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The clinical success of engineered, CD19-directed chimeric antigen receptor (CAR) T cells in relapsed, refractory B-cell acute lymphoblastic leukemia (B-ALL) has generated great enthusiasm for the use of CAR T cells in patients with cytogenetics that portend a poor prognosis with conventional cytotoxic therapies. One such group includes infants and children with mixed lineage leukemia (MLL1, KMT2A) rearrangements (MLL-r), who fare much worse than patients with low- or standard-risk B-ALL. Although early clinical trials using CD19 CAR T cells for MLL-r B-ALL produced complete remission in most patients, relapse with CD19-negative disease was a common mechanism of treatment failure. Whereas CD19neg relapse has been observed across a broad spectrum of B-ALL patients treated with CD19-directed therapy, patients with MLL-r have manifested the emergence of AML, often clonally related to the B-ALL, suggesting that the inherent heterogeneity or lineage plasticity of MLL-r B-ALL may predispose patients to a myeloid relapse. Understanding the factors that enable and drive myeloid relapse may be important to devise strategies to improve durability of remissions. In this review, we summarize clinical observations to date with MLL-r B-ALL and generally discuss lineage plasticity as a mechanism of escape from immunotherapy.

Existing enhancement methods are empirically expected to help the high-level end computer vision task: however, that is observed to not always be the case in practice. We focus on object or face detection in poor visibility enhancements caused by bad weathers (haze, rain) and low light conditions. To provide a more thorough examination and fair comparison, we introduce three benchmark sets collected in real-world hazy, rainy, and low-light conditions, respectively, with annotated objects/faces. We launched the UG2+ challenge Track 2 competition in IEEE CVPR 2019, aiming to evoke a comprehensive discussion and exploration about whether and how low-level vision techniques can benefit the high-level automatic visual recognition in various scenarios. To our best knowledge, this is the first and currently largest effort of its kind. Baseline results by cascading existing enhancement and detection models are reported, indicating the highly challenging nature of our new data as well as the large room for further technical innovations. Thanks to a large participation from the research community, we are able to analyze representative team solutions, striving to better identify the strengths and limitations of existing mindsets as well as the future directions.

Perturbation of Fe(III)-bearing oxic environments by reduced species such as sulfide occurs widely in natural and engineered systems. However, whether hydroxyl radicals (OH) can be produced in these environments remains unexplored. Here we show that sulfide drives OH production in Fe(III) oxyhydroxides suspensions under neutral and oxic conditions. For lepidocrocite, ferrihydrite and goethite suspensions at 11.2 mM Fe, the addition of 0.5 mM sulfide produced 14.2, 14.3 and 22.4 μM OH within 120 min, respectively. With addition of sulfide to lepidocrocite suspensions at 11.2 mM Fe, the cumulative OH concentration within 120 min increased from 0 to 14.2, 25.2, 52.6 and 63.1 μM when sulfide dosage increased from 0 to 0.5, 2.5, 5 and 7.5 mM, respectively. At a fixed sulfide dosage of 5 mM, the cumulative OH concentration increased with increasing the number of sulfide additions. The mechanisms of OH production were attributed to the generation of surface-bound Fe(II), most likely in the form of >FeIIOH2+, and Fe(II) in the solid phase or FeS from the reactions between sulfide and Fe(III), followed by O2 activation. OH production could take place until depletion of sulfide. Finally, we found that the generated OH could oxidize the coexisting redox-active substances like phenol under neutral and oxic conditions. Our findings reveal that sulfide perturbation of Fe(III)-bearing oxic environments is a new source of OH, and contaminants oxidation by OH necessitates consideration in these environments.

The study was conducted to evaluate the application of human umbilical cord mesenchymal stem cells (hUCMSCs) in the treatment of tubal factor infertility (TFI) caused by Chlamydia trachomatis, and investigate their effect on fertility in animal models of chronic salpingitis. In this study, we investigated the therapy effects of the transplantation of hUCMSCs in tubal factor infertility using a chronic salpingitis murine model which induced Chlamydia trachomatis. Twenty rats were divided into two groups: control group (n = 10) and treatment group (n = 10). hUCMSCs were given to mice after exposure to C. trachomatis for 4 weeks. After treatment for 4 weeks, five mice were randomly selected from each of the two groups to sacrifice and we examined the organ morphology and pathology, inflammatory cytokines, proliferation, and apoptosis in fallopian tube (FT).The remaining five mice from each group were caged 2:1 with male mice for another 4 weeks, the numbers of pregnant mice and the mean number of pups in the different groups were enumerated and calculated. Intravaginal inoculation of hUCMSCs alleviated hydrosalpinx of the oviduct. EdU-labeled hUCMSCs are located at the interstitial site of the fallopian tube. Macrophage (F4/80) infiltration was significantly reduced in the treatment group compared with the control group and expression levels of the anti-inflammatory cytokine IL10 were increased after hUCMSCs treatment. Furthermore, mRNA and protein expression levels of PCNA and Caspase-3 were increased and decreased, respectively, in the hUCMSCs’ treatment group compared with the control. Moreover, hUCMSCs’ transplantation improved murine fertility. Anti-inflammatory and anti-apoptotic effects of hUCMSCs may play an important role in TFI. Our data suggest that hUCMSCs’ transplantation contributed to the repair of tubal injury and improvement of fertility, providing a basis for assessing the contribution of stem cells in the oviduct for direct repair of the tube to assist reproduction.

Background Glioblastoma multiforme (GBM) is the leading cause of death among adult brain cancer patients. Glutathione peroxidase 2 (GPX2), as a factor in oxidative stress, plays an important role in carcinogenesis. However, its role in GBM has not been well established. The study aimed to investigate the clinical significance of GPX2 with GBM prognosis. Methods Data of GBM and healthy individuals were retrospectively collected from oncomine, cancer cell line encyclopedia (CCLE), gene expression profiling interactive analysis (GEPIA), UALCAN, and Human Protein Atlas. GPX2 mRNA expression was first assessed across various cancer types in oncomine and cancer cell lines from CCLE. The mRNA expression of GPX2 was compared between normal and GBM tissues using GEPIA (normal = 207; GBM = 163) and UALCAN (normal = 5; GBM = 156). The GPX2 methylation was analyzed using data from UALCAN (normal = 2; GBM = 140). The prognostic value of GPX2 in GBM was explored in GEPIA and UALCAN using Kaplan–Meier method. STRING database was used to construct protein–protein interaction (PPI) network and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Statistical significance was set as Results The current study revealed no significant differences in GPX2 expression between normal and GBM from GEPIA data (P > 0.05) and UALCAN (P = 0.257). Patients with higher GPX2 intended to have a poorer prognosis (P = 0.0089). The KEGG pathways found that chemokine-signaling pathway were the more preferred. Conclusions The findings demonstrated that GPX2 might be a potential diagnosis and prognostic indicator for GBM. Chemokine-signaling pathway may be involved in GPX2 function.

The tumor suppressor p53 is one of the most important proteins for protection of genomic stability and cancer prevention. Cancers often inactivate it by either mutating its gene or disabling its function. Thus, activating p53 becomes an attractive approach for the development of molecule-based anti-cancer therapy. The past decade and half have witnessed tremendous progress in this area. This essay offers readers with a grand review on this progress with updated information about small molecule activators of p53 either still at bench work or in clinical trials.

In this study, the effect of absorption pressure and temperature towards the CO2 absorption capacity and rate of choline chloride - monoethanol amine deep eutectic solvent (ChCl-MEA DES) was evaluated. Water mixing into ChCl-MEA DES was also examined as a method to improve CO2 absorption behavior. Equilibrium experiments were done in a batch reactor and the data was analyzed using response surface methodology (RSM). Results suggested that the dominant mode of CO2 absorption by ChCl-MEA DES was physical absorption. The maximum capacity of CO2 absorption obtained in this study was 0.379 mol-CO2/mol-DES from absorption at (10 bar, 40 °C) using DES with 50 %v water. Water mixing up to 50 %v was found to nearly double the CO2 absorption capacity of ChCl-MEA DES compared to neat DES. Study into CO2 absorption rate by ChCl-MEA DES found that it is mainly influenced positively by pressure and water content, while not significantly influenced by temperature. CO2 absorption rate of ChCl-MEA DES with 50 %v water was found to be on average twice of that of neat DES. It was also found that water content up to 50 %v does not change the mechanism of CO2 absorption by ChCl-MEA DES.

Interaction of mackinawite (FeS) with O2 has attracted much attention recently for contaminant transformation due to reactive oxidant production. However, the effect of in situ generated Fe (oxyhydr)oxide coatings on FeS reactivity and the resultant reactive oxidant production remains poorly understood. To clarify this effect, we specially prepared partially oxidized FeS with in situ generated Fe (oxyhydr)oxide coatings, and then stored it in the anoxic environment to explore the interactions between FeS and Fe (oxyhydr)oxide coatings, and characterized the variation of morphology and Fe(II) species by STEM, XRD, Mossbauer spectroscopy and XPS. We found that the reactivity of FeS upon oxygenation and the resultant OH production for phenol oxidation were prominently accelerated after anoxic settling. XRD patterns exhibited the formation of more crystalline Fe (oxyhydr)oxide coatings, Mossbauer spectra identified the generation of a new Fe(II) species, and XPS results revealed the increase in Fe(II) fraction on the surface during anoxic settling. These variations were most probably attributed to the electron transfer between FeS core and Fe (oxyhydr)oxide coatings driven by the redox potential gradient. Our findings deepened the mechanistic understanding of FeS reactivity and the resultant oxidizing impact on contaminant transformation under O2-perturbed conditions.

Multi-layer light field displays are a type of computational three-dimensional (3D) display which has recently gained increasing interest for its holographic-like effect and natural compatibility with 2D displays. However, the major shortcoming, depth limitation, still cannot be overcome in the traditional light field modeling and reconstruction based on multi-layer liquid crystal displays (LCDs). Considering this disadvantage, our paper incorporates a salience guided depth optimization over a limited display range to calibrate the displayed depth and present the maximum area of salience region for multi-layer light field display. Different from previously reported cascaded light field displays that use the fixed initialization plane as the depth center of display content, our method automatically calibrates the depth initialization based on the salience results derived from the proposed contrast enhanced salience detection method. Experiments demonstrate that the proposed method provides a promising advantage in visual perception for the compressive light field displays from both software simulation and prototype demonstration. National Research Foundation (NRF) Accepted version Dr. WANG Shizheng is financially supported by the Chinese Academy of Science, HundredTalent Program (2018-2020). This work was supported by National Research Foundation Singapore (NRF-CRP11- 2012-01).

Although ribosomal proteins are known for playing an essential role in ribosome assembly and protein translation, their ribosome-independent functions have also been greatly appreciated. Over the past decade, more than a dozen of ribosomal proteins have been found to activate the tumor suppressor p53 pathway in response to ribosomal stress. In addition, these ribosomal proteins are involved in various physiological and pathological processes. This review is composed to overview the current understanding of how ribosomal stress provokes the accumulation of ribosome-free ribosomal proteins, as well as the ribosome-independent functions of ribosomal proteins in tumorigenesis, immune signaling, and development. We also propose the potential of applying these pieces of knowledge to the development of ribosomal stress-based cancer therapeutics.

In the present work, a novel photocatalytic fuel cell (PFC) system involving a dual heterojunction photoelectrodes, viz. polyaniline/TiO2 nanotubes (PANI/TiO2 NTs) photoanode and CuO/Co3O4 nanorods (CuO/Co3O4 NRs) photocathode, has been designed. Compared to TiO2 NTs electrode of PFC, the present heterojunction design not only enhances the visible light absorption but also offers the higher efficiency in degrading Rhodamine B–a model organic pollutant. The study includes an evaluation of the dual performance of the photoelectrodes as well. Under visible-light irradiation of 3 mW cm−2, the cell composed of the photoanode PANI/TiO2 NTs and CuO/Co3O4 NRs photocathode forms an interior bias of +0.24 V within the PFC system. This interior bias facilitated the transfer of electrons from the photoanode to photocathode across the external circuit and combined with the holes generated therein along with a simultaneous power production. In this manner, the separation of electron/hole pair was achieved in the photoelectrodes by releasing the holes and electrons of PANI/TiO2 NTs photoanode and CuO/Co3O4 NRs photocathode, respectively. Using this PFC system, the degradation of Rhodamine B in aqueous media was achieved to an extent of 68.5% within a reaction duration of a four-hour period besides a simultaneous power generation of 85 μA cm−2.

TAp63, a member of the p53 family, has been shown to regulate energy metabolism. Here, we report coiled coil domain-containing 3 (CCDC3) as a new TAp63 target. TAp63, but not ΔNp63, p53 or p73, upregulates CCDC3 expression by directly binding to its enhancer region. The CCDC3 expression is markedly reduced in TAp63-null mouse embryonic fibroblasts and brown adipose tissues and by tumor necrosis factor alpha that reduces p63 transcriptional activity, but induced by metformin, an anti-diabetic drug that activates p63. Also, the expression of CCDC3 is positively correlated with TAp63 levels, but conversely with ΔNp63 levels, during adipocyte differentiation. Interestingly, CCDC3, as a secreted protein, targets liver cancer cells and increases long chain polyunsaturated fatty acids, but decreases ceramide in the cells. CCDC3 alleviates glucose intolerance, insulin resistance and steatosis formation in transgenic CCDC3 mice on high-fat diet (HFD) by reducing the expression of hepatic PPARγ and its target gene CIDEA as well as other genes involved in de novo lipogenesis. Similar results are reproduced by hepatic expression of ectopic CCDC3 in mice on HFD. Altogether, these results demonstrate that CCDC3 modulates liver lipid metabolism by inhibiting liver de novo lipogenesis as a downstream player of the p63 network.

The electrochemical degradation behavior of microcystin-LR (MC-LR) in aqueous electrolyte at boron-doped diamond (BDD) anode was investigated under neutral pH condition. Hydroxyl radicals (OH) formed were detected by photoluminescence (PL) technique using terephthalic acid as a probe molecule, and it was observed to be predominant reactive specie. The intermediates formed in the MC-LR decomposition reaction were identified by LC–MS/MS, among which, two (m/z 1011.8 and 1029.5) were found to have multiple peaks in total ion current (TIC) chromatogram. The degradation of MC-LR was found to be mainly due to OH attack that involved hydroxylation of MC-LR via substitution/addition with a simultaneous isomerization, oxidation and oxidative bond cleavage reaction processes. The destruction of conjugated double bond of Adda was achieved by different mechanistic steps involving addition and substitution of OH that generated primary by product at m/z 1029.5. The destruction of diene bond of the Mdha, produced an adduct which was observed to be more stable, owing to a very less barrier than its substitution counterpart.

NF-κB has been broadly implicated in the survival of acute myeloid leukemia (AML) through distinct mechanisms. MLL fusion oncoprotein (MLL-FP) leukemia is thought to require NF-κB activity based on several publications. First, RelA collaborates with MLL1/MLL-FPs to sustain leukemogenic genetic programs. Second, the IL-1/IRAK signaling axis has been connected to a mechanism of MLL1/MLL-FP competition. Third, our recent data shows that NFκB-dependent target genes are globally reduced by MLL1/MLL2 deletion in murine and human AML. To address the role of the NF-κB pathway in MLL-FP-driven AML, we pursued several orthogonal approaches. Pharmacologic inhibition of IRAK1/4 activity reduces MLL-FP AML proliferation and delays leukemia progression in mice. Inhibiting IRAK1/4 blocks phosphorylation of the ubiquitin ligase UBE2O, preventing degradation of WT MLL1 protein. Stabilization of MLL1 is then thought to impede genome-wide MLL-FP chromatin occupancy and activation of oncogenic programs. To address the ability of MLL1 to compete with MLL-FP in AML, we developed a doxycycline-dependent MLL1 inducible model. Increasing WT MLL1 during MLL-AF9-driven leukemogenesis did not affect disease phenotype, latency, or penetrance. Furthermore, WT MLL1 levels did not affect the sensitivity of murine or human MLL-FP cells to IRAK1/4 inhibition. Ongoing experiments focus on the survival role of IL1/IRAK/UBE2O signaling in MLL1-deficient AML. Furthermore, to investigate the potential of MLL2 inhibition as a therapeutic strategy in AML and to study the connection to NF-κB, we expressed a series of peptides designed to hinder MLL2’s chromatin occupancy. The impact and specificity of these peptides was compared to MLL2 loss in several systems. These approaches collectively aim to identify the most effective strategy for targeting survival pathways in MLL-rearranged AML.

The fabrication of Ag/AgCl/TiO2 nanotube arrays electrode was achieved by a two-step method involving an electrochemical anodization process and an electrodeposition process. The Ag/AgCl/TiO2 nanotube arrays electrode was employed for the photoelectrocatalytic (PEC) degradation of microcystin-LR (MC-LR) and found to be an effective visible-light-driven (VLD) PEC material. The reactive oxidative species (ROS) are observed to be generated from the hole (h+) and electron (e−) in the PEC process. The mechanism for PEC degradation of the MC-LR is investigated using different scavengers and found that the major reactive species generated in situ are h+, OH and O2-, which are actually responsible for the degradation of MC-LR. The effect of operating parameters, such as initial pH of MC-LR solution and the type of anions, are studied. And the results show that the degradation of MC-LR was highly promoted in NaCl electrolyte, and the degradation was enhanced in an acid medium.

New high performance transparent UV-curable composites with simultaneously improved integrated performance were successfully developed, which consist of silicone-acrylate (SA) resin and poly(methyl methacrylate) grafted ZnO (ZnO-PMMA). The composites made up of SA resin and ZnO were also prepared for systematically investigating the effect of the surface nature of ZnO on the structure and property of the composites. Results show that the surface nature of ZnO determines the interfacial and morphological features of the composites, and thus leads to different integrated properties. Compared with ZnO/SA composites, ZnO-PMMA/SA composites possess higher UV-shielding efficiency and transmittance of the visible light, better thermal stability and lower dielectric loss. Specifically, the addition of a small amount (0.05 wt.%) of ZnO-PMMA to SA resin can significantly improve the UV-shielding efficiency (the composite absorbs 97% of UV light at 340 nm) while maintaining high transmittance of the visible light (88% at 650 nm); moreover, the composite also has high thermal stability and favorable dielectric property. These attractive features of ZnO-PMMA/SA composites suggest that the method proposed herein is a new approach to develop high performance transparent optoelectronic materials for cutting-edge industries.

Previously, we reported that IκB kinase-β(IKKβ) phosphorylates and stabilizes TAp63γ. However, the effect of this phosphorylation on TAp63γ transcriptional activity remains unclear. In this study, we showed that overexpression of IKKβ, but not its kinase dead mutant and IKKα, can surprisingly inhibit TAp63γ transcriptional activity as measured by luciferase assays and real-time PCR analyses of p63 target genes. This inhibition was impaired by ACHP, an IKKβ inhibitor, and enhanced by TNFα that activates IKKβ. Consistently, IKKβ inhibited the binding between TAp63γ and p300, a co-activator of TAp63γ, and consequently counteracted the positive effect of p300 on TAp63γ transcriptional activity. Through phosphorylation site prediction and mass spectrometry, we identified that Ser-4 and Ser-12 of p63 are IKKβ-targeting residues. As expected, IKKβ fails to suppress the transcriptional activity of the S4A/S12A double mutant p63. These results indicate that IKKβ can suppress TAp63γ activity by interfering with the interaction between TAp63γ and p300.

Forkhead box O (FOXO) transcriptional protein family members, including FOXO1 and FOXO3, are involved in the modulation of autophagy. However, whether there is redundancy between FOXO1 and FOXO3 in the ability to induce autophagy remains unclear. In this study, we showed that FOXO3 induced a transcription-dependent autophagy, and FOXO1 was required for this process. Overexpression of wild-type FOXO3 (WT) or FOXO3 (3A), which harbors alanine mutations at residues Thr32, Ser253 and Ser315, but not transcription-inactive FOXO3 (∆DB3A), significantly induced autophagy in the human embryonic kidney cell line HEK293T and mouse embryonic fibroblast (MEF) cell lines. Interestingly, depletion of FOXO1 by siRNA attenuated FOXO3-induced autophagy. Our data also showed that FOXO3 overexpression did not increase the expression of FOXO1 at the protein level, although FOXO3 was capable of binding the promoter region of FOXO1 and inducing an increase in the transcription of FOXO1 mRNA. Furthermore, our results showed that FOXO3 promoted the translocation of FOXO1 from the nucleus to the cytoplasm, resulting in an increase in FOXO1-induced autophagy. Moreover, our results supported a mechanism whereby FOXO3 dramatically increased the expression of the class I PtdIns3K catalytic subunit PIK3CA, leading to an increase in AKT1 activity, which resulted in the phosphorylation and nuclear export of FOXO1. To the best of our knowledge, our data are the first to suggest that FOXO1 plays a central role in FOXO3-induced autophagy.

Although Beclin 1 and mTOR are considered to be the main molecules to modulate the autophagic process, searching for other autophagy-regulating molecules is still an ongoing challenge to scientists. Here we demonstrated that FoxO1, a forkhead O family protein, is a mediator of autophagy. Upon oxidative stress or serum starvation, endogenous FoxO1 was required for autophagy in human cancer cell lines, and this process was independent of FoxO1's transcriptional activity as well as mTOR or Beclin 1. In response to stress, FoxO1 dissociated from an NAD+-dependent histone deacetylase SIRT2, and FoxO1 thus became acetylated, and in turn bound to Atg7, an E1-like protein, to influence the autophagic process leading to cell death. In particular, cytosolic FoxO1 suppressed tumor xenograft growth in nude mice in an autophagy-dependent manner. Our studies provide evidence that cytosolic FoxO1-induced autophagy is associated with tumor suppression function.

Background Amino acid absorption in the form of di- and tripeptides is mediated by the intestinal proton-coupled peptide transporter PEPT-1 (formally OPT-2) in Caenorhabditits elegans. Transporter-deficient animals (pept-1(lg601)) show impaired growth, slowed postembryonal development and major changes in amino acid status. Principal Findings Here we demonstrate that abolished intestinal peptide transport also leads to major metabolic alterations that culminate in a two fold increase in total body fat content. Feeding of C. elegans with [U-13C]-labelled E. coli revealed a decreased de novo synthesis of long-chain fatty acids in pept-1(lg601) and reduced levels of polyunsaturated fatty acids. mRNA profiling revealed increased transcript levels of enzymes/transporters needed for peroxisomal β-oxidation and decreased levels for those required for fatty acid synthesis, elongation and desaturation. As a prime and most fundamental process that may account for the increased fat content in pept-1(lg601) we identified a highly accelerated absorption of free fatty acids from the bacterial food in the intestine. Conclusions The influx of free fatty acids into intestinal epithelial cells is strongly dependent on alterations in intracellular pH which is regulated by the interplay of PEPT-1 and the sodium-proton exchanger NHX-2. We here provide evidence for a central mechanism by which the PEPT-1/NHX-2 system strongly influences the in vivo fat content of C. elegans. Loss of PEPT-1 decreases intestinal proton influx leading to a higher uptake of free fatty acids with fat accumulation whereas loss of NHX-2 causes intracellular acidification by the PEPT-1 mediated proton/dipeptide symport with an almost abolished uptake of fatty acids and a lean phenotype.