An Ultrasensitive Ti3 C2 Tx MXene-based Soft Contact Lens for Continuous and Nondestructive Intraocular Pressure Monitoring.

Wearable soft contact lens sensors for continuous and nondestructive intraocular pressure (IOP) monitoring are highly desired as glaucoma and postoperative myopia patients grow, especially as the eyestrain crowd increases. Herein, a smart closed-loop system is presented that combines a Ti3 C2 Tx MXene-based soft contact lens (MX-CLS) sensor, wireless data transmission units, display, and warning components to realize continuous and nondestructive IOP monitoring/real-time display. The fabricated MX-CLS device exhibits an extremely high sensitivity of 7.483 mV mmHg-1 , good linearity on silicone eyeballs, excellent stability under long-term pressure-release measurement, sufficient transparency with 67.8% transmittance under visible illumination, and superior biocompatibility with no discomfort when putting the MX-CLS sensor onto the Rabbit eyes. After integrating with the wireless module, users can realize real-time monitoring and warning of IOP via smartphones, the demonstrated MX-CLS device together with the IOP monitoring/display system opens up promising platforms for Ti3 C2 Tx materials as the base for multifunctional contact lens-based sensors and continuous and nondestructive IOP measurement system.

The Synergistic Effect on the Mimetic Optical Structure of Feline Eyes toward Household Health Monitoring of Acute and Chronic Diseases.

A breakthrough in the performance of bionic optical structures will only be achieved if we can obtain an in-depth understanding of the synergy mechanisms operating in natural optical structures and find ways to imitate them. In this work, inspired by feline eyes, an optical substrate that takes advantage of a synergistic effect that occurs between resonant and reflective structures was designed. The synergistic effect between the reflective and resonant components leads to a Raman enhancement factor (EF) of 1.16 × 107, which is much greater than that achieved using the reflective/resonant cavities on their own. Finite-difference time-domain (FDTD) simulations and experimental results together confirm that the mechanism of this synergistic effect is achieved by realizing multiple reflections and repeated absorptions of light, generating a strong local electric field. Thus, a 2-3 order of magnitude increase in sensitivity could be achieved. More importantly, with the homemade centrifugal device, above optical substrates were further used to develop a rapidly highly sensitive household health monitoring system (detection time <3 min). It can thus be used to give early warning of acute diseases with high risk (e.g., acute myocardial infarction (AMI) and cerebral peduncle). Due to the good reusability and storability (9% and 8% reduction in EF after washing 30 times and 9 months of storage, respectively) of the substrates, the substrates thus reduce detection costs (to ∼$1), making them much cheaper to use than the current gold-standard methods (e.g., ∼$16 for gout detection).

Hypothalamic warm-sensitive neurons require TRPC4 channel for detecting internal warmth and regulating body temperature in mice.

Precise monitoring of internal temperature is vital for thermal homeostasis in mammals. For decades, warm-sensitive neurons (WSNs) within the preoptic area (POA) were thought to sense internal warmth, using this information as feedback to regulate body temperature (Tcore). However, the cellular and molecular mechanisms by which WSNs measure temperature remain largely undefined. Via a pilot genetic screen, we found that silencing the TRPC4 channel in mice substantially attenuated hypothermia induced by light-mediated heating of the POA. Loss-of-function studies of TRPC4 confirmed its role in warm sensing in GABAergic WSNs, causing additional defects in basal temperature setting, warm defense, and fever responses. Furthermore, TRPC4 antagonists and agonists bidirectionally regulated Tcore. Thus, our data indicate that TRPC4 is essential for sensing internal warmth and that TRPC4-expressing GABAergic WSNs function as a novel cellular sensor for preventing Tcore from exceeding set-point temperatures. TRPC4 may represent a potential therapeutic target for managing Tcore.

CD169+ subcapsular sinus macrophage-derived microvesicles are associated with light zone follicular dendritic cells.

Follicular dendritic cells (FDCs) are a specialized type of stromal cells that exclusively reside in B-cell follicles. When inflammation occurs, the FDC network is reorganized to support germinal center (GC) polarization into the light zone (LZ) and dark zone (DZ). Despite the indispensable role of FDCs in supporting humoral responses, the FDC regulatory requirements remain incompletely defined. In this study, we unexpectedly observed an accumulation of CD169+ subcapsular sinus macrophage (SSM)-derived microvesicles (MVs) in the B-cell zone, which were tightly associated with the FDC network. Interestingly, a selective deposition of CD169+ MVs was detected in both GC LZ FDCs in secondary follicles and on predetermined LZ FDCs in primary follicles. The ablation of CD169+ MVs, resulting from SSM depletion, resulted in significantly decreased expression of LZ-related genes in FDCs. In addition, we found that CD169+ MVs could colocalize with fluorescently tagged antigen-containing immune complexes (ICs), supporting a possible role of CD169+ MVs in transporting antigens to the FDC network. Thus, our data reveal intimate crosstalk between FDCs and SSMs located outside B-cell follicles via SSM-released MVs, providing a novel perspective on the mechanisms underlying the regulation of FDC maturation and polarization.

Distributed implantation of a flexible microelectrode array for neural recording.

Flexible multichannel electrode arrays (fMEAs) with multiple filaments can be flexibly implanted in various patterns. It is necessary to develop a method for implanting the fMEA in different locations and at various depths based on the recording demands. This study proposed a strategy for reducing the microelectrode volume with integrated packaging. An implantation system was developed specifically for semiautomatic distributed implantation. The feasibility and convenience of the fMEA and implantation platform were verified in rodents. The acute and chronic recording results provied the effectiveness of the packaging and implantation methods. These methods could provide a novel strategy for developing fMEAs with more filaments and recording sites to measure functional interactions across multiple brain regions.

Investigation of a Highly Sensitive Surface-Enhanced Raman Scattering Substrate Formed by a Three-Dimensional/Two-Dimensional Graphene/Germanium Heterostructure.

Three-dimensional graphene (3D-graphene) is used in surface-enhanced Raman spectroscopy (SERS) because of its plasmonic nanoresonator structure and good ability to interact with light. However, a thin (3-5 nm) layer of amorphous carbon (AC) inevitably appears as a template layer between the 3D-graphene and object substrate when the 3D-graphene layer is synthesized, weakening the enhancement factor. Herein, two-dimensional graphene (2D-graphene) is employed as a template layer to directly synthesize 3D-graphene on a germanium (Ge) substrate via plasma-assisted chemical vapor deposition, bypassing the formation of an AC layer. The interaction and photoinduced charge transfer ability of the 3D-graphene/Ge heterojunction with incident light are improved. Moreover, the high density of electronic states close to the Fermi level of the heterojunction induces the adsorbed probe molecules to efficiently couple to the 3D-graphene-based SERS substrate. Our experimental results imply that the lowest concentrations of rhodamine 6G and rhodamine B that can be detected on the 3D/2D-graphene/Ge SERS substrate correspond to 10-10 M; for methylene blue, it is 10-8 M. The detection limits of the 3D/2D-graphene/Ge SERS substrate with respect to 3-hydroxytyramine hydrochloride and melamine (in milk) are both less than 1 ppm. This work may provide a viable and convenient alternative method for preparing 3D-graphene SERS substrates. It also constitutes a new approach to developing SERS substrates with remarkable performance levels.

A functional motif of long noncoding RNA Nron against osteoporosis.

Long noncoding RNAs are widely implicated in diverse disease processes. Nonetheless, their regulatory roles in bone resorption are undefined. Here, we identify lncRNA Nron as a critical suppressor of bone resorption. We demonstrate that osteoclastic Nron knockout mice exhibit an osteopenia phenotype with elevated bone resorption activity. Conversely, osteoclastic Nron transgenic mice exhibit lower bone resorption and higher bone mass. Furthermore, the pharmacological overexpression of Nron inhibits bone resorption, while caused apparent side effects in mice. To minimize the side effects, we further identify a functional motif of Nron. The delivery of Nron functional motif to osteoclasts effectively reverses bone loss without obvious side effects. Mechanistically, the functional motif of Nron interacts with E3 ubiquitin ligase CUL4B to regulate ERα stability. These results indicate that Nron is a key bone resorption suppressor, and the lncRNA functional motif could potentially be utilized to treat diseases with less risk of side effects.

Sensitive, Reusable, Surface-Enhanced Raman Scattering Sensors Constructed with a 3D Graphene/Si Hybrid.

Surface-enhanced Raman scattering (SERS) substrates based on graphene and its derivatives have recently attracted attention among those interested in the detection of trace molecules; however, these substrates generally show poor uniformity, an unsatisfactory enhancement factor, and require a complex fabrication process. Herein, we design and fabricate three-dimensional (3D) graphene/silicon (3D-Gr/Si) heterojunction SERS substrates to detect various types of molecules. Notably, the detection limit of 3D-Gr/Si can reach 10-10 M for rhodamine 6G (R6G) and rhodamine B (RB), 10-7 M for crystal violet (CRV), copper(II) phthalocyanine (CuPc), and methylene blue (MB), 10-8 M for dopamine (DA), 10-6 M for bovine serum albumin (BSA), and 10-5 M for melamine (Mel), which is superior to most reported graphene-based SERS substrates. Besides, the proposed 3D-Gr/Si heterojunction SERS substrates can achieve a high uniformity with relative standard deviations (RSDs) of less than 5%. Moreover, the 3D-Gr/Si SERS substrates are reusable after washing with ethyl alcohol to remove the adsorbed molecules. These excellent SERS performances are attributed to the novel 3D structure and abundantly exposed atomically thin edges, which facilitate charge transfer between 3D-Gr and probe molecules. We believe that the 3D-Gr/Si heterojunction SERS substrates offer potential for practical applications in biochemical molecule detection and provide insight into the design of high-performance SERS substrates.

MAP3K2-regulated intestinal stromal cells define a distinct stem cell niche.

Intestinal stromal cells are known to modulate the propagation and differentiation of intestinal stem cells1,2. However, the precise cellular and molecular mechanisms by which this diverse stromal cell population maintains tissue homeostasis and repair are poorly understood. Here we describe a subset of intestinal stromal cells, named MAP3K2-regulated intestinal stromal cells (MRISCs), and show that they are the primary cellular source of the WNT agonist R-spondin 1 following intestinal injury in mice. MRISCs, which are epigenetically and transcriptomically distinct from subsets of intestinal stromal cells that have previously been reported3-6, are strategically localized at the bases of colon crypts, and function to maintain LGR5+ intestinal stem cells and protect against acute intestinal damage through enhanced R-spondin 1 production. Mechanistically, this MAP3K2 specific function is mediated by a previously unknown reactive oxygen species (ROS)-MAP3K2-ERK5-KLF2 axis to enhance production of R-spondin 1. Our results identify MRISCs as a key component of an intestinal stem cell niche that specifically depends on MAP3K2 to augment WNT signalling for the regeneration of damaged intestine.

SIRT3-mediated deacetylation of NLRC4 promotes inflammasome activation.

Salmonella typhimurium (S. typhimurium) infection of macrophage induces NLRC4 inflammasome-mediated production of the pro-inflammatory cytokines IL-1ß. Post-translational modifications on NLRC4 are critical for its activation. Sirtuin3 (SIRT3) is the most thoroughly studied mitochondrial nicotinamide adenine dinucleotide (NAD+) -dependent deacetylase. We wondered whether SIRT3 mediated-deacetylation could take part in NLRC4 inflammasome activation. Methods: We initially tested IL-1ß production and pyroptosis after cytosolic transfection of flagellin or S. typhimurium infection in wild type and SIRT3-deficient primary peritoneal macrophages via immunoblotting and ELISA assay. These results were confirmed in SIRT3-deficient immortalized bone marrow derived macrophages (iBMDMs) which were generated by CRISPR-Cas9 technology. In addition, in vivo experiments were conducted to confirm the role of SIRT3 in S. typhimurium-induced cytokines production. Then NLRC4 assembly was analyzed by immune-fluorescence assay and ASC oligomerization assay. Immunoblotting, ELISA and flow cytometry were performed to clarify the role of SIRT3 in NLRP3 and AIM2 inflammasomes activation. To further investigate the mechanism of SIRT3 in NLRC4 activation, co-immunoprecipitation (Co-IP), we did immunoblot, cellular fractionation and in-vitro deacetylation assay. Finally, to clarify the acetylation sites of NLRC4, we performed liquid chromatography-mass spectrometry (LC-MS) and immunoblotting analysis. Results: SIRT3 deficiency led to significantly impaired NLRC4 inflammasome activation and pyroptosis both in vitro and in vivo. Furthermore, SIRT3 promotes NLRC4 inflammasome assembly by inducing more ASC speck formation and ASC oligomerization. However, SIRT3 is dispensable for NLRP3 and AIM2 inflammasome activation. Moreover, SIRT3 interacts with and deacetylates NLRC4 to promote its activation. Finally, we proved that deacetylation of NLRC4 at Lys71 or Lys272 could promote its activation. Conclusions: Our study reveals that SIRT3 mediated-deacetylation of NLRC4 is pivotal for NLRC4 activation and the acetylation switch of NLRC4 may aid the clearance of S. typhimurium infection.

Wearable Contact Lens Sensor for Non-invasive Continuous Monitoring of Intraocular Pressure.

Intraocular pressure (IOP) is an essential indicator of the diagnosis and treatment of glaucoma. IOP has an apparent physiological rhythm, and it often reaches its peak value at night. To avoid missing the peak value at night and sample the entire rhythm cycle, the continuous monitoring of IOP is urgently needed. A wearable contact lens IOP sensor based on a platinum (Pt) strain gauge is fabricated by the micro-electro-mechanical (MEMS) process. The structure and parameters of the strain gauge are optimized to improve the sensitivity and temperature stability. Tests on an eyeball model indicate that the IOP sensor has a high sensitivity of 289.5 µV/mmHg and excellent dynamic cycling performance at different speeds of IOP variation. The temperature drift coefficient of the sensor is 33.4 µV/°C. The non-invasive IOP sensor proposed in this report exhibits high sensitivity and satisfactory stability, promising a potential in continuous IOP monitoring.

Application of graphene nanowalls in an intraocular pressure sensor.

As the second leading cause of blindness in the world, glaucoma is mainly caused by persistent high intraocular pressure (IOP) that compresses the optic nerve and causes permanent damage. Noninvasive continuous monitoring of IOP is an essential method for the diagnosis and treatment of glaucoma. In this paper, we propose a new strain gauge material based on graphene nanowalls (GNWs) for continuous monitoring of IOP with high sensitivity in a wide range. By simulation, we studied the relationship between the strain of the cornea and contact lens and IOP. The structure and the location of the GNWs in the contact lens are optimized. A method for transferring GNWs on contact lenses with the assistance of a gold film is proposed. The simulated tests on porcine eyes in vitro show that the resistance response of the device to normal IOP fluctuation reaches 1.014 kΩ mmHg-1. Its normal sensitivity of 42 250 ppm mmHg-1 and the response range of 0-75 mmHg are far more than those of most noninvasive methods reported before. This study shows the enormous potential of GNWs for continuous IOP monitoring with high sensitivity and low power consumption.

Author Correction: Requirement for the basic helix-loop-helix transcription factor Dec2 in initial TH2 lineage commitment.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Interface Engineering-Assisted 3D-Graphene/Germanium Heterojunction for High-Performance Photodetectors.

Three-dimensional graphene (3D-Gr) with excellent light absorption properties has received enormous interest, but in conventional processes to prepare 3D-Gr, amorphous carbon layers are inevitably introduced as buffer layers that may degrade the performance of graphene-based devices. Herein, 3D-Gr is prepared on germanium (Ge) using two-dimensional graphene (2D-Gr) as the buffer layer. 2D-Gr as the buffer layer facilitates the in situ synthesis of 3D-Gr on Ge by plasma-enhanced chemical vapor deposition (PECVD) by promoting 2D-Gr nucleation and reducing the barrier height. The growth mechanism is investigated and described. The enhanced light absorption as confirmed by theoretical calculation and 3D-Gr/2D-Gr/Ge with a Schottky junction improves the performance of optoelectronic devices without requiring pre- and post-transfer processes. The photodetector constructed with 3D-Gr/2D-Gr/Ge shows an excellent responsivity of 1.7 A W-1 and detectivity 3.42 × 1014 cm Hz1/2 W-1 at a wavelength of 1550 nm. This novel hybrid structure that incorporates 3D- and 2D-Gr into Ge-based integrated circuits and photodetectors delivers excellent performance and has large commercial potential.

Polarizing Graphene Quantum Dots toward Long-Acting Intracellular Reactive Oxygen Species Evaluation and Tumor Detection.

The evaluation of intracellular reactive oxygen species (ROS) would greatly deepen the understanding of cell metabolism/proliferation and tumor detection. However, current long-acting level tracking techniques for intracellular ROS remain unsuited to practical applications. To solve this problem, we synthesized cyclotriphosphazene-doped graphene quantum dots (C-GQDs) whose quantum yield is highly sensitive to ROS (increased by 400% from 0.12 to 0.63). Electron cloud polarization of oxidized cyclotriphosphazene rings in C-GQDs is confirmed to account for this novel optical property by density functional theory calculations and experimental results. In combination with excellent biological stability, C-GQDs achieve a long-acting evaluation of intracellular ROS level (more than 72 h) with an accuracy of 98.3%. In addition, recognition rates exceeding 90% are demonstrated to be feasible for eight kinds of tumor cell lines cultured with C-GQDs, which can also be expanded to in vivo detection. C-GQDs also show a high recognition rate (82.33%) and sensitivity (79.65%) for tumor cells in blood samples.

PLK4 deubiquitination by Spata2-CYLD suppresses NEK7-mediated NLRP3 inflammasome activation at the centrosome.

The innate immune sensor NLRP3 assembles an inflammasome complex with NEK7 and ASC to activate caspase-1 and drive the maturation of proinflammatory cytokines IL-1ß and IL-18. NLRP3 inflammasome activity must be tightly controlled, as its over-activation is involved in the pathogenesis of inflammatory diseases. Here, we show that NLRP3 inflammasome activation is suppressed by a centrosomal protein Spata2. Spata2 deficiency enhances NLRP3 inflammasome activity both in the macrophages and in an animal model of peritonitis. Mechanistically, Spata2 recruits the deubiquitinase CYLD to the centrosome for deubiquitination of polo-like kinase 4 (PLK4), the master regulator of centrosome duplication. Deubiquitination of PLK4 facilitates its binding to and phosphorylation of NEK7 at Ser204. NEK7 phosphorylation in turn attenuates NEK7 and NLRP3 interaction, which is required for NLRP3 inflammasome activation. Pharmacological or shRNA-mediated inhibition of PLK4, or mutation of the NEK7 Ser204 phosphorylation site, augments NEK7 interaction with NLRP3 and causes increased NLRP3 inflammasome activation. Our study unravels a novel centrosomal regulatory pathway of inflammasome activation and may provide new therapeutic targets for the treatment of NLRP3-associated inflammatory diseases.

Cotton Candy-Templated Fabrication of Three-Dimensional Ceramic Pathway within Polymer Composite for Enhanced Thermal Conductivity.

With the minimization and higher power of electronic devices, materials with effective heat dissipation and high electrical insulation have attracted relentless interest. Especially, highly thermally conductive, highly electrically insulating but low filler content of polymer-based composites are desirable. Herein, a facile and eco-friendly cotton candy-templated method (CTM) to construct three-dimensional heat transport pathways inside epoxy resin is reported. The fabricated Al2O3/epoxy composites with enhanced heat transport capability feature a 15-fold increase in thermal conductivity at a filler content of 36.2 vol % compared to pristine epoxy. Moreover, the remarkable thermal conductive property has excellent stability over a wide range of temperature before and after heating and cooling cycles. Meanwhile, the CTM composite still retain highly electrical insulation. The cotton candy-templated method proposed in this work is a new avenue for the preparation of three-dimensional heat transport pathways within polymer-based composites for microelectronic packaging and electrical engineering systems.

Fate Mapping via Ms4a3-Expression History Traces Monocyte-Derived Cells.

Most tissue-resident macrophage (RTM) populations are seeded by waves of embryonic hematopoiesis and are self-maintained independently of a bone marrow contribution during adulthood. A proportion of RTMs, however, is constantly replaced by blood monocytes, and their functions compared to embryonic RTMs remain unclear. The kinetics and extent of the contribution of circulating monocytes to RTM replacement during homeostasis, inflammation, and disease are highly debated. Here, we identified Ms4a3 as a specific gene expressed by granulocyte-monocyte progenitors (GMPs) and subsequently generated Ms4a3TdT reporter, Ms4a3Cre, and Ms4a3CreERT2 fate-mapping models. These models traced efficiently monocytes and granulocytes, but no lymphocytes or tissue dendritic cells. Using these models, we precisely quantified the contribution of monocytes to the RTM pool during homeostasis and inflammation. The unambiguous identification of monocyte-derived cells will permit future studies of their function under any condition.

Graphene foam-embedded epoxy composites with significant thermal conductivity enhancement.

High thermal conductivity polymer composites at low filler loading are of considerable interest because of their wide range of applications. The construction of three-dimensional (3D) interconnected networks can offer a high-efficiency increase for the thermal conductivity of polymer composites. In this work, a facile and scalable method to prepare graphene foam (GF) via sacrificial commercial polyurethane (PU) sponge templates was developed. Highly thermally conductive composites were then prepared by impregnating epoxy resin into the GF structure. An ultrahigh thermal conductivity of 8.04 W m-1 K-1 was obtained at a low graphene loading of 6.8 wt%, which corresponds to a thermal conductivity enhancement of about 4473% compared to neat epoxy. This strategy provides a facile, low-cost and scalable method to construct a 3D filler network for high-performance composites with potential to be used in advanced electronic packaging.

Promising Fast Energy Transfer System Between Graphene Quantum Dots and the Application in Fluorescent Bioimaging.

Tunable photoluminescence performance of graphene quantum dots (GQDs) is one of the most important topics for the development of GQDs. In this paper, we report lattice-doped GQDs (boron-doped GQDs (B-GQDs) and phosphorus-doped GQDs (P-GQDs)). Because of the matched band structure, the fast energy transfer between blue-emitted B-GQDs (emission wavelength: 460 nm) and orange-emitted P-GQDs (emission wavelength: 630 nm) can induce an efficient fluorescence emission in P-GQDs once B-GQDs are excited under the optimal excitation wavelength of 460 nm. Moreover, with the effective energy transfer, the quantum yield of P-GQDs increased to 0.48, which is much higher than that of pure P-GQDs. We also demonstrated the potentials of this system for fluorescent bioimaging in vitro.