To fully understand the allelic variation that underlies common diseases, complete genome sequencing for many individuals with and without disease is required. This is still not technically feasible. ...However, recently it has become possible to carry out partial surveys of the genome by genotyping large numbers of common SNPs in genome-wide association studies. Here, we outline the main factors - including models of the allelic architecture of common diseases, sample size, map density and sample-collection biases - that need to be taken into account in order to optimize the cost efficiency of identifying genuine disease-susceptibility loci.
Social Media Apps (SMA) are widely used to facilitate individual communications. In company situations, they are utilized as a channel to communicate with their customers. However, studies examining ...how SMA have been utilized in the Business-to-Business (Social Media Benchmarking Report, 2014) context are lacking. Using a model based on Media Synchronicity Theory (MST), we present one of the first empirical studies investigating the relationship between the capabilities of SMA (transmission velocity, parallelism, symbol sets, rehearsability, and reprocessability) and B2B communication and business performance. Five case studies based on face-to-face interviews with the senior managers/owners of SME (Small and Medium Enterprises) were conducted. The data were analyzed and the findings confirmed the SMA media capabilities as explained by MST. The findings also revealed a missing SMA capability, that of information security and control, which has been added to the proposed model and which may be an important addition to MST. This study calls for more research to verify this finding.
Cells select from a diverse repertoire of migration strategies. Recent developments in tunable biomaterials have helped identify how extracellular matrix properties influence migration, however, many ...settings lack the fibrous architecture characteristic of native tissues. To investigate migration in fibrous contexts, we independently varied the alignment and stiffness of synthetic 3D fiber matrices and identified two phenotypically distinct migration modes. In contrast to stiff matrices where cells migrated continuously in a traditional mesenchymal fashion, cells in deformable matrices stretched matrix fibers to store elastic energy; subsequent adhesion failure triggered sudden matrix recoil and rapid cell translocation. Across a variety of cell types, traction force measurements revealed a relationship between cell contractility and the matrix stiffness where this migration mode occurred optimally. Given the prevalence of fibrous tissues, an understanding of how matrix structure and mechanics influences migration could improve strategies to recruit repair cells to wound sites or inhibit cancer metastasis.
Abstract
The brain tracks and encodes multi‐level speech features during spoken language processing. It is evident that this speech tracking is dominant at low frequencies (<8 Hz) including delta and ...theta bands. Recent research has demonstrated distinctions between delta‐ and theta‐band tracking but has not elucidated how they differentially encode speech across linguistic levels. Here, we hypothesised that delta‐band tracking encodes prediction errors (enhanced processing of unexpected features) while theta‐band tracking encodes neural sharpening (enhanced processing of expected features) when people perceive speech with different linguistic contents. EEG responses were recorded when normal‐hearing participants attended to continuous auditory stimuli that contained different phonological/morphological and semantic contents: (1) real‐words, (2) pseudo‐words and (3) time‐reversed speech. We employed multivariate temporal response functions to measure EEG reconstruction accuracies in response to acoustic (spectrogram), phonetic and phonemic features with the partialling procedure that singles out unique contributions of individual features. We found higher delta‐band accuracies for pseudo‐words than real‐words and time‐reversed speech, especially during encoding of phonetic features. Notably, individual time‐lag analyses showed that significantly higher accuracies for pseudo‐words than real‐words started at early processing stages for phonetic encoding (<100 ms post‐feature) and later stages for acoustic and phonemic encoding (>200 and 400 ms post‐feature, respectively). Theta‐band accuracies, on the other hand, were higher when stimuli had richer linguistic content (real‐words > pseudo‐words > time‐reversed speech). Such effects also started at early stages (<100 ms post‐feature) during encoding of all individual features or when all features were combined. We argue these results indicate that delta‐band tracking may play a role in predictive coding leading to greater tracking of pseudo‐words due to the presence of unexpected/unpredicted semantic information, while theta‐band tracking encodes sharpened signals caused by more expected phonological/morphological and semantic contents. Early presence of these effects reflects rapid computations of sharpening and prediction errors. Moreover, by measuring changes in EEG alpha power, we did not find evidence that the observed effects can be solitarily explained by attentional demands or listening efforts. Finally, we used directed information analyses to illustrate feedforward and feedback information transfers between prediction errors and sharpening across linguistic levels, showcasing how our results fit with the hierarchical Predictive Coding framework. Together, we suggest the distinct roles of delta and theta neural tracking for sharpening and predictive coding of multi‐level speech features during spoken language processing.
Endothelial injury is an initial mechanism mediating cardiovascular disease.
Here, we investigated the effect of hyperhomocysteinemia on programed cell death in endothelial cells (EC).
We established ...a novel flow-cytometric gating method to define pyrotosis (Annexin V(-)/Propidium iodide(+)). In cultured human EC, we found that: (1) homocysteine and lipopolysaccharide individually and synergistically induced inflammatory pyroptotic and noninflammatory apoptotic cell death; (2) homocysteine/lipopolysaccharide induced caspase-1 activation before caspase-8, caspase-9, and caspase-3 activations; (3) caspase-1/caspase-3 inhibitors rescued homocysteine/lipopolysaccharide-induced pyroptosis/apoptosis, but caspase-8/caspase-9 inhibitors had differential rescue effect; (4) homocysteine/lipopolysaccharide-induced nucleotide-binding oligomerization domain, and leucine-rich repeat and pyrin domain containing protein 3 (NLRP3) protein caused NLRP3-containing inflammasome assembly, caspase-1 activation, and interleukin (IL)-1β cleavage/activation; (5) homocysteine/lipopolysaccharide elevated intracellular reactive oxygen species, (6) intracellular oxidative gradient determined cell death destiny as intermediate intracellular reactive oxygen species levels are associated with pyroptosis, whereas high reactive oxygen species corresponded to apoptosis; (7) homocysteine/lipopolysaccharide induced mitochondrial membrane potential collapse and cytochrome-c release, and increased B-cell lymphoma 2-associated X protein/B-cell lymphoma 2 ratio which were attenuated by antioxidants and caspase-1 inhibitor; and (8) antioxidants extracellular superoxide dismutase and catalase prevented homocysteine/lipopolysaccharide -induced caspase-1 activation, mitochondrial dysfunction, and pyroptosis/apoptosis. In cystathionine β-synthase-deficient (Cbs(-/-)) mice, severe hyperhomocysteinemia-induced caspase-1 activation in isolated lung EC and caspase-1 expression in aortic endothelium, and elevated aortic caspase-1, caspase-9 protein/activity and B-cell lymphoma 2-associated X protein/B-cell lymphoma 2 ratio in Cbs(-/-) aorta and human umbilical vein endothelial cells. Finally, homocysteine-induced DNA fragmentation was reversed in caspase-1(-/-) EC. Hyperhomocysteinemia-induced aortic endothelial dysfunction was rescued in caspase-1(-/-) and NLRP3(-/-) mice.
Hyperhomocysteinemia preferentially induces EC pyroptosis via caspase-1-dependent inflammasome activation leading to endothelial dysfunction. We termed caspase-1 responsive pyroptosis and apoptosis as pyrop-apoptosis.
Reactive oxygen species (ROS) are critical for the progression of cardiovascular diseases, inflammations and tumors. However, the mechanisms of how ROS sense metabolic stress, regulate metabolic ...pathways and initiate proliferation, inflammation and cell death responses remain poorly characterized. In this analytic review, we concluded that: 1) Based on different features and functions, eleven types of ROS can be classified into seven functional groups: metabolic stress-sensing, chemical connecting, organelle communication, stress branch-out, inflammasome-activating, dual functions and triple functions ROS. 2) Among the ROS generation systems, mitochondria consume the most amount of oxygen; and nine types of ROS are generated; thus, mitochondrial ROS systems serve as the central hub for connecting ROS with inflammasome activation, trained immunity and immunometabolic pathways. 3) Increased nuclear ROS production significantly promotes cell death in comparison to that in other organelles. Nuclear ROS systems serve as a convergent hub and decision-makers to connect unbearable and alarming metabolic stresses to inflammation and cell death. 4) Balanced ROS levels indicate physiological homeostasis of various metabolic processes in subcellular organelles and cytosol, while imbalanced ROS levels present alarms for pathological organelle stresses in metabolic processes. Based on these analyses, we propose a working model that ROS systems are a new integrated network for sensing homeostasis and alarming stress in metabolic processes in various subcellular organelles. Our model provides novel insights on the roles of the ROS systems in bridging metabolic stress to inflammation, cell death and tumorigenesis; and provide novel therapeutic targets for treating those diseases. (Word count: 246).
Vascular Endothelial Cells and Innate Immunity Shao, Ying; Saredy, Jason; Yang, William Y ...
Arteriosclerosis, thrombosis, and vascular biology,
2020-June, Letnik:
40, Številka:
6
Journal Article
Recenzirano
Odprti dostop
In addition to the roles of endothelial cells (ECs) in physiological processes, ECs actively participate in both innate and adaptive immune responses. We previously reported that, in comparison to ...macrophages, a prototypic innate immune cell type, ECs have many innate immune functions that macrophages carry out, including cytokine secretion, phagocytic function, antigen presentation, pathogen-associated molecular patterns-, and danger-associated molecular patterns-sensing, proinflammatory, immune-enhancing, anti-inflammatory, immunosuppression, migration, heterogeneity, and plasticity. In this highlight, we introduce recent advances published in both
and many other journals: (1) several significant characters classify ECs as novel immune cells not only in infections and allograft transplantation but also in metabolic diseases; (2) several new receptor systems including conditional danger-associated molecular pattern receptors, nonpattern receptors, and homeostasis associated molecular patterns receptors contribute to innate immune functions of ECs; (3) immunometabolism and innate immune memory determine the innate immune functions of ECs; (4) a great induction of the immune checkpoint receptors in ECs during inflammations suggests the immune tolerogenic functions of ECs; and (5) association of immune checkpoint inhibitors with cardiovascular adverse events and cardio-oncology indicates the potential contributions of ECs as innate immune cells.
Mitochondrial proton leak is the principal mechanism that incompletely couples substrate oxygen to ATP generation. This chapter briefly addresses the recent progress made in understanding the role of ...proton leak in the pathogenesis of cardiovascular diseases. Majority of the proton conductance is mediated by uncoupling proteins (UCPs) located in the mitochondrial inner membrane. It is evident that the proton leak and reactive oxygen species (ROS) generated from electron transport chain (ETC) in mitochondria are linked to each other. Increased ROS production has been shown to induce proton conductance, and in return, increased proton conductance suppresses ROS production, suggesting the existence of a positive feedback loop that protects the biological systems from detrimental effects of augmented oxidative stress. There is mounting evidence attributing to proton leak and uncoupling proteins a crucial role in the pathogenesis of cardiovascular disease. We can surmise the role of "uncoupling" in cardiovascular disorders as follows; First, the magnitude of the proton leak and the mechanism involved in mediating the proton leak determine whether there is a protective effect against ischemia-reperfusion (IR) injury. Second, uncoupling by UCP2 preserves vascular function in diet-induced obese mice as well as in diabetes. Third, etiology determines whether the proton conductance is altered or not during hypertension. And fourth, proton leak regulates ATP synthesis-uncoupled mitochondrial ROS generation, which determines pathological activation of endothelial cells for recruitment of inflammatory cells. Continue effort in improving our understanding in the role of proton leak in the pathogenesis of cardiovascular and metabolic diseases would lead to identification of novel therapeutic targets for treatment.
Angiogenesis is a complex morphogenetic process that involves intimate interactions between multicellular endothelial structures and their extracellular milieu. In vitro models of angiogenesis can ...aid in reducing the complexity of the in vivo microenvironment and provide mechanistic insight into how soluble and physical extracellular matrix cues regulate this process. To investigate how microenvironmental cues regulate angiogenesis and the function of resulting microvasculature, we multiplexed an established angiogenesis-on-a-chip platform that affords higher throughput investigation of 3D endothelial cell sprouting emanating from a parent vessel through defined biochemical gradients and extracellular matrix. We found that two fundamental endothelial cell functions, migration and proliferation, dictate endothelial cell invasion as single cells vs. multicellular sprouts. Microenvironmental cues that elicit excessive migration speed incommensurate with proliferation resulted in microvasculature with poor barrier function and an inability to transport fluid across the microvascular bed. Restoring the balance between migration speed and proliferation rate rescued multicellular sprout invasion, providing a new framework for the design of pro-angiogenic biomaterials that guide functional microvasculature formation for regenerative therapies.
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