Miracle-dz/UniFAR-FTUs huggingface dataset:
Au2phen and Auoxo6, Two Dinuclear Oxo-Bridged Gold(III) Compounds, Induce Apoptotic Signaling in Human Ovarian A2780 Cancer Cells

Au2phen ((2,9-dimethyl-1,10-phenanthroline)2Au2(µ-O)2)(PF6)2 and Auoxo6 ((6,6′-dimethyl-2,2′-bipyridine)2Au2(µ-O)2)(PF6)2 are two structurally related gold(III) complexes that were previously reported to display relevant and promising anticancer properties in vitro toward a large number of human cancer cell lines. To expand the knowledge on the molecular mechanisms through which these gold(III) complexes trigger apoptosis in cancer cells, further studies have been performed using A2780 ovarian cancer cells as reference models. For comparative purposes, parallel studies were carried out on the gold(III) complex AuL12 (dibromo(ethylsarcosinedithiocarbamate)gold(III)), whose proapoptotic profile had been earlier characterized in several cancer cell lines. Our results pointed out that all these gold(III) compounds manifest a significant degree of similarity in their cellular and proapoptotic effects; the main observed perturbations consist of potent thioredoxin reductase inhibition, disruption of the cell redox balance, impairment of the mitochondrial membrane potential, and induction of associated metabolic changes. In addition, evidence was gained of the remarkable contribution of ASK1 (apoptosis-signal-regulating kinase-1) and AKT pathways to gold(III)-induced apoptotic signaling. Overall, the observed effects may be traced back to gold(III) reduction and subsequent formation and release of gold(I) species that are able to bind and inhibit several enzymes responsible for the intracellular redox homeostasis, in particular the selenoenzyme thioredoxin reductase.
Structural and Functional Alterations in Mitochondria-Associated Membranes (MAMs) and in Mitochondria Activate Stress Response Mechanisms in an In Vitro Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by the accumulation of extracellular plaques composed by amyloid-β (Aβ) and intracellular neurofibrillary tangles of hyperphosphorylated tau. AD-related neurodegenerative mechanisms involve early changes of mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) and impairment of cellular events modulated by these subcellular domains. In this study, we characterized the structural and functional alterations at MAM, mitochondria, and ER/microsomes in a mouse neuroblastoma cell line (N2A) overexpressing the human amyloid precursor protein (APP) with the familial Swedish mutation (APPswe). Proteins levels were determined by Western blot, ER-mitochondria contacts were quantified by transmission electron microscopy, and Ca2+ homeostasis and mitochondria function were analyzed using fluorescent probes and Seahorse assays. In this in vitro AD model, we found APP accumulated in MAM and mitochondria, and altered levels of proteins implicated in ER-mitochondria tethering, Ca2+ signaling, mitochondrial dynamics, biogenesis and protein import, as well as in the stress response. Moreover, we observed a decreased number of close ER-mitochondria contacts, activation of the ER unfolded protein response, reduced Ca2+ transfer from ER to mitochondria, and impaired mitochondrial function. Together, these results demonstrate that several subcellular alterations occur in AD-like neuronal cells, which supports that the defective ER-mitochondria crosstalk is an important player in AD physiopathology.
Effects of Ferulic Acid Supplementation on Growth Performance, Carcass Traits and Histochemical Characteristics of Muscle Fibers in Finishing Pigs

Simple Summary Different compounds with potential phytogenic activity are being studied in the feeding of monogastrics and ruminants. The present study evaluated the effect of ferulic acid (FA) dietary supplementation on the growth performance, carcass quality and histochemical characteristics of the Longissimus thoracis muscle from finishing pigs. The growth performance, carcass quality, histomorphometric characteristics, and histochemical characteristics of skeletal muscle were affected by FA supplementation. The addition of FA on diet improved average daily gain, 12th rib fat depth and Longissimus muscle area in the same way as ractopamine treatment. Histochemical analysis indicated that FA treatment induces a shift in muscle fiber, a lower cross-sectional area, and a greater number of muscle fibers per area. The findings indicate that ferulic acid supplementation without extra-lysine can replace the use of ractopamine as a growth promoter in finishing pigs. Abstract FA dietary supplementation on the growth performance, carcass traits and histochemical characteristics of the Longissimus thoracis muscle from finishing pigs was investigated. Four hundred and twenty pigs were used in this study, and 105 animals (with five replicate pens and 21 pigs per pen) were assigned to one of four treatments: basal diet (BD) without additives (C−); BD + 10 ppm ractopamine hydrochloride + 0.97% lysine (C+); BD + 25 ppm of FA (FA); and BD + 25 ppm of FA + 0.97% lysine (FA-Lys). Dietary supplementation with FA or ractopamine increased both the average daily gain (14%) and loin muscle area (19%), while fat deposition decreased by 53%, in comparison with C− (p < 0.05). The growth performance of pigs treated with FA was similar to those of ractopamine (p > 0.05). The histochemical analysis showed that FA and C+ treatments induced a shift in muscle fiber types: from fast fibers to intermediate (alkaline ATPase) and from oxidative to glycolytic fibers. Muscle tissues from animals treated with FA or ractopamine had a lower cross-sectional area and a greater number of muscle fibers per area (p < 0.05). Findings regarding growth performance and carcass traits indicate that FA supplementation at 25 ppm without extra-lysine can replace the use of ractopamine as a growth promoter in finishing pigs.
Identification of Potentially Related Genes and Mechanisms Involved in Skeletal Muscle Atrophy Induced by Excessive Exercise in Zebrafish

Simple Summary Excessive exercise can lead to muscle atrophy, which is particularly concerning in professional athletes. However, the effects of excessive exercise on the skeletal muscle system remain unclear. Here, we used a zebrafish model of excessive exercise to identify genes that are dysregulated during excessive exercise. We mapped the identified genes to regulatory networks to gain an understanding of their functions during muscle atrophy. We identified several important mechanisms by which excessive exercise can lead to muscle wasting and prevent regeneration. Our findings provide fundamental knowledge on the effect of overtraining on the skeletal muscle system, and will enable better monitoring of muscle condition in athletes. Abstract Long-term imbalance between fatigue and recovery may eventually lead to muscle weakness or even atrophy. We previously reported that excessive exercise induces pathological cardiac hypertrophy. However, the effect of excessive exercise on the skeletal muscles remains unclear. In the present study, we successfully established an excessive-exercise-induced skeletal muscle atrophy zebrafish model, with decreased muscle fiber size, critical swimming speed, and maximal oxygen consumption. High-throughput RNA-seq analysis identified differentially expressed genes in the model system compared with control zebrafish. Gene ontology and KEGG enrichment analysis revealed that the upregulated genes were enriched in autophagy, homeostasis, circadian rhythm, response to oxidative stress, apoptosis, the p53 signaling pathway, and the FoxO signaling pathway. Protein–protein interaction network analysis identified several hub genes, including keap1b, per3, ulk1b, socs2, esrp1, bcl2l1, hsp70, igf2r, mdm2, rab18a, col1a1a, fn1a, ppih, tpx2, uba5, nhlrc2, mcm4, tac1, b3gat3, and ddost, that correlate with the pathogenesis of skeletal muscle atrophy induced by excessive exercise. The underlying regulatory pathways and muscle-pressure-response-related genes identified in the present study will provide valuable insights for prescribing safe and accurate exercise programs for athletes and the supervision and clinical treatment of muscle atrophy induced by excessive exercise.
Transcriptome Analysis Identifies Doublesex and Mab-3 Related Transcription Factor (DMRT3) in Nasal Polyp Epithelial Cells of Patients Suffering from Non-Steroidal Anti-Inflammatory Drug-Exacerbated Respiratory Disease (AERD)

Background: Aspirin-exacerbated respiratory disease (AERD) is a syndrome characterised by chronic rhinosinusitis, nasal polyps, asthma and aspirin intolerance. An imbalance of eicosanoid metabolism with anover-production of cysteinyl leukotrienes (CysLTs) has been associated with AERD. However, the precise mechanisms underlying AERD are unknown. Objective: To establish the transcriptome of the nasal polyp airway epithelial cells derived from AERD patients to discover gene expression patterns in this disease. Methods: Nasal airway epithelial cells were isolated from 12 AERD polyps and 8 AERD non-polyp nasal mucosa samples as controls from the same subjects. Utilising the Illumina HiSeq 2500 platform, RNA samples were sequenced. Potential gene candidate DMRT3 was selected from the differentially-expressed genes for validation. Results: Comparative transcriptome profiling of nasal epithelial cells was accomplished in AERD. A total of 20 genes had twofold mean regulation expression differences or greater. In addition, 8 genes were upregulated, including doublesex and mab-3 related transcription factor 3 (DMRT3), and 12 genes were downregulated. Differentially regulated genes comprised roles in inflammation, defence and immunity. Metabolic process and embryonic development pathways were significantly enriched. Enzyme-linked immune sorbent assay (ELISA) results of DMRT3 in AERD patients were significantly upregulated compared to controls (p = 0.03). Immunohistochemistry (IHC) of AERD nasal polyps localised DMRT3 and was predominantly released in the airway epithelia. Conclusion: Findings suggest that DMRT3 could be potentially involved in nasal polyp development in AERD patients. Furthermore, several genes are downregulated, hinting at the dedifferentiation phenomenon in AERD polyps. However, further studies are imperative to confirm the exact mechanism of polyp formation in AERD patients.
Diagnostic Role of Diffusion-Weighted and Dynamic Contrast-Enhanced Perfusion MR Imaging in Paragangliomas and Schwannomas in the Head and Neck

DCE-MR imaging parameters identified significant statistical differences between schwannomas and paragangliomas with AUCs of 0.70–0.99, though no significant differences in ADC values were identified. Vp was the most promising parameter to differentiate the 2 tumor types. BACKGROUND AND PURPOSE: Distinguishing schwannomas from paragangliomas in the head and neck and determining succinate dehydrogenase (SDH) mutation status in paragangliomas are clinically important. We aimed to assess the clinical usefulness of DWI and dynamic contrast-enhanced MR imaging in differentiating these 2 types of tumors, as well as the SDH mutation status of paragangliomas. MATERIALS AND METHODS: This retrospective study from June 2016 to June 2020 included 42 patients with 15 schwannomas and 27 paragangliomas (10 SDH mutation-positive and 17 SDH mutation-negative). ADC values, dynamic contrast-enhanced MRI parameters, and tumor imaging characteristics were compared between the 2 tumors and between the mutation statuses of paragangliomas as appropriate. Multivariate stepwise logistic regression analysis was performed to identify significant differences in these parameters. RESULTS: Fractional plasma volume (P ≤ .001), rate transfer constant (P = .038), time-to-maximum enhancement (P < .001), maximum signal-enhancement ratio (P < .001) and maximum concentration of contrast agent (P < .001), velocity of enhancement (P = .002), and tumor characteristics including the presence of flow voids (P = .001) and enhancement patterns (P = .027) showed significant differences between schwannomas and paragangliomas, though there was no significant difference in ADC values. In the multivariate logistic regression analysis, fractional plasma volume was identified as the most significant value for differentiation of the 2 tumor types (P = .014). ADC values were significantly higher in nonhereditary than in hereditary paragangliomas, while there was no difference in dynamic contrast-enhanced MR imaging parameters. CONCLUSIONS: Dynamic contrast-enhanced MR imaging parameters show promise in differentiating head and neck schwannomas and paragangliomas, while DWI can be useful in detecting SDH mutation status in paragangliomas.
Sarcomeric deficits underlie MYBPC1-associated myopathy with myogenic tremor

Myosin binding protein-C slow (sMyBP-C) comprises a subfamily of cytoskeletal proteins encoded by MYBPC1 that is expressed in skeletal muscles where it contributes to myosin thick filament stabilization and actomyosin cross-bridge regulation. Recently, our group described the causal association of dominant missense pathogenic variants in MYBPC1 with an early-onset myopathy characterized by generalized muscle weakness, hypotonia, dysmorphia, skeletal deformities, and myogenic tremor, occurring in the absence of neuropathy. To mechanistically interrogate the etiologies of this MYBPC1-associated myopathy in vivo, we generated a knock-in mouse model carrying the E248K pathogenic variant. Using a battery of phenotypic, behavioral, and physiological measurements spanning neonatal to young adult life, we found that heterozygous E248K mice faithfully recapitulated the onset and progression of generalized myopathy, tremor occurrence, and skeletal deformities seen in human carriers. Moreover, using a combination of biochemical, ultrastructural, and contractile assessments at the level of the tissue, cell, and myofilaments, we show that the loss-of-function phenotype observed in mutant muscles is primarily driven by disordered and misaligned sarcomeres containing fragmented and out-of-register internal membranes that result in reduced force production and tremor initiation. Collectively, our findings provide mechanistic insights underscoring the E248K-disease pathogenesis and offer a relevant preclinical model for therapeutic discovery.
Endosomal Phosphatidylinositol-3-Phosphate-Associated Functions Are Dispensable for Establishment of the Cytomegalovirus Pre-Assembly Compartment but Essential for the Virus Growth

Murine cytomegalovirus (MCMV) initiates the stepwise establishment of the pre-assembly compartment (pre-AC) in the early phase of infection by the expansion of the early endosome (EE)/endosomal recycling compartment (ERC) interface and relocation of the Golgi complex. We depleted Vps34-derived phosphatidylinositol-3-phosphate (PI(3)P) at EEs by VPS34-IN1 and inhibited PI(3)P-associated functions by overexpression of 2xFYVE- and p40PX PI(3)P-binding modules to assess the role of PI(3)P-dependent EE domains in the pre-AC biogenesis. We monitored the accumulation of Rab10 and Evectin-2 in the inner pre-AC and the relocation of GM130-positive cis-Golgi organelles to the outer pre-AC by confocal microscopy. Although PI(3)P- and Vps34-positive endosomes build a substantial part of pre-AC, the PI(3)P depletion and the inhibition of PI(3)P-associated functions did not prevent the establishment of infection and progression through the early phase. The PI(3)P depletion in uninfected and MCMV-infected cells rapidly dispersed PI(3)P-bond proteins and reorganized EEs, including ablation of EE-to-ERC transport and relocation of Rab11 endosomes. The PI(3)P depletion one hour before pre-AC initiation and overexpression of 2xFYVE and p40PX domains neither prevented Rab10- and Evectin-2 accumulation, nor Golgi unlinking and relocation. These data demonstrate that PI(3)P-dependent functions, including the Rab11-dependent EE-to-ERC route, are dispensable for pre-AC initiation. Nevertheless, the virus growth was drastically reduced in PI(3)P-depleted cells, indicating that PI(3)P-associated functions are essential for the late phase of infection.
Psychological aspect of patients with inflammatory bowel disease, which may be related to the quality of life, sleep and disease characteristics

Abstract Objectives Inflammatory bowel disease (IBD) usually present with systemic and gastrointestinal problems. This may result in both physical and psychological burden. The aim of the study was to investigate the association between psychological burden and Health Related Quality of Life (HRQoL), sleep quality and disease characteristics. Methods A total of 106 patients and 165 general populations were enrolled in this study. The demographic information, disease characteristics of participants were investigated. The SCL-90 was self-administered to evaluate psychometric properties. SF-36 and IBDQ were both used to the assessment of HRQoL, and PSQI to quality of sleep. Results The SCL-90 score of IBD was significantly higher than that of the control (p = .0007), especially in somatization, anxiety, depression, hostility and psychosis dimensions. Similar to IBDQ (p < .0001), the results of SF-36 (p < .0001) showed that the HRQoL of both Ulcerative colitis (UC) and Crohn’s disease (CD) were somehow inferior to control. However, undifferentiated results were noted in patients between UC and CD. Good linear relationship between disease activity and SCL-90 (RUC = 0.53, pUC = .001; RCD = 0.36, pCD = .002), SF-36 (RUC = −0.42, pUC = .01; RCD = −0.49, pCD < .0001), IBDQ (RUC = −0.57, pUC = .0005; RCD = −0.52, pCD < .0001), PSQI (RUC = 0.50, pUC = .003; RCD = 0.27, pCD = .02) were observed. With the score of SCL-90 of patients increased, the SF-36 (R = −0.78, p < .0001) and IBDQ decreased (R = −0.74, p < .0001), PSQI increased (R = −0.70, p < .0001). Multiple stepwise regression analysis revealed that disease activity, extraintestinal manifestations, weight loss may contribute to identify the psychological anomalies. Conclusions Altered psychological status can be found in IBD, reflecting the necessity of providing psychological care for them. The disease itself results in lower HRQoL. Better HRQoL and sleep quality are in concordance with better psychological health.
Exploring possibilities for shortening the 22‐item Sino‐Nasal Outcome Test (SNOT‐22) using item response theory

Even with a high‐quality instrument, such as the 22‐item Sino‐Nasal Outcome Test (SNOT‐22), patients can be overwhelmed by repeated completion of questionnaires, leading to nonadherence and reduced data quality. The aim of this study was to evaluate whether the SNOT‐22 could be made more concise without losing the valuable information that it provides.
Large Platelet and Endothelial Extracellular Vesicles in Cord Blood of Preterm Newborns: Correlation with the Presence of Hemolysis

Different biomarkers are investigated to detect the causes of severe complications in preterm infants. Extracellular vesicles (EVs) are recognized as an important part of cell-to-cell communication, and their increased levels were reported in numerous pathological states. We aimed to increase our knowledge about the incidence of platelet and endothelial EVs in cord blood of preterm newborns using conventional flow cytometry. The presence of platelet (CD36+CD41+), activated platelet (CD41+CD62+), and endothelial (CD31+CD105+) EVs was analyzed. Immune electron microscopy was used to confirm the presence of EVs and the specificity of their labeling. The size of detected extracellular vesicles was in the range 400–2000 nm. The differences in the counts of EVs between the preterm and control group were not significant and no correlation of EVs count with gestation age was recorded. Cord blood plasma samples with free hemoglobin level > 1 mg/mL had more than threefold higher counts of CD36+CD41+ and CD41+CD62+ EVs (p < 0.001), while the count of CD31+CD105+ EVs was only moderately increased (p < 0.05). Further studies utilizing cytometers with improved sensitivity are needed to confirm that the analysis of large platelet and endothelial EVs mirrors the quantitative situation of their whole plasma assemblage.
Proteomic Analysis of Hydromethylthionine in the Line 66 Model of Frontotemporal Dementia Demonstrates Actions on Tau-Dependent and Tau-Independent Networks

Abnormal aggregation of tau is the pathological hallmark of tauopathies including frontotemporal dementia (FTD). We have generated tau-transgenic mice that express the aggregation-prone P301S human tau (line 66). These mice present with early-onset, high tau load in brain and FTD-like behavioural deficiencies. Several of these behavioural phenotypes and tau pathology are reversed by treatment with hydromethylthionine but key pathways underlying these corrections remain elusive. In two proteomic experiments, line 66 mice were compared with wild-type mice and then vehicle and hydromethylthionine treatments of line 66 mice were compared. The brain proteome was investigated using two-dimensional electrophoresis and mass spectrometry to identify protein networks and pathways that were altered due to tau overexpression or modified by hydromethylthionine treatment. Overexpression of mutant tau induced metabolic/mitochondrial dysfunction, changes in synaptic transmission and in stress responses, and these functions were recovered by hydromethylthionine. Other pathways, such as NRF2, oxidative phosphorylation and protein ubiquitination were activated by hydromethylthionine, presumably independent of its function as a tau aggregation inhibitor. Our results suggest that hydromethylthionine recovers cellular activity in both a tau-dependent and a tau-independent fashion that could lead to a wide-spread improvement of homeostatic function in the FTD brain.
A Simple Linear-Type Negative Permittivity Metamaterials Substrate Microstrip Patch Antenna

A microstrip patch antenna (MPA) loaded with linear-type negative permittivity metamaterials (NPMMs) is designed. The simple linear-type metamaterials have negative permittivity at 1–10 GHz. Four groups of antennas at different frequency bands are simulated in order to study the effect of linear-type NPMMs on MPA. The antennas working at 5.0 GHz are processed and measured. The measured results illustrate that the gain is enhanced by 2.12 dB, the H-plane half-power beam width (HPBW) is converged by 14°, and the effective area is increased by 62.5%. It can be concluded from the simulation and measurements that the linear-type metamaterials loaded on the substrate of MAP can suppress surface waves and increase forward radiation well.