Miracle-dz/UniFAR-FTUs huggingface dataset:
Anticipating catastrophes through extreme value modelling

Summary. When catastrophes strike it is easy to be wise after the event. It is also often argued that such catastrophic events are unforeseeable, or at least so implausible as to be negligible for planning purposes. We consider these issues in the context of daily rainfall measurements recorded in Venezuela. Before 1999 simple extreme value techniques were used to assess likely future levels of extreme rainfall, and these gave no particular cause for concern. In December 1999 a daily precipitation event of more than 410 mm, almost three times the magnitude of the previously recorded maximum, caused devastation and an estimated 30000 deaths. We look carefully at the previous history of the process and offer an extreme value analysis of the data—with some methodological novelty—that suggests that the 1999 event was much more plausible than the previous analyses had claimed. Deriving design parameters from the results of such an analysis may have had some mitigating effects on the consequences of the subsequent disaster. The themes of the new analysis are simple: the full exploitation of available data, proper accounting of uncertainty, careful interpretation of asymptotic limit laws and allowance for non‐stationarity. The effect on the Venezuelan data analysis is dramatic. The broader implications are equally dramatic; that a naïve use of extreme value techniques is likely to lead to a false sense of security that might have devastating consequences in practice.
Relationships between Virulence Genes and Antibiotic Resistance Phenotypes/Genotypes in Campylobacter spp. Isolated from Layer Hens and Eggs in the North of Tunisia: Statistical and Computational Insights

Globally, Campylobacter is a significant contributor to gastroenteritis. Efficient pathogens are qualified by their virulence power, resistance to antibiotics and epidemic spread. However, the correlation between antimicrobial resistance (AR) and the pathogenicity power of pathogens is complex and poorly understood. In this study, we aimed to investigate genes encoding virulence and AR mechanisms in 177 Campylobacter isolates collected from layer hens and eggs in Tunisia and to assess associations between AR and virulence characteristics. Virulotyping was determined by searching 13 virulence genes and AR-encoding genes were investigated by PCR and MAMA-PCR. The following genes were detected in C. jejuni and C. coli isolates: tet(O) (100%/100%), blaOXA-61 (18.82%/6.25%), and cmeB (100%/100%). All quinolone-resistant isolates harbored the Thr-86-Ile substitution in GyrA. Both the A2074C and A2075G mutations in 23S rRNA were found in all erythromycin-resistant isolates; however, the erm(B) gene was detected in 48.38% and 64.15% of the C. jejuni and C. coli isolates, respectively. The machine learning algorithm Random Forest was used to determine the association of virulence genes with AR phenotypes. This analysis showed that C. jejuni virulotypes with gene clusters encompassing the racR, ceuE, virB11, and pldA genes were strongly associated with the majority of phenotypic resistance. Our findings showed high rates of AR and virulence genes among poultry Campylobacter, which is a cause of concern to human health. In addition, the correlations of specific virulence genes with AR phenotypes were established by statistical analysis.
Tutte polynomials and random-cluster models in Bernoulli cell complexes

This paper studies Bernoulli cell complexes from the perspective of persistent homology, Tutte polynomials, and random-cluster models. Following the previous work [9], we first show the asymptotic order of the expected lifetime sum of the persistent homology for the Bernoulli cell complex process on the $\ell$-cubical lattice. Then, an explicit formula of the expected lifetime sum using the Tutte polynomial is derived. Furthermore, we study a higher dimensional generalization of the random-cluster model derived from the Edwards-Sokal type coupling, and show some basic results such as the positive association and the relation to the Tutte polynomial.
Single Nucleotide Polymorphism (SNP) Arrays and Their Sensitivity for Detection of Genetic Changes in Human Pluripotent Stem Cell Cultures

Human pluripotent stem cells (hPSCs) can be grown in culture indefinitely, making them a valuable tool for use in basic biology, disease modeling, and regenerative medicine. However, over prolonged periods in culture, hPSCs tend to acquire genomic aberrations that confer growth advantages, similar to those seen in some cancers. Monitoring the genomic stability of cultured hPSCs is critical to ensuring their efficacy and safety as a therapeutic tool. Most commonly employed methods for monitoring of hPSC genomes are cytogenetic methods, such as G‐banding. Nonetheless, such methods have limited resolution and sensitivity for detecting mosaicism. Single nucleotide polymorphism (SNP) array platforms are a potential alternative that could improve detection of abnormalities. Here, we outline protocols for SNP array whole‐genome screening of hPSCs. Moreover, we detail the procedure for assessing the SNP array's sensitivity in detecting low‐level mosaic copy‐number changes. We show that mosaicism can be confidently identified in samples only once they contain 20% variants, although samples containing 10% variants typically display enough variation to warrant further investigation and confirmation, for example by using a more sensitive targeted method. Finally, we highlight the advantages and limitations of SNP arrays, including a cost comparison of SNP arrays versus other commonly employed methods for detection of genetic changes in hPSC cultures. © 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.
The heliospheric current sheet

The heliospheric current sheet (HCS) is the boundary between open oppositely directed magnetic field lines which commonly originate as the outward extension of the solar magnetic dipole. The dipole tilt, the rotation of the Sun, and the outward propagation of the solar wind cause peaks and valleys in the current sheet which spiral outward. The HCS extends throughout the heliosphere to the greatest distances reached by Pioneer and Voyager. It serves as a magnetic equator, and solar wind parameters including speed, temperature, density, and composition vary with distance from the HCS. Extrapolated back to the Sun, especially near solar minimum, the HCS corresponds to the low-latitude streamer belt. Both features are closely related to a neutral line obtained by extrapolating photospheric magnetic fields to a source surface at several solar radii. The current sheet and sector structure persist throughout the solar cycle including solar maximum. At 1 AU the width of the HCS is approximately 10,000 km while a surrounding plasma sheet is thicker by a factor of ∼30. The field inside the HCS does not simply decrease to a null and then reappear with the opposite sense. Instead, the field rotates at nearly constant magnitude from one polarity to the other. In spite of theoretical expectations that fields on opposite sides of the HCS will merge or reconnect, there is little evidence that such is occurring. Many scientific questions remain unanswered. What are the global properties of the HCS near solar maximum, and how faithfully are they reproduced by source surface models? Are multiple HCS crossings caused by waves on the current sheet or by multiple current sheets? What is the effect of coronal mass ejections on the HCS and vice versa?
Rectal organoid-guided CFTR modulator therapy restores lung function in a cystic fibrosis patient with the rare 1677delTA/R334W genotype

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have revolutionised cystic fibrosis (CF) care, leading to significant improvements in lung function, decreased frequency of pulmonary exacerbations and improved quality of life [1]. The list of variants eligible for CFTR modulators has increased over time, currently covering almost 90% of individuals with CF in Caucasian populations. For rare and poorly characterised CF-causing variants, ex vivo analysis of intestinal organoids may assess CFTR function and guide personalised therapy [2, 3]. We report the case of an individual with CF whose rectal organoids were used to evaluate response to CFTR modulators and to guide therapeutic decision. Ex vivo analysis of intestinal organoids has great translational potential as a precision medicine tool for the prediction of clinical efficacy of CFTR modulators and, for patients with rare variants, may hold the key to these life-changing therapies http://bit.ly/3G1FkDp
Transpositions of the great arteries versus aortic dextropositions. A review of some embryogenetic and morphological aspects

This review examines and discusses the morphology and embryology of two main groups of conotruncal cardiac malformations: (a) transposition of the great arteries (complete transposition and incomplete/partial transposition namely double outlet right ventricle), and (b) aortic dextroposition defects (tetralogy of Fallot and Eisenmenger malformation). In both groups, persistent truncus arteriosus was included because maldevelopment of the neural crest cell supply to the outflow tract, contributing to the production of the persistent truncus arteriosus, is shared by both groups of malformations. The potentially important role of the proximal conal cushions in the rotatory sequence of the conotruncus is emphasized. Most importantly, this study emphasizes the differentiation between the double‐outlet right ventricle, which is a partial or incomplete transposition of the great arteries, and the Eisenmenger malformation, which is an aortic dextroposition. Special emphasis is also given to the leftward shift of the conoventricular junction, which covers an important morphogenetic role in both aortic dextropositions and transposition defects as well as in normal development, and whose molecular genetic regulation seems to remain unclear at present. Emphasis is placed on the distinct and overlapping roles of Tbx1 and Pitx2 transcription factors in modulating the development of the cardiac outflow tract.
Cultural influence on clock drawing test: A systematic review

Abstract Objective: Dementia among migrants is an emerging phenomenon worldwide and the development of neuropsychological tests sensitive to cultural differences is increasingly regarded as a priority. The Clock Drawing Test (CDT) is one of the most used screening tools for the detection of cognitive decline. Nevertheless, there is still a debate about its adoption as a cross-cultural assessment. Methods: To identify cultural variables influencing performance at CDT, we performed a systematic review of literature on three databases of all studies considering the role of at least one of the following: (1) language; (2) education; (3) literacy; (4) acculturation; and (5) ethnicity. Results: We extrapolated 160 analyses from 105 studies. Overall, an influence of cultural determinants on performance at CDT was found in 127 analyses (79.4%). Regarding specific cultural factors, 22 analyses investigated the effect of ethnicity on CDT scores, reporting conflicting results. Only two scoring systems turned out to be sufficiently accurate in a multicultural population. Language influenced performance in only 1 out of 8 analyses. A higher level of education positively influenced test performance in 118 out of 154 analyses (76.6%), and a better quality of education in 1 analysis out of 2. A negative influence of illiteracy on CDT performance emerged in 9 out of 10 analyses. Acculturation affected performances at CDT in 1 out of 2 studies. Conclusions: Based on the present findings, caution is needed when using CDT in a multicultural context, even if it requires limited linguistic competence.
Microenvironment‐Based Diabetic Foot Ulcer Nanomedicine

Diabetic foot ulcers (DFU), one of the most serious complications of diabetes, are essentially chronic, nonhealing wounds caused by diabetic neuropathy, vascular disease, and bacterial infection. Given its pathogenesis, the DFU microenvironment is rather complicated and characterized by hyperglycemia, ischemia, hypoxia, hyperinflammation, and persistent infection. However, the current clinical therapies for DFU are dissatisfactory, which drives researchers to turn attention to advanced nanotechnology to address DFU therapeutic bottlenecks. In the last decade, a large number of multifunctional nanosystems based on the microenvironment of DFU have been developed with positive effects in DFU therapy, forming a novel concept of “DFU nanomedicine”. However, a systematic overview of DFU nanomedicine is still unavailable in the literature. This review summarizes the microenvironmental characteristics of DFU, presents the main progress of wound healing, and summaries the state‐of‐the‐art therapeutic strategies for DFU. Furthermore, the main challenges and future perspectives in this field are discussed and prospected, aiming to fuel and foster the development of DFU nanomedicines successfully.
The Role of Preparedness for Caregiving on the Relationship Between Caregiver Distress and Potentially Harmful Behaviors

This work extends research suggesting a link between indicators of distress among informal caregivers (CG) (e.g., depression and burden), and potentially harmful behaviors (PHB), including feeling like yelling or screaming at the care recipient (CR). We tested three hypotheses regarding the role of a novel predictor, CG preparedness for caregiving, which were: 1) a direct effect between CG preparedness and PHB, 2) CG distress mediates the relationship between the direct effect of CG preparedness on PHB, and finally, 3) CG preparedness is only related to PHB through their shared associations with indicators of caregiver distress, an indirect effects model. Examining two indicators of PHB and CG depression and CG burden, results supported the indirect effects model. Higher CG preparedness was associated with lower CG distress, which in turn was associated with lower risk of PHB. These findings highlight the importance of CG preparedness as a target for caregiver intervention research.
Path Sampling Simulations Reveal How the Q61L Mutation Alters the Dynamics of KRas

Flexibility is essential for many proteins to function, but can be difficult to characterize. Experiments lack resolution in space and time, while the time scales involved are prohibitively long for straightforward molecular dynamics simulations. In this work, we present a multiple state transition path sampling simulation study of a protein that has been notoriously difficult to characterize in its active state. The GTPase enzyme KRas is a signal transduction protein in pathways for cell differentiation, growth, and division. When active, KRas tightly binds guanosine triphosphate (GTP) in a rigid state. The protein–GTP complex can also visit more flexible states, in which it is not active. KRas mutations can affect the conversion between these rigid and flexible states, thus prolonging the activation of signal transduction pathways, which may result in tumor formation. In this work, we apply path sampling simulations to investigate the dynamic behavior of KRas-4B (wild type, WT) and the oncogenic mutant Q61L (Q61L). Our results show that KRas visits several conformational states, which are the same for WT and Q61L. The multiple state transition path sampling (MSTPS) method samples transitions between the different states in a single calculation. Tracking which transitions occur shows large differences between WT and Q61L. The MSTPS results further reveal that for Q61L, a route to a more flexible state is inaccessible, thus shifting the equilibrium to more rigid states. The methodology presented here enables a detailed characterization of protein flexibility on time scales not accessible with brute-force molecular dynamics simulations.
Validation of the prognostic value of CD3 and CD8 cell densities analogous to the Immunoscore® by stage and location of colorectal cancer: an independent patient cohort study

In addition to the traditional staging system in colorectal cancer (CRC), the Immunoscore® has been proposed to characterize the level of immune infiltration in tumor tissue and as a potential prognostic marker. The aim of this study was to examine and validate associations of an immune cell score analogous to the Immunoscore® with established molecular tumor markers and with CRC patient survival in a routine setting. Patients from a population‐based cohort study with available CRC tumor tissue blocks were included in this analysis. CD3+ and CD8+ tumor infiltrating lymphocytes in the tumor center and invasive margin were determined in stained tumor tissue slides. Based on the T‐cell density in each region, an immune cell score closely analogous to the concept of the Immunoscore® was calculated and tumors categorized into IS‐low, IS‐intermediate, or IS‐high. Logistic regression models were used to assess associations between clinicopathological characteristics with the immune cell score, and Cox proportional hazards models to analyze associations with cancer‐specific, relapse‐free, and overall survival. From 1,535 patients with CRC, 411 (27%) had IS‐high tumors. Microsatellite instability (MSI‐high) was strongly associated with higher immune cell score levels (p < 0.001). Stage I–III patients with IS‐high had better CRC‐specific and relapse‐free survival compared to patients with IS‐low (hazard ratio [HR] = 0.42 [0.27–0.66] and HR = 0.45 [0.31–0.67], respectively). Patients with microsatellite stable (MSS) tumors and IS‐high had better survival (HRCSS = 0.60 [0.42–0.88]) compared to MSS/IS‐low patients. In this population‐based cohort of CRC patients, the immune cell score was significantly associated with better patient survival. It was a similarly strong prognostic marker in patients with MSI‐high tumors and in the larger group of patients with MSS tumors. Additionally, this study showed that it is possible to implement an analogous immune cell score approach and validate the Immunoscore® using open source software in an academic setting. Thus, the Immunoscore® could be useful to improve the traditional staging system in colon and rectal cancer used in clinical practice.
Implementation of a machine learning algorithm for automated thematic annotations in avatar: A linear support vector classifier approach

Avatar Therapy (AT) is a modern therapeutic alternative for patients with schizophrenia suffering from persistent auditory verbal hallucinations. Its intrinsic therapeutical process is currently qualitatively analyzed via human coders that annotate session transcripts. This process is time and resource demanding. This creates a need to find potential algorithms that can operate on small datasets and perform such annotations. The first objective of this study is to conduct the automated text classification of interactions in AT and the second objective is to assess if this classification is comparable to the classification done by human coders. A Linear Support Vector Classifier was implemented to perform automated theme classifications on Avatar Therapy session transcripts with the use of a limited dataset with an accuracy of 66.02% and substantial classification agreement of 0.647. These results open the door to additional research such as predicting the outcome of a therapy.
Prevention of bleomycin‐induced lung fibrosis via inhibition of the MRTF/SRF transcription pathway

Bleomycin‐induced lung fibrosis is a debilitating disease, linked to high morbidity and mortality in chemotherapy patients. The MRTF/SRF transcription pathway has been proposed as a potential therapeutic target, as it is critical for myofibroblast differentiation, a hallmark of fibrosis. In human lung fibroblasts, the MRTF/SRF pathway inhibitor, CCG‐257081, effectively decreased mRNA levels of downstream genes: smooth muscle actin and connective tissue growth factor, with IC50s of 4 and 15 μM, respectively. The ability of CCG‐257081 to prevent inflammation and fibrosis, measured via pulmonary collagen content and histopathology, was tested in a murine model of bleomycin‐induced lung fibrosis. Animals were given intraperitoneal bleomycin for 4 weeks and concurrently dosed with CCG‐257081 (0, 10, 30, and 100 mg/kg PO), a clinical anti‐fibrotic (nintedanib) or the clinical standard of care (prednisolone). Mice treated with 100 mg/kg CCG‐257081 gained weight vs. vehicle‐treated control mice, while those receiving nintedanib and prednisolone lost significant weight. Hydroxyproline content and histological findings in tissue of animals on 100 mg/kg CCG‐257081 were not significantly different from naive tissue, indicating successful prevention. Measures of tissue fibrosis were comparable between CCG‐257081 and nintedanib, but only the MRTF/SRF inhibitor decreased plasminogen activator inhibitor‐1 (PAI‐1), a marker linked to fibrosis, in bronchoalveolar lavage fluid. In contrast, prednisolone led to marked increases in lung fibrosis by all metrics. This study demonstrates the potential use of MRTF/SRF inhibitors to prevent bleomycin‐induced lung fibrosis in a clinically relevant model of the disease.
Preparation of targeted theranostic red blood cell membranes-based nanobubbles for treatment of colon adenocarcinoma

ABSTRACT Objectives Designing and fabrication of theranostic systems based on nanoscale gaseous vesicular systems, named nanobubbles (NBs), attracted enormous interest in recent years. Biomimetic vesicular platform (V-RBC-M) can improve the pharmacokinetics of the prepared platform due to augmented circulation half-life, desirable biodegradability and biocompatibility and reduced immunogenicity. Methods V-RBC-M were used for the encapsulation of lipophilic camptothecin (CPT) in the bilayer of vesicles through top-down method, followed by filling the core of V-RBC-M with inert SF6 gas to fabricate NBs with ultrasonic contrast enhancement capability (SF6-NB-CPT). In the next step, targeted NBs were formed via decoration of MUC1 aptamer on the surface of NBs (Apt-SF6-NB-CPT). Results The designed bio-NBs indicated high encapsulation efficiency and the sustained release of CPT at pH 7.4. In vitro study demonstrated higher cellular uptake and cytotoxicity of Apt-SF6-NB-CPT compared to SF6-NB-CPT in MUC1-overexpressing cells (C26). In vivo antitumor efficacy of the prepared NBs on C26 bearing BALB/c mice showed greater therapeutic efficacy and survival rate for Apt-SF6-NB-CPT. In this regard, SF6-NB-CPT showed 58% tumor growth suppression while Apt-SF6-NB-CPT system provided 95% tumor growth suppression. Furthermore, echogenic capability of SF6-NB-CPT was demonstrated through in vitro and in vivo ultrasonic imaging. Conclusions Our finding demonstrated that the prepared targeted NBs are a promising theranostic platform with effective therapeutic and diagnotic potentials. ABSTRACT
Quantum Moduli Spaces of Flat Connections

Using the formalism of discrete quantum group gauge theory, one can construct the quantum algebras of observables for the Hamiltonian Chern-Simons model. The resulting moduli algebras provide quantizations of the algebra of functions on the moduli spaces of flat connections on a punctured 2-dimensional surface. In this note we describe some features of these moduli algebras with special emphasis on the natural action of mapping class groups. This leads, in particular, to a closed formula for representations of the mapping class groups on conformal blocks.