the gut of the migratory locust. We named this strain W. confusa LM1, which is the first genome of an insect-derived W. confusa strain with one complete chromosome and one complete plasmid. Among all W. confusa strains, W. confusa LM1 had the largest genome. Its genome was the closest to that of W. confusa 1001271B_151109_G12, a strain from human feces. Our results provided accurate evolutionary relationships of known Weissella species and W. confusa strains. Based on genomic analysis, the pan-genome of W. confusa is in an open state. Most strains of W. confusa had the unique genes, indicating that these strains can adapt to different ecological niches and organisms. However, the variation of strain-specific genes did represent significant correlations with their hosts and ecological niches. These strains were predicted to have low potential to produce secondary metabolites. Furthermore, no antibiotic resistance genes were identified. At the same time, virulence factors associated with toxin production and secretion system were not found, indicating that W. confusa strains were not sufficient to perform virulence. Our study facilitated the discovery of the functions of W. confusa LM1 in locust biology and their potential application to locust management.
Characterization of Phytochemicals in Ulva intestinalis L. and Their Action Against SARS-CoV-2 Spike Glycoprotein Receptor-Binding Domain

Coronavirus disease-2019 (COVID-19) has caused a severe impact on almost all aspects of human life and economic development. Numerous studies are being conducted to find novel therapeutic strategies to overcome COVID-19 pandemic in a much effective way. Ulva intestinalis L. (Ui), a marine microalga, known for its antiviral property, was considered for this study to determine the antiviral efficacy against severe acute respiratory syndrome-associated Coronavirus-2 (SARS-CoV-2). The algal sample was dried and subjected to ethanolic extraction, followed by purification and analysis using gas chromatography-coupled mass spectrometry (GC-MS). Forty-three known compounds were identified and docked against the S1 receptor binding domain (RBD) of the spike (S) glycoprotein. The compounds that exhibited high binding affinity to the RBD of S1 protein were further analyzed for their chemical behaviour using conceptual density-functional theory (C-DFT). Finally, pharmacokinetic properties and drug-likeliness studies were carried out to test if the compounds qualified as potential leads. The results indicated that mainly phenols, polyenes, phytosteroids, and aliphatic compounds from the extract, such as 2,4-di-tert-butylphenol (2,4-DtBP), doconexent, 4,8,13-duvatriene-1,3-diol (DTD), retinoyl-β-glucuronide 6′,3′-lactone (RBGUL), and retinal, showed better binding affinity to the target. Pharmacokinetic validation narrowed the list to 2,4-DtBP, retinal and RBGUL as the possible antiviral candidates that could inhibit the viral spike protein effectively.