HSD17B13 liquid-liquid phase separation promotes leukocyte adhesion in chronic liver inflammation.

The rs72613567:TA polymorphism in 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) has been found to reduce the progression from steatosis to nonalcoholic steatohepatitis. In this study, we sought to define the pathogenic role of HSD17B13 in triggering liver inflammation. Here we find that HSD17B13 forms liquid-liquid phase separation (LLPS) around lipid droplets in the livers of nonalcoholic steatohepatitis patients. The dimerization of HSD17B13 supports the LLPS formation and promotes its enzymatic function. HSD17B13 LLPS increases the biosynthesis of platelet activating factor (PAF), which in turn promotes fibrinogen synthesis and leukocyte adhesion. Blockade of PAFR or STAT3 pathway inhibited the fibrinogen synthesis and leukocyte adhesion. Importantly, adeno-associated viral-mediated xeno-expression of human HSD17B13 exacerbated western diet/carbon tetrachloride-induced liver inflammation in Hsd17b13-/- mice. In conclusion, our results suggest that HSD17B13 LLPS triggers liver inflammation by promoting PAF-mediated leukocyte adhesion, and targeting HSD17B13 phase transition could be a promising therapeutic approach for treating hepatic inflammation in chronic liver disease.

When chronic obstructive pulmonary disease meets small cell lung cancer: an unusual case report of rapid progression.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease and a risk factor for lung cancer. Small cell lung cancer is a neuroendocrine tumor with a high degree of malignancy and an overall five-year survival rate of less than 7%. CASES PRESENTATION: Herein, we report the case of an 68-year-old male presented to the respiratory department with cough, sputum, and dyspnea. He was diagnosed as community acquired pneumonia and treated with intravenous anti-infection. Previous pulmonary function was definitively diagnosed as COPD. About 7 months after discharge, the patient returned to the hospital for cough and dyspnea. After diagnosis of the tumor, cisplatin, etoposide and durvalumab were administered. Finally the patient died of respiratory failure approximately 9 months after his diagnosis. CONCLUSIONS: For COPD patients with immunocompromised manifestations, it is necessary to be alert to complications and shorten the follow-up interval of chest CT. COPD may accelerate the formation and progression of SCLC.

ATRX loss suppresses the type I interferon response in sarcoma cells through chromatin remodeling.

Sarcomas constitute a heterogeneous group of mesenchymal cancers and are particularly common in children and adolescents, leading to significant lethality. Therefore, it is necessary to understand the underlying mechanisms by which genetic alterations promote sarcoma progression. Here, we demonstrate that loss-of-function of ATRX, a member of the SWI/SNF DNA-remodeling family, represses the interferon (IFN)-ß response by inducing chromatin remodeling in sarcoma cells. We show that ATRX mutations are associated with worse prognosis and attenuate IFN-α/ß response in patients with specific types of sarcomas. Using poly(I:C) as a stimulation model, we show that natural ATRX mutation or ATRX depletion via CRISPR/Cas9 or siRNA significantly suppresses the expression of IFNB1 and other cytokines in sarcoma cells. Moreover, RNA-seq data reveal that ATRX ablation globally influences the expression pattern of poly(I:C)-stimulated genes (PSGs). Through ATAC-seq, we show that ATRX loss enhance chromatin accessibility generally, which consistent with the heterochromatin modulating function of ATRX. However, a set of PSGs display a decrease of chromatin accessibility after ATRX depletion, indicating that ATRX promote the transcription of these genes through chromatin remodeling. Thus, we highlight that ATRX mutation plays critical roles in blocking Type I IFN signaling in sarcoma cells and point out the clinical importance of this effect on sarcoma treatment.

Apically-located P4-ATPase1-Lem1 complex internalizes phosphatidylserine and regulates motility-dependent invasion and egress in Toxoplasma gondii.

The membrane asymmetry regulated by P4-ATPases is crucial for the functioning of eukaryotic cells. The underlying spatial translocation or flipping of specific lipids is usually assured by respective P4-ATPases coupled to conforming non-catalytic subunits. Our previous work has identified five P4-ATPases (TgP4-ATPase1-5) and three non-catalytic partner proteins (TgLem1-3) in the intracellular protozoan pathogen, Toxoplasma gondii. However, their flipping activity, physiological relevance and functional coupling remain unknown. Herein, we demonstrate that TgP4-ATPase1 and TgLem1 work together to translocate phosphatidylserine (PtdSer) during the lytic cycle of T. gondii. Both proteins localize in the plasma membrane at the invasive (apical) end of its acutely-infectious tachyzoite stage. The genetic knockout of P4-ATPase1 and conditional depletion of Lem1 in tachyzoites severely disrupt the asexual reproduction and translocation of PtdSer across the plasma membrane. Moreover, the phenotypic analysis of individual mutants revealed a requirement of lipid flipping for the motility, egress and invasion of tachyzoites. Not least, the proximity-dependent biotinylation and reciprocal immunoprecipitation assays demonstrated the physical interaction of P4-ATPase1 and Lem1. Our findings disclose the mechanism and significance of PtdSer flipping during the lytic cycle and identify the P4-ATPase1-Lem1 heterocomplex as a potential drug target in T. gondii.

Postnatal exposure to hypobaric hypoxia and its impact on inflammation and injury indexes after a cardiac valve procedure.

OBJECTIVES: There is accumulating evidence that hypobaric hypoxia adaptation confers cardiac protection. We investigated whether postnatal exposure to a high-altitude hypoxia environment results in less inflammation injury and better clinical indexes after a cardiac valve procedure. METHODS: A total of 326 consecutively eligible patients undergoing mitral valve surgery from May 2013 through May 2019 in Sichuan Provincial People's Hospital were retrospectively included and stratified by the altitude of residence: the northwest Sichuan plateau residents (altitude 3000-4000 m, group A, n = 101) and the Sichuan basin residents (altitude <1000 m, group B, n = 225). The primary end point indexes included myocardial injury and inflammatory response indexes, which were assessed by measurements of the levels of cardiac troponin I and high-sensitivity C-reactive protein and of the neutrophil-lymphocyte ratio, in addition to lactate levels. Secondary end point outcomes were ventilation time, chest tube drainage volume and length of stay in the intensive care unit and the hospital. RESULTS: No differences in baseline data except for haemoglobin concentration were observed between the 2 groups. The serum levels of high-sensitivity C-reactive protein, cardiac troponin I and lactate and the neutrophil-lymphocyte ratio at each time point within 24 h postoperatively were lower in group A than in group B, respectively. The ventilation time was 9 ± 5 and 11 ± 7 h in group A and in group B, respectively (P = 0.004). The chest tube drainage volume was 647 ± 231 and 715 ± 164 ml in group A and in group B, respectively (P = 0.003). CONCLUSIONS: Compared with the low-altitude residents, high-altitude patients exposed to postnatal hypoxia experienced less severe inflammatory reactions, less ischaemic injury and favourable postoperative recovery when undergoing a primary mitral valve procedure.