Miracle-dz/UniFAR-FTUs huggingface dataset:
Re-Evaluating the Oxidative Phenotype: Can Endurance Exercise Save the Western World?

Mitochondria are popularly called the “powerhouses” of the cell. They promote energy metabolism through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, which in contrast to cytosolic glycolysis are oxygen-dependent and significantly more substrate efficient. That is, mitochondrial metabolism provides substantially more cellular energy currency (ATP) per macronutrient metabolised. Enhancement of mitochondrial density and metabolism are associated with endurance training, which allows for the attainment of high relative VO2 max values. However, the sedentary lifestyle and diet currently predominant in the Western world lead to mitochondrial dysfunction. Underdeveloped mitochondrial metabolism leads to nutrient-induced reducing pressure caused by energy surplus, as reduced nicotinamide adenine dinucleotide (NADH)-mediated high electron flow at rest leads to “electron leak” and a chronic generation of superoxide radicals (O2−). Chronic overload of these reactive oxygen species (ROS) damages cell components such as DNA, cell membranes, and proteins. Counterintuitively, transiently generated ROS during exercise contributes to adaptive reduction-oxidation (REDOX) signalling through the process of cellular hormesis or “oxidative eustress” defined by Helmut Sies. However, the unaccustomed, chronic oxidative stress is central to the leading causes of mortality in the 21st century—metabolic syndrome and the associated cardiovascular comorbidities. The endurance exercise training that improves mitochondrial capacity and the protective antioxidant cellular system emerges as a universal intervention for mitochondrial dysfunction and resultant comorbidities. Furthermore, exercise might also be a solution to prevent ageing-related degenerative diseases, which are caused by impaired mitochondrial recycling. This review aims to break down the metabolic components of exercise and how they translate to athletic versus metabolically diseased phenotypes. We outline a reciprocal relationship between oxidative metabolism and inflammation, as well as hypoxia. We highlight the importance of oxidative stress for metabolic and antioxidant adaptation. We discuss the relevance of lactate as an indicator of critical exercise intensity, and inferring from its relationship with hypoxia, we suggest the most appropriate mode of exercise for the case of a lost oxidative identity in metabolically inflexible patients. Finally, we propose a reciprocal signalling model that establishes a healthy balance between the glycolytic/proliferative and oxidative/prolonged-ageing phenotypes. This model is malleable to adaptation with oxidative stress in exercise but is also susceptible to maladaptation associated with chronic oxidative stress in disease. Furthermore, mutations of components involved in the transcriptional regulatory mechanisms of mitochondrial metabolism may lead to the development of a cancerous phenotype, which progressively presents as one of the main causes of death, alongside the metabolic syndrome.
Analysis of Intra-Tumoral Macrophages and T Cells in Non-Small Cell Lung Cancer (NSCLC) Indicates a Role for Immune Checkpoint and CD200-CD200R Interactions

Simple Summary Lung cancer is the leading cause of cancer-related death worldwide, accounting for nearly one-fifth of all cancer-related deaths. Immunotherapy with immune checkpoint inhibitors has become one of the most promising approaches in the treatment of advanced lung cancer, although beneficial responses are seen only in a proportion of patients. To improve immunotherapy treatment responses in lung cancer, we need to identify which immunosuppression mechanisms are activated in the tumor microenvironment. In this study, we investigated gene expression profiles in intra-tumoral immune cells in lung cancer, focusing on tumor-associated macrophages, and interactions with CD4+ and CD8+ T cells. Our data highlight two newly described immunosuppressive pathways, which may represent novel innate immune checkpoints dampening the anti-tumor T cell immune response in lung cancer. Our results substantiate the importance of tumor-associated macrophages as a mediator of immunosuppression and a promising target for immunotherapy. Abstract Non-small cell lung carcinoma (NSCLC) is one of the most commonly diagnosed cancers and a leading cause of cancer-related deaths. Immunotherapy with immune checkpoint inhibitors shows beneficial responses, but only in a proportion of patients. To improve immunotherapy in NSCLC, we need to map the immune checkpoints that contribute immunosuppression in NSCLC-associated immune cells and to identify novel pathways that regulate immunosuppression. Here, we investigated the gene expression profiles of intra-tumoral immune cells isolated from NSCLC patients and compared them to the expression profiles of their counterparts in adjacent healthy tissue. Transcriptome analysis was performed on macrophages, CD4+ and CD8+ T cells. The data was subjected to Gene Ontology (GO) term enrichment and weighted correlation network analysis in order to identify mediators of immunosuppression in the tumor microenvironment in NSCLC. Immune cells from NSCLC revealed a consistent differential expression of genes involved in interactions between myeloid cells and lymphocytes. We further identified several immunosuppressive molecules and pathways that may be activated in tumor-associated macrophages in NSCLC. Importantly, we report novel data on immune cell expression of the newly described CD200/CD200R1 pathway, and the leukocyte immunoglobulin-like receptors (LILRs), which may represent novel innate immune checkpoints, dampening the anti-tumor T cell immune response in NSCLC. Our study substantiates the importance of tumor-associated macrophages as a mediator of immunosuppression and a promising target for immunotherapy.
Breakfast and Exercise Improve Academic and Cognitive Performance in Adolescents

This study examined the combined effects of breakfast and exercise on short-term academic and cognitive performance in adolescents. Eighty-two adolescents (64 female), aged 14–19 years, were randomized to four groups over a 4-hour morning: (i) a group who fasted and were sedentary (F-S); (ii) a group who ate breakfast but were sedentary (B-S); (iii) a group who fasted but completed a 30-min exercise bout (F-E); and (iv) a group who ate breakfast and completed a 30-min exercise bout (B-E). Individuals completed academic and cognitive tests over the morning. Adolescents in B-E significantly improved their mathematics score (B-E: 15.2% improvement on correct answers, vs. F-S: 6.7% improvement on correct answers; p = 0.014) and computation time for correct answers (B-E: 16.7% improvement, vs. F-S: 7.4% improvement; p = 0.004) over the morning compared with the F-S group. The B-E group had faster reaction times for congruent, incongruent and control trials of the Stroop Color-Word Task compared with F-S mid-morning (all p < 0.05). Morning breakfast and exercise combine to improve short-term mathematical task performance and speed in adolescents.
DNA2 in Chromosome Stability and Cell Survival—Is It All about Replication Forks?

The conserved nuclease-helicase DNA2 has been linked to mitochondrial myopathy, Seckel syndrome, and cancer. Across species, the protein is indispensable for cell proliferation. On the molecular level, DNA2 has been implicated in DNA double-strand break (DSB) repair, checkpoint activation, Okazaki fragment processing (OFP), and telomere homeostasis. More recently, a critical contribution of DNA2 to the replication stress response and recovery of stalled DNA replication forks (RFs) has emerged. Here, we review the available functional and phenotypic data and propose that the major cellular defects associated with DNA2 dysfunction, and the links that exist with human disease, can be rationalized through the fundamental importance of DNA2-dependent RF recovery to genome duplication. Being a crucial player at stalled RFs, DNA2 is a promising target for anti-cancer therapy aimed at eliminating cancer cells by replication-stress overload.
Anti-VEGF Drugs Influence Epigenetic Regulation and AMD-Specific Molecular Markers in ARPE-19 Cells

Our study assesses the effects of anti-VEGF (Vascular Endothelial Growth Factor) drugs and Trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC) activity, on cultured ARPE-19 (Adult Retinal Pigment Epithelial-19) cells that are immortalized human retinal pigment epithelial cells. ARPE-19 cells were treated with the following anti-VEGF drugs: aflibercept, ranibizumab, or bevacizumab at 1× and 2× concentrations of the clinical intravitreal dose (12.5 μL/mL and 25 μL/mL, respectively) and analyzed for transcription profiles of genes associated with the pathogenesis age-related macular degeneration (AMD). HDAC activity was measured using the Fluorometric Histone Deacetylase assay. TSA downregulated HIF-1α and IL-1β genes, and upregulated BCL2L13, CASPASE-9, and IL-18 genes. TSA alone or bevacizumab plus TSA showed a significant reduction of HDAC activity compared to untreated ARPE-19 cells. Bevacizumab alone did not significantly alter HDAC activity, but increased gene expression of SOD2, BCL2L13, CASPASE-3, and IL-18 and caused downregulation of HIF-1α and IL-18. Combination of bevacizumab plus TSA increased gene expression of SOD2, HIF-1α, GPX3A, BCL2L13, and CASPASE-3, and reduced CASPASE-9 and IL-β. In conclusion, we demonstrated that anti-VEGF drugs can: (1) alter expression of genes involved in oxidative stress (GPX3A and SOD2), inflammation (IL-18 and IL-1β) and apoptosis (BCL2L13, CASPASE-3, and CASPASE-9), and (2) TSA-induced deacetylation altered transcription for angiogenesis (HIF-1α), apoptosis, and inflammation genes.
Efficacy, Feasibility, Adherence, and Cost Effectiveness of a mHealth Telerehabilitation Program in Low Risk Cardiac Patients: A Study Protocol

Individual and group cardiac rehabilitation (CR) programs reduce cardiovascular morbidity and mortality by reducing recurrent events, improving risk factors, aiding compliance with drug treatment, and improving quality of life through physical activity and education. Home-based programs are equally effective in improving exercise capacity, risk factors, mortality, and health-related quality of life outcomes compared to hospital-based intervention. Cardio-telerehabilitation (CTR) programs are a supplement or an alternative to hospital rehabilitation programs providing similar benefits to usual hospital and home care. Despite this statement, implementation in the public and private healthcare environment is still scarce and limited. The main objective of this research was to evaluate the efficacy, feasibility, and adherence of a personalized eight-week mHealth telerehabilitation program in low-risk cardiac patients in the hospital of Melilla (Spain). The secondary aims were to investigate patient satisfaction, identify barriers of implementation and adverse events, and assess cost-effectiveness from a health system perspective. A study protocol for a single center prospective controlled trial was conducted at the Regional Hospital of Melilla (Spain), with a sample size of (n = 30) patients with a diagnosis of low-risk CVD with class I heart failure according to NYHA (New York Heart Association). Outcomes of this study, will add new evidence that could support the use of CTR in cardiac patients clinical guidelines.
Single-Trial Kernel-Based Functional Connectivity for Enhanced Feature Extraction in Motor-Related Tasks

Motor learning is associated with functional brain plasticity, involving specific functional connectivity changes in the neural networks. However, the degree of learning new motor skills varies among individuals, which is mainly due to the between-subject variability in brain structure and function captured by electroencephalographic (EEG) recordings. Here, we propose a kernel-based functional connectivity measure to deal with inter/intra-subject variability in motor-related tasks. To this end, from spatio-temporal-frequency patterns, we extract the functional connectivity between EEG channels through their Gaussian kernel cross-spectral distribution. Further, we optimize the spectral combination weights within a sparse-based ℓ2-norm feature selection framework matching the motor-related labels that perform the dimensionality reduction of the extracted connectivity features. From the validation results in three databases with motor imagery and motor execution tasks, we conclude that the single-trial Gaussian functional connectivity measure provides very competitive classifier performance values, being less affected by feature extraction parameters, like the sliding time window, and avoiding the use of prior linear spatial filtering. We also provide interpretability for the clustered functional connectivity patterns and hypothesize that the proposed kernel-based metric is promising for evaluating motor skills.
Allelic Diversity at Abiotic Stress Responsive Genes in Relationship to Ecological Drought Indices for Cultivated Tepary Bean, Phaseolus acutifolius A. Gray, and Its Wild Relatives

Some of the major impacts of climate change are expected in regions where drought stress is already an issue. Grain legumes are generally drought susceptible. However, tepary bean and its wild relatives within Phaseolus acutifolius or P. parvifolius are from arid areas between Mexico and the United States. Therefore, we hypothesize that these bean accessions have diversity signals indicative of adaptation to drought at key candidate genes such as: Asr2, Dreb2B, and ERECTA. By sequencing alleles of these genes and comparing to estimates of drought tolerance indices from climate data for the collection site of geo-referenced, tepary bean accessions, we determined the genotype x environmental association (GEA) of each gene. Diversity analysis found that cultivated and wild P. acutifolius were intermingled with var. tenuifolius and P. parvifolius, signifying that allele diversity was ample in the wild and cultivated clade over a broad sense (sensu lato) evaluation. Genes Dreb2B and ERECTA harbored signatures of directional selection, represented by six SNPs correlated with the environmental drought indices. This suggests that wild tepary bean is a reservoir of novel alleles at genes for drought tolerance, as expected for a species that originated in arid environments. Our study corroborated that candidate gene approach was effective for marker validation across a broad genetic base of wild tepary accessions.
A Framework of Visual Checkout System Using Convolutional Neural Networks for Bento Buffet

In recent years, the technology of artificial intelligence (AI) and robots is rapidly spreading to countries around the world. More and more scholars and industry experts have proposed AI deep learning models and methods to solve human life problems and improve work efficiency. Modern people’s lives are very busy, which led us to investigate whether the demand for Bento buffet cafeterias has gradually increased in Taiwan. However, when eating at a buffet in a cafeteria, people often encounter two problems. The first problem is that customers need to queue up to check out after they have selected and filled their dishes from the buffet. However, it always takes too much time waiting, especially at lunch or dinner time. The second problem is sometimes customers question the charges calculated by cafeteria staff, claiming they are too expensive at the checkout counter. Therefore, it is necessary to develop an AI-enabled checkout system. The AI-enabled self-checkout system will help the Bento buffet cafeterias reduce long lineups without the need to add additional workers. In this paper, we used computer vision and deep-learning technology to design and implement an AI-enabled checkout system for Bento buffet cafeterias. The prototype contains an angle steel shelf, a Kinect camera, a light source, and a desktop computer. Six baseline convolutional neural networks were applied for comparison on food recognition. In our experiments, there were 22 different food categories in a Bento buffet cafeteria employed. Experimental results show that the inception_v4 model can achieve the highest average validation accuracy of 99.11% on food recognition, but it requires the most training and recognition time. AlexNet model achieves a 94.5% accuracy and requires the least training time and recognition time. We propose a hierarchical approach with two stages to achieve good performance in both the recognition accuracy rate and the required training and recognition time. The approach is designed to perform the first step of identification and the second step of recognizing similar food images, respectively. Experimental results show that the proposed approach can achieve a 96.3% accuracy rate on our test dataset and required very little recognition time for input images. In addition, food volumes could be estimated using the depth images captured by the Kinect camera, and a framework of visual checkout system was successfully built.
Pop-In Phenomenon as a Fundamental Plasticity Probed by Nanoindentation Technique

The attractive strain burst phenomenon, so-called “pop-in”, during indentation-induced deformation at a very small scale is discussed as a fundamental deformation behavior in various materials. The nanoindentation technique can probe a mechanical response to a very low applied load, and the behavior can be mechanically and physically analyzed. The pop-in phenomenon can be understood as incipient plasticity under an indentation load, and dislocation nucleation at a small volume is a major mechanism for the event. Experimental and computational studies of the pop-in phenomenon are reviewed in terms of pioneering discovery, experimental clarification, physical modeling in the thermally activated process, crystal plasticity, effects of pre-existing lattice defects including dislocations, in-solution alloying elements, and grain boundaries, as well as atomistic modeling in computational simulation. The related non-dislocation behaviors are also discussed in a shear transformation zone in bulk metallic glass materials and phase transformation in semiconductors and metals. A future perspective from both engineering and scientific views is finally provided for further interpretation of the mechanical behaviors of materials.
Integrated Metabolomics and Transcriptomics Using an Optimised Dual Extraction Process to Study Human Brain Cancer Cells and Tissues

The integration of untargeted metabolomics and transcriptomics from the same population of cells or tissue enhances the confidence in the identified metabolic pathways and understanding of the enzyme–metabolite relationship. Here, we optimised a simultaneous extraction method of metabolites/lipids and RNA from ependymoma cells (BXD-1425). Relative to established RNA (mirVana kit) or metabolite (sequential solvent addition and shaking) single extraction methods, four dual-extraction techniques were evaluated and compared (methanol:water:chloroform ratios): cryomill/mirVana (1:1:2); cryomill-wash/Econospin (5:1:2); rotation/phenol-chloroform (9:10:1); Sequential/mirVana (1:1:3). All methods extracted the same metabolites, yet rotation/phenol-chloroform did not extract lipids. Cryomill/mirVana and sequential/mirVana recovered the highest amounts of RNA, at 70 and 68% of that recovered with mirVana kit alone. sequential/mirVana, involving RNA extraction from the interphase of our established sequential solvent addition and shaking metabolomics-lipidomics extraction method, was the most efficient approach overall. Sequential/mirVana was applied to study a) the biological effect caused by acute serum starvation in BXD-1425 cells and b) primary ependymoma tumour tissue. We found (a) 64 differentially abundant metabolites and 28 differentially expressed metabolic genes, discovering four gene-metabolite interactions, and (b) all metabolites and 62% lipids were above the limit of detection, and RNA yield was sufficient for transcriptomics, in just 10 mg of tissue.
Untargeted Metabolomics Insights into Newborns with Congenital Zika Infection

Zika virus (ZIKV), an emerging virus belonging to the Flaviviridae family, causes severe neurological clinical complications and has been associated with Guillain-Barré syndrome, fetal abnormalities known collectively as congenital Zika syndrome, and microcephaly. Studies have shown that ZIKV infection can alter cellular metabolism, directly affecting neural development. Brain growth requires controlled cellular metabolism, which is essential for cell proliferation and maturation. However, little is known regarding the metabolic profile of ZIKV-infected newborns and possible associations related to microcephaly. Furthering the understanding surrounding underlying mechanisms is essential to developing personalized treatments for affected individuals. Thus, metabolomics, the study of the metabolites produced by or modified in an organism, constitutes a valuable approach in the study of complex diseases. Here, 26 serum samples from ZIKV-positive newborns with or without microcephaly, as well as controls, were analyzed using an untargeted metabolomics approach involving gas chromatography–mass spectrometry (GC-MS). Significant alterations in essential and non-essential amino acids, as well as carbohydrates (including aldohexoses, such as glucose or mannose) and their derivatives (urea and pyruvic acid), were observed in the metabolic profiles analyzed. Our results provide insight into relevant metabolic processes in patients with ZIKV and microcephaly.
Beneficial Effects of Cyclic Ether 2-Butoxytetrahydrofuran from Sea Cucumber Holothuria scabra against Aβ Aggregate Toxicity in Transgenic Caenorhabditis elegans and Potential Chemical Interaction

The pathological finding of amyloid-β (Aβ) aggregates is thought to be a leading cause of untreated Alzheimer’s disease (AD). In this study, we isolated 2-butoxytetrahydrofuran (2-BTHF), a small cyclic ether, from Holothuria scabra and demonstrated its therapeutic potential against AD through the attenuation of Aβ aggregation in a transgenic Caenorhabditis elegans model. Our results revealed that amongst the five H. scabra isolated compounds, 2-BTHF was shown to be the most effective in suppressing worm paralysis caused by Aβ toxicity and in expressing strong neuroprotection in CL4176 and CL2355 strains, respectively. An immunoblot analysis showed that CL4176 and CL2006 treated with 2-BTHF showed no effect on the level of Aβ monomers but significantly reduced the toxic oligomeric form and the amount of 1,4-bis(3-carboxy-hydroxy-phenylethenyl)-benzene (X-34)-positive fibril deposits. This concurrently occurred with a reduction of reactive oxygen species (ROS) in the treated CL4176 worms. Mechanistically, heat shock factor 1 (HSF-1) (at residues histidine 63 (HIS63) and glutamine 72 (GLN72)) was shown to be 2-BTHF’s potential target that might contribute to an increased expression of autophagy-related genes required for the breakdown of the Aβ aggregate, thus attenuating its toxicity. In conclusion, 2-BTHF from H. scabra could protect C. elegans from Aβ toxicity by suppressing its aggregation via an HSF-1-regulated autophagic pathway and has been implicated as a potential drug for AD.