Non-Hermitian topological whispering gallery.

In 1878, Lord Rayleigh observed the highly celebrated phenomenon of sound waves that creep around the curved gallery of St Paul's Cathedral in London1,2. These whispering-gallery waves scatter efficiently with little diffraction around an enclosure and have since found applications in ultrasonic fatigue and crack testing, and in the optical sensing of nanoparticles or molecules using silica microscale toroids. Recently, intense research efforts have focused on exploring non-Hermitian systems with cleverly matched gain and loss, facilitating unidirectional invisibility and exotic characteristics of exceptional points3,4. Likewise, the surge in physics using topological insulators comprising non-trivial symmetry-protected phases has laid the groundwork in reshaping highly unconventional avenues for robust and reflection-free guiding and steering of both sound and light5,6. Here we construct a topological gallery insulator using sonic crystals made of thermoplastic rods that are decorated with carbon nanotube films, which act as a sonic gain medium by virtue of electro-thermoacoustic coupling. By engineering specific non-Hermiticity textures to the activated rods, we are able to break the chiral symmetry of the whispering-gallery modes, which enables the out-coupling of topological 'audio lasing' modes with the desired handedness. We foresee that these findings will stimulate progress in non-destructive testing and acoustic sensing.

Suppressed Droplet Splashing on Positively Skewed Surfaces for High-Efficiency Evaporation Cooling.

Two types of functional surfaces with the same roughness but completely different surface topographies are prepared, namely positively skewed surfaces filled with micropillar arrays (Sa ≈4.4 µm, Ssk >0) and negatively skewed surfaces filled with microcavity arrays (Sa ≈4.4 µm, Ssk <0), demonstrating promoting droplet splashing. Remarkably, the critical Weber number for generating satellite droplets on the negatively skewed surfaces is significantly lower than that on the positively skewed surfaces, indicating that the negatively skewed surface with microcavity arrays is more likely to promote droplet splashing. It is mainly attributed to the fact that air on the negatively skewed surface can make the liquid film take on a Cassie-Baxter state on the surface so that the stabilizing capillary force of the liquid film exceeds the destabilizing stress of the air film. Moreover, the surface topography promoting droplet spreading and the mechanical properties of three-phase moving contact lines are analyzed from the perspective of microscopic interface mechanics. Finally, it is demonstrated the designed positively skewed surfaces can be employed for large-area heat dissipation by means of high-efficiency evaporation.

Transcriptomic and physiological analyses of Trichoderma citrinoviride HT-1 assisted phytoremediation of Cd contaminated water by Phragmites australis.

Plant growth promoting microbe assisted phytoremediation is considered a more effective approach to rehabilitation than the single use of plants, but underlying mechanism is still unclear. In this study, we combined transcriptomic and physiological methods to explore the mechanism of plant growth promoting microbe Trichoderma citrinoviride HT-1 assisted phytoremediation of Cd contaminated water by Phragmites australis. The results show that the strain HT-1 significantly promoted P. australis growth, increased the photosynthetic rate, enhanced antioxidant enzyme activities. The chlorophyll content and the activity of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and ascorbate peroxidase (APX) were increased by 83.78%, 23.17%, 47.60%, 97.14% and 12.23% on average, and decreased the content of malondialdehyde (MDA) by 31.10%. At the same time, strain HT-1 improved the absorption and transport of Cd in P. australis, and the removal rate of Cd was increased by 7.56% on average. Transcriptome analysis showed that strain HT-1 induced significant up-regulated the expression of genes related to oxidative phosphorylation and ribosome pathways, and these upregulated genes promoted P. australis remediation efficiency and resistance to Cd stress. Our results provide a mechanistic understanding of plant growth promoting microbe assisted phytoremediation under Cd stress.

Honeycomb effect elimination in differential phase fiber-bundle-based endoscopy.

Fiber-bundle-based endoscopy, with its ultrathin probe and micrometer-level resolution, has become a widely adopted imaging modality for in vivo imaging. However, the fiber bundles introduce a significant honeycomb effect, primarily due to the multi-core structure and crosstalk of adjacent fiber cores, which superposes the honeycomb pattern image on the original image. To tackle this issue, we propose an iterative-free spatial pixel shifting (SPS) algorithm, designed to suppress the honeycomb effect and enhance real-time imaging performance. The process involves the creation of three additional sub-images by shifting the original image by one pixel at 0, 45, and 90 degree angles. These four sub-images are then used to compute differential maps in the x and y directions. By performing spiral integration on these differential maps, we reconstruct a honeycomb-free image with improved details. Our simulations and experimental results, conducted on a self-built fiber bundle-based endoscopy system, demonstrate the effectiveness of the SPS algorithm. SPS significantly improves the image quality of reflective objects and unlabeled transparent scattered objects, laying a solid foundation for biomedical endoscopic applications.

Highly sensitive self-focused ultrasound transducer with a bionic back-reflector for multiscale-resolution photoacoustic microscopy.

In this study, we designed a self-focused ultrasonic transducer made of polyvinylidene fluoride (PVDF). This transducer involves a back-reflector, which is modeled after tapetum lucidum in the eyes of some nocturnal animals. The bionic structure reflects the ultrasound, which passes through the PVDF membrane, back to PVDF and provides a second chance for the PVDF to convert the ultrasound to electric signals. This design increases the amount of ultrasound absorbed by the PVDF, thereby improving the detection sensitivity. Both ultrasonic and photoacoustic (PA) experiments were conduct to characterize the performance of the transducer. The results show that the fabricated transducer has a center frequency of 13.07 MHz, and a bandwidth of 96% at -6 dB. With an acoustic numerical aperture (NA) of 0.64, the transducer provides a lateral resolution of 140µm. Importantly, the bionic design improves the detection sensitivity of the transducer about 30%. Finally, we apply the fabricated transducer to optical-resolution (OR) and acoustic-resolution photoacoustic microscopy (AR-PAM) to achieve multiscale-resolution PA imaging. Imaging of the bamboo leaf and the leaf skeleton demonstrates that the proposed transducer can provide high spatial resolution, better imaging intensity and contrast. Therefore, the proposed transducer design will be useful to enhance the performance of multiscale-resolution PAM.

Both protein and non-protein components in extracellular vesicles of human seminal plasma improve human sperm function via CatSper-mediated calcium signaling.

STUDY QUESTION: What is the significance and mechanism of human seminal plasma extracellular vesicles (EVs) in regulating human sperm functions? SUMMARY ANSWER: EV increases the intracellular Ca2+ concentrations [Ca2+]i via extracellular Ca2+ influx by activating CatSper channels, and subsequently modulate human sperm motility, especially hyperactivated motility, which is attributed to both protein and non-protein components in EV. WHAT IS KNOWN ALREADY: EVs are functional regulators of human sperm function, and EV cargoes from normal and asthenozoospermic seminal plasma are different. Pre-fusion of EV with sperm in the acidic and non-physiological sucrose buffer solution could elevate [Ca2+]i in human sperm. CatSper, a principle Ca2+ channel in human sperm, is responsible for the [Ca2+]i regulation when sperm respond to diverse extracellular stimuli. However, the role of CatSper in EV-evoked calcium signaling and its potential physiological significance remain unclear. STUDY DESIGN, SIZE, DURATION: EV isolated from the seminal plasma of normal and asthenozoospermic semen were utilized to investigate the mechanism by which EV regulates calcium signal in human sperm, including the involvement of CatSper and the responsible cargoes in EV. In addition, the clinical application potential of EV and EV protein-derived peptides were also evaluated. This is a laboratory study that went on for more than 5 years and involved more than 200 separate experiments. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen donors were recruited in accordance with the Institutional Ethics Committee on human subjects of the Affiliated Hospital of Nantong University and Jiangxi Maternal and Child Health Hospital. The Flow NanoAnalyzer, western blotting, and transmission electron microscope were used to systematically characterize seminal plasma EV. Sperm [Ca2+]i responses were examined by fluorimetric measurement. The whole-cell patch-clamp technique was performed to record CatSper currents. Sperm motility parameters were assessed by computer-assisted sperm analysis. Sperm hyperactivation was also evaluated by examining their penetration ability in viscous methylcellulose media. Protein and non-protein components in EV were analyzed by liquid chromatography-mass spectrum. The levels of prostaglandins, reactive oxygen species, malonaldehyde, and DNA integrity were detected by commercial kits. MAIN RESULTS AND THE ROLE OF CHANCE: EV increased [Ca2+]i via an extracellular Ca2+ influx, which could be suppressed by a CatSper inhibitor. Also, EV potentiated CatSper currents in human sperm. Furthermore, the EV-in [Ca2+]i increase and CatSper currents were absent in a CatSper-deficient sperm, confirming the crucial role of CatSper in EV induced Ca2+ signaling in human sperm. Both proteins and non-protein components of EV contributed to the increase of [Ca2+]i, which were important for the effects of EV on human sperm. Consequently, EV and its cargos promoted sperm hyperactivated motility. In addition, seminal plasma EV protein-derived peptides, such as NAT1-derived peptide (N-P) and THBS-1-derived peptide (T-P), could activate the sperm calcium signal and enhance sperm function. Interestingly, EV derived from asthenozoospermic semen caused a lower increase of [Ca2+]i than that isolated from normal seminal plasma (N-EV), and N-EV significantly improved sperm motility and function in both asthenozoospermic samples and frozen-thawed sperm. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: This was an in vitro study and caution must be taken when extrapolating the physiological relevance to in vivo regulation of sperm. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate that the CatSper-mediated-Ca2+ signaling is involved in EV-modulated sperm function under near physiological conditions, and EV and their derivates are a novel CatSper and sperm function regulators with potential for clinical application. They may be developed to improve sperm motility resulting from low [Ca2+]i response and/or freezing and thawing. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the National Natural Science Foundation of China (32271167), the Social Development Project of Jiangsu Province (BE2022765), the Nantong Social and People's Livelihood Science and Technology Plan (MS22022087), the Basic Science Research Program of Nantong (JC22022086), and the Jiangsu Innovation and Entrepreneurship Talent Plan (JSSCRC2021543). The authors declare no conflict of interest.

Enhancing tissue imaging contrast in photoacoustic tomography using the ultrasound thermal effect.

Photoacoustic imaging is a powerful technique for obtaining high-resolution images of vascular distribution and physiological information about blood by utilizing the light absorption coefficient as an imaging contrast. However, visualizing weakly light-absorbing components without specific contrast agents or multi-wavelength techniques presents a challenge due to significant differences in light absorption between these components and blood. In this study, we propose a novel method that leverages the thermal effect of ultrasound to induce temperature differences and enhance the contrast of photoacoustic imaging. We conducted phantom experiments to verify the feasibility of our method. Our method effectively highlighted weakly light-absorbing components with strong acoustic absorption, even in the presence of highly light-absorbing components such as blood or melanin. Furthermore, it enabled the differentiation of components with similar light absorption but different acoustic absorption.

Optical path optimization of chromatic line confocal displacement sensor for high resolution and wide range.

This study introduces the optical path-optimized dual-grating chromatic line confocal imaging (DG-LCI) technique for high-resolution and wide-range surface topography measurements. Chromatic line confocal imaging (LCI) finds extensive applications in high-speed 3D imaging of surface morphology, roughness analysis in industrial production, and quality inspection. A key advantage of LCI is its ability to achieve a large depth of focus, enabling the imaging system to measure a wide range in the Z direction. However, the challenge lies in the trade-off between the measurement range and resolution. Increasing the measurement range reduces the resolution, making it unsuitable for precise measurements required in industrial processing. Conversely, enhancing the resolution limits the measurement range, thereby sacrificing the advantage of LCI systems' broad measurement capabilities. Addressing this limitation, we propose a dual optical path dual-grating structure using a simplified and ingenious optical path optimization design. This design overcomes the challenge of sacrificing the millimeter-level measurement range while simultaneously improving the resolution. Rigorous simulations and experiments validate the effectiveness and validity of our proposed method.

Timing Correlated-Electron Emission from Strong Field Atomic Double Ionization with Polarization-Gated Attoclock.

Attoclock provides a powerful tool for probing the ultrafast electron dynamics in strong laser fields. However, this technique has remained restricted to single electron or sequential double ionized electron dynamics. Here, we propose a novel attoclock scheme with a polarization-gated few-cycle laser pulse and demonstrate its application in timing the correlated-electron emission in strong field double ionization of argon. Our experimental measurements reveal that the correlated-electron emission occurs mainly through two channels with time differences of 234±22 as and 1043±73 as, respectively. Classical model calculations well reproduce the experimental results and deepen our understanding of ultrafast electron correlation dynamics.

FOXA1/2 depletion drives global reprogramming of differentiation state and metabolism in a human liver cell line and inhibits differentiation of human stem cell-derived hepatic progenitor cells.

FOXA factors are critical members of the developmental gene regulatory network (GRN) composed of master transcription factors (TF) which regulate murine cell fate and metabolism in the gut and liver. How FOXA factors dictate human liver cell fate, differentiation, and simultaneously regulate metabolic pathways is poorly understood. Here, we aimed to determine the role of FOXA2 (and FOXA1 which is believed to compensate for FOXA2) in controlling hepatic differentiation and cell metabolism in a human hepatic cell line (HepG2). siRNA mediated knockdown of FOXA1/2 in HepG2 cells significantly downregulated albumin (p < .05) and GRN TF gene expression (HNF4α, HEX, HNF1ß, TBX3) (p < .05) and significantly upregulated endoderm/gut/hepatic endoderm markers (goosecoid [GSC], FOXA3, and GATA4), gut TF (CDX2), pluripotent TF (NANOG), and neuroectodermal TF (PAX6) (p < .05), all consistent with partial/transient reprograming. shFOXA1/2 targeting resulted in similar findings and demonstrated evidence of reversibility of phenotype. RNA-seq followed by bioinformatic analysis of shFOXA1/2 knockdown HepG2 cells demonstrated 235 significant downregulated genes and 448 upregulated genes, including upregulation of markers for alternate germ layers lineages (cardiac, endothelial, muscle) and neurectoderm (eye, neural). We found widespread downregulation of glycolysis, citric acid cycle, mitochondrial genes, and alterations in lipid metabolism, pentose phosphate pathway, and ketogenesis. Functional metabolic analysis agreed with these findings, demonstrating significantly diminished glycolysis and mitochondrial respiration, with concomitant accumulation of lipid droplets. We hypothesized that FOXA1/2 inhibit the initiation of human liver differentiation in vitro. During human pluripotent stem cells (hPSC)-hepatic differentiation, siRNA knockdown demonstrated de-differentiation and unexpectedly, activation of pluripotency factors and neuroectoderm. shRNA knockdown demonstrated similar results and activation of SOX9 (hepatobiliary). These results demonstrate that FOXA1/2 controls hepatic and developmental GRN, and their knockdown leads to reprogramming of both differentiation and metabolism, with applications in studies of cancer, differentiation, and organogenesis.

Idebenone Antagonizes P53-Mediated Neuronal Oxidative Stress Injury by Regulating CD38-SIRT3 Protein Level.

Idebenone, an antioxidant used in treating oxidative damage-related diseases, has unclear neuroprotective mechanisms. Oxidative stress affects cell and mitochondrial membranes, altering Adp-ribosyl cyclase (CD38) and Silent message regulator 3 (SIRT3) protein expression and possibly impacting SIRT3's ability to deacetylate Tumor protein p53 (P53). This study explores the relationship between CD38, SIRT3, and P53 in H2O2-injured HT22 cells treated with Idebenone. Apoptosis was detected using flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining after determining appropriate H2O2 and Idebenone concentrations.In this study, Idebenone was found to reduce apoptosis and decrease P53 and Caspase3 expression in H2O2-injured HT22 cells by detecting apoptosis-related protein expression. Through bioinformatics methods, CD38 was identified as the target of Idebenone, and it further demonstrated that Idebenone decreased the expression of CD38 and increased the level of SIRT3. An increased NAD+/NADH ratio was detected, suggesting Idebenone induces SIRT3 expression and protects HT22 cells by decreasing apoptosis-related proteins. Knocking down SIRT3 downregulated acetylated P53 (P53Ac), indicating SIRT3's importance in P53 deacetylation.These results supported that CD38 was used as a target of Idebenone to up-regulate SIRT3 to deacetylate activated P53, thereby protecting HT22 cells from oxidative stress injury. Thus, Idebenone is a drug that may show great potential in protecting against reactive oxygen species (ROS) induced diseases such as Parkinson's disease, and Alzheimer's disease. And it might be able to compensate for some of the defects associated with CD38-related diseases.

Armored Superhydrophobic Surfaces with Excellent Drag Reduction in Complex Environmental Conditions.

Superhydrophobic surfaces (SHSs) have possibilities for achieving significantly reduced solid-liquid frictional drag in the marine sector due to their excellent water-repelling properties. Although the stability of SHSs plays a key role in drag reduction, little consideration was given to the effect of extreme environments on the ability of SHSs to achieve drag reduction underwater, particularly when subjected to acidic conditions. Here, we propose interconnected microstructures to protect superhydrophobic coatings with the aim of enhancing the stability of SHSs in extreme environments. The stability of armored SHSs (ASHSs) was demonstrated by the contact angle and bounce time of droplets on superhydrophobic surfaces treated by various methods, resulting in an ASHS surface with excellent stability under extreme environmental conditions. Additionally, inspired by microstructures protecting superhydrophobic nanomaterials from frictional wear, the armored superhydrophobic spheres (ASSPs) were designed to explain from theoretical and experimental perspectives why ASSPs can achieve sustainable drag reduction and demonstrate that the ASSPs can achieve drag reduction of over 90.4% at a Reynolds number of 6.25 × 104 by conducting water entry experiments on spheres treated in various solutions. These studies promote a fundamental understanding of what drives the application of SHSs under extreme environmental conditions and provide practical strategies to maximize frictional drag reduction.

Cascade-Targeted Nanoplatforms for Synergetic Antibiotic/ROS/NO/Immunotherapy against Intracellular Bacterial Infection.

Intracellular bacteria in dormant states can escape the immune response and tolerate high-dose antibiotic treatment, leading to severe infections. To overcome this challenge, cascade-targeted nanoplatforms that can target macrophages and intracellular bacteria, exhibiting synergetic antibiotic/reactive oxygen species (ROS)/nitric oxide (NO)/immunotherapy, were developed. These nanoplatforms were fabricated by encapsulating trehalose (Tr) and vancomycin (Van) into phosphatidylserine (PS)-coated poly[(4-allylcarbamoylphenylboric acid)-ran-(arginine-methacrylamide)-ran-(N,N'-bisacryloylcystamine)] nanoparticles (PABS), denoted as PTVP. PS on PTVP simulates a signal of "eat me" to macrophages to promote cell uptake (the first-step targeting). After the uptake, the nanoplatform in the acidic phagolysosomes could release Tr, and the exposed phenylboronic acid on the nanoplatform could target bacteria (the second-step targeting). Nanoplatforms can release Van in response to infected intracellular overexpressed glutathione (GSH) and weak acid microenvironment. l-arginine (Arg) on the nanoplatforms could be catalyzed by upregulated inducible nitric oxide synthase (iNOS) in the infected macrophages to generate nitric oxide (NO). N,N'-Bisacryloylcystamine (BAC) on nanoplatforms could deplete GSH, allow the generation of ROS in macrophages, and then upregulate proinflammatory activity, leading to the reinforced antibacterial capacity. This nanoplatform possesses macrophage and bacteria-targeting antibiotic delivery, intracellular ROS, and NO generation, and pro-inflammatory activities (immunotherapy) provides a new strategy for eradicating intracellular bacterial infections.

Predictors of mortality for dermatomyositis patients positive with anti-melanoma differentiation-related gene 5 and optimal treatment.

OBJECTIVES: To explore the risk factors of early death in dermatomyositis patients positive with anti-melanoma differentiation-related gene 5 antibody (anti-MDA5-DM). To explore the optimal treatment regimen for patients with anti-MDA5-DM. METHODS: Patients with newly onset anti-MDA5-DM from June 2018 to October 2021 in our centre were retrospectively reviewed for 6 months. Patients were divided into five groups based on initial treatments. The major outcome was mortality in 6 months. Secondary outcomes included remission and severe infection. RESULTS: A total of 214 patients were included in the study. During 6 month follow-up, 63 patients (30.14%) died, 112 patients (53.59%) achieved remission, 52 patients (24.88%) experienced serious infection and 5 patients (2.34%) were lost. Independent risk factors of mortality in the first 6 months after diagnosis were as follows: age> 53 years, skin ulcer, peripheral blood lymphocyte count (LYMP)≤ 0.6×109/L, lactate dehydrogenase (LDH) > 500 U/L, C reactive protein (CRP) > 5mg/L, anti-Ro52 antibody and ground-glass opacity (GGO) score> 2. On the contrary, prophylactic use of the compound sulfamethoxazole (SMZ Co) was independent protective factor. The five-category treatment was not an independent influencing factor of early death, but subgroup analysis found that patients with rapidly progressive interstitial lung disease (RPILD) responded better to a triple combination of high-dose glucocorticoids (GC), calcineurin inhibitors (CNI) and cyclophosphamide (CYC) or a triple combibation of GC, CNI and tofacitinib (TOF). CONCLUSIONS: Advanced age, skin ulcer, lymphopenia, anti-Ro52 antibody and higher levels of LDH, CRP and GGO score increase the risk of early death for MDA5-DM, while prophylactic use of SMZ Co is protective. Aggressive therapy with combined immunosuppressants may improve the short-term prognosis of anti-MDA5-DM with RPILD.

An analysis of differences in Carbapenem-resistant Enterobacterales in different regions: a multicenter cross-sectional study.

OBJECTIVE: This study aimed to explore the characteristics of carbapenem-resistant Enterobacterales (CRE) patients in the intensive care unit (ICU) in different regions of Henan Province to provide evidence for the targeted prevention and treatment of CRE. METHODS: This was a cross-sectional study. CRE screening was conducted in the ICUs of 78 hospitals in Henan Province, China, on March 10, 2021. The patients were divided into provincial capital hospitals and nonprovincial capital hospitals for comparative analysis. RESULTS: This study involved 1009 patients in total, of whom 241 were CRE-positive patients, 92 were in the provincial capital hospital and 149 were in the nonprovincial capital hospital. Provincial capital hospitals had a higher rate of CRE positivity, and there was a significant difference in the rate of CRE positivity between the two groups. The body temperature; immunosuppressed state; transfer from the ICU to other hospitals; and use of enemas, arterial catheters, carbapenems, or tigecycline at the provincial capital hospital were greater than those at the nonprovincial capital hospital (P < 0.05). However, there was no significant difference in the distribution of carbapenemase strains or enzymes between the two groups. CONCLUSIONS: The detection rate of CRE was significantly greater in provincial capital hospitals than in nonprovincial capital hospitals. The source of the patients, invasive procedures, and use of advanced antibiotics may account for the differences. Carbapenem-resistant Klebsiella pneumoniae (CR-KPN) was the most prevalent strain. Klebsiella pneumoniae carbapenemase (KPC) was the predominant carbapenemase enzyme. The distributions of carbapenemase strains and enzymes were similar in different regions.

Experimental study of slow-released Angiogenin by silicon micro-needle in improving blood support to multiple-territory perforator flaps in rats.

This research aimed to investigate the effect of slow-released angiogenin by silicon micro-needle on angiogenesis in the Choke zone of dorsal multiple-territory perforator flap in rats, as well as its mechanism. Thirty-six adult Sprague-Dawley (SD) rats were randomly divided into control group, model group, and four experimental groups. In model group, slow-release saline through a silicon micro-needle was placed in choke II zone of the flap 7 days before the operation. For rats in four experimental groups, angiogenin was released via micro-needle in the choke I and choke II zones of the cross-zone flap 7 days before and 3 days before flap surgery, respectively. A 12 cm × 3 cm cross-zone perforator flap model was made on the back of all five groups. The flap survival rate in slow-release angiopoietin group was statistically higher than that in model group (P<0.05). Angiogenin in choke zone of the flap was increased in slow-release angiogenin group (P<0.05). In slow-release angiogenin group, the micro-vessel density was increased and the arteriovenous diameter was decreased, while the arteriovenous diameter was increased in model group (P<0.05). The levels of vascular endothelial growth factor A (VEGF-A) and angiotensin 1 (ANG-1) in choke zone were both elevated in slow-release angiogenin group (P<0.05). The expression of CD31 was significantly elevated in flaps of experimental groups (P<0.05). Micro-needle to slow release Angiogenin can increase the drug concentration in the tissues of the choke zone, promote the vascularization of rat dorsal crossover area perforator flap, reduce the possibility of flap ischemic necrosis, and improve the flap survival rate.

Tuning d-orbitals to control spin-orbit coupling in terminated MXenes.

Theory and experiment have revealed that spin-orbit coupling (SOC) strongly depends on the relativistic effect in topological insulators (TIs), while the influence of orbitals is always ignored. Herein, we provide a direct way of controlling effective SOC with the help of orbital effects, reducing the dependence on elements. Taking 5d W2CO2 and 4d Mo2CO2 MXenes as a specific example, we predict that by decreasing the hybridization strength of W atoms with C or O atoms in 2D W2CO2, the nontrivial bandgaps at the Γ-point are directly enhanced. The weak hybridization of W atoms with ligand elements enhances the electron localization of degenerate d-orbitals of three groups under the triangular prism crystal field, inducing stronger on-site Coulomb repulsion that enhances orbital polarization as well as boosts the SOC effect. Meanwhile, similar results have also been observed in 4d Mo2CO2. This implies that the orbital effects are an efficient and straightforward way to control the nontrivial bandgap in 2D MXene TIs. Our work not only provides an alternative perspective on designing large nontrivial bandgaps but also brings a possibility to control the SOC effect for TI devices.

Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells.

Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies1-3. In this strategy, the T cell genome is modified by integration of viral vectors or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells4,5. Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient's second TET2 allele. TET2-disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient's CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies.

Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells.

Multiple clinical studies have treated mesothelin (MSLN)-positive solid tumors by administering MSLN-directed chimeric antigen receptor (CAR) T cells. Although these products are generally safe, efficacy is limited. Therefore, we generated and characterized a potent, fully human anti-MSLN CAR. In a phase 1 dose-escalation study of patients with solid tumors, we observed two cases of severe pulmonary toxicity following intravenous infusion of this product in the high-dose cohort (1-3 × 108 T cells per m2). Both patients demonstrated progressive hypoxemia within 48 h of infusion with clinical and laboratory findings consistent with cytokine release syndrome. One patient ultimately progressed to grade 5 respiratory failure. An autopsy revealed acute lung injury, extensive T cell infiltration, and accumulation of CAR T cells in the lungs. RNA and protein detection techniques confirmed low levels of MSLN expression by benign pulmonary epithelial cells in affected lung and lung samples obtained from other inflammatory or fibrotic conditions, indicating that pulmonary pneumocyte and not pleural expression of mesothelin may lead to dose-limiting toxicity. We suggest patient enrollment criteria and dosing regimens of MSLN-directed therapies consider the possibility of dynamic expression of mesothelin in benign lung with a special concern for patients with underlying inflammatory or fibrotic conditions.

Psychache status and associated contributing factors among the Hakka elderly in Fujian, China.

BACKGROUND: Little is known about the state of psychological distress of the elderly in China, and research on specific subgroups such as Hakka older adults is almost lacking. This study investigates psychache and associated factors among Hakka elderly in Fujian, China. METHODS: The data analysed in this study were derived from China's Health-Related Quality of Life Survey for Older Adults 2018. The Chinese version of the Psychache Scale (PAS) was used to assess the frequency and intensity of psychache in Hakka older adults. Generalized linear regression analysis was conducted to identify the main socio-demographic factors associated with psychache overall and its frequency and intensity. RESULTS: A total of 1,262 older adults participated, with mean scores of 18.27 ± 6.88 for total PAS, 12.50 ± 4.79 for PAS-Frequency and 5.77 ± 2.34 for PAS-Intensity. On average, females scored higher than males on PAS-Frequency (ß = 0.84, 95% CI = 0.34, 1.35) and PAS-Intensity (ß = 0.48, 95% CI = 0.22, 0.73). Older adults currently living in towns (ß = -2.18, 95% CI = -2.81, -1.54), with their spouse only (ß = -3.71, 95% CI = -4.77, -2.65), or with children (ß = -3.24, 95% CI = -4.26, -2.22) were more likely to score lower on PAS-Frequency. Conversely, older adults who were regular sleepers (ß = -1.19, 95% CI =-1.49, -0.88) or lived with their spouse only (ß = -1.25, 95% CI = -1.78, -0.72) were more likely to score lower on PAS-Intensity. CONCLUSION: Among Hakka elderly, we found a higher frequency and greater intensity of psychache in females, those with poor health status, irregular sleepers, rural residents, solo dwellers, those with below CNY 10,000 in personal savings, and the medically uninsured. The study's findings indicate that policymakers should give more attention to the susceptible population and implement practical interventions to reduce their psychological burden.