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Objective: PANoptosis, a new form of regulated cell death, concomitantly manifests hallmarks for pyroptosis, apoptosis, and necroptosis. It has been usually observed in macrophages, a class of widely distributed innate immune cells in various tissues, upon pathogenic infections. The second-generation curaxin, CBL0137, can trigger necroptosis and apoptosis in cancer-associated fibroblasts. This study aimed to explore whether CBL0137 induces PANoptosis in macrophages in vitro and in mouse tissues in vivo. Methods: Bone marrow-derived macrophages and J774A.1 cells were treated with CBL0137 or its combination with LPS for indicated time periods. Cell death was assayed by propidium iodide staining and immunoblotting. Immunofluorescence microscopy was used to detect cellular protein distribution. Mice were administered with CBL0137 plus LPS and their serum and tissues were collected for biochemical and histopathological analyses, respectively. Results: The results showed that CBL0137 alone or in combination with LPS induced time- and dose-dependent cell death in macrophages, which was inhibited by a combination of multiple forms of cell death inhibitors but not each alone. This cell death was independent of NLRP3 expression. CBL0137 or CBL0137 + LPS-induced cell death was characterized by simultaneously increased hallmarks for pyroptosis, apoptosis and necroptosis, indicating that this is PANoptosis. Induction of PANoptosis was associated with Z-DNA formation in the nucleus and likely assembly of PANoptosome. ZBP1 was critical in mediating CBL0137 + LPS-induced cell death likely by sensing Z-DNA. Moreover, intraperitoneal administration of CBL0137 plus LPS induced systemic inflammatory responses and caused multi-organ (including the liver, kidney and lung) injury in mice due to induction of PANoptosis in these organs. Conclusions: CBL0137 alone or plus inflammatory stimulation induces PANoptosis both in vitro and in vivo, which is associated with systemic inflammatory responses in mice. [ABSTRACT FROM AUTHOR]

Iodine acetonitrile (IAN) is an important halogenated acetonitrile (HANs) with potential toxic effect on organism. However, no in vivo toxicological study has been reported on IAN. To quantify the toxicity of IAN, we sought to use adult Drosophila as a model for studying IAN-induced neurotoxicity. Adult Drosophila flies were exposed to 1000 mg/L, 100 mg/L, 10 mg/L, and 1 mg/L IAN or dibromoacetonitrile (DBAN, used as positive control) for 4 days to observe fly survival rate, and for 7 days to study climbing behavior. One hundred percent lethality was observed at 1000 mg/L IAN or DBAN. Kaplan‒Meier survival curves demonstrated that the overall survival of flies treated with 1 mg/L IAN was significantly shorter than that of flies treated with 1 mg/L DBAN. The climbing assay showed that the 10 mg/L IAN and 100 mg/L DBAN conditions started to reduce the climbing ability of the flies, suggesting that IAN and DBAN are neurotoxicity. In conclusion, IAN is more toxic than DBAN. It is recommended that attention be paid to toxicity, and IAN be included in the water test criteria to limit its concentration. In addition, IAN exposure was associated with changes in climbing behavior in flies, which might be associated with neurotoxicity. [ABSTRACT FROM AUTHOR]

Itaconate is an unsaturated dicarboxylic acid that is derived from the decarboxylation of the Krebs cycle intermediate cis-aconitate and has been shown to exhibit anti-inflammatory and anti-bacterial/viral properties. But the mechanisms underlying itaconate's anti-inflammatory activities are not fully understood. Necroptosis, a lytic form of regulated cell death (RCD), is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) signaling. It has been involved in the pathogenesis of organ injury in many inflammatory diseases. In this study, we aimed to explore whether itaconate and its derivatives can inhibit necroptosis in murine macrophages, a mouse MPC-5 cell line and a human HT-29 cell line in response to different necroptotic activators. Our results showed that itaconate and its derivatives dose-dependently inhibited necroptosis, among which dimethyl itaconate (DMI) was the most effective one. Mechanistically, itaconate and its derivatives inhibited necroptosis by suppressing the RIPK1/RIPK3/MLKL signaling and the oligomerization of MLKL. Furthermore, DMI promoted the nuclear translocation of Nrf2 that is a critical regulator of intracellular redox homeostasis, and reduced the levels of intracellular reactive oxygen species (ROS) and mitochondrial superoxide (mtROS) that were induced by necroptotic activators. Consistently, DMI prevented the loss of mitochondrial membrane potential induced by the necroptotic activators. In addition, DMI mitigated caerulein-induced acute pancreatitis in mice accompanied by reduced activation of the necroptotic signaling in vivo. Collectively, our study demonstrates that itaconate and its derivatives can inhibit necroptosis by suppressing the RIPK1/RIPK3/MLKL signaling, highlighting their potential applications for treating necroptosis-associated diseases. [ABSTRACT FROM AUTHOR]

Using first-principles calculations, we predict a new type of two-dimensional (2D) beryllium(Be)-decorated T-graphene named BeC2, where Be atoms are inserted into C–C bonds linking the carbon tetrarings of T-graphene. The band structure shows that BeC2 is metallic, thus, the possible phonon-mediated superconductivity is explored based on the Eliashberg equation. The calculated electron-phonon coupling (EPC) constant λ is up to 4.07, and the corresponding superconducting critical temperature (Tc) is 72.1 K, approaching the liquid nitrogen temperature. The reason for the high Tc is the strong EPC. And it is proved to be an anisotropic single-gap superconductor by analyzing the superconducting gap Δk of BeC2. The electronic susceptibility calculation shows strong nesting effect in BeC2. Since rare 2D superconductors show such a strong EPC constant λ which originates from the coupling between electrons in C–pz orbital and in-plane vibrations of Be and C atoms, the predicted BeC2 provides a new platform for investigating strong EPC 2D superconductor. [ABSTRACT FROM AUTHOR]

Macrophages represent the first lines of innate defense against pathogenic infections and are poised to undergo multiple forms of regulated cell death (RCD) upon infections or toxic stimuli, leading to multiple organ injury. Triptolide, an active compound isolated from Tripterygium wilfordii Hook F., possesses various pharmacological activities including anti-tumor and anti-inflammatory effects, but its applications have been hampered by toxic adverse effects. It remains unknown whether and how triptolide induces different forms of RCD in macrophages. In this study, we showed that triptolide exhibited significant cytotoxicity on cultured macrophages in vitro, which was associated with multiple forms of lytic cell death that could not be fully suppressed by any one specific inhibitor for a single form of RCD. Consistently, triptolide induced the simultaneous activation of pyroptotic, apoptotic and necroptotic hallmarks, which was accompanied by the co-localization of ASC specks respectively with RIPK3 or caspase-8 as well as their interaction with each other, indicating the formation of PANoptosome and thus the induction of PANoptosis. Triptolide-induced PANoptosis was associated with mitochondrial dysfunction and ROS production. PANoptosis was also induced by triptolide in mouse peritoneal macrophages in vivo. Furthermore, triptolide caused kidney and liver injury, which was associated with systemic inflammatory responses and the activation of hallmarks for PANoptosis in vivo. Collectively, our data reveal that triptolide induces PANoptosis in macrophages in vitro and exhibits nephrotoxicity and hepatotoxicity associated with induction of PANoptosis in vivo, suggesting a new avenue to alleviate triptolide's toxicity by harnessing PANoptosis. [ABSTRACT FROM AUTHOR]

This study differentiates myocardial infarction (MI) and strangulation death (STR) from the perspective of amino acid metabolism. In this study, MI mice model via subcutaneous injection of isoproterenol and STR mice model by neck strangulation were constructed, and were randomly divided into control (CON), STR, mild MI (MMI), and severe MI (SMI) groups. The metabolomics profiles were obtained by liquid chromatography-mass spectrometry (LC–MS)-based untargeted metabolomics. Principal component analysis, partial least squares-discriminant analysis, volcano plots, and heatmap were used for discrepancy metabolomics analysis. Pathway enrichment analysis was performed and the expression of proteins related to metabolomics was detected using immunohistochemical and western blot methods. Differential metabolites and metabolite pathways were screened. In addition, we found the expression of PPM1K was significantly reduced in the MI group, but the expression of p-mTOR and p-S6K1 were significantly increased (all P < 0.05), especially in the SMI group (P < 0.01). The expression of Cyt-C was significantly increased in each group compared with the CON group, especially in the STR group (all P < 0.01), and the expression of AMPKα1 was significantly increased in the STR group (all P < 0.01). Our study for the first time revealed significant differences in amino acid metabolism between STR and MI. [ABSTRACT FROM AUTHOR]

These years, two-dimensional (2D) superconductors have attracted more and more attentions. The critical temperature ( T c ) of superconductors can be modified by hole/electron doping, atom adsorption, strain and other means, so as to realize superconductivity with higher T c . In this paper, using first-principles calculations, we study the superconductivity of monolayer hexagonal boron phosphide (h-BP) by metal atoms adsorption. The electronic structure and electron-phonon coupling (EPC) of MBP (M=Li, Na, Ti) are studied. It is found that monolayer h-BP transforms from a semiconductor to a metal after metal atoms adsorption. Based on the conventional EPC mechanism, the coupling between electrons and the out-of-plane vibration of B atoms and P atoms contributes greatly to the EPC. For MBP (M=Li, Na, Ti), the calculated total EPC λ are 1.76, 0.64, and 1.54, and the corresponding T c are 26.38, 6.05, and 14.58 K, respectively. Thus, the predicted MBP (M=Li, Na, Ti) are new 2D superconductors which might be used in future superconducting electronic devices. [ABSTRACT FROM AUTHOR]

LRP1, the low-density lipoprotein receptor 1, would be a novel candidate gene of epilepsy according to our bioinformatic results and the animal study. In this study, we explored the role of LRP1 in epilepsy and whether beta-hydroxybutyrate, the principal ketone body of the ketogenic diet, can treat epilepsy caused by LRP1 deficiency in drosophila. UAS/GAL4 system was used to establish different genotype models. Flies were given standard, high-sucrose, and ketone body food randomly. The bang-sensitive test was performed on flies and seizure-like behavior was assessed. In morphologic experiments, we found that LRP1 deficiency caused partial loss of the ellipsoidal body and partial destruction of the fan-shaped body. Whole-body and glia LRP1 defect flies had a higher seizure rate compared to the control group. Ketone body decreased the seizure rate in behavior test in all LRP1 defect flies, compared to standard and high sucrose diet. Overexpression of glutamate transporter gene Eaat1 could mimic the ketone body effect on LRP1 deficiency flies. This study demonstrated that LRP1 defect globally or in glial cells or neurons could induce epilepsy in drosophila. The ketone body efficaciously rescued epilepsy caused by LRP1 knockdown. The results support screening for LRP1 mutations as discriminating conduct for individuals who require clinical attention and further clarify the mechanism of the ketogenic diet in epilepsy, which could help epilepsy patients make a precise treatment case by case. [ABSTRACT FROM AUTHOR]

Severe hand, foot, and mouth disease (HFMD) caused by enterovirus 71 (EV71) infection is associated with high mortality and disability. DC-SIGN, a receptor for EV71, is widely distributed in dendritic cells and may influence the severity of HFMD caused by EV71 infection. This observational study attempts to explore whether single-nucleotide polymorphisms (SNPs) in DC-SIGN are related to the severity of EV71-associated HFMD. Based on linkage disequilibrium and functional predictions, two DC-SIGN SNPs were selected and tested to explore their potential association with the severity of HFMD caused by EV71 infection. Two hundred sixteen Han Chinese children with HFMD caused by EV71 were enrolled to obtain clinical data, including the severity of HFMD, serum DC-SIGN levels, and DC-SIGN SNPs. We found a significant association between the rs7248637 polymorphism (A vs. G: OR = 0.644, 95% CI = 0.515-0.806) and the severity of HFMD caused by EV71 infection, as well as the rs4804800 polymorphism (A vs. G: OR = 1.539, 95% CI =1.229-1.928). These two DC-SIGN SNPs may have an effect on the severity of HFMD caused by EV71 infection. [ABSTRACT FROM AUTHOR]

The variability in multi-pulse gamma-ray bursts (GRBs) may help to reveal the mechanism of underlying processes from the central engine. To investigate whether the self-organized criticality (SOC) phenomena exist in the prompt phase of GRBs, we statistically study the properties of GRBs with more than 3 pulses in each burst by fitting the distributions of several observed physical variables with a Markov Chain Monte Carlo approach, including the isotropic energy Eiso, the duration time T, and the peak count rate P of each pulse. Our sample consists of 454 pulses in 93 GRBs observed by the CGRO/BATSE satellite. The best-fitting values and uncertainties for these power-law indices of the differential frequency distributions are: α E d = 1.54 ± 0.09 , α T d = 1.82 ± 0.15 + 0.14 a n d α P d = 2.09 − 019 + 0.18 , while the power-law indices in the cumulative frequency distributions are: α E c = 1.44 −s 0.10 + 0.08 , α T c = 1.75 − 0.13 + 0.141 a n d α P c = 1.99 − 019 + 0.16 . We find that these distributions are roughly consistent with the physical framework of a Fractal-Diffusive, Self-Organized Criticality (FD-SOC) system with the spatial dimension S = 3 and the classical diffusion β=1. Our results support that the jet responsible for the GRBs should be magnetically dominated and magnetic instabilities (e.g., kink model, or tearing-model instability) lead the GRB emission region into the SOC state. [ABSTRACT FROM AUTHOR]

To evaluate the epigenetic regulation of the VDR gene in enterovirus 71 (EV71)-associated severe hand, foot, and mouth disease (HFMD), a total of 116 patients with EV71-HFMD, including 58 with mild EV71-HFMD and 58 with severe EV71-HFMD, as well as 60 healthy controls, were enrolled in this study. Quantitative real-time PCR was used to measure the relative levels of VDR mRNA expression, and the methylation status of the VDR promoter was assessed using a MethylTarget™ assay. The DNA methylation levels of the VDR promoter in children with EV71-associated severe HFMD were lower than those in the healthy controls and in children with mild HFMD (P < 0.05). Hypomethylation at CpG site 133 and hypermethylation at the CpG 42 sites and 68 downregulated VDR expression. Moreover, the methylation level of VDR could be used for differential diagnosis of mild and severe EV71-associated HFMD (AUC56, 0.73; AUC68, 0.699; AUC42, 0.694; AUC66, 0.693). VDR expression and promoter methylation were associated with the progression of EV71 infection. Determining the VDR promoter status might help clinicians initiate the appropriate strategy for treatment of EV71-associated HFMD. [ABSTRACT FROM AUTHOR]

The standard redox electrode potential ( E°) values of metallocene compounds are obtained theoretically with density functional theory (DFT) method at B3LYP/6-311++G( d, p) level and experimentally with cyclic voltammetry (CV). The theoretical E° values of metallocene compounds are in good agreement with experimental ones. We investigate the substituent effects on the redox properties of metallocene compounds. Among the four metallocene compounds, the E° values is largest for titanocene dichloride and smallest for ferrocene. [ABSTRACT FROM AUTHOR]

The mitochondrial toxicity induced by GSH-CdTe Quantum dots (QDs) of different sizes was investigated. The decreases in absorbance and transmission electron microscopy images show that QDs induce the swelling of mitochondria. Results of flow cytometry indicate that QDs cause a reduction of mitochondrial membrane potential (MMP). A remarkable increase in fluidity of protein regions of mitochondrial membrane is observed, whereas the lipid regions are not obviously affected. Cyclosporin A (CsA) effectively prevents the QD-induced mitochondrial swelling. On the basis of these results, it is proposed that QDs induce mitochondrial permeability transition (MPT). Moreover, with increasing QDs size, a pronounced MPT is observed. The difference between the membrane fluidity induced by QDs and Cadmium ion and the ineffective protective effects of EDTA suggests that the mitochondrial toxicity of QDs cannot be only attributed to the release of metal ion. The protective effects of HSA indicate that the interaction of QDs with pore-forming protein gives rise to the increase in membrane fluidity. This hypothesis is demonstrated by the interaction of QDs with model membranes and proteins using differential scanning calorimetry and isothermal titration microcalorimetry. In conclusion, as the size of QDs increases, the binding affinity of QDs with membrane protein increases, and therefore causes a pronounced mitochondrial damage. [ABSTRACT FROM AUTHOR]

Proportional fair resource allocation plays a critical role to balance the spectrum efficiency and fairness for cognitive orthogonal frequency division multiplexing (OFDM) network. However, due to the lack of cooperation between cognitive radio (CR) network and primary network, channel state information between CR base station (CRBS) and primary user (PU) could not be estimated precisely. Therefore, the interference of CRBS-PU couldn't be computed precisely and chance-constrained programming is adopted to formulate the resource allocation problem. In this work, we study the proportional fair resource allocation problem based on chance-constrained programming for cognitive OFDM network. The objective function maximizes the spectral efficiency of cognitive OFDM network over subcarrier and power allocation. The constraint conditions include the interference constraint of PU with the target probability requirement and the proportional fair rate requirement of CR users. In order to solve the above optimization problem, two steps are taken to develop hybrid immune optimization algorithm (HIOA). In the first step, the probabilistic interference constraint condition is transformed as an uncertain function which is computed by a generalized regression neural network (GRNN). In the second step, we combine immune optimization algorithm and GRNN to develop HIOA. Simulation results demonstrate that HIOA yields higher spectral efficiency while the probabilistic interference constraint condition and the proportional fair rate constraint condition could be satisfied very well. [ABSTRACT FROM AUTHOR]

The objective of this study was to establish and optimize high-performance thin-layer chromatography (HPTLC) analysis of gatifloxacin and related substances by the method of design of experiment (DOE). First, preliminary screening of 22 solvents was performed using uniform design (UD) to establish the developing solvent proposed to be optimized. The optimal proportions of components in the developing solvent were established by using central composite design (CCD) to establish and validate HPTLC analysis of gatifloxacin and related substances. Using DOE, it was found that the optimal proportions (by volume) of components in the developing solvent in the HPTLC analytical method were methanol-1,2-dichloroethane-concentrated ammonia solution-acetonitrile (2.8:7.2:0.5:0.5, v/v). Methodological validation showed that the established HPTLC method could separate gatifloxacin and 8 related substances with similar structures effectively. In particular, impurity pairs with the greatest separation difficulty (due to their similar polarities and dipole moments), e.g., impurity #3 (8-fluorogatifloxacin) and impurity #8 (gatifloxacin 2-methylpiperazine), impurity #3, and substance #9 (gatifloxacin), could also be separated effectively. The HPTLC method was simple, accurate, reliable, and suitable for rapid qualitative analysis of gatifloxacin and related substances in routine tests. Additionally, the analytical results presented here may provide useful supplemental information on the current reversed phase high-performance liquid chromatography (RP-HPLC) method, especially in terms of the mechanism of normal-phase separation. [ABSTRACT FROM AUTHOR]