Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients

Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control

Conformational change of RNA-helicase DHX30 by ALS/FTD-linked FUS induces mitochondrial dysfunction and cytosolic aggregates.

Genetic mutations in fused in sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS). Although mitochondrial dysfunction and stress granule have been crucially implicated in FUS proteinopathy, the molecular basis remains unclear. Here, we show that DHX30, a component of mitochondrial RNA granules required for mitochondrial ribosome assembly, interacts with FUS, and plays a crucial role in ALS-FUS. WT FUS did not affect mitochondrial localization of DHX30, but the mutant FUS lowered the signal of mitochondrial DHX30 and promoted the colocalization of cytosolic FUS aggregates and stress granule markers. The immunohistochemistry of the spinal cord from an ALS-FUS patient also confirmed the colocalization, and the immunoelectron microscope demonstrated decreased mitochondrial DHX30 signal in the spinal motor neurons. Subcellular fractionation by the detergent-solubility and density-gradient ultracentrifugation revealed that mutant FUS also promoted cytosolic mislocalization of DHX30 and aggregate formation. Interestingly, the mutant FUS disrupted the DHX30 conformation with aberrant disulfide formation, leading to impaired mitochondrial translation. Moreover, blue-native gel electrophoresis revealed an OXPHOS assembly defect caused by the FUS mutant, which was similar to that caused by DHX30 knockdown. Collectively, our study proposes DHX30 as a pivotal molecule in which disulfide-mediated conformational change mediates mitochondrial dysfunction and cytosolic aggregate formation in ALS-FUS

千葉県君津市川谷地域に露出する中部更新統柿ノ木台層から産出する冷湧水化石群集: その時空分布と共産する自生炭酸塩

金沢大学国際基幹教育院 GS教育系冷湧水性群集が房総半島の中部更新統柿ノ木台層の陸棚相から産出する．群集は，化学合成二枚貝類から排他的になり，著しく13Cに枯渇した自生炭酸塩と共産することから，AOM（嫌気的メタン酸化）に依存していたと考えられる．自生炭酸塩は巣穴壁面と巣穴周囲の堆積物中に沈殿し，巣穴からスナモグリ類の爪化石と糞化石が産出することから，これらはスナモグリ類の巣穴であると考えられる．スナモグリ類はメタン生成帯まで巣穴を堀り，海水を巣穴深部へ供給し，AOMを活性化させることによって巣穴中の硫化水素イオン濃度を上昇させた．溶存酸素濃度が高い巣穴浅部では，硫黄酸化菌が繁茂し，スナモグリ類の食糧となった．巣穴深部では，浮遊する生物源炭酸塩などを核とした針状アラゴナイトが重力方向に沈下して炭酸塩ジオペタル状構造を形成し，巣穴周囲の堆積物中では，リン酸イオン濃度の上昇により高Mgカルサイトが，また硫酸イオンの枯渇によりドロマイトが沈殿した．Cold-seep-dependent molluscan assemblages occur in the outer-shelf facies of the middle Pleistocene Kakinokidai Formation of the Kazusa Group, a forearc basin-fill sequence on the Pacific side of central Japan, in strata corresponding to the interval 707.6-667.0 ka. The assemblages consist exclusively of chemosymbiotic bivalves (lucinids, thyasirids, and solemyids) and are associated with 13C-depleted authigenic carbonates (δ13C = −61.60‰ to −10.96‰ VPDB), which suggest that their main carbon source was anaerobic oxidation of methane (AOM). Authigenic carbonate precipitates are common on burrow walls (mainly acicular aragonite) and the surrounding sediments (mainly micritic high-Mg calcite and dolomite). The burrows are cylindrical, 1.5-3.0 cm in diameter, and >1 m long. Callianassid claws and the trace fossil Palaxius (probable callianassid fecal pellets) in the burrow carbonates suggest that the burrows were produced by sediment-dwelling callianassid decapods.\nWe propose the following formation mechanism of burrows and their related authigenic carbonates. Firstly, callianassids produced deep burrows, penetrating the AOM zone and reaching the methanogenic zone. Methane then seeped into the burrows and AOM occurred in its deeper parts, promoted by a supply of seawater via callianassid activity, resulting in an increase in the concentration of hydrogen sulfide ions. Thiobacteria flourished in the shallower parts of the burrows, which were enriched in dissolved oxygen, and provided a source of food for the callianassids. In the deeper parts of the burrows, acicular aragonite precipitated around suspended carbonate nuclei and sank to the bottoms of the burrows, forming geopetal-like carbonate structures. In the surrounding sediment, high-Mg calcite precipitated in response to an increase in the concentration of phosphate ions (due to the decomposition of organic matter), and dolomite precipitated in response to decreasing concentrations of sulfate ions (caused by active AOM)

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

青森県民の健康寿命アップ対策としての「心疾患10年リスク」の活用について(青森県の健康寿命アップと保健大学の取り組み, 第2回青森県立保健大学学術研究集会)

publisher青森市国立情報学研究所の「学術雑誌公開支援事業」により電子化されました

Synthesis of dinuclear palladium complexes having two parallel isocyanide ligands, and their application as catalysts to pyrrole formation from tert-butylisocyanide and alkynes

autho

Specific Incorporation of Polyunsaturated Fatty Acids into the sn-2 Position of Phosphatidylglycerol Accelerates Photodamage to Photosystem II under Strong Light

Free fatty acids (FFAs) are generated by the reaction of lipases with membrane lipids. Generated polyunsaturated fatty acids (PUFAs) containing more than two double bonds have toxic effects in photosynthetic organisms. In the present study, we examined the effect of exogenous FFAs in the growth medium on the activity of photosystem II (PSII) under strong light in the cyanobacterium Synechocystis sp. PCC 6803 (Synechocystis). PUFAs but not monounsaturated fatty acids accelerated the rate of photodamage to PSII by inactivating electron transfer at the oxygen-evolving complex. Moreover, supplemented PUFAs were specifically incorporated into the sn-2 position of phosphatidylglycerol (PG), which usually contains C16 fatty acids at the sn-2 position in Synechocystis cells. The disruption of the gene for an acyl-ACP synthetase reduced the effect of PUFAs on the photoinhibition of PSII. Thus, the specific incorporation of PUFAs into PG molecules requires acyl-ACP synthetase and leads to an unstable PSII, thereby accelerating photodamage to PSII. Our results are a breakthrough into elucidating the molecular mechanism of the toxicity of PUFAs to photosynthetic organisms