To curb the high cost of drug development, there is an urgent need to develop more predictive tissue models using human cells to determine drug efficacy and safety in advance of clinical testing. ...Recent insights gained through fundamental biological studies have validated the importance of dynamic cell environments and cellular communication to the expression of high fidelity organ function. Building on this knowledge, emerging organ-on-a-chip technology is poised to fill the gaps in drug screening by offering predictive human tissue models with methods of sophisticated tissue assembly. Organ-on-a-chip start-ups have begun to spawn from academic research to fill this commercial space and are attracting investment to transform the drug discovery industry. This review traces the history, examines the scientific foundation and envisages the prospect of these renowned organ-on-a-chip technologies. It serves as a guide for new members of this dynamic field to navigate the existing scientific and market space.
The basic helix-loop-helix-PAS transcription factor (CLOCK, Circadian locomotor output cycles protein kaput) was discovered in 1994 as a circadian clock. Soon after its discovery, the circadian ...clock, Aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL, also call BMAL1), was shown to regulate adiposity and body weight by controlling on the brain hypothalamic suprachiasmatic nucleus (SCN). Farther, circadian clock genes were determined to exert several of lipid metabolic and diabetes effects, overall indicating that CLOCK and BMAL1 act as a central master circadian clock. A master circadian clock acts through the neurons and hormones, with expression in the intestine, liver, kidney, lung, heart, SCN of brain, and other various cell types of the organization. Among circadian clock genes, numerous metabolic syndromes are the most important in the regulation of food intake (via regulation of circadian clock genes or clock-controlled genes in peripheral tissue), which lead to a variation in plasma phospholipids and tissue phospholipids. Circadian clock genes affect the regulation of transporters and proteins included in the regulation of phospholipid metabolism. These genes have recently received increasing recognition because a pharmacological target of circadian clock genes may be of therapeutic worth to make better resistance against insulin, diabetes, obesity, metabolism syndrome, atherosclerosis, and brain diseases. In this book chapter, we focus on the regulation of circadian clock and summarize its phospholipid effect as well as discuss the chemical, physiology, and molecular value of circadian clock pathway regulation for the treatment of plasma lipids and atherosclerosis.
Understanding the hydraulic fracture (HF) re-orientation mechanism from artificial weaknesses is critical to screen-out prevention in the petroleum industry and caveability management in the mining ...industry. An improved discrete element method is proposed and incorporated in the Universal Distinct Element Code (UDEC) to simulate hydraulic fracturing in heterogeneous rocks, and its reliability is validated against previous laboratory experiments. The effects of rock heterogeneity and rock strength on HF re-orientation are unveiled to fill the research gaps in the existing knowledge. The results show that the proposed UDEC T-W (Trigon-Weibull distribution) model can well simulate HF propagation in rock samples of different homogeneity degrees and yields more realistic simulation results compared with the classic extended finite element method (XFEM). The HF re-orientation process depends on the combined effect of all the influencing factors. HFs tend to be directed by perforations if hydraulic fracturing is performed in relatively heterogeneous rocks, while the differential stress is more likely to dictate the HF propagation paths if rocks become relatively homogeneous. We also find that higher rock strength weakens the impact of the differential stress and favours the control of perforations over HF propagation. Finally, recommendations are provided for effective utilization of hydraulic fracturing at the mine site.
Despite the complexity and structural sophistication that 3D organoid models provide, their lack of vascularization and perfusion limit the capability of these models to recapitulate organ physiology ...effectively. A microfluidic platform named IFlowPlate is engineered, which can be used to culture up to 128 independently perfused and vascularized colon organoids in vitro. Unlike traditional microfluidic devices, the vascularized organoid‐on‐chip device with an “open‐well” design does not require any external pumping systems and allows tissue extraction for downstream analyses, such as histochemistry or even in vivo transplantation. By optimizing both the extracellular matrix (ECM) and the culture media formulation, patient‐derived colon organoids are co‐cultured successfully within a self‐assembled vascular network, and it is found that the colon organoids grow significantly better in the platform under constant perfusion versus conventional static condition. Furthermore, a colon inflammation model with an innate immune function where circulating monocytes can be recruited from the vasculature, differentiate into macrophage, and infiltrate the colon organoids in response to tumor necrosis factor (TNF)‐ inflammatory cytokine stimulation is developed using the platform. With the ability to grow vascularized colon organoids under intravascular perfusion, the IFlowPlate platform could unlock new possibilities for screening potential therapeutic targets or modeling relevant diseases.
In recent years, there has been significant interest in organoid systems for biological modeling. However, organoids usually lack vascularization and are cultured under static conditions. In this work, a customized 384‐well plate platform is developed, named IFlowPlate, which can be used to vascularize and perfuse organoids readily. This is the first system that has demonstrated organoid vascularization with intravascular perfusion.
Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and ...platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca2+ transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and we demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.
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•Positive force frequency and post-rest potentiation are achieved in human tissues•Engineered atrial and ventricular tissues have distinct electrophysiology and drug responses•Atrio-ventricular tissues show spatially confined drug responses•Long-term electrical conditioning enables polygenic cardiac disease modeling
A scalable cardiac tissue cultivation platform enables assessment of multiple parameters of atrial and ventricular tissue function, drug testing, and disease modeling.
The study of flow behaviour of water-sand mixtures in fractured rocks is of great necessity to understand the producing mechanism and prevention of water inrush and sand gushing accidents. A ...self-developed seepage test system is used in this paper to conduct laboratory experiments in order to study the influence of the particle size distribution, the void ratio, and the initial mass of Aeolian sand on the flow behavior. It is concluded that the water flow velocity is insensitive to the initial mass of the Aeolian sand but increases with the power exponent in the Talbot formula and the specimen height. The outflow of the Aeolian sand increases with the power exponent in the Talbot formula, the specimen height, and the initial mass of the Aeolian sand. Besides, the outflow of the Aeolian sand changes exponentially with the water flow velocity. Finally, it is found that the fractured specimen has a maximum sand filtration capacity beyond which the outflow of the Aeolian sand significantly increases with the initial mass of the Aeolian sand.
Photo-electrochemical (PEC) and photocatalytic (PC) water splitting are promising solutions to achieve solar-powered hydrogen production. In the present work, to integrate the merits of PEC and PC ...techniques, a p–n conjugated two-electrode water-splitting system was miniaturized into one particle (denoted as electrode particle) for PC reactions. Specifically, a p-type Rh-doped strontium titanate (Rh:SrTiO3) photocathode material was selectively deposited on the electron-accumulated facet of a particulate n-type Mo-doped bismuth vanadate (Mo:BiVO4) photoanode with inserting a partly oxidized In@InO x interlayer as a grain binder and charge conductor. The photoexcited charge migration and accumulation were visualized through light-assisted Kelvin probe force microscopy. Benefited from efficient interfacial charge transfer and effective surface modification, visible light-driven PC overall water splitting into H2 and O2 was achieved over the prepared Mo:BiVO4/In@InO x /Rh:SrTiO3 electrode particle with an intense-light stability up to 40 h, an ambient pressure endurability from 5 to 95 kPa, and a solar-to-hydrogen energy conversion efficiency of 1.2 × 10–2%. This work develops a strategy of designing an efficient composite photocatalyst for PC overall water splitting and provides insights toward the enhancement of charge transfer efficiency across hetero-semiconductors.
•CMS-induced M1 microglia contribute to neuroinflammatory and inhibit neurogenesis.•SalB rebalances the dysregulation of cytokines by regulating microglial phenotype.•M2 microglia reversed the ...CMS-induced deficits in neurogenesis and behaviors.•Targeting microglial phenotypes may represent a new strategy for depression therapy.
Although accumulating evidence suggests that activated microglia are associated with deficits in neurogenesis and contribute to the physiopathology of major depressive disorder, the role of microglia in treating depression remains poorly understood. Our previous study showed that salvianolic acid (SalB) has the regulation of neuroinflammatory responses and antidepressant-like effects. Here, we hypothesized that SalB’s therapeutic effects occur because it modulates microglial phenotypes that are associated with neurogenesis. To test this hypothesis, we treated CMS-exposed C57BL/6 mice with SalB (20mg/kg, intraperitoneally, once daily) for 3weeks and investigated microglial phenotypic profiles and hippocampal neurogenesis. The results showed that the SalB treatment skewed M1 microglial polarization toward M2 activation in the hippocampus and cortex and remedied CMS-induced deficits in hippocampal neurogenesis. SalB (40µM) inhibited LPS-stimulated microglial M1 activation as well as induced M2 activation in vitro, and the cultured microglia with the SalB treatment showed enhanced neural precursor cell proliferation, differentiation, and survival. SalB treatment also ameliorated the depressive-like behaviors of the CMS-treated mice in sucrose preference, forced swimming, and tail suspension tests. These findings suggest a possible antidepressive mechanism for anti-inflammatory agents that is correlated with microglial polarization and hippocampal neurogenesis and which may provide a new microglia-targeted strategy for depression therapy.
Millennia of directional human selection has reshaped the genomic architecture of cultivated cotton relative to wild counterparts, but we have limited understanding of the selective retention and ...fractionation of genomic components.
We construct a comprehensive genomic variome based on 1961 cottons and identify 456 Mb and 357 Mb of sequence with domestication and improvement selection signals and 162 loci, 84 of which are novel, including 47 loci associated with 16 agronomic traits. Using pan-genome analyses, we identify 32,569 and 8851 non-reference genes lost from Gossypium hirsutum and Gossypium barbadense reference genomes respectively, of which 38.2% (39,278) and 14.2% (11,359) of genes exhibit presence/absence variation (PAV). We document the landscape of PAV selection accompanied by asymmetric gene gain and loss and identify 124 PAVs linked to favorable fiber quality and yield loci.
This variation repertoire points to genomic divergence during cotton domestication and improvement, which informs the characterization of favorable gene alleles for improved breeding practice using a pan-genome-based approach.
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