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Background. Realgar (REA), a Chinese herbal decoction, has been used to treat various tumors and has produced positive outcomes; however, there is a lack of convincing evidence for the treatment of esophageal cancer. The present study aimed to investigate the effects of REA on esophageal cancer (EC) and explore its mechanism. Methods. EC cells Eca109 and KYSE150 were selected for this study, and different groups of treated cells were set up. We studied the inhibition rate and half inhibition concentration (IC50) by CCK-8 method, the clone formation assay was used to detect the clone formation ability, the scratch assay is used to determine the cell migration ability, the Transwell assay was used to detect the cell invasion ability, the protein expressions of E-cadherin, Slug, N-cadherin, ASK1, p38 MAPK, p-p38 MAPK, and GPX4 were determined using Western blot, the mRNA expressions of ASK1 and p38 MAPK were assessed using qRT-PCR, transmission electron microscopy was used to observe the cellular ultrastructure, Prussian blue staining was used to observe the intracellular iron particle distribution, and biochemical analysis of cellular MDA, SOD, GSH, and GPXS activities, flow cytometric analysis of cellular ROS levels, immunofluorescence staining to detect cellular GPX4 expression, and JC-1 method to detect mitochondrial membrane potential were used. Results. REA inhibited the proliferation of Eca109 and KYSE150 cells in a time- and concentration-dependent manner, and REA significantly inhibited the migration and invasion of Eca109 and KYSE150 cells and activated the cellular ferroptosis and ROS-ASK1-p38 MAPK signaling pathways ( P < 0.05 ). Inhibition of activation of the ROS-ASK1-p38 MAPK signaling pathway promoted the inhibition of proliferation, migration, and invasion of Eca109 and KYSE150 cells and the induction of ferroptosis by REA. Conclusion. REA induced ferroptosis and inhibited the migration of EC cells by activating the ROS-ASK1-p38 MAPK signaling pathway.

Background The aim of this study is to retrospectively review the effectiveness and safety of personalized Gamma Knife radiosurgery (GKRS) for cavernous sinus hemangiomas (CSHs) and to summarize experience of personalized GKRS treatment for different volume of CSHs. Methods 187 CSHs patients who received personalized GKRS treatment in our center from January 1, 2011 to December 31, 2020 were enrolled in this study and classified into small and medium CSHs ( Results After a mean follow-up duration of 28 months (range 12–124 months), the tumor control rate was 100%, and the mean shrinkage rate of CSHs was 93.2% (61.3%–100%) in the last follow-up. Of the 115 patients with preexisting symptoms, 43 (37.5%) patients showed symptom disappearance, 17 (14.7%) patients demonstrated improvement, and 55 (47.8%) patients remained with no change. Previous surgical resection of CSHs (OR = 0.025, 95% CI 0.007–0.084, P = .000) was identified to be an independent risk factor for no symptom improvement after GKRS treatment. Conclusions Personalized GKRS is an effective and safe treatment for different volume of CSHs, which is capable of shrinking the tumor and improving symptoms with extremely low incidence of adverse effects and might be considered as the primary treatment strategy for CSHs.

Supplementary Data

F-box and WD repeat domain containing 7 (FBXW7) is a substrate receptor of the ubiquitin ligase SKP1-Cullin1-F-box complex and a potent tumor suppressor that prevents unregulated cell growth and tumorigenesis. However, little is known about FBXW7-mediated control of cell metabolism and related functions in cancer therapy. Here, we report that FBXW7 expression inversely correlates with the expression levels of the key metabolic enzyme isocitrate dehydrogenase 1 (IDH1) in patients with glioma and public glioma datasets. Deletion of FBXW7 significantly increased both wild-type (WT) and mutant IDH1 expression, which was mediated by blocking degradation of sterol regulatory element binding protein 1 (SREBP1). The upregulation of neomorphic mutant IDH1 by FBXW7 deletion stimulated production of the oncometabolite 2-hydroxyglutarate at the expense of increasing pentose phosphate pathway activity and NADPH consumption, limiting the buffering ability against radiation-induced oxidative stress. In addition, FBXW7 knockout and IDH1 mutations induced nonhomologous end joining and homologous recombination defects, respectively. In vitro and in vivo, loss of FBXW7 dramatically enhanced the efficacy of radiation treatment in IDH1-mutant cancer cells. Taken together, this work identifies FBXW7 deficiency as a potential biomarker representing both DNA repair and metabolic vulnerabilities that sensitizes IDH1-mutant cancers to radiotherapy.Significance:Deficiency of FBXW7 causes defects in DNA repair and disrupts NADPH homeostasis in IDH1-mutant glioma cells, conferring high sensitivity to radiotherapy.

An easily operated Mg purification scheme is developed for extremely low-Mg (MgO down to 0.05 wt%) felsic rocks. Extremely low-Mg geostandards JR-1 and JR-3 are reported on for the first time.

Dopamine (DA) level in the nucleus accumbens (NAc) is critical for reward and aversion encoding. DA released from the ventral mesencephalon (VM) DAergic neurons increases the excitability of VM-projecting D1-dopamine receptor-expressing medium spiny neurons (D1-MSNs) in the NAc to enhance DA release and augment rewards. However, how such a DA positive feedback loop is regulated to maintain DA homeostasis and reward-aversion balance remains elusive. Here we report that the ventral pallidum (VP) projection of NAc D1-MSNs (D1NAc-VP) is inhibited by rewarding stimuli and activated by aversive stimuli. In contrast to the VM projection of D1-MSN (D1NAc-VM), activation of D1NAc-VP projection induces aversion, but not reward. D1NAc-VP MSNs are distinct from the D1NAc-VM MSNs, which exhibit conventional functions of D1-MSNs. Activation of D1NAc-VP projection stimulates VM GABAergic transmission, inhibits VM DAergic neurons, and reduces DA release into the NAc. Thus, D1NAc-VP and D1NAc-VM MSNs cooperatively control NAc dopamine balance and reward-aversion states.

Background: Realgar, a Chinese herbal decoction, has been used to treat various types of tumors with positive outcomes; however, there is a lack of convincing evidence on its use for the treatment of esophageal cancer (EC). In this study, the role of the p62-Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the regulation of EC cell proliferation, migration, and ferroptosis in response to realgar was assessed Methods: Different concentrations of realgar (0, 10, 20, 40, 60, 80, and 100 µmol/L) were applied to the EC cell lines Eca109 and KYSE150. The inhibition rate and half-inhibitory concentration (IC50) were determined using the Cell Counting Kit-8 (CCK-8) method. Subsequently, the cells were treated with realgar (1/2IC50, IC50, 2IC50). Cell migration was measured using the scratch assay, and cell invasion was measured using the transwell assay. The mRNA expression of p62, Keap1, and Nrf2 was measured by quantitative real-time polymerase chain reaction (qRT-PCR), and the protein expression of p62, Keap1, Nrf2, matrix metalloproteinase (MMP)-2, MMP-9, E-cadherin, Slug, N-cadherin, and vimentin was measured by Western blot. The control, 2IC50, shRNA-NC, shRNA-p62, 2IC50 + shRNA-NC, 2IC50 + shRNA-p62, shRNA-Keap1, 2IC50 + shRNA-Keap1, and 2IC50 + shRNA-p62 + shRNA-Keap1 groups were defined. The CCK-8 method was used to measure the cell inhibition rate, and the clone formation assay was used to measure the clone formation ability. Moreover, the scratch assay was used to detect the cell migration ability, and the transwell assay was used to detect the cell invasion ability. Transmission electron microscopy was used to observe the mitochondrial morphology, Prussian blue staining was used to observe the intracellular iron particle distribution, and flow cytometry was used to detect changes in intracellular reactive oxygen species. In addition, qRT-PCR was performed to detect p62, Keap1, Nrf2, and glutathione peroxidase 4 (GPX4) mRNA expression, and Western blot was performed to detect p62, Keap1, Nrf2, E-cadherin, Slug, N-cadherin, and GPX4 protein expression. Results: Realgar inhibited Eca109 and KYSE150 cell proliferation in a time- and concentrationdependent manner. It also significantly inhibited the migration and invasion of Eca109 and KYSE150 cells and affected the mRNA and protein expression of p62, Keap1, and Nrf2. In response to realgar, low p62 expression inhibited the proliferation, migration, and invasion of Eca109 and KYSE150 cells, as well as ferroptosis induction. Conclusion: The findings demonstrate that inhibiting the p62-Keap1-Nrf2 signaling pathway promotes the inhibitory effects of realgar on EC cells.

Photoreceptor degeneration diseases, such as retinitis pigmentosa and age-related macular degeneration, are major causes of blindness. Photovoltaic devices or materials activates retinal cells in response to light, hence are promising retinal prosthesis in treating blind patients. The restoration of image-forming vision with high sensitivity is the key. Here we demonstrated that Au nanoparticle-coated titania (TiO2-x) nanowire (NW) arrays can restore vision in blind mice and non-human primates with photoreceptor degeneration. We first showed that blind mice with subretinal implant of NW arrays were capable of detecting static, moving and flashing objects with low light intensity threshold for 22 months, having a visual acuity of 0.3 cpd (0.4 cpd in normal mice). Results in chronic in vivo calcium imaging in primary visual cortex (V1) collectively suggested the plastic change in V1 neurons as well as the improvement in visual information encoding for natural images after NW implant. What’s more, macaque monkeys with subretinal implant of NW arrays were capable of detecting an LED of 0.5º in diameter at 10 μW·mm-2 in visually-guided saccade experiments. Our findings opened up the possibility to utilize nanomaterials as artificial photoreceptors to ameliorate visual deficits of patients with photoreceptor degeneration.

Diphenylarsinic acid (DPAA) is an emerging phenylarsenic compound derived from chemical warfare agents. It has been suggested that biostimulation of sulfate reduction decreases the concentrations of DPAA in soils. However, biostimulation often induces Fe(III) reduction which may affect the mobility and thereby the transformation of DPAA. Here, a soil incubation experiment was carried out to elucidate the impact of Fe(III) reduction on the mobilization and transformation of DPAA in a biostimulated Acrisol with the addition of sulfate and lactate. DPAA was significantly mobilized and then thionated in the sulfide soil (amended with sulfate and sodium lactate) compared with the anoxic soil (without addition of sulfate or sodium lactate). At the start of the incubation period, 41.8% of the total DPAA in sulfide soil was mobilized, likely by the addition of sodium lactate, and DPAA was then almost completely released into the solution after 2 weeks of incubation, likely due to Fe(III) reduction. The relatively low fraction of oxalate-extractable Fe in Acrisol, which contributes significantly to DPAA sorption and is more active and reduction-susceptible, may explain the observation that only

Graphene/poly-(sodium-4-styrene sulfonate)(PSS)/poly-(allylamine hydrochloride) (PAH) composite is a frequently adopted system for fabricating polyelectrolyte multilayer films. Swelling is the bottleneck limiting its applications, and its effects on the conductivity is still controversial. Herein, we report successful swelling of a graphene/PSS/PAH composite in a vapor atmosphere, and the relation with the mass fraction of water is uncovered. The composite was prepared via a layer-by-layer assembly technique and systematically characterized. The results indicated that the average thickness for each bilayer was about 0.95 nm. The hardness and modulus were 2.5 ± 0.2 and 68 ± 5 GPa, respectively, and both were independent of thickness. The sheet resistance decreased slightly with the prolongation of immersion time, but was distinct from that of the water mass fraction. It reduced from 2.44 × 105 to 2.34 × 105 ohm/sq, and the change accelerated as the water mass fraction rose, especially when it was larger than 5%. This could be attributing to the lubrication effect of the water molecules, which sped up the migration of charged groups in the polyelectrolytes. Moreover, molecular dynamics simulations confirmed that a microphase separation occurred when the fraction reached an extreme value owing to the dominated interaction between PSS and PAH. These results provide support for the structural stability of this composite material and its applications in devices.

Photoreceptor degeneration diseases, such as retinitis pigmentosa and age-related macular degeneration, are major causes of blindness. Here we evaluate the performance of Au nanoparticle-coated titania (TiO2-x) nanowire (NW) arrays as artificial photoreceptors to restore image-forming vision in blind mice and non-human primates with photoreceptor degeneration. We first demonstrated that blind mice with the subretinal implant of NW arrays were capable of detecting static, moving and flashing objects, with a visual acuity of 0.3 cpd, measured up to 9 months after the implant surgery. Using chronic in vivo calcium imaging, we continuously monitored light-induced responses of neurons in the primary visual cortex (V1) in NW-implanted blind mice for over 14 weeks. Light responses of V1 neurons first appeared at 2 days after the surgery and the number of light-responsive V1 neurons peaked 1 week after the implant surgery, and the latency of these responses decreased over time. These results collectively suggested the plasticity and improvement in the encoding of visual information in V1 after NW implant surgery. We then implanted NW arrays subretinally in macaque monkeys, showing that the NW arrays did not cause adverse responses 8 weeks post surgery. Finally, visually-guided saccades were restored in macaque monkeys with the subretinal implant of NW arrays. Our findings demonstrated the possibility to utilize nanomaterials as artificial photoreceptors to ameliorate visual deficits of patients with photoreceptor degeneration.

Natural selenium (Se)-rich areas in China are generally characterized by high geological background of cadmium (Cd). However, the interaction between Se and Cd in the soil-rice-human continuum in such areas remains elusive. The concentrations, bioaccessibilities, and biomarkers of Se and Cd in a typical Se-Cd rich area were determined through chemical analysis, in vitro digestion model and cross-sectional study, respectively. The results showed that the molar ratio of available Se/Cd in the soil was averaged at 0.55 and soil Se did not reduce Cd accumulation and transportation in rice. Se bioaccessibility increased from the gastric phase to the intestinal phase, but the opposite was the case for Cd bioaccessibility. Moreover, bioaccessible concentration of Cd was positively correlated to corresponding total concentration in rice but negatively associated with the logarithm of molar ratio of Se/Cd. The risk of Cd-induced nephrotoxicity for the exposure group was not higher than the reference group, which could be ascribed to the mitigative effect of Se. Males and elders were at higher risk of Cd-induced injury owing to higher urinary Cd (U-Cd) and β2-microglobulin (U-β2-MG), and lower urinary Se (U-Se). Our results suggested that Cd-induced health risk should be assessed from a soil-rice-human perspective and the interaction between Se and Cd should be taken into account.

Photocoagulation is used for the treatment of retinal ischemic disease. However, due to the invasive nature of photocoagulation and variety of melanin concentrations between individuals, it is challenging to avoid damaging the adjacent photoreceptors and inducing several side effects. Previous studies indicate the role of laser power, duration, and spot size on retinal lesions, but the effect of interspot distance of the laser pulses needs to be considered in panretinal photocoagulation. In this study, we examine different parameters of photocoagulation on lesions of the retina in rabbit, finding that the lesion level of the outer nuclear layer of the retina depended on the pulse duration and laser spot size, and decreasing interspot distance could completely abolish the photoreceptor layer. The degeneration of the photoreceptor by photocoagulation occurred in 24 h and was not restored afterward. We then conducted panretinal photocoagulation in rabbit and found that oxidative stress was decreased in the inner nuclear layer of the retina, and pupillary light reflex and ERG signals were impaired. Our study could provide a rabbit model to explore the mechanism of photoreceptor degeneration and therapies for the side effects after photocoagulation.

The mobility of arsenic (As) in soils is fundamentally affected by the clay mineral fraction and its composition. Diphenylarsinic acid (DPAA) is an organoarsenic contaminant derived from chemical warfare agents. Understanding how DPAA interacts with soil clay mineral fractions will enhance understanding of the mobility and transformation of DPAA in the soil-water environment. The objective of this study was to investigate the speciation and sorption structure of DPAA in the clay mineral fractions. Twelve soils were collected from nine Chinese cities which known as chemical weapons burial sites and artificially contaminated with DPAA. A sequential extraction procedure (SEP) was employed to elucidate the speciation of DPAA in the clay mineral fractions of soils. Pearson’s correlation analysis was used to derive the relationship between DPAA sorption and the selected physicochemical properties of the clay mineral fractions. Extended X-ray absorption fine structure (EXAFS) LIII-edge As was measured using the beamline BL14W1 at Shanghai Synchrotron Radiation Facility (SSRF) to identify the coordination environment of DPAA in clay mineral fractions. The SEP results showed that DPAA predominantly existed as specifically fraction (18.3–52.8%). A considerable amount of DPAA was also released from non-specifically fraction (8.2–46.7%) and the dissolution of amorphous, poorly crystalline, and well-crystallized Fe/Al (hydr)oxides (20.1–46.2%). A combination of Pearson’s correlation analysis and SEP study demonstrated that amorphous and poorly crystalline Fe (hydr)oxides contributed most to DPAA sorption in the clay mineral fractions of soils. The EXAFS results further demonstrated that DPAA formed inner-sphere complexes on Fe (hydr)oxides, with As-Fe distances of 3.18–3.25 A. It is likely that the steric hindrance caused by phenyl substitution and hence the instability of DPAA/Fe complexes explain why a substantial amount of DPAA presented as weakly bound forms. DPAA in clay mineral fractions predominantly existed as specifically, amorphous, poorly crystalline, and crystallized Fe/Al (hydr)oxides associated fractions. Amorphous/poorly crystalline Fe rather than total Fe contributed more to DPAA sorption and DPAA formed inner-sphere complexes on Fe (hydr)oxides.

To investigate the impact of particle size on in vitro/vivo performance of praziquantel (PZQ), nanocrystals (NCs) and microcrystals (MCs) of PZQ were prepared using the methods of wet milling and jet milling, respectively. PZQ NCs and MCs were characterized with dynamic light scattering, laser particle size analyzer, transmission electron microscopy, differential scanning calorimetry, X-ray powder diffraction and fourier transform infrared spectroscopy. The average diameters of PZQ NCs and MCs were 364.4 nm and 3.7 µm, respectively. No change in crystalline form was observed. Dissolution tests were performed in two different media, where the cumulative dissolution and dissolution rate of NCs were significantly improved in comparison with those of MCs and KANGQING® in non-sink condition. Similarly, oral bioavailability of PZQ NCs in beagle dogs was 1.68 (P, Graphical abstract Praziquantel nanocrystals were prepared successfully by wet milling methods with the particle size of 364.4 nm. Compared with commercially available tablets and praziquantel microcrystals, praziquantel nanocrystals showed increased dissolution rate in vitro and oral bioavailability in vivo. Image, graphical abstract

As an alternative route to produce liquid fuels, Fischer–Tropsch synthesis (FTS) has received considerable attention. Phase equilibria have been one of the key issues in the design and operation of not only an FTS reactor, but also relevant downstream processing, e.g., stepwise condensation of FTS products, wastewater treatment, and the recovery of α-olefins. These issues are extremely complex due to a wide spectrum of FTS products and the presence of noncondensable gas, nonpolar components, associating components, and highly polar components. To address these issues, the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state (EoS) was evaluated using phase equilibrium data of binary and ternary mixtures containing water, alcohols, hydrocarbons, and noncondensable gases. The parameter values are available via a three-step parametrization strategy established in our previous work [Zheng et al. Ind. Eng. Chem. Res. 2018, 57, 3014]. A couple of popular benchmark models, namely the S...

This study examined the selenium (Se) and cadmium (Cd) uptake by rice from soil and analyzed the relationship between Se and Cd in naturally occurred Se-rich paddy fields with a high geological background of Cd. Significant correlations were observed between soil Se and plant biomass Se, but not between soil Cd and plant biomass Cd. High concentrations of Cd were detected in rice plants and particularly in rice grains, suggesting potential health risks to human. Contrary to results from other previous studies, our results showed that high soil Se did not reduce Cd uptake by rice, although it decreased the availability of Cd in soil. Rather, soil Se and internal Se pool in rice were positively correlated to the transfer of Cd from root to straw. The effect of Se on the uptake and translocation of Cd in rice in field is therefore different from those in pot experiments.

Enteroviruses belong to the genus Enterovirus of the family Picornaviridae and include four human enterovirus groups (EV-A to -D): the epidemic of enteroviruses such as human enterovirus A71 (EV-A71) and coxsackievirus A16 (CVA16) is a threat to global public health. Enteroviral protein 2C is the most conserved nonstructural protein among all enteroviruses and possesses RNA helicase activity that plays pivotal roles during enteroviral life cycles, which makes 2C an attractive target for developing antienterovirus drugs. In this study, we designed a peptide, named 2CL, based on the structure of EV-A71 2C. This peptide effectively impaired the oligomerization of EV-A71 2C protein and inhibited the RNA helicase activities of 2C proteins encoded by EV-A71 and CVA16, both of which belong to EV-A, and showed potent antiviral efficacy against EV-A71 and CVA16 in cells. Moreover, the 2CL treatment elicited a strong in vivo protective efficacy against lethal EV-A71 challenge. In addition, the antiviral strategy of targeting the 2C helicase activity can be applied to inhibit the replication of EV-B. Either 2CL or B-2CL, the peptide redesigned based on the 2CL-corresponding sequence of EV-Bs, could exert effective antiviral activity against two important EV-Bs, coxsackievirus B3 and echovirus 11. Together, our findings demonstrated that targeting the helicase activity of 2C with a rationally designed peptide is an efficient antiviral strategy against enteroviruses, and 2CL and B-2CL show promising clinical potential to be further developed as broad-spectrum antienterovirus drugs. IMPORTANCE Enteroviruses are a large group of positive-sense single-stranded RNA viruses and include numerous human pathogens, such as enterovirus A71 (EV-A71), coxsackieviruses, and echoviruses. However, no approved EV antiviral drugs are available. Enteroviral 2C is the most conserved nonstructural protein among all enteroviruses and contains the RNA helicase activity critical for the viral life cycle. Herein, according to the structure of EV-A71 2C, we designed a peptide that effectively inhibited the RNA helicase activities of EV-A71- and coxsackievirus A16 (CVA16)-encoded 2C proteins. Moreover, this peptide exerted potent antiviral effects against EV-A71 and CVA16 in cells and elicited therapeutic efficacy against lethal EV-A71 challenge in vivo. Furthermore, we demonstrate that the strategy of targeting the 2C helicase activity can be used for other relevant enteroviruses, including coxsackievirus B3 and echovirus 11. In summary, our findings provide compelling evidence that the designed peptides targeting the helicase activity of 2C could be broad-spectrum antivirals for enteroviruses.

OBJECTIVE Cavernous sinus hemangiomas (CSHs) are rare benign tumors originating from the cavernous sinus. Gamma Knife radiosurgery (GKRS) has been recommended as a primary treatment for small- to medium-sized CSHs. The optimal treatment for giant CSHs is still controversial. In this study, the authors retrospectively reviewed the effectiveness and safety of staged GKRS treatment for giant CSHs. METHODS Twenty-two patients with giant CSH who received staged GKRS treatment in the Gamma Knife Treatment Center of Henan Province during the period from January 1, 2011, to December 31, 2018, were enrolled in this study. Six patients had received microsurgery before GKRS, the other 16 patients were diagnosed according to clinical symptoms and MR images. All of the enrolled patients received 2-stage GKRS, and the mean interval between the two GKRS treatments was 6.5 months (range 6–12 months). For the first GKRS, the median isodose line was 48% (range 45%–50%), the median marginal dose was 13 Gy (range 11.5–14 Gy), and the median coverage of CSHs was 80% (range 70%–88%). For the second GKRS treatment, the median isodose line was 50% (range 45%–55%), the median marginal dose to the CSHs was 10.5 Gy (range 9–12.5 Gy), and the median coverage of the CSHs was 88% (range 80%–94%). RESULTS All of the patients received an outpatient review of an enhanced MR image of the head and a clinical physical check every 6 months after the first GKRS treatment. The mean follow-up duration was 52 months (range 24–84 months). The tumor control rate was 100% 24 months after staged GKRS, and at the last follow-up the mean tumor shrinkage rate was 96.7% (range 90.6%–100%) and the mean residual CSH volume was 2.1 ml (range 0–8.5 ml). Twenty patients suffered central nervous system (CNS) injury symptoms to varying degrees before staged GKRS treatment. Complete symptom recovery was found in 11 (55%) patients, improved symptoms in 5 (25%) patients, and no change in 4 (20%) patients after treatment. Only 1 patient suffered temporary preexisting headache aggravation and 1 patient suffered temporary preexisting diplopia aggravation 1 week after receiving the first GKRS treatment. Subacute or chronic complications were not detected after staged GKRS. CONCLUSIONS Staged GKRS is an effective treatment for giant CSHs. Because of the impressively low incidence of adverse effects, staged GKRS may be considered as a primary treatment for giant CSHs.

Rationale: Children usually develop less severe symptoms responding to Coronavirus Disease 2019 (COVID-19) than adults. However, little is known about the molecular alterations and pathogenesis of COVID-19 in children. Methods: We conducted plasma proteomic and metabolomic profilings of the blood samples of a cohort containing 18 COVID-19-children with mild symptoms and 12 healthy children, which were enrolled from hospital admissions and outpatients, respectively. Statistical analyses were performed to identify molecules specifically altered in COVID-19-children. We also developed a machine learning-based pipeline named inference of biomolecular combinations with minimal bias (iBM) to prioritize proteins and metabolites strongly altered in COVID-19-children, and experimentally validated the predictions. Results: By comparing to the multi-omic data in adults, we identified 44 proteins and 249 metabolites differentially altered in COVID-19-children against healthy children or COVID-19-adults. Further analyses demonstrated that both deteriorative immune response/inflammation processes and protective antioxidant or anti-inflammatory processes were markedly induced in COVID-19-children. Using iBM, we prioritized two combinations that contained 5 proteins and 5 metabolites, respectively, each exhibiting a total area under curve (AUC) value of 100% to accurately distinguish COVID-19-children from healthy children or COVID-19-adults. Further experiments validated that all the 5 proteins were up-regulated upon coronavirus infection. Interestingly, we found that the prioritized metabolites inhibited the expression of pro-inflammatory factors, and two of them, methylmalonic acid (MMA) and mannitol, also suppressed coronaviral replication, implying a protective role of these metabolites in COVID-19-children. Conclusion: The finding of a strong antagonism of deteriorative and protective effects provided new insights on the mechanism and pathogenesis of COVID-19 in children that mostly underwent mild symptoms. The identified metabolites strongly altered in COVID-19-children could serve as potential therapeutic agents of COVID-19.

The cystine/glutamate antiporter xCT (SLC7A11) is frequently upregulated in many cancers, including glioblastoma (GBM). SLC7A11-mediated cystine taken up is reduced to cysteine, a precursor amino acid for glutathione synthesis and antioxidant cellular defense. However, little is known about the biological functions of SLC7A11 and its effect on therapeutic response in GBM. Here, we report that the expression of SLC7A11 is higher in GBM compared with normal brain tissue, but is negatively associated with tumor grades and positively impacts survival in the bioinformatic analysis of TCGA and CGGA database. Additionally, a negative association between SLC7A11 and mismatch repair (MMR) gene expression was identified by Pearson correlation analysis. In the GBM cells with glucose-limited culture conditions, overexpression of SLC7A11 significantly decreased MMR gene expression, including MLH1, MSH6, and EXO1. SLC7A11-overexpressed GBM cells demonstrated elevated double-strand break (DSB) levels and increased sensitivity to radiation treatment. Taken together, our work indicates that SLC7A11 might be a potential biomarker for predicting a better response to radiotherapy in GBM.