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Regiocontrol in traditional cycloaddition reactions between unsaturated carbon compounds is often challenging. The increasing focus in modern medicinal chemistry on benzocyclobutene (BCB) scaffolds indicates the need for alternative, more selective routes to diverse rigid carbocycles rich in C(sp 3 ) character. Here, we report a palladium-catalyzed double C–H activation of two adjacent methylene units in carboxylic acids, enabled by bidentate amide-pyridone ligands, to achieve a regio-controllable synthesis of BCBs through a formal [2+2] cycloaddition involving σ bonds only (two C–H bonds and two aryl–halogen bonds). A wide range of cyclic and acyclic aliphatic acids, as well as dihaloheteroarenes, are compatible, generating diversely functionalized BCBs and hetero-BCBs present in drug molecules and bioactive natural products.

Neurofibromatosis type 1 (NF1) patients are predisposed to develop plexiform neurofibromas (PNFs). Three endoplasmic reticulum (ER) stress response pathways restore cellular homeostasis. The unfolded protein response (UPR) sensors contribute to tumor initiation in many cancers. We found that all three UPR pathways were activated in mouse and human PNFs, with protein kinase RNA [PKR]-like ER kinase (PERK) the most highly expressed. We tested if neurofibroma cells adapt to ER stress, leading to their growth. Pharmacological or genetic inhibition of PERK reduced mouse neurofibroma-sphere number, and genetic inhibition in PERK in Schwann cell precursors (SCPs) decreased tumor-like lesion numbers in a cell transplantation model. Further, in a PNF mouse model, deletion of PERK in Schwann cells (SCs) and SCPs reduced tumor size, number, and increased survival. Mechanistically, loss of Nf1 activated PERK-eIF2α-ATF4 signaling and increased ATF4 downstream target gene p21 translocation from nucleus to cytoplasm. This nucleus-cytoplasm translocation was mediated by exportin-1. Runx transcriptionally activated ribosome gene expression and increased protein synthesis to allow SCs to adapt to ER stress and tumor formation. We propose that targeting proteostasis might provide cytotoxic and/or potentially durable novel therapy for PNFs.

Reconstruction on the surface of an SCFO perovskite oxide by acid treatment leads to improved OER performance.

The first sodium borate-squarate, Na2(C4O4)(H3BO3)(H2O)4·H3BO3, with strong SHG response obtained by the synergy effect between two planar NLO-active motifs.

Both n- and p-type ohmic contact to MoS2 can be obtained via different CuS surfaces, due to the weak metallicity and large work function variation of the CuS surfaces, and due to interface quasi-bonding between CuS and MoS2.

This paper is concerned with the security issue in the state estimation problem for a networked control system (NCS). A new model of joint false data injection (FDI) attack is established wherein attacks are injected to both the remote estimator and the communication channels. Such a model is general that includes most existing FDI attack models as special cases. The joint FDI attacks are subjected to limited access and/or resource constraints, and this gives rise to a few attack scenarios to be examined one by one. Our objective is to establish the so-called insecurity conditions under which there exists an attack sequence capable of driving the estimation bias to infinity while bypassing the anomaly detector. By resorting to the generalized inverse theory, necessary and sufficient conditions are derived for the insecurity under different attack scenarios. Subsequently, easy-to-implement algorithms are proposed to generate attack sequences on insecure NCSs with respect to different attack scenarios. In particular, by using a matrix splitting technique, the constraint-induced sparsity of the attack vectors is dedicatedly investigated. Several numerical examples are

pH is one of the important parameters of a biological microenvironment, which is closely related to cell growth, development, vitality, division, and differentiation. Monitoring the pH of a microenvironment is helpful to monitor the cell metabolism as well as to understand the cellular life cycle. The sensitivity of liquid metals (LMs) to hydrogen ions has aroused our interest. Here, we propose a novel but facile pH sensor using liquid gallium (LM for short) droplet morphological change as the readout. The pH sensing characteristics of the LM droplet were examined, especially the shape response. LM can form solid native oxide skin rapidly in oxygenated solution, and the oxide layer will be removed in acidic or alkaline solutions, which will cause a great change in surface tension. The phenomenon is the change of LM morphology from macroscopic observation. We explored the electrochemical characteristics of LM at different pH values, explained the mechanism of surface change, and calibrated the relationship curve between LM morphology and pH and the interference of impurity ions on the sensor. Finally, we proposed a detection algorithm for the LM pH morphology sensor and tried to automatically detect pH with a mobile app, which was applied to the pH detection of cell culture solution. We believe that the response characteristics of LM to hydrogen ions have great potential in microenvironment detection.

tRNA molecules contain dense, abundant modifications that affect tRNA structure, stability, mRNA decoding and tsRNA formation. tRNA modifications and related enzymes are responsive to environmental cues and are associated with a range of physiological and pathological processes. However, there is a lack of resources that can be used to mine and analyse these dynamically changing tRNA modifications. In this study, we established tModBase (https://www.tmodbase.com/) for deciphering the landscape of tRNA modification profiles from epitranscriptome data. We analysed 103 datasets generated with second- and third-generation sequencing technologies and illustrated the misincorporation and termination signals of tRNA modification sites in ten species. We thus systematically demonstrate the modification profiles across different tissues/cell lines and summarize the characteristics of tRNA-associated human diseases. By integrating transcriptome data from 32 cancers, we developed novel tools for analysing the relationships between tRNA modifications and RNA modification enzymes, the expression of 1442 tRNA-derived small RNAs (tsRNAs), and 654 DNA variations. Our database will provide new insights into the features of tRNA modifications and the biological pathways in which they participate.

Estimating the evolutionary power spectral density (EPSD) of non-stationary winds (e.g., tropical storms and downbursts) is necessary to predict the response of structures under such extreme winds. Following the review of the existing direct estimation methods of EPSD, this paper offers a two-step unified formulation, i.e., raw estimation and associated error reduction. The raw estimation is expressed in terms of a time-frequency transform with a general kernel function. It is shown that if the kernel function is described by a time-frequency analysis tool such as the short-time Fourier transform, the wavelet transform, and the S-transform, the generalized raw EPSD estimation becomes a particular case of the existing methods. The unified estimation method presented here can be viewed as a filter bank with adjustable time and frequency resolution. The analysis of error in the raw estimation is carried out on the bias and random errors accounting for the approximation in both the time and frequency domains. Various techniques for reducing such errors are then summarized and recast in the unified formulation, including series expansion, short-time window smoothing, and multi-tapering. Based on the unified perspective, a discussion and some prospects of EPSD estimating are provided.

There have been a number of studies on the Plateau–Rayleigh instability and the influence of the initial jet perturbation on the jet breakup. Our study observed that the threshold lengths of jet breakup varied with the voltage applied to the piezoelectric sheets during the droplet generation for extreme-ultraviolet (EUV) source and wafer cleaning. Combining acoustics and fluid mechanics, we investigated the process and mechanism to interpret the impact of the horn vibration on the jet breakup. The whole process of the vibration delivery from the horn to the jet was summarized: generated by the horn, the vibration transmits into the water, spreads in the chamber, stimulates the jet through the orifice, and grows continuously, causing the jet breakup. In order to validate the analysis, a series of experiments were carried out and compared with the theoretical predictions. The vibration mode and amplitude of the horn were determined by the scanning laser vibrometer. With the hydrophone detection, the distribution of the vibration in the axial direction at the nozzle outlet was studied, and the delivery of the vibration in the chamber was discussed. To verify the influence of the vibration in the chamber on the jet breakup, we compared the results of jet breakup under different sound pressures. Besides, a theoretical model of the jet breakup length versus the piezoelectric sheet voltage was proposed. The study of the whole process provides guidance for changing the jet breakup length by adjusting the voltage and helps to investigate other parameters of the jet breakup process.

STUDY QUESTION Is there an efficient and cost-effective detection platform for different genetic conditions about embryos? SUMMARY ANSWER A multifunctional haplotyping-based preimplantation genetic testing platform was provided for detecting different genetic conditions. WHAT IS KNOWN ALREADY Genetic disease and chromosomal rearrangement have been known to significantly impact fertility and development. Therefore, preimplantation genetic testing for aneuploidy (PGT-A), monogenic disorders (PGT-M) and structural rearrangements (PGT-SR), a part of ART, has been presented together to minimize the fetal genetic risk and increase pregnancy rate. For patients or their families who are suffering from chromosome abnormality, monogenic disease, unexplained repeated spontaneous abortion or implantation failure, after accepting genetic counseling, they may be suggested to accept detection from more than one PGT platforms about the embryos to avoid some genetic diseases. However, PGT platforms work through different workflows. The high costliness, lack of material and long-time operation of combined PGT platforms limit their application. STUDY DESIGN, SIZE, DURATION All 188 embryonic samples from 43 families were tested with HaploPGT platform, and most of their genetic abnormalities had been determined by different conventional PGT methods beforehand. Among them, there were 12 families only carrying structural rearrangements (115 embryos) in which 9 families accepted implantation and 5 families had normal labor ART outcomes, 7 families only carrying monogenic diseases (26 embryos) and 3 families carrying both structural rearrangements and monogenic diseases (26 embryos). Twelve monopronucleated zygotes (1PN) samples and 9 suspected triploid samples were collected from 21 families. PARTICIPANTS/MATERIALS, SETTINGS, METHODS Here, we raised a comprehensive PGT method called HaploPGT, combining reduced representation genome sequencing, read-count analysis, B allele frequency and haplotyping analysis, to simultaneously detect different genetic disorders in one single test. MAIN RESULTS AND THE ROLE OF CHANCE With 80 million reads (80M) genomic data, the proportion of windows (1 million base pairs (Mb)) containing two or more informative single nucleotide polymorphism (SNP) sites was 97.81%, meanwhile the genotyping error rate stabilized at a low level (2.19%). Furthermore, the informative SNPs were equally distributed across the genome, and whole-genomic haplotyping was established. Therefore, 80M was chosen to balance the cost and accuracy in HaploPGT. HaploPGT was able to identify abnormal embryos with triploid, global and partial loss of heterozygosity, and even to distinguish parental origin of copy number variation in mosaic and non-mosaic embryos. Besides, by retrospectively analyzing 188 embryonic samples from 43 families, HaploPGT revealed 100% concordance with the available results obtained from reference methods, including PGT-A, PGT-M, PGT-SR and PGT-HLA. LIMITATIONS, REASON FOR CAUTION Despite the numerous benefits HaploPGT could bring, it still required additional family members to deduce the parental haplotype for identifying balanced translocation and monogenic mutation in tested embryos. In terms of PGT-SR, the additional family member could be a reference embryo with unbalanced translocation. For PGT-M, a proband was normally required. In both cases, genomic information from grandparents or parental siblings might help for haplotyping theoretically. Another restriction was that haploid, and diploid resulting from the duplication of a haploid, could not be told apart by HaploPGT, but it was able to recognize partial loss of heterozygosity in the embryonic genome. In addition, it should be noted that the location of rearrangement breakpoints and the situation of mutation sites were complicated, which meant that partial genetic disorders might not be completely detected. WIDER IMPLICATIONS OF THE FINDINGS HaploPGT is an efficient and cost-effective detection platform with high clinical value for detecting genetic status. This platform could promote the application of PGT in ART, to increase pregnancy rate and decrease the birth of children with genetic diseases. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by grants from the National Natural Science Foundation of China (81873478, to L.H.), National Key R&D Program of China (2018YFC1003100, to L.H.), the Natural Science Foundation of Hunan Province (Grant 2022JJ30414, to P.X.), Hunan Provincial Grant for Innovative Province Construction (2019SK4012) and the Scientific Research Foundation of Reproductive and Genetic Hospital of China International Trust & Investment Corporation (CITIC)-Xiangya (YNXM-201910). Haplotyping analysis has been licensed to Basecare Co., Ltd. L.K., Y.M., K.K., D.Z., N.L., J.Z. and R.D. are Basecare Co., Ltd employees. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.

Triploids are rare in nature because of difficulties in meiotic and gametogenic processes, especially in vertebrates. The Carassius complex of cyprinid teleosts contains sexual tetraploid crucian carp/goldfish (C. auratus) and unisexual hexaploid gibel carp/Prussian carp (C. gibelio) lineages, providing a valuable model for studying the evolution and maintenance mechanism of unisexual polyploids in vertebrates. Here we sequence the genomes of the two species and assemble their haplotypes, which contain two subgenomes (A and B), to the chromosome level. Sequencing coverage analysis reveals that C. gibelio is an amphitriploid (AAABBB) with two triploid sets of chromosomes; each set is derived from a different ancestor. Resequencing data from different strains of C. gibelio show that unisexual reproduction has been maintained for over 0.82 million years. Comparative genomics show intensive expansion and alterations of meiotic cell cycle-related genes and an oocyte-specific histone variant. Cytological assays indicate that C. gibelio produces unreduced oocytes by an alternative ameiotic pathway; however, sporadic homologous recombination and a high rate of gene conversion also exist in C. gibelio. These genomic changes might have facilitated purging deleterious mutations and maintaining genome stability in this unisexual amphitriploid fish. Overall, the current results provide novel insights into the evolutionary mechanisms of the reproductive success in unisexual polyploid vertebrates.

Ligand-enabled Pd-catalyzed regioselective α,β-dehydrogenation of carbonyl compounds via β-methylene C-H activation has recently emerged as a promising transformation. Herein, we report the realization of β,γ-dehydrogenation and subsequent vinyl C-H olefination reactions of free carboxylic acids, thus providing a unique method for the structural diversification of aliphatic acids containing α-quaternary centers through sequential functionalizations of two β-C-H bonds and one γ-C-H bond. This tandem dehydrogenation-olefination-lactonization reaction offers a one-step preparation of β-alkylidene-γ-lactones, which are often difficult to prepare through conventional methods, from inexpensive and abundant free aliphatic acids. A variety of free aliphatic acids, such as isosteviol and grandiflorolic acid natural products, and olefins are compatible with the reported protocol. The newly designed bidentate oxime ether-pyridone and morpholine-pyridone ligands are crucial for this tandem reaction to proceed. Notably, these ligands also enable preferential methylene C-H activation over the previously reported, competing process of methyl C-H bond olefination.

The use of light to regulate photocatalyzed reversible deactivation radical polymerization (RDRP) under mild conditions, especially driven by broadband light or sunlight directly, is highly desired. But the development of a suitable photocatalyzed polymerization system for large-scale production of polymers, especially block copolymers, has remained a big challenge. Herein, we report the development of a phosphine-based conjugated hypercrosslinked polymer (PPh3-CHCP) photocatalyst for an efficient large-scale photoinduced copper-catalyzed atom transfer radical polymerization (Cu-ATRP). Monomers including acrylates and methyl acrylates can achieve near-quantitative conversions under a wide range (450–940 nm) of radiations or sunlight directly. The photocatalyst could be easily recycled and reused. The sunlight-driven Cu-ATRP allowed the synthesis of homopolymers at 200 mL from various monomers, and monomer conversions approached 99% in clouds intermittency with good control over polydispersity. In addition, block copolymers at 400 mL scale can also be obtained, which demonstrates its great potential for industrial applications.

Species coculture can increase agro-biodiversity and therefore constitutes an ecological intensification measure for agriculture. Rice-aquatic animal coculture, one type of species coculture, has been practiced and researched widely. Here, we review recent studies and present results of a quantitative analysis of literature on rice–aquatic animal coculture systems. We address three questions: (i) can rice yield and soil fertility be maintained or increased with less chemical input through rice-aquatic animal coculture? (ii) how do aquatic animals benefit the paddy ecosystem? (iii) how can coculture be implemented for ecological intensification? Meta-analysis based on published papers showed that rice-aquatic animal cocultures increased rice yield, soil organic carbon, and total nitrogen and decreased insect pests and weeds compared to rice monocultures. Studies also showed that rice-aquatic animal cocultures reduced pesticide and fertilizer application compared to rice monocultures. Rice plants provide a beneficial environment for aquatic animals, leading to high animal activities in the field. Aquatic animals, in turn, help remove rice pests and act as ecological engineers that affect soil conditions, which favor the growth of rice plants. Aquatic animals promote nutrient cycling and the complementary use of nutrients between rice and aquatic animals, which enhances nutrient-use efficiency in the coculture. To generate beneficial outcomes, how to develop compatible partnerships between rice and aquatic animals, and compatible culturing strategies for coculture systems are the key points. Investigating which traits of aquatic animals and rice varieties could best match to create productive and sustainable coculture systems could be one of the future focuses.

Background Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of chemotherapy with poorly understood mechanisms and few treatments. High-mobility group box 1 (HMGB1)-induced neuroinflammation is the main cause of CIPN. Here, we aimed to illustrate the role of the macrophage scavenger receptor A1 (SR-A1) in HMGB1 clearance and CIPN resolution. Methods Oxaliplatin (L-OHP) was used to establish a CIPN model. Recombinant HMGB1 (rHMGB1) (his tag) was used to evaluate the phagocytosis of HMGB1 by macrophages. Results In the clinic, HMGB1 expression and MMP-9 activity were increased in the plasma of patients with CIPN. Plasma HMGB1 expression was positively correlated with the cumulative dose of L-OHP and the visual analog scale. In vitro, engulfment and degradation of rHMGB1 increased and inflammatory factor expression decreased after AMP-activated protein kinase (AMPK) activation. Neutralizing antibodies, inhibitors, or knockout of SR-A1 abolished the effects of AMPK activation on rHMGB1 engulfment. In vivo, AMPK activation increased SR-A1 expression in the dorsal root ganglion, decreased plasma HMGB1 expression and MMP-9 activity, and attenuated CIPN, which was abolished by AMPK inhibition or SR-A1 knockout in the CIPN mice model. Conclusion Activation of the AMPK/SR-A1 axis alleviated CIPN by increasing macrophage-mediated HMGB1 engulfment and degradation. Therefore, promoting HMGB1 clearance may be a potential treatment strategy for CIPN.

Background To investigate the anti-inflammatory and antioxidative effects of gallic acid (GA) on human corneal epithelial cells (HCECs) and RAW264.7 macrophages as well as its therapeutic effects in an experimental dry eye (EDE) mouse model. Methods A cell counting kit-8 (CCK-8) assay was used to test the cytotoxicity of GA. The effect of GA on cell migration was evaluated using a scratch wound healing assay. The anti-inflammatory and antioxidative effects of GA in vitro were tested using a hypertonic model (HCECs) and an inflammatory model (RAW264.7 cells). The in vivo biocompatibility of GA was detected by irritation tests in rabbits, whereas the preventive and therapeutic effect of GA in vivo was evaluated using a mouse model of EDE. Results In the range of 0–100 μM, GA showed no cytotoxicity in RAW264.7 cells or HCECs and did not delay the HCECs monolayer wound healing within 24 h. Ocular tolerance to GA in the in vivo irritation test was good after seven days. In terms of antioxidative activity, GA significantly reduced the intracellular reactive oxygen species (ROS) in lipopolysaccharide (LPS) activated RAW264.7 macrophages and HCECs exposed to hyperosmotic stress. Furthermore, after pre-treatment with GA, the expression levels of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and NADPH quinone oxidoreductase-1 (NQO-1) were significantly upregulated in RAW264.7 macrophages. GA also exhibits excellent anti-inflammatory properties. This is mainly demonstrated by the ability of GA to effectively downregulate the nuclear transcription factor-κB (NF-κB) pathway in LPS-activated RAW264.7 macrophages and to reduce inflammatory factors, such as nitric oxide (NO), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α). In vivo efficacy testing results in a mouse model of EDE showed that GA can effectively prevent and inhibit the apoptosis of corneal epithelial cells (CECs), reduce inflammatory factors in the cornea and conjunctiva as well as protect goblet cells. Conclusion In vitro and in vivo results indicate that GA possesses potent anti-inflammatory and antioxidative properties with no apparent cytotoxicity within the range of 0–100 μM. It is a promising eye drop formulation for the effective prevention and treatment of dry eye disease (DED).

Background: IL-37 (interleukin-37), a natural suppressor of innate inflammatory and immune responses, is increased in patients with myocardial infarction. Platelets play an important role in the progress of myocardial infarction, but the direct effects of IL-37 on platelet activation and thrombosis, as well as the underlying mechanisms, still remain unclear. Methods: We evaluated the direct effects of IL-37 on agonists-induced platelet activation and thrombus formation, as well as revealed the underlying mechanisms using platelet-specific IL-1R8 (IL-1 receptor 8)–deficient mice. Using myocardial infarct model, we explored the effects of IL-37 on microvascular obstruction and myocardial injury. Results: IL-37 directly inhibited agonists-induced platelet aggregation, dense granule ATP release, P-selectin exposure, integrin αIIbβ3 activation, platelet spreading, and clot retraction. IL-37 inhibited thrombus formation in vivo in a FeCl 3 -injured mesenteric arteriole thrombosis mouse model and ex vivo in a microfluidic whole-blood perfusion assay. Mechanistic studies using platelet-specific IL-1R8–deficient mice revealed that IL-37 bound to platelet IL-1R8 and IL-18Rα, and IL-1R8 deficiency impaired the inhibitory effects of IL-37 on platelet activation. Using PTEN (phosphatase and tensin homolog)-specific inhibitor and PTEN-deficient platelets, we found that IL-37 combined with IL-1R8 to enhance PTEN activity, inhibit Akt (protein kinase B), mitogen-activated protein kinases, and spleen tyrosine kinase pathways, as well as decrease the generation of reactive oxygen species to regulate platelet activation. Exogenous IL-37 injection suppressed microvascular thrombosis to protect against myocardial injury in wild-type mice but not in platelet-specific IL-1R8–deficient mice after permanent ligation of the left anterior descending coronary. Finally, a negative correlation between plasma IL-37 concentration and platelet aggregation was observed in patients with myocardial infarction. Conclusions: IL-37 directly attenuated platelet activation, thrombus formation, and myocardial injury via IL-1R8 receptor. Accumulated IL-37 in plasma inhibited platelet activation to ameliorate atherothrombosis and infarction expansion, and thus may have therapeutic advantages as potential antiplatelet drugs.

In this study, three different parameters of the serrated joint interface design are proposed to improve the strength of the joint,and the relationship between joint design and mechanical properties was studied in detail. In addition, the influence of joint design on welding was also studied.The results show that the joint strength increases first and then decreases with the increase of the width of the serrated joint. When the width of serrated joint is 1.5mm, the ultimate tensile strength of the joint is the highest (383Mpa). With the width of the serrated joint increases, the effective load bearing area increases and the energy caused by work hardening increases. When the width of the joint is too wide, defects such as holes will occur at the bottom of the material, ultimately resulting in decreased strength.In addition, the number of fine hook structures formed at the interface is related to the width of the joint design. The wider the width of the serrated joint, the more hook structures are formed.