Miracle-dz/UniFAR-FTUs huggingface dataset:
Genomic Comparison and Genetic Marker Identification of the White-Spotted Bamboo Shark Chiloscyllium plagiosum

The white-spotted bamboo shark (Chiloscyllium plagiosum) is an ecologically and commercially important marine cartilaginous fish in the Indo-Western Pacific. However, the resources of this species are declining in recent years due to habitat degradation and overfishing. Studies on genomics and genetic markers can provide valuable information for sound management and conservation of C. plagiosum. In this study, genome resequencing data of a domesticated C. plagiosum individual were generated for genomic comparison between wild and domesticated samples. Based on 281.17 Gb of clean sequencing data, the genome size of the domesticated sample was estimated as 4.99 Gb, with heterozygosity of 0.51% and repeat ratio of 74.67%, which is about 1 Gb larger than that of the wild sample (3.85 Gb with a repeat ratio of 63.53%). By using a reference-based approach, we assembled a nearly 3.45 Gb genome sequence of the domesticated sample, with the scaffold N50 of 69.45 Mb. Subsequent identification of genome-wide microsatellite markers confirmed the different abundance of repeat elements in wild and domesticated C. plagiosum. Additionally, a total of 8,703,211 single-nucleotide polymorphisms (SNPs) were detected and annotated. The demographic analysis based on identified SNPs revealed a large and constant effective population size of C. plagiosum after the last population expansion (~0.3 million years ago). The genomic data and identified genetic markers in this study can provide fundamental and useful information for further comparative genomics, evolutionary biology, and conservation genetics of C. plagiosum.
Evolutionary Relationships Between Dysregulated Genes in Oral Squamous Cell Carcinoma and Oral Microbiota

Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers in the world. Changes in the composition and abundance of oral microbiota are associated with the development and metastasis of OSCC. To elucidate the exact roles of the oral microbiota in OSCC, it is essential to reveal the evolutionary relationships between the dysregulated genes in OSCC progression and the oral microbiota. Thus, we interrogated the microarray and high-throughput sequencing datasets to obtain the transcriptional landscape of OSCC. After identifying differentially expressed genes (DEGs) with three different methods, pathway and functional analyses were also performed. A total of 127 genes were identified as common DEGs, which were enriched in extracellular matrix organization and cytokine related pathways. Furthermore, we established a predictive pipeline for detecting the coevolutionary of dysregulated host genes and microbial proteomes based on the homology method, and this pipeline was employed to analyze the evolutionary relations between the seven most dysregulated genes (MMP13, MMP7, MMP1, CXCL13, CRISPO3, CYP3A4, and CRNN) and microbiota obtained from the eHOMD database. We found that cytochrome P450 3A4 (CYP3A4), a member of the cytochrome P450 family of oxidizing enzymes, was associated with 45 microbes from the eHOMD database and involved in the oral habitat of Comamonas testosteroni and Arachnia rubra. The peptidase M10 family of matrix metalloproteinases (MMP13, MMP7, and MMP1) was associated with Lacticaseibacillus paracasei, Lacticaseibacillus rhamnosus, Streptococcus salivarius, Tannerella sp. _HMT_286, and Streptococcus infantis in the oral cavity. Overall, this study revealed the dysregulated genes in OSCC and explored their evolutionary relationship with oral microbiota, which provides new insight for exploring the microbiota–host interactions in diseases.
“Sandwich” Strategy to Intensify EGFR Blockade by Concurrent Tyrosine Kinase Inhibitor and Monoclonal Antibody Treatment in Highly Selected Patients

EGFR TKIs are not curative, and targeted resistance inevitably results in therapeutic failure. Additionally, there are numerous uncommon EGFR mutations that are insensitive to EGFR TKIs, and there is a lack of clinical strategies to overcome these limitations. EGFR TKI and mAbs target EGFR at different sites, and a combination regimen for delaying/preventing resistance to targeted therapy or obtaining more intensive inhibition for uncommon mutations at cellular, animal and human levels has been explored. This review critically focuses on a combination strategy for uncommon EGFR mutation-positive NSCLC, and discuss the preclinical data, clinical implications, limitations and future prospects of the combination strategy.
Solving stochastic dynamic facility layout problems using proposed hybrid AC-CS-SA meta-heuristic algorithm

This paper proposes a novel hybrid algorithm in which simulated annealing algorithm starts with a population of good initial solutions constructed by combining ant colony, clonal selection, and robust layout design approaches. The proposed algorithm can be used to solve a dynamic (multi-period) facility layout problem in both deterministic and stochastic cases. In the stochastic environment, product demands are assumed to be normally distributed random variables with known probability density function that changes from period to period at random. In addition, a quadratic assignment-based mathematical model, which is used in the proposed hybrid algorithm, is developed to design a robust layout for the stochastic dynamic layout problem. Finally, the performance of the proposed algorithm is evaluated by solving a large number of randomly generated test problems and some test problems from the literature in stochastic and deterministic cases respectively. The results show that the hybrid algorithm has an outstanding performance from both solution quality and computational time points of view.
Treatment of Cardiovascular Dysfunction with PDE3-Inhibitors in Moderate and Severe Hypothermia—Effects on Cellular Elimination of Cyclic Adenosine Monophosphate and Cyclic Guanosine Monophosphate

Introduction: Rewarming from accidental hypothermia is often complicated by hypothermia-induced cardiovascular dysfunction, which could lead to shock. Current guidelines do not recommend any pharmacological treatment at core temperatures below 30°C, due to lack of knowledge. However, previous in vivo studies have shown promising results when using phosphodiesterase 3 (PDE3) inhibitors, which possess the combined effects of supporting cardiac function and alleviating the peripheral vascular resistance through changes in cyclic nucleotide levels. This study therefore aims to investigate whether PDE3 inhibitors milrinone, amrinone, and levosimendan are able to modulate cyclic nucleotide regulation in hypothermic settings. Materials and methods: The effect of PDE3 inhibitors were studied by using recombinant phosphodiesterase enzymes and inverted erythrocyte membranes at six different temperatures—37°C, 34°C, 32°C, 28°C, 24°C, and 20°C- in order to evaluate the degree of enzymatic degradation, as well as measuring cellular efflux of both cAMP and cGMP. The resulting dose-response curves at every temperature were used to calculate IC50 and Ki values. Results: Milrinone IC50 and Ki values for cGMP efflux were significantly lower at 24°C (IC50: 8.62 ± 2.69 µM) and 20°C (IC50: 7.35 ± 3.51 µM), compared to 37°C (IC50: 22.84 ± 1.52 µM). There were no significant changes in IC50 and Ki values for enzymatic breakdown of cAMP and cGMP. Conclusion: Milrinone, amrinone and levosimendan, were all able to suppress enzymatic degradation and inhibit extrusion of cGMP and cAMP below 30°C. Our results show that these drugs have preserved effect on their target molecules during hypothermia, indicating that they could provide an important treatment option for hypothermia-induced cardiac dysfunction.
Implications of Diabetes-Induced Altered Metabolites on Retinal Neurodegeneration

Diabetic retinopathy (DR) is one of the major complications of diabetic eye diseases, causing vision loss and blindness worldwide. The concept of diabetic retinopathy has evolved from microvascular disease into more complex neurovascular disorders. Early in the disease progression of diabetes, the neuronal and glial cells are compromised before any microvascular abnormalities clinically detected by the ophthalmoscopic examination. This implies understanding the pathophysiological mechanisms at the early stage of disease progression especially due to diabetes-induced metabolic alterations to damage the neural retina so that early intervention and treatments options can be identified to prevent and inhibit the progression of DR. Hyperglycemia has been widely considered the major contributor to the progression of the retinal damage, even though tight control of glucose does not seem to have a bigger effect on the incidence or progression of retinal damage that leads to DR. Emerging evidence suggests that besides diabetes-induced hyperglycemia, dyslipidemia and amino acid defects might be a major contributor to the progression of early neurovascular retinal damage. In this review, we have discussed recent advances in the alterations of key metabolites of carbohydrate, lipid, and amino acids and their implications for neurovascular damage in DR.
Platelet Aggregation Before Aspirin Initiation in Pediatric Patients With Congenital Heart Disease at High Risk of Thrombosis

Background Aspirin following unfractionated heparin is the most common anticoagulation strategy for pediatric patients who experienced cardiac surgery at high risk of thrombosis. The platelet aggregation test is the golden method to evaluate the aspirin effect on platelet function. However, the platelet aggregation basal status before postoperative aspirin initiation and the related clinical influencing factors hasn't been investigated systemically in this population. Methods In a prospective cohort of 247 children, arachidonic acid-induced platelet aggregation (PAG-AA) was measured by means of light transmission aggregometry (LTA) before the first dose of aspirin after cardiac surgical procedure and the perioperative variables were also collected. Distribution of this population's PAG-AA basal status was described. Univariate and multivariate logistic regression analysis were performed to identify the main influencing factors of PAG-AA. Results The median time of aspirin administration was 2 (1–27) days after surgery and the corresponding median value of basal PAG-AA was 20.70% (1.28–86.49%), with 67.6% population under 55% and 47.8% population under 20%. Patients undergoing cardiopulmonary bypass (CPB) had a significantly lower basal PAG-AA than those without (30.63 ± 27.35 vs. 57.91 ± 27.58, p = 0.013). While patients whose test done within 3 days after CPB had a significantly lower PAG-AA than those out of 3 days (25.61 ± 25.59 vs. 48.59 ± 26.45, p = 0.001). Univariate analysis implied that the influencing factors of the basal PAG-AA including CPB use, test time point, cyanosis, and platelet count. Multivariate regression analysis indicated that only CPB use, test time point, and platelet count were the main independent influencing factors for the basal PAG-AA. Conclusion The majority of children have impaired basal platelet aggregometry responses before postoperative aspirin initiation. The main influencing factors are CPB use, test time point, and platelet count. To establish the platelet aggregometry baseline prior to commencement of aspirin therapy, testing should be performed 3 days later following the procedure when effect of CPB is basically over.
Brain Region- and Age-Dependent 5-Hydroxymethylcytosine Activity in the Non-Human Primate

Because of the difficulty in collecting fresh brains of humans at different ages, it remains unknown how epigenetic regulation occurs in the primate brains during aging. In the present study, we examined the genomic distribution of 5hmC, an indicator of DNA methylation, in the brain regions of non-human primates (rhesus monkey) at the ages of 2 (juvenile), 8 (young adult), and 17 (old) years. We found that genomic 5hmC distribution was accumulated in the monkey brain as age increased and displayed unique patterns in the cerebellum and striatum in an age-dependent manner. We also observed a correlation between differentially hydroxymethylated regions (DhMRs) and genes that contribute to brain region-related functions and diseases. Our studies revealed, for the first time, the brain-region and age-dependent 5hmC modifications in the non-human primate and the association of these 5hmC modifications with brain region-specific function and potentially aging-related brain diseases.
Single-Cell Metabolomics in Hematopoiesis and Hematological Malignancies

Aberrant metabolism contributes to tumor initiation, progression, metastasis, and drug resistance. Metabolic dysregulation has emerged as a hallmark of several hematologic malignancies. Decoding the molecular mechanism underlying metabolic rewiring in hematological malignancies would provide promising avenues for novel therapeutic interventions. Single-cell metabolic analysis can directly offer a meaningful readout of the cellular phenotype, allowing us to comprehensively dissect cellular states and access biological information unobtainable from bulk analysis. In this review, we first highlight the unique metabolic properties of hematologic malignancies and underscore potential metabolic vulnerabilities. We then emphasize the emerging single-cell metabolomics techniques, aiming to provide a guide to interrogating metabolism at single-cell resolution. Furthermore, we summarize recent studies demonstrating the power of single-cell metabolomics to uncover the roles of metabolic rewiring in tumor biology, cellular heterogeneity, immunometabolism, and therapeutic resistance. Meanwhile, we describe a practical view of the potential applications of single-cell metabolomics in hematopoiesis and hematological malignancies. Finally, we present the challenges and perspectives of single-cell metabolomics development.
The Safety and Efficacy of Nanosecond Pulsed Electric Field in Patients With Hepatocellular Carcinoma: A Prospective Phase 1 Clinical Study Protocol

Background Hepatocellular carcinoma (HCC) is a highly aggressive malignancy. Irreversible electroporation (IRE) is an ablative modality that uses high-voltage electrical pulses to permeabilize the cell membrane leading to cell necrosis. Unlike traditional thermal ablation, IRE is hardly affected by the “heat-sink” effect and can prevent damage of the adjacent vital structures. Nanosecond pulsed electric field (nsPEF) is a new IRE technique using ultra-short pulses (nanosecond duration), can not only penetrate the cell membranes, but also act on the organelles. Sufficient preclinical researches have shown that nsPEF can eliminate HCC without damaging vital organs, and elicit potent anti-tumor immune response. Objective This is the first clinical study to evaluate feasibility, efficacy, and safety of nsPEF for the treatment of HCC, where thermal ablation is unsuitable due to proximity to critical structures. Methods and analysis We will conduct an open-labeled, single-arm, prospective, multicenter, and objective performance criteria trial. One hundred and ninety-two patients with HCC, in which the tumor is located immediately (<0.5 cm) adjacent to the portal vein, hepatic veins, bile duct, gastrointestinal tract, or diaphragm, will be enrolled among 4 academic medical centers. The primary outcomes are the rate of complete ablation at 1 month and adverse events. Secondary outcomes include technical success, technique efficacy, nsPEF procedural characteristics, local tumor progression, and local progression-free survival. Ethics and dissemination The trial will be conducted according to the ethical principles of the Declaration of Helsinki and has been approved by the ethics committee of all participating centers. The results of this study will be published in peer-reviewed scientific journals and presented at relevant academic conferences. Conclusions This study is the Phase 1 clinical trial to evaluate the efficacy and safety of nsPEF in patients with HCC at high-risk locations where thermal ablation is contra-indicated. The results may expand the options and offer an alternative therapy for HCC. Clinical Trial Registration ClinicalTrials.gov, identifier NCT04309747.
Effects of Tree Composition and Soil Depth on Structure and Functionality of Belowground Microbial Communities in Temperate European Forests

Depending on their tree species composition, forests recruit different soil microbial communities. Likewise, the vertical nutrient gradient along soil profiles impacts these communities and their activities. In forest soils, bacteria and fungi commonly compete, coexist, and interact, which is challenging for understanding the complex mechanisms behind microbial structuring. Using amplicon sequencing, we analyzed bacterial and fungal diversity in relation to forest composition and soil depth. Moreover, employing random forest models, we identified microbial indicator taxa of forest plots composed of either deciduous or evergreen trees, or their mixtures, as well as of three soil depths. We expected that forest composition and soil depth affect bacterial and fungal diversity and community structure differently. Indeed, relative abundances of microbial communities changed more across soil depths than in relation to forest composition. The microbial Shannon diversity was particularly affected by soil depth and by the proportion of evergreen trees. Our results also reflected that bacterial communities are primarily shaped by soil depth, while fungi were influenced by forest tree species composition. An increasing proportion of evergreen trees did not provoke differences in main bacterial metabolic functions, e.g., carbon fixation, degradation, or photosynthesis. However, significant responses related to specialized bacterial metabolisms were detected. Saprotrophic, arbuscular mycorrhizal, and plant pathogenic fungi were related to the proportion of evergreen trees, particularly in topsoil. Prominent microbial indicator taxa in the deciduous forests were characterized to be r-strategists, whereas K-strategists dominated evergreen plots. Considering simultaneously forest composition and soil depth to unravel differences in microbial communities, metabolic pathways and functional guilds have the potential to enlighten mechanisms that maintain forest soil functionality and provide resistance against disturbances.
Altered Intestinal Microbiomes and Lipid Metabolism in Patients With Prolonged Disorders of Consciousness

The intestinal microbiota regulate the brain function of the host through the production of a myriad of metabolites and are associated with various neurological diseases. Understanding the intestinal microbiome of patients with prolonged disorders of consciousness (DoC) is important for the evaluation and treatment of the disease. To investigate the differences in the intestinal microbiome and short-chain fatty acids (SCFAs) among patients in a vegetative state (VS), a minimally conscious state (MCS), and emerged from MCS (EMCS), as well as the influence of antibiotics on these patients, 16S ribosomal RNA (16S rRNA) sequencing and targeted lipidomics were performed on fecal samples from patients; in addition, analysis of the electroencephalogram (EEG) signals was performed to evaluate the brain function of these patients. The results showed that the intestinal microbiome of the three groups differed greatly, and some microbial communities showed a reduced production of SCFAs in VS patients compared to the other two groups. Moreover, reduced microbial communities and five major SCFAs, along with attenuated brain functional connectivity, were observed in MCS patients who were treated with antibiotics compared to those who did not receive antibiotic treatment, but not in the other pairwise comparisons. Finally, three genus-level microbiota—Faecailbacterium, Enterococcus, and Methanobrevibacter—were considered as potential biomarkers to distinguish MCS from VS patients, with high accuracy both in the discovery and validation cohorts. Together, our findings improved the understanding of patients with prolonged DoC from the intestinal microbiome perspective and provided a new reference for the exploration of therapeutic targets.
Novel Microorganisms Contribute to Biosulfidogenesis in the Deep Layer of an Acidic Pit Lake

Cueva de la Mora is a permanently stratified acidic pit lake with extremely high concentrations of heavy metals at depth. In order to evaluate the potential for in situ sulfide production, we characterized the microbial community in the deep layer using metagenomics and metatranscriptomics. We retrieved 18 high quality metagenome-assembled genomes (MAGs) representing the most abundant populations. None of the MAGs were closely related to either cultured or non-cultured organisms from the Genome Taxonomy or NCBI databases (none with average nucleotide identity >95%). Despite oxygen concentrations that are consistently below detection in the deep layer, some archaeal and bacterial MAGs mapped transcripts of genes for sulfide oxidation coupled with oxygen reduction. Among these microaerophilic sulfide oxidizers, mixotrophic Thermoplasmatales archaea were the most numerous and represented 24% of the total community. Populations associated with the highest predicted in situ activity for sulfate reduction were affiliated with Actinobacteria, Chloroflexi, and Nitrospirae phyla, and together represented about 9% of the total community. These MAGs, in addition to a less abundant Proteobacteria MAG in the genus Desulfomonile, contained transcripts of genes in the Wood-Ljungdahl pathway. All MAGs had significant genetic potential for organic carbon oxidation. Our results indicate that novel acidophiles are contributing to biosulfidogenesis in the deep layer of Cueva de la Mora, and that in situ sulfide production is limited by organic carbon availability and sulfur oxidation.
Genome-Wide Insights Into the Organelle Translocation of Photosynthetic NDH-1 Genes During Evolution

Translocation of chloroplast-located genes to mitochondria or nucleus is considered to be a safety strategy that impedes mutation of photosynthetic genes and maintains their household function during evolution. The organelle translocation strategy is also developed in photosynthetic NDH-1 (pNDH-1) genes but its understanding is still far from complete. Here, we found that the mutation rate of the conserved pNDH-1 genes was gradually reduced but their selection pressure was maintained at a high level during evolution from cyanobacteria to angiosperm. By contrast, oxygenic photosynthesis-specific (OPS) pNDH-1 genes had an opposite trend, explaining the reason why they were transferred from the reactive oxygen species (ROS)-enriched chloroplast to the ROS-barren nucleus. Further, genome-wide sequence analysis supported the possibility that all conserved pNDH-1 genes lost in chloroplast genomes of Chlorophyceae and Pinaceae were transferred to the ROS-less mitochondrial genome as deduced from their truncated pNDH-1 gene fragments. Collectively, we propose that the organelle translocation strategy of pNDH-1 genes during evolution is necessary to maintain the function of the pNDH-1 complex as an important antioxidant mechanism for efficient photosynthesis.
Fish Behavior as a Neural Proxy to Reveal Physiological States

Behaviors are the integrative outcomes of the nervous system, which senses and responds to the internal physiological status and external stimuli. Teleosts are aquatic organisms which are more easily affected by the surrounding environment compared to terrestrial animals. To date, behavioral tests have been widely used to assess potential environmental risks using fish as model animals. In this review, we summarized recent studies regarding the effects of internal and external stimuli on fish behaviors. We concluded that behaviors reflect environmental and physiological changes, which have possible implications for environmental and physiological assessments.