Immune rejection is the major limitation for porcine xenograft survival in primate recipients. Proinflammatory cytokines play important roles in immune rejection and have been found to mediate the ...pathological effects in various clinical and experimental transplantation trials. IL-17 and TNF-α play critical pathological roles in immune disorders, such as psoriasis and rheumatoid arthritis. However, the pathological roles of human IL-17 (hIL-17) and human TNF-α (hTNF-α) in xenotransplantation remain unclear. Here we found that hIL-17 and hTNF-α additively or synergistically regulate the expression of 697 genes in porcine aortic endothelial cells (PAECs). Overall, 415 genes were found to be synergistically regulated, while 282 genes were found to be additively regulated. Among these, 315 genes were upregulated and 382 genes were downregulated in PAECs. Furthermore, we found that hIL-17 and hTNF-α additively or synergistically induced the expression of various proinflammatory cytokines and chemokines ( e . g ., IL1α, IL6, and CXCL8) and decreased the expression of certain anti-inflammatory genes ( e . g ., IL10). Moreover, hIL-17 plus hTNF-α increased the expression of IL1R1 and IL6ST, receptors for IL1 and IL6, respectively, and decreased anti-inflammatory gene receptor expression (IL10R). hIL-17 and hTNF-α synergistically or additively induced CXCL8 and CCL2 expression and consequently promoted primary human neutrophil and human leukemia monocytic cell migration, respectively. In addition, hIL-17 and hTNF-α induced pro-coagulation gene (SERPINB2 and F3) expression and decreased anti-coagulation gene (TFPI, THBS1, and THBD) expression. Additionally, hIL-17 and hTNF-α synergistically decreased occludin expression and consequently promoted human antibody-mediated complement-dependent cytotoxicity. Interestingly, hTNF-α increased swine leukocyte antigen (SLA) class I expression; however, hIL-17 decreased TNF-α-mediated SLA-I upregulation. We concluded that hIL-17 and hTNF-α likely promote the inflammatory response, coagulation cascade, and xenoantibody-mediated cell injury. Thus, blockade of hIL-17 and hTNF-α together might be beneficial for xenograft survival in recipients.
Chimeric antigen receptor (CAR) T cell therapy suffers from complications including cytokine release syndromes and T cell exhaustion. To curb these drawbacks, Jianfeng Zhou, Wenshe Ray Liu et al. ...report in their Research Article (e202109550) a chemogenetic switch that can be reversibly turned on and off to control the expression of CAR using a clinically approved small‐molecule drug, asunaprevir. This novel technique will potentially enable delicate modulation of CAR‐T activation during cancer treatment.
Despite being a member of the chromodomain helicase DNA-binding protein family, little is known about the exact role of CHD6 in chromatin remodeling or cancer disease. Here we show that CHD6 binds to ...chromatin to promote broad nucleosome eviction for transcriptional activation of many cancer pathways. By integrating multiple patient cohorts for bioinformatics analysis of over a thousand prostate cancer datasets, we found CHD6 expression elevated in prostate cancer and associated with poor prognosis. Further comprehensive experiments demonstrated that CHD6 regulates oncogenicity of prostate cancer cells and tumor development in a murine xenograft model. ChIP-Seq for CHD6, along with MNase-Seq and RNA-Seq, revealed that CHD6 binds on chromatin to evict nucleosomes from promoters and gene bodies for transcriptional activation of oncogenic pathways. These results demonstrated a key function of CHD6 in evicting nucleosomes from chromatin for transcriptional activation of prostate cancer pathways.
A rapid, reliable and reproducible method based on microemulsion electrokinetic chromatography (MEEKC) for simultaneous determination of 13 kinds of water- and fat-soluble vitamins has been developed ...in this work. A novel microemulsion system consisting of 1.2% (w/w) sodium lauryl sulphate (SDS), 21% (v/v) 1-butanol, 18% (v/v) acetonitrile, 0.8% (w/w)
n-hexane, 20
mM borax buffer (pH 8.7) was applied to improve selectivity and efficiency, as well as shorten analysis time. The composition of microemulsion used as the MEEKC running buffer was investigated thoroughly to obtain stable separation medium, as well as the optimum determination conditions. Acetonitrile as the organic solvent modifier, pH of the running buffer and 1-butanol as the co-surfactant played the most important roles for the separation of the fat-soluble vitamins, water-soluble vitamins and stabilization of system, respectively. The 13 water- and fat-soluble vitamins were baseline separated within 30
min. The system was applied to determine water- and fat-soluble vitamins in commercial multivitamin pharmaceutical formulation, good accuracy and precision were obtained with recoveries between 97% and 105%, relative standard derivations (RSDs) less than 1.8% except vitamin C, and acceptable quantitative results corresponding to label claim.
MicroRNAs have been shown to potentially function in cerebral ischemia/reperfusion (IR) injury. This study aimed to examine the expression of microRNA-320 (miR-320) in cerebral IR injury and its ...involvement in cerebral mitochondrial function, oxidative stress, and inflammatory responses by targeting the HMGB1/ NF-κB axis. Sprague-Dawley rats were subjected to middle cerebral artery occlusion to simulate cerebral IR injury. The cerebral expression of miR-320 was assessed using qRT-PCR. Neurological function, cerebral infarct volume, mitochondrial function, oxidative stress, and inflammatory cytokines were evaluated using relevant methods, including staining, fluorometry, and ELISA. HMGB1 expression was analyzed through Western blotting. The levels of miR-320, HMGB1, neurological deficits, and cerebral infarction were significantly higher after IR induction. Intracerebral overexpression of miR-320 resulted in substantial neurological deficits, increased infarct volume, elevated levels of 8-isoprostane, NF-κBp65, TNF-α, IL-1β, ICAM-1, VCAM-1, and HMGB1 expression. It also promoted the loss of mitochondrial membrane potential and ROS levels while reducing MnSOD and GSH levels. Downregulation of miR-320 and inhibition of HMGB1 activity significantly reversed the outcomes of cerebral IR injury. MiR-320 plays a negative role in regulating cerebral inflammatory/oxidative reactions induced by IR injury by enhancing HMGB1 activity and modulating mitochondrial function.
The efficient utilization of propeller slipstream energy is important for improving the ultra-short takeoff and landing capability of Distributed Electric Propulsion (DEP) aircraft. This paper ...presents a quasi-three-dimensional (2.5D) high-lift wing design approach considering the three-dimensional (3D) effects of slipstream for DEP aircraft, aiming at maximizing the comprehensive lift enhancement benefit of the airframe-propulsion coupling unit. A high-precision and efficient momentum source method is adopted to simulate the slipstream effects, and the distributed propellers are replaced by a rectangular actuator disk to reduce the difficulty of grid generation and improve the grid quality. A detailed comparison of the 2.5D and 3D configurations based on the X-57 Mod Ⅳ is performed in terms of flow characteristics and computational cost to demonstrate the rationality of the above design approach. The optimization results of the high-lift wing of the X-57 Mod Ⅳ show that the aerodynamic performance of the landing configuration is significantly improved, for instance, the lift coefficient increases by 0.094 at the angle of attack of 7°, and 0.097 at the angle of attack of 14°. This novel approach achieves efficient and effective design of high-lift wings under the influence of distributed slipstream, which has the potential to improve the design level of DEP aircraft.
Nanoscaled HfO2-based ferroelectric thin films are a favored candidate for the integration of next-generation memory and logic devices. The unique advantage is that the ferroelectric polarization ...becomes more robust than the traditional perovskite ferroelectrics when the size is reduced. Understanding and controlling the ferroelectricity requires high-quality epitaxial thin films to explore intrinsic ferroelectric mechanism and evaluate device applications. Here, we report a semicoherent growth of ITO as a bottom electrode that enables genuine ultrathin epitaxial films of Si-doped HfO2 on YSZ001/110/111 substrates. The deposited films, which are under epitaxial compressive strain, display large ferroelectric polarization values up to 42 μC/cm2 and do not need wake-up cycling. Structural characterization reveals the presence of crystalline domains with short axes of the tetragonal structure oriented perpendicular to the substrate. Using piezoforce microscopy, polar domains can be written and read and can be reversibly switched with a phase change of 180o. Ferroelectric polarization can be controlled by ITO surface polarity which can easily exploit the interfacial valance mismatch to influence the electrostatic potential across the interface. These findings have implications for our understanding of ferroelectric switching and offer easy method to manipulate domain reversal state in HfO2-based ferroelectric materials.
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•A bluish-white emitting phosphor was synthesized.•K(Ba,Sr,Ca)BP2O8:Eu2+ exhibit a broad emission band.•WLED is fabricated by mixing of KBaBP2O8:Eu2+ and CaAlSiN3:Eu2+.
A series of Eu2+-activated ...K(Ba,Sr,Ca)BP2O8 phosphors was synthesized and evaluated as a candidate for white light emitting diodes (WLEDs). The photoluminescence spectra of KBaBP2O8:Eu2+ exhibited a broad emission band from 400 to 650nm under excitation at 380nm. By partially substituting Ba by Sr or Ca, the emission peak was blue-shifted, giving a blue color. A warm WLED was fabricated using bluish-white-emitting KBaBP2O8:Eu2+ and red-emitting CaAlSiN3:Eu2+ phosphors pumped by a 380nm near-UV chip, and the Ra value and reduced color temperature were found to be 91 and 5995K, respectively. The results reveal that the mixture of KBaBP2O8:Eu2+ and CaAlSiN3:Eu2+ phosphors may have promising applications for near-UV WLEDs.
Electroreduction of N
to NH
at ambient conditions using renewable electricity is promising, but developing efficient electrocatalysts is still challenging due to the inertness of N≡N bonds. Layer ...double hydroxides (LDHs) composed of first-row transition metals with empty d-orbitals are theoretically promising for N
electroreduction (NRR) but rarely reported. Herein, hollow NiCo-LDH nanocages with different Ni/Co ratios were prepared, and their electronic structures and atomic arrangements were critical. The synergetic mechanisms of Ni and Co ions were revealed, and the optimized catalytic sites were proposed. Besides, in-situ Raman spectroscopy and
N
isotopic labeling studies were applied to detect reaction intermediates and confirm the origin of NH
. As a result, high NH
yield of 52.8 μg h
mg
and faradaic efficiency of 11.5 % were obtained at -0.7 V, which are top-ranking among Co/Ni-based NRR electrocatalysts. This work elucidates the structure-activity relationship between LDHs and NRR and is instructive for rational design of LDH-based electrocatalysts.
Background: Levodopa (or l-DOPA) is the current standard of care for the management of Parkinson's disease (PD), but its chronic administration has been associated with the development of LID ...(l-DOPA-induced dyskinesia). Fisetin is a dietary flavonoid known for its neuroprotective efficacy. Aim: To determine the neuroprotective potential of fisetin in 6-hydroxydopamine (6-OHDA)-lesioned LID animals. Methods: 6-OHDA (12 µg and L-ascorbic acid 10 µL) was injected in a substantial nigra of Sprague-Dawley rat to develop PD followed by l-DOPA (20 mg/kg and benserazide HCl 5 mg/kg, 42 days) to induce LID. Rats were concomitantly administered with vehicle or amantadine (40 mg/kg), or fisetin (5, 10, and 25 mg/kg, p.o.) for 42 days with l-DOPA. Results: Chronic l-DOPA administration resulted in progressive abnormal involuntary movements (AIMs viz. axial, forelimb, and orolingual), akinesia (forelimb adjusting steps, FAS), muscular rigidity (catalepsy bar test), muscular coordination, and neurological impairments. Fisetin at doses of 10 and 25 mg/kg effectively reduced (P < .05) these LID-induced AIMs and behavioral changes. Furthermore, fisetin treatment markedly (P < .05) attenuated LID-induced diminished striatal mitochondrial complex activities, striatal monoamines (serotonin 5-HT and dopamine DA), elevated monoamines turnover (DA: DOPAC and 5-HT: 5-HIAA). In addition, fisetin treatment effectively (P < .05) reversed the upregulated expressions of striatal cFOS, FosB, Homer, Nurr-77, Parkin, and Pdyn. Conclusion: Our study demonstrated that fisetin offered neuroprotection via amelioration of striatum mitochondrial dysfunction and monoamine (5-HT and DA) turnover to halt further development of abnormal involuntary movement and dyskinesia.
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