Mitophagy is a highly conserved cellular process that maintains the mitochondrial quantity by eliminating dysfunctional or superfluous mitochondria through autophagy machinery. The mitochondrial ...outer membrane protein BNIP3L/Nix serves as a mitophagy receptor by recognizing autophagosomes. BNIP3L is initially known to clear the mitochondria during the development of reticulocytes. Recent studies indicated it also engages in a variety of physiological and pathological processes. In this review, we provide an overview of how BNIP3L induces mitophagy and discuss the biological functions of BNIP3L and its regulation at the molecular level. We further discuss current evidence indicating the involvement of BNIP3L-mediated mitophagy in human disease, particularly in cancer and neurological disorders.
Therapies that targeted PD-1 have shown remarkable rates of durable clinical responses in patients with various tumor types. However, the extent and knowledge of pulmonary toxicities associated with ...PD-1 blockade, mainly manifested as pneumonitis, remains obscure. In this study, a total of 6360 subjects from 16 phase II/III clinical trials were pooled for meta-analysis to evaluate the overall incidence and risk of PD-1 inhibitors-related pneumonitis in cancer patients. The incidence of pneumonitis during anti-PD-1 immunotherapy was 2.92% (95%CI: 2.18-3.90%) for all-grade and 1.53% (95%CI: 1.15-2.04%) for high-grade pneumonitis. Compared with routine chemotherapy, PD-1 inhibitors were associated with a significant increased risk of pneumonitis. Moreover, among the types of tumor treated with PD-1 inhibitors, the melanoma patients have the lowest incidence of pneumonitis, while the non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients have the highest. Furthermore, no significant differences were detected in the incidences of all- and high-grade pneumonitis between high-dose and low-dose groups of PD-1 inhibitors. In conclusion, PD-1 inhibitors were probably associated with an increased risk of pneumonitis in a dose-independent manner, compared with routine chemotherapeutic agents. The frequency and severity of treatment-mediated pneumonitis was quite different in patients with various tumor types.
Cerebral ischemia induces massive mitochondrial damage. These damaged mitochondria are cleared, thus attenuating brain injury, by mitophagy. Here, we identified the involvement of BNIP3L/NIX in ...cerebral ischemia-reperfusion (I-R)-induced mitophagy. Bnip3l knockout (bnip3l
−/−
) impaired mitophagy and aggravated cerebral I-R injury in mice, which can be rescued by BNIP3L overexpression. The rescuing effects of BNIP3L overexpression can be observed in park2
−/−
mice, which showed mitophagy deficiency after I-R. Interestingly, bnip3l and park2 double-knockout mice showed a synergistic mitophagy deficiency with I-R treatment, which further highlighted the roles of BNIP3L-mediated mitophagy as being independent from PARK2. Further experiments indicated that phosphorylation of BNIP3L serine 81 is critical for BNIP3L-mediated mitophagy. Nonphosphorylatable mutant BNIP3L
S81A
failed to counteract both mitophagy impairment and neuroprotective effects in bnip3l
−/−
mice. Our findings offer insights into mitochondrial quality control in ischemic stroke and bring forth the concept that BNIP3L could be a potential therapeutic target for ischemic stroke, beyond its accepted role in reticulocyte maturation.
Microplastics (MPs) pollution has drawn increasing concern due to its widespread occurrence and potential risks in the environment. The reliable methods and instruments for fast analysis of ...microplastics (MPs) less than 5 mm are urgently needed. In this study, a new method based on custom-made portable pyrolysis-mass spectrometry (Pyr-MS) is developed, which enables rapid identification and mass related quantification of MPs. MPs are decomposed in the compact pyrolyzer and then directly analyzed in the portable MS by the chemical fingerprints of polymers including characteristic ions and their special ratio. It avoids the complex extraction and separation procedures of the pyrolysis/thermogravimetric–gas chromatography–mass spectrometry (Pyr/TGA-GC-MS), realizes the rapid analysis of MPs in 5 min, and thus can practically apply to a large number of MPs samples. In comparison to Fourier transform infrared spectroscopy (FT-IR) and Raman, this method is not limited by the shape, size, and color of MPs. Four common plastics including polyethylene (PE), polypropylene (PP), polystyrene (PS), and poly(methyl methacrylate) (PMMA) were investigated to verify the feasibility of this method. The environmental MPs samples collected from a beach were successfully identified and quantified, demonstrating the simplicity and practicality of this approach. The influence of plastics aging on the chemical fingerprints and the potential of mixed plastics detection by Pyr-MS are also assessed. The portable Pyr-MS could provide a promising tool for in-field analysis of MPs such as ship-based marine MPs surveys.
Cerebral ischemia-reperfusion (I-R) is a complex pathological process. Although autophagy can be evoked by ischemia, its involvement in the reperfusion phase after ischemia and its contribution to ...the fate of neurons remains largely unknown. In the present investigation, we found that autophagy was activated in the reperfusion phase, as revealed in both mice with middle cerebral artery occlusion and oxygen-glucose deprived cortical neurons in culture. Interestingly, in contrast to that in permanent ischemia, inhibition of autophagy (by 3-methyladenine, bafilomycin A
1
, Atg7 knockdown or in atg5
−/−
MEF cells) in the reperfusion phase reinforced, rather than reduced, the brain and cell injury induced by I-R. Inhibition of autophagy either with 3-methyladenine or Atg7 knockdown enhanced the I-R-induced release of cytochrome c and the downstream activation of apoptosis. Moreover, MitoTracker Red-labeled neuronal mitochondria increasingly overlapped with GFP-LC3-labeled autophagosomes during reperfusion, suggesting the presence of mitophagy. The mitochondrial clearance in I-R was reversed by 3-methyladenine and Atg7 silencing, further suggesting that mitophagy underlies the neuroprotection by autophagy. In support, administration of the mitophagy inhibitor mdivi-1 in the reperfusion phase aggravated the ischemia-induced neuronal injury both in vivo and in vitro. PARK2 translocated to mitochondria during reperfusion and Park2 knockdown aggravated ischemia-induced neuronal cell death. In conclusion, the results indicated that autophagy plays different roles in cerebral ischemia and subsequent reperfusion. The protective role of autophagy during reperfusion may be attributable to mitophagy-related mitochondrial clearance and inhibition of downstream apoptosis. PARK2 may be involved in the mitophagy process.
A polygon can represent the boundary of curved text more compactly than a rectangle. However, predicting reasonable polygon lacks of solutions due to the complex spatial relationships caused by ...having more vertices. The two main challenges are how to satisfy the constraints between vertices and how to cope with data conflicts caused by inconsistent annotation standards. To address these problems, we propose a divide and conquer methodology, in which a polygon is considered as a set of convex quadrangles. By predicting quadrangles in sequence, the vertices of the polygon are obtained consecutively and constrained by the previous ones. Then, we propose a measure for the overlap between convex quadrangles, with which the IoU between two polygons is calculated densely. Our method is derivable and can be trained end-to-end. Also, the polygon prediction branch that we proposed is universal and transplantable. We select basic architecture as the backbone, and the text/non-text classification branch adopts an online hard example mining strategy. Experiments on curved benchmark datasets, namely Total Text and CTW1500, demonstrate that our approach achieves state-of-the-art accuracy. It also maintains a high level of inferring efficiency.
Abstract
Negative symptoms in schizophrenia strongly contribute to poor functional outcomes, however its pathogenesis is still unclear. Here, we found that histamine H
1
receptor (H
1
R) expression ...in basal forebrain (BF) cholinergic neurons was decreased in patients with schizophrenia having negative symptoms. Deletion of H
1
R gene in cholinergic neurons in mice resulted in functional deficiency of cholinergic projections from the BF to the prefrontal cortex and in the formation of sensorimotor gating deficit, social impairment and anhedonia-like behavior. These behavioral deficits can be rescued by re-expressing H
1
R or by chemogenetic activation of cholinergic neurons in the BF. Direct chemogenetic inhibition of BF cholinergic neurons produced such behavioral deficits and also increased the susceptibility to hyperlocomotion. Our results suggest that the H
1
R deficiency in BF cholinergic neurons is critical for sensorimotor gating deficit, social impairments and anhedonia-like behavior. This finding may help to understand the genetic and biochemical bases of negative symptoms in schizophrenia.
Mitophagy protects against ischemic neuronal injury by eliminating damaged mitochondria, but it is unclear how mitochondria in distal axons are cleared. We find that oxygen and glucose ...deprivation-reperfusion reduces mitochondrial content in both cell bodies and axons. Axonal mitochondria elimination was not abolished in
;nes-
neurons, suggesting the absence of direct mitophagy in axons. Instead, axonal mitochondria were enwrapped by autophagosomes in soma and axon-derived mitochondria prioritized for elimination by autophagy. Intriguingly, axonal mitochondria showed prompt loss of anterograde motility but increased retrograde movement upon reperfusion. Anchoring of axonal mitochondria by syntaphilin blocked neuronal mitophagy and aggravated injury. Conversely, induced binding of mitochondria to dynein reinforced retrograde transport and enhanced mitophagy to prevent mitochondrial dysfunction and attenuate neuronal injury. Therefore, we reveal somatic autophagy of axonal mitochondria in ischemic neurons and establish a direct link of retrograde mitochondrial movement with mitophagy. Our findings may provide a new concept for reducing ischemic neuronal injury by correcting mitochondrial motility.
Prompt reperfusion after cerebral ischemia is critical for neuronal survival. Any strategies that extend the limited reperfusion window will be of great importance. Acidic postconditioning (APC) is a ...mild acidosis treatment that involves inhaling CO
during reperfusion following ischemia. APC attenuates ischemic brain injury although the underlying mechanisms have not been elucidated. Here we report that APC reinforces ischemia-reperfusion-induced mitophagy in middle cortical artery occlusion (MCAO)-treated mice, and in oxygen-glucose deprivation (OGD)-treated brain slices and neurons. Inhibition of mitophagy compromises neuroprotection conferred by APC. Furthermore, mitophagy and neuroprotection are abolished in Park2 knockout mice, indicating that APC-induced mitophagy is facilitated by the recruitment of PARK2 to mitochondria. Importantly, in MCAO mice, APC treatment extended the effective reperfusion window from 2 to 4 h, and this window was further extended to 6 h by exogenously expressing PARK2. Taken together, we found that PARK2-dependent APC-induced mitophagy renders the brain resistant to ischemic injury. APC treatment could be a favorable strategy to extend the thrombolytic time window for stroke therapy.
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