Large-scale Prospective Validation Study of a Multiplex RNA Urine Test for Noninvasive Detection of Upper Tract Urothelial Carcinoma.

BACKGROUND: Current approaches for diagnosis and monitoring of upper tract urothelial carcinoma (UTUC) are often invasive, costly, and not efficient for early-stage and low-grade tumors. OBJECTIVE: To validate a noninvasive urine-based RNA test for accurate UTUC diagnosis. DESIGN, SETTING, AND PARTICIPANTS: Urine samples were prospectively collected from 61 patients with UTUC and 99 controls without urothelial carcinomas, in five clinical centers between October 2022 and August 2023 prior to any invasive test (cystoscope or ureteroscope) or treatment. All samples were analyzed with a urine-based RNA test composed of eight genes (CA9, CCL18, ERBB2, IGF2, MMP12, PPP1R14D, SGK2, and SWINGN). The test results were presented with a risk score for each participant, which was applied to categorize patients into low- or high-risk groups. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The diagnosis of UTUC was based mainly on preoperative radiological examination criteria and confirmed by postoperative pathological results. The recursive feature elimination and support vector machine algorithms, χ2, and Student t test were used. RESULTS AND LIMITATIONS: The eight-gene urine test accurately detected UTUC patients and controls with an area under the curve (AUC) of 0.901 in a single-center testing cohort (n = 93) and an AUC of 0.926 in a multicenter clinical validation cohort (n = 66). In the merged validation cohort, the eight-gene urine test achieved high sensitivity of 90.16%, specificity of 88.89%, and overall accuracy of 89.38%. Remarkably, excellent performance was achieved in 11 low-grade UTUC patients with accuracy of 100%. However, this study collected the urine of UTUC patients only at a single preoperative time point and did not perform continuous tests during the pathological process of UTUC in the surveillance population. CONCLUSIONS: Our results demonstrated that the eight-gene urine test can differentiate accurately between UTUC and other urological diseases with high sensitivity and specificity. In clinical practice, it may be used for identifying UTUC patients effectively, leading to reduced reliance on ureteroscopy and blind surgery. PATIENT SUMMARY: In this study, we investigated a multiplex RNA urine test for noninvasive upper tract urothelial carcinoma (UTUC) diagnosis before treatment. We found that the risk scores derived from the multiplex RNA urine test differed significantly between UTUC patients and corresponding controls.

Comprehensive molecular and cellular characterization of endoplasmic reticulum stress-related key genes in renal ischemia/reperfusion injury.

Background: Renal ischemia-reperfusion injury (RIRI) is an inevitable complication in the process of kidney transplantation and lacks specific therapy. The study aims to determine the underlying mechanisms of RIRI to uncover a promising target for efficient renoprotection. Method: Four bulk RNA-seq datasets including 495 renal samples of pre- and post-reperfusion were collected from the GEO database. The machine learning algorithms were utilized to ascertain pivotal endoplasmic reticulum stress genes. Then, we incorporated correlation analysis and determined the interaction pathways of these key genes. Considering the heterogeneous nature of bulk-RNA analysis, the single-cell RNA-seq analysis was performed to investigate the mechanisms of key genes at the single-cell level. Besides, 4-PBA was applied to inhibit endoplasmic reticulum stress and hence validate the pathological role of these key genes in RIRI. Finally, three clinical datasets with transcriptomic profiles were used to assess the prognostic role of these key genes in renal allograft outcomes after RIRI. Results: In the bulk-RNA analysis, endoplasmic reticulum stress was identified as the top enriched pathway and three endoplasmic reticulum stress-related genes (PPP1R15A, JUN, and ATF3) were ranked as top performers in both LASSO and Boruta analyses. The three genes were found to significantly interact with kidney injury-related pathways, including apoptosis, inflammatory response, oxidative stress, and pyroptosis. For oxidative stress, these genes were more strongly related to oxidative markers compared with antioxidant markers. In single-cell transcriptome, the three genes were primarily upregulated in endothelium, distal convoluted tubule cells, and collecting duct principal cells among 12 cell types of renal tissues in RIRI. Furthermore, distal convoluted tubule cells and collecting duct principal cells exhibited pro-inflammatory status and the highest pyroptosis levels, suggesting their potential as main effectors of three key genes for mediating RIRI-associated injuries. Importantly, inhibition of these key genes using 4-phenyl butyric acid alleviated functional and histological damage in a mouse RIRI model. Finally, the three genes demonstrated highly prognostic value in predicting graft survival outcomes. Conclusion: The study identified three key endoplasmic reticulum stress-related genes and demonstrated their prognostic value for graft survival, providing references for individualized clinical prevention and treatment of postoperative complications after renal transplantation.

Pseudo-transistors for emerging neuromorphic electronics.

Artificial synaptic devices are the cornerstone of neuromorphic electronics. The development of new artificial synaptic devices and the simulation of biological synaptic computational functions are important tasks in the field of neuromorphic electronics. Although two-terminal memristors and three-terminal synaptic transistors have exhibited significant capabilities in the artificial synapse, more stable devices and simpler integration are needed in practical applications. Combining the configuration advantages of memristors and transistors, a novel pseudo-transistor is proposed. Here, recent advances in the development of pseudo-transistor-based neuromorphic electronics in recent years are reviewed. The working mechanisms, device structures and materials of three typical pseudo-transistors, including tunneling random access memory (TRAM), memflash and memtransistor, are comprehensively discussed. Finally, the future development and challenges in this field are emphasized.

TIPE2 deletion improves the therapeutic potential of adoptively transferred NK cells.

BACKGROUND: To enhance the efficacy of adoptive NK cell therapy against solid tumors, NK cells must be modified to resist exhaustion in the tumor microenvironment (TME). However, the molecular checkpoint underlying NK cell exhaustion in the TME remains elusive. METHODS: We analyzed the correlation between TIPE2 expression and NK cell functional exhaustion in the TME both in humans and mice by single-cell transcriptomic analysis and by using gene reporter mice. We investigated the effects of TIPE2 deletion on adoptively transferred NK cell therapy against cancers by using NK cells from NK-specific Tipe2-deficient mice or peripheral blood-derived or induced pluripotent stem cell (iPSC)-derived human NK cells with TIPE2 deletion by CRISPR/Cas9. We also investigated the potential synergy of double deletion of TIPE2 and another checkpoint molecule, CISH. RESULTS: By single-cell transcriptomic analysis and by using gene reporter mice, we found that TIPE2 expression correlated with NK cell exhaustion in the TME both in humans and mice and that the TIPE2 high NK cell subset correlated with poorer survival of tumor patients. TIPE2 deletion promoted the antitumor activity of adoptively transferred mouse NK cells and adoptively transferred human NK cells, either derived from peripheral blood or differentiated from iPSCs. TIPE2 deletion rendered NK cells with elevated capacities for tumor infiltration and effector functions. TIPE2 deletion also synergized with CISH deletion to further improve antitumor activity in vivo. CONCLUSIONS: This study highlighted TIPE2 targeting as a promising approach for enhancing adoptive NK cell therapy against solid tumors.

Checkpoint TIPE2 Limits the Helper Functions of NK Cells in Supporting Antitumor CD8+ T Cells.

Natural killer (NK) cells not only are innate effector lymphocytes that directly participate in tumor surveillance but are also essential helpers in the antitumor CD8+ T-cell response. However, the molecular mechanisms and potential checkpoints regulating NK cell helper functions remain elusive. Here, it is shown that the T-bet/Eomes-IFN-γ axis in NK cells is essential for CD8+ T cell-dependent tumor control, whereas T-bet-dependent NK cell effector functions are required for an optimal response to anti-PD-L1 immunotherapy. Importantly, NK cell-expressed TIPE2 (tumor necrosis factor-alpha-induced protein-8 like-2) represents a checkpoint molecule for NK cell helper function, since Tipe2 deletion in NK cells not only enhances NK-intrinsic antitumor activity but also indirectly improves the antitumor CD8+ T cell response by promoting T-bet/Eomes-dependent NK cell effector functions. These studies thus reveal TIPE2 as a checkpoint for NK cell helper function, whose targeting might boost the antitumor T cell response in addition to T cell-based immunotherapy.

Flexible Floating-Gate Electric-Double-Layer Organic Transistor for Neuromorphic Computing.

The key to the study of flexible neuromorphic computing is the excellent weight update characteristic of neuromorphic devices. Electric-double-layer transistors (EDLTs) include high transconductance, excellent stability of threshold voltage, linear weight updates, and repetitive ion-concentration-dependent switching properties. However, up to now, there is no report on a flexible EDLT that provides all the aforementioned performance characteristics. Here, a planar flexible floating-gate EDLT including an excellent linear/symmetric weight update, a large number (>800) of conductance states, repetitive switching endurance (>100 cycles), and low variation in weight update is reported. After 800 signal stimulations, it is found that the nonlinearity values of LTP are between 0.20 and 0.85, those of LTD fall between 0.66 and 1.55, the symmetricity values are between 120.7 and 639.8, and the dynamic range is between 150 and 352 nS. The study of 8 × 8 flexible floating-gate EDLT arrays shows that the average deviation and standard deviation between the experimental and theoretical values are 1.36 and 1.93, respectively, indicating that the conductance regulation in the array has a relatively small deviation. The different bending angles and the mechanical stability of the floating-gate EDLT are also studied, which exhibit the excellent bending properties. Furthermore, we studied the recognition of MNIST handwritten digit images by a three-layer perceptron artificial neural network with the experimental weight update, and the maximal recognition accuracy is up to 87.8%.

Integrated Piezoresistive Normal Force Sensors Fabricated Using Transfer Processes with Stiction Effect Temporary Handling.

Tactile sensation is a highly desired function in robotics. Furthermore, tactile sensor arrays are crucial sensing elements in pulse diagnosis instruments. This paper presents the fabrication of an integrated piezoresistive normal force sensor through surface micromachining. The force sensor is transferred to a readout circuit chip via a temporary stiction effect handling process. The readout circuit chip comprises two complementary metal-oxide semiconductor operational amplifiers, which are redistributed to form an instrumentation amplifier. The sensor is released and temporarily bonded to the substrate before the transfer process due to the stiction effect to avoid the damage and movement of the diaphragm during subsequent flip-chip bonding. The released sensor is pulled off from the substrate and transferred to the readout circuit chip after being bonded to the readout circuit chip. The size of the transferred normal force sensor is 180 µm × 180 µm × 1.2 µm. The maximum misalignment of the flip-chip bonding process is approximately 1.5 µm, and sensitivity is 93.5 µV/µN/V. The routing of the piezoresistive Wheatstone bridge can be modified to develop shear force sensors; consequently, this technique can be used to develop tactile sensors that can sense both normal and shear forces.

Rapid Increase in China's Industrial Ammonia Emissions: Evidence from Unit-Based Mapping.

Ammonia (NH3) is an important precursor of secondary inorganic aerosols and greatly impacts nitrogen deposition and acid rain. Previous studies have mainly focused on the agricultural NH3 emissions, while recent research has noted that industrial sources could be significant in China. However, detailed estimates of NH3 emitted from industrial sectors in China are lacking. Here, we established an unprecedented high-spatial-resolution data set of China's industrial NH3 emissions using up-to-date measurements of NH3 and point source-level information covering eight major industries and 27 subdivided process categories. We found that China emitted 798 (90% confidence interval: 668-933) gigagrams of industrial NH3 into the atmosphere in 2019, equivalent to 44 ± 20% of the industrial emissions worldwide; this flux is 3-fold larger than that in 1998 and has fluctuated since 2014. Furthermore, although fertilizer production is responsible for approximately half of the emissions in China, the emissions from cement production and coal-fired power plants increased dramatically from near zero to 164 and 41 gigagrams, respectively, in the past two decades, primarily due to the NH3 escape caused by the large-scale application of the denitration process. Our results reveal that, unlike other major air pollutants, China's industrial NH3 emission control is still in a critical period, and stricter NH3 emission standards and innovation in pollution control technologies are highly desirable.

Transfer of Tactile Sensors Using Stiction Effect Temporary Handling.

A novel method for transfer of tactile sensors using stiction effect temporary handling (SETH) is presented to simplify the microelectromechanical-system (MEMS)/CMOS integration process, improve the process reliability and electrical performance, and reduce material constriction. The structure of the tactile sensor and the reroute substrate were first manufactured separately. Following the release process, the stiction-contact structures, which are designed to protect the low-stress silicon nitride diaphragm of the tactile sensor and prevent the low-stress silicon nitride diaphragm from moving during the subsequent bonding process, are temporarily bonded to the substrate owing to the stiction effect. After the released tactile sensor is bonded to the reroute substrate by Au-Si eutectic flip-chip bonding, a pulling force perpendicular to the bonded die is applied to break away the temporary supported beam of the tactile sensor, and the tactile sensor is then successfully transferred to the reroute substrate. The size of the transferred tactile sensor is as small as 180 µm × 180 µm × 1.2 µm, and the force area of the tactile sensor is only 120 µm × 120 µm × 1.2 µm. The maximum misalignment of the flip-chip bonding process is approximately 1.5 µm. The tactile sensors are tested from 0 to 17.1 kPa when the power supply is 5 V, resulting in a sensitivity of 0.22 mV/V/kPa, 0.26 mV/V/kPa, 0.27 mV/V/kPa and 0.27 mV/V/kPa, separately. The stress caused by the Au-Si eutectic flip-chip bonding ranges from -5.83 to +5.54 kPa. The temporary bonding strength caused by stiction is calculated to be larger than 7.06 kPa and less than 22.31 kPa. The shear strength of the bonded test structure is approximately 30.74 MPa and the yield of the transferred tactile sensors is as high as 90%.

TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity.

The maturation process of NK cells determines their functionality during which IL-15 plays a critical role. However, very few checkpoints specifically targeting this process have been discovered. Here, we report that TIPE2 expression gradually increased during NK cell ontogenesis correlating to their maturation stages in both mice and humans. NK-specific TIPE2 deficiency increased mature NK cells in mice, and these TIPE2-deficient NK cells exhibited enhanced activation, cytotoxicity, and IFN-γ production upon stimulation and enhanced response to IL-15 for maturation. Moreover, TIPE2 suppressed IL-15­triggered mTOR activity in both human and murine NK cells. Consequently, blocking mTOR constrained the effect of TIPE2 deficiency on NK cell maturation in response to IL-15. Last, NK-specific TIPE2-deficient mice were resistant to tumor growth in vivo. Our results uncover a potent checkpoint in NK cell maturation and antitumor immunity in both mice and humans, suggesting a promising approach of targeting TIPE2 for NK cell­based immunotherapies.

Cd0.8Mn0.2S/MoO3 composites with an S-scheme heterojunction for efficient photocatalytic hydrogen evolution.

High-performance and noble metal-free MoO3/Cd0.8Mn0.2S nanocomposites were synthesized via a simple direct physical mixing process. Consequently, from the many characterization methods, the obtained MoO3/Cd0.8Mn0.2S composites exhibited excellent photocatalytic hydrogen production performance and stability. The enhanced photocatalytic activity of the MoO3/Cd0.8Mn0.2S catalyst could be ascribed to the close contact interfaces and well-matched band structure of MoO3 and Mn0.8Cd0.2S, which is beneficial to the transport and separation of photonic excitons. Besides, the hydrogen production performance of the MoO3/Cd0.8Mn0.2S composite catalyst was 1.7 times higher than that of the pure MoO3. Based on the results of time-resolved fluorescence (TRPL) and electrochemical measurements, the possible S-scheme heterojunction mechanism of the photocatalytic hydrogen evolution of MoO3/Cd0.8Mn0.2S was proposed. This work has contributed to the transformation of solar energy into chemical energy.

Exogenous oxidative stress suppresses IL-33 -driven proliferation programming in group 2 innate lymphoid cells.

Although exogenous oxidative stress has been suggested to promote the pathogenesis of airway inflammation, previous trials using conventional antioxidant therapy in asthma have been largely ineffective, suggesting the complex roles of oxidative stress in the regulation of airway inflammation and of its critical mediating lymphocyte populations. Group 2 innate lymphoid cells (ILC2s) proliferate and induce eosinophilia in response to tissue alarminsin the early phase of airway inflammation. We previously showed that IL-33 -induced endogenous reactive oxygen species is required for optimal metabolic activation of ILC2 functions, however, the role of exogenous oxidative stress in regulating ILC2 functions has not been investigated. Here, we found that exogenous oxidative stress induced by injection of ROS -generating reagent alleviated IL-33 -triggered ILC2 response and inflammation both in the airway and in the liver. Exogenous oxidative stress in ILC2s also compromised IL-33 -mediated accumulation of these cells, as well as subsequent recruitment of eosinophils, after adoptive transferring into ILC2 deficient hosts. Mechanistically, exogenous oxidative stress in ILC2s compromised the proliferation program, while preserving the expression levels of effector molecules in ILC2s. Impaired proliferation under exogenous oxidative stress led to reduced numbers of ILC2s, and an overall decrease in ILC2 response to IL-33 stimulation. Collectively, these data indicate that exogenous oxidative stress suppresses the proliferation program in ILC2s and alleviates IL-33 -triggered inflammation, suggesting that therapeutic induction of oxidative stress might alleviate ILC2 -mediated inflammation in the airway, and possibly also in other organs.

Establishment of High-Resolution Atmospheric Mercury Emission Inventories for Chinese Cement Plants Based on the Mass Balance Method.

China is the world's largest cement-related mercury emitter. Atmospheric mercury inventories for China's cement industry are essential for appraising global mercury emissions and have been widely developed in previous studies associated with considerable uncertainties. In this study, we compiled high tempo-spatial resolution atmospheric mercury emission inventories for Chinese cement plants using the mass balance method and plant-level input-output data. The effects of industry policies were investigated based on the inventories for 2007 and 2015. Nationwide emissions increased from 80 to 113 t due to rapid expansion of production and kiln-type substitution yet partly offset by policies involving capacity structure reformation. Pollution decreased in winter in northern China, thanks to the targeting policies. Mercury input, output, and storage in cement kilns in China were estimated. The uncertainty remarkably decreased relative to previous inventories. This study demonstrates the feasibility of establishing high-resolution emission inventories with the application of the mass balance method for all the individual plants nationwide and thus has implications for similar studies. This work also improves our understanding of the spatial patterns and temporal evolution of mercury emissions in China, thus offering references for the implementation of environment policies and the Minamata Convention on Mercury in China.

1,8-Substituted Pyrene Derivatives for High-Performance Organic Field-Effect Transistors.

There have been many reports on the application of pyrene derivatives as organic semiconductors, but 1,8-subsituted pyrene semiconductors are less well-developed. Two p-type 1,8-substituted pyrene derivatives were synthesized that were composed of a pyrene core, thiophene or bithiophene arms, and end-capped octyl chains. These structures were not completely symmetrical and the dihedral angles between the pyrene core and the adjacent thiophene units had a difference of approximately two degrees. The field-effect performance of these materials was tested on a variety of dielectric surfaces. The performance of both materials with a spin-coated polystyrene layer on SiO2 (PS-treated SiO2 ) was better than that with an octadecyltrichlorosilane self-assembled monolayer on SiO2 (OTS-treated SiO2 ), which was mainly attributed to the presence of large grains on the low-leakage and high-capacitance PS films. The thiophene-contained compound presented a hole mobility of up to 0.18 cm2 V-1 s-1 on PS-treated SiO2 , which was 45 times that of the bithiophene-contained compound, owing to less steric hindrance, high crystallinity, and large grain size.

Impaired cytolytic activity of asthma-associated natural killer cells is linked to dysregulated transcriptional program in energy metabolism.

Natural killer (NK) cells are a cytotoxic subset of the innate lymphoid cells, playing essential roles in host defense against tumors and infections, which, however, are usually functionally compromised in chronic diseases. Atopic diseases, such as allergic asthma, characterized by type 2 immune responses, are usually associated with chronic inflammations. Whether asthma -associated immune environment affects the cytolytic function of NK cells has not been elucidated. Here, YTS, a human NK cell line, was exposed to serum from healthy donors or asthma patients for analysis of its cytolytic function. We found that, serum from asthma patients reduced the cytolytic activity of YTS cells against Raji human B lymphoblasts, in comparison with normal serum. The impairment of cytolytic activity of these YTS cells was accompanied with decreased degranulation potentials, weakened conjugation formation with Raji cells, and premature termination of ERK phosphorylation upon stimulation. Meanwhile, apoptosis or cell death of YTS cells was not increased after exposure to serum from asthma patients. Importantly, such impairment of cytolytic activity of asthma -associated YTS NK cells was accompanied with aberrantly enriched genes involved in oxidative phosphorylation. Taken together, these results demonstrate that the serum of asthma patients directly suppresses the cytolytic function of NK cells, possibly through dysregulation of energy metabolism in NK cells.

Charge-Storage Aromatic Amino Compounds for Nonvolatile Organic Transistor Memory Devices.

Here, charge-storage nonvolatile organic field-effect transistor (OFET) memory devices based on interfacial self-assembled molecules are proposed. The functional molecules contain various aromatic amino moieties (N-phenyl-N-pyridyl amino- (PyPN), N-phenyl amino- (PN), and N,N-diphenyl amino- (DPN)) which are linked by a propyl chain to a triethoxysilyl anchor group and act as the interface modifiers and the charge-storage elements. The PyPN-containing pentacene-based memory device (denoted as PyPN device) presents the memory window of 48.43 V, while PN and DPN devices show the memory windows of 24.88 and 8.34 V, respectively. The memory characteristic of the PyPN device can remain stable along with 150 continuous write-read-erase-read cycles. The morphology analysis confirms that three interfacial layers show aggregation due to the N atomic self-catalysis and hydrogen bonding effects. The large aggregate-covered PyPN layer has the full contact area with the pentacene molecules, leading to the high memory performance. In addition, the energy level matching between PyPN molecules and pentacene creates the smallest tunneling barrier and facilitates the injection of the hole carriers from pentacene to the PyPN layer. The experimental memory characteristics are well in agreement with the computational calculation.

Large Planar π-Conjugated Porphyrin for Interfacial Engineering in p-i-n Perovskite Solar Cells.

In hybrid organic-inorganic perovskite solar cells (PSCs), interfacial engineering can efficiently improve the photovoltaic performance. In this work, the planar π-conjugated porphyrin, zinc(II) 5,10,15,20-tetrakis[5-(p-acetylthiopentyloxy)phenyl]porphyrin, was developed to modify the interface between poly(3,4-ethylenedioxythiophene):poly(styrenesulfonic acid) (PEDOT:PSS) and perovskite. The modified devices increased their highest power conversion efficiency (PCE) to 14.05% relative to 11.35% for the reference devices without modification. Such enhancement in efficiency is mainly attributed to the improved open-circuit voltage (Voc) and fill factor (FF), which benefit from fast hole-extraction and low charge recombination after the employment of well-aligned interlayer.