NB-LRR-encoding genes conferring susceptibility to organophosphate pesticides in sorghum

Organophosphate is the commonly used pesticide to control pest outbreak, such as those by aphids in many crops. Despite its wide use, however, necrotic lesion and/or cell death following the application of organophosphate pesticides has been reported to occur in several species. To understand this phenomenon, called organophosphate pesticide sensitivity (OPS) in sorghum, we conducted QTL analysis in a recombinant inbred line derived from the Japanese cultivar NOG, which exhibits OPS. Mapping OPS in this population identified a prominent QTL on chromosome 5, which corresponded to Organophosphate-Sensitive Reaction (OSR) reported previously in other mapping populations. The OSR locus included a cluster of three genes potentially encoding nucleotide-binding leucine-rich repeat (NB-LRR, NLR) proteins, among which NLR-C was considered to be responsible for OPS in a dominant fashion. NLR-C was functional in NOG, whereas the other resistant parent, BTx623, had a null mutation caused by the deletion of promoter sequences. Our finding of OSR as a dominant trait is important not only in understanding the diversified role of NB-LRR proteins in cereals but also in securing sorghum breeding free from OPS

Crystallographic texture- and grain boundary density-independent improvement of corrosion resistance in austenitic 316L stainless steel fabricated via laser powder bed fusion

Improvement of corrosion resistance of austenitic 316L stainless steel via laser powder bed fusion (LPBF) is currently a prominent research topic; however, the effects of crystallographic texture and the related grain boundary density on the corrosion resistance of LPBF-fabricated parts have not been elucidated. For biomedical applications, crystallographic texture control from a single crystalline-like to randomly oriented polycrystalline microstructure is highly attractive for optimizing the mechanical properties (particularly the Young's modulus) of implants. An investigation of the impacts of crystallographic planes and grain boundaries exposed to the biological environment on corrosion behavior is necessary. 316L stainless steels with different crystallographic textures and grain boundary densities were successfully fabricated via LPBF. The corrosion resistances of the LPBF-fabricated specimens were comprehensively assessed by anodic polarization, dissolution, and crevice corrosion repassivation tests. The LPBF-fabricated specimens showed extremely high pitting potentials in the physiological saline compared with the commercially available counterparts, and importantly, excellent pitting corrosion resistance was observed irrespective of the crystallographic planes and grain boundary density exposed. Moreover, the LPBF-fabricated specimens did not show metastable pitting corrosion even in an accelerated test using an acid solution. The repassivation behavior of the specimens was not affected by LPBF. Such a drastic improvement in the corrosion resistances of the LPBF-fabricated specimens might be attributed to suppression of inclusion coarsening owing to the rapid cooling rate during solidification in LPBF. By using LPBF, the desired crystallographic texture can be introduced based on the desired mechanical properties without concern for corrosiveness.Tsutsumi Y., Ishimoto T., Oishi T., et al. Crystallographic texture- and grain boundary density-independent improvement of corrosion resistance in austenitic 316L stainless steel fabricated via laser powder bed fusion. Additive Manufacturing, 45, 102066. https://doi.org/10.1016/j.addma.2021.102066

Potential Neuroprotective Effects of an LSD1 Inhibitor in Retinal Ganglion Cells via p38 MAPK Activity

Citation: Tsutsumi T, Iwao K, Hayashi H, et al. Potential neuroprotective effects of an LSD1 inhibitor in retinal ganglion cells via p38 MAPK activity. Invest Ophthalmol Vis Sci. 2016;57:6461-6473. DOI:10.1167/ iovs.16-19494 PURPOSE. The epigenetic mechanisms associated with ocular neurodegenerative diseases remain unclear. The present study aimed to determine the role of lysine-specific demethylase 1 (LSD1), which represses transcription by removing the methyl group from methylated lysine 4 of histone H3, in retinal ganglion cell (RGC) survival, and to investigate the details of the neuroprotective mechanism of tranylcypromine, a major LSD1 inhibitor. METHODS. The authors evaluated whether tranylcypromine contributes to neuronal survival following stress-induced damage using primary cultured rat RGCs and in vivo N-methyl-Daspartate (NMDA)-induced excitotoxicity. Additionally, the molecules associated with tranylcypromine treatment were assessed by microarray and immunoblot analysis. RESULTS. Tranylcypromine significantly suppressed neuronal cell death following glutamate neurotoxicity and oxidative stress. Microarray and immunoblot analyses revealed that p38 mitogen-activated protein kinase (MAPK)c was a key molecule involved in the neuroprotective mechanisms induced by tranylcypromine because the significant suppression of p38 MAPKc by glutamate was reversed by tranylcypromine. Moreover, although pharmacologic inhibition of the phosphorylation of the total p38 MAPKs interfered with neuroprotective effects of tranylcypromine, the specific inhibition of p38 MAPKa and p38 MAPKb did not influence RGC survival. This suggests that the non-p38 MAPKa/b isoforms have important roles in neuronal survival by tranylcypromine. Additionally, the intravitreal administration of tranylcypromine significantly saved RGC numbers in an in vivo glaucoma model employing NMDA-induced excitotoxicity. CONCLUSIONS. These findings indicate that tranylcypromine-induced transcriptional and epigenetic regulation modulated RGC survival via the promotion of p38 MAPKc activity. Therefore, pharmacologic treatments that suppress LSD1 activity may be a novel therapeutic strategy that can be used to treat neurodegenerative diseases

Dietary Supplementation with Monosodium Glutamate Suppresses Chemotherapy-Induced Downregulation of the T1R3 Taste Receptor Subunit in Head and Neck Cancer Patients

(Background) We investigated the effect of dietary supplementation with monosodium glutamate (MSG) on chemotherapy-induced downregulation of the T1R3 taste receptor subunit expression in the tongue of patients with advanced head and neck cancer. (Methods) Patients undergoing two rounds of chemoradiotherapy were randomly allocated to a control or intervention group (dietary supplementation with MSG at 2.7 g/day during the second round of chemotherapy). The relative expression of T1R3, a subunit of both umami and sweet taste receptors, in the tongue was assessed by quantitative polymerase chain reaction analysis. Dysgeusia was assessed with a visual analog scale and daily energy intake was evaluated. (Results) T1R3 expression levels in the tongue, taste sensitivity, and daily energy intake were significantly reduced after the first round of chemotherapy compared with before treatment. Furthermore, these parameters significantly decreased after the second round of chemotherapy, but the extent of decrease was significantly attenuated in the MSG group compared with the control group. (Conclusions) MSG supplementation suppresses chemotherapy-induced dysgeusia, possibly due to the inhibition of the T1R3-containing taste receptor downregulation in the tongue, thereby increasing energy intake in patients with advanced head and neck cancer

Carcinogenicity evaluation for the application of carbon nanotubes as biomaterials in rasH2 mice

The application of carbon nanotubes (CNTs) as biomaterials is of wide interest, and studies examining their application in medicine have had considerable significance. Biological safety is the most important factor when considering the clinical application of CNTs as biomaterials, and various toxicity evaluations are required. Among these evaluations, carcinogenicity should be examined with the highest priority; however, no report using transgenic mice to evaluate the carcinogenicity of CNTs has been published to date. Here, we performed a carcinogenicity test by implanting multi-walled CNTs (MWCNTs) into the subcutaneous tissue of rasH2 mice, using the carbon black present in black tattoo ink as a reference material for safety. The rasH2 mice did not develop neoplasms after being injected with MWCNTs; instead, MWCNTs showed lower carcinogenicity than carbon black. Such evaluations should facilitate the clinical application and development of CNTs for use in important medical fields.ArticleSCIENTIFIC REPORTS. 2:498 (2012)journal articl

Tumor deposits in colorectal cancer: improving the value of modern staging - a systematic review and meta-analysis

PURPOSE: Colorectal cancer (CRC) treatment is largely determined by tumor stage. Despite improvements made in the treatment of various types of metastatic disease, staging has not been refined. The role of tumor deposits (TD) in staging remains under debate. We have assessed the relation of TD with metastatic pattern, to evaluate whether TD might add significant new information to staging. METHODS: We performed a systematic literature search focused on the role of TD in CRC. Studies with neoadjuvant treated patients were excluded. Data on stage, histological factors and outcome were extracted. Data from four large cohorts were analyzed for the relevance of the presence of TD, lymph node metastases (LNM) and extramural vascular invasion (EMVI) on the pattern of metastases and outcomes. RESULTS: Of the 10,106 included CRC patients 22% presented with TD. TD are invariably associated with poor outcome. The presence of TD was associated with the presence of LNM and EMVI. In a pair wise comparison, the effects of TD were stronger than both LNM and EMVI. In the logistic regression model, TD in combination with LNM is the strongest predictor for liver (odds ratio (OR) 5.5), lung (OR 4.3) and peritoneal metastases (OR 7.0). The presence of EMVI adds information for liver and lung metastases, but not for peritoneal metastases. CONCLUSION: We have shown that TD are not equal to LNM or EMVI, with respect to biology and outcome. We lose valuable prognostic information by allocating TD into nodal category N1c and only considering TD in the absence of LNM. Therefore, we propose that the number of TD should be added to the number of LNM to derive a final N stage

Detection of the Onset of Ischemia and Carcinogenesis by Hypoxia-Inducible Transcription Factor-Based In Vivo Bioluminescence Imaging

An animal model for the early detection of common fatal diseases such as ischemic diseases and cancer is desirable for the development of new drugs and treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that regulates oxygen homeostasis and plays key roles in a number of diseases, including cancer. Here, we established transgenic (Tg) mice that carry HRE/ODD-luciferase (HOL) gene, which generates bioluminescence in an HIF-1-dependent manner and was successfully used in this study to monitor HIF-1 activity in ischemic tissues. To monitor carcinogenesis in vivo, we mated HOL mice with rasH2 Tg mice, which are highly sensitive to carcinogens and are used for short-term carcinogenicity assessments. After rasH2-HOL Tg mice were treated with N-methyl-N-nitrosourea, bioluminescence was detected noninvasively as early as 9 weeks in tissues that contained papillomas and malignant lesions. These results suggest that the Tg mouse lines we established hold significant potential for monitoring the early onset of both ischemia and carcinogenesis and that these lines will be useful for screening chemicals for carcinogenic potential

Mobile DHHC palmitoylating enzyme mediates activity-sensitive synaptic targeting of PSD-95

Protein palmitoylation is the most common posttranslational lipid modification; its reversibility mediates protein shuttling between intracellular compartments. A large family of DHHC (Asp-His-His-Cys) proteins has emerged as protein palmitoyl acyltransferases (PATs). However, mechanisms that regulate these PATs in a physiological context remain unknown. In this study, we efficiently monitored the dynamic palmitate cycling on synaptic scaffold PSD-95. We found that blocking synaptic activity rapidly induces PSD-95 palmitoylation and mediates synaptic clustering of PSD-95 and associated AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors. A dendritically localized DHHC2 but not the Golgi-resident DHHC3 mediates this activity-sensitive palmitoylation. Upon activity blockade, DHHC2 translocates to the postsynaptic density to transduce this effect. These data demonstrate that individual DHHC members are differentially regulated and that dynamic recruitment of protein palmitoylation machinery enables compartmentalized regulation of protein trafficking in response to extracellular signals