Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, ...pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor's glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.
Recently, metasurfaces composed of artificially fabricated subwavelength structures have shown remarkable potential for the manipulation of light with unprecedented functionality. Here, we first ...demonstrate a metasurface application to realize a compact near-eye display system for augmented reality with a wide field of view. A key component is a see-through metalens with an anisotropic response, a high numerical aperture with a large aperture, and broadband characteristics. By virtue of these high-performance features, the metalens can overcome the existing bottleneck imposed by the narrow field of view and bulkiness of current systems, which hinders their usability and further development. Experimental demonstrations with a nanoimprinted large-area see-through metalens are reported, showing full-color imaging with a wide field of view and feasibility of mass production. This work on novel metasurface applications shows great potential for the development of optical display systems for future consumer electronics and computer vision applications.
We consider a worker's job search problem in which firms arrive sequentially, observe the worker's unemployment duration, and conduct an interview to learn about her unobservable productivity. Firms ...engage in fully flexible information acquisition subject to a uniformly posterior‐separable cost function. We provide a closed‐form characterization of equilibrium job search dynamics and demonstrate that endogenous information amplifies the “stigma” effect of long unemployment duration relative to exogenous information. We also show that lowering firms' information‐acquisition costs has ambiguous implications for a worker's unemployment duration.
Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has ...been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412-668×) validated by site-specific amplicon sequencing (100-347,499×) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.
We aimed to identify whether neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are more useful predictors after initial intention to treat than at the time of diagnosis.
We ...collected the medical data of 533 patients. The results of the peripheral blood sampling before the primary treatments were labeled as initial cohort, and those obtained between 24 and 36 months after initial treatment were defined as the 2nd cohort. Delayed metastasis has been defined as distant metastasis 2 years after treatment, and survival outcome was estimated and compared across groups.
Median follow-up duration was 74 months (24-162 months), and 53 patients experienced delayed metastasis. In univariate analysis, metastasis-free survival, patient age at diagnosis, tumor size, axillary lymph node metastasis, HER-2 status, initial NLR and PLR, and 2nd NLR and PLR were found to be significantly associated with delayed metastasis. However, in multivariate analysis, only the 2nd NLR and PLR were found to be significantly associated with delayed metastasis, excluding initial NLR and PLR. Metastasis-free survival was analyzed through the pattern changes of NLR or PLR. The results revealed that patients with continued low NLR and PLR values at pre- and post-treatment (low initial values and 2nd values) showed a significantly better prognosis than those with a change in value or continued high NLR and PLR.
We identified that patients with persistent high NLR and PLR after initial treatment have significant worse prognosis in terms of late metastasis. Therefore, these results suggest that NLR and PLR are more useful in predicting prognosis post-treatment.
The micropatterning of conductive composites is of great importance for the integration of elastic conductors with functional micro-geometries in a stretchable platform. We present a simple and rapid ...micropatterning method for conductive composites that relies on single-step contact transfer printing (sCTP). A conductive polydimethylsiloxane (PDMS) composite is readily synthesized by dispersing conductive carbon black nanoparticles into a PDMS matrix and is easily patterned on insulative PDMS substrates with negligible dimensional errors by the proposed method. In addition to simplicity and accuracy in fabrication, superior process scalability is revealed through investigation of both multiple-stack and large-area patterning approaches. We also demonstrate an all-elastomeric-platformed piezoresistive strain sensor capable of measuring higher tensile strains compared to conventional metal foil gauges, with highly linear, good cyclic electrical performance, and mechanical robustness. As a potential application, we integrate the strain sensors onto a glove to measure the motions of human fingers in real time. We further demonstrate a rosette-type gauge that can detect both the magnitude and direction of the principal strains with patterning accuracy and uniformity facilitated by the proposed sCTP technique.
A transparent and stretchable all‐graphene multifunctional electronic‐skin sensor matrix is developed. Three different functional sensors are included in this matrix: humidity, thermal, and pressure ...sensors. These are judiciously integrated into a layer‐by‐layer geometry through a simple lamination process.
Mitochondria are energy-generating organelles and mitochondrial biogenesis is stimulated to meet energy requirements in response to extracellular stimuli, including exercise. However, the mechanisms ...underlying mitochondrial biogenesis remain unknown. Here, we demonstrate that transcriptional coactivator with PDZ-binding motif (TAZ) stimulates mitochondrial biogenesis in skeletal muscle. In muscle-specific TAZ-knockout (mKO) mice, mitochondrial biogenesis, respiratory metabolism, and exercise ability were decreased compared to wild-type mice. Mechanistically, TAZ stimulates the translation of mitochondrial transcription factor A via Ras homolog enriched in brain (Rheb)/Rheb like 1 (Rhebl1)-mTOR axis. TAZ stimulates Rhebl1 expression via TEA domain family transcription factor. Rhebl1 introduction by adeno-associated virus or mTOR activation recovered mitochondrial biogenesis in mKO muscle. Physiologically, mKO mice did not stimulate exercise-induced mitochondrial biogenesis. Collectively, our results suggested that TAZ is a novel stimulator for mitochondrial biogenesis and exercise-induced muscle adaptation.
Degradation of the extracellular matrix (ECM), a critical step in cancer metastasis, is determined by the balance between MMPs (matrix metalloproteinases) and their inhibitors TIMPs (tissue ...inhibitors of metalloproteinases). In cancer cells, this balance is shifted towards MMPs, promoting ECM degradation. Here, we show that EZH2 plays an active role in this process by repressing the expression of TIMP2 and TIMP3 in prostate cancer cells. The TIMP genes are derepressed by knockdown of EZH2 expression in human prostate cancer cells but repressed by overexpression of EZH2 in benign human prostate epithelial cells. EZH2 catalyzes H3K27 trimethylation and subsequent DNA methylation of the TIMP gene promoters. Overexpression of EZH2 confers an invasive phenotype on benign prostate epithelial cells; however, this phenotype is suppressed by cooverexpression of TIMP3. EZH2 knockdown markedly reduces the proteolytic activity of MMP-9, thereby decreasing the invasive activity of prostate cancer cells. These results suggest that the transcriptional repression of the TIMP genes by EZH2 may be a major mechanism to shift the MMPs/TIMPs balance in favor of MMP activity and thus to promote ECM degradation and subsequent invasion of prostate cancer cells.
Organic–inorganic hybrid perovskite light‐emitting diodes (PeLEDs) are promising for next‐generation optoelectronic devices due to their potential to achieve high color purity, efficiency, and ...brightness. Although the external quantum efficiency (EQE) of PeLEDs has recently surpassed 20%, various strategies are being pursued to increase EQE further and reduce the EQE gap compared to other LED technologies. A key point to further boost EQE of PeLEDs is linked to the high refractive index of the perovskite emissive layer, leading to optical losses of more than 70% of emitted photons. Here, it is demonstrated that a randomly distributed nanohole array with high‐index contrast can effectively enhance outcoupling efficiency in PeLEDs. Based on a comprehensive optical analysis on the perovskite thin film and outcoupling structure, it is confirmed that the nanohole array effectively distributes light into the substrate for improved outcoupling, allowing for 1.64 times higher light extraction. As a result, highly efficient red/near‐infrared PeLEDs with a peak EQE of 14.6% are demonstrated.
A highly efficient red/near‐infrared perovskite light‐emitting diode (PeLED) with a peak external quantum efficiency of 14.6% is demonstrated using a randomly distributed nanohole array (NHA) with high‐index contrast. The NHA properly compensates the disadvantage of high refractive index of the perovskite emissive layer without altering the PeLED structure, allowing for a 1.64‐times enhanced outcoupling.
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