bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of glucocorticoid receptor activation regulated expression of thrombospondin-1
Authors: Wang Yan-Yan , Song Yi-Yi , Jiang Wen-Yi , Zhang Hao-Tian , Chen Jing-Wei , Murao Koji , Sun Wan-Ping , Zhang Guo-Xing 
Published: April 2023

AbstractObjective:Thrombospondin-1 (TSP-1) plays an important role in platelet activation and aggregation and aggravates thrombosis. Chronic stress can cause a variety of diseases, including coagulation disorders, increased thrombosis, atherosclerosis, and a series of cardiovascular and cerebrovascular diseases. However, it is still unknown how chronic stress regulates the expression of TSP-1 after glucocorticoid receptor activation.Approach and Results:rats chronic unpredictable mild stress model was applied and the changes of TSP-1 and microRNAs in plasma were examined. Effects of glucocorticoid receptor activation on human umbilical vein endothelial cells and platelets were observed. Glucocorticoid receptor (GR) activation upregulated the expression of TSP-1 and downregulated the expression of microRNA-1-3p accompanied with increase of phosphorylation of p38 mitogen-activated protein kinase (MAPK) and argonaute-2 (AGO-2). Blockade of p38 MAPK phosphorylation resulted in decrease of phosphorylation level of AGO-2, increase of microRNA-1-3p expression, and decrease of TSP-1 expression. Transfection of AGO-2 Y393F point mutant plasmid, increased microRNA-1-3p expression and decreased TSP-1 expression, transfection of microRNA-1-3p mimic also decreased TSP-1 expression, while transfection of microRNA-1-3p inhibitor increased TSP-1 expression. Finally, GR activation led to an increase in the phosphorylation level of p38 MAPK in platelets and an increase in the level of TSP-1 in the supernatant.Conclusions:our study demonstrates that GR activation in HUVEC stimulates the phosphorylation of p38 MAPK, which in turn promotes the phosphorylation of AGO-2 and inhibits the maturation of microRNA-1-3p, leading to elevated expression of TSP-1, GR activation in platelets leads to the release of TSP-1.Abstract FigureGraphical AbstractHSS: Hydrocortisone sodium succinate
Synergistic Screening of Peptide-Based Biotechnological Drug Candidates for Neurodegenerative Diseases using Yeast Display and Phage Display
Authors: Özçelik Cemile Elif , Beğli Özge , Hınçer Ahmet , Ahan Recep Erdem , Kesici Mehmet Seçkin , Kasırga Talip Serkan , Özçubukçu Salih , Şeker Urartu Özgür Şafak 
Published: April 2023

AbstractPeptide therapeutics are robust and promising molecules for treating diverse disease conditions. These molecules can be developed from naturally occurring or mimicking native peptides, through rational design and peptide libraries. We developed a new platform for the rapid screening of the peptide therapeutics for disease targets. In the course of the study, we aimed to employ our platform to screen a new generation of peptide therapeutics candidates against aggregation prone protein targets. Two peptide drug candidates for the protein aggregation prone diseases namely Parkinson’s and Alzheimer’s diseases were screened. Currently, there are several therapeutic applications that are only effective in masking or slowing down symptom development. Nonetheless, different approaches are developed for inhibiting amyloid aggregation in the secondary nucleation phase, which is critical for amyloid fibril formation. Instead of targeting secondary nucleated protein structures, we tried to inhibit monomeric amyloid units as a novel approach for halting disease-condition. To achieve this, we combined yeast surface display and phage display library platforms. We expressed α-synuclein, amyloid β40, and amyloid β42on yeast surface, and we selected peptides by using phage display library. After iterative biopanning cycles optimized for yeast cells, several peptides were selected for interaction studies. All of the peptides have been usedin vitrocharacterization methods which are QCM-D measurement, AFM imaging, and ThT assay, and they have yielded promising results in order to block fibrillization or interact with amyloid units as a sensor molecule candidate. Therefore, peptides are good choice for diverse disease-prone molecule inhibition particularly those inhibiting fibrillization. Additionally, these selected peptides can be used as drugs and sensors to detect disease quickly and halt disease progression.Abstract Figure
Eco-evolutionary feedbacks shape the evolution of constitutive and inducible defences
Authors: Watson Bridget N. J. , Pursey Elizabeth , Gandon Sylvain , Westra Edze R. 
Published: April 2023

AbstractOrganisms have evolved a range of constitutive (always active) and inducible (elicited by parasites) defence mechanisms, but we have limited understanding of what drives the evolution of these orthogonal defence strategies. Bacteria and their phages offer a tractable system to study this: bacteria can acquire constitutive resistance by mutation of the phage receptor (surface mutation,sm) or induced resistance through their CRISPR-Cas adaptive immune system. Using a combination of theory and experiments we demonstrate that the mechanism that establishes first has a strong advantage because it weakens selection for the alternative resistance mechanism. As a consequence, ecological factors that alter the relative frequencies at which the different resistances are acquired have a strong and lasting impact: high growth conditions promote the evolution ofsmresistance by increasing the influx of receptor mutation events during the early stages of the epidemic, whereas a high infection risk during this stage of the epidemic promotes the evolution of CRISPR immunity, since it fuels the (infection-dependent) acquisition of CRISPR immunity. This work highlights the strong and lasting impact of the transient evolutionary dynamics during the early stages of an epidemic on the long-term evolution of constitutive and induced defences, which may be leveraged to manipulate phage resistance evolution in clinical and applied settings.
β1 integrin signaling governs necroptosis via the chromatin remodeling factor CHD4
Authors: Sun Zhiqi , Cernilogar Filippo M. , Horvatic Helena , Yeroslaviz Assa , Abdullah Zeinab , Schotta Gunnar , Hornung Veit 
Published: April 2023

AbstractFibrosis, characterized by sustained activation of myofibroblasts and excessive extracellular matrix (ECM) deposition, is known to be associated with chronic inflammation. RIPK3, the central kinase of necroptosis signaling, is upregulated in fibrosis and contributes to the TNF-mediated inflammation. In bile duct ligation-induced liver fibrosis, we found that myofibroblasts are the major cell type expressing RIPK3. Genetic ablation of β1 integrins, the major profibrotic ECM receptors in fibroblasts, not only abolished ECM fibrillogenesis but also blunted RIPK3 expression via an epigenetic mechanism mediated by the chromatin remodeling factor CHD4. While the function of CHD4 has been conventionally linked to NuRD and ChAHP complexes, we found that CHD4 potently repressed a set of genes, includingRipk3, with high locus specificity but independent of either the NuRD or ChAHP complex. Thus, our data uncover that β1 integrin intrinsically links fibrotic signaling to RIPK3-driven inflammation via a novel mode of action of CHD4.
LSD microdosing attenuates the impact of temporal priors in time perception
Authors: Sadibolova Renata , Murray-Lawson Clare , Family Neiloufar , Williams Luke T. J. , Luke David P. , Terhune Devin B. 
Published: April 2023

AbstractRecent theoretical work embedded within the predictive processing framework has proposed that the neurocognitive and therapeutic effects of psychedelics are driven by the modulation of priors (Carhart-Harris & Friston, 2019). We conducted pre-registered re-analyses of previous research (Yanakieva et al., 2019) to examine whether microdoses of lysergic acid diethylamide (LSD) alleviate the temporal reproduction bias introduced by priors, as predicted by this theoretical framework. In a between-groups design, participants were randomly assigned to one of four groups receiving LSD (5, 10, or 20 μg) or placebo (0 μg) and completed a visual temporal reproduction task spanning subsecond to suprasecond intervals (0.8 to 4 sec). Using mixed-effects modelling, we evaluated the impact of the treatment group, and of the overall history of stimulus intervals (globalpriors) and the local stimulus history (localpriors), weighted by their respective precision weights (inverse of variance), on temporal reproduction. Our principal finding was that the precision-weighted local priors and their precision weights reduced the under-reproduction bias observed under LSD in the original research. Furthermore, controlling for the precision- weighted local prior eliminated the reduced temporal reproduction bias under LSD, indicating that LSD microdosing mitigated the temporal under-reproduction by reducing the relative weighting of priors. These results suggest that LSD microdosing alters human time perception by decreasing the influence of local temporal priors.
Gap junctions in Turing-type periodic feather pattern formation
Authors: Tseng Chun-Chih , Woolley Thomas E. , Jiang Ting-Xin , Wu Ping , Maini Philip K. , Widelitz Randall B. , Chuong Cheng-Ming 
Published: April 2023

AbstractPeriodic patterning requires coordinated cell-cell interactions at the tissue level. Turing showed, using mathematical modeling, how spatial patterns could arise from the reactions of a diffusive activator-inhibitor pair in an initially homogenous two-dimensional field. Most activators and inhibitors studied in biological systems are proteins, and the roles of cell-cell interaction, ions, bioelectricity, etc. are only now being identified. Gap junctions (GJs) mediate direct exchanges of ions or small molecules between cells, enabling rapid long-distance communications in a cell collective. They are therefore good candidates for propagating non-protein-based patterning signals that may act according to the Turing principles. Here, we explore the possible roles of GJs in Turing-type patterning using feather pattern formation as a model. We found seven of the twelve investigated GJ isoforms are highly dynamically expressed in the developing chicken skin.In ovofunctional perturbations of the GJ isoform, connexin 30, by siRNA and the dominant-negative mutant applied before placode development led to disrupted primary feather bud formation, including patches of smooth skin and buds of irregular sizes. Later, after the primary feather arrays were laid out, inhibition of gap junctional intercellular communication in theex vivoskin explant culture allowed the emergence of new feather buds in temporal waves at specific spatial locations relative to the existing primary buds. The results suggest that gap junctional communication may facilitate the propagation of long-distance inhibitory signals. Thus, the removal of GJ activity would enable the emergence of new feather buds if the local environment is competent and the threshold to form buds is reached. We propose Turing-based computational simulations that can predict the appearance of these ectopic bud waves. Our models demonstrate how a Turing activator-inhibitor system can continue to generate patterns in the competent morphogenetic field when the level of intercellular communication at the tissue scale is modulated.
Activation loop plasticity and active site coupling in the MAP kinase, ERK2
Authors: Pegram Laurel , Riccardi Demian , Ahn Natalie 
Published: April 2023

AbstractChanges in the dynamics of the protein kinase, ERK2, have been shown to accompany its activation by dual phosphorylation. However, our knowledge about the conformational changes represented by these motions is incomplete. Previous NMR relaxation dispersion studies showed that active, dual-phosphorylated ERK2 undergoes global exchange between at least two energetically similar conformations. These findings, combined with measurements by hydrogen exchange mass spectrometry (HX-MS), suggested that the global conformational exchange involves motions of the activation loop (A-loop) that are coupled to regions surrounding the kinase active site. In order to better understand the contribution of dynamics to the activation of ERK2, we applied long conventional molecular dynamics (MD) simulations starting from crystal structures of active, phosphorylated (2P), and inactive, unphosphorylated (0P) ERK2. Individual trajectories were run for (5 to 25)µs and totaled 727µs. The results showed that the A-loop is unexpectedly flexible in both 2P- and 0P-ERK2, and able to adopt multiple long-lived (>5µs) conformational states. Simulations starting from the X-ray structure of 2P-ERK2 (2ERK) revealed A-loop states corresponding to restrained dynamics within the N-lobe, including regions surrounding catalytic residues. One A-loop conformer forms lasting interactions with the C-terminal L16 segment and shows reduced RMSF and greater compaction in the active site. By contrast, simulations starting from the most common X-ray conformation of 0P-ERK2 (5UMO) reveal frequent excursions of A-loop residues away from a C-lobe docking site pocket and towards a new state that shows greater dynamics in the N-lobe and disorganization around the active site. Thus, the A-loop in ERK2 appears to switch between distinct conformational states that reflect allosteric coupling with the active site, likely occurringviathe L16 segment. Analyses of crystal packing interactions across many structural datasets suggest that the A-loop observed in X-ray structures of ERK2 may be driven by lattice contacts and less representative of the solution structure. The novel conformational states identified by MD expand our understanding of ERK2 regulation, by linking the activated state of the kinase to reduced dynamics and greater compaction surrounding the catalytic site.
Inferring parameters of pyramidal neuron excitability in mouse models of Alzheimer’s disease using biophysical modeling and deep learning
Authors: Saghafi Soheil , Rumbell Timothy , Gurev Viatcheslav , Kozloski James , Tamagnini Francesco , Wedgwood Kyle C. A. , Diekman Casey O. 
Published: April 2023

AbstractAlzheimer’s disease (AD) is believed to occur when abnormal amounts of the proteins amyloid beta and tau aggregate in the brain, resulting in a progressive loss of neuronal function. Hippocampal neurons in transgenic mice with amyloidopathy or tauopathy exhibit altered intrinsic excitability properties. We introduce a novel parameter inference technique, deep hybrid modeling (DeepHM), that combines deep learning with biophysical modeling to map experimental data recorded from hippocampal CA1 neurons in transgenic AD mice and age-matched wildtype littermate controls to the parameter space of a conductance-based CA1 model. Although mechanistic modeling and machine learning methods are by themselves powerful tools for approximating biological systems and making accurate predictions from data, when used in isolation these approaches suffer from distinct shortcomings: model and parameter uncertainty limit mechanistic modeling, whereas machine learning methods disregard the underlying biophysical mechanisms. DeepHM addresses these shortcomings by using conditional generative adversarial networks (cGANs) to provide an inverse mapping of data to mechanistic models that identifies the distributions of mechanistic modeling parameters coherent to the data. Here, we demonstrate that DeepHM accurately infers parameter distributions of the conductance-based model and outperforms a Markov chain Monte Carlo method on several test cases using synthetic data. We then use DeepHM to estimate parameter distributions corresponding to the experimental data and infer which ion channels are altered in the Alzheimer’s mouse models compared to their wildtype controls at 12 and 24 months. We find that the conductances most disrupted by tauopathy, amyloidopathy, and aging are delayed rectifier potassium, transient sodium, and hyperpolarization-activated potassium, respectively.
From scalp to cortex, the whole isn’t greater than the sum of its parts: introducing GetTissueThickness (GTT) to assess age and sex differences in tissue thicknesses
Authors: Van Hoornweder Sybren , Geraerts Marc , Verstraelen Stefanie , Nuyts Marten , Caulfield Kevin A. , Meesen Raf 
Published: April 2023

AbstractNoninvasive techniques to record and stimulate the brain rely on passing through the tissues in between the scalp and cortex. Currently, there is no method to obtain detailed information about these scalp-to-cortex distance (SCD) tissues. We introduce GetTissueThickness (GTT), an open-source, automated approach to quantify SCD, and unveil how tissue thicknesses differ across age groups, sexes and brain regions (n = 250). We show that men have larger SCD in lower scalp regions and women have similar-to-larger SCD in regions closer to the vertex, with aging resulting in increased SCD in fronto-central regions. Soft tissue thickness varies by sex and age, with thicker layers and greater age-related decreases in men. Compact and spongy bone thickness also differ across sexes and age groups, with thicker compact bone in women in both age groups and an age-related thickening. Older men generally have the thickest cerebrospinal fluid layer and younger women and men having similar cerebrospinal fluid layers. Aging mostly results in grey matter thinning. Concerning SCD, the whole isn’t greater than the sum of its parts. GTT enables rapid quantification of the SCD tissues. The distinctive sensitivity of noninvasive recording and stimulation modalities to different tissues underscores the relevance of GTT.
Tackling emerging artemisinin resistance by modulating the defensive oxido-reductive mechanism of human malaria parasite by repurposing Nitrofurantoin
Authors: Shafi Sadat , Gupta Sonal , Jain Ravi , Shoaib Rumaisha , Munjal Akshay , Maurya Preeti , Najmi Abul Kalam , Singh Shailja 
Published: April 2023

AbstractOxidative stress mediated cell death has remained the prime parasiticidal mechanism of front line anti-malarial, artemisinin (ART). The emergence of resistantPlasmodiumparasites characterized by oxidative stress management due to impaired activation of ART as well as enhanced ROS detoxification has decreased its clinical efficacy. This gap can be filled by development of alternative chemotherapeutic agents to combat resistance defense mechanism. Interestingly, repositioning of clinically approved drugs presents an emerging approach for expediting anti-malarial drug development and resistance management. Herein, we evaluated the anti-malarial potential of Nitrofurantoin (NTF), a clinically used antibacterial drug, against intra-erythrocytic stages of ART-sensitive (Pf3D7) and resistant (PfKelch13R539T) strains ofPlasmodium falciparum(Pf), alone and in combination with ART. NTF exhibited growth inhibitory effect at sub micro molar concentration by arresting parasite growth at trophozoite stage. It also inhibited the survival of resistant parasites as revealed by ring survival assay. Concomitantly,in vitrocombination assay revealed synergistic association of NTF with ART. NTF was found to enhance the reactive oxygen and nitrogen species as well as induced mitochondrial membrane depolarization in parasite. Furthermore, we found that exposure of parasites to NTF disrupted their redox balance by impedingPfGlutathione Reductase activity, which manifests in enhanced oxidative stress, inducing parasite death.In vivoadministration of NTF, alone and in combination with ART inP. berghei ANKA infected mice blocked parasite multiplication and enhanced mean survival time. Overall, our results indicate NTF as a promising repurposable drug with therapeutic potential against drug sensitive as well as resistant parasites.
Anex vivohuman precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy
Authors: Pechous Roger D. , Malaviarachchi Priyangi A. , Banerjee Srijon K. , Byrum Stephanie D. , Alkam Duah H. , Ghaffarieh Alireza , Kurten Richard C. , Kennedy Joshua L. , Zhang Xuming 
Published: April 2023

ABSTRACTCOVID-19 has claimed millions of lives since the emergence of SARS-CoV-2, and lung disease appears the primary cause of the death in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive, and there is no existing model where the human disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of anex vivohuman precision-cut lung slice (hPCLS) platform for studying SARS-CoV-2 pathogenicity and innate immune responses, and for evaluating the efficacy of antiviral drugs against SARS-CoV-2. We show that while SARS-CoV-2 continued to replicate during the course of infection of hPCLS, infectious virus production peaked within 2 days, and rapidly declined thereafter. Although most proinflammatory cytokines examined were induced by SARS-CoV-2 infection, the degree of induction and types of cytokines varied significantly among hPCLS from individual donors, reflecting the heterogeneity of human populations. In particular, two cytokines (IP-10 and IL-8) were highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination revealed focal cytopathic effects late in the infection. Transcriptomic and proteomic analyses identified molecular signatures and cellular pathways that are largely consistent with the progression of COVID-19 in patients. Furthermore, we show that homoharringtonine, a natural plant alkaloid derived fromCephalotoxus fortunei, not only inhibited virus replication but also production of pro-inflammatory cytokines, and ameliorated the histopathological changes of the lungs caused by SARS-CoV-2 infection, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs.SIGNIFICANCEHere we established anex vivohuman precision-cut lung slice platform for assessing SARS-CoV-2 infection, viral replication kinetics, innate immune response, disease progression, and antiviral drugs. Using this platform, we identified early induction of specific cytokines, especially IP-10 and IL-8, as potential predictors for severe COVID-19, and uncovered a hitherto unrecognized phenomenon that while infectious virus disappears at late times of infection, viral RNA persists and lung histopathology commences. This finding may have important clinical implications for both acute and post-acute sequelae of COVID-19. This platform recapitulates some of the characteristics of lung disease observed in severe COVID-19 patients and is therefore a useful platform for understanding mechanisms of SARS-CoV-2 pathogenesis and for evaluating the efficacy of antiviral drugs.