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1
Zhang, Bing, Weijuan Huang, Sen Pei, Jinfeng Zeng, Wei Shen, Daoze Wang, Gang Wang, et al. "Mechanisms for the circulation of influenza A(H3N2) in China: A spatiotemporal modelling study." PLOS Pathogens 18, no. 12 (December 16, 2022): e1011046. http://dx.doi.org/10.1371/journal.ppat.1011046.
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Circulation of seasonal influenza is the product of complex interplay among multiple drivers, yet characterizing the underlying mechanism remains challenging. Leveraging the diverse seasonality of A(H3N2) virus and abundant climatic space across regions in China, we quantitatively investigated the relative importance of population susceptibility, climatic factors, and antigenic change on the dynamics of influenza A(H3N2) through an integrative modelling framework. Specifically, an absolute humidity driven multiscale transmission model was constructed for the 2013/2014, 2014/2015 and 2016/2017 influenza seasons that were dominated by influenza A(H3N2). We revealed the variable impact of absolute humidity on influenza transmission and differences in the occurring timing and magnitude of antigenic change for those three seasons. Overall, the initial population susceptibility, climatic factors, and antigenic change explained nearly 55% of variations in the dynamics of influenza A(H3N2). Specifically, the additional variation explained by the initial population susceptibility, climatic factors, and antigenic change were at 33%, 26%, and 48%, respectively. The vaccination program alone failed to fully eliminate the summer epidemics of influenza A(H3N2) and non-pharmacological interventions were needed to suppress the summer circulation. The quantitative understanding of the interplay among driving factors on the circulation of influenza A(H3N2) highlights the importance of simultaneous monitoring of fluctuations for related factors, which is crucial for precise and targeted prevention and control of seasonal influenza.
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Abbasi, Omid, Nadine Steingräber, Nikos Chalas, Daniel S. Kluger, and Joachim Gross. "Spatiotemporal dynamics characterise spectral connectivity profiles of continuous speaking and listening." PLOS Biology 21, no. 7 (July 21, 2023): e3002178. http://dx.doi.org/10.1371/journal.pbio.3002178.
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Speech production and perception are fundamental processes of human cognition that both rely on intricate processing mechanisms that are still poorly understood. Here, we study these processes by using magnetoencephalography (MEG) to comprehensively map connectivity of regional brain activity within the brain and to the speech envelope during continuous speaking and listening. Our results reveal not only a partly shared neural substrate for both processes but also a dissociation in space, delay, and frequency. Neural activity in motor and frontal areas is coupled to succeeding speech in delta band (1 to 3 Hz), whereas coupling in the theta range follows speech in temporal areas during speaking. Neural connectivity results showed a separation of bottom-up and top-down signalling in distinct frequency bands during speaking. Here, we show that frequency-specific connectivity channels for bottom-up and top-down signalling support continuous speaking and listening. These findings further shed light on the complex interplay between different brain regions involved in speech production and perception.
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Mentkowski, Kyle I., Lindsey M. Euscher, Akshar Patel, B. Rita Alevriadou, and Jennifer K. Lang. "Monocyte recruitment and fate specification after myocardial infarction." American Journal of Physiology-Cell Physiology 319, no. 5 (November 1, 2020): C797—C806. http://dx.doi.org/10.1152/ajpcell.00330.2020.
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Monocytes are critical mediators of the inflammatory response following myocardial infarction (MI) and ischemia-reperfusion injury. They are involved in both initiation and resolution of inflammation and play an integral role in cardiac repair. The antagonistic nature of their function is dependent on their subset heterogeneity and biphasic response following injury. New advancements in single-cell transcriptomics and mass cytometry have allowed us to identify smaller, transcriptionally distinct clusters that may have functional relevance in disease and homeostasis. Additionally, recent insights into the spatiotemporal dynamics of monocytes following ischemic injury and their subsequent interactions with the endothelium and other immune cells reveal a complex interplay between monocytes and the cardiac milieu. In this review, we highlight recent findings on monocyte functional heterogeneity, present new mechanistic insight into monocyte recruitment and fate specification following MI, and discuss promising therapeutic avenues targeting monocytes for the treatment of ischemic heart disease.
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Munaron, Luca. "A Tridimensional Model of Proangiogenic Calcium Signals in Endothelial Cells." Open Biology Journal 2, no. 1 (October 20, 2009): 114–29. http://dx.doi.org/10.2174/1874196700902010114.
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Angiogenic factors, including bFGF and VEGF, induce cytosolic calcium (Cac) increases in endothelial cells, critically involved in angiogenesis progression. At low agonist concentrations, Cac elevation is mainly due to calcium entry controlled by a complex interplay between two intracellular messengers, arachidonic acid (AA) and nitric oxide (NO), released upon stimulation with proangiogenic factors: they trigger spatially localized calcium signals restricted to the cell periphery, and such a spatiotemporal pattern could contribute to the specificity of cellular responses. Based on experimental measurements, here we provide the first quantitative spatiotemporal 3D modeling of proangiogenic calcium events in endothelial cells using Virtual Cell framework. The main aims were to validate previously proposed signaling pathways and to suggest new experimental protocols. The most relevant conclusions are: 1. The interplay between AA and NO, previously proposed to be responsible for VEGF/bFGF-dependent calcium entry in endothelial cells, triggers peripheral calcium signals that reproduce the experimental measurements; 2. Spatial restriction is not an artefact due to the calcium-sensitive dye; 3. Channels clusterization in thin lamellipodia plays a key role in the generation of the peripheral-restricted proangiogenic calcium signals; 4. A model containing two distinct channels, named AAAC and NOAC, respectively activated by AA or NO, explains the basic properties of proangiogenic calcium signals. This could be considered an ‘open model’ containing the simplest conditions leading to a satisfactory reproduction of the experimental results: it should be implemented in order to make it more complete and to maximize physical and biochemical constraints.
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Litwin, Piotr, Beata Zybura, and Paweł Motyka. "Tactile information counteracts the attenuation of rubber hand illusion attributable to increased visuo-proprioceptive divergence." PLOS ONE 15, no. 12 (December 30, 2020): e0244594. http://dx.doi.org/10.1371/journal.pone.0244594.
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Sense of body ownership is an immediate and distinct experience of one’s body as belonging to oneself. While it is well-recognized that ownership feelings emerge from the integration of visual and somatosensory signals, the principles upon which they are integrated are still intensely debated. Here, we used the rubber hand illusion (RHI) to examine how the interplay of visual, tactile, and proprioceptive signals is governed depending on their spatiotemporal properties. For this purpose, the RHI was elicited in different conditions varying with respect to the extent of visuo-proprioceptive divergence (i.e., the distance between the real and fake hands) and differing in terms of the availability and spatiotemporal complexity of tactile stimulation (none, simple, or complex). We expected that the attenuating effect of distance on illusion strength will be more pronounced in the absence of touch (when proprioception gains relatively higher importance) and absent in the presence of complex tactile signals. Additionally, we hypothesized that participants with greater proprioceptive acuity—assessed using an elbow joint position discrimination task—will be less susceptible to the illusion, but only under the conditions of limited tactile stimulation. In line with our prediction, RHI was attenuated at the farthest distance only when tactile information was absent or simplified, but the attenuation was effectively prevented by the use of complex tactile stimulation—in this case, RHI was comparably vivid at both distances. However, passive proprioceptive acuity was not related to RHI strength in either of the conditions. The results indicate that complex-structured tactile signals can override the influence of proprioceptive signals in body attribution processes. These findings extend our understanding of body ownership by showing that it is primarily determined by informative cues from the most relevant sensory domains, rather than mere accumulation of multisensory evidence.
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Fink, Charles C., Boris Slepchenko, Ion I. Moraru, James Schaff, James Watras, and Leslie M. Loew. "Morphological Control of Inositol-1,4,5-Trisphosphate–Dependent Signals." Journal of Cell Biology 147, no. 5 (November 29, 1999): 929–36. http://dx.doi.org/10.1083/jcb.147.5.929.
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Inositol-1,4,5-trisphosphate (InsP3)-mediated calcium signals represent an important mechanism for transmitting external stimuli to the cell. However, information about intracellular spatial patterns of InsP3 itself is not generally available. In particular, it has not been determined how the interplay of InsP3 generation, diffusion, and degradation within complex cellular geometries can control the patterns of InsP3 signaling. Here, we explore the spatial and temporal characteristics of [InsP3]cyt during a bradykinin-induced calcium wave in a neuroblastoma cell. This is achieved by using a unique image-based computer modeling system, Virtual Cell, to integrate experimental data on the rates and spatial distributions of the key molecular components of the process. We conclude that the characteristic calcium dynamics requires rapid, high-amplitude production of [InsP3]cyt in the neurite. This requisite InsP3 spatiotemporal profile is provided, in turn, as an intrinsic consequence of the cell's morphology, demonstrating how geometry can locally and dramatically intensify cytosolic signals that originate at the plasma membrane. In addition, the model predicts, and experiments confirm, that stimulation of just the neurite, but not the soma or growth cone, is sufficient to generate a calcium response throughout the cell.
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Dharmadana, Durga, Nicholas P. Reynolds, Charlotte E. Conn, and Céline Valéry. "Molecular interactions of amyloid nanofibrils with biological aggregation modifiers: implications for cytotoxicity mechanisms and biomaterial design." Interface Focus 7, no. 4 (June 16, 2017): 20160160. http://dx.doi.org/10.1098/rsfs.2016.0160.
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Amyloid nanofibrils are ubiquitous biological protein fibrous aggregates, with a wide range of either toxic or beneficial activities that are relevant to human disease and normal biology. Protein amyloid fibrillization occurs via nucleated polymerization, through non-covalent interactions. As such, protein nanofibril formation is based on a complex interplay between kinetic and thermodynamic factors. The process entails metastable oligomeric species and a highly thermodynamically favoured end state. The kinetics, and the reaction pathway itself, can be influenced by third party moieties, either molecules or surfaces. Specifically, in the biological context, different classes of biomolecules are known to act as catalysts, inhibitors or modifiers of the generic protein fibrillization process. The biological aggregation modifiers reviewed here include lipid membranes of varying composition, glycosaminoglycans and metal ions, with a final word on xenobiotic compounds. The corresponding molecular interactions are critically analysed and placed in the context of the mechanisms of cytotoxicity of the amyloids involved in diverse pathologies and the non-toxicity of functional amyloids (at least towards their biological host). Finally, the utilization of this knowledge towards the design of bio-inspired and biocompatible nanomaterials is explored.
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Gessner, Isabel, and Ines Neundorf. "Nanoparticles Modified with Cell-Penetrating Peptides: Conjugation Mechanisms, Physicochemical Properties, and Application in Cancer Diagnosis and Therapy." International Journal of Molecular Sciences 21, no. 7 (April 6, 2020): 2536. http://dx.doi.org/10.3390/ijms21072536.
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Based on their tunable physicochemical properties and the possibility of producing cell-specific platforms through surface modification with functional biomolecules, nanoparticles (NPs) represent highly promising tools for biomedical applications. To improve their potential under physiological conditions and to enhance their cellular uptake, combinations with cell-penetrating peptides (CPPs) represent a valuable strategy. CPPs are often cationic peptide sequences that are able to translocate across biological membranes and to carry attached cargos inside cells and have thus been recognized as versatile tools for drug delivery. Nevertheless, the conjugation of CPP to NP surfaces is dependent on many properties from both individual components, and further insight into this complex interplay is needed to allow for the fabrication of highly stable but functional vectors. Since CPPs per se are nonselective and enter nearly all cells likewise, additional decoration of NPs with homing devices, such as tumor-homing peptides, enables the design of multifunctional platforms for the targeted delivery of chemotherapeutic drugs. In this review, we have updated the recent advances in the field of CPP-NPs, focusing on synthesis strategies, elucidating the influence of different physicochemical properties, as well as their application in cancer research.
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Cloete, Karen J., Žiga Šmit, and Alessandra Gianoncelli. "Multidimensional Profiling of Human Body Hairs Using Qualitative and Semi-Quantitative Approaches with SR-XRF, ATR-FTIR, DSC, and SEM-EDX." International Journal of Molecular Sciences 24, no. 4 (February 19, 2023): 4166. http://dx.doi.org/10.3390/ijms24044166.
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This study aimed to assess the potential of a multidimensional approach to differentiate body hairs based on their physico-chemical properties and whether body hairs can replace the use of scalp hair in studies linked to forensic and systemic intoxication. This is the first case report controlling for confounding variables to explore the utility of multidimensional profiling of body hair using synchrotron synchrotron microbeam X-ray fluorescence (SR-XRF) for longitudinal and hair morphological region mapping) and benchtop methods, including attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) (complemented with chemometrics analysis), energy dispersive X-ray analysis (EDX) (complemented with heatmap analysis), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM) analysis (complemented by descriptive statistics) to profile different body hairs in terms of their elemental, biochemical, thermal, and cuticle properties. This multidimensional approach provided supportive information to emphasize the intricate and rather complex interplay between the organization and levels of elements and biomolecules within the crystalline and amorphous matrix of different body hairs responsible for the differences in physico-chemical properties between body hairs that are predominantly affected by the growth rate, follicle or apocrine gland activity, and external factors such as cosmetic use and exposure to environmental xenobiotics. The data from this study may have important implications for forensic science, toxicology and systemic intoxication, or other studies involving hair as a research matrix.
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Torok, Justin, Pedro D. Maia, Parul Verma, Christopher Mezias, and Ashish Raj. "Emergence of directional bias in tau deposition from axonal transport dynamics." PLOS Computational Biology 17, no. 7 (July 27, 2021): e1009258. http://dx.doi.org/10.1371/journal.pcbi.1009258.
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Defects in axonal transport may partly underpin the differences between the observed pathophysiology of Alzheimer’s disease (AD) and that of other non-amyloidogenic tauopathies. Particularly, pathological tau variants may have molecular properties that dysregulate motor proteins responsible for the anterograde-directed transport of tau in a disease-specific fashion. Here we develop the first computational model of tau-modified axonal transport that produces directional biases in the spread of tau pathology. We simulated the spatiotemporal profiles of soluble and insoluble tau species in a multicompartment, two-neuron system using biologically plausible parameters and time scales. Changes in the balance of tau transport feedback parameters can elicit anterograde and retrograde biases in the distributions of soluble and insoluble tau between compartments in the system. Aggregation and fragmentation parameters can also perturb this balance, suggesting a complex interplay between these distinct molecular processes. Critically, we show that the model faithfully recreates the characteristic network spread biases in both AD-like and non-AD-like mouse tauopathy models. Tau transport feedback may therefore help link microscopic differences in tau conformational states and the resulting variety in clinical presentations.
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Corniani, Giulia, Miguel A. Casal, Stefano Panzeri, and Hannes P. Saal. "Population coding strategies in human tactile afferents." PLOS Computational Biology 18, no. 12 (December 7, 2022): e1010763. http://dx.doi.org/10.1371/journal.pcbi.1010763.
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Sensory information is conveyed by populations of neurons, and coding strategies cannot always be deduced when considering individual neurons. Moreover, information coding depends on the number of neurons available and on the composition of the population when multiple classes with different response properties are available. Here, we study population coding in human tactile afferents by employing a recently developed simulator of mechanoreceptor firing activity. First, we highlight the interplay of afferents within each class. We demonstrate that the optimal afferent density to convey maximal information depends on both the tactile feature under consideration and the afferent class. Second, we find that information is spread across different classes for all tactile features and that each class encodes both redundant and complementary information with respect to the other afferent classes. Specifically, combining information from multiple afferent classes improves information transmission and is often more efficient than increasing the density of afferents from the same class. Finally, we examine the importance of temporal and spatial contributions, respectively, to the joint spatiotemporal code. On average, destroying temporal information is more destructive than removing spatial information, but the importance of either depends on the stimulus feature analysed. Overall, our results suggest that both optimal afferent innervation densities and the composition of the population depend in complex ways on the tactile features in question, potentially accounting for the variety in which tactile peripheral populations are assembled in different regions across the body.
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Lombardi, Aniello, Peter Jedlicka, Heiko Luhmann, and Werner Kilb. "Interactions between Membrane Resistance, GABA-A Receptor Properties, Bicarbonate Dynamics and Cl−-Transport Shape Activity-Dependent Changes of Intracellular Cl− Concentration." International Journal of Molecular Sciences 20, no. 6 (March 20, 2019): 1416. http://dx.doi.org/10.3390/ijms20061416.
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The effects of ionotropic γ-aminobutyric acid receptor (GABA-A, GABAA) activation depends critically on the Cl−-gradient across neuronal membranes. Previous studies demonstrated that the intracellular Cl−-concentration ([Cl−]i) is not stable but shows a considerable amount of activity-dependent plasticity. To characterize how membrane properties and different molecules that are directly or indirectly involved in GABAergic synaptic transmission affect GABA-induced [Cl−]i changes, we performed compartmental modeling in the NEURON environment. These simulations demonstrate that GABA-induced [Cl−]i changes decrease at higher membrane resistance, revealing a sigmoidal dependency between both parameters. Increase in GABAergic conductivity enhances [Cl−]i with a logarithmic dependency, while increasing the decay time of GABAA receptors leads to a nearly linear enhancement of the [Cl−]i changes. Implementing physiological levels of HCO3−-conductivity to GABAA receptors enhances the [Cl−]i changes over a wide range of [Cl−]i, but this effect depends on the stability of the HCO3− gradient and the intracellular pH. Finally, these simulations show that pure diffusional Cl−-elimination from dendrites is slow and that a high activity of Cl−-transport is required to improve the spatiotemporal restriction of GABA-induced [Cl−]i changes. In summary, these simulations revealed a complex interplay between several key factors that influence GABA-induced [Cl]i changes. The results suggest that some of these factors, including high resting [Cl−]i, high input resistance, slow decay time of GABAA receptors and dynamic HCO3− gradient, are specifically adapted in early postnatal neurons to facilitate limited activity-dependent [Cl−]i decreases.
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Hetmanski, Joseph H. R., Matthew C. Jones, Fatima Chunara, Jean-Marc Schwartz, and Patrick T. Caswell. "Combinatorial mathematical modelling approaches to interrogate rear retraction dynamics in 3D cell migration." PLOS Computational Biology 17, no. 3 (March 10, 2021): e1008213. http://dx.doi.org/10.1371/journal.pcbi.1008213.
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Cell migration in 3D microenvironments is a complex process which depends on the coordinated activity of leading edge protrusive force and rear retraction in a push-pull mechanism. While the potentiation of protrusions has been widely studied, the precise signalling and mechanical events that lead to retraction of the cell rear are much less well understood, particularly in physiological 3D extra-cellular matrix (ECM). We previously discovered that rear retraction in fast moving cells is a highly dynamic process involving the precise spatiotemporal interplay of mechanosensing by caveolae and signalling through RhoA. To further interrogate the dynamics of rear retraction, we have adopted three distinct mathematical modelling approaches here based on (i) Boolean logic, (ii) deterministic kinetic ordinary differential equations (ODEs) and (iii) stochastic simulations. The aims of this multi-faceted approach are twofold: firstly to derive new biological insight into cell rear dynamics via generation of testable hypotheses and predictions; and secondly to compare and contrast the distinct modelling approaches when used to describe the same, relatively under-studied system. Overall, our modelling approaches complement each other, suggesting that such a multi-faceted approach is more informative than methods based on a single modelling technique to interrogate biological systems. Whilst Boolean logic was not able to fully recapitulate the complexity of rear retraction signalling, an ODE model could make plausible population level predictions. Stochastic simulations added a further level of complexity by accurately mimicking previous experimental findings and acting as a single cell simulator. Our approach highlighted the unanticipated role for CDK1 in rear retraction, a prediction we confirmed experimentally. Moreover, our models led to a novel prediction regarding the potential existence of a ‘set point’ in local stiffness gradients that promotes polarisation and rapid rear retraction.
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Mony, Ullas, Theertha M, Neeraj Sidharthan, Veeraraghavan Vishnu Priya, and Praveen K. Varma. "IL-1β, IL-17A, and IL-10: A Novel Axis Linked to Immunological Dysfunction May Pre-Empt Early Diagnosis of Sepsis after Cardiac Surgery." Blood 138, Supplement 1 (November 5, 2021): 4957. http://dx.doi.org/10.1182/blood-2021-152143.
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Abstract INTRODUCTION Sepsis caused by a dysregulated host response to infection, is a serious healthcare problem that results in very high mortality every year-round the globe. When left untreated, sepsis can potentially turn fulminant, making early diagnosis and intervention an essential component of the therapeutic strategy. Proinflammatory cytokines are necessary for initiating an effective inflammatory response against infection, whereas their excess production has been associated with tissue injury in multiple organ systems leading to increased mortality. In contrast, anti-inflammatory cytokines seem to be a prerequisite for controlling and down regulating the initial inflammatory response. But a sustained release of these biomolecules leads to a turn-down of immune activation within the host organism. In the clinical conundrums associated with sepsis, it was often observed that pathogen-responsive cells were exposed to a complex cytokine milieu. The excess production of proinflammatory cytokines is essential for the survival, replication and activation of phagocytic and cytotoxic immune cells. In conjunction with this proinflammatory activity, anti-inflammatory cytokines are also released which are involved in the occurrence of cellular anergy and impaired response to aetiologic agents, causing a compensatory anti-inflammatory response syndrome (CARS). Current practice in cardiac surgery is to review laboratory test results (CRP, PCT, blood culture) and clinical criteria (SOFA and STS) 48 h after surgery to diagnose sepsis. CRP and PCT lack sensitivity and specificity, whereas blood culture requires a long turnaround time and lacks sensitivity. Sepsis being an interplay between pro and anti-inflammatory response, the relative expression of immune biomarkers may provide a useful criterion for early diagnosis of sepsis. Thus, we aimed at investigating the variations in circulating levels of prominent cytokines and their potential use as a diagnostic marker of adult sepsis post cardiac surgery. MATERIALS AND METHODS In this double-blinded cohort study, blood samples of adult patients undergoing cardiac surgery were collected before surgery (D -1), and on the post-operative day 1 (D +1) after the approval from the appropriate Institutional Ethics Committee. Patients who were deemed risky by EuroSCORE II risk stratification were included and immuno-compromised as well as patients with active infection before surgery were excluded. Plasma levels of IL-1β, IL-5, IL-6, IL-10, IL-17A and TNFα were determined using cytometric bead assay by flow cytometry and the results were analyzed using FCAP Array™ software. The data sets were analyzed (GraphPad Prism 5.02) and a p value of < 0.05 was considered statistically significant. RESULTS The study was conducted with 34 patients (n=34) and un-blinded after retrieval of data. The cohort has 8 patients diagnosed with sepsis and 26 without sepsis based on STS criteria. Demographic details for both groups are summarized in Table 1. Cytokine and other biomarker expression levels before (D-1) and after (D+1) Surgery is summarized in Table 2. At D +1, IL-1β, TNF-α, IL-17A and IL-10 showed significantly higher concentration in sepsis group compared to non-sepsis group (Fig 1B). CRP, PCT, WBC and differential blood count were not showing any discriminatory potential between sepsis and non-sepsis patients at D +1. The ROC curves of the above four cytokine expression levels at D+1 was analyzed between sepsis and non-sepsis groups. A plasma IL-1β level of 0.25 pg/ml had a sensitivity of 87.5 % and a specificity of 53.8 % and a plasma IL-17A level of 1.78 pg/ml had a sensitivity of 75 % and specificity of 46.2 %. In addition, IL-10 level of 8.99 pg/ml in plasma showed a diagnostic sensitivity of 87.5 % and a specificity of 53.8% (Fig 1C). Based on the current observation we proposed a model of inflammatory cytokine dynamics involving IL-1β, IL-17A and IL-10 suggesting their role, which may lead to the development of sepsis (Fig 1D). CONCLUSION We identified a significant up regulation of circulating inflammatory cytokines at 24 h in patients who developed sepsis after cardiac surgery, earlier than any noticeable changes in conventional sepsis biomarkers. These results suggest the possibility of inflammatory cytokines as a diagnostic marker and may be a potential therapeutic target as well. The study needs to be validated further on a larger cohort of patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Bock, Lars V., Sara Gabrielli, Michal H. Kolář, and Helmut Grubmüller. "Simulation of Complex Biomolecular Systems: The Ribosome Challenge." Annual Review of Biophysics 52, no. 1 (January 31, 2023). http://dx.doi.org/10.1146/annurev-biophys-111622-091147.
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Large biomolecular systems are at the heart of many essential cellular processes. The dynamics and energetics of an increasing number of these systems are being studied by computer simulations. Pushing the limits of length- and timescales that can be accessed by current hard- and software has expanded the ability to describe biomolecules at different levels of detail. We focus in this review on the ribosome, which exemplifies the close interplay between experiment and various simulation approaches, as a particularly challenging and prototypic nanomachine that is pivotal to cellular biology due to its central role in translation. We sketch widely used simulation methods and demonstrate how the combination of simulations and experiments advances our understanding of the function of the translation apparatus based on fundamental physics. Expected final online publication date for the Annual Review of Biophysics, Volume 52 is May 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Chen, Emile P., Roy S. Song, and Xueer Chen. "Mathematical model of hypoxia and tumor signaling interplay reveals the importance of hypoxia and cell-to-cell variability in tumor growth inhibition." BMC Bioinformatics 20, no. 1 (October 21, 2019). http://dx.doi.org/10.1186/s12859-019-3098-5.
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Abstract Background Human tumor is a complex tissue with multiple heterogeneous hypoxic regions and significant cell-to-cell variability. Due to the complexity of the disease, the explanation of why anticancer therapies fail cannot be attributed to intrinsic or acquired drug resistance alone. Furthermore, there are inconsistent reports of hypoxia-induced kinase activities in different cancer cell-lines, where increase, decreases, or no change has been observed. Thus, we asked, why are there widely contrasting results in kinase activity under hypoxia in different cancer cell-lines and how does hypoxia play a role in anti-cancer drug sensitivity? Results We took a modeling approach to address these questions by analyzing the model simulation to explain why hypoxia driven signals can have dissimilar impact on tumor growth and alter the efficacy of anti-cancer drugs. Repeated simulations with varying concentrations of biomolecules followed by decision tree analysis reveal that the highly differential effects among heterogeneous subpopulation of tumor cells could be governed by varying concentrations of just a few key biomolecules. These biomolecules include activated serine/threonine-specific protein kinases (pRAF), mitogen-activated protein kinase kinase (pMEK), protein kinase B (pAkt), or phosphoinositide-4,5-bisphosphate 3-kinase (pPI3K). Additionally, the ratio of activated extracellular signal-regulated kinases (pERK) or pAkt to its respective total was a key factor in determining the sensitivity of pERK or pAkt to hypoxia. Conclusion This work offers a mechanistic insight into how hypoxia can affect the efficacy of anti-cancer drug that targets tumor signaling and provides a framework to identify the types of tumor cells that are either sensitive or resistant to anti-cancer therapy.
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McCausland, Joshua W., Xinxing Yang, Georgia R. Squyres, Zhixin Lyu, Kevin E. Bruce, Melissa M. Lamanna, Bill Söderström, et al. "Treadmilling FtsZ polymers drive the directional movement of sPG-synthesis enzymes via a Brownian ratchet mechanism." Nature Communications 12, no. 1 (January 27, 2021). http://dx.doi.org/10.1038/s41467-020-20873-y.
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AbstractThe FtsZ protein is a central component of the bacterial cell division machinery. It polymerizes at mid-cell and recruits more than 30 proteins to assemble into a macromolecular complex to direct cell wall constriction. FtsZ polymers exhibit treadmilling dynamics, driving the processive movement of enzymes that synthesize septal peptidoglycan (sPG). Here, we combine theoretical modelling with single-molecule imaging of live bacterial cells to show that FtsZ’s treadmilling drives the directional movement of sPG enzymes via a Brownian ratchet mechanism. The processivity of the directional movement depends on the binding potential between FtsZ and the sPG enzyme, and on a balance between the enzyme’s diffusion and FtsZ’s treadmilling speed. We propose that this interplay may provide a mechanism to control the spatiotemporal distribution of active sPG enzymes, explaining the distinct roles of FtsZ treadmilling in modulating cell wall constriction rate observed in different bacteria.
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Fusaro, Alice, Bianca Zecchin, Bram Vrancken, Celia Abolnik, Rose Ademun, Abdou Alassane, Abdelsatar Arafa, et al. "Disentangling the role of Africa in the global spread of H5 highly pathogenic avian influenza." Nature Communications 10, no. 1 (November 22, 2019). http://dx.doi.org/10.1038/s41467-019-13287-y.
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AbstractThe role of Africa in the dynamics of the global spread of a zoonotic and economically-important virus, such as the highly pathogenic avian influenza (HPAI) H5Nx of the Gs/GD lineage, remains unexplored. Here we characterise the spatiotemporal patterns of virus diffusion during three HPAI H5Nx intercontinental epidemic waves and demonstrate that Africa mainly acted as an ecological sink of the HPAI H5Nx viruses. A joint analysis of host dynamics and continuous spatial diffusion indicates that poultry trade as well as wild bird migrations have contributed to the virus spreading into Africa, with West Africa acting as a crucial hotspot for virus introduction and dissemination into the continent. We demonstrate varying paths of avian influenza incursions into Africa as well as virus spread within Africa over time, which reveal that virus expansion is a complex phenomenon, shaped by an intricate interplay between avian host ecology, virus characteristics and environmental variables.
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Xiong, Liyang, Yuansheng Cao, Robert Cooper, Wouter-Jan Rappel, Jeff Hasty, and Lev Tsimring. "Flower-like patterns in multi-species bacterial colonies." eLife 9 (January 14, 2020). http://dx.doi.org/10.7554/elife.48885.
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Diverse interactions among species within bacterial colonies lead to intricate spatiotemporal dynamics, which can affect their growth and survival. Here, we describe the emergence of complex structures in a colony grown from mixtures of motile and non-motile bacterial species on a soft agar surface. Time-lapse imaging shows that non-motile bacteria 'hitchhike' on the motile bacteria as the latter migrate outward. The non-motile bacteria accumulate at the boundary of the colony and trigger an instability that leaves behind striking flower-like patterns. The mechanism of the front instability governing this pattern formation is elucidated by a mathematical model for the frictional motion of the colony interface, with friction depending on the local concentration of the non-motile species. A more elaborate two-dimensional phase-field model that explicitly accounts for the interplay between growth, mechanical stress from the motile species, and friction provided by the non-motile species, fully reproduces the observed flower-like patterns.
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Nabizadeh, Mohammad, and Safa Jamali. "Life and death of colloidal bonds control the rate-dependent rheology of gels." Nature Communications 12, no. 1 (July 13, 2021). http://dx.doi.org/10.1038/s41467-021-24416-x.
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AbstractColloidal gels exhibit rich rheological responses under flowing conditions. A clear understanding of the coupling between the kinetics of the formation/rupture of colloidal bonds and the rheological response of attractive gels is lacking. In particular, for gels under different flow regimes, the correlation between the complex rheological response, the bond kinetics, microscopic forces, and an overall micromechanistic view is missing in previous works. Here, we report the bond dynamics in short-range attractive particles, microscopically measured stresses on individual particles and the spatiotemporal evolution of the colloidal structures in different flow regimes. The interplay between interparticle attraction and hydrodynamic stresses is found to be the key to unraveling the physical underpinnings of colloidal gel rheology. Attractive stresses, mostly originating from older bonds dominate the response at low Mason number (the ratio of shearing to attractive forces) while hydrodynamic stresses tend to control the rheology at higher Mason numbers, mostly arising from short-lived bonds. Finally, we present visual mapping of particle bond numbers, their life times and their borne stresses under different flow regimes.
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Lam, Daniel D., Ana Antic Nikolic, Chen Zhao, Nazanin Mirza-Schreiber, Wojciech Krężel, Konrad Oexle, and Juliane Winkelmann. "Intronic elements associated with insomnia and restless legs syndrome exhibit cell-type-specific epigenetic features contributing to MEIS1 regulation." Human Molecular Genetics, December 9, 2021. http://dx.doi.org/10.1093/hmg/ddab355.
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Abstract A highly evolutionarily conserved myeloid ecotropic viral integration site 1 (MEIS1) intronic region is strongly associated with restless legs syndrome (RLS) and insomnia. To understand its regulatory function, we dissected the region by analyzing chromatin accessibility, enhancer-promoter contacts, DNA methylation and expression quantitative trait locus (eQTLs) in different human neural cell types and tissues. We observed specific activity with respect to cell type and developmental maturation, indicating a prominent role for distinct highly conserved intronic elements in forebrain inhibitory neuron differentiation. Two elements were hypomethylated in neural cells with higher MEIS1 expression, suggesting a role of enhancer demethylation in gene regulation. MEIS1 eQTLs showed a striking modular chromosomal distribution, with forebrain eQTLs clustering in intron 8/9. Clustered regularly interspersed short palindromic repeats interference targeting of individual elements in this region attenuated MEIS1 expression, revealing a complex regulatory interplay of distinct elements. In summary, we found that MEIS1 regulation is organized in a modular pattern. Disease-associated intronic regulatory elements control MEIS1 expression with cell type and maturation stage specificity, particularly in the inhibitory neuron lineage. The precise spatiotemporal activity of these elements likely contributes to the pathogenesis of insomnia and RLS.
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Jain, Ishita, Ian C. Berg, Ayusha Acharya, Maddie Blaauw, Nicholas Gosstola, Pablo Perez-Pinera, and Gregory H. Underhill. "Delineating cooperative effects of Notch and biomechanical signals on patterned liver differentiation." Communications Biology 5, no. 1 (October 7, 2022). http://dx.doi.org/10.1038/s42003-022-03840-9.
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AbstractControlled in vitro multicellular culture systems with defined biophysical microenvironment have been used to elucidate the role of Notch signaling in the spatiotemporal regulation of stem and progenitor cell differentiation. In addition, computational models incorporating features of Notch ligand-receptor interactions have provided important insights into Notch pathway signaling dynamics. However, the mechanistic relationship between Notch-mediated intercellular signaling and cooperative microenvironmental cues is less clear. Here, liver progenitor cell differentiation patterning was used as a model to systematically evaluate the complex interplay of cellular mechanics and Notch signaling along with identifying combinatorial mechanisms guiding progenitor fate. We present an integrated approach that pairs a computational intercellular signaling model with defined microscale culture configurations provided within a cell microarray platform. Specifically, the cell microarray-based experiments were used to validate and optimize parameters of the intercellular Notch signaling model. This model incorporated the experimentally established multicellular dimensions of the cellular microarray domains, mechanical stress-related activation parameters, and distinct Notch receptor-ligand interactions based on the roles of the Notch ligands Jagged-1 and Delta-like-1. Overall, these studies demonstrate the spatial control of mechanotransduction-associated components, key growth factor and Notch signaling interactions, and point towards a possible role of E-Cadherin in translating intercellular mechanical gradients to downstream Notch signaling.
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Xu, Shou-Ling, Ruben Shrestha, Sumudu S. Karunadasa, and Pei-Qiao Xie. "Proximity Labeling in Plants." Annual Review of Plant Biology 74, no. 1 (February 28, 2023). http://dx.doi.org/10.1146/annurev-arplant-070522-052132.
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Proteins are workhorses in the cell; they form stable and more often dynamic transient protein–protein interactions, assemblies, and networks and have an intimate interplay with DNA and RNA. These network interactions underlie fundamental biological processes and play essential roles in cellular function. The proximity-dependent biotinylation labeling approach combined with mass spectrometry (PL-MS) has recently emerged as a powerful technique to dissect the complex cellular network at the molecular level. In PL-MS, by fusing a genetically encoded proximity-labeling (PL) enzyme to a protein or a localization signal peptide, the enzyme is targeted to a protein complex of interest or to an organelle, allowing labeling of proximity proteins within a zoom radius. These biotinylated proteins can then be captured by streptavidin beads and identified and quantified by mass spectrometry. Recently engineered PL enzymes such as TurboID have a much-improved enzymatic activity, enabling spatiotemporal mapping with a dramatically increased signal-to-noise ratio. PL-MS has revolutionized the way we perform proteomics by overcoming several hurdles imposed by traditional technology, such as biochemical fractionation and affinity purification mass spectrometry. In this review, we focus on biotin ligase–based PL-MS applications that have been or are likely to be adopted by the plant field. We discuss the experimental designs and review the different choices for engineered biotin ligases, enrichment, and quantification strategies. Lastly, we review the validation and discuss future perspectives. Expected final online publication date for the Annual Review of Plant Biology, Volume 74 is May 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Loers, Jens Uwe, and Vanessa Vermeirssen. "SUBATOMIC: a SUbgraph BAsed mulTi-OMIcs clustering framework to analyze integrated multi-edge networks." BMC Bioinformatics 23, no. 1 (September 5, 2022). http://dx.doi.org/10.1186/s12859-022-04908-3.
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Abstract Background Representing the complex interplay between different types of biomolecules across different omics layers in multi-omics networks bears great potential to gain a deep mechanistic understanding of gene regulation and disease. However, multi-omics networks easily grow into giant hairball structures that hamper biological interpretation. Module detection methods can decompose these networks into smaller interpretable modules. However, these methods are not adapted to deal with multi-omics data nor consider topological features. When deriving very large modules or ignoring the broader network context, interpretability remains limited. To address these issues, we developed a SUbgraph BAsed mulTi-OMIcs Clustering framework (SUBATOMIC), which infers small and interpretable modules with a specific topology while keeping track of connections to other modules and regulators. Results SUBATOMIC groups specific molecular interactions in composite network subgraphs of two and three nodes and clusters them into topological modules. These are functionally annotated, visualized and overlaid with expression profiles to go from static to dynamic modules. To preserve the larger network context, SUBATOMIC investigates statistically the connections in between modules as well as between modules and regulators such as miRNAs and transcription factors. We applied SUBATOMIC to analyze a composite Homo sapiens network containing transcription factor-target gene, miRNA-target gene, protein–protein, homologous and co-functional interactions from different databases. We derived and annotated 5586 modules with diverse topological, functional and regulatory properties. We created novel functional hypotheses for unannotated genes. Furthermore, we integrated modules with condition specific expression data to study the influence of hypoxia in three cancer cell lines. We developed two prioritization strategies to identify the most relevant modules in specific biological contexts: one considering GO term enrichments and one calculating an activity score reflecting the degree of differential expression. Both strategies yielded modules specifically reacting to low oxygen levels. Conclusions We developed the SUBATOMIC framework that generates interpretable modules from integrated multi-omics networks and applied it to hypoxia in cancer. SUBATOMIC can infer and contextualize modules, explore condition or disease specific modules, identify regulators and functionally related modules, and derive novel gene functions for uncharacterized genes. The software is available at https://github.com/CBIGR/SUBATOMIC.