Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed ...cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of glutathione peroxidase 4 (Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible Gpx4(-/-) mice, we elucidate an essential role for the glutathione/Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called Liproxstatin-1, which is able to suppress ferroptosis in cells, in Gpx4(-/-) mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection.
Optical link ASICs for LHC upgrades Gan, K.K.; Kagan, H.P.; Kass, R.D. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
05/2011, Letnik:
633
Journal Article
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We have designed three ASICs for possible applications in a new pixel layer (insertable B-layer or IBL) for the ATLAS detector for the first phase of the LHC luminosity upgrade. The ASICs are a ...high-speed driver for the vertical-cavity surface-emitting laser (VCSEL), a receiver/decoder to decode the signal received at the PIN diode to extract the data and clock, and a clock multiplier to produce a higher frequency clock to serialize the data for transmission. These ASICs were designed using a 130
nm CMOS process to enhance the radiation-hardness. We have characterized the ASICs and the submission has been mostly successful. We irradiated the ASICs with 24
GeV/c protons at CERN to a dosage of 70
Mrad. We observed no significant degradation except the driver circuit in the VCSEL driver fabricated using the thick oxide process in order to provide sufficient voltage to drive a VCSEL. The degradation is due to the radiation induced large threshold shifts in the PMOS transistors used.
Advancement of biomedical applications of carbonaceous nanomaterials is hampered by their biopersistence and pro-inflammatory action in vivo. Here, we used myeloperoxidase knockout B6.129X1-MPO (MPO ...k/o) mice and showed that oxidation and clearance of single walled carbon nanotubes (SWCNT) from the lungs of these animals after pharyngeal aspiration was markedly less effective whereas the inflammatory response was more robust than in wild-type C57Bl/6 mice. Our results provide direct evidence for the participation of MPO - one of the key-orchestrators of inflammatory response - in the in vivo pulmonary oxidative biodegradation of SWCNT and suggest new ways to control the biopersistence of nanomaterials through genetic or pharmacological manipulations.
We synthesize and characterize derivatives of the two-dimensional hybrid perovskite (2DHP) phenethylammonium lead iodide ((PEA)2PbI4) in which the para H on the cation is replaced with F, Cl, CH3, or ...Br. These substitutions increase the length of the cation but leave the cross-sectional area unchanged, resulting in structurally similar PbI4 2– frameworks with increasing interlayer spacing. Longer cations result in broader, blue-shifted excitonic absorption spectra with reduced or eliminated structure, indicating greater energetic disorder. Photoluminescence spectra are largely invariant and insensitive to cation length, suggesting polaron formation stabilizes a structural and electronic minimum. Temperature-dependent line width analysis reveals excitons couple to a vibration on the organic framework that is weakly sensitive to these cation substitutions, and Raman spectra and electronic structure calculations support the presence of such a cationic mode. Despite carriers being confined to the inorganic framework, the length of the organic cation alters the optical and electronic properties of 2DHPs.
Multidrug resistance in Gram-negative bacteria has led to a resurgence in colistin use. No pharmacokinetic data exist for burn patients. A 17-year-old boy suffered a 71% TBSA full-thickness burn with ...deep necrosis and compartment syndrome. He developed multidrug-resistant Acinetobacter baumannii burn wound sepsis/septic shock with acute renal failure requiring dialysis. The organism was resistant to all tested antibiotics except colistin. He received colistin 2.5 mg/kg every 24 hours. Peak and trough serum concentrations, area under the concentration-time curve, and elimination half-lives of colistin were 3.6 ± 1.0 μg/ml, 0.9 ± 0.5 μg/ml, 47.1 ± 14.4 mg · hr/L, and 12.3 ± 9.4 hours (mean ± SD), respectively. Serum levels were at or above the minimum inhibitory concentration for >90% of therapy. Nevertheless, salvage therapy with colistin proved futile as the patient developed acidosis, coagulopathy, and was vasopressor-dependent without any wound healing. He died on hospital day 52. Microbiologically, the serum levels of colistin were seemingly adequate, as repeat cultures were negative. Given the peak and trough levels of colistin relative to the minimum inhibitory concentration for the organism (0.5 μg/ml), it would seem that the dosage of 2.5 mg/kg administered every 24 hours for this patient on dialysis was appropriate. Patients on dialysis infected with an organism possessing a higher inhibitory concentration (≥1 μg/ml) should probably receive the same dosage every 12 hours to avoid subtherapeutic concentrations. Large-scale study of the pharmacokinetics of colistin in patients with burn injury is urgently needed.
Mitophagy is critical for cell homeostasis. Externalization of the inner mitochondrial membrane phospholipid, cardiolipin (CL), to the surface of the outer mitochondrial membrane (OMM) was identified ...as a mitophageal signal recognized by the microtubule-associated protein 1 light chain 3. However, the CL-translocating machinery remains unknown. Here we demonstrate that a hexameric intermembrane space protein, NDPK-D (or NM23-H4), binds CL and facilitates its redistribution to the OMM. We found that mitophagy induced by a protonophoric uncoupler, carbonyl cyanide m-chlorophenylhydrazone (CCCP), caused externalization of CL to the surface of mitochondria in murine lung epithelial MLE-12 cells and human cervical adenocarcinoma HeLa cells. RNAi knockdown of endogenous NDPK-D decreased CCCP-induced CL externalization and mitochondrial degradation. A R90D NDPK-D mutant that does not bind CL was inactive in promoting mitophagy. Similarly, rotenone and 6-hydroxydopamine triggered mitophagy in SH-SY5Y cells was also suppressed by knocking down of NDPK-D. In situ proximity ligation assay (PLA) showed that mitophagy-inducing CL-transfer activity of NDPK-D is closely associated with the dynamin-like GTPase OPA1, implicating fission-fusion dynamics in mitophagy regulation.
Ammonium thiocyanate (NH4SCN) is introduced to exchange the long, insulating ligands used in colloidal nanocrystal (NC) synthesis. The short, air-stable, environmentally benign thiocyanate ligand ...electrostatically stabilizes a variety of semiconductor and metallic NCs in polar solvents, allowing solution-based deposition of NCs into thin-film NC solids. NH4SCN is also effective in replacing ligands on NCs after their assembly into the solid state. The spectroscopic properties of this ligand provide unprecedented insight into the chemical and electronic nature of the surface of the NCs. Spectra indicate that the thiocyanate binds to metal sites on the NC surface and is sensitive to atom type and NC surface charge. The short, thiocyanate ligand gives rise to significantly enhanced electronic coupling between NCs as evidenced by large bathochromic shifts in the absorption spectra of CdSe and CdTe NC thin films and by conductivities as high as (2 ± 0.7) × 103 Ω–1 cm–1 for Au NC thin films deposited from solution. NH4SCN treatment of PbTe NC films increases the conductivity by 1013, allowing the first Hall measurements of nonsintered NC solids, with Hall effect mobilities of 2.8 ± 0.7 cm2/(V·s). Thiocyanate-capped CdSe NC thin films form photodetectors exhibiting sensitive photoconductivity of 10–5 Ω–1 cm–1 under 30 mW/cm2 of 488 nm illumination with I photo/I dark > 103 and form n-channel thin-film transistors with electron mobilities of 1.5 ± 0.7 cm2/(V·s), a current modulation of >106, and a subthreshold swing of 0.73 V/decade.
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