Retinal pigment epithelium (RPE) cell damage is implicated in the pathogenesis of age‐related macular degeneration (AMD). An increase of interferon‐γ (IFN‐γ) levels was observed in patients with AMD, ...but whether inflammatory factors are causally related to AMD progression is unclear. Here, we demonstrate a direct causal relationship between IFN‐γ and RPE cell death. IFN‐γ induced human retinal pigment epithelial cell (ARPE‐19) death accompanied by increases in Fe2+, reactive oxygen species, lipid peroxidation, and glutathione (GSH) depletion, which are main characteristics of ferroptosis. Mechanistically, IFN‐γ upregulates the level of intracellular Fe2+ through inhibiting Fe2+ efflux protein SLC40A1 and induces GSH depletion by blocking cystine/glutamate antiporter, System xc‐. At the same time, treatment with IFN‐γ decreases the level of glutathione peroxidase 4 (GPx4), rendering the cells more sensitive to ferroptosis. JAK1/2 and STAT1 inhibitors could reverse the reduction of SLC7A11, GPx4 and GSH expression induced by IFN‐γ, indicating IFN‐γ induces ARPE‐19 cell ferroptosis via activation of the JAK1‐2/STAT1/SLC7A11 signaling pathway. The above results were largely confirmed in IFN‐γ‐treated mice in vivo. Finally, we used sodium iodate (NaIO3)‐induced retinal degeneration to further explore the role of ferroptosis in AMD in vivo. Consistent with the role of IFN‐γ, treatment with NaIO3 decreased SLC7A11, GPx4 and SLC40A1 expressions. NaIO3‐induced RPE damage was accompanied by increased iron, lipid peroxidation products (4‐hydroxynonenal, malondialdehyde), and GSH depletion, and ferroptosis inhibitors could reverse the above phenomenon. Taken together, our findings suggest that inhibiting ferroptosis or reducing IFN‐γ may serve as a promising target for AMD.
IFN‐γ downregulates the expression of SLC7A11 via JAK1‐2/STAT1 signaling pathway, which results in decreases in cysteine transport and, subsequently, decreased GSH synthesis. Simultaneously, IFN‐γ increases intracellular Fe2+ levels through the inhibition of SLC40A1. GSH depletion and Fe2+ accumulation cause retinal pigment epithelial cells ferroptosis and accelerate the progression of AMD.
The immunosuppressive microenvironment that is shaped by hepatic metastatic pancreatic ductal adenocarcinoma (PDAC) is essential for tumor cell evasion of immune destruction. Neutrophils are ...important components of the metastatic tumor microenvironment and exhibit heterogeneity. However, the specific phenotypes, functions and regulatory mechanisms of neutrophils in PDAC liver metastases remain unknown. Here, we show that a subset of P2RX1-negative neutrophils accumulate in clinical and murine PDAC liver metastases. RNA sequencing of murine PDAC liver metastasis-infiltrated neutrophils show that P2RX1-deficient neutrophils express increased levels of immunosuppressive molecules, including PD-L1, and have enhanced mitochondrial metabolism. Mechanistically, the transcription factor Nrf2 is upregulated in P2RX1-deficient neutrophils and associated with PD-L1 expression and metabolic reprogramming. An anti-PD-1 neutralizing antibody is sufficient to compromise the immunosuppressive effects of P2RX1-deficient neutrophils on OVA-activated OT1 CD8+ T cells. Therefore, our study uncovers a mechanism by which metastatic PDAC tumors evade antitumor immunity by accumulating a subset of immunosuppressive P2RX1-negative neutrophils.
2D ferroelectric material has emerged as an attractive building block for high‐density data storage nanodevices. Although monolayer van der Waals ferroelectrics have been theoretically predicted, a ...key experimental breakthrough for such calculations is still not realized. Here, hexagonally stacking α‐In2Se3 nanoflake, a rarely studied van der Waals polymorph, is reported to exhibit out‐of‐plane (OOP) and in‐plane (IP) ferroelectricity at room temperature. Ferroelectric multidomain states in a hexagonal α‐In2Se3 nanoflake with uniform thickness can survive to 6 nm. Most strikingly, the electric‐field‐induced polarization switching and hysteresis loop are, respectively, observed down to the bilayer and monolayer (≈1.2 nm) thicknesses, which designates it as the thinnest layered ferroelectric and verifies the corresponding theoretical calculation. In addition, two types of ferroelectric nanodevices employing the OOP and IP polarizations in 2H α‐In2Se3 are developed, which are applicable for nonvolatile memories and heterostructure‐based nanoelectronics/optoelectronics.
The thinnest layered ferroelectric is demonstrated for the first time at room temperature. The semiconducting hexagonal α‐In2Se3 nanoflakes exhibit out‐of‐plane and in‐plane ferroelectricity that are closely intercorrelated. The polarization switching and hysteresis loops can be realized in the thickness as thin as ≈2.3 nm (bilayer) and ≈1.2 nm (monolayer). Two types of ferroelectric switchable devices are proposed to show the potential application in nonvolatile memories.
Immunotherapy has been incorporated into the first- and second-line treatment strategies for non-small cell lung cancer (NSCLC), profoundly ushering in a new treatment landscape. However, both ...adaptive signaling and oncogenic (epidermal growth factor receptor (EGFR)-driven) signaling may induce PD-L1 upregulation in NSCLC. Nevertheless, the superiority of immune checkpoint inhibitors (ICIs) in advanced EGFR-mutant NSCLC is only moderate. ICIs appear to be well tolerated, but clinical activity for some advanced EGFR-mutant NSCLC patients has only been observed in a small proportion of trials. Hence, there are still several open questions about PD-L1 axis inhibitors in patients with NSCLC whose tumors harbor EGFR mutations, such as the effect of EGFR tyrosine kinase inhibitors (TKIs) or EGFR mutations in the tumor microenvironment (TME). Finding the answers to these questions requires ongoing trials and preclinical studies to identify the mechanisms explaining this possible increased susceptibility and to identify prognostic molecular and clinical markers that may predict benefits with PD-1 axis inhibition in this specific NSCLC subpopulation. The presence of multiple mechanisms, including dynamic immune TME profiles, changes in PD-L1 expression and low tumor mutational burdens, may explain the conflicting data regarding the correlation between PD-L1 axis inhibitors and EGFR mutation status. We conducted a review of this currently controversial topic in an attempt to aid in the decision-making process.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The pathogenesis of severe fever with thrombocytopenia syndrome (SFTS) remained unclear. We aimed to profile the metabolic alterations in urine of SFTS patients and provide new evidence for its ...pathogenesis.
A case-control study was conducted in the 154th hospital in China. Totally 88 cases and 22 controls aged ≥ 18 years were enrolled. The cases were selected from laboratory-confirmed SFTS patients. The controls were selected among SFTSV-negative population. Those with diabetes, cancer, hepatitis and other sexually transmitted diseases were excluded in both groups. Fatal cases and survival cases were 1:1 matched. Inter-group differential metabolites and pathways were obtained, and the inter-group discrimination ability was evaluated.
Tryptophan metabolism and phenylalanine metabolism were the top one important metabolism pathway in differentiating the control and case groups, and the survival and fatal groups, respectively. The significant increase of differential metabolites in tryptophan metabolism, including 5-hydroxyindoleacetate (5-HIAA), L-kynurenine (KYN), 5-hydroxy-L-tryptophan (5-HTP), 3-hydroxyanthranilic acid (3-HAA), and the increase of phenylpyruvic acid and decrease of hippuric acid in phenylalanine metabolism indicated the potential metabolic alterations in SFTSV infection. The increase of 5-HIAA, KYN, 5-HTP, phenylpyruvic acid and hippuric acid were involved in the fatal progress of SFTS patients.
Tryptophan metabolism and phenylalanine metabolism might be involved in the pathogenesis of SFTSV infection. These findings provided new evidence for the pathogenesis and treatment of SFTS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Indoor photovoltaics are promising to enable self‐powered electronic devices for the Internet of Things. Here, reported is a triple‐anion CH3NH3PbI2−xBrClx perovskite film, of which the bandgap is ...specially designed for indoor light harvesting to achieve a record high efficiency of 36.2% with distinctive high open circuit voltage (Voc) of 1.028 V under standard 1000 lux fluorescent light. The involvement of both bromide and chloride suppresses the trap‐states and nonradiative recombination loss, exhibiting a remarkable ideality factor of 1.097. The introduction of chloride successfully restrains the halide segregation of iodide and bromide, stabilizing the triple‐anion perovskite film. The devices show an excellent long‐term performance, sustaining over 95% of original efficiency under continuous light soaking over 2000 h. These findings show the importance and potential of I/Br/Cl triple‐anion perovskite with tailored bandgap and suppressed trap‐states in stable and efficient indoor light recycling.
I/Br/Cl triple‐anion perovskite material with bandgap of 1.8 eV is tailored for indoor light harvesting, which realizes a record high indoor efficiency of 36.2% with increased open circuit voltage (Voc) and minimal short‐circuit current ( Jsc) loss. The I/Br halide segregation is restrained by Cl‐involvement, realizing a long‐term stability of over 95% after 2000 h.
Connectome-based predictive modeling (CPM; Finn et al., 2015; Shen et al., 2017) was recently developed to predict individual differences in traits and behaviors, including fluid intelligence (Finn ...et al., 2015) and sustained attention (Rosenberg et al., 2016a), from functional brain connectivity (FC) measured with fMRI. Here, using the CPM framework, we compared the predictive power of three different measures of FC (Pearson's correlation, accordance, and discordance) and two different prediction algorithms (linear and partial least square PLS regression) for attention function. Accordance and discordance are recently proposed FC measures that respectively track in-phase synchronization and out-of-phase anti-correlation (Meskaldji et al., 2015). We defined connectome-based models using task-based or resting-state FC data, and tested the effects of (1) functional connectivity measure and (2) feature-selection/prediction algorithm on individualized attention predictions. Models were internally validated in a training dataset using leave-one-subject-out cross-validation, and externally validated with three independent datasets. The training dataset included fMRI data collected while participants performed a sustained attention task and rested (N = 25; Rosenberg et al., 2016a). The validation datasets included: 1) data collected during performance of a stop-signal task and at rest (N = 83, including 19 participants who were administered methylphenidate prior to scanning; Farr et al., 2014a; Rosenberg et al., 2016b), 2) data collected during Attention Network Task performance and rest (N = 41, Rosenberg et al., in press), and 3) resting-state data and ADHD symptom severity from the ADHD-200 Consortium (N = 113; Rosenberg et al., 2016a). Models defined using all combinations of functional connectivity measure (Pearson's correlation, accordance, and discordance) and prediction algorithm (linear and PLS regression) predicted attentional abilities, with correlations between predicted and observed measures of attention as high as 0.9 for internal validation, and 0.6 for external validation (all p's < 0.05). Models trained on task data outperformed models trained on rest data. Pearson's correlation and accordance features generally showed a small numerical advantage over discordance features, while PLS regression models were usually better than linear regression models. Overall, in addition to correlation features combined with linear models (Rosenberg et al., 2016a), it is useful to consider accordance features and PLS regression for CPM.
•Functional connectivity can predict individual differences in attention.•We compared different connectivity measures and feature selection algorithms.•Four different data sets permitted both internal and external validation.•For rest data, PLS regression models were numerically better than linear regression.•Pearson’s correlation, accordance, and discordance did not meaningfully differ.
Identification of the defective patterns of the wafer maps can provide insights for the quality control in the semiconductor wafer fabrication systems (SWFSs). In real SWFSs, the collected wafer maps ...are usually imbalanced from the defective types, which will result in misidentification. In this paper, a novel deep learning model called adaptive balancing generative adversarial network (AdaBalGAN) is proposed for the defective pattern recognition (DPR) of wafer maps with imbalanced data. In addition, a categorical generative adversarial network is improved to generate simulated wafer maps in high fidelity and classify the patterns with high accuracy for all defective categories. Taking consideration of the various learning abilities of the DPR model for different patterns into account, an adaptive generative controller is designed to balance the number of samples of each defective type according to the classification accuracy. The experiment results indicated that the proposed AdaBalGAN model outperforms conventional models with higher accuracy and stability for the DPR of wafer maps. Further results of comparative experiments revealed that the proposed adaptive generative mechanism can enhance and balance the recognition accuracy for all categories in the DPR of wafer maps.
Two novel C(sp3)−H functionalization of inert alkanes and visible‐light promoted oxidation decarboxylation of N‐hydroxyphthalimide (NHP) esters to access polycyclic quinazolinones have been ...described. These methods do not involve metal catalysts and are carried out in water or water/DMSO media. The wide substrate scope, even including the seven‐membered ring under mild reaction conditions, demonstrate the practicability of these strategies.
This work describes the cleavage of the C(sp3)−H bond of inert alkanes and the visible‐light promoted oxidation decarboxylation of NHP‐esters to form alkyl radicals, which then efficiently synthesize valuable polycyclic quinazolinones through radical addition and cyclization. Both methods were carried out in water or water/DMSO media without metal catalysts with good functional group compatibility.
Genetic analyses have linked microRNA-137 (MIR137) to neuropsychiatric disorders, including schizophrenia and autism spectrum disorder. miR-137 plays important roles in neurogenesis and neuronal ...maturation, but the impact of miR-137 loss-of-function in vivo remains unclear. Here we show the complete loss of miR-137 in the mouse germline knockout or nervous system knockout (cKO) leads to postnatal lethality, while heterozygous germline knockout and cKO mice remain viable. Partial loss of miR-137 in heterozygous cKO mice results in dysregulated synaptic plasticity, repetitive behavior, and impaired learning and social behavior. Transcriptomic and proteomic analyses revealed that the miR-137 mRNA target, phosphodiesterase 10a (Pde10a), is elevated in heterozygous knockout mice. Treatment with the Pde10a inhibitor papaverine or knockdown of Pde10a ameliorates the deficits observed in the heterozygous cKO mice. Collectively, our results suggest that MIR137 plays essential roles in postnatal neurodevelopment and that dysregulation of miR-137 potentially contributes to neuropsychiatric disorders in humans.
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