Search

Background: Binding of P-selectin to P-selectin glycoprotein ligand-1 (PSGL-1) makes neutrophils roll on and adhere to inflammatory site. Intracellular calcium bursting of adhered neutrophils is a key event for subsequent arresting firmly at and migrating into the injured tissue. But, it remains unclear how the cytoplasmic calcium signaling of the cells were modulated by the fluid shear stress. Here, we focus on mechanical regulation of P-selectin-induced calcium signaling of neutrophil-like HL-60 cells under flow.Methods: HL-60 cells were loaded with Fluo-4 AM for fluorescent detection of intracellular calcium ion, and then perfused over P-selectin-coated bottom of parallel-plate flow chamber. The intracellular calcium concentration of firmly adhered cell under flow was observed in real time by fluorescence microscopy.Results: Force triggered, enhanced and quickened cytoplasmic calcium bursting of HL-60 on P-selectin. This force-dependent calcium signaling was induced by the immobilized P-selectin coated on substrates in absence of chemokine. Increasing of both shear stress and P-selectin concentration made the calcium signaling intensive, through quickening the cytosolic calcium release and upregulating both probability and peak level of calcium signaling.Conclusions: Immobilized P-selectin-induced calcium signaling of HL-60 cells is P-selectin concentration- and mechanical force-dependent. The higher both the P-selectin concentration and the external force on cell, the more intensive the calcium signaling. It might provide a novel insight into the mechano-chemical regulation mechanism for intracellular signaling pathways induced by adhesion molecules. [ABSTRACT FROM AUTHOR]

Background: Interaction between immunoglobulin-like receptor glycoprotein VI (GPVI) and collagen plays a central role in platelet activation and sequent firm adhesion. Of various antithrombotic agents targeting GPVI, antibody 10B12 is of great potential to block the GPVI-collagen interaction, but less is known about 10B12 paratope and GPVI epitope.Methods: Along the pathway in the computer strategy presented in our previous work, the 10B12/GPVI complex model was constructed through homology modeling and rigid-body docking, and the molecular dynamics (MD) simulation was used to detect the paratope residues on 10B12 and their partners on GPVI. Quantified by free and steered MD simulations, the stabilities of hydrogen bonds and salt bridges were used to rank the contributions of interface residues to binding of 10B12 and GPVI.Results: We predicted 12 key and seven dispensable residues in interaction of 10B12 to GPVI with present computational procedure. Besides of the 12 key residues, two are epitope residues (LYS41 and LYS59) which had been identified by previous mutation experiments, and others, including four epitope residues (ARG38, SER44, ARG46 and TYR47 on GPVI) and six paratope residues (GLU1, ASP98, GLU102, ASP107, ASP108 and ASP111 on 10B12), were newly found and also might be important for the 10B12-GPVI binding. The seven predicted dispensable residues on GPVI were had been illustrated in previous mutation experiments.Conclusions: The present computer strategy combining homology modeling, rigid body docking and MD simulation was illustrated to be effective in mapping paratope on antithrombotic antibody 10B12 to epitope on GPVI, and have large potential in drug discovery and antibody research. [ABSTRACT FROM AUTHOR]

Background: Trigeminal neuralgia is an episodic severe neuralgic pain and can be managed both medically and surgically. If possible, this should be directed by a Multidisciplinary Team (MDT) of specialised surgeons, physicians, dentists, psychologists and specialist nurses with access to all treatment modalities, which enables patients to make an informed decision about their future management., Objective: The aim of this study was to review the outcomes of patients managed by an MDT clinic, in a single institute over an eleven-year period., Methods: A prospective database was used to identify patients with trigeminal neuralgia or its variants who had attended a joint MDT clinic. The electronic notes were examined for demographics, onset and duration of trigeminal neuralgia, medications history, pain scores and details of surgical procedures if any by two independent assessors., Results: Three hundred thirty-four patients attended the MDT between 2008-2019. Forty-nine of them had surgery before being referred to the service and were included but analysed as a subgroup. Of the remaining patients, 54% opted to have surgery following the MDT either immediately or at a later date. At the last reported visit 55% of patients who opted to have surgery were pain free and off medications, compared to 15.5% of medically managed patients. Surgical complications were mostly attributable to numbness and in the majority of cases this was temporary. All patients who were not pain free, had complications after surgery or opted to remain on medical therapy were followed up in a facial pain clinic which has access to pain physicians, clinical nurse specialists and a tailored pain management program. Regular patient related outcome measures are collected to evaluate outcomes., Conclusion: An MDT clinic offers an opportunity for shared decision making with patients deciding on their personal care pathway which is valued by patients. Not all patients opt for surgery, and some continue to attend a multidisciplinary follow up program. Providing a full range of services including psychological support, improves outcomes., (© 2022. The Author(s).)

Background: Trigeminal neuralgia (TN) is an orofacial condition defined by reoccurring, spontaneous, short-lived but excruciating stabbing pain. Pharmacological interventions constitute the first-line treatment for TN, with antiepileptic drugs commonly prescribed. People treated for TN pain with antiepileptic drugs describe cognitive and motor difficulties affecting activities of daily living, and report poorer quality of life. We undertook the first comprehensive objective evaluation of sensorimotor and cognitive performance in participants being treated for TN pain with antiepileptic drugs relative to age-matched controls., Methods: Participants (43 TN, 41 control) completed a battery of sensorimotor (steering, aiming and tracking) and cognitive (working memory, processing speed, inhibition) tasks., Results: The TN group performed significantly worse than controls on the sensorimotor tracking and aiming tasks and across all cognitive measures., Conclusions: The data explain why patients treated with antiepileptic drugs report impairment when conducting activities of daily living (given the need for cognitive and motor capability within most of these). The study is an important first step in: (i) ensuring there is adequate information on the impact of pharmacological treatment; (ii) identifying measures to determine optimal medication dosage and track change over time; (iii) creating an evidence base that could allow scientific justification of alternative pain treatment options for TN (e.g. the costs/benefits of surgery).

Background: Binding of P-selectin to P-selectin glycoprotein ligand-1 (PSGL-1) makes neutrophils roll on and adhere to inflammatory site. Intracellular calcium bursting of adhered neutrophils is a key event for subsequent arresting firmly at and migrating into the injured tissue. But, it remains unclear how the cytoplasmic calcium signaling of the cells were modulated by the fluid shear stress. Here, we focus on mechanical regulation of P-selectin-induced calcium signaling of neutrophil-like HL-60 cells under flow., Methods: HL-60 cells were loaded with Fluo-4 AM for fluorescent detection of intracellular calcium ion, and then perfused over P-selectin-coated bottom of parallel-plate flow chamber. The intracellular calcium concentration of firmly adhered cell under flow was observed in real time by fluorescence microscopy., Results: Force triggered, enhanced and quickened cytoplasmic calcium bursting of HL-60 on P-selectin. This force-dependent calcium signaling was induced by the immobilized P-selectin coated on substrates in absence of chemokine. Increasing of both shear stress and P-selectin concentration made the calcium signaling intensive, through quickening the cytosolic calcium release and upregulating both probability and peak level of calcium signaling., Conclusions: Immobilized P-selectin-induced calcium signaling of HL-60 cells is P-selectin concentration- and mechanical force-dependent. The higher both the P-selectin concentration and the external force on cell, the more intensive the calcium signaling. It might provide a novel insight into the mechano-chemical regulation mechanism for intracellular signaling pathways induced by adhesion molecules.

Background: Uncovering complex network structures from a biological system is one of the main topic in system biology. The network structures can be inferred by the dynamical Bayesian network or Granger causality, but neither techniques have seriously taken into account the impact of environmental inputs., Results: With considerations of natural rhythmic dynamics of biological data, we propose a system biology approach to reveal the impact of environmental inputs on network structures. We first represent the environmental inputs by a harmonic oscillator and combine them with Granger causality to identify environmental inputs and then uncover the causal network structures. We also generalize it to multiple harmonic oscillators to represent various exogenous influences. This system approach is extensively tested with toy models and successfully applied to a real biological network of microarray data of the flowering genes of the model plant Arabidopsis Thaliana. The aim is to identify those genes that are directly affected by the presence of the sunlight and uncover the interactive network structures associating with flowering metabolism., Conclusion: We demonstrate that environmental inputs are crucial for correctly inferring network structures. Harmonic causal method is proved to be a powerful technique to detect environment inputs and uncover network structures, especially when the biological data exhibit periodic oscillations.

Background: Progressive advances in the measurement of complex multifactorial components of biological processes involving both spatial and temporal domains have made it difficult to identify the variables (genes, proteins, neurons etc.) significantly changed activities in response to a stimulus within large data sets using conventional statistical approaches. The set of all changed variables is termed hot-spots. The detection of such hot spots is considered to be an NP hard problem, but by first establishing its theoretical foundation we have been able to develop an algorithm that provides a solution., Results: Our results show that a first-order phase transition is observable whose critical point separates the hot-spot set from the remaining variables. Its application is also found to be more successful than existing approaches in identifying statistically significant hot-spots both with simulated data sets and in real large-scale multivariate data sets from gene arrays, electrophysiological recording and functional magnetic resonance imaging experiments., Conclusion: In summary, this new statistical algorithm should provide a powerful new analytical tool to extract the maximum information from complex biological multivariate data.