A metal-poor star with abundances from a pair-instability supernova.

The most massive and shortest-lived stars dominate the chemical evolution of the pre-galactic era. On the basis of numerical simulations, it has long been speculated that the mass of such first-generation stars was up to several hundred solar masses1-4. The very massive first-generation stars with a mass range from 140 to 260 solar masses are predicted to enrich the early interstellar medium through pair-instability supernovae (PISNe)5. Decades of observational efforts, however, have not been able to uniquely identify the imprints of such very massive stars on the most metal-poor stars in the Milky Way6,7. Here we report the chemical composition of a very metal-poor (VMP) star with extremely low sodium and cobalt abundances. The sodium with respect to iron in this star is more than two orders of magnitude lower than that of the Sun. This star exhibits very large abundance variance between the odd- and even-charge-number elements, such as sodium/magnesium and cobalt/nickel. Such peculiar odd-even effect, along with deficiencies of sodium and α elements, are consistent with the prediction of primordial pair-instability supernova (PISN) from stars more massive than 140 solar masses. This provides a clear chemical signature indicating the existence of very massive stars in the early universe.

Accelerating diabetic wound healing by ROS-scavenging lipid nanoparticle-mRNA formulation.

Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA. TS2-IL4 LNP-mRNA effectively scavenges excess ROS at the wound site and induces the expression of IL4 in macrophages, promoting the polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype at the wound site. In a diabetic wound model of db/db mice, treatment with this formulation significantly accelerates wound healing by enhancing the formation of an intact epidermis, angiogenesis, and myofibroblasts. Overall, this TS LNP-mRNA platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care.

Single-Atom Catalysts Mediated Bioorthogonal Modulation of N6-Methyladenosine Methylation for Boosting Cancer Immunotherapy.

Bioorthogonal reactions provide a powerful tool to manipulate biological processes in their native environment. However, the transition-metal catalysts (TMCs) for bioorthogonal catalysis are limited to low atomic utilization and moderate catalytic efficiency, resulting in unsatisfactory performance in a complex physiological environment. Herein, sulfur-doped Fe single-atom catalysts with atomically dispersed and uniform active sites are fabricated to serve as potent bioorthogonal catalysts (denoted as Fe-SA), which provide a powerful tool for in situ manipulation of cellular biological processes. As a proof of concept, the N6-methyladensoine (m6A) methylation in macrophages is selectively regulated by the mannose-modified Fe-SA nanocatalysts (denoted as Fe-SA@Man NCs) for potent cancer immunotherapy. Particularly, the agonist prodrug of m6A writer METTL3/14 complex protein (pro-MPCH) can be activated in situ by tumor-associated macrophage (TAM)-targeting Fe-SA@Man, which can upregulate METTL3/14 complex protein expression and then reprogram TAMs for tumor killing by hypermethylation of m6A modification. Additionally, we find the NCs exhibit an oxidase (OXD)-like activity that further boosts the upregulation of m6A methylation and the polarization of macrophages via producing reactive oxygen species (ROS). Ultimately, the reprogrammed M1 macrophages can elicit immune responses and inhibit tumor proliferation. Our study not only sheds light on the design of single-atom catalysts for potent bioorthogonal catalysis but also provides new insights into the spatiotemporal modulation of m6A RNA methylation for the treatment of various diseases.

In Vitro Detection of S100B and Severity Evaluation of Traumatic Brain Injury Based on Biomimetic Peptide-Modified Nanochannels.

The diagnosis and evaluation of traumatic brain injury (TBI) are crucial steps toward the treatment and prognosis of patients. A common question remains as to whether it is possible to introduce an ideal device for signal detection and evaluation that can directly connect digital signals with TBI, thereby enabling prompt response of the evaluation signal and sensitive and specific functioning of the detection process. Herein, a method is presented utilizing polymetric porous membranes with TRTK-12 peptide-modified nanochannels for the detection of S100B (a TBI biomarker) and assessment of TBI severity. The method leverages the specific bonding force between TRTK-12 peptide and S100B protein, along with the nanoconfinement effect of nanochannels, to achieve high sensitivity (LOD: 0.002 ng mL-1) and specificity (∆I/I0: 44.7%), utilizing ionic current change as an indicator. The proposed method, which is both sensitive and specific, offers a simple yet responsive approach for real-time evaluation of TBI severity. This innovative technique provides valuable scientific insights into the advancement of future diagnostic and therapeutic integration devices.

TransFlow: a Snakemake workflow for transmission analysis of Mycobacterium tuberculosis whole-genome sequencing data.

MOTIVATION: Whole-genome sequencing (WGS) is increasingly used to aid the understanding of Mycobacterium tuberculosis (MTB) transmission. The epidemiological analysis of tuberculosis based on the WGS technique requires a diverse collection of bioinformatics tools. Effectively using these analysis tools in a scalable and reproducible way can be challenging, especially for non-experts. RESULTS: Here, we present TransFlow (Transmission Workflow), a user-friendly, fast, efficient and comprehensive WGS-based transmission analysis pipeline. TransFlow combines some state-of-the-art tools to take transmission analysis from raw sequencing data, through quality control, sequence alignment and variant calling, into downstream transmission clustering, transmission network reconstruction and transmission risk factor inference, together with summary statistics and data visualization in a summary report. TransFlow relies on Snakemake and Conda to resolve dependencies among consecutive processing steps and can be easily adapted to any computation environment. AVAILABILITY AND IMPLEMENTATION: TransFlow is free available at https://github.com/cvn001/transflow. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Cell membrane-camouflaged liposomes for tumor cell-selective glycans engineering and imaging in vivo.

The dynamic change of cell-surface glycans is involved in diverse biological and pathological events such as oncogenesis and metastasis. Despite tremendous efforts, it remains a great challenge to selectively distinguish and label glycans of different cancer cells or cancer subtypes. Inspired by biomimetic cell membrane-coating technology, herein, we construct pH-responsive azidosugar liposomes camouflaged with natural cancer-cell membrane for tumor cell-selective glycan engineering. With cancer cell-membrane camouflage, the biomimetic liposomes can prevent protein corona formation and evade phagocytosis of macrophages, facilitating metabolic glycans labeling in vivo. More importantly, due to multiple membrane receptors, the biomimetic liposomes have prominent cell selectivity to homotypic cancer cells, showing higher glycan-labeling efficacy than a single-ligand targeting strategy. Further in vitro and in vivo experiments indicate that cancer cell membrane-camouflaged azidosugar liposomes not only realize cell-selective glycan imaging of different cancer cells and triple-negative breast cancer subtypes but also do well in labeling metastatic tumors. Meanwhile, the strategy is also applicable to the use of tumor tissue-derived cell membranes, which shows the prospect for individual diagnosis and treatment. This work may pave a way for efficient cancer cell-selective engineering and visualization of glycans in vivo.

Emergence and evolution of drug-resistant Mycobacterium tuberculosis in eastern China: A six-year prospective study.

Understanding the emergence and evolution of drug resistance can inform public health intervention to combat tuberculosis (TB). In this prospective molecular epidemiological surveillance study from 2015 to 2021 in eastern China, we prospectively collected whole-genome sequencing and epidemiological data on TB patients. We dissect the ordering of drug resistance mutation acquisition for nine commonly used anti-TB drugs, and we found that the katG S315T mutation first appeared around 1959, followed by rpoB S450L (1969), rpsL L43A (1972), embB M306V (1978), rrs 1401 (1981), fabG1 (1982), pncA (1985) and folC (1988) mutations. GyrA gene mutations appeared after the year of 2000. We observed that the first expansion of Mycobacterium tuberculosis (M.tb) resistance population among eastern China appeared after the introduction of isoniazid, streptomycin and para-amino salicylic acid, and the second expansion after the ethambutol, rifampicin, pyrazinamide, ethionamide and aminoglycosides. We speculate these two expansions are linked with population shift historically. By geospatial analysis, we found drug-resistant isolates migrated within eastern China. With epidemiological data of clonal strains, we observed some strains can evolve continuously in individuals and transmit readily in a population. In conclusion, this study mirrored the emergence and evolution of drug-resistant M.tb in eastern China were linked to the sequence and timing of introduction of anti-TB drugs, and multiple factors may contribute to the resistant population enlarged. To resolve the epidemic of drug-resistant TB, it requires applying anti-TB drugs carefully and/or identifying resistant patients timely to prevent them from developing high-level resistance and transmitting to others.

An Antibody Engineered Metalloenzyme for Mediating Cell-Cell Communication and Activation of Immuno- and Chemotherapy.

Artificial metalloenzymes (ArMs) are gaining much attention in life sciences. However, the function of the present ArMs for disease treatment is still in its infancy, which may impede the possible therapeutic potential. Herein, we construct an antibody engineered ArM by using the Fc region of IgG and bioorthogonal chemistry, which endows the ArM with the capability of manipulating cell-cell communication and bioorthogonal catalysis for tumor immuno- and chemotherapy. Specially, Fc-Pd ArM is modified on the cancer cell surface by metabolic glycoengineering to catalyze the bioorthogonal activation of prodrug for tumor chemotherapy. More importantly, the antibody-based ArM can mediate cell-cell communication between cancer cells and NK cells, activating the ADCC effect for immunotherapy. In vivo antitumor applications suggest that the ArM can not only eliminate primary tumor but also inhibit tumor lung metastasis. Our work provides a new attempt to develop artificial metalloenzymes with cell-cell communication the ability for bioorthogonal catalysis and combination therapy.

Bioorthogonal-Activated In Situ Vaccine Mediated by a COF-Based Catalytic Platform for Potent Cancer Immunotherapy.

Personalized tumor vaccines have become a promising modality for cancer immunotherapy. However, in situ personalized tumor vaccines generated from immunogenic cancer cell death (ICD) and adjuvants are mired by toxic side effects and unsatisfactory efficiency. Herein, by functionalizing the reticular structure to optimize the catalytic activity of the materials, a series of biocompatible covalent organic framework (COF)-based catalysts have been designed and screened for establishing a bioorthogonal-activated in situ cancer vaccine in an efficient and safe way. Especially, pro-doxorubicin (pro-DOX) could be bioorthogonally activated in situ by the COF-based Fe(II) catalysts, which elicited ICD and released tumor-associated antigens (TAAs). This in situ prodrug activation strategy could minimize drug side effects and maximize treatment effects. More importantly, the system could also catalytically activate pro-imiquimod (pro-IMQ, a TLR7/8 immune agonist), which served as an adjuvant to amplify the antitumor immunity. Notably, this bioorthogonal-activated in situ cancer vaccine not only facilitated a strong antitumor immune response but also prevented the dose-dependent side effects of chemotherapeutic drugs, including systemic inflammation caused by the random distribution of adjuvants. To the best of our knowledge, it is the first time to devise an efficient catalytic platform for generating an in situ bioorthogonal-activated cancer vaccine, which would provide a paradigm for achieving secure and robust immunotherapy.

Bioorthogonal Disruption of Pyroptosis Checkpoint for High-Efficiency Pyroptosis Cancer Therapy.

Pyroptosis is an inflammatory form of programmed cell death that holds great promise in cancer therapy. However, autophagy as the crucial pyroptosis checkpoint and the self-protective mechanism of cancer cells significantly weakens the therapeutic efficiency. Here, a bioorthogonal pyroptosis nanoregulator is constructed to induce pyroptosis and disrupt the checkpoint, enabling high-efficiency pyroptosis cancer therapy. The nanoregulator allows the in situ synthesis and accumulation of the photosensitizer PpIX in the mitochondria of cancer cells to directly produce mitochondrial ROS, thus triggering pyroptosis. Meanwhile, the in situ generated autophagy inhibitor via palladium-catalyzed bioorthogonal chemistry can disrupt the pyroptosis checkpoint to boost the pyroptosis efficacy. With the biomimetic cancer cell membrane coating, this platform for modulating pyroptosis presents specificity to cancer cells and poses no harm to normal tissue, resulting in a highly efficient and safe antitumor treatment. To our knowledge, this is the first report on a disrupting intrinsic protective mechanism of cancer cells for tumor pyroptosis therapy. This work highlights that autophagy as a checkpoint plays a key regulative role in pyroptosis therapy, which would motivate the future design of therapeutic regimens.

Design, synthesis and evaluation of quinoline-O-carbamate derivatives as multifunctional agents for the treatment of Alzheimer's disease.

A series of novel quinoline-O-carbamate derivatives was rationally designed for treating Alzheimer's disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated by AChE/BuChE inhibition and anti-inflammatory property. The in vitro activities showed that compound 3f was a reversible dual eeAChE/eqBuChE inhibitor with IC50 values of 1.3 µM and 0.81 µM, respectively. Moreover, compound 3f displayed good anti-inflammatory property by decreasing the production of IL-6, IL-1ß and NO. In addition, compound 3f presented significant neuroprotective effect on Aß25-35-induced PC12 cell injury. Furthermore, compound 3f presented good stabilities in artificial gastrointestinal fluids, liver microsomes in vitro and plasma. Furthermore, compound 3f could improve AlCl3-induced zebrafish AD model by increasing the level of ACh. Therefore, compound 3f was a promising multifunctional agent for the treatment of AD.

Quantum Fourier analysis.

Quantum Fourier analysis is a subject that combines an algebraic Fourier transform (pictorial in the case of subfactor theory) with analytic estimates. This provides interesting tools to investigate phenomena such as quantum symmetry. We establish bounds on the quantum Fourier transform F, as a map between suitably defined [Formula: see text] spaces, leading to an uncertainty principle for relative entropy. We cite several applications of quantum Fourier analysis in subfactor theory, in category theory, and in quantum information. We suggest a topological inequality, and we outline several open problems.

Target-Specific Bioorthogonal Reactions for Precise Biomedical Applications.

Bioorthogonal chemistry is a promising toolbox for dissecting biological processes in the native environment. Recently, bioorthogonal reactions have attracted considerable attention in the medical field for treating diseases, since this approach may lead to improved drug efficacy and reduced side effects via in situ drug synthesis. For precise biomedical applications, it is a prerequisite that the reactions should occur in the right locations and on the appropriate therapeutic targets. In this minireview, we highlight the design and development of targeted bioorthogonal reactions for precise medical treatment. First, we compile recent strategies for achieving target-specific bioorthogonal reactions. Further, we emphasize their application for the precise treatment of different therapeutic targets. Finally, a perspective is provided on the challenges and future directions of this emerging field for safe, efficient, and translatable disease treatment.

A Polyoxometalate-Based Pathologically Activated Assay for Efficient Bioorthogonal Catalytic Selective Therapy.

Since polyoxometalates (POMs) can undergo reversible multi-electron redox transformations, they have been used to modulate the electronic environment of metal nanoparticles for catalysis. Besides, POMs possess unique electronic structures and acid-responsive self-assembly ability. These properties inspired us to tackle the drawbacks of the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction in biomedical applications, such as low catalytic efficiency and unsatisfactory disease selectivity. Herein, we construct molybdenum (Mo)-based POM nanoclusters doped with Cu (Cu-POM NCs) as a highly efficient bioorthogonal catalyst, which is responsive to pathologicallyacid and H2 S for selective antibiofilm therapy. Leveraging the merits of POMs, the Cu-POM NCs exhibit biofilm-responsive self-assembly behavior, efficient CuAAC-mediated in situ synthesis of antibacterial molecules, and a NIR-II photothermal effect selectively triggered by H2 S in pathogens. The consumption of bacterial H2 S at the pathological site by Cu-POM NCs extremely decreases the number of persisterbacteria, which is conducive to the inhibition of bacterial tolerance and elimination of biofilms. Unlocked at pathological sites and endowed with NIR-II photothermal property, the constructed POM-based bioorthogonal catalytic platform provides new insights into the design of efficient and selective bioorthogonal catalysts for disease therapy.

Liquid Metal as Bioinspired and Unusual Modulator in Bioorthogonal Catalysis for Tumor Inhibition Therapy.

Bioorthogonal catalysis mediated by Pd-based transition metal catalysts has sparked increasing interest in combating diseases. However, the catalytic and therapeutic efficiency of current Pd0 catalysts is unsatisfactory. Herein, inspired by the concept that ligands around metal sites could enable enzymes to catalyze astonishing reactions by changing their electronic environment, a LM-Pd catalyst with liquid metal (LM) as an unusual modulator has been designed to realize efficient bioorthogonal catalysis for tumor inhibition. The LM matrix can serve as a "ligand" to afford an electron-rich environment to stabilize the active Pd0 and promote nucleophilic turnover of the π-allylpalladium species to accelerate the uncaging process. Besides, the photothermal properties of LM can lead to the enhanced removal of tumor cells by photo-enhanced catalysis and photothermal effect. We believe that our work will broaden the application of LM and motivate the design of bioinspired bioorthogonal catalysts.

Development of naringenin-O-alkylamine derivatives as multifunctional agents for the treatment of Alzheimer's disease.

In this study, a series of naringenin-O-alkylamine derivatives were designed and obtained by introducing an alkylamine fragment into the naringenin skeleton. The in vitro biological activity results revealed that compounds 5f and 7k showed good antioxidant activity with ORAC values of 2.3eq and 1.2eq, respectively. Compounds 5f and 7k were reversible and excellent huAChE inhibitors with IC50 values of 0.91 µM and 0.57 µM, respectively. Moreover, compounds 5f and 7k could inhibit self-induced Aß1-42 aggregation with 62.1% and 43.8% inhibition rate, respectively, and significantly inhibited huAChE-Aß1-40 aggregation with 51.7% and 43.4% inhibition rate, respectively. In addition, compounds 5f and 7k were selective metal chelators and remarkably inhibited Cu2+-induced Aß1-42 aggregation with 73.5% and 68.7% inhibition rates, respectively. Furthermore, compounds 5f and 7k could cross the blood-brain barrier in vitro and displayed good neuroprotective effects and anti-inflammatory properties. Further investigation showed that compound 5f did not show obvious hepatotoxicity and displayed a good hepatoprotective effect by its antioxidant activity. The in vivo study displayed that compound 5f significantly improved scopolamine-induced mice memory impairment. Therefore, compound 5f was a potential multifunctional candidate for the treatment of AD.

Mid-State Kalman Filter for Nonlinear Problems.

When tracking very long-range targets, wide-band radars capable of measuring targets with high precision at ranges have severe measurement nonlinearities. The existing nonlinear filtering technology, such as the extended Kalman filter and untracked Kalman filter, will have significant consistency problems and loss in tracking accuracy. A novel mid-state Kalman filter is proposed to avoid loss and preserve the filtering consistency. The observed state and its first-order state derivative are selected as the mid-state vector. The update process is transformed into the measurement space to ensure the Gaussian measurement distribution and the linearization of the measurement equation. In order to verify the filter performance in comparison, an iterative formulation of Cramér-Rao Low Bound for the nonlinear system is further derived and given in this paper. Simulation results show that the proposed method has excellent performance of high filtering accuracy and fast convergence by comparing the filter state estimation accuracy and consistency.

Resequencing of 296 cultivated and wild lotus accessions unravels its evolution and breeding history.

Lotus (family: Nelumbonaceae) are perennial aquatic plants that represent one of the most ancient basal dicots. In the present study, we resequenced 296 lotus accessions from various geographical locations and germplasms to explore their genomic diversity and population structure. This germplasm set consisted of four accessions of American wild lotus and 292 accessions of Asian lotus, which were divided into four subgroups: wild, rhizome, flower and seed. Total single nucleotide polymorphisms (SNPs) suggested that the wild lotus had the highest variant number (7 191 010). Population structure and genome diversity analysis indicated that the American wild lotus demonstrated a distant genetic relationship with the Asian lotus. Furthermore, the seed and rhizome lotus groups had not originated from a single source but rather had a more complex multisource origin. Besides that, the seed lotus showed higher genetic diversity, which might have been due to the gene flow from the flower lotus to seed lotus by artificial crossing, and the rhizome lotus showed a much lower genetic diversity than the other groups. The present study provides SNP markers for lotus genomic diversity analysis, which will be useful for guiding lotus breeding.

Associations of genetic variants at TAP1 and TAP2 with pulmonary tuberculosis risk among the Chinese population.

Tuberculosis (TB) is a common infectious disease, and the present study aims to explore the associations of single nucleotide polymorphisms (SNPs) at rs1135216 and rs1057141 of transporter-associated antigen processing (TAP1) and rs2228396 of TAP2 with pulmonary tuberculosis (PTB) risk. A case-control study including 168 smear-positive PTB cases and 251 controls was conducted. Genotyping of the SNPs at rs1135216, rs1057141 and rs2228396 was performed, and their associations with PTB risk were analysed with SPSS software version 19.0. After conducting stratification for age, a significant association was detected for rs1057141 with increased PTB risk (OR = 0.17, 95% CI 0.04-0.79) among those aged ≥60 years. For those aged <60 years, a marginally significant association was detected between rs1135216 TC/CC and PTB risk (OR = 1.97, 95% CI 0.93-4.19). Haplotype analysis revealed that the haplotype AT at rs1135216 and rs2228396, as well as AAT at rs1057141, rs1135216 and rs2228396, was associated with increased PTB risk, and the ORs were 2.83 (95% CI 1.30-6.14) and 2.89 (95% CI 1.34-6.27), respectively. Rs1057141 is a genetic predictor of reduced PTB risk for those aged ≥60 years, while rs1135216 might be a potential genetic predictor for those aged <60 years. Haplotype AT at rs1135216 and rs2228396, as well as AAT at rs1057141, rs1135216 and rs2228396, is a genetic marker that may predict PTB risk.

Three-dimensional polymer mode (de)multiplexer with cascaded tapered couplers for on-board optical interconnects.

A three-dimensional polymer mode (de)multiplexer based on mode evolution is proposed. The proposed configuration is mainly composed of cascaded two tapered couplers where waveguides with different heights are inversely tapered to achieve mode conversions of the E11,E21, and E31 modes. The dimensional parameters and characteristics are analyzed by the beam propagation method. This mode (de)multiplexer exhibits the coupling ratio greater than 0.97, excess loss lower than 0.15 dB and extinction ratio higher than 20 dB for TE and TM polarizations over the wavelength range 1530∼1625nm (the C+L band). This design has weak wavelength dependence and polarization dependence, which is promising to be applied to broadband on-board mode multiplexing.