Miracle-dz/UniFAR-FTUs huggingface dataset:
Proinflammatory Cytokine Modulates Intracellular Calcium Handling and Enhances Ventricular Arrhythmia Susceptibility

Background: The mechanism of Interleukin-17 (IL-17) induced ventricular arrhythmia (VA) remains unclear. This study aimed to investigate the effect of intracellular calcium (Cai) handling and VA susceptibility by IL-17. Methods: The electrophysiological properties of isolated perfused rabbit hearts under IL-17 (20 ng/ml, N = 6) and the IL-17 with neutralizer (0.4 μg/ml, N = 6) were evaluated using an optical mapping system. The action potential duration (APD) and Cai transient duration (CaiTD) were examined, and semiquantitative reverse transcriptase-polymerase chain reaction analysis of ion channels was performed. Results: There were longer APD80, CaiTD80 and increased thresholds of APD and CaiTD alternans, the maximum slope of APD restitution and induction of VA threshold in IL-17 group compared with those in IL-17 neutralizer and baseline groups. During ventricular fibrillation, the number of phase singularities and dominant frequency were both significantly greater in IL-17 group than in baseline group. The mRNA expressions of the Na+/Ca2+ exchanger, phospholamban, and ryanodine receptor Ca2+ release channel were upregulated, and the subunit of L-type Ca2+ current and sarcoplasmic reticulum Ca2+-ATPase 2a were significantly reduced in IL-17 group compared to baseline and IL-17 neutralizer group. Conclusions: IL-17 enhanced CaiTD and APD alternans through disturbances in calcium handling, which may increase VA susceptibility.
Magnetic and dielectric properties study of cobalt ferrite nanoparticles synthesized by co-precipitation method

Cobalt ferrite nanoparticles were prepared by co-precipitation method and were heat treated at 100 o C, 200 o C, 400 o C and 600 o C for 2 h to increase the particle size. Phase purity of samples was confirmed by X-ray diffraction. Scherrer formula calculations showed crystallite size varied from 12 to 24 nm when heated from 100 o C to 600 o C. Transmission electron microscopy reveals a uniform and narrow particle size distribution about 12 nm for as-prepared cobalt ferrite particles. Room temperature saturation magnetization was found to vary from 40.8 to 67.0 emu/g as the particle size increased from12 nm to 24 nm. Increase in saturation magnetization with increase in particle size was attributed to the presence of magnetic inert layer on the surface of nanoparticles. Inert layer thickness calculated at 10 K and 300 K was 6 A and 11 A respectively. The dielectric properties e’, tanδ, Z and θ have been studied as a function of frequency and particles size. For the 12 nm grain size, the dielectric constant is one order higher than that of bulk cobalt ferrite. Increase in the grain size showed an increase in the dielectric constant. The increase in the conductivity with grain size is mainly due to the grain size effects. The present study shows that the dielectric properties can be tailor-made to suit the requirement of a particular application by controlling the grain size.
Staphylococcus aureus-Specific Tissue-Resident Memory CD4+ T Cells Are Abundant in Healthy Human Skin

The skin is an immunocompetent tissue that harbors several kinds of immune cells and a plethora of commensal microbes constituting the skin microbiome. Staphylococcus aureus is a prominent skin pathogen that colonizes a large proportion of the human population. We currently have an incomplete understanding of the correlates of protection against S. aureus infection, however genetic and experimental evidence has shown that CD4+ T cells play a key role in orchestrating a protective anti-S. aureus immune response. A high S. aureus-specific memory CD4+ T cell response has been reported in the blood of healthy subjects. Since T cells are more abundant in the skin than in blood, we hypothesized that S. aureus-specific CD4+ T cells could be present in the skin of healthy individuals. Indeed, we observed proliferation of tissue-resident memory CD4+ T cells and production of IL-17A, IL-22, IFN-γ and TNF-β by cells isolated from abdominal skin explants in response to heat-killed S. aureus. Remarkably, these cytokines were produced also during an ex vivo epicutaneous S. aureus infection of human skin explants. These findings highlight the importance of tissue-resident memory CD4+ T cells present at barrier sites such as the skin, a primary entry site for S. aureus. Further phenotypical and functional characterization of these cells will ultimately aid in the development of novel vaccine strategies against this elusive pathogen.
SP600125, a JNK-Specific Inhibitor, Regulates in vitro Auricular Cartilage Regeneration by Promoting Cell Proliferation and Inhibiting Extracellular Matrix Metabolism

In vitro construction is a major trend involved in cartilage regeneration and repair. Satisfactory in vitro cartilage regeneration depends on a suitable culture system. Current chondrogenic culture systems with a high content of transforming growth factor beta-1 effectively promote cartilaginous extracellular matrix (ECM) production but inhibit chondrocyte survival. As is known, inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway acts in blocking the progression of osteoarthritis by reducing chondrocyte apoptosis and cartilage destruction. However, whether inhibiting JNK signaling resists the inhibitory effect of current chondrogenic medium (CM) on cell survival and affects in vitro auricular cartilage regeneration (including cell proliferation, ECM synthesis, and degradation) has not been investigated. In order to address these issues and optimize the chondrogenic culture system, we generated a three-dimensional in vitro auricular cartilage regeneration model to investigate the effects of SP600125 (a JNK-specific inhibitor) on chondrocyte proliferation and ECM metabolism. SP600125 supplementation efficiently promoted cell proliferation at both cellular and tissue levels and canceled the negative effect of our chondrogenic culture system on cell survival. Moreover, it significantly inhibited ECM degradation by reducing the expressions of tumor necrosis factor-alpha, interleukin-1-beta, and matrix metalloproteinase 13. In addition, SP600125 inhibited ECM synthesis at both cellular and tissue levels, but this could be canceled and even reversed by adding chondrogenic factors; yet this enabled a sufficient number of chondrocytes to be retained at the same time. Thus, SP600125 had a positive effect on in vitro auricular cartilage regeneration in terms of cell proliferation and ECM degradation but a negative effect on ECM synthesis, which could be reversed by adding CM. Therefore, a combination of SP600125 and CM might help in optimizing current chondrogenic culture systems and achieve satisfactory in vitro cartilage regeneration by promoting cell proliferation, reducing ECM degradation, and enhancing ECM synthesis.
LHPP-Mediated Histidine Dephosphorylation Suppresses the Self-Renewal of Mouse Embryonic Stem Cells

Self-renewal of embryonic stem cells (ESCs) is orchestrated by a vast number of genes at the transcriptional and translational levels. However, the molecular mechanisms of post-translational regulatory factors in ESC self-renewal remain unclear. Histidine phosphorylation, also known as hidden phosphorylation, cannot be detected by conventional experimental methods. A recent study defined phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) as a histidine phosphatase, which regulates various biological behaviors in cells via histidine dephosphorylation. In this study, the doxycycline (DOX)-induced hLHPP-overexpressing mouse ESCs and mouse LHPP silenced mESCs were constructed. Quantitative polymerase chain reaction (qPCR), western blotting analysis, immunofluorescence, Flow cytometry, colony formation assays, alkaline phosphatase (AP) and bromodeoxyuridine (Brdu) staining were performed. We found that the histidine phosphorylation level was strikingly reduced following LHPP overexpression. Besides, the expression of Oct4 and Lefty1, indispensable genes in the process of ESCs self-renewal, was significantly down-regulated, while markers related to the differentiation were markedly elevated. Moreover, LHPP-mediated histidine dephosphorylation induced G0/G1 phase arrest in mESCs, suggesting LHPP was implicated in cell proliferation and cell cycle. Conversely, silencing of Lhpp promoted the self-renewal of mESCs and reversed the RA induced increased expression of genes associated with differentiation. Mechanistically, our findings suggested that the enzymatic active site of LHPP was the cysteine residue at position 226, not 53. LHPP-mediated histidine dephosphorylation lowered the expression levels of β-catenin and the cell cycle-related genes CDK4 and CyclinD1, while it up-regulated the cell cycle suppressor genes P21 and P27. Taken together, our findings reveal that LHPP-mediated histidine dephosphorylation plays a role in the self-renewal of ESCs. LHPP-mediated histidine dephosphorylation inhibited the self-renewal of ESCs by negatively regulating the Wnt/β-catenin pathway and downstream cell cycle-related genes, providing a new perspective and regulatory target for ESCs self-renewal.
lncRNA Gm16410 Mediates PM2.5-Induced Macrophage Activation via PI3K/AKT Pathway

PM2.5 refers to atmospheric particulate matters with a diameter of less than 2.5 μm. The deposit of PM2.5 in lung cells can cause oxidative stress, leading to changes in macrophage polarity, which can subsequently cause pulmonary inflammation. Long-chain non-coding RNA (lncRNA) is a class of transcripts that regulate biological processes through multiple mechanisms. However, the role of lncRNA in PM2.5-induced lung inflammation has not been established. In this study, the biological effects and associated mechanism of lncRNA in PM2.5-induced change in macrophage polarity were investigated. The lncRNA-mediated PM2.5-induced macrophage inflammation and lung inflammation-associated injury were also determined. Mice were exposed to chronic levels of PM2.5, and changes in the expression of lncRNA in the lung were measured by lncRNA microarray. lncRNAs that showed significant changes in expression in response to PM2.5 were identified. lncRNA showing the biggest change was subjected to further analysis to determine its functional roles and mechanisms with respect to macrophage activation. The result showed that a significant reduction in expression of one lncRNA, identified as lncGm16410, was observed in the lung of mice and RAW264.7 cells following exposure to PM2.5. lncGm16410 suppressed PM2.5-induced macrophage activation via the SRC protein-mediated PI3K/AKT signaling pathway. PM2.5 promoted lung inflammation by downregulating the expression of lncGm16410, enhancing the activation of macrophages. Thus, lncGm16410 might provide new insight into the prevention of PM2.5 injury.
Monomeric C-Reactive Protein Localized in the Cerebral Tissue of Damaged Vascular Brain Regions Is Associated With Neuro-Inflammation and Neurodegeneration-An Immunohistochemical Study

Monomeric C-reactive protein (mCRP) is now accepted as having a key role in modulating inflammation and in particular, has been strongly associated with atherosclerotic arterial plaque progression and instability and neuroinflammation after stroke where a build-up of the mCRP protein within the brain parenchyma appears to be connected to vascular damage, neurodegenerative pathophysiology and possibly Alzheimer's Disease (AD) and dementia. Here, using immunohistochemical analysis, we wanted to confirm mCRP localization and overall distribution within a cohort of AD patients showing evidence of previous infarction and then focus on its co-localization with inflammatory active regions in order to provide further evidence of its functional and direct impact. We showed that mCRP was particularly seen in large amounts within brain vessels of all sizes and that the immediate micro-environment surrounding these had become laden with mCRP positive cells and extra cellular matrix. This suggested possible leakage and transport into the local tissue. The mCRP-positive regions were almost always associated with neurodegenerative, damaged tissue as hallmarked by co-positivity with pTau and β-amyloid staining. Where this occurred, cells with the morphology of neurons, macrophages and glia, as well as smaller microvessels became mCRP-positive in regions staining for the inflammatory markers CD68 (macrophage), interleukin-1 beta (IL-1β) and nuclear factor kappa B (NFκB), showing evidence of a perpetuation of inflammation. Positive staining for mCRP was seen even in distant hypothalamic regions. In conclusion, brain injury or inflammatory neurodegenerative processes are strongly associated with mCRP localization within the tissue and given our knowledge of its biological properties, it is likely that this protein plays a direct role in promoting tissue damage and supporting progression of AD after injury.
The Emerging Trend of Bio-Engineering Approaches for Microbial Nanomaterial Synthesis and Its Applications

Micro-organisms colonized the world before the multi-cellular organisms evolved. With the advent of microscopy, their existence became evident to the mankind and also the vast processes they regulate, that are in direct interest of the human beings. One such process that intrigued the researchers is the ability to grow in presence of toxic metals. The process seemed to be simple with the metal ions being sequestrated into the inclusion bodies or cell surfaces enabling the conversion into nontoxic nanostructures. However, the discovery of genome sequencing techniques highlighted the genetic makeup of these microbes as a quintessential aspect of these phenomena. The findings of metal resistance genes (MRG) in these microbes showed a rather complex regulation of these processes. Since most of these MRGs are plasmid encoded they can be transferred horizontally. With the discovery of nanoparticles and their many applications from polymer chemistry to drug delivery, the demand for innovative techniques of nanoparticle synthesis increased dramatically. It is now established that microbial synthesis of nanoparticles provides numerous advantages over the existing chemical methods. However, it is the explicit use of biotechnology, molecular biology, metabolic engineering, synthetic biology, and genetic engineering tools that revolutionized the world of microbial nanotechnology. Detailed study of the micro and even nanolevel assembly of microbial life also intrigued biologists and engineers to generate molecular motors that mimic bacterial flagellar motor. In this review, we highlight the importance and tremendous hidden potential of bio-engineering tools in exploiting the area of microbial nanoparticle synthesis. We also highlight the application oriented specific modulations that can be done in the stages involved in the synthesis of these nanoparticles. Finally, the role of these nanoparticles in the natural ecosystem is also addressed.
A Theoretical Formula for the Solubility of Hydrogen in Metals

1— In certain metals such as Cu, hydrogen appears to be dissolved in the metal in the form of free protons, which do not affect the normal metal lattice, even when present at very considerable concentrations. In other metals such as Ti, definite metal hydrides are formed which have a different lattice structure from the pure metal. The metal Pd is intermediate since the hydrogen affects the lattice constant. It is the properties of the former group of metals which are first to be discussed here, since the fact that the normal metal lattice is (practically) unaffected seems to justify a very simple theoretical treatment of the solubility, and it is of some interest to examine how the theory compares with the facts. We shall find that we can bring the facts and the theory into satisfactory order together. The various types of solubility curve are shown in fig. 1. 2— From evidence such as the well-known p 1/2 law for the rate of diffusion of hydrogen through metals we may certainly assume that the hydrogen in the metal is atomic. For the present we shall neglect the difference between atoms of hydrogen and protons plus electrons, and merely assume that the atoms are present as such in the metal, without specific interaction with particular metallic atoms; the metal merely provides a region in which hydrogen atoms can exist and move in a definite field of potential energy. Specific contributions by the electrons of the hydrogen atoms will be considered later, when the hydrogen atoms in the metal will be considered as protons plus electrons.
Advances in Aptamer-Based Biomarker Discovery

The discovery and identification of biomarkers promote the rational and fast development of medical diagnosis and therapeutics. Clinically, the application of ideal biomarkers still is limited due to the suboptimal technology in biomarker discovery. Aptamers are single-stranded deoxyribonucleic acid or ribonucleic acid molecules and can selectively bind to varied targets with high affinity and specificity. Compared with antibody, aptamers have desirable advantages, such as flexible design, easy synthesis and convenient modification with different functional groups. Currently, different aptamer-based technologies have been developed to facilitate biomarker discovery, especially CELL-SELEX and SOMAScan technology. CELL-SELEX technology is mainly used to identify cell membrane surface biomarkers of various cells. SOMAScan technology is an unbiased biomarker detection method that can analyze numerous and even thousands of proteins in complex biological samples at the same time. It has now become a large-scale multi-protein biomarker discovery platform. In this review, we introduce the aptamer-based biomarker discovery technologies, and summarize and highlight the discovered emerging biomarkers recently in several diseases.
An Arabidopsis Prolyl 4 Hydroxylase Is Involved in the Low Oxygen Response

Plant responses to flooding, submergence and waterlogging are important for adaptation to climate change environments. Therefore, the characterization of the molecular mechanisms activated under hypoxic and anoxic conditions might lead to low oxygen resilient crops. Although in mammalian systems prolyl 4 hydroxylases (P4Hs) are involved in the oxygen sensing pathway, their role in plants under low oxygen has not been extensively investigated. In this report, an Arabidopsis AtP4H3 T-DNA knock out mutant line showed higher sensitivity to anoxic treatment possibly due to lower induction of the fermentation pathway genes, ADH and PDC1, and of sucrose synthases, SUS1 and SUS4. This sensitivity to anoxia was accompanied by lower protein levels of AGPs-bound epitopes such as LM14 in the mutant line and induction of extensins-bound epitopes, while the expression levels of the majority of the AGPs genes were stable throughout a low oxygen time course. The lower AGPs content might be related to altered frequency of proline hydroxylation occurrence in the p4h3 line. These results indicate active involvement of proline hydroxylation, a post-translational modification, to low oxygen response in Arabidopsis.
Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition

Poxviruses are dangerous pathogens, which can cause fatal infection in unvaccinated individuals. The causative agent of smallpox in humans, variola virus, is closely related to the bovine vaccinia virus, yet the molecular basis of their selectivity is currently incompletely understood. Here, we examine the role of the electrostatics in the selectivity of the smallpox protein SPICE and vaccinia protein VCP toward the human and bovine complement protein C3b, a key component of the complement immune response. Electrostatic calculations, in-silico alanine-scan and electrostatic hotspot analysis, as introduced by Kieslich and Morikis (PLoS Comput. Biol. 2012), are used to assess the electrostatic complementarity and to identify sites resistant to local perturbation where the electrostatic potential is likely to be evolutionary conserved. The calculations suggest that the bovine C3b is electrostatically prone to selectively bind its VCP ligand. On the other hand, the human isoform of C3b exhibits a lower electrostatic complementarity toward its SPICE ligand. Yet, the human C3b displays a highly preserved electrostatic core, which suggests that this isoform could be less selective in binding different ligands like SPICE and the human Factor H. This is supported by experimental cofactor activity assays revealing that the human C3b is prone to bind both SPICE and Factor H, which exhibit diverse electrostatic properties. Additional investigations considering mutants of SPICE and VCP that revert their selectivity reveal an “electrostatic switch” into the central modules of the ligands, supporting the critical role of the electrostatics in the selectivity. Taken together, these evidences provide insights into the selectivity mechanism of the complement regulator proteins encoded by the variola and vaccinia viruses to circumvent the complement immunity and exert their pathogenic action. These fundamental aspects are valuable for the development of novel vaccines and therapeutic strategies.
Treatment of Cystic Fibrosis: From Gene- to Cell-Based Therapies

Prognosis of patients with cystic fibrosis (CF) varies extensively despite recent advances in targeted therapies that improve CF transmembrane conductance regulator (CFTR) function. Despite being a multi-organ disease, extensive lung tissue destruction remains the major cause of morbidity and mortality. Progress towards a curative treatment strategy that implements a CFTR gene addition-technology to the patients’ lungs has been slow and not yet developed beyond clinical trials. Improved delivery vectors are needed to overcome the body’s defense system and ensure an efficient and consistent clinical response before gene therapy is suitable for clinical care. Cell-based therapy–which relies on functional modification of allogenic or autologous cells ex vivo, prior to transplantation into the patient–is now a therapeutic reality for various diseases. For CF, pioneering research has demonstrated proof-of-principle for allogenic transplantation of cultured human airway stem cells into mouse airways. However, applying a cell-based therapy to the human airways has distinct challenges. We review CF gene therapies using viral and non-viral delivery strategies and discuss current advances towards autologous cell-based therapies. Progress towards identification, correction, and expansion of a suitable regenerative cell, as well as refinement of pre-cell transplant lung conditioning protocols is discussed.