Low Temperature Photo-oxidation of Chloroperoxidase Compound II

Oxidation of the heme-thiolate enzyme chloroperoxidase (CPO) from Caldariomyces fumago with peroxynitrite (PN) gave the Compound II intermediate, which was photo-oxidized with 365 nm light to give a reactive oxidizing species. Cryo-solvents at pH ≈ 6 were employed, and reactions were conducted at temperatures as low as − 50 °C. The activity of CPO as evaluated by the chlorodimedone assay was unaltered by treatment with PN or by production of the oxidizing transient and subsequent reaction with styrene. EPR spectra at 77 K gave the amount of ferric protein at each stage in the reaction sequence. The PN oxidation step gave a 6:1 mixture of Compound II and ferric CPO, the photolysis step gave an approximate 1:1 mixture of active oxidant and ferric CPO, and the final mixture after reaction with excess styrene contained ferric CPO in 80% yield. In single turnover reactions at − 50 °C, styrene was oxidized to styrene oxide in high yield. Kinetic studies of styrene oxidation at − 50 °C displayed saturation kinetics with an equilibrium constant for formation of the complex of Kbind = 3.8 × 104 M− 1 and an oxidation rate constant of kox = 0.30 s− 1. UV–Visible spectra of mixtures formed in the photo-oxidation sequence at ca. − 50 °C did not contain the signature Q-band absorbance at 690 nm ascribed to CPO Compound I prepared by chemical oxidation of the enzyme, indicating that different species were formed in the chemical oxidation and the photo-oxidation sequence

Attention Performance Measured by Attention Network Test Is Correlated with Global and Regional Efficiency of Structural Brain Networks

Functional neuroimaging studies have indicated the involvement of separate brain areas in three distinct attention systems: alerting, orienting and executive control (EC). However, the structural correlates underlying attention remains unexplored. Here, we utilized graph theory to examine the neuroanatomical substrates of the three attention systems measured by attention network test (ANT) in 65 healthy subjects. White matter connectivity, assessed with DTI deterministic tractography was modeled as a structural network comprising 90 nodes defined by the Automated Anatomical Labeling (AAL) template. Linear regression analyses were conducted to explore the relationship between topological parameters and the three attentional effects. We found a significant positive correlation between EC function and global efficiency of the whole brain network. At the regional level, node-specific correlations were discovered between regional efficiency and all three ANT components, including dorsolateral superior frontal gyrus, thalamus and parahippocampal gyrus for EC, thalamus and inferior parietal gyrus for alerting, and paracentral lobule and inferior occipital gyrus for orienting. Our findings highlight the fundamental architecture of interregional structural connectivity involved in attention and could provide new insights into the anatomical basis underlying human behavior

Assist disabled to control electronic devices and access computer functions by voice commands

10.1145/1328491.1328502i-CREATe 2007 - Proceedings of the 1st International Convention on Rehabilitation Engineering and Assistive Technology in Conjunction with 1st Tan Tock Seng Hospital Neurorehabilitation Meeting37-4

Nucleophilic functionalization of thianthrenium salts under basic conditions

In recent years, S-(alkyl)thianthrenium salts have become an important means of functionalizing alcohol compounds. However, additional transition metal catalysts and/or visible light are required. Herein, a direct thioetherification/amination reaction of thianthrenium salts is realized under metal-free conditions. This strategy exhibits good functional-group tolerance, operational simplicity, and an extensive range of compatible substrates

CK20 and lymph node involvement predict adverse outcome of malignant intraductal papillary neoplasm of the bile duct

Objectives. To identify prognostic factors of malignant intraductal papillary neoplasm of the bile duct (m-IPNB). Materials and Methods. We included 38 consecutive cases which underwent surgical resection and diagnosed as IPNB with malignant component from January 2003 to January 2017. Clinicopathological variables were collected to conduct survival analysis and identify prognostic factors. Results. The median overall survival (OS) of m- IPNB was 76.0 months, with 1-, 3-, and 5-year survival rates of 97.2%, 73.5%, and 59.8%, respectively. The median recurrence-free survival (RFS) was 48.0 months with 1-, 3-, and 5-year RFS rate was 83.2%, 59.8%, and 44.6%, respectively. Univariate analysis showed that elevation of carcinoembrionic antigen (CEA), lymph node involvement, resection margin status, degree of periductal invasion, and positive expression of CK20 were associated with both OS and RFS of m-IPNB. After multivariate Cox models analysis, lymph node involvement and positive expression of CK20 were identified as independent prognostic factors for OS, while lymph node involvement and resection margin status were independent prognostic factors for RFS. The median OS of patients with m-IPNB involving lymphatic metastases and positive expression of CK20 was 27.0±8.8 months and 51.0±12.4 months, respectively. The median RFS of cases with lymph node involvement and R1 resection was 10.0±3.3 months and 25.0±6.9 months, respectively. However, there was no significant difference in OS or RFS between cases of pancreaticobiliary and intestinal subtype. Conclusions. Lymph node involvement and positive expression of CK20 are independent prognostic factors for shorter OS of m-IPNB, while patients with lymph node involvement and positive resection margin are at higher risk of tumor recurrence

Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC

Oncometabolite D-2-hydroxyglutarate—dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia

Abstract Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 μM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia

Band-Gap Tuning of Organic–Inorganic Hybrid Palladium Perovskite Materials for a Near-Infrared Optoelectronics Response

Organic–inorganic hybrid material is a recent hot topic in the scientific community. The best band gap for the entire solar absorption spectrum is about 1.1 eV. However, the lead perovskite band gap is about 1.5 eV. Therefore, developing organic–inorganic hybrid material toward the broader light harvesting of the solar spectrum is extremely urgent. In this study, we prepare three kinds of organic–inorganic hybrid palladium perovskite materials, including (CH3NH3)2PdCl4, (CH3NH3)2PdCl4–xBrx, and CH3NH3PdI3, for an optoelectronic response. The absorption cut offs of (CH3NH3)2PdCl4, (CH3NH3)2PdCl4–xBrx, and CH3NH3PdI3 are approximately 600, 700, and 1000 nm, respectively. The band gaps of (CH3NH3)2PdCl4, (CH3NH3)2PdCl4–xBrx, and CH3NH3PdI3 are determined to be approximately 2.15, 1.87, and 1.25 eV, respectively. To the best of our knowledge, this is the first study that discusses adsorption properties and photoelectric behavior of organic–inorganic hybrid palladium perovskite materials. Interestingly, the photoelectric response of the devices based on CH3NH3PdI3 reaches 950 nm. The results will attract attention in the fields of optical recorders, optical memory, security, light capture, and light treatment