Miracle-dz/UniFAR-FTUs huggingface dataset:
Cholesterol Is a Dose-Dependent Positive Allosteric Modulator of CCR3 Ligand Affinity and G Protein Coupling

Cholesterol as an allosteric modulator of G protein-coupled receptor (GPCR) function is well documented. This quintessential mammalian lipid facilitates receptor–ligand interactions and multimerization states. Functionally, this introduces a complicated mechanism for the homeostatic modulation of GPCR signaling. Chemokine receptors are Class A GPCRs responsible for immune cell trafficking through the binding of endogenous peptide ligands. CCR3 is a CC motif chemokine receptor expressed by eosinophils and basophils. It traffics these cells by transducing the signal stimulated by the CC motif chemokine primary messengers 11, 24, and 26. These behaviors are close to the human immunoresponse. Thus, CCR3 is implicated in cancer metastasis and inflammatory conditions. However, there is a paucity of experimental evidence linking the functional states of CCR3 to the molecular mechanisms of cholesterol–receptor cooperativity. In this vein, we present a means to combine codon harmonization and a maltose-binding protein fusion tag to produce CCR3 from E. coli. This technique yields ∼2.6 mg of functional GPCR per liter of minimal media. We leveraged this protein production capability to investigate the effects of cholesterol on CCR3 function in vitro. We found that affinity for the endogenous ligand CCL11 increases in a dose-dependent manner with cholesterol concentration in both styrene:maleic acid lipid particles (SMALPs) and proteoliposomes. This heightened receptor activation directly translates to increased signal transduction as measured by the GTPase activity of the bound G-protein α inhibitory subunit 3 (Gα i3). This work represents a critical step forward in understanding the role of cholesterol-GPCR allostery in regulation of signal transduction.
Role of NLRP3 Inflammasome in Lupus Nephritis and Therapeutic Targeting by Phytochemicals

Systemic lupus erythematosus (SLE) is a multisystem autoimmune inflammatory condition that affects multiple organs and provokes extensive and severe clinical manifestations. Lupus nephritis (LN) is one of the main clinical manifestations of SLE. It refers to the deposition of immune complexes in the glomeruli, which cause kidney inflammation. Although LN seriously affects prognosis and represents a key factor of disability and death in SLE patients, its mechanism remains unclear. The NACHT, leucine-rich repeat (LRR), and pyrin (PYD) domains-containing protein 3 (NLRP3) inflammasome regulates IL-1β and IL-18 secretion and gasdermin D-mediated pyroptosis and plays a key role in innate immunity. There is increasing evidence that aberrant activation of the NLRP3 inflammasome and downstream inflammatory pathways play an important part in the pathogenesis of multiple autoimmune diseases, including LN. This review summarizes research progress on the elucidation of NLRP3 activation, regulation, and recent clinical trials and experimental studies implicating the NLRP3 inflammasome in the pathophysiology of LN. Current treatments fail to provide durable remission and provoke several sides effects, mainly due to their broad immunosuppressive effects. Therefore, the identification of a safe and effective therapeutic approach for LN is of great significance. Phytochemicals are found in many herbs, fruits, and vegetables and are secondary metabolites of plants. Evidence suggests that phytochemicals have broad biological activities and have good prospects in a variety of diseases, including LN. Therefore, this review reports on current research evaluating phytochemicals for targeting NLRP3 inflammasome pathways in LN therapy.
Generic Paradoxical Tensions, Appraisals, Work Motivation, and Performance: Insights From a Weekly Repeated-Measures Study

Drawing on the paradox theory, the author developed a theoretical model of appraisal–motivational responses to generic paradoxical tensions. The author postulated that paradoxical tensions are appraised both as a challenge and as a threat, in turn prompting mixed effects, positive and negative, on performance. The dual effects of paradoxical tensions are explained by the intermittent role of motivation toward work and a dispositional boundary condition—individual' adaptability—cross-situation variability of behaviors. The results from an eight-wave weekly repeated measures study spanning a period of 2 months (N = 178, total observations = 1,355) provided support for the proposed theoretical model. By illuminating the nuanced intraindividual psychological process, the present study brings forward novel insights on cognitive appraisals and motivations of paradoxical tensions advancing microfoundation of the paradox research.
Finite Models for a Spatial Logic with Discrete and Topological Path Operators

This paper analyses models of a spatial logic with path operators based on the class of neighbourhood spaces, also called pretopological or closure spaces, a generalisation of topological spaces. For this purpose, we distinguish two dimensions: the type of spaces on which models are built, and the type of allowed paths. For the spaces, we investigate general neighbourhood spaces and the subclass of quasi-discrete spaces, which closely resemble graphs. For the paths, we analyse the cases of quasi-discrete paths, which consist of an enumeration of points, and topological paths, based on the unit interval. We show that the logic admits finite models over quasi-discrete spaces, both with quasi-discrete and topological paths. Finally, we prove that for general neighbourhood spaces, the logic does not have the finite model property, either for quasi-discrete or topological paths. 2012
Genetic Susceptibility to Fungal Infections and Links to Human Ancestry

Over the ages, fungi have associated with different parts of the human body and established symbiotic associations with their host. They are mostly commensal unless there are certain not so well-defined factors that trigger the conversion to a pathogenic state. Some of the factors that induce such transition can be dependent on the fungal species, environment, immunological status of the individual, and most importantly host genetics. In this review, we discuss the different aspects of how host genetics play a role in fungal infection since mutations in several genes make hosts susceptible to such infections. We evaluate how mutations modulate the key recognition between the pathogen associated molecular patterns (PAMP) and the host pattern recognition receptor (PRR) molecules. We discuss the polymorphisms in the genes of the immune system, the way it contributes toward some common fungal infections, and highlight how the immunological status of the host determines fungal recognition and cross-reactivity of some fungal antigens against human proteins that mimic them. We highlight the importance of single nucleotide polymorphisms (SNPs) that are associated with several of the receptor coding genes and discuss how it affects the signaling cascade post-infection, immune evasion, and autoimmune disorders. As part of personalized medicine, we need the application of next-generation techniques as a feasible option to incorporate an individual’s susceptibility toward invasive fungal infections based on predisposing factors. Finally, we discuss the importance of studying genomic ancestry and reveal how genetic differences between the human race are linked to variation in fungal disease susceptibility.
Marching Cubes Algorithm for Transforming Images

—A Marching Cubes algorithm modification is presented in this work. This proposal is used to make from surface image discretized on volumetric pixels, called voxels, a three-dimensional representation from a flat image is raised. To achieve this effect, each component is connected continuously (without gaps) regardless of the values of the image surface. The aim is to achieve this effect, optimizing computational resources. The ambiguous elimination cases as well as the identification of non-trivial cases are among the main features attended. Once identified, the modelling process is optimized, seeking congruence with the edges of the volume, applying techniques that allow connecting the edges adjacent to the corners, generating the triangulation of the cube, and introducing a new set of edge equivalence classes and cube faces. The obtained results allow to observe the effective performance of the implemented modification.
The Functional Role of Hyperpolarization Activated Current (If) on Cardiac Pacemaking in Human vs. in the Rabbit Sinoatrial Node: A Simulation and Theoretical Study

The cardiac hyperpolarization-activated “funny” current (If), which contributes to sinoatrial node (SAN) pacemaking, has a more negative half-maximal activation voltage and smaller fully-activated macroscopic conductance in human than in rabbit SAN cells. The consequences of these differences for the relative roles of If in the two species, and for their responses to the specific bradycardic agent ivabradine at clinical doses have not been systematically explored. This study aims to address these issues, through incorporating rabbit and human If formulations developed by Fabbri et al. into the Severi et al. model of rabbit SAN cells. A theory was developed to correlate the effect of If reduction with the total inward depolarising current (Itotal) during diastolic depolarization. Replacing the rabbit If formulation with the human one increased the pacemaking cycle length (CL) from 355 to 1,139 ms. With up to 20% If reduction (a level close to the inhibition of If by ivabradine at clinical concentrations), a modest increase (~5%) in the pacemaking CL was observed with the rabbit If formulation; however, the effect was doubled (~12.4%) for the human If formulation, even though the latter has smaller If density. When the action of acetylcholine (ACh, 0.1 nM) was considered, a 20% If reduction markedly increased the pacemaking CL by 37.5% (~27.3% reduction in the pacing rate), which is similar to the ivabradine effect at clinical concentrations. Theoretical analysis showed that the resultant increase of the pacemaking CL is inversely proportional to the magnitude of Itotal during diastolic depolarization phase: a smaller If in the model resulted in a smaller Itotal amplitude, resulting in a slower pacemaking rate; and the same reduction in If resulted in a more significant change of CL in the cell model with a smaller Itotal. This explained the mechanism by which a low dose of ivabradine slows pacemaking rate more in humans than in the rabbit. Similar results were seen in the Fabbri et al. model of human SAN cells, suggesting our observations are model-independent. Collectively, the results of study explain why low dose ivabradine at clinically relevant concentrations acts as an effective bradycardic agent in modulating human SAN pacemaking.
The Spleen as a Target to Characterize Immunomodulatory Effects of Down-Stream Processed Cyberlindnera jadinii Yeasts in Atlantic Salmon Exposed to a Dietary Soybean Meal Challenge

Aquaculture feeds have changed dramatically from being largely based on fishmeal (FM) towards increased use of plant protein sources, which could impact the fish’s immune response. In order to characterize immunomodulatory properties of novel functional ingredients, this study used four diets, one based on FM, a challenging diet with 40% soybean meal (SBM), and two diets containing 40% SBM with 5% of Cyberlindnera jadinii yeast exposed to different down-stream processing conditions: heat-inactivated (ICJ) or autolysation (ACJ). The immunomodulatory effects of the diets were analyzed in the spleen of Atlantic salmon after 37 days of feeding, using a transcriptomic evaluation by RNA sequencing (RNA-seq) and the detection of specific immunological markers at the protein level through indirect Enzyme-linked Immunosorbent Assay (indirect ELISA). The results showed that SBM (compared to FM) induced a down-regulation of pathways related to ion binding and transport, along with an increase at the protein level of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ). On the other hand, while ICJ (compared to FM-group) maintain the inflammatory response associated with SBM, with higher levels of TNFα and IFNγ, and with an upregulation of creatine kinase activity and phosphagen metabolic process, the inclusion of ACJ was able to modulate the response of Atlantic salmon compared to fish fed the SBM-diet by the activation of biological pathways related to endocytosis, Pattern recognition receptor (PPRs)-signal transduction and transporter activity. In addition, ACJ was also able to control the pro-inflammatory profile of SBM, increasing Interleukin 10 (IL-10) levels and decreasing TNFα production, triggering an immune response similar to that of fish fed an FM-based diet. Finally, we suggest that the spleen is a good candidate to characterize the immunomodulatory effects of functional ingredients in Atlantic salmon. Moreover, the inclusion of ACJ in fish diets, with the ability to control inflammatory processes, could be considered in the formulation of sustainable salmon feed.
Molecular Dynamics Simulations Reveal the Interaction Fingerprint of Remdesivir Triphosphate Pivotal in Allosteric Regulation of SARS-CoV-2 RdRp

The COVID-19 pandemic has now strengthened its hold on human health and coronavirus’ lethal existence does not seem to be going away soon. In this regard, the optimization of reported information for understanding the mechanistic insights that facilitate the discovery towards new therapeutics is an unmet need. Remdesivir (RDV) is established to inhibit RNA-dependent RNA polymerase (RdRp) in distinct viral families including Ebola and SARS-CoV-2. Therefore, its derivatives have the potential to become a broad-spectrum antiviral agent effective against many other RNA viruses. In this study, we performed comparative analysis of RDV, RMP (RDV monophosphate), and RTP (RDV triphosphate) to undermine the inhibition mechanism caused by RTP as it is a metabolically active form of RDV. The MD results indicated that RTP rearranges itself from its initial RMP-pose at the catalytic site towards NTP entry site, however, RMP stays at the catalytic site. The thermodynamic profiling and free-energy analysis revealed that a stable pose of RTP at NTP entrance site seems critical to modulate the inhibition as its binding strength improved more than its initial RMP-pose obtained from docking at the catalytic site. We found that RTP not only occupies the residues K545, R553, and R555, essential to escorting NTP towards the catalytic site, but also interacts with other residues D618, P620, K621, R624, K798, and R836 that contribute significantly to its stability. From the interaction fingerprinting it is revealed that the RTP interact with basic and conserved residues that are detrimental for the RdRp activity, therefore it possibly perturbed the catalytic site and blocked the NTP entrance site considerably. Overall, we are highlighting the RTP binding pose and key residues that render the SARS-CoV-2 RdRp inactive, paving crucial insights towards the discovery of potent inhibitors.
Silicon Application Modulates the Growth, Rhizosphere Soil Characteristics, and Bacterial Community Structure in Sugarcane

Silicon (Si) deficiency, caused by acidic soil and rainy climate, is a major constraint for sugarcane production in southern China. Si application generally improves sugarcane growth; however, there are few studies on the relationships between enhanced plant growth, changes in rhizosphere soil, and bacterial communities. A field experiment was conducted to measure sugarcane agronomic traits, plant nutrient contents, rhizosphere soil enzyme activities and chemical properties, and the rhizosphere bacterial community diversity and structure of three predominant sugarcane varieties under two Si treatments, i.e., 0 and 200 kg of silicon dioxide (SiO2) ha−1 regarded as Si0 and Si200, respectively. Results showed that Si application substantially improved the sugarcane stalk fresh weight and Si, phosphorus (P), and potassium (K) contents comparing to Si0, and had an obvious impact on rhizosphere soil pH, available Si (ASi), available P (AP), available K (AK), total phosphorus (TP), and the activity of acid phosphatase. Furthermore, the relative abundances of Proteobacteria showed a remarkable increase in Si200, which may be the dominant group in sugarcane growth under Si application. Interestingly, the AP was noticed as a major factor that caused bacterial community structure differences between the two Si treatments according to canonical correspondence analysis (CCA). In addition, the association network analysis indicated that Si application enriched the rhizosphere bacterial network, which could be beneficial to sugarcane growth. Overall, appropriate Si application, i.e., 200 kg SiO2 ha−1 promoted sugarcane growth, changed rhizosphere soil enzyme activities and chemical properties, and bacterial community structures.
Integrated Analysis of mRNA and Non-coding RNA Transcriptome in Pepper (Capsicum chinense) Hybrid at Seedling and Flowering Stages

Pepper is an important vegetable in the world. In this work, mRNA and ncRNA transcriptome profiles were applied to understand the heterosis effect on the alteration in the gene expression at the seedling and flowering stages between the hybrid and its parents in Capsicum chinense. Our phenotypic data indicated that the hybrid has dominance in leaf area, plant scope, plant height, and fruit-related traits. Kyoto Encyclopedia of Genes and Genomes analysis showed that nine members of the plant hormone signal transduction pathway were upregulated in the seedling and flowering stages of the hybrid, which was supported by weighted gene coexpression network analysis and that BC332_23046 (auxin response factor 8), BC332_18317 (auxin-responsive protein IAA20), BC332_13398 (ethylene-responsive transcription factor), and BC332_27606 (ethylene-responsive transcription factor WIN1) were candidate hub genes, suggesting the important potential role of the plant hormone signal transduction in pepper heterosis. Furthermore, some transcription factor families, including bHLH, MYB, and HSF were greatly over-dominant. We also identified 2,525 long ncRNAs (lncRNAs), 47 micro RNAs (miRNAs), and 71 circle RNAs (circRNAs) in the hybrid. In particular, downregulation of miR156, miR169, and miR369 in the hybrid suggested their relationship with pepper growth vigor. Moreover, we constructed some lncRNA–miRNA–mRNA regulatory networks that showed a multi-dimension to understand the ncRNA relationship with heterosis. These results will provide guidance for a better understanding of the molecular mechanism involved in pepper heterosis.
Prognostic Role of EGFR/p-EGFR in Patients With Nasopharyngeal Carcinoma: A Meta-Analysis

Background The prognostic value of epidermal growth factor receptor (EGFR)/phosphorylated EGFR (p-EGFR) expression in nasopharyngeal carcinoma remains controversial. A meta-analysis was performed to investigate prognostic significance of EGFR/p-EGFR expression in patients with nasopharyngeal carcinoma. Methods Literatures published before November 2020 were systematically searched in relevant databases, including PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wan fang databases. STATA 13 statistical software was used to analyze the pooled hazard ratio (HR) and 95% confidence interval (CI). Heterogeneity of the studies was examined by I2. Sensitivity and subgroup analysis were performed to explore sources of heterogeneity. The potential publication bias was assessed using both Egger’s and Begg’s tests. Results A total of 20 literatures with 1545 patients were included for the meta-analysis. The meta-analysis results suggested that high expression of EGFR was significantly associated with poor overall survival (OS) (HR = 1.70, 95% CI: 1.24–3.15, P = 0.001) and disease-free survival (DFS) (HR = 2.58, 95% CI: 1.87–3.56, P = 0.000). However, it was not significantly associated with progression-free survival (PFS) (HR = 1.85, 95% CI: 0.90–3.82, P = 0.09) and distant metastasis-free survival (DMFS) (HR = 1.39, 95% CI: 0.73–2.67, P = 0.319). The subgroup analysis indicated that patients with EGFR high expression in studies of higher TNM stage (III–IV) ratio had significantly poor OS (HR = 2.27, 95% CI: 1.09–4.73, P = 0.03), but heterogeneity existed in studies (I2 = 95.1%, P = 0.000). Sensitivity analyses revealed that EGFR expression did not significantly affect OS by an individual study solely, indicating there was inherent heterogeneity in OS cohorts. There was no significant heterogeneity among eight studies in the DFS cohorts (I2 = 0%, P = 0.606). There was significant heterogeneity between EGFR expression and DMFS (I2 = 82.8%, P = 0.000). Sub-group analysis in differentiated carcinoma demonstrated a smaller heterogeneity (I2 = 33.2%). In addition, p-EGFR high expression had no significant correlation with OS (HR = 1.00, 95% CI: 0.88–1.14, P = 0.982) and DMFS (HR = 1.21, 95% CI: 0.96–1.52, P = 0.112). The heterogeneity among p-EGFR and OS studies was small (I2 = 21%, P = 0.26). There was no significant heterogeneity in the DMFS cohorts (I2 = 0%, P = 0.497). Conclusion EGFR high-expression was significantly associated with poor OS and DFS, which may serve as a prognostic predictor for nasopharyngeal cancer. Systematic Review Registration [https://www.crd. york.ac. uk/PROSPERO], identifier [number CRD42021258457].
The Primary Cilium on Cells of Developing Skeletal Rudiments; Distribution, Characteristics and Response to Mechanical Stimulation

Embryo movement is important for tissue differentiation and the formation of functional skeletal elements during embryonic development: reduced mechanical stimulation results in fused joints and misshapen skeletal rudiments with concomitant changes in the signaling environment and gene expression profiles in both mouse and chick immobile embryos. Despite the clear relationship between movement and skeletogenesis, the precise mechanisms by which mechanical stimuli influence gene regulatory processes are not clear. The primary cilium enables cells to sense mechanical stimuli in the cellular environment, playing a crucial mechanosensory role during kidney development and in articular cartilage and bone but little is known about cilia on developing skeletal tissues. Here, we examine the occurrence, length, position, and orientation of primary cilia across developing skeletal rudiments in mouse embryos during a period of pronounced mechanosensitivity and we report differences and similarities between wildtype and muscle-less mutant (Pax3Spd/Spd) rudiments. Strikingly, joint regions tend to have cilia positioned and oriented away from the joint, while there was a less obvious, but still significant, preferred position on the posterior aspect of cells within the proliferative and hypertrophic zones. Regions of the developing rudiments have characteristic proportions of ciliated cells, with more cilia in the resting and joint zones. Comparing wildtype to muscle-less mutant embryos, cilia are shorter in the mutant with no significant difference in the proportion of ciliated cells. Cilia at the mutant joint were also oriented away from the joint line.