Miracle-dz/UniFAR-FTUs huggingface dataset:
Hexavalent chromium promotes differential binding of CTCF to its cognate sites in Euchromatin

ABSTRACT Hexavalent chromium compounds are well-established respiratory carcinogens to which humans are commonly exposed in industrial and occupational settings. In addition, natural and anthropogenic sources of these compounds contribute to the exposure of global populations through multiple routes, including dermal, ingestion and inhalation that elevate the risk of cancer by largely unresolved mechanisms. Cr(VI) has genotoxic properties that include ternary adduct formation with DNA, increases in DNA damage, mostly by double-strand break formation, and altered transcriptional responses. Our previous work using ATAC-seq showed that CTCF motifs were enriched in Cr(VI)-dependent differentially accessible chromatin, suggesting that CTCF, a key transcription factor responsible for the regulation of the transcriptome, might be a chromium target. To test this hypothesis, we investigated the effect of Cr(VI) treatment on the binding of CTCF to its cognate sites and ensuing changes in transcription-related histone modifications. Differentially bound CTCF sites were enriched by Cr(VI) treatment within transcription-related regions, specifically transcription start sites and upstream genic regions. Functional annotation of the affected genes highlighted biological processes previously associated with Cr(VI) exposure. Notably, we found that differentially bound CTCF sites proximal to the promoters of this subset of genes were frequently associated with the active histone marks H3K27ac, H3K4me3, and H3K36me3, in agreement with the concept that Cr(VI) targets CTCF in euchromatic regions of the genome. Our results support the conclusion that Cr(VI) treatment promotes the differential binding of CTCF to its cognate sites in genes near transcription-active boundaries, targeting these genes for dysregulation.
Convalescent plasma treatment of persistent severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection in patients with lymphoma with impaired humoral immunity and lack of neutralising antibodies

Bruno M egarbane Alain St epanian Department of Hematology, Lariboisi ere Hospital, Paris University, EA 3518, Paris University, INSERM, UMRS 1140, Paris University, Department of Internal Medicine, Lariboisi ere Hospital, Paris University, Department of Anesthesiology and Critical Care, Lariboisi ere Hospital, Paris University, INSERM, UMRS 942, Universit e de Paris, Department of Medical and Toxicological Critical Care, Lariboisi ere Hospital, Paris University, INSERM, UMRS 1144, Paris University, Department of Clinical Physiology, Lariboisi ere Hospital, Paris University, INSERM U1265, INSERM, Universit e de Paris and INSERM U1148-Laboratory for Vascular and Translational Science, Universit e de Paris, Paris, France. E-mail: alain.stepanian@aphp.fr
Efficacy of Nilotinib in Patients With Moderately Advanced Parkinson Disease

Key Points Question Do the safety, tolerability, exploratory clinical outcomes, brain penetration, and biomarker profile of nilotinib in aggregate support its development for treatment of Parkinson disease (PD)? Findings In this 6-month, multicenter, randomized placebo-controlled clinical trial of 76 participants with moderately advanced PD, nilotinib at 150-mg and 300-mg daily doses met prespecified safety and tolerability criteria. There was no evidence of symptomatic benefit of nilotinib on any measures of PD disability and there was trend toward worsening in the motor function in active treatment arms; in the cerebrospinal fluid, nilotinib level was less than 0.3% of that in the serum and failed to change dopamine metabolites levels. Meaning While nilotinib demonstrated acceptable safety and tolerability in this cohort, the low cerebrospinal fluid exposure, lack of biomarkers effects, and efficacy data trending in the negative direction indicate that further testing of nilotinib in treatment of Parkinson disease is not warranted.
Acute disseminated encephalomyelitis (ADEM) associated with COVID-19

A 53-year-old man admitted to the critical care secondary to respiratory failure due to COVID-19 developed agitation and global hypotonia. Brain MRI revealed bilateral hyperintense lesions throughout the brain and cerebrospinal fluid identified oligoclonal bands. Intravenous high-dose glucocorticoids were administered followed by an oral tapering dose and the patient clinically improved. Acute disseminated encephalomyelitis should be considered in patients with COVID-19 who present with altered mentation and polyfocal neurological deficits.
The evolution of age‐specific choosiness when mating

Mate choice is a crucial element of many processes in evolutionary biology. Empirical research has shown that mating preference and choosiness often change with age. Understanding the evolutionary causes of patterns of age‐specific choosiness is challenging because different mechanisms can give rise to the same pattern. Instead of focusing on the optimal age‐specific choosiness strategy given fitness trade‐offs, we approach this question from a more general standpoint and ask how the strength of selection on choosiness changes with the age at which it is expressed. We show that the strength of selection on a modifier of choosiness at a given age depends on the relative contribution of this age class to the pool of offspring but does not depend directly on the strength of selection on fitness components at the age affected by the modifier. We illustrate our results by contrasting two life histories from the literature. We further show how mutation–selection balance at the choosiness locus can shape age‐specific choosiness. Our results provide new insights for understanding the evolution of choosiness throughout life, with implications for understanding the evolution of mate choice and reproductive isolation.
Pyridoxal kinase inhibition by artemisinins down-regulates inhibitory neurotransmission

Significance Information processing in the central nervous system relies on chemical synapses where neurotransmitters such as the inhibitory neurotransmitter γ-aminobutyric acid (GABA) are released at presynaptic nerve endings. GABA is synthesized by glutamic acid decarboxylase (GAD), an enzyme requiring pyridoxal 5'-phosphate (PLP or vitamin B6) as cofactor, the latter being synthesized by pyridoxal kinase (PDXK). Here, we show that the antimalarial drug artemisinin inhibits PDXK and describe the structural basis of this inhibition. The decrease in PLP production reduces the amount of GABA being produced, which, in turn, impacts the efficacy of GABAergic transmission. This study combined with our previous data sheds light on how artemisinins can influence inhibitory synaptic transmissions both presynaptically, as described here, and postsynaptically. The antimalarial artemisinins have also been implicated in the regulation of various cellular pathways including immunomodulation of cancers and regulation of pancreatic cell signaling in mammals. Despite their widespread application, the cellular specificities and molecular mechanisms of target recognition by artemisinins remain poorly characterized. We recently demonstrated how these drugs modulate inhibitory postsynaptic signaling by direct binding to the postsynaptic scaffolding protein gephyrin. Here, we report the crystal structure of the central metabolic enzyme pyridoxal kinase (PDXK), which catalyzes the production of the active form of vitamin B6 (also known as pyridoxal 5′-phosphate [PLP]), in complex with artesunate at 2.4-Å resolution. Partially overlapping binding of artemisinins with the substrate pyridoxal inhibits PLP biosynthesis as demonstrated by kinetic measurements. Electrophysiological recordings from hippocampal slices and activity measurements of glutamic acid decarboxylase (GAD), a PLP-dependent enzyme synthesizing the neurotransmitter γ-aminobutyric acid (GABA), define how artemisinins also interfere presynaptically with GABAergic signaling. Our data provide a comprehensive picture of artemisinin-induced effects on inhibitory signaling in the brain.
Embedding Perspective Analysis Into Multi-Column Convolutional Neural Network for Crowd Counting

The crowd counting is challenging for deep networks due to several factors. For instance, the networks can not efficiently analyze the perspective information of arbitrary scenes, and they are naturally inefficient to handle the scale variations. In this work, we deliver a simple yet efficient multi-column network, which integrates the perspective analysis method with the counting network. The proposed method explicitly excavates the perspective information and drives the counting network to analyze the scenes. More concretely, we explore the perspective information from the estimated density maps and quantify the perspective space into several separate scenes. We then embed the perspective analysis into the multi-column framework with a recurrent connection. Therefore, the proposed network matches various scales with the different receptive fields efficiently. Secondly, we share the parameters of the branches with various receptive fields. This strategy drives the convolutional kernels to be sensitive to the instances with various scales. Furthermore, to improve the evaluation accuracy of the column with a large receptive field, we propose a transform dilated convolution. The transform dilated convolution breaks the fixed sampling structure of the deep network. Moreover, it needs no extra parameters and training, and the offsets are constrained in a local region, which is designed for the congested scenes. The proposed method achieves state-of-the-art performance on five datasets (ShanghaiTech, UCF CC 50, WorldEXPO’10, UCSD, and TRANCOS).
Targeted Therapy of TERT-Rearranged Neuroblastoma with BET Bromodomain Inhibitor and Proteasome Inhibitor Combination Therapy

Purpose: TERT gene rearrangement with transcriptional superenhancers leads to TERT overexpression and neuroblastoma. No targeted therapy is available for clinical trials in patients with TERT-rearranged neuroblastoma. Experimental Design: Anticancer agents exerting the best synergistic anticancer effects with BET bromodomain inhibitors were identified by screening an FDA-approved oncology drug library. The synergistic effects of the BET bromodomain inhibitor OTX015 and the proteasome inhibitor carfilzomib were examined by immunoblot and flow cytometry analysis. The anticancer efficacy of OTX015 and carfilzomib combination therapy was investigated in mice xenografted with TERT-rearranged neuroblastoma cell lines or patient-derived xenograft (PDX) tumor cells, and the role of TERT reduction in the anticancer efficacy was examined through rescue experiments in mice. Results: The BET bromodomain protein BRD4 promoted TERT-rearranged neuroblastoma cell proliferation through upregulating TERT expression. Screening of an approved oncology drug library identified the proteasome inhibitor carfilzomib as the agent exerting the best synergistic anticancer effects with BET bromodomain inhibitors including OTX015. OTX015 and carfilzomib synergistically reduced TERT protein expression, induced endoplasmic reticulum stress, and induced TERT-rearranged neuroblastoma cell apoptosis which was blocked by TERT overexpression and endoplasmic reticulum stress antagonists. In mice xenografted with TERT-rearranged neuroblastoma cell lines or PDX tumor cells, OTX015 and carfilzomib synergistically blocked TERT expression, induced tumor cell apoptosis, suppressed tumor progression, and improved mouse survival, which was largely reversed by forced TERT overexpression. Conclusions: OTX015 and carfilzomib combination therapy is likely to be translated into the first clinical trial of a targeted therapy in patients with TERT-rearranged neuroblastoma.
Genealogy and clinical course of catecholaminergic polymorphic ventricular tachycardia caused by the ryanodine receptor type 2 P2328S mutation

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited arrhythmic disease associated with a risk of syncope and sudden cardiac death (SCD). Aims We aimed at identifying RYR2 P2328S founder mutation carriers and describing the clinical course associated with the mutation. Methods The study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry, and from the present genealogical study. Kaplan-Meier graphs, log-rank test and Cox regression model were used to evaluate the clinical course. Results Genealogical study revealed a common ancestor couple living in the late 17th century. A total of 1837 living descendants were tested for RYR2 P2328S mutation unveiling 62 mutation carriers aged mean 39±23 years old. No arrhythmic deaths were documented among genotyped subjects, but 11 SCDs were detected in non-genotyped family members since 1970. Three genotyped patients (5%) suffered an aborted cardiac arrest (ACA), and 15 (25%) had a syncope triggered by exercise or stress. Rate of cardiac events was higher among patients who in exercise stress test showed a maximum rate of premature ventricular contractions >30/min (68% vs 17%, p<0.01; hazard ratio = 7.1, p = 0.02), in comparison to patients without the respective finding. A cardioverter-defibrillator (ICD) was implanted to 13 (22%) patients, with an appropriate ICD shock in four (31%) subjects. All ICD shocks, one ACA, and one syncope occurred during β-blocker medication. Conclusions Previously undiagnosed CPVT patients may be identified by well-conducted genealogical studies. The RYR2 P2328S mutation causes a potentially severe phenotype, but its expression is variable, thus calling for additional studies on modifying factors.
Diagnostic Value of Contrast-Enhanced Ultrasonography With SonoVue in the Differentiation of Benign and Malignant Breast Lesions: A Meta-Analysis

Purpose: A meta-analysis was conducted to evaluate the diagnostic performance of contrast-enhanced ultrasonography using the contrast agent SonoVue to differentiate benign from malignant breast lesions. Method: A comprehensive search of the literature was performed using the Embase, PubMed, and Web of Science databases to retrieve studies published before February 2020. Data were extracted, and pooled sensitivity, specificity, and diagnostic odds ratios were calculated with meta-analysis software. Heterogeneity was evaluated via the Q test and I2 statistic. Meta-regression and subgroup analyses were applied to evaluate potential sources of heterogeneity. Publication bias was assessed using the Deeks’ funnel plot asymmetry test. A summary receiver operating characteristic curve (SROC) was constructed. Results: A total of 27 studies including 5378 breast lesions subjected to CEUS examination with SonoVue were included in the meta-analysis. The pooled sensitivity and specificity values were 0.90 (95% confidence interval [CI], 0.88–0.91; inconsistency index [I2 ] = 75.7%) and 0.83 (95% CI, 0.82–0.85; I2 = 91.0%), respectively. The pooled diagnostic odds ratio was 48.35% (95% CI, 31.22–74.89; I2 = 77.6%). The area under the summary receiver operating characteristic curve (AUC) was 0.9354. Meta-regression analysis revealed the region of patient residence and dose of contrast agent as potential sources of heterogeneity (P < .01). Subgroup analysis showed a higher area under the summary receiver operating characteristic curve for European and higher contrast agent dose subgroups (P < .05). Conclusion: Contrast-enhanced ultrasonography with SonoVue displays high sensitivity, specificity, and accuracy when differentiating benign from malignant breast lesions. Despite its current limitations, this technique presents a promising tool for diagnosing breast lesions in clinical practice.
Comparison of several lime requirement methods for agricultural soils in Pennsylvania

Abstract Two new double‐buffer methods have been proposed recently by Yuan and McLean, et al. to more accurately predict the lime requirement (L.R.) in sandy, low buffer capacity soils and in low L.R. soils respectively. The L.R. of 20 typical acid agricultural soils in Pennsylvania were determined by a 6 month incubation with a series of CaCO3 concentrations. These incubation L.R. values were then compared with the two double buffer methods as well as the more established SMP, Woodruff, Adams‐Evans, BaCl2 triethanol amine (BaCl2‐TEA) and Ca(OH)2 titration methods to determine which of these methods most accurately predicted the true, (CaCO3‐incubation), L.R. of these soils. All methods were very well correlated with the incubation L.R. (r = 0.919 to 0.987) but only the SMP single buffer was reasonably accurate in predicting the incubation L.R. for both low and high L.R. soils. A modification in recomnendation was proposed to eliminate the slight SMP underestimation of L.R. for low L.R. soils. The two dou.
Folfirinox versus gemcitabine-cisplatin combination as first-line therapy in treatment of pancreaticobiliary cancer

Background/aim The purpose of this study was to compare efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine-cisplatin as first-line therapy in patients with pancreatic cancer. Materials and methods Pancreaticobiliary cancer patients who had Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating greater severity of illness) were evaluated to receive folfirinox or gemcitabine plus cisplatin. The primary endpoints were progression-free and overall survival time. Safety analysis was also evaluated as secondary measures. Results There were 32 patients in the folfirinox group and 36 patients in the gemcitabine-cisplatin group. The median overall survival was 18.1 months (7.5–28.7) in the folfirinox group as compared with 9.7 months (6.5–13) in the gemcitabine-cisplatin group (p = 0.009). Median progression-free survival was 16.2 months (9–23.4) in the folfirinox group and 6.9 months (6.1–7.6) in the gemcitabine-cisplatin group (p = 0.001). Conclusion Folfirinox is an option for the first-line treatment of patients with pancreatic cancer and good performance status.
Development and Validation of an In Vitro Resazurin-Based Susceptibility Assay against Madurella mycetomatis

We present an in vitro susceptibility assay for Madurella mycetomatis hyphae using resazurin for endpoint reading. Using this assay, reproducible MICs were obtained for amphotericin B, itraconazole, voriconazole, posaconazole, terbinafine, and micafungin. ABSTRACT We present an in vitro susceptibility assay for Madurella mycetomatis hyphae using resazurin for endpoint reading. Using this assay, reproducible MICs were obtained for amphotericin B, itraconazole, voriconazole, posaconazole, terbinafine, and micafungin. Results were comparable with those of a 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide salt (XTT)-based susceptibility assay. The lowest MICs were obtained for itraconazole and posaconazole (MIC50, 0.016 µg/ml) followed by voriconazole (MIC50, 0.063 µg/ml). Amphotericin B, micafungin, and terbinafine appeared much less effective.
Some characteristic phenomena in a transverse Ising nanotube

The phase diagram and magnetizations of a cylindrical nanotube described by the transverse Ising model are investigated by the use of the effective field theory with correlations. Some comparisons between the nanotube and the nanowire have been given for the phase diagrams. In particular, the temperature dependences of longitudinal magnetization in the system with a negative shell–core interaction are investigated. Some characteristic phenomena (new types in ferrimagnetism) which have not been observed in the nanowire as well as similar phenomena are found in the thermal variations, depending on the ratio of the physical parameters in the surface shell and the core. The possibilities of two compensation points and a field induced compensation point in the nanotube are also discussed.
Prediction of Cardiovascular Events by Type I Central Systolic Blood Pressure

Supplemental Digital Content is available in the text. Compared with brachial blood pressure (BP), central systolic BP (SBP) can provide a better indication of the hemodynamic strain inflicted on target organs, but it is unclear whether this translates into improved cardiovascular risk stratification. We aimed to assess which of central or brachial BP best predicts cardiovascular risk and to identify the central SBP threshold associated with increased risk of future cardiovascular events. This study included 13 461 participants of CARTaGENE with available central BP and follow-up data from administrative databases but without cardiovascular disease or antihypertensive medication. Central BP was estimated by radial artery tonometry, calibrated for brachial SBP and diastolic BP (type I), and a generalized transfer function (SphygmoCor). The outcome was major adverse cardiovascular events. Cox proportional-hazards models, differences in areas under the curves, net reclassification indices, and integrated discrimination indices were calculated. Youden index was used to identify SBP thresholds. Over a median follow-up of 8.75 years, 1327 major adverse cardiovascular events occurred. The differences in areas under the curves, net reclassification indices, and integrated discrimination indices were of 0.2% ([95% CI, 0.1–0.3] P<0.01), 0.11 ([95% CI, 0.03–0.20] P=0.01), and 0.0004 ([95% CI, −0.0001 to 0.0014] P=0.3), all likely not clinically significant. Central and brachial SBPs of 112 mm Hg (95% CI, 111.2–114.1) and 121 mm Hg (95% CI, 120.2–121.9) were identified as optimal BP thresholds. In conclusion, central BP measured with a type I device is statistically but likely not clinically superior to brachial BP in a general population without prior cardiovascular disease. Based on the risk of major adverse cardiovascular events, the optimal type I central SBP appears to be 112 mm Hg.
Co-Cu Metal Alloys from LaCo1-xCuxO3 Perovskites as Catalysts for Higher Alcohol Synthesis from Syngas

The specific surface area of ground perovskites is strongly dependent on the synthesis and pretreatment conditions. Calcining the ground LaCo1-xCuxO3-? perovskites at 5000C causes a decrease of their specific surface, but the further reductive pretreatment of the calcined sample in hydrogen leads to only a minor change in the specific surface area.The introduction of extra- and intra-perovskite lattice copper has different effects on the structure stability, reducibility and catalytic properties of LaCoO3 perovskites. Under the same pretreatment conditions the basic structure of both LaCoO3 and Cu2O/LaCoO3 samples is retained at the reduction temperature of 5000C (90 min) while that of Co-Cu based perovskites is completely collapsed producing a high dispersion of bimetallic metals and Co-Cu alloys supported on amorphous La2O3. For a series of LaCo1-xCuxO3 samples, increasing the copper content in the perovskite structure leads to an increase in the metal surface area of the reduced phase. The pretreated catalysts were tested for CO dissociation and for alcohol synthesis from syngas. The results indicated that the copper sites neighboring with cobalt atoms in the reduced perovskites decrease the activity in CO dissociation and increase the rate of higher alcohol synthesis while extra-perovkite lattice copper tends to produce methanol, methane and CO2. The overall activity in syngas conversion and higher alcohol productivity are proportional to the Co-Cu metal surface. The role of dual sites of Co and Cu for the synthesis of higher alcohols is discussed. The catalytic activity and alcohol productivity as well as product distribution depend strongly on reaction temperature and pretreatment conditions. The highest productivity of alcohols in the present study is about 73 mg/gcat/h for sample LaCo0.7Cu0. 3O3.