IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease.

Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) also has an immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient (Ido1-/-) BMT to understand why myeloid IDO limits the severity of GVHD. Hosts with Ido1-/- BM exhibited increased lethality, with enhanced proinflammatory and reduced regulatory T cell responses compared with wild type (WT) allo-BMT controls. Despite the comparable expression of the myeloid-derived suppressor cell (MDSC) mediators, arginase-1, inducible nitric oxide synthase, and interleukin 10, Ido1-/- Gr-1+CD11b+ cells from allo-BMT or in vitro BM culture showed compromised immune-suppressive functions and were skewed toward the Ly6ClowLy6Ghi subset, compared with the WT counterparts. Importantly, Ido1-/-Gr-1+CD11b+ cells exhibited elevated levels of reactive oxygen species (ROS) and neutrophil numbers. These characteristics were rescued by human IDO1 with intact heme-binding and catalytic activities and were recapitulated by the treatment of WT cells with the IDO1 inhibitor L1-methyl tryptophan. ROS scavenging by N-acetylcysteine reverted the Ido1-/-Gr-1+CD11b+ composition and function to an MDSC state, as well as improved the survival of GVHD hosts with Ido1-/- BM. In summary, myeloid-derived IDO1 enhances GVHD survival by regulating ROS levels and limiting the ability of Gr-1+CD11b+ MDSCs to differentiate into proinflammatory neutrophils. Our findings provide a mechanistic insight into the immune-regulatory roles of the metabolic enzyme IDO1.

Permselective Ionic-Shield for High-Performance Lithium-Sulfur Batteries.

Lithium-sulfur batteries (LiSBs) are promising next-generation batteries because of their low cost and high theoretical energy densities. Despite remarkable advances over the decades, polysulfide (PS) shuttling during battery cycling remains a challenge in the development of commercial LiSBs and is accelerated under practical conditions. Herein, we report a permselective ionic shield between the electrodes that blocks PS shuttles and passes Li ions to high-performance LiSBs. This shield is easily built onto the separator by ionic complexation and intermolecular bonding of functional polymers, thereby improving the battery performance and safety. The LiSB with the developed shield delivers a remarkable discharge capacity of 917 mAh g-1 after 1000 cycles at 2 C. In addition, the behavior of LiSBs under practical conditions that can realize a high energy density is investigated to achieve the optimal balance in this system. This study provides new insights into the imminent development of separators for practical LiSBs.

Recycling respirator masks to a high-value product: From COVID-19 prevention to highly efficient battery separator.

COVID-19 is a pandemic that has caused serious disruption in almost every day-to-day life around the world, and wearing a mask is essential for human safety from this virus. However, masks are non-recyclable materials, and the accumulation of masks used every day causes serious environmental issues. In this study, we investigate the recycling of mask materials for addressing the environmental problems and transforming as a high value-added material through chemical modification of masks. The recycled mask is applied as a separator for aqueous rechargeable batteries, and shows outstanding safety and electrochemical performance than the existing separator. This approach will lead to an advanced energy technology considering nature after overcoming COVID-19.

Fast-Charging Lithium-Sulfur Batteries Enabled via Lean Binder Content.

Next-generation energy storage devices such as lithium-sulfur batteries (LSBs) face several challenges including fast charging and high-power delivery. Thus, it is necessary to improve the stability of the electrodes with efficient electrochemical system. In this work, a durable sulfur cathode even at high rates is enabled via lean binder content. The binder consists of a chitosan cross-linked with a carboxylated nitrile-butadiene rubber (XNBR), which exhibits high affinity toward lithium polysulfide along with robust mechanical properties because of the synergistic effect of the polar chitosan and the elastomeric XNBR. Despite using extremely small content of binder (3 wt%), the LSB shows a highly stable long-term cycling performance with capacity retention decay values of 0.026% and 0.029% after 500 cycles at 5 and 10 C. Moreover, the cell shows an outstanding specific capacity of 228 mAh g-1 at an ultrahigh charge-discharge rate of 20 C. This approach may significantly improve the design of the sulfur cathode and pave a facile way to fabricate commercially viable next-generation energy storage devices.

Gut microorganisms and their metabolites modulate the severity of acute colitis in a tryptophan metabolism-dependent manner.

PURPOSE: Growing evidence shows that nutrient metabolism affects inflammatory bowel diseases (IBD) development. Previously, we showed that deficiency of indoleamine 2,3-dioxygenase 1 (Ido1), a tryptophan-catabolizing enzyme, reduced the severity of dextran sulfate sodium (DSS)-induced colitis in mice. However, the roles played by intestinal microbiota in generating the differences in disease progression between Ido1+/+ and Ido1-/- mice are unknown. Therefore, we aimed to investigate the interactions between the intestinal microbiome and host IDO1 in governing intestinal inflammatory responses. METHODS: Microbial 16s rRNA sequencing was conducted in Ido1+/+ and Ido1-/- mice after DSS treatment. Bacteria-derived tryptophan metabolites were measured in urine. Transcriptome analysis revealed the effects of the metabolite and IDO1 expression in HCT116 cells. Colitis severity of Ido1+/+ was compared to Ido1-/- mice following fecal microbiota transplantation (FMT). RESULTS: Microbiome analysis through 16S-rRNA gene sequencing showed that IDO1 deficiency increased intestinal bacteria that use tryptophan preferentially to produce indolic compounds. Urinary excretion of 3-indoxyl sulfate, a metabolized form of gut bacteria-derived indole, was significantly higher in Ido1-/- than in Ido1+/+ mice. Transcriptome analysis showed that tight junction transcripts were significantly increased by indole treatment in HCT116 cells; however, the effects were diminished by IDO1 overexpression. Using FMT experiments, we demonstrated that bacteria from Ido1-/- mice could directly attenuate the severity of DSS-induced colitis. CONCLUSIONS: Our results provide evidence that a genetic defect in utilizing tryptophan affects intestinal microbiota profiles, altering microbial metabolites, and colitis development. This suggests that the host and intestinal microbiota communicate through shared nutrient metabolic networks.

Ultrasensitive Detection of Amyloid-ß Using Cellular Prion Protein on the Highly Conductive Au Nanoparticles-Poly(3,4-ethylene dioxythiophene)-Poly(thiophene-3-acetic acid) Composite Electrode.

A highly sensitive electrochemical impedance sensor for amyloid beta oligomer (AßO) was fabricated using a cellular prion protein (PrPC) bioreceptor linked with poly(thiophene-3-acetic acid) transducer. An additional thin layer of poly(3,4-ethylene dioxythiophene) embedded with gold nanoparticles was employed to provide high electrical conductivity and a large surface area. The sensing performace was investigated in terms of sensitivity and detection range. The fabricated sensor exhibited extremely low detection limit at a subfemtomolar level with a wide detection range from 10-8 to 104 nM and its utility was established in mice infected with Alzheimer's disease (AD). The developed AßO sensor could be utilized for early diagnosis of AD.

Inherently variable responses to glucocorticoid stress among endogenous retroviruses isolated from 23 mouse strains.

Active participation of endogenous retroviruses (ERVs) in disease processes has been exemplified by the finding that the HERV (human ERV)-W envelope protein is involved in the pathogenesis of multiple sclerosis, an autoimmune disease. We also demonstrated that injury-elicited stressors alter the expression of murine ERVs (MuERVs), both murine leukemia virus-type and mouse mammary tumor virus (MMTV)-type (MMTV-MuERV). In this study, to evaluate MMTV-MuERVs' responses to stress (e.g., injury, infection)-elicited systemic glucocorticoid (GC) levels, we examined the GC-stress response of 64 MMTV-MuERV promoters isolated from the genomes of 23 mouse strains. All 64 promoters responded to treatment with a synthetic GC, dexamethasone (DEX), at a wide range from a 0.6- to 85.7-fold increase in reporter activity compared to no treatment. An analysis of the 10 lowest and 10 highest DEX responders revealed specific promoter elements exclusively present in either the three lowest or the two highest responders. Each promoter had a unique profile of transcription regulatory elements and the glucocorticoid response element (GRE) was identified in all promoters with the number of GREs ranging from 2 to 7. The three lowest DEX responders were the only promoters with two GREs. The findings from this study suggest that certain MMTV-MuERVs are more responsive to stress-elicited systemic GC elevation compared to the others. The mouse strain-specific genomic MMTV-MuERV profiles and individual MMTV-MuERVs' differential responses to GC-stress might explain, at least in part, the variable inflammatory responses to injury and/or infection, often observed among different mouse strains. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju.

Interaction of CD99 with its paralog CD99L2 positively regulates CD99L2 trafficking to cell surfaces.

Mouse CD99 and its paralog CD99-like 2 (CD99L2) are surface proteins implicated in cellular adhesion and migration. Although their distributions overlap in a wide variety of cells, their physical/functional relationship is currently unknown. In this study, we show the interaction between the two molecules and its consequence for membrane trafficking of mouse (m)CD99L2. The interaction was analyzed by bimolecular fluorescence complementation, immunoprecipitation, and fluorescence resonance energy transfer assays. When coexpressed, mCD99 formed heterodimers with mCD99L2, as well as homodimers, and the heterodimers were localized more efficiently at the plasma membrane than were the homodimers. Their interaction was cytoplasmic domain-dependent and enhanced mCD99L2 trafficking to the plasma membrane regardless of whether it was transiently overexpressed or endogenously expressed. Surface levels of endogenous mCD99L2 were markedly low on thymocytes, splenic leukocytes, and CTL lines derived from CD99-deficient mice. Importantly, the surface levels of mCD99L2 on mCD99-deficient cells recovered significantly when wild-type mCD99 was exogenously introduced, but they remained low when a cytoplasmic domain mutant of mCD99 was introduced. Our results demonstrate a novel role for mCD99 in membrane trafficking of mCD99L2, providing useful insights into controlling transendothelial migration of leukocytes.

Divergent and dynamic activity of endogenous retroviruses in burn patients and their inflammatory potential.

Genes constitute ~3% of the human genome, whereas human endogenous retroviruses (HERVs) represent ~8%. We examined post-burn HERV expression in patients' blood cells, and the inflammatory potentials of the burn-associated HERVs were evaluated. Buffy coat cells, collected at various time points from 11 patients, were screened for the expression of eight HERV families, and we identified their divergent expression profiles depending on patient, HERV, and time point. The population of expressed HERV sequences was patient-specific, suggesting HERVs' inherent genomic polymorphisms and/or differential expression potentials depending on characteristics of patients and courses of injury response. Some HERVs were shared among the patients, while the others were divergent. Interestingly, one burn-associated HERV gag gene from a patient's genome induced IL-6, IL-1ß, Ptgs-2, and iNOS. These findings demonstrate that injury stressors initiate divergent HERV responses depending on patient, HERV, and disease course and implicate HERVs as genetic elements contributing to polymorphic injury pathophysiology.

REViewer: a tool for linear visualization of repetitive elements within a sequence query.

A species-specific population of arrangements of repetitive elements (REs), called RE arrays, exists in the human and mouse genomes. We developed an RE analytical tool, named REViewer, for visualizing RE occurrences within RE arrays and other genomic regions as an interactive line map. REViewer utilizes an RE reference library which is established with two RE types: 1) REMiner-generated undefined REs and 2) RepeatMasker-derived defined REs. RE occurrences within queries are visualized as a line map using these two RE types. The REViewer's controller provides analytical options, such as zoom, customization of axis unit, and RE type selection. The functionality of REViewer was evaluated using the human chromosome Y sequence. The REViewer is determined to be an efficient tool that facilitates visualization of up to 6000 REs in RE arrays and other genomic regions. The maximum query size is linked to the RE mining tools (e.g., REMiner, RepeatMasker), not to REViewer.

REMiner-II: a tool for rapid identification and configuration of repetitive element arrays from large mammalian chromosomes as a single query.

Genes occupy ~3% of the human and mouse genomes whereas repetitive elements (REs), whose biologic functions are largely uncharacterized, constitute greater than 50%. A heterogeneous population of RE arrays (arrangement structures) is formed by combinations of various REs in mammalian genomes. In this study, REMiner-II was refined from the original REMiner for a more efficient identification and configuration of RE arrays from large queries (e.g., human chromosomes) using an unbiased self-alignment protocol. Chromosome-wide RE array profiles for the entire sets of human and mouse chromosomes were obtained using REMiner-II on a personal computer. REMiner-II provides 10 adjustable parameters and three data output modes to accommodate different experimental settings and/or goals. Examination of the human and mouse chromosome data using the REMiner-II viewer revealed species-specific libraries of complexly organized RE arrays. In conclusion, REMiner-II is an efficient tool for chromosome-wide identification and characterization of RE arrays from mammalian genomes.

ERE database: a database of genomic maps and biological properties of endogenous retroviral elements in the C57BL/6J mouse genome.

Endogenous retroviral elements (EREs), a family of transposable elements, constitute a substantial fraction of mammalian genomes. It is expected that profiles of the ERE sequences and their genomic locations are unique for each individual. Comprehensive characterization of the EREs' genomic locations and their biological properties is essential for understanding their roles in the pathophysiology of the host. In this study, we identified and mapped putative EREs (a total of 111 endogenous retroviruses [ERVs] and 488 solo long terminal repeats [sLTRs]) within the C57BL/6J mouse genome. The biological properties of individual ERE isolates (both ERVs and sLTRs) were then characterized in the following aspects: transcription potential, tropism trait, coding potential, recombination event, integration age, and primer binding site for replication. In addition, a suite of database management system programs was developed to organize and update the data acquired from current and future studies and to make the data accessible via internet.

Electropolymerisation Technologies for Next-Generation Lithium-Sulphur Batteries.

Lithium-sulphur batteries (LiSBs) have garnered significant attention as the next-generation energy storage device because of their high theoretical energy density, low cost, and environmental friendliness. However, the undesirable "shuttle effect" by lithium polysulphides (LPSs) severely inhibits their practical application. To alleviate the shuttle effect, conductive polymers have been used to fabricate LiSBs owing to their improved electrically conducting pathways, flexible mechanical properties, and high affinity to LPSs, which allow the shuttle effect to be controlled. In this study, the applications of various conductive polymers prepared via the simple yet sophisticated electropolymerisation (EP) technology are systematically investigated based on the main components of LiSBs (cathodes, anodes, separators, and electrolytes). Finally, the potential application of EP technology in next-generation batteries is comprehensively discussed.

Harnessing aptamers for electrochemical detection of endotoxin.

Lipopolysaccharide (LPS), also known as endotoxin, triggers a fatal septic shock; therefore, fast and accurate detection of LPS from a complex milieu is of primary importance. Several LPS affinity binders have been reported so far but few of them have proved their efficacy in developing electrochemical sensors capable of selectively detecting LPS from crude biological liquors. In this study, we identified 10 different single-stranded DNA aptamers showing specific affinity to LPS with dissociation constants (K(d)) in the nanomolar range using a NECEEM-based non-SELEX method. Based on the sequence and secondary structure analysis of the LPS binding aptamers, an aptamer exhibiting the highest affinity to LPS (i.e., B2) was selected to construct an impedance biosensor on a gold surface. The developed electrochemical aptasensor showed excellent sensitivity and specificity in the linear detection range from 0.01 to 1 ng/mL of LPS with significantly reduced detection time compared with the traditional Limulus amoebocyte lysate (LAL) assay.

Age-dependent and tissue-specific structural changes in the C57BL/6J mouse genome.

We tested the hypothesis that structural changes in the genome parallel age- and organ-specific phenotypes in conjunction with the differential transposition activities of retroelements. The genomes of the liver from C57BL/6J mice were larger than other organs, coinciding with an increase in genomic copies of certain retroelements. In addition, there were differential increments in the genome size of the liver with increasing age, which peaked at 5 weeks. The findings that the genome structure of an individual is variable depending on age and organ type in association with the transposition of retroelements may have broad implications in understanding biologic phenomena.

Electromechanically driven variable-focus lens based on transparent dielectric elastomer.

Dielectric elastomers with low elastic stiffness and high dielectric constant are smart materials that produce large strains (up to 300%) and belong to the group of electroactive polymers. Dielectric elastomer actuators are made from films of dielectric elastomers coated on both sides with compliant electrode material. Poly(3,4-ethylenedioxythiophene) (PEDOT), which is known as a transparent conducting polymer, has been widely used as an interfacial layer or polymer electrode in polymer electronic devices. In this study, we propose the transparent dielectric elastomer as a material of actuator driving variable-focus lens system using PEDOT as a transparent electrode. The variable-focus lens module has light transmittance up to 70% and maximum displacement up to 450. When voltage is applied to the fabricated lens module, optical focal length is changed. We anticipate our research to be a starting point for new model of variable-focus lens system. This system could find applications in portable devices, such as digital cameras, camcorder, and cell phones.

REMiner: a tool for unbiased mining and analysis of repetitive elements and their arrangement structures of large chromosomes.

Repetitive elements (REs) constitute a substantial portion of the genomes of human and other species; however, the RE profiles (type, density, and arrangement) within the individual genomes have not been fully characterized. In this study, we developed an RE analysis tool, called REMiner, for a chromosome-wide investigation into the occurrence of individual REs and arrangement of clusters of REs, and REMiner's functional features were examined using the human chromosome Y. The algorithm implemented by REMiner focused on unbiased mining of REs in large chromosomes and data interface within a viewer. The data from the chromosome demonstrated that REMiner is an efficient tool in regard to its capacity for a large query size and the availability of a high-resolution viewer, featuring instant retrieval of alignment data and control of magnification and identity ratio. The chromosome-wide survey identified a diverse population of ordered RE arrangements, which may participate in the genome biology.

Binder-Free and High-Loading Cathode Realized by Hierarchical Structure for Potassium-Sulfur Batteries.

Potassium-sulfur batteries have attracted significant research attention owing to the naturally abundant resources of potassium and sulfur, and have promising applications in large-scale energy storage systems. However, the sluggish reaction kinetics of K+ , low reaction activity of sulfur species, shuttling effect of polysulfides, and large volume change impede the development of these batteries. Moreover, the conventional electrode fabrication method with binders and current collectors renders it difficult to improve the areal sulfur loading and energy density. In this study, a binder-free and freestanding sulfur cathode is prepared by phase inversion and sulfurization of polyacrylonitrile. This sulfur cathode, with a hierarchically porous network, enables a high reversible capacity of 1345 mAh g-1 and a stable cycling performance with a capacity decay of 0.15% per cycle. Importantly, areal capacities of 3.1 and 4.2 mAh cm-2 are achieved even at high sulfur loadings of 3 and 7 mg cm-2 , owing to the favorable electron/ion transport in the cathode. The facile preparation method and excellent electrochemical properties reported herein can pave the way for developing high-performance K-S batteries.

Highly Stable Potassium-Ion Battery Enabled by Nanoengineering of an Sb Anode.

We present the nanoengineering of Sb particles assisted by a conductive and stress-relieving network of carbon quantum dots (CQDs) and poly(3,4-ethylene dioxythiophene) poly(styrenesulfonate) (PEDOT:PSS), in the proper design of anode materials with high specific capacity and excellent stability for potassium-ion batteries (KIBs). The nanosized Sb particles are prepared by the CQDs as functional tuners in the morphology and surface, which tune the size to nanolevel and provide fast ionic channels and a soft matrix to relieve the volume changes. As the additional conductive and stress-relieving network layer, PEDOT:PSS offers enhanced electron/ion pathways and maintains the integrity of the Sb@CQD composite electrode. In the KIB, the prepared Sb anode exhibits battery performance with a high specific capacity of 480 mA h g-1 at 0.5 A g-1 and a high-capacity retention of 95.4% over 350 cycles.

Influence of the amount of skeletal muscle mass on rocuronium-induced neuromuscular block.

OBJECTIVE: To evaluate the effects of skeletal muscle mass on the rocuronium-induced neuromuscular block. DESIGN: A prospective, double-blinded, observational study. SETTING: A tertiary care university hospital. POPULATION: One hundred one patients aged 18-65 years who were scheduled to undergo major surgery lasting more than 1 h under general anaesthesia. METHODS: All participants underwent body composition analysis before anaesthesia and were allocated into two groups; the muscular and non-muscular group, according to skeletal muscle mass. During anaesthesia induction, rocuronium 1.0 mg kg-1 of total body weight was injected followed by neuromuscular monitoring using train-of-four stimulation every 15 s. MAIN OUTCOME MEASURES: The onset time of rocuronium included the elapsed time from the rocuronium injection until 95% depression of first twitch (T1) and the time to no response to TOF stimulation. The duration was evaluated as the elapsed time from the rocuronium injection to 25% recovery of the final T1 (TDUR25), and the time to the reappearance of T1 (TTOF1) and T4 (TTOF4). These pharmacologic data were compared between two groups. RESULTS: There was no significant difference in the onset time of rocuronium between the two groups. However, TDUR25 (min) was significantly shorter in the muscular group than in the non-muscular group (p = 0.035 and p = 0.014 in males and females, respectively). TTOF1 and TTOF4 were also shorter in the muscular group than in the non-muscular group. CONCLUSIONS: Total body weight-based dosing of rocuronium might prolong the neuromuscular relaxation effect in patients with a small amount of skeletal muscle.