Contribution of monocyte and macrophage extracellular traps to neutrophilic airway inflammation in severe asthma.

BACKGROUND: Increased blood/sputum neutrophil counts are related to poor clinical outcomes of severe asthma (SA), where we hypothesized that classical monocytes (CMs)/CM-derived macrophages (Mφ) are involved. We aimed to elucidate the mechanisms of how CMs/Mφ induce the activation of neutrophils/innate lymphoid cells (ILCs) in SA. METHODS: Serum levels of monocyte chemoattractant protein-1 (MCP-1) and soluble suppression of tumorigenicity 2 (sST2) were measured from 39 patients with SA and 98 those with nonsevere asthma (NSA). CMs/Mφ were isolated from patients with SA (n = 19) and those with NSA (n = 18) and treated with LPS/interferon-gamma. Monocyte/M1Mφ extracellular traps (MoETs/M1ETs) were evaluated by western blotting, immunofluorescence, and PicoGreen assay. The effects of MoETs/M1ETs on neutrophils, airway epithelial cells (AECs), ILC1, and ILC3 were assessed in vitro and in vivo. RESULTS: The SA group had significantly higher CM counts with increased migration as well as higher levels of serum MCP-1/sST2 than the NSA group. Moreover, the SA group had significantly greater production of MoETs/M1ETs (from CMs/M1Mφ) than the NSA group. The levels of MoETs/M1ETs were positively correlated with blood neutrophils and serum levels of MCP-1/sST2, but negatively correlated with FEV1%. In vitro/in vivo studies demonstrated that MoETs/M1ETs could activate AECs, neutrophils, ILC1, and ILC3 by increased migration as well as proinflammatory cytokine production. CONCLUSIONS: CM/Mφ-derived MoETs/M1ETs could contribute to asthma severity by enhancing neutrophilic airway inflammation in SA, where modulating CMs/Mφ may be a potential therapeutic option.

Topological Microlaser with a Non-Hermitian Topological Bulk.

Bulk-edge correspondence, with quantized bulk topology leading to protected edge states, is a hallmark of topological states of matter and has been experimentally observed in electronic, atomic, photonic, and many other systems. While bulk-edge correspondence has been extensively studied in Hermitian systems, a non-Hermitian bulk could drastically modify the Hermitian topological band theory due to the interplay between non-Hermiticity and topology, and its effect on bulk-edge correspondence is still an ongoing pursuit. Importantly, including non-Hermicity can significantly expand the horizon of topological states of matter and lead to a plethora of unique properties and device applications, an example of which is a topological laser. However, the bulk topology, and thereby the bulk-edge correspondence, in existing topological edge-mode lasers is not well defined. Here, we propose and experimentally probe topological edge-mode lasing with a well-defined non-Hermitian bulk topology in a one-dimensional (1D) array of coupled ring resonators. By modeling the Hamiltonian with an additional degree of freedom (referred to as synthetic dimension), our 1D structure is equivalent to a 2D non-Hermitian Chern insulator with precise mapping. Our Letter may open a new pathway for probing non-Hermitian topological effects and exploring non-Hermitian topological device applications.

Cereblon contributes to cardiac dysfunction by degrading Cav1.2α.

AIMS: Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction is a critical player in heart failure with reduced ejection fraction (HFrEF). However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Cav1.2α during cardiac dysfunction remain unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Cav1.2α activity and examining how it can serve as a target to address myocardial dysfunction. METHODS AND RESULTS: Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN-/-) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) exhibited enhanced cardiac contractility with increased LTCC current (ICaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Cav1.2α. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminal of Cav1.2α. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Cav1.2α and decreased ICaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and enhanced ICaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. CONCLUSION: Cereblon selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction. A targeted approach or an efficient method of reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics.

Down-regulated surfactant protein B in obese asthmatics.

BACKGROUND: Obesity is a common comorbid condition in adult asthmatics and known as a feature of asthma severity. However, the molecular mechanism under obesity-induced inflammation has not yet been fully understood. OBJECTIVE: Considering the essential role of hydrophobic surfactant protein B (SP-B) in lung function, SP-B was targeted to examine its involvement in the development of obesity-induced airway inflammation in asthmatics. METHODS: The aim was to examine an alteration in circulating SP-B according to obesity in adult asthmatics, 129 asthmatics were enrolled and classified into 3 groups (obese, overweight and normal-weight groups) according to body mass index (BMI). Circulating SP-B levels were determined by enzyme-linked immunosorbent assay. Four single nucleotide polymorphisms of SFTPB gene were genotyped. Serum ceramide levels were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Significantly lower serum SP-B levels were noted in the obese group than in the overweight or normal-weight group (p = .002). The serum SP-B level was significantly correlated with serum levels of C18:0 ceramide and transforming growth factor beta 1 as well as BMI (r = -0.200; r = -0.215; r = -0.332, p < .050 for all). An inverse correlation was noted between serum SP-B and fractional exhaled nitric oxide levels in female asthmatics (r = -0.287, p = .009). Genetic predisposition of the SFTPB gene at 9306 A>G to the obese and overweight groups was noted. CONCLUSION: Obesity altered ceramide metabolism leading to pulmonary surfactant dysfunction and impaired resolution of airway inflammation, finally contributing to the phenotypes of obese asthmatics.

Health-related quality of life using WHODAS 2.0 and associated factors 1 year after stroke in Korea: a multi-centre and cross-sectional study.

BACKGROUND: Little is known about the self-perceived level of disability of stroke survivors in the community. We aimed to characterise Health-related quality of life (HRQoL) 1 year after stroke and investigate how sociodemographic and stroke-related factors and medical adherence explain the self-perceived level of disability in a Korean stroke population. METHODS: This was a multicentre cross-sectional study. A total of 382 ischaemic stroke survivors at 1 year after onset from 11 university hospitals underwent a one-session assessment, including socioeconomic variables, the modified Rankin Scale (mRS), various neurological sequelae, the Morisky, Green and Levin-Medication Adherence Questionnaire (MGL), and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) 36-items. The relationship between disability and different variables was analysed using ordinal logistic regression. RESULTS: The prevalence of disability based on global WHODAS 2.0 was 62.6% (mild, 41.6%; moderate, 16.0%; severe, 5.0%). The prevalence of severe disability was higher in participation in society (16.8%) and getting around (11.8%) than in other domains. Low MGL- motivation was the only factor determining a significant association between all six domains of disability after adjustment. Different predictors for specific domains were age, mRS, dysarthria, trouble seeing, cognition problems, and MGL-motivation for understanding and communicating; age, recurrent stroke, mRS, hemiplegia, facial palsy, general weakness, and MGL-motivation for getting around; age, education, mRS, hemiplegia, and MGL-motivation for self-care; education, recurrent stroke, hemiplegia, dysarthria, and MGL-motivation for getting along with people; age, education, income, mRS, hemiplegia, dysarthria, MGL-knowledge, and MGL-motivation for life activities; living without a spouse, mRS, hemiplegia, dysarthria, trouble seeing, cognition problems, general weakness, and MGL-motivation for participation in society. CONCLUSIONS: Self-perceived disability according to the WHODAS 2.0 at 1 year after stroke was highly prevalent. Each disability domain showed a different prevalence and associated factors. Interventions promoting medical adherence to motivation seemed to help achieve high HRQoL in all domains.

Data Collection Framework for Context-Aware Virtual Reality Application Development in Unity: Case of Avatar Embodiment.

Virtual Reality (VR) has been adopted as a leading technology for the metaverse, yet most previous VR systems provide one-size-fits-all experiences to users. Context-awareness in VR enables personalized experiences in the metaverse, such as improved embodiment and deeper integration of the real world and virtual worlds. Personalization requires context data from diverse sources. We proposed a reusable and extensible context data collection framework, ManySense VR, which unifies data collection from diverse sources for VR applications. ManySense VR was implemented in Unity based on extensible context data managers collecting data from data sources such as an eye tracker, electroencephalogram, pulse, respiration, galvanic skin response, facial tracker, and Open Weather Map. We used ManySense VR to build a context-aware embodiment VR scene where the user's avatar is synchronized with their bodily actions. The performance evaluation of ManySense VR showed good performance in processor usage, frame rate, and memory footprint. Additionally, we conducted a qualitative formative evaluation by interviewing five developers (two males and three females; mean age: 22) after they used and extended ManySense VR. The participants expressed advantages (e.g., ease-of-use, learnability, familiarity, quickness, and extensibility), disadvantages (e.g., inconvenient/error-prone data query method and lack of diversity in callback methods), future application ideas, and improvement suggestions that indicate potential and can guide future development. In conclusion, ManySense VR is an efficient tool for researchers and developers to easily integrate context data into their Unity-based VR applications for the metaverse.

A cyclodextrin-decorated plasmonic gold nanosatellite substrate for selective detection of bipyridylium pesticides.

A cyclodextrin-decorated gold nanosatellite (AuNSL) substrate was developed as a surface-enhanced Raman scattering sensor for the selective sensing of bipyridylium pesticides such as paraquat (PQ), diquat (DQ), and difenzoquat (DIF). The AuNSL structure was fabricated via vacuum deposition of gold nanoparticles (AuNPs) on a gold nanopillar substrate, and a large density of hot-spots was formed for Raman signal enhancement. Thiolated ß-cyclodextrin (SH-CD) was surface-modified on the AuNSL as a chemical receptor. The detection limit of PQ, DQ, and DIF on the SH-CD-coated AuNSL (CD-AuNSL) was 0.05 ppm for each, and showed linear correlation in a concentration range of 10 ppm-0.05 ppm. Then, selective bipyridylium pesticide detection was performed by comparing the Raman intensity of each pesticide with and without the washing step. After the washing step, 90% of the PQ, DQ, and DIF Raman signals were maintained on the CD-AuNSL substrate with a uniform selectivity in a mapping area of 200 µm × 200 µm. Furthermore, selective pesticide detection was performed using a ground-apple solution without pretreatment. Raman signals were clearly observed after the washing step and they showed a limit of detection down to a concentration of 0.05 ppm for each pesticide. Principal component analysis (PCA) of the binary and ternary mixtures of PQ, DQ, and DIF showed that each component could be easily identified via the typical Raman fingerprint analysis. The developed CD-AuNSL is expected to be applied for various chemical sensors, especially for pyridine-containing toxic substances in the environment and metabolite biomarkers in biofluids.

Manganese Ferrite Nanoparticles Enhance the Sensitivity of Hepa1-6 Hepatocellular Carcinoma to Radiation by Remodeling Tumor Microenvironments.

We evaluated the effect of manganese ferrite nanoparticles (MFN) on radiosensitization and immunologic responses using the murine hepatoma cell line Hepa1-6 and the syngeneic mouse model. The clonogenic survival of Hepa1-6 cells was increased by hypoxia, while being restricted by ionizing radiation (IR) and/or MFN. Although MFN suppressed HIF-1α under hypoxia, the combination of IR and MFN enhanced apoptosis and DNA damage in Hepa1-6 cells. In the Hepa1-6 syngeneic mouse model, the combination of IR and MFN notably limited the tumor growth compared to the single treatment with IR or MFN, and also triggered more frequent apoptosis in tumor tissues than that observed under other conditions. Increased expression of PD-L1 after IR was not observed with MFN alone or the combination of IR and MFN in vitro and in vivo, and the percentage of tumor-infiltrating T cells and cytotoxic T cells increased with MFN, regardless of IR, in the Hepa1-6 syngeneic mouse model, while IR alone led to T cell depletion. MFN might have the potential to overcome radioresistance by alleviating hypoxia and strengthening antitumor immunity in the tumor microenvironment.

Ceramide/sphingosine-1-phosphate imbalance is associated with distinct inflammatory phenotypes of uncontrolled asthma.

BACKGROUND: Asthma is associated with inflammatory dysregulation, but the underlying metabolic signatures are unclear. This study aimed to classify asthma inflammatory phenotypes based on cellular and metabolic features. METHODS: To determine cellular and metabolic profiles, we assessed inflammatory cell markers using flow cytometry, sphingolipid (SL) metabolites using LC-MS/MS, and serum cytokines using ELISA. Targeted gene polymorphisms were determined to identify genetic predispositions related to the asthma inflammatory phenotype. RESULTS: In total, 137 patients with asthma and 20 healthy controls (HCs) were enrolled. Distinct cellular and metabolic profiles were found between them; patients with asthma showed increased expressions of inflammatory cell markers and higher levels of SL metabolites compared to HCs (P < .05 for all). Cellular markers (CD66+ neutrophils, platelet-adherent eosinophils) and SL metabolic markers (C16:0 and C24:0 ceramides) for uncontrolled asthma were also identified; higher levels were observed in uncontrolled asthma compared to controlled asthma (P < .05 for all). Asthmatics patients with higher levels of CD66+ neutrophils had lower FEV1(%), higher ACQ (but lower AQLO) scores, and higher sphingosine and C16:0 ceramide levels compared to those with low levels of CD66+ neutrophils. Asthmatics patients with higher levels of platelet-adherent eosinophils had higher S1P levels compared to those with lower levels of platelet-adherent eosinophils. Patients carrying TT genotype of ORMDL3 had more CD66+ neutrophils; those with AG/ GG genotypes of SGMS1 exhibited higher platelet-adherent eosinophils. CONCLUSION: Patients with uncontrolled asthma possess distinct inflammatory phenotypes including increased CD66+ neutrophils and platelet-adherent eosinophils, with an imbalanced ceramide/S1P rheostat, potentially involving ORMDL3 and SGMS1 gene polymorphisms. Ceramide/S1P synthesis could be targeted to control airway inflammation.

ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways.

ATPase inhibitory factor 1 (IF1) is an ATP synthase-interacting protein that suppresses the hydrolysis activity of ATP synthase. In this study, we observed that the expression of IF1 was up-regulated in response to electrical pulse stimulation of skeletal muscle cells and in exercized mice and healthy men. IF1 stimulates glucose uptake via AMPK in skeletal muscle cells and primary cultured myoblasts. Reactive oxygen species and Rac family small GTPase 1 (Rac1) function in the upstream and downstream of AMPK, respectively, in IF1-mediated glucose uptake. In diabetic animal models, the administration of recombinant IF1 improved glucose tolerance and down-regulated blood glucose level. In addition, IF1 inhibits ATP hydrolysis by ß-F1-ATPase in plasma membrane, thereby increasing extracellular ATP and activating the protein kinase B (Akt) pathway, ultimately leading to glucose uptake. Thus, we suggest that IF1 is a novel myokine and propose a mechanism by which AMPK and Akt contribute independently to IF1-mediated improvement of glucose tolerance impairment. These results demonstrate the importance of IF1 as a potential antidiabetic agent.-Lee, H. J., Moon, J., Chung, I., Chung, J. H., Park, C., Lee, J. O., Han, J. A., Kang, M. J., Yoo, E. H., Kwak, S.-Y., Jo, G., Park, W., Park, J., Kim, K. M., Lim, S., Ngoei, K. R. W., Ling, N. X. Y., Oakhill, J. S., Galic, S., Murray-Segal, L., Kemp, B. E., Mantzoros, C. S., Krauss, R. M., Shin, M.-J., Kim, H. S. ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways.

Continuous-wave operation in directly patterned perovskite distributed feedback light source at room temperature.

We report a directly patterned perovskite distributed feedback (DFB) resonator and show narrow amplified spontaneous emission (ASE) at pump powers as low as 0.1 W/cm2 under continuous-wave (CW) optical pumping conditions at room temperature. Compared to the pristine thin film photoluminescence spectrum, a 16-fold reduction in emission linewidth in the MAPbI3 DFB cavity was observed. The direct nanostructuring of perovskites was achieved by thermal nanoimprint lithography. Our findings pave the way toward realizing CW pumped perovskite lasers at room temperature and energy-efficient perovskite light sources.

Nanoimprinted perovskite metasurface for enhanced photoluminescence.

Recently, solution-processed hybrid halide perovskite has emerged as promising materials for advanced optoelectronic devices such as photovoltaics, photodetectors, light emitting diodes and lasers. In the mean time, all-dielectric metasurfaces with high-index materials have attracted attention due to their low-loss and high-efficient optical resonances. Because of its tunable by composition band gap in the visible frequencies, organolead halide perovskite could serve as a powerful platform for realizing high-index, low-loss metasurfaces. However, direct patterning of perovskite by lithography-based technique is not feasible due to material instability under moisture. Here we report novel organolead halide perovskite metasurfaces created by the cost-effective thermal nanoimprint technology. The nanoimprinted perovskite metasurface showed improved surface morphology and enhanced optical absorption properties. Significantly enhanced optical emission with an eight-fold enhancement in photoluminescence (PL) intensity was observed under room temperature. Temperature-dependent PL of perovskite nanograting metasurface was also investigated. Based on our results, we believe that thermal nanoimprint is a simple and cost-effective technique to fabricate perovskite-based metasurfaces, which could have broad impact on optoelectronic and photonic applications.

Case report: fainting during acupuncture stimulation at acupuncture point LI4.

BACKGROUND: Fainting is one of the major adverse events that can occur as a result of acupuncture treatment. However, the observation of changes in biological parameters is rarely available when fainting occurs. In this case report, we could observe changes in the electroencephalogram (EEG) in a participant who fainted while participating in a clinical trial aiming to observe a relationship between acupuncture stimulation at LI4 acupuncture point and EEG in healthy adults. CASE PRESENTATION: The EEG pattern of participant changed twice. The first change was in response to the acupuncture needle insertion, and the second change occurred during fainting. Both changes consisted of a burst in EEG amplitude, but the pattern of details was different. Multiple areas of the cortex were activated, and the increased ratio of the γ wave was not observed during fainting. While acupuncture needle insertion, only the sensory cortex were activated and increased the ratio of the γ wave. CONCLUSIONS: This single case is presented to improve the understanding of fainting during acupuncture as an adverse event and to explore the mechanism of acupuncture treatment, despite the absence of statistics and repeatability. This information can provide a new viewpoint about the mechanism of acupuncture treatment and the possibility of new techniques based on acupuncture.

Development of ssDNA aptamers as potent inhibitors of Mycobacterium tuberculosis acetohydroxyacid synthase.

Acetohydroxyacid synthase (AHAS) from Mycobacterium tuberculosis (Mtb) is a promising potential drug target for an emerging class of new anti-tuberculosis agents. In this study, we identify short (30-mer) single-stranded DNA aptamers as a novel class of potent inhibitors of Mtb-AHAS through an in vitro DNA-SELEX method. Among all tested aptamers, two candidate aptamers (Mtb-Apt1 and Mtb-Apt6) demonstrated the greatest inhibitory potential against Mtb-AHAS activity with IC50 values in the low nanomolar range (28.94±0.002 and 22.35±0.001 nM respectively). Interestingly, inhibition kinetics analysis of these aptamers showed different modes of enzyme inhibition (competitive and mixed type of inhibition respectively). Secondary structure-guided mutational modification analysis of Mtb-Apt1 and Mtb-Apt6 identified the minimal region responsible for their inhibitory action and consequently led to 17-mer and 20-mer shortened aptamers that retained equivalent or greater inhibitory potential. Notably, a modeling and docking exercise investigated the binding site of these two potent inhibitory aptamers on the target protein and showed possible involvement of some key catalytic dimer interface residues of AHAS in the DNA-protein interactions that lead to its potent inhibition. Importantly, these two short candidate aptamers, Mtb-Apt1 (17-mer) and Mtb-Apt6 (20-mer), also demonstrated significant growth inhibition against multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains of tuberculosis with very low MIC of 5.36 µg/ml and 6.24 µg/ml, respectively and no significant cytotoxicity against mammalian cell line. This is the first report of functional inhibitory aptamers against Mtb-AHAS and provides the basis for development of these aptamers as novel and strong anti-tuberculosis agents.

Farmers' Cohort for Agricultural Work-Related Musculoskeletal Disorders (FARM) Study: Study Design, Methods, and Baseline Characteristics of Enrolled Subjects.

BACKGROUND: The ongoing Farmers' Cohort for Agricultural Work-related Musculoskeletal Disorders (FARM) study was developed to evaluate health status and related factors in farmers. METHODS: Farmers in Kangwon Province, South Korea, were recruited. Baseline characteristics were determined using questionnaires about sociodemographic and health characteristics and agricultural work-related factors. In addition, laboratory examinations (lumbar spinal radiography and serologic testing) were conducted. RESULTS: The FARM study covers eight rural areas and recruited 1013 subjects (534 women; mean [standard deviation {SD}] age, 57.2 [7.5] years). Musculoskeletal pain in multiple areas was reported by 925 subjects (91.3%), and low back pain (63.8%) was the most frequent site of pain. Farmer's Stress Inventory (mean [SD], 77.7 [10.2]; range, 28-112] and subjective stress index (mean [SD], 5.3 [2.4]; range, 0-10) were above median scale values, reflecting a stressful condition, while the EuroQol-5D-3L index and the EuroQol-Visual Analog Scale scores were high (mean [SD], 0.9 [0.1]; range -0.171-1 and mean [SD], 67.7 [18.7]; range 0-100, respectively), reflecting good life quality. In total, 53% of participants had worked in farming for more than 30 years, and workers involved in dry-field farming comprised the largest subgroup (41.5%). Most participants (94.3%) had no more than a high school education, and families with annual income below 20 million won constituted the largest subgroup (36.3%). CONCLUSIONS: The FARM study may provide data on the current health status and related sociodemographic and agricultural work-related risk factors in Korean farmers, with the goal of providing a scientific basis for developing coping interventions and preventive strategies.

Public Awareness of Stroke and Its Predicting Factors in Korea: a National Public Telephone Survey, 2012 and 2014.

The aim of this study was to investigate time trends in the public awareness of stroke and its predicting factors. The target population was 9,600 community-dwelling adults, aged 19-79 years, in 16 metropolitan cities and provinces in Korea. The survey samples in 2012 and 2014 were selected separately (entirely different sets of subjects) using a proportionate quota sampling method. Information concerning knowledge of stroke and demographics was collected by trained telephone interviewers using random digit dialing. After excluding subjects with a non-response or refusal to answer any question, the analyses included 8,191 subjects in 2012 and 8,127 subjects in 2014. Respondents' awareness of stroke warning signs (numbness or weakness, difficulty speaking or understanding speech, dizziness, visual impairment, and severe headache) was highest for difficulty speaking or understanding speech (80.9% in 2012 and 86.4% in 2014). There were significant increases in the proportion of respondents understanding the appropriate action (i.e., calling an ambulance) at the time of stroke occurrence (59.6% to 67.1%), and in the proportion aware of the general need for prompt treatment (86.7% to 89.8%). In multivariable logistic regression analysis, older age, higher education level, higher household income, current non-smoking, exposure to stroke-related public relations materials, and experience of stroke education were significantly associated with both high knowledge of stroke warning signs and awareness of the need for prompt treatment. Between 2012 and 2014, the public's awareness of stroke increased significantly. More specialized interventions, including public relations materials and education, should focus on subgroups who have lower stroke knowledge.

Arginase inhibition ameliorates adipose tissue inflammation in mice with diet-induced obesity.

This study examined whether oral administration of an arginase inhibitor regulates adipose tissue macrophage infiltration and inflammation in mice with high fat diet (HFD)-induced obesity. Male C57BL/6 mice (n = 30) were randomly assigned to control (CTL, n = 10), HFD only (n = 10), and HFD with arginase inhibitor N(ω)-hydroxy-nor-l-arginine (HFD with nor-NOHA, n = 10) groups. Plasma and mRNA levels of cytokines in epididymal adipose tissues (EAT), macrophage infiltration into EAT, and macrophage phenotype polarization were measured in the animals after 12 weeks. Additionally, the effects of nor-NOHA on adipose tissue macrophage infiltration and mRNA expression of cytokines were measured in co-cultured 3T3-L1 adipocytes and RAW 264.7 macrophages. Macrophage infiltration into the adipocytes was significantly suppressed by nor-NOHA treatment in adipocyte/macrophage co-culture system and mice with HFD-induced obesity. Pro-inflammatory cytokines, including monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), were significantly downregulated, and the anti-inflammatory cytokine IL-10 was significantly upregulated in nor-NOHA-treated co-cultured cells. In the mice with HFD-induced obesity, plasma and mRNA levels of MCP-1 significantly reduced after supplementation with nor-NOHA. In addition, oral supplement of nor-NOHA modified M1/M2 phenotype ratio in the EAT. Oral supplementation of an arginase inhibitor, nor-NOHA, altered M1/M2 macrophage phenotype and macrophage infiltration into HFD-induced obese adipose tissue, thereby improved adipose tissue inflammatory response. These results may indicate that arginase inhibition ameliorates obesity-induced adipose tissue inflammation.

Spinal sigma-1 receptor activation increases the production of D-serine in astrocytes which contributes to the development of mechanical allodynia in a mouse model of neuropathic pain.

We have previously demonstrated that activation of the spinal sigma-1 receptor (Sig-1R) plays an important role in the development of mechanical allodynia (MA) via secondary activation of the N-methyl-d-aspartate (NMDA) receptor. Sig-1Rs have been shown to localize to astrocytes, and blockade of Sig-1Rs inhibits the pathologic activation of astrocytes in neuropathic mice. However, the mechanism by which Sig-1R activation in astrocytes modulates NMDA receptors in neurons is currently unknown. d-serine, synthesized from l-serine by serine racemase (Srr) in astrocytes, is an endogenous co-agonist for the NMDA receptor glycine site and can control NMDA receptor activity. Here, we investigated the role of d-serine in the development of MA induced by spinal Sig-1R activation in chronic constriction injury (CCI) mice. The production of d-serine and Srr expression were both significantly increased in the spinal cord dorsal horn post-CCI surgery. Srr and d-serine were only localized to astrocytes in the superficial dorsal horn, while d-serine was also localized to neurons in the deep dorsal horn. Moreover, we found that Srr exists in astrocytes that express Sig-1Rs. The CCI-induced increase in the levels of d-serine and Srr was attenuated by sustained intrathecal treatment with the Sig-1R antagonist, BD-1047 during the induction phase of neuropathic pain. In behavioral experiments, degradation of endogenous d-serine with DAAO, or selective blockade of Srr by LSOS, effectively reduced the development of MA, but not thermal hyperalgesia in CCI mice. Finally, BD-1047 administration inhibited the development of MA and this inhibition was reversed by intrathecal treatment with exogenous d-serine. These findings demonstrate for the first time that the activation of Sig-1Rs increases the expression of Srr and d-serine in astrocytes. The increased production of d-serine induced by CCI ultimately affects dorsal horn neurons that are involved in the development of MA in neuropathic mice.

Jatrophihabitans soli sp. nov., isolated from soil.

One bacterial strain, designated KIS75-12T, isolated from a soil sample collected from Wonsando island located in Boryeong city, Republic of Korea, was characterized as aerobic, Gram-stain-positive, non-flagellated and a short rod. It grew between temperatures of 15-37 °C, pH 4-9 and 0-3.0 % (w/v) NaCl. The 16S rRNA gene analysis showed the strain was moderately related to Jatrophihabitans endophyticus S9-650T (97.7 %) and revealed low sequence similarity (≤94.7 %) with all the other species with validly published names. Its major fatty acid was iso-C16 : 0. The predominant menaquinone of strain KIS75-12T was MK-9(H4). The polar lipids consisted of diphosphatidylglycerol and several small amounts of phosphatidylinositol, aminolipids and glycolipid. The peptidoglycan contained meso-A2pm as diagnostic diamino acid and the peptidoglycan type is A4γ. The genomic DNA G+C content of the type strain was 72.1 mol%. The combined phenotypic, chemotaxonomic and phylogenetic data showed that strain KIS75-12T could be clearly distinguished from the only member of the genus Jatrophihabitans,J. endophyticus. Therefore, the results of this study indicate the existence of a representative of a novel species of the genus Jatrophihabitans, for which we propose the name Jatrophihabitans soli sp. nov., with strain KIS75-12T ( = KACC 17298T = DSM 45908T  = NBRC 109658T) as the type strain. An emended description of the genus Jatrophihabitans is also given.