Miracle-dz/UniFAR-FTUs huggingface dataset:
Low Basal CB2R in Dopamine Neurons and Microglia Influences Cannabinoid Tetrad Effects

There are two well-characterized cannabinoid receptors (CB1R and CB2R and other candidates): the central nervous system (CNS) enriched CB1R and peripheral tissue enriched CB2R with a wide dynamic range of expression levels in different cell types of human tissues. Hepatocytes and neurons express low baseline CB1R and CB2R, respectively, and their cell-type-specific functions are not well defined. Here we report inducible expression of CB1R in the liver by high-fat and high sugar diet and CB2R in cortical neurons by methamphetamine. While there is less controversy about hepatocyte CB1R, the presence of functional neuronal CB2R is still debated to date. We found that neuron CB2R basal expression was higher than that of hepatocyte CB1R by measuring mRNA levels of specific isoform CB2A in neurons isolated by fluorescence-activated cell sorting (FACS) and CB1A in hepatocytes isolated by collagenase perfusion of liver. For in vivo studies, we generated hepatocyte, dopaminergic neuron, and microglia-specific conditional knockout mice (Abl-Cnr1Δ, Dat-Cnr2Δ, and Cx3cr1-Cnr2Δ) of CB1R and CB2R by crossing Cnr1f/f and Cnr2f/f strains to Abl-Cre, Dat-Cre, and Cx3cr1-Cre deleter mouse strains, respectively. Our data reveals that neuron and microglia CB2Rs are involved in the “tetrad” effects of the mixed agonist WIN 55212-2, CB1R selective agonist arachidonyl-2′-chloroethylamide (ACEA), and CB2R selective agonist JWH133. Dat-Cnr2Δ and Cx3cr1-Cnr2Δ mice showed genotypic differences in hypomobility, hypothermia, analgesia, and catalepsy induced by the synthetic cannabinoids. Alcohol conditioned place preference was abolished in DAT-Cnr2Δ mice and remained intact in Cx3cr1-Cnr2Δ mice in comparison to WT mice. These Cre-loxP recombinant mouse lines provide unique approaches in cannabinoid research for dissecting the complex endocannabinoid system that is implicated in many chronic disorders.
Concept‐metacognition

Abstract Concepts are our tools for thinking. They enable us to engage in explicit reasoning about things in the world. Like physical tools, they can be more or less good, given the ways we use them—more or less dependable for categorisation, learning, induction, action‐planning, and so on. Do concept users appreciate, explicitly or implicitly, that concepts vary in dependability? Do they feel that some concepts are in some way defective? If so, we metacognise our concepts. This article offers a preliminary taxonomy of different forms of metacognition directed at concepts and suggests that concept‐metacognition impacts on several different cognitive processes.
Endothelial Progenitor Cells as a Potential Biomarker in Interstitial Lung Disease Associated with Rheumatoid Arthritis

Interstitial lung disease (ILD) increases morbidity and mortality in patients with rheumatoid arthritis (RA). Although the pathogenesis of ILD associated with RA (RA-ILD+) remains poorly defined, vascular tissue is crucial in lung physiology. In this context, endothelial progenitor cells (EPC) are involved in endothelial tissue repair. However, little is known about their implication in RA-ILD+. Accordingly, we aimed to investigate the potential role of EPC related to endothelial damage in RA-ILD+. EPC quantification in peripheral blood from 80 individuals (20 RA-ILD+ patients, 25 RA-ILD− patients, 21 idiopathic pulmonary fibrosis (IPF) patients, and 14 healthy controls) was performed by flow cytometry. EPC were considered as CD34+, CD45low, CD309+ and CD133+. A significant increase in EPC frequency in RA-ILD+ patients, as well as in RA-ILD− and IPF patients, was found when compared with controls (p < 0.001, p = 0.02 and p < 0.001, respectively). RA-ILD+ patients exhibited a higher EPC frequency than the RA-ILD− ones (p = 0.003), but lower than IPF patients (p < 0.001). Our results suggest that EPC increase may represent a reparative compensatory mechanism in patients with RA-ILD+. The degree of EPC frequency may help to identify the presence of ILD in RA patients and to discriminate RA-ILD+ from IPF.
HDL-Mediated Cholesterol Efflux and Plasma Loading Capacities Are Altered in Subjects with Metabolically- but Not Genetically Driven Non-Alcoholic Fatty Liver Disease (NAFLD)

Background. Non-alcoholic fatty liver disease (NAFLD) increases the risk of atherosclerosis but this risk may differ between metabolically- vs. genetically-driven NAFLD. High-density lipoprotein (HDL)-mediated cholesterol efflux (CEC) and plasma loading capacity (CLC) are key factors in atherogenesis. Aims. To test whether CEC and CLC differ between metabolically- vs. genetically-determined NAFLD. Methods: CEC and CLC were measured in 19 patients with metabolic NAFLD and wild-type PNPLA3 genotype (Group M), 10 patients with genetic NAFLD carrying M148M PNPLA3 genotype (Group G), and 10 controls PNPLA3 wild-types and without NAFLD. CEC and CLC were measured ex vivo by isotopic and fluorimetric techniques using cellular models. Results: Compared with Group G, Group M showed reduced total CEC (−18.6%; p < 0.001) as well as that mediated by cholesterol transporters (−25.3% ABCA1; −16.3% ABCG1; −14.8% aqueous diffusion; all p < 0.04). No difference in CEC was found between Group G and controls. The presence of metabolic syndrome further impaired ABCG1-mediated CEC in Group M. Group M had higher plasma-induced CLC than Group G and controls (p < 0.001). Conclusions: Metabolically-, but not genetically-, driven NAFLD associates with dysfunctional HDL-meditated CEC and abnormal CLC. These data suggest that the mechanisms of anti-atherogenic protection in metabolic NAFLD are impaired.
Dual TMPRSS2:ERG Fusion in a Patient with Lung and Prostate Cancers

The TMPRSS2:ERG fusion is considered prostate specific and has been rarely described in other tumors. We describe the case of a patient who developed lung and prostate cancers, both harboring the TMPRSS2:ERG fusion. The patient developed a cancer of the prostate with lymph node metastases and after two years a nodule of the thoracic wall. The histology and immunohistochemical profile of the two tumors were typical of prostate and lung cancers. The presence of the TMPRSS2:ERG fusion was demonstrated by next-generation sequencing on both malignancies, leading to the assumption that the lung nodule was a metastasis from the prostate cancer. The patient failed to respond to antiandrogen therapy, while chemotherapy for lung cancer led to a significant objective response. To our knowledge, this is the first case of a lung cancer harboring the TMPRSS2:ERG fusion, widening the spectrum of lung cancer-associated molecular alterations.
A Review of the Evidence for and against a Role for Mast Cells in Cutaneous Scarring and Fibrosis

Scars are generated in mature skin as a result of the normal repair process, but the replacement of normal tissue with scar tissue can lead to biomechanical and functional deficiencies in the skin as well as psychological and social issues for patients that negatively affect quality of life. Abnormal scars, such as hypertrophic scars and keloids, and cutaneous fibrosis that develops in diseases such as systemic sclerosis and graft-versus-host disease can be even more challenging for patients. There is a large body of literature suggesting that inflammation promotes the deposition of scar tissue by fibroblasts. Mast cells represent one inflammatory cell type in particular that has been implicated in skin scarring and fibrosis. Most published studies in this area support a pro-fibrotic role for mast cells in the skin, as many mast cell-derived mediators stimulate fibroblast activity and studies generally indicate higher numbers of mast cells and/or mast cell activation in scars and fibrotic skin. However, some studies in mast cell-deficient mice have suggested that these cells may not play a critical role in cutaneous scarring/fibrosis. Here, we will review the data for and against mast cells as key regulators of skin fibrosis and discuss scientific gaps in the field.
X-Ray Single-Grating Interferometry for Wavefront Measurement and Correction of Hard X-Ray Nanofocusing Mirrors

X-ray single-grating interferometry was applied to conduct accurate wavefront corrections for hard X-ray nanofocusing mirrors. Systematic errors in the interferometer, originating from a grating, a detector, and alignment errors of the components, were carefully examined. Based on the measured wavefront errors, the mirror shapes were directly corrected using a differential deposition technique. The corrected X-ray focusing mirrors with a numerical aperture of 0.01 attained two-dimensionally diffraction-limited performance. The results of the correction indicate that the uncertainty of the wavefront measurement was less than λ/72 in root-mean-square value.
Multi- and Single-Joint Resistance Exercises Promote Similar Plantar Flexor Activation in Resistance Trained Men

The present study aimed to compare soleus, lateral, and medial gastrocnemius muscles activation during leg press and calf raise exercises in trained men. The study involved 22 trained men (27.1 ± 3.6 years, 82.7 ± 6.6 kg, 177.5 ± 5.2 cm, 3.6 ± 1.4 experience years) who performed one set of each exercise using a 10-repetition maximum (10RM) load in a counterbalanced randomized order and separated by 10 min of rest. The electromyographic signal was measured for the three major plantar flexors: soleus, medial, and lateral gastrocnemius. A comparison between exercises showed that the mean adjusted by peak values during the leg press were 49.20% for the gastrocnemius lateralis, 51.31% for the gastrocnemius medialis, and 50.76% for the soleus. Values for calf raise were 50.70%, 52.19%, and 51.34% for the lateral, medial gastrocnemius, and soleus, respectively. There were no significant differences between exercises for any muscle (lateral gastrocnemius (p = 0.230), medial gastrocnemius (p = 0.668), and soleus (p = 0.535)). The present findings suggest that both leg press and calf raises can be used with the purpose to recruit triceps surae muscles. This bring the suggestion that one can chose between exercises based on personal preferences and practical aspects, without any negative impact on muscle activation.
Practical Aspects of Two-Dimensional Proton-Detected 15N Spin Relaxation Measurements

Abstract An investigation has been made into several aspects of the acquisition and processing of NMR data used to obtain heteronuclear relaxation parameters in proteins. Pulse sequences are described that reduce the time required to acquire relaxation data by a factor of two without sacrificing precision or accuracy of the results. In addition, a number of factors that influence the accuracy and precision of measured relaxation parameters, including uncertainties in peak intensities, overlap between resonances, and amide-proton exchange with solvent, are examined theoretically and experimentally. The results provide guidelines for maximizing the reliability of investigations of spin relaxation in proteins.
Nomogram Based on Risk Factors for Type 2 Diabetes Mellitus Patients with Coronary Heart Disease

Introduction This study aimed to study risk factors for coronary heart disease (CHD) in type 2 diabetes mellitus (T2DM) patients and establish a clinical prediction model. Research Design and Methods A total of 3402 T2DM patients were diagnosed by clinical doctors and recorded in the electronic medical record system (EMRS) of six Community Health Center Hospitals from 2015 to 2017, including the communities of Huamu, Jinyang, Yinhang, Siping, Sanlin and Daqiao. From September 2018 to September 2019, 3361 patients (41 patients were missing) were investigated using a questionnaire, physical examination, and biochemical index test. After excluding the uncompleted data, 3214 participants were included in the study and randomly divided into a training set (n = 2252) and a validation set (n = 962) at a ratio of 3:1. Through lead absolute shrinkage and selection operator (LASSO) regression analysis and logistic regression analysis of the training set, risk factors were determined and included in a nomogram. The C-index, receiver operating characteristic (ROC) curve, calibration plot and decision curve analysis (DCA) were used to validate the distinction, calibration and clinical practicality of the model. Results Age, T2DM duration, hypertension (HTN), hyperuricaemia (HUA), body mass index (BMI), glycosylated haemoglobin A1c (HbA1c), high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C) were significant factors in this study. The C-index was 0.750 (0.724–0.776) based on the training set and 0.767 (0.726–0.808) based on the validation set. Through ROC analysis, the set area was 0.750 for the training set and 0.755 for the validation set. The calibration test indicated that the S:P of the prediction model was 0.982 in the training set and 0.499 in the validation set. The decision curve analysis showed that the threshold probability of the model was 16–69% in the training set and 16–73% in the validation set. Conclusion Based on community surveys and data analysis, a prediction model of CHD in T2DM patients was established.
Histone Variant H3.3 Mutations in Defining the Chromatin Function in Mammals

The systematic mutation of histone 3 (H3) genes in model organisms has proven to be a valuable tool to distinguish the functional role of histone residues. No system exists in mammalian cells to directly manipulate canonical histone H3 due to a large number of clustered and multi-loci histone genes. Over the years, oncogenic histone mutations in a subset of H3 have been identified in humans, and have advanced our understanding of the function of histone residues in health and disease. The oncogenic mutations are often found in one allele of the histone variant H3.3 genes, but they prompt severe changes in the epigenetic landscape of cells, and contribute to cancer development. Therefore, mutation approaches using H3.3 genes could be relevant to the determination of the functional role of histone residues in mammalian development without the replacement of canonical H3 genes. In this review, we describe the key findings from the H3 mutation studies in model organisms wherein the genetic replacement of canonical H3 is possible. We then turn our attention to H3.3 mutations in human cancers, and discuss H3.3 substitutions in the N-terminus, which were generated in order to explore the specific residue or associated post-translational modification.
Ionic Environment Affects Biomolecular Interactions of Amyloid-β: SPR Biosensor Study

In early stages of Alzheimer’s disease (AD), amyloid beta (Aβ) accumulates in the mitochondrial matrix and interacts with mitochondrial proteins, such as cyclophilin D (cypD) and 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10). Multiple processes associated with AD such as increased production or oligomerization of Aβ affect these interactions and disbalance the equilibrium between the biomolecules, which contributes to mitochondrial dysfunction. Here, we investigate the effect of the ionic environment on the interactions of Aβ (Aβ1–40, Aβ1–42) with cypD and 17β-HSD10 using a surface plasmon resonance (SPR) biosensor. We show that changes in concentrations of K+ and Mg2+ significantly affect the interactions and may increase the binding efficiency between the biomolecules by up to 35% and 65% for the interactions with Aβ1–40 and Aβ1–42, respectively, in comparison with the physiological state. We also demonstrate that while the binding of Aβ1–40 to cypD and 17β-HSD10 takes place preferentially around the physiological concentrations of ions, decreased concentrations of K+ and increased concentrations of Mg2+ promote the interaction of both mitochondrial proteins with Aβ1–42. These results suggest that the ionic environment represents an important factor that should be considered in the investigation of biomolecular interactions taking place in the mitochondrial matrix under physiological as well as AD-associated conditions.
Data-Independent Acquisition for the Quantification and Identification of Metabolites in Plasma

A popular fragmentation technique for non-targeted analysis is called data-independent acquisition (DIA), because it provides fragmentation data for all analytes in a specific mass range. In this work, we demonstrated the strengths and weaknesses of DIA. Two types of chromatography (fractionation/3 min and hydrophilic interaction liquid chromatography (HILIC)/18 min) and three DIA protocols (variable sequential window acquisition of all theoretical mass spectra (SWATH), fixed SWATH and MSALL) were used to evaluate the performance of DIA. Our results show that fast chromatography and MSALL often results in product ion overlap and complex MS/MS spectra, which reduces the quantitative and qualitative power of these DIA protocols. The combination of SWATH and HILIC allowed for the correct identification of 20 metabolites using the NIST library. After SWATH window customization (i.e., variable SWATH), we were able to quantify ten structural isomers with a mean accuracy of 103% (91–113%). The robustness of the variable SWATH and HILIC method was demonstrated by the accurate quantification of these structural isomers in 10 highly diverse blood samples. Since the combination of variable SWATH and HILIC results in good quantitative and qualitative fragmentation data, it is promising for both targeted and untargeted platforms. This should decrease the number of platforms needed in metabolomics and increase the value of a single analysis.
Synthesis and Matrix Properties of α-Cyano-5-phenyl-2,4-pentadienic Acid (CPPA) for Intact Proteins Analysis by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry

The effectiveness of a synthesized matrix, α-cyano-5-phenyl-2,4-pentadienic acid (CPPA), for protein analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) in complex samples such as foodstuff and bacterial extracts, is demonstrated. Ultraviolet (UV) absorption along with laser desorption/ionization mass spectrometry (LDI-MS) experiments were systematically conducted in positive ion mode under standard Nd:YLF laser excitation with the aim of characterizing the matrix in terms of wavelength absorption and proton affinity. Besides, the results for standard proteins revealed that CPPA significantly enhanced the protein signals, reduced the spot-to-spot variability and increased the spot homogeneity. The CPPA matrix was successful employed to investigate intact microorganisms, milk and seed extracts for protein profiling. Compared to conventional matrices such as sinapinic acid (SA), α-cyano-4-hydroxycinnamic acid (CHCA) and 4-chloro-α-cyanocinnamic acid (CClCA), CPPA exhibited better signal-to-noise (S/N) ratios and a uniform response for most examined proteins occurring in milk, hazelnut and in intact bacterial cells of E. coli. These findings not only provide a reactive proton transfer MALDI matrix with excellent reproducibility and sensitivity, but also contribute to extending the battery of useful matrices for intact protein analysis.
Chromosome Instability in Fanconi Anemia: From Breaks to Phenotypic Consequences

Fanconi anemia (FA), a chromosomal instability syndrome, is caused by inherited pathogenic variants in any of 22 FANC genes, which cooperate in the FA/BRCA pathway. This pathway regulates the repair of DNA interstrand crosslinks (ICLs) through homologous recombination. In FA proper repair of ICLs is impaired and accumulation of toxic DNA double strand breaks occurs. To repair this type of DNA damage, FA cells activate alternative error-prone DNA repair pathways, which may lead to the formation of gross structural chromosome aberrations of which radial figures are the hallmark of FA, and their segregation during cell division are the origin of subsequent aberrations such as translocations, dicentrics and acentric fragments. The deficiency in DNA repair has pleiotropic consequences in the phenotype of patients with FA, including developmental alterations, bone marrow failure and an extreme risk to develop cancer. The mechanisms leading to the physical abnormalities during embryonic development have not been clearly elucidated, however FA has features of premature aging with chronic inflammation mediated by pro-inflammatory cytokines, which results in tissue attrition, selection of malignant clones and cancer onset. Moreover, chromosomal instability and cell death are not exclusive of the somatic compartment, they also affect germinal cells, as evidenced by the infertility observed in patients with FA.
Ethnicity-related DMD Genotype Landscapes in European and Non-European Countries

Genetic diagnosis and mutation identification are now compulsory for Duchenne (DMD) and Becker muscular dystrophies (BMD), which are due to dystrophin (DMD) gene mutations, either for disease prevention or personalized therapies. To evaluate the ethnic-related genetic assortments of DMD mutations, which may impact on DMD genetic diagnosis pipelines, we studied 328 patients with DMD and BMD from non-European countries.We performed a full DMD mutation detection in 328 patients from 10 Eastern European countries (Poland, Hungary, Lithuania, Romania, Serbia, Croatia, Bosnia, Bulgaria, Ukraine, and Russia) and 2 non-European countries (Cyprus and Algeria). We used both conventional methods (multiplex ligation-dependent probe amplification [MLPA] followed by gene-specific sequencing) and whole-exome sequencing (WES) as a pivotal study ran in 28 patients where DMD mutations were already identified by standard techniques. WES output was also interrogated for DMD gene modifiers.We identified DMD gene mutations in 222 male patients. We identified a remarkable allele heterogeneity among different populations with a mutation landscape often country specific. We also showed that WES is effective for picking up all DMD deletions and small mutations and its adoption could allow a detection rate close to 90% of all occurring mutations. Gene modifiers haplotypes were identified with some ethnic-specific configurations.Our data provide unreported mutation landscapes in different countries, suggesting that ethnicity may orient genetic diagnosis flowchart, which can be adjusted depending on the mutation type frequency, with impact in drug eligibility.