Van der Waals polarity-engineered 3D integration of 2D complementary logic.

Vertical three-dimensional integration of two-dimensional (2D) semiconductors holds great promise, as it offers the possibility to scale up logic layers in the z axis1-3. Indeed, vertical complementary field-effect transistors (CFETs) built with such mixed-dimensional heterostructures4,5, as well as hetero-2D layers with different carrier types6-8, have been demonstrated recently. However, so far, the lack of a controllable doping scheme (especially p-doped WSe2 (refs. 9-17) and MoS2 (refs. 11,18-28)) in 2D semiconductors, preferably in a stable and non-destructive manner, has greatly impeded the bottom-up scaling of complementary logic circuitries. Here we show that, by bringing transition metal dichalcogenides, such as MoS2, atop a van der Waals (vdW) antiferromagnetic insulator chromium oxychloride (CrOCl), the carrier polarity in MoS2 can be readily reconfigured from n- to p-type via strong vdW interfacial coupling. The consequential band alignment yields transistors with room-temperature hole mobilities up to approximately 425 cm2 V-1 s-1, on/off ratios reaching 106 and air-stable performance for over one year. Based on this approach, vertically constructed complementary logic, including inverters with 6 vdW layers, NANDs with 14 vdW layers and SRAMs with 14 vdW layers, are further demonstrated. Our findings of polarity-engineered p- and n-type 2D semiconductor channels with and without vdW intercalation are robust and universal to various materials and thus may throw light on future three-dimensional vertically integrated circuits based on 2D logic gates.

Spectrum-Dependent Image Convolutional Processing via a Two-Dimensional Polarization-Sensitive Photodetector.

Currently, the improvement in the processing capacity of traditional processors considerably lags behind the demands of real-time image processing caused by the advancement of photodetectors and the widespread deployment of high-definition image sensors. Therefore, achieving real-time image processing at the sensor level has become a prominent research domain in the field of photodetector technology. This goal underscores the need for photodetectors with enhanced multifunctional integration capabilities than can perform real-time computations using optical or electrical signals. In this study, we employ an innovative p-type semiconductor GaTe0.5Se0.5 to construct a polarization-sensitive wide-spectral photodetector. Leveraging the wide-spectral photoresponse, we realize three-band imaging within a wavelength range of 390-810 nm. Furthermore, real-time image convolutional processing is enabled by configuring appropriate convolution kernels based on the polarization-sensitive photocurrents. The innovative design of the polarization-sensitive wide-spectral GaTe0.5Se0.5-based photodetector represents a notable contribution to the domain of real-time image perception and processing.

Hypomethylation-associated ELF3 helps nasopharyngeal carcinoma to escape immune surveillance via MUC16-mediated glycolytic metabolic reprogramming.

Immune escape and metabolic reprogramming are two essential hallmarks of cancer. Mucin-16 (MUC16) has been linked to glycolysis and immune response in different cancers. However, its involvement in nasopharyngeal carcinoma (NPC) has not been well described. We seek to dissect the functions and detailed mechanisms of MUC16 in NPC. Bioinformatics prediction was performed to identify NPC-related molecules. MUC16 was significantly enhanced in NPC tissues, which was correlated with the advanced tumor stage of patients. Lentiviral plasmids-mediated MUC16 deletion inhibited the malignant behavior of NPC cells, and glycolysis inhibition by MUC16 deletion blocked immune escape in NPC cells. E74-like factor 3 (ELF3) bound to the MUC16 promoter promotes the transcription of MUC16. MUC16 overexpression reversed the repressive effect of ELF3 silencing on glycolysis and immune escape in NPC and accelerated tumor growth in vivo. Overexpression of ELF3 in NPC was associated with reduced DNA methylation in its promoter. Our findings revealed the role of the ELF3/MUC16 axis in the immune escape and metabolic reprogramming of NPC, providing potential therapeutic targets for NPC.NEW & NOTEWORTHY We identified the functions of E74-like factor 3 (ELF3) in glycolysis and immune escape of nasopharyngeal carcinoma cells for the first time. As a transcription factor, ELF3 promoted mucin-16 (MUC16) expression by binding to its promoter, leading to the glycolysis-mediated immune escape of nasopharyngeal carcinoma (NPC) cells. Targeting the ELF3/MUC16 axis generates a superior antitumor immune response, which will help establish a novel approach to restore protective antitumor immunity for NPC immunotherapy.

Phosphorylation of STAT3 at Tyr705 contributes to TFEB-mediated autophagy-lysosomal pathway dysfunction and leads to ischemic injury in rats.

We previously reported that permanent ischemia induces marked dysfunction of the autophagy-lysosomal pathway (ALP) in rats, which is possibly mediated by the transcription factor EB (TFEB). However, it is still unclear whether signal transducer and activator of transcription 3 (STAT3) is responsible for the TFEB-mediated dysfunction of ALP in ischemic stroke. In the present study, we used AAV-mediated genetic knockdown and pharmacological blockade of p-STAT3 to investigate the role of p-STAT3 in regulating TFEB-mediated ALP dysfunction in rats subjected to permanent middle cerebral occlusion (pMCAO). The results showed that the level of p-STAT3 (Tyr705) in the rat cortex increased at 24 h after pMCAO and subsequently led to lysosomal membrane permeabilization (LMP) and ALP dysfunction. These effects can be alleviated by inhibitors of p-STAT3 (Tyr705) or by STAT3 knockdown. Additionally, STAT3 knockdown significantly increased the nuclear translocation of TFEB and the transcription of TFEB-targeted genes. Notably, TFEB knockdown markedly reversed STAT3 knockdown-mediated improvement in ALP function after pMCAO. This is the first study to show that the contribution of p-STAT3 (Tyr705) to ALP dysfunction may be partly associated with its inhibitory effect on TFEB transcriptional activity, which further leads to ischemic injury in rats.

High histone H3K18 lactylation level is correlated with poor prognosis in epithelial ovarian cancer.

Protein lactylation has a poor prognosis in malignant tumors, but its impact on the prognosis of epithelial ovarian cancer (EOC) remains unknown. We analyzed 112 patients with EOC. Immunohistochemical staining was used to detect the level of pan lactylation (Pan Kla) and histone H3K18 lactylation (H3K18la) in the EOC tissues and normal ovarian tissues. The result showed that the protein lactylation level in EOC was higher than in normal tissues. Then, we analyzed the relationship between overall survival (OS), progression-free survival (PFS) of EOC, and lactylation. The result showed that patients with high histone H3K18la levels had poorer OS (p=0.028) and PFS (p<0.001). Multivariate Cox regression analysis of PFS showed histone H3K18la was an independent risk factor (p=0.001). In addition, we found that both histone H3K18la and Pan Kla in the cytoplasm were associated with platinum recurrence time (p=0.002/p=0.003). The results also indicated that the H3K18la level was related to a tumor stage (p=0.037). Furthermore, we explored the effects of lactylation on the metastasis of ovarian cancer. The results indicated a significant increase in migration in the promoter group compared to the negative control group and inhibitor group. In conclusion, high histone H3K18la level is associated with poor prognosis in EOC. Protein lactylation may have a significant impact on EOC and could potentially be used as a target for EOC therapy in the future.

Efficacy of respiratory rehabilitation in patients with COVID-19: a retrospective study.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of confirmed cases and deaths globally. The purpose of this study was to investigate the therapeutic effect of airway clearance technology combined with prone ventilation on patients infected with COVID-19. METHODS: 38 patients with COVID-19 (severe) who were treated in the intensive rehabilitation group of Shengli Oilfield Central Hospital. They were randomly divided into a control group and an observation group. The control group received prone position ventilation intervention, and the observation group received airway clearance technology combined with prone position ventilation intervention. The changes of oxygen and index, procalcitonin (PCT), interleukin-6 (IL-6) and chest X-ray image indexes were compared between the two groups. RESULT: There was no significant difference in age, gender and other general data between the control group and the observation group. The results showed that oxygen index, PCT, IL-6 and chest X-ray image index in the observation group were better than that indexes in the control group. CONCLUSION: Airway clearance technology combined with prone ventilation intervention in patients with COVID-19 can improve the total effective rate and oxygenation index, improve the inflammatory indicators and respiratory function of patients. And it may be widely promoted and used in the treatment of patients with COVID-19 (severe).

Agonistic analog of growth hormone-releasing hormone promotes neurofunctional recovery and neural regeneration in ischemic stroke.

Ischemic stroke can induce neurogenesis. However, most stroke-generated newborn neurons cannot survive. It has been shown that MR-409, a potent synthetic agonistic analog of growth hormone-releasing hormone (GHRH), can protect against some life-threatening pathological conditions by promoting cell proliferation and survival. The present study shows that long-term treatment with MR-409 (5 or 10 µg/mouse/d) by subcutaneous (s.c.) injection significantly reduces the mortality, ischemic insult, and hippocampal atrophy, and improves neurological functional recovery in mice operated on for transient middle cerebral artery occlusion (tMCAO). Besides, MR-409 can stimulate endogenous neurogenesis and improve the tMCAO-induced loss of neuroplasticity. MR-409 also enhances the proliferation and inhibits apoptosis of neural stem cells treated with oxygen and glucose deprivation-reperfusion. The neuroprotective effects of MR-409 are closely related to the activation of AKT/CREB and BDNF/TrkB pathways. In conclusion, the present study demonstrates that GHRH agonist MR-409 has remarkable neuroprotective effects through enhancing endogenous neurogenesis in cerebral ischemic mice.

Tamarixetin ameliorates cerebral ischemia-reperfusion injury via suppressing nicotinamide adenine dinucleotide phosphate oxidase 2/nucleotide-binding oligomerization domain like receptor family pyrin domain-containing 3 inflammasome activation.

Tamarixetin, a natural dietary flavone, exhibits remarkable potential for the treatment of ischemic stroke. The present article aimed to explore the impact of tamarixetin on ischemic stroke and elucidate the underlying mechanisms. Effects of tamarixetin on ischemic stroke were evaluated in rats using the middle cerebral artery occlusion and reperfusion (MCAO/R) model, by assessing the neurological deficit scores, brain water content, brain infraction, and neuronal damage. The levels of proinflammatory cytokines, NLRP3 inflammasome activation, reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression were measured in MCAO/R rats and lipopolysaccharide-stimulated cells. Tamarixetin administration improved the neurological dysfunction and neuronal loss in MCAO/R rats. In addition, tamarixetin reduced microglial hyperactivation and proinflammatory cytokines expression in vivo and in vitro. Tamarixetin attenuated NF-κB p65 phosphorylation and promoter activity, reduced NLRP3 expression and caspase-1 cleavage, and downregulated IL-1ß and IL-18 secretions to suppress NLRP3 inflammasome activation. The levels of superoxide anion, hydrogen peroxide, and ROS were also suppressed by tamarixetin. The downregulation of NADP+ and NADPH levels, and gp91phox expression indicated the ameliorative effects of tamarixetin on NADPH oxidase activation. In the gp91phox knockdown cells treated with lipopolysaccharide, the effects of tamarixetin on NADPH oxidase activation, ROS generation, and NLRP3 inflammasome activation were diminished. Moreover, tamarixetin protects neurons against microglial hyperactivation in vitro. Our findings support the potential of tamarixetin as a therapeutic agent for ischemic stroke, and its mechanism of action involves the inhibition of NADPH oxidase-NLRP3 inflammasome signaling.

The microstructural abnormalities of cingulum was related to patients with mild cognitive impairment: a diffusion kurtosis imaging study.

OBJECTIVE: Our study aimed to investigate the correlations between microstructural changes of cingulum and patients with mild cognitive impairment (MCI) by diffusion kurtosis imaging (DKI) technique. METHOD: A total of 104 patients with cerebral small vessel diseases (cSVD) were retrospectively enrolled in this study. According to Montreal Cognitive Assessment Scale (MoCA) scores, these patients were divided into MCI group (n = 59) and non-MCI group (n = 45). The general clinical data was collected and analyzed. The regions of interests (ROIs) were selected for investigation in cingulum. The values of DKI parameters were measured in each ROI and compared between the two groups, the correlations between DKI parameters and MoCA scores were examined. RESULTS: Compared to non-MCI group, MCI patients had more severe white matter hyperintensities (WMHs) (P = 0.038) and lower MoCA scores (P < 0.01). MCI patients showed significantly decreased fractional anisotropy (FA), axial kurtosis (AK), mean kurtosis (MK), radial kurtosis (RK), and kurtosis fractional anisotropy (KFA) in the left cingulum in the cingulated cortex (CgC) region (all P < 0.0125). In the left CgC region, FA, AK, MK, RK, and KFA were positively correlated with MoCA scores (r = 0.348, 0.409, 0.310, 0.441, 0.422, all P < 0.001). Meanwhile, FA, AK, MK, RK, and KFA were also positively correlated with MoCA scores (r = 0.338, 0.352, 0.289, 0.380, 0.370, all P < 0.001) in the right CgC region. CONCLUSION: DKI technique could be used to explore the microstructural changes of cingulum in MCI patients and DKI-derived parameters might be feasible to evaluate MCI patients.

S100A4 Promotes BCG-Induced Pyroptosis of Macrophages by Activating the NF-κB/NLRP3 Inflammasome Signaling Pathway.

Pyroptosis is a host immune strategy to defend against Mycobacterium tuberculosis (Mtb) infection. S100A4, a calcium-binding protein that plays an important role in promoting cancer progression as well as the pathophysiological development of various non-tumor diseases, has not been explored in Mtb-infected hosts. In this study, transcriptome analysis of the peripheral blood of patients with pulmonary tuberculosis (PTB) revealed that S100A4 and GSDMD were significantly up-regulated in PTB patients' peripheral blood. Furthermore, there was a positive correlation between the expression of GSDMD and S100A4. KEGG pathway enrichment analysis showed that differentially expressed genes between PTB patients and healthy controls were significantly related to inflammation, such as the NOD-like receptor signaling pathway and NF-κB signaling pathway. To investigate the regulatory effects of S100A4 on macrophage pyroptosis, THP-1 macrophages infected with Bacillus Calmette-Guérin (BCG) were pre-treated with exogenous S100A4, S100A4 inhibitor or si-S100A4. This research study has shown that S100A4 promotes the pyroptosis of THP-1 macrophages caused by BCG infection and activates NLRP3 inflammasome and NF-κB signaling pathways, which can be inhibited by knockdown or inhibition of S100A4. In addition, inhibition of NF-κB or NLRP3 blocks the promotion effect of S100A4 on BCG-induced pyroptosis of THP-1 macrophages. In conclusion, S100A4 activates the NF-κB/NLRP3 inflammasome signaling pathway to promote macrophage pyroptosis induced by Mtb infection. These data provide new insights into how S100A4 affects Mtb-induced macrophage pyroptosis.

Endoplasmic Reticulum Stress Mediated NLRP3 Inflammasome Activation and Pyroptosis in THP-1 Macrophages Infected with Bacillus Calmette-Guérin.

Tuberculosis (TB) is a zoonotic infectious disease caused by Mycobacterium tuberculosis (Mtb). Mtb is a typical intracellular parasite, and macrophages are its main host cells. NLRP3 inflammasome-mediated pyroptosis is a form of programmed cell death implicated in the clearance of pathogenic infections. The bidirectional regulatory effect of endoplasmic reticulum stress (ERS) plays a crucial role in determining cell survival and death. Whether ERS is involved in macrophage pyroptosis with Mtb infection remains unclear. This article aims to explore the regulation of the NLRP3 inflammasome and pyroptosis by ERS in THP-1 macrophages infected with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). The results showed that BCG infection induced THP-1 macrophage ERS, NLRP3 inflammasome activation and pyroptosis, which was inhibited by ERS inhibitor TUDCA. NLRP3 inhibitor MCC950 inhibited THP-1 macrophage NLRP3 inflammasome activation and pyroptosis caused by BCG infection. Compared with specific Caspase-1 inhibitor VX-765, pan-Caspase inhibitor Z-VAD-FMK showed a more significant inhibitory effect on BCG infection-induced pyroptosis of THP-1 macrophages. Taken together, this study demonstrates that ERS mediated NLRP3 inflammasome activation and pyroptosis after BCG infection of THP-1 macrophages, and that BCG infection of THP-1 macrophages induces pyroptosis through canonical and noncanonical pathways.

GSK2656157, a PERK Inhibitor, Alleviates Pyroptosis of Macrophages Induced by Mycobacterium Bacillus Calmette-Guerin Infection.

Tuberculosis (TB) is the leading cause of human death worldwide due to Mycobacterium tuberculosis (Mtb) infection. Mtb infection can cause macrophage pyroptosis. PERK, as a signaling pathway protein on the endoplasmic reticulum, plays an important role in infectious diseases. It is not clear whether PERK is involved in the regulation of pyroptosis of macrophages during Mtb infection. In this study, Bacillus Calmette-Guerin (BCG) infection resulted in high expression of pro-caspase-1, caspase-1 p20, GSDMD-N, and p-PERK in the THP-1 macrophage, being downregulated with the pre-treatment of GSK2656157, a PERK inhibitor. In addition, GSK2656157 inhibited the secretion of IL-1ß and IL-18, cell content release, and cell membrane rupture, as well as the decline in cell viability induced by BCG infection. Similarly, GSK2656157 treatment downregulated the expressions of pro-caspase-1, caspase-1 p20, caspase-11, IL-1ß p17, IL-18 p22, GSDMD, GSDMD-N, and p-PERK, as well as reducing fibrous tissue hyperplasia, inflammatory infiltration, and the bacterial load in the lung tissue of C57BL/6J mice infected with BCG. In conclusion, the inhibition of PERK alleviated pyroptosis induced by BCG infection, which has an effect of resisting infection.

Correction: Nie et al. Endoplasmic Reticulum Stress Mediated NLRP3 Inflammasome Activation and Pyroptosis in THP-1 Macrophages Infected with Bacillus Calmette-Guérin. Int. J. Mol. Sci. 2023, 24, 11692.

Lei Liu was not included as an author in the original publication [...].

Space-time resolved inference-based neurophysiological process imaging: Application to resting-state alpha rhythm.

Neural processes are complex and difficult to image. This paper presents a new space-time resolved brain imaging framework, called Neurophysiological Process Imaging (NPI), that identifies neurophysiological processes within cerebral cortex at the macroscopic scale. By fitting uncoupled neural mass models to each electromagnetic source time-series using a novel nonlinear inference method, population averaged membrane potentials and synaptic connection strengths are efficiently and accurately inferred and imaged across the whole cerebral cortex at a resolution afforded by source imaging. The efficiency of the framework enables return of the augmented source imaging results overnight using high performance computing. This suggests it can be used as a practical and novel imaging tool. To demonstrate the framework, it has been applied to resting-state magnetoencephalographic source estimates. The results suggest that endogenous inputs to cingulate, occipital, and inferior frontal cortex are essential modulators of resting-state alpha power. Moreover, endogenous input and inhibitory and excitatory neural populations play varied roles in mediating alpha power in different resting-state sub-networks. The framework can be applied to arbitrary neural mass models and has broad applicability to image neural processes of different brain states.

Wnt5a regulates autophagy in Bacille Calmette-Guérin (BCG)-Infected pulmonary epithelial cells.

Autophagy functions as a critical process that can suppress the proliferation of Mycobacterium tuberculosis (Mtb) within infected host cells. Wnt5a is a secreted protein that plays a range of physiological functions, activating several signaling pathways and thereby controlling cellular responses to particular stimuli. The importance of Wnt5a as a regulator of protection against Mtb infection, however, has yet to be fully characterized. Here, changes in murine pulmonary epithelial-like TC-1 cell morphology, autophagy, the Wnt/Ca2+ signaling pathway, and the mTOR autophagy pathway were analyzed following infection with the Mtb model pathogen Bacille Calmette-Guerin (BCG) in order to understand the regulatory role of Wnt5a in this context. These experiments revealed that Wnt5a was upregulated and autophagy was enhanced in TC-1 cells infected with BCG, and Wnt5a overexpression was found to drive BCG-induced autophagy in these cells upon infection, whereas the inhibition or knockdown of Wnt5a yielded the opposite effect. At the mechanistic level, Wnt5a was found to mediate non-canonical Wnt/Ca2+ signaling and thereby inhibit mTOR-dependent pathway activation, promoting autophagic induction within BCG-infected TC-1 cells. These data offer new insight regarding how Wnt5a influences Mtb-induced autophagy within pulmonary epithelial cells, providing a foundation for further research exploring the immunological control of this infection through the modulation of autophagy.

Ror2-mediated cholesterol accumulation regulates autophagic activity within BCG-infected macrophages.

Ror2 is a primary binding partner for the non-classical Wnt signaling pathway regulator Wnt5a that plays a central role in regulating the metabolic processing of lipids within the cell. Mycobacterium tuberculosis is an intracellular pathogen that utilizes the lipid substrate cholesterol as its primary source of carbon. Cholesterol accumulation can regulate autophagy, which is in turn associated with a variety of pathological conditions. This study was designed to explore the pathways that modulate Ror2-regulated cholesterol accumulation within macrophages infected by the mycobacterium Bacillus Calmette-Guerin (BCG). BCG infection of RAW264.7 cells resulted in increased Ror2 expression, cholesterol accumulation, and autophagic activity in addition to promoting the upregulation of cholesterol synthesis-related proteins and the downregulation of cholesterol transporter proteins. Ror2 knockdown, in contrast, reversed these phenotypic changes. Treatment with T0901317 decreased the aggregation of cholesterol within cells and suppressed BCG-induced autophagy, while OX-LDL had the opposite effect. Knocking down Ror2 further reduced cholesterol levels in the context of T0901317 or OX-LDL pretreatment, alleviating BCG-induced autophagy irrespective of either of these pretreatments. Together, these data indicate that Ror2 can shape the autophagic activity induced within macrophages upon BCG infection by modulating intracellular cholesterol levels.

Microscale thermophoresis and fluorescence polarization assays of calcineurin-peptide interactions.

Calcineurin is a Ca2+/calmodulin-dependent phosphatase. It is very important to study the affinity between calcineurin and its substrate or other interacting proteins. Two conserved motifs have been reported on the interactive proteins of calcineurin, namely, the PxIxIT motif and the LxVP motif. Here, we used 5(6)-carboxyfluorescein to fluorescently label the N-terminus of the short peptides derived from the two motifs and then determined the affinity between the protein and polypeptides. Microscale thermophoresis (MST) is very suitable for determining calcineurin with peptides containing the LxVP motif. The Kd values of the binding of calcineurin with NFATc1-YLAVP, NHE1-YLTVP, and A238L-FLCVK peptides were 6.72 ± 0.19 µM, 17.14 ± 0.35 µM, and 15.57 ± 0.10 µM, respectively. The GST pull-down results further confirmed the binding trend of the three peptides to calcineurin. However, fluorescently labeled PxIxIT polypeptides are not suitable for MST due to their own aggregation. We determined the binding affinity of the RCAN1-PSVVVH polypeptide to calcineurin by the fluorescence polarization (FP) method. MST and FP assays are fast and accurate in determining the affinity between protein-peptide interactions. Our research laid the foundation for screening the molecules that affect the binding between calcineurin and its substrates in the future.

Epileptic seizure onset predicts its duration.

BACKGROUND: Epilepsy is characterized by recurrent seizures that have a variety of manifestations. The severity of, and risks for patients associated with, seizures are largely linked to the duration of seizures. Methods that determine seizure duration based on seizure onsets could be used to help mitigate the risks associated with what might be extended seizures by guiding timely interventions. METHODS: Using long-term intracranial electroencephalography (iEEG) recordings, this article presents a method for predicting whether a seizure is going to be long or short by analyzing the seizure onset. The definition of long and short depends on each patient's seizure distribution. By analyzing 2954 seizures from 10 patients, patient-specific classifiers were built to predict seizure duration given the first few seconds from the onset. RESULTS: The proposed methodology achieved an average area under the receiver operating characteristic curve (AUC) performance of 0.7 for the 5 of 10 patients with above chance prediction performance (p value from 0.04 to 10-9 ). CONCLUSIONS: Our results imply that the duration of seizures can be predicted from the onset in some patients. This could form the basis of methods for predicting status epilepticus or optimizing the amount of electrical stimulation delivered by seizure control devices.

Low-Loss Zero-Index Materials.

Materials with a zero refractive index support electromagnetic modes that exhibit stationary phase profiles. While such materials have been realized across the visible and near-infrared spectral range, radiative and dissipative optical losses have hindered their development. We reduce losses in zero-index, on-chip photonic crystals by introducing high-Q resonances via resonance-trapped and symmetry-protected states. Using these approaches, we experimentally obtain quality factors of 2.6 × 103 and 7.8 × 103 at near-infrared wavelengths, corresponding to an order-of-magnitude reduction in propagation loss over previous designs. Our work presents a viable approach to fabricate zero-index on-chip nanophotonic devices with low-loss.

CAPN1 (Calpain1)-Mediated Impairment of Autophagic Flux Contributes to Cerebral Ischemia-Induced Neuronal Damage.

Background and Purpose: CAPN1 (calpain1)­an intracellular Ca2+-regulated cysteine protease­can be activated under cerebral ischemia. However, the mechanisms by which CAPN1 activation promotes cerebral ischemic injury are not defined. Methods: In the present study, we used adeno-associated virus-mediated genetic knockdown and pharmacological blockade (MDL-28170) of CAPN1 to investigate the role of CAPN1 in the regulation of the autophagy-lysosomal pathway and neuronal damage in 2 models, rat permanent middle cerebral occlusion in vivo model and oxygen-glucose­deprived primary neuron in vitro model. Results: CAPN1 was activated in the cortex of permanent middle cerebral occlusion­operated rats and oxygen-glucose deprivation­exposed neurons. Genetic and pharmacological inhibition of CAPN1 significantly attenuated ischemia-induced lysosomal membrane permeabilization and subsequent accumulation of autophagic substrates in vivo and in vitro. Moreover, inhibition of CAPN1 increased autophagosome formation by decreasing the cleavage of the autophagy regulators BECN1 (Beclin1) and ATG (autophagy-related gene) 5. Importantly, the neuron-protective effect of MDL-28170 on ischemic insult was reversed by cotreatment with either class III-PI3K (phosphatidylinositol 3-kinase) inhibitor 3-methyladenine or lysosomal inhibitor chloroquine (chloroquine), suggesting that CAPN1 activation-mediated impairment of autophagic flux is crucial for cerebral ischemia-induced neuronal damage. Conclusions: The present study demonstrates for the first time that ischemia-induced CAPN1 activation impairs lysosomal function and suppresses autophagosome formation, which contribute to the accumulation of substrates and aggravate the ischemia-induced neuronal cell damage. Our work highlights the vital role of CAPN1 in the regulation of cerebral ischemia­mediated autophagy-lysosomal pathway defects and neuronal damage.