Since most variants that impact polygenic disease phenotypes localize to non-coding genomic regions, understanding the consequences of regulatory element variants will advance understanding of human ...disease mechanisms. Here, we report that the systemic lupus erythematosus (SLE) risk variant rs2431697 as likely causal for SLE through disruption of a regulatory element, modulating miR-146a expression. Using epigenomic analysis, genome-editing and 3D chromatin structure analysis, we show that rs2431697 tags a cell-type dependent distal enhancer specific for miR-146a that physically interacts with the miR-146a promoter. NF-kB binds the disease protective allele in a sequence-specific manner, increasing expression of this immunoregulatory microRNA. Finally, CRISPR activation-based modulation of this enhancer in the PBMCs of SLE patients attenuates type I interferon pathway activation by increasing miR-146a expression. Our work provides a strategy to define non-coding RNA functional regulatory elements using disease-associated variants and provides mechanistic links between autoimmune disease risk genetic variation and disease etiology.
Plant cell membranes are the sites of sensing and initiation of rapid responses to changing environmental factors including salinity stress. Understanding the mechanisms involved in membrane ...remodeling is important for studying salt tolerance in plants. This task remains challenging in complex tissue due to suboptimal subcellular membrane isolation techniques. Here, we capitalized on the use of a surface charge-based separation method, free flow electrophoresis, to isolate the tonoplast (TP) and plasma membrane (PM) from leaf tissue of the halophyte ice plant (Mesembryanthemum crystallinum L.). Results demonstrated a membrane-specific lipidomic remodeling in this plant under salt conditions, including an increased proportion of bilayer forming lipid phosphatidylcholine in the TP and an increase in nonbilayer forming and negatively charged lipids (phosphatidylethanolamine and phosphatidylserine) in the PM. Quantitative proteomics showed salt-induced changes in proteins involved in fatty acid synthesis and desaturation, glycerolipid, and sterol synthesis, as well as proteins involved in lipid signaling, binding, and trafficking. These results reveal an essential plant mechanism for membrane homeostasis wherein lipidome remodeling in response to salt stress contributes to maintaining the physiological function of individual subcellular compartments.
Abstract Subthreshold depression (StD) is a highly prevalent condition associated with increased service utilization and social morbidity. Nevertheless, due to limitations in current diagnostic ...systems that set the boundary for major depressive disorder (MDD), very few brain imaging studies on the neurobiology of StD have been carried out, and its underlying neurobiological mechanism remains unclear. In recent years, accumulating evidence suggests that the disruption of the default mode network (DMN), a network involved in self-referential processing, affective cognition, and emotion regulation, is involved in major depressive disorder. Using independent component analysis, we investigated resting-state default mode network (DMN) functional connectivity (FC) changes in two cohorts of StD patients with different age ranges (young and middle-aged, n = 57) as well as matched controls (n = 79). We found significant FC increase between the DMN and ventral striatum (key region in the reward network), in both cohorts of StD patients in comparison with controls. In addition, we also found the FC between the DMN and ventral striatum was positively and significantly associated with scores on the Center for Epidemiologic Studies Depression Scale (CES-D), a measurement of depressive symptomatology. We speculate that this enhanced FC between the DMN and the ventral striatum may reflect a self-compensation to ameliorate the lowered reward function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Currently, major concerns about the safety and efficacy of RNA interference (RNAi)-based bone anabolic strategies still exist because of the lack of direct osteoblast-specific delivery systems for ...osteogenic siRNAs. Here we screened the aptamer CH6 by cell-SELEX, specifically targeting both rat and human osteoblasts, and then we developed CH6 aptamer-functionalized lipid nanoparticles (LNPs) encapsulating osteogenic pleckstrin homology domain-containing family O member 1 (Plekho1) siRNA (CH6-LNPs-siRNA). Our results showed that CH6 facilitated in vitro osteoblast-selective uptake of Plekho1 siRNA, mainly via macropinocytosis, and boosted in vivo osteoblast-specific Plekho1 gene silencing, which promoted bone formation, improved bone microarchitecture, increased bone mass and enhanced mechanical properties in both osteopenic and healthy rodents. These results indicate that osteoblast-specific aptamer-functionalized LNPs could act as a new RNAi-based bone anabolic strategy, advancing the targeted delivery selectivity of osteogenic siRNAs from the tissue level to the cellular level.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
FLT3 internal tandem duplication (FLT3-ITD) is an activating mutation found in 20-30% of patients with acute myeloid leukemia (AML), which makes FLT3 an attractive target for the treatment of AML. ...Although FLT3-mutant patients respond to current FLT3 inhibitors, relapse usually happens because of the acquisition of resistant secondary mutations at the FLT3 catalytic domain, which is mainly on D835. In the search for compounds with broad FLT3 inhibition activities, we screened a kinase inhibitor library by using our unique FLT3 substrate and identified JAK3 inhibitor VI (designated JI6 hereafter) as a novel FLT3 inhibitor, which selectively targets FLT3 D835 mutants as well as FLT3-ITD. JI6 effectively inhibited FLT3-ITD-containing MV4-11 cells and HCD-57 cells transformed with FLT3-ITD and D835 mutants. Furthermore, administration of JI6 effectively targeted FLT3 signaling in vivo and suppressed the myeloproliferative phenotypes in FLT3-ITD knock-in mice, and significantly prolonged the survival of immunodeficient mice implanted with the transformed HCD-57 cells. Therefore, JI6 is a promising candidate for the development of next-generation anti-AML drugs.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Purpose
The purpose of our study was to investigate an underlying mechanism that hydrogen peroxide-induced mitophagy contributed to laryngeal cancer cells survivals under oxidative stress condition.
...Methods
Tumor tissue and serum samples were collected from patients with laryngeal cancer. The Hep2 cell, a human laryngeal carcinoma cell, was used in in vitro experiments. The levels of lipid peroxidation were analyzed by ELISA. Knockdown of FUNDC1 was performed by RNAi. The changes of target proteins were determined by qRT-PCR and western blot. The cells were analyzed for changes in proliferation using cell counting kit-8 and mitophagy by the mitochondrial membrane potential assay and transmission electron microscopy.
Results
FUNDC1 in laryngeal cancer tissues were relative to the levels of lipid peroxidation in laryngeal cancer patients, which suggested that FUNDC1 was associated with the status of oxidative stress in the laryngeal cancer patients. Hydrogen peroxide significantly induced the elevation of FUNDC1, a mitophagic factor, in a time- and dose-dependent manner in laryngeal cancer cells, which was dependent on ERK signal activation. Knockdown of FUNDC1 by the siRNA attenuated the survival of laryngeal cancer cells under hydrogen peroxide stimulation. Moreover, the elevated FUNDC1 was required for the occurrence of mitophagy under hydrogen peroxide stimulation, which was identified by transmission electron microscopy, the alterations of mitochondrial permeability transition and the specific mitochondrial protein, hsp60. Inhibition of mitophagy with cyclosporine A could also effectively attenuate the laryngeal cancer cells survival under hydrogen peroxide stimulation.
Conclusions
Hydrogen peroxide upregulated the expression of FUNDC1 through the activation of ERK1/2 signal to trigger a mitophagic response, giving laryngeal cancer cells a befit for survival. These findings suggested that FUNDC1 might be a potential target for the treatment of laryngeal cancer accompanied with high lipid peroxidation status.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•The unique layered model induces two Dzyaloshinskii-Moriya interaction areas.•Skyrmion’s stable motion can happen on the ferromagnetic nanodisk of this model.•The ferromagnetic skyrmion STNO has ...good performances on frequency and linewidth.•The effects of current density, radius and damping have been also discussed.
Magnetic skyrmions have attracted great interest in recent years due to their potential wide-scale applications in spintronic devices, such as the spin torque nano-oscillator (STNO) and racetrack memory. The spin-transfer torque can drive the motion of skyrmions on a ferromagnetic nanodisk, where skyrmions are stabilized by the Dzyaloshinskii-Moriya interaction (DMI). However, the Magnus force acted on a skyrmion can drive the skyrmion moving toward either the nanodisk center or edge, which may lead to the destruction of skyrmion at edge, and thus reduce the performance of skyrmion-based STNO. In order to overcome this problem, we designed a ferromagnet/spacer/ferromagnet/heavy metal STNO model, in which the inner and outer areas of the ferromagnetic nanodisk have different DMI, and those skyrmions could move along the boundary between inner and outer areas. We investigated the dynamics of skyrmions in such a STNO model by adjusting several geometrical and material parameters. We obtained an optimal frequency of skyrmion oscillation of 3.43 GHz. Our results may be useful for designing future STNOs based on skyrmions, where the Magnus-force-induced destruction of skyrmions can be effectively avoided.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Osteosarcoma (OS) is a highly aggressive pediatric cancer, characterized by frequent lung metastasis and pathologic bone destruction. Vascular endothelial growth factor A (VEGFA), highly expressed in ...OS, not only contributes to angiogenesis within the tumor microenvironment via paracrine stimulation of vascular endothelial cells, but also acts as an autocrine survival factor for tumor cell themselves, thus making it a promising therapeutic target for OS. CRISPR/Cas9 is a versatile genome editing technology and holds tremendous promise for cancer treatment. However, a major bottleneck to achieve the therapeutic potential of the CRISPR/Cas9 is the lack of in vivo tumor-targeted delivery systems. Here, we screened an OS cell-specific aptamer (LC09) and developed a LC09-functionalized PEG-PEI-Cholesterol (PPC) lipopolymer encapsulating CRISPR/Cas9 plasmids encoding VEGFA gRNA and Cas9. Our results demonstrated that LC09 facilitated selective distribution of CRISPR/Cas9 in both orthotopic OS and lung metastasis, leading to effective VEGFA genome editing in tumor, decreased VEGFA expression and secretion, inhibited orthotopic OS malignancy and lung metastasis, as well as reduced angiogenesis and bone lesion with no detectable toxicity. The delivery system simultaneously restrained autocrine and paracrine VEGFA signaling in tumor cells and could facilitate translating CRISPR-Cas9 into clinical cancer treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Low-grade gliomas (LGGs) are the most common childhood brain tumor in the general population and in individuals with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Surgical biopsy ...is rarely performed prior to treatment in the setting of NF1, resulting in a paucity of tumor genomic information. To define the molecular landscape of NF1-associated LGGs (NF1-LGG), we integrated clinical data, histological diagnoses, and multi-level genetic/genomic analyses on 70 individuals from 25 centers worldwide. Whereas, most tumors harbored bi-allelic
NF1
inactivation as the only genetic abnormality, 11% had additional mutations. Moreover, tumors classified as non-pilocytic astrocytoma based on DNA methylation analysis were significantly more likely to harbor these additional mutations. The most common secondary alteration was
FGFR1
mutation, which conferred an additional growth advantage in multiple complementary experimental murine
Nf1
models. Taken together, this comprehensive characterization has important implications for the management of children with NF1-LGG, distinct from their sporadic counterparts.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Refractory multi-principal element alloys (RMPEAs) are promising materials for high-temperature structural applications. Here, we investigate the role of short-range ordering (SRO) on dislocation ...glide in the MoNbTi and TaNbTi RMPEAs using a multi-scale modeling approach. Monte carlo/molecular dynamics simulations with a moment tensor potential show that MoNbTi exhibits a much greater degree of SRO than TaNbTi and the local composition has a direct effect on the unstable stacking fault energies (USFEs). From mesoscale phase-field dislocation dynamics simulations, we find that increasing SRO leads to higher mean USFEs and stress required for dislocation glide. The gliding dislocations experience significant hardening due to pinning and depinning caused by random compositional fluctuations, with higher SRO decreasing the degree of USFE dispersion and hence, amount of hardening. Finally, we show how the morphology of an expanding dislocation loop is affected by the applied stress.
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