Hybrid Membrane-Camouflaged Biomimetic Immunomodulatory Nanoturrets with Sequential Multidrug Release for Potentiating T Cell-Mediated Anticancer Immunity.

Ascorbic acid (AA) has been attracting great attention with its emerging potential in T cell-dependent antitumor immunity. However, premature blood clearance and immunologically "cold" tumors severely compromise its immunotherapeutic outcomes. As such, the reversal of the immunosuppressive tumor microenvironment (TME) has been the premise for improving the effectiveness of AA-based immunotherapy, which hinges upon advanced AA delivery and amplified immune-activating strategies. Herein, a novel Escherichia coli (E. coli) outer membrane vesicle (OMV)-red blood cell (RBC) hybrid membrane (ERm)-camouflaged immunomodulatory nanoturret is meticulously designed based on gating of an AA-immobilized metal-organic framework (MOF) onto bortezomib (BTZ)-loaded magnesium-doped mesoporous silica (MMS) nanovehicles, which can realize immune landscape remodeling by chemotherapy-assisted ascorbate-mediated immunotherapy (CAMIT). Once reaching the acidic TME, the acidity-sensitive MOF gatekeeper and MMS core within the nanoturret undergo stepwise degradation, allowing for tumor-selective sequential release of AA and BTZ. The released BTZ can evoke robust immunogenic cell death (ICD), synergistically promote dendritic cell (DC) maturation in combination with OMV, and ultimately increase T cell tumor infiltration together with Mg2+. The army of T cells is further activated by AA, exhibiting remarkable antitumor and antimetastasis performance. Moreover, the CD8-deficient mice model discloses the T cell-dependent immune mechanism of the AA-based CAMIT strategy. In addition to providing a multifunctional biomimetic hybrid nanovehicle, this study is also anticipated to establish a new immunomodulatory fortification strategy based on the multicomponent-driven nanoturret for highly efficient T cell-activation-enhanced synergistic AA immunotherapy.

Multi-laser source interference suppression using the time-coding method for SPAD-based flash DToF systems.

Flash-type direct time-of-flight (DToF) image sensors use an in-pixel successive approximation register time-to-digital converter (SAR TDC) for time quantization. However, in a scene where multiple DToF systems exist simultaneously, different laser signals from multiple sources will produce mutual signal interference between DToF systems, causing the DToF system's incorrect measurement. In this paper, we present a method called time coding, which inserts delay time bins between different working periods to suppress the interference laser together with the SAR TDC. The time-coding method is designed using a 110 nm complementary metal oxide semiconductor (CMOS) technology and verified by behavioral model and circuit simulation. Regardless of traditional systems or systems equipped with time coding, DToF systems with certain patterns of time coding can reduce interference noise by at least 95%, maintaining a measurement accuracy of 99% or higher at long distances.

Effects of Long-Term Simulated Weightlessness on Retinal Microcirculation and Visual Electrophysiology.

Objective: To investigate the mechanisms of ocular injuries in astronauts due to gravity deficit by examining changes in retinal microcirculation and visual electrophysiology in macaques subjected to simulated weightlessness. Methods: The head-down recumbency of macaques was used to simulate the movement of blood to the side of the head that occurs without microgravity. Head-down recumbency was performed with the head tilted downwards at a recommended angle of 10°. The macaques in the control group were similarly tethered to the rope but could be held in a normal position. The whole experiment lasted for 6 weeks and retinal microcirculation and visual electrophysiology information was collected at weeks 0, 3 and 6. Results: The retinal microcirculation of macaques was affected by 3 weeks of weightlessness. This includes morphological changes, such as dilation and tortuosity of the retinal microvasculature in macaques at day 21. OCT and OCTA results showed an increase in retinal and choroidal thickness and a significant decrease in vessel length density within 6×6 mm of the macula. Sustained simulated weightlessness (42 days) significantly exacerbated retina-related damage. This was evidenced by a significant decrease in the perfusion density of microcirculatory vessels, such as the macular 3×3 mm mesial vessels and the macular 6*6 mm central and medial vessels. The FAZ density in the macula 3×3 mm area began to increase. Retinal oxygen saturation testing showed a slight increase in arterial oxygen saturation. Simultaneous changes in visual electrophysiology occurred, including a significant decrease in a- and b-wave amplitudes on the dark-vision electroretinogram and a significant decrease in the amplitude of the bright-vision negative wave response. The peak timing of the flash visual evoked potential component P1 was significantly delayed compared to its baseline and time-matched control. Conclusions: Sustained simulated weightlessness (42 days) significantly exacerbated retina-related damage, with both reduced macular blood supply and increased FAZ density suggesting the development of retinal ischemic changes, which disrupt visual electrophysiology. Retinal damage in human astronauts under long-term outer space conditions may be prevented by intervening in ischemic changes in the retina during the early stages of weightlessness.

Polysaccharides from Porphyra haitanensis: A Review of Their Extraction, Modification, Structures, and Bioactivities.

Porphyra haitanensis (P. haitanensis), an important food source for coastal residents in China, has a long history of medicinal and edible value. P. haitanensis polysaccharides are some of the main active ingredients in P. haitanensis. It is worth noting that P. haitanensis polysaccharides have a surprising and satisfactory biological activity, which explains the various benefits of P. haitanensis to human health, such as anti-oxidation, immune regulation, anti-allergy, and anticancer properties. Hence, a systematic review aimed at comprehensively summarizing the recent research advances in P. haitanensis polysaccharides is necessary for promoting their better understanding. In this review, we systematically and comprehensively summarize the research progress on the extraction, purification, structural characterization, modification, and biological activity of P. haitanensis polysaccharides and address the shortcomings of the published research and suggest area of focus for future research, providing a new reference for the exploitation of polysaccharides from P. haitanensis in the fields of medicine and functional foods.

The reliability of regional ecological knowledge to build local interaction networks: a test using seed-dispersal networks across land-bridge islands.

Building ecological networks is the fundamental basis of depicting how species in communities interact, but sampling complex interaction networks is extremely labour intensive. Recently, indirect ecological information has been applied to build interaction networks. Here we propose to extend the source of indirect ecological information, and applied regional ecological knowledge to build local interaction networks. Using a high-resolution dataset consisting of 22 locally observed networks with 17 572 seed-dispersal events, we test the reliability of indirectly derived local networks based on regional ecological knowledge (REK) across islands. We found that species richness strongly influenced 'local interaction rewiring' (i.e. the proportion of locally observed interactions among regionally interacting species), and all network properties were biased using REK-based networks. Notably, species richness and local interaction rewiring strongly affected estimations of REK-based network structures. However, locally observed and REK-based networks detected the same trends of how network structure correlates to island area and isolation. These results suggest that we should use REK-based networks cautiously for reflecting actual interaction patterns of local networks, but highlight that REK-based networks have great potential for comparative studies across environmental gradients. The use of indirect regional ecological information may thus advance our understanding of biogeographical patterns of species interactions.

The short and long-term impact of nonpharmaceutical interventions on the prevalence of varicella in Xi'an during the COVID-19 pandemic.

Varicella is a highly prevalent infectious disease with a similar transmission pathway to coronavirus disease 2019 (COVID-19). In the context of the COVID-19 pandemic, anti-COVID-19 nonpharmaceutical interventions (NPIs) have been implemented to prevent the spread of the infection. This study aims to analyze varicella's epidemiological characteristics and further investigate the effect of anti-COVID-19 NPIs on varicella in Xi'an, northwestern China. Based on the varicella surveillance data, search engine indices, meteorological factors from 2011 to 2021 in Xi'an, and different levels of emergency response to COVID-19 during the pandemic, we applied Bayesian Structural Time Series models and interrupted time series analysis to predict the counterfactual incidence of varicella and quantify the impact of varying NPIs intensities on varicella. From 2011 to 2021, varicella incidence increased, especially in 2019, with a high incidence of 111.69/100 000. However, there was a sharp decrease of 43.18% in 2020 compared with 2019, and the peak of varicella incidence in 2020 was lower than in previous years from the 21st to the 25th week. In 2021, the seasonality of varicella incidence gradually returned to a seasonal pattern in 2011-2019. The results suggest that anti-COVID-19 NPIs effectively reduce the incidence of varicella, and the reduction has spatiotemporal heterogeneity.

Covalent Organic Framework-Supported Metallocene for Ethylene Polymerization.

The loading of homogeneous catalysts with support can dramatically improve their performance in olefin polymerization. However, the challenge lies in the development of supported catalysts with well-defined pore structures and good compatibility to achieve high catalytic activity and product performance. Herein, we report the use of an emergent class of porous material-covalent organic framework material (COF) as a carrier to support metallocene catalyst-Cp2 ZrCl2 for ethylene polymerization. The COF-supported catalyst demonstrates a higher catalytic activity of 31.1×106  g mol-1 h-1 at 140 °C, compared with 11.2×106  g mol-1 h-1 for the homogenous one. The resulting polyethylene (PE) products possess higher weight-average molecular weight (Mw ) and narrower molecular weight distribution (Ð) after COF supporting, that is, Mw increases from 160 to 308 kDa and Ð drops from 3.3 to 2.2. The melting point (Tm ) is also increased by up to 5.2 °C. Moreover, the PE product possesses a characteristic filamentous microstructure and demonstrates an increased tensile strength from 19.0 to 30.7 MPa and elongation at break from 350 to 1400 % after catalyst loading. We believe that the use of COF carriers will facilitate the future development of supported catalysts for highly efficient olefin polymerization and high-performance polyolefins.

The impact of GmTSA and GmALS on soybean salt tolerance: uncovering the molecular landscape of amino acid and secondary metabolism pathways.

KEY MESSAGE: GmTSA and GmALS were screened out for salt stress in soybean and explore the poteintial amino acid secondary metabolism pathways. Soybean (Glycine max L.) is an oil and protein crop of global importance, and salinity has significant effects on soybean growth. Here, a population of soybean chromosome segment substitution lines was screened to identify highly salt-tolerant lines. In total, 24 quantitative trait loci (QTLs) on seven chromosomes were associated with salt tolerance, and CSSL_R71 was selected for further analysis. Although numerous genes were differentially expressed in CSSL_R71 in response to salt statically no differently, transcript levels of classical salt-response genes, including those of the salt overly sensitive pathway. Rather, salt tolerance in CSSL_R71 was associated with changes in amino acid and lipid metabolism. In particular, changes in p-coumaric acid, shikimic acid, and pyrrole-2-carboxylic acid levels accompanied salt tolerance in CSSL_R71. Eleven differentially expressed genes (DEGs) related to amino acid and secondary metabolism were identified as candidate genes on the substituted chromosome fragment. Six of these showed differences in coding sequence between the parental genotypes. Crucially, overexpression of GmTSA (Glyma.03G158400, tryptophan synthase) significantly enhanced salt tolerance in soybean hairy roots, whereas overexpression of GmALS (Glyma.13G241000, acetolactate synthase) decreased salt tolerance. Two KASP markers were developed for GmALS and used to genotype salt-tolerant and salt-sensitive lines in the CSSL population. Non-synonymous mutations were directly associated with salt tolerance. Taken together, these data provide evidence that changes in amino acid and secondary metabolism have the potential to confer salt tolerance in soybean.

Neohesperidin Alleviates the Neuropathic Pain Behavior of Rats by Downregulating the P2X4 Receptor.

Neuropathic pain (NP) is a type of chronic pain affecting 6-8% of human health as no effective drug exists. The purinergic 2X4 receptor (P2X4R) is involved in NP. Neohesperidin (NH) is a dihydroflavonoside compound, which has anti-inflammatory and antioxidative properties. This study aimed to investigate whether NH has an effect on P2X4R-mediated NP induced by chronic constriction injury (CCI) of the sciatic nerve in rats. In this study, the CCI rat model was established to observe the changes of pain behaviors, P2X4R, and satellite glial cells (SGCs) activation in dorsal root ganglion (DRG) after NH treatment by using RT-PCR, immunofluorescence double labeling and Western blotting. Our results showed CCI rats had mechanical and thermal hyperalgesia with an increased level of P2X4R. Furthermore, SGCs were activated as indicated by increased expression of glial fibrillary acidic protein and increased tumor necrosis factor-alpha receptor 1and interleukin-1ß. In addition, phosphorylated extracellular regulated protein kinases and interferon regulatory factor 5 in CCI rats increased. After NH treatment in CCI rats, the levels of above protein decreased, and the pain reduced. Overall, NH can markedly alleviate NP by reducing P2X4R expression and SGCs activation in DRG.

Design, synthesis and biological evaluation of KRASG12C-PROTACs.

Several small-molecule covalent inhibitors of KRASG12C have made breakthrough progress in the treatment of KRAS mutant cancer. However, the clinical application of KRASG12C small-molecule inhibitors may be limited by adaptive resistance. Emerging PROTAC strategy can achieve complementary advantages with small molecule inhibitors and improve anti-tumor efficacy. Based on AMG-510, a series of novel KRASG12C-PROTACs were designed and synthesized. The protein degradation assay showed that PROTACs I-1, II-1, III-2 and IV-1 had binding and degradation ability to KRASG12C. III-2 and IV-1 showed potent inhibitory effect on downstream p-ERK and were more potent than AMG-510. Mechanistic studies demonstrated that PROTACs exerted degradation effects through the ubiquitin-proteasome pathway. Using cell lines sensitive to KRASG12C, anti-proliferative activities of compounds were assessed. PROTACs tested showed overall anti-proliferative activities. Besides,the structure-activity relationships (SARs) of KRASG12C-PROTACs were summarized. These results supported the use of the PROTAC strategy to degrade oncogene KRASG12C and provided clues for structural optimization of KRASG12C-PROTACs.

Scattering of arbitrarily incident Laguerre-Gaussian vortex electromagnetic beams by electrically large-scaled complex targets.

We implement an algorithm, termed parallel-processing physical optics, providing an efficient high-frequency approximation method to characterize the scattering of Laguerre-Gaussian (LG) vortex electromagnetic (EM) beams by electrically large-scaled complex targets. The incident beam is described by vector expressions in terms of electric and magnetic fields, and it is combined with rotation Euler angles to achieve an arbitrary incidence of the vortex beam. The validity and capability of the proposed method are illustrated numerically, and the effects of various beam parameters as well as target geometric models such as a blunt cone and Tomahawk-A missile on monostatic and bistatic radar cross section distributions are investigated. Results show that the scattering features of the vortex beam vary significantly with the parameters of the vortex beam and the target. These results are helpful to reveal the scattering mechanism of LG vortex EM beams and provide a reference for the application of vortex beams to detect electrically large-scaled targets.

Ambient light rejection method for multiphoton coincidence detection in single-photon avalanche diode-based DToF sensors.

This paper presents an adaptive control method used for multiphoton coincidence detection to reduce the effect of ambient light that exists in accessing flight time. Behavioral and statistical models are used to demonstrate the working principle with MATLAB, and the method is achieved through a compact circuit. The adaptive coincidence detection in accessing flight time achieves a higher probability of 66.5% than fixed parameter coincidence detection's 46%, while ambient light intensity is 75 klux. Additionally, it also can achieve a dynamic detection range 43.8 times higher than the fixed parameter detection. The circuit is designed in 0.11 µm complementary metal-oxide semiconductor process, and the area consumption is 0.00178m m 2. The postsimulation experiment through Virtuoso shows that the histogram of coincidence detection under adaptive control circuit is consistent with the behavioral model. The proposed method acieves the coefficient of variance as 0.0495 smaller than fixed parameter coincidence's 0.0853, which means better ambient light tolerance in accessing flight time for three-dimensional imaging.

The impact of anti-COVID-19 nonpharmaceutical interventions on hand, foot, and mouth disease-A spatiotemporal perspective in Xi'an, northwestern China.

Growing evidence has shown that anti-COVID-19 nonpharmaceutical interventions (NPIs) can support prevention and control of various infectious diseases, including intestinal diseases. However, most studies focused on the short-term mitigating impact and neglected the dynamic impact over time. This study is aimed to investigate the dynamic impact of anti-COVID-19 NPIs on hand, foot, and mouth disease (HFMD) over time in Xi'an City, northwestern China. Based on the surveillance data of HFMD, meteorological and web search data, Bayesian Structural Time Series model and interrupted time series analysis were performed to quantitatively measure the impact of NPIs in sequent phases with different intensities and to predict the counterfactual number of HFMD cases. From 2013 to 2021, a total number of 172,898 HFMD cases were reported in Xi'an. In 2020, there appeared a significant decrease in HFMD incidence (-94.52%, 95% CI: -97.54% to -81.95%) in the first half of the year and the peak period shifted from June to October by a small margin of 6.74% compared to the previous years of 2013 to 2019. In 2021, the seasonality of HFMD incidence gradually returned to the bimodal temporal variation pattern with a significant average decline of 61.09%. In particular, the impact of NPIs on HFMD was more evident among young children (0-3 years), and the HFMD incidence reported in industrial areas had an unexpected increase of 51.71% in 2020 autumn and winter. Results suggested that both direct and indirect NPIs should be implemented as effective public health measures to reduce infectious disease and improve surveillance strategies, and HFMD incidence in Xi'an experienced a significant rebound to the previous seasonality after a prominent decline influenced by the anti-COVID-19 NPIs.

Metal-free aminofluorination of α-diazo 2H-benzopyran-4-one: convenient access to ß-fluoramides.

We have developed a convenient synthesis of a series of ß-fluoramides in 65% yield. The process involved a tandem fluorination/Ritter reaction to synthesize ß-fluoramides using α-diazo 2H-benzopyran-4-one compounds. Selectfluor was used as the electrophilic fluoride source in acetonitrile to build the ß-fluorinated quaternary carbon center and amide derivatives of 2H-benzopyran-4-one in one step. The products N-(2-(2-fluoro-2,3-dihydro-3-oxobenzofuran-2-yl)propan-2-yl)acetamides were a series of bifunctional compounds with a 2-fluoro-2,3-dihydro-3-oxobenzofuran motif and amide groups.

Predicting the Spatial-Temporal Distribution of Human Brucellosis in Europe Based on Convolutional Long Short-Term Memory Network.

Brucellosis is a chronic infectious disease caused by brucellae or other bacteria directly invading human body. Brucellosis presents the aggregation characteristics and periodic law of infectious diseases in temporal and spatial distribution. Taking major European countries as an example, this study established the temporal and spatial distribution sequence of brucellosis, analyzed the temporal and spatial distribution characteristics of brucellosis, and quantitatively predicted its epidemic law by using different traditional or machine learning models. This paper indicates that the epidemic of brucellosis in major European countries has statistical periodic characteristics, and in the same cycle, brucellosis has the characteristics of piecewise trend. Through the comparison of the prediction results of the three models, it is found that the prediction effect of long short-term memory and convolutional long short-term memory models is better than autoregressive integrated moving average model. The first mock exam using Conv layer and data vectorizations predicted that the convolutional long short-term memory model outperformed the traditional long short-term memory model. Compared with the monthly scale, the prediction of the trend stage of brucellosis can achieve better results under the single model prediction. These findings will help understand the development trend and liquidity characteristics of brucellosis, provide corresponding scientific basis and decision support for potential risk assessment and brucellosis epidemic prevention and control, and reduce the loss of life and property.

Enhanced production of seed oil with improved fatty acid composition by overexpressing NAD+ -dependent glycerol-3-phosphate dehydrogenase in soybean.

There is growing interest in expanding the production of soybean oils (mainly triacylglycerol, or TAG) to meet rising feed demand and address global energy concerns. We report that a plastid-localized glycerol-3-phosphate dehydrogenase (GPDH), encoded by GmGPDHp1 gene, catalyzes the formation of glycerol-3-phosphate (G3P), an obligate substrate required for TAG biosynthesis. Overexpression of GmGPDHp1 increases soybean seed oil content with high levels of unsaturated fatty acids (FAs), especially oleic acid (C18:1), without detectably affecting growth or seed protein content or seed weight. Based on the lipidomic analyses, we found that the increase in G3P content led to an elevated diacylglycerol (DAG) pool, in which the Kennedy pathway-derived DAG was mostly increased, followed by PC-derived DAG, thereby promoting the synthesis of TAG containing relatively high proportion of C18:1. The increased G3P levels induced several transcriptional alterations of genes involved in the glycerolipid pathways. In particular, genes encoding the enzymes responsible for de novo glycerolipid synthesis were largely upregulated in the transgenic lines, in-line with the identified biochemical phenotype. These results reveal a key role for GmGPDHp1-mediated G3P metabolism in enhancing TAG synthesis and demonstrate a strategy to modify the FA compositions of soybean oils for improved nutrition and biofuel.

Co-expression analysis aids in the identification of genes in the cuticular wax pathway in maize.

Epicuticular waxes provide a hydrophobic barrier that protects land plants from environmental stresses. To elucidate the molecular functions of maize glossy mutants that reduce the accumulation of epicuticular waxes, eight non-allelic glossy mutants were subjected to transcriptomic comparisons with their respective wild-type siblings. Transcriptomic comparisons identified 2279 differentially expressed (DE) genes. Other glossy genes tended to be down-regulated in glossy mutants; by contrast stress-responsive pathways were induced in mutants. Gene co-expression network (GCN) analysis found that glossy genes were clustered, suggestive of co-regulation. Genes that potentially regulate the accumulation of glossy gene transcripts were identified via a pathway level co-expression analysis. Expression data from diverse organs showed that maize glossy genes are generally active in young leaves, silks, and tassels, while largely inactive in seeds and roots. Through reverse genetics, a DE gene homologous to Arabidopsis CER8 and co-expressed with known glossy genes was confirmed to participate in epicuticular wax accumulation. GCN data-informed forward genetics approach enabled cloning of the gl14 gene, which encodes a putative membrane-associated protein. Our results deepen understanding of the transcriptional regulation of the genes involved in the accumulation of epicuticular wax, and provide two maize glossy genes and a number of candidate genes for further characterization.

Design, synthesis and biological activity of bicyclic carboxamide derivatives as TRK inhibitors.

'precision medicine' is characterized by the selection of targeted drugs based on genetic characteristics of tumor from patients, and no longer selected basis on the type of cancer tissue. Among them, clinical trials on neurotrophin receptor tyrosine kinase genes (NTRK) have proven that great anti-cancer effects can be achieved in different cancer patients. In this paper, a novel total of twenty compounds in two categories have been designed and synthesized. Results of Kinase activity tests showed that I-9 (TRKA IC50 = 1.3 nM, TRKAG595R IC50 = 6.1 nM), and I-10 (TRKA IC50 = 1.1 nM, TRKAG595R IC50 = 5.3 nM) have significant inhibitory activity, and results of cell viability tests showed that I-9 and I-10 can maintain a great inhibitory effect in the Ba/F3-LMNA-NTRK1 cell line(IC50 = 81.1 nM and 41.7 nM, respectively), and in Ba/F3-LMNA-NTRK1-G595R cell line, I-9 and I-10 have better cell activity (IC50 was 495.3 nM, 336.6 nM, respectively) compared with the positive control drug LOXO-101. These results indicate that I-9 and I-10 are potential TRK inhibitors that can overcome drug resistance for further investigation.

[Research progress on neural mechanism of peripheral inflammation in Parkinson's disease].

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by loss of dopaminergic (DA) neurons in the dense part of the substantia nigra (SNpc). Postmortem analysis of PD patients and experimental animal studies found that microglial cell activation and increased levels of pro-inflammatory factors were common features of PD brain tissue. At the same time, the invasion and accumulation of peripheric immune cells were detected in the brain of PD patients. In this paper, peripheral inflammation across the blood-brain barrier (BBB), the misfolded α-synuclein (α-syn)-induced microglial cell activation and intracerebral inflammation in PD are summarized, providing potential therapeutic measures for delaying the onset of PD.

Biodistribution and PET imaging of 89-zirconium labeled cerium oxide nanoparticles synthesized with several surface coatings.

Cerium oxide nanoparticles (CONPs) have unique surface chemistry allowing catalyst-like antioxidant properties, and are being investigated for several disease indications in medicine. Studies have utilized surface modified CONPs toward this application, but have been lacking in comprehensive biodistribution and pharmacokinetic data and a direct comparison to uncoated CONPs. We developed an enhanced single-pot synthesis of several coated CONPs and an efficient intrinsic core labeling of CONPs with the clinical PET isotope, zirconium-89, allowing detailed PET imaging and ex vivo biodistribution. All coated [89Zr]-CONPs showed benefit in terms of biodistribution compared to uncoated [89Zr]-CONPs, while retaining the intrinsic antioxidant properties. Among these, poly(acrylic acid) coated CONPs demonstrated excellent candidacy for clinical implementation due to their enhanced renal clearance and low reticuloendothelial system uptake. This work also demonstrates the value of intrinsic core labeling and PET imaging for evaluation of nanoparticle constructs to better inform future studies towards clinical use.