Protective effect of brain and muscle arnt-like protein-1 against ethanol-induced ferroptosis by activating Nrf2 in mice liver and HepG2 cells

Alcohol abuse has recently become a serious health concern worldwide,and the incidence of alcoholic liver disease(ALD)is rapidly increasing with high morbidity and mortality.Ferroptosis is a newly recognized form of regulated cell death caused by the iron-dependent accumulation of lipid peroxidation.Here we showed that the circadian clock protein brain and muscle arnt-like protein-1(BMAL1)in hepatocytes is both necessary and sufficient to protect against ALD by mitigating ferroptosis.U pon exposure to alcohol(5%Lieber-DeCarli liquid alcohol diet for 10 days before binged alcohol with 5 g/kg body weight in vivo,300 mmol/L for 12 h in vitro,respectively),the content of iron,reactive oxygen species(ROS)and malondialdehyde(MDA)was boosted signifi cantly while glutathione(GSH)was decreased that mainly based on the downregulated protein expression of ferritin heavy chain(FTH),ferroportin(FPN),heme oxygenase1(HO-1)and anti-cystine/glutamate antiporter(SLC7A11),while these changes could be abolished by ferroptosis inhibitor Ferrostatin-1[Fer-1(5 mg/kg body weight for 10 days in vivo,10μmol/L for 2 h in vitro,respectively)].Further study indicated that the alcohol could activate the protein expression of BMAL1 which exerts a protective effect against ferroptosis through promoting nuclear factor erythroid 2-related factor 2(Nrf2)translocation into nuclear and subsequently stimulating its downstream proteins FTH,FPN,glutathione peroxidase 4 activity(GPX4),HO-1,SLC7A11,while knockdown of BMAL1 and Nrf2 by RNA interference further downregulated the expression of these protein and thus promoting ferroptosis in response to alcohol.Collectively,our results unveiled that the protective action of BMAL1 during alcohol challenge depends on its ability to activate Nrf2-ARE antiferroptosis pathway and targeting hepatic BMAL1 to dampen hepatic ferroptosis signaling may have therapeutic potential for ALD.

Pressure effect in the Kondo semimetal CeRu4Sn6 with nontrivial topology

Kondo semimetal CeRu4Sn6 is attracting renewed attention due to the theoretically predicted nontrivial topology in its electronic band structure. We report hydrostatic and chemical pressure effects on the transport properties of single- and poly-crystalline samples. The electrical resistivity p （T） is gradually enhanced by applying pressure over a wide temperature range from room temperature down to 25 mK. Two thermal activation gaps estimated from high- and low-temperature windows are found to increase with pressure. A flat p（T） observed at the lowest temperatures below 300 mK appears to be robust against both pressure and field. This feature as well as the increase of the energy gaps calls for more intensive investigations with respect to electron correlations and band topology.

Parkin promotes proteasomal degradation of p62： implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson＇s disease

Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson＇s disease （PD）, respectively, which manifested with the selective vulnerability of neuronal ceils in substantia nigra （SN） and striatum （STR） regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.

Item Response Theory Based Ensemble in Machine Learning

In this article,we propose a novel probabilistic framework to improve the accuracy of a weighted majority voting algorithm.In order to assign higher weights to the classifiers which can correctly classify hard-to-classify instances,we introduce the item response theory(IRT)framework to evaluate the samples′difficulty and classifiers′ability simultaneously.We assigned the weights to classifiers based on their abilities.Three models are created with different assumptions suitable for different cases.When making an inference,we keep a balance between the accuracy and complexity.In our experiment,all the base models are constructed by single trees via bootstrap.To explain the models,we illustrate how the IRT ensemble model constructs the classifying boundary.We also compare their performance with other widely used methods and show that our model performs well on 19 datasets.