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AbstractIn this study, four series of piperazine derivatives were designed, synthesised and subjected to biological test, and compound 6a with potential antidepressant activity was obtained. An affinity assay of compound 6a with 5-hydroxytryptamine (serotonin, 5-HT)1A receptor (5-HT1AR) was undertaken, and the effects on the 5-HT level in the brains of mice were also tested. The results showed that compound 6a had the best affinity with 5-HT1AR (Ki = 1.28 nM) and significantly increased the 5-HT level. The expression levels of 5-HT1AR, BDNF, and PKA in the hippocampus were analysed by western blot and immunohistochemistry analyses. The results showed that the expression of 5-HT1AR, BDNF, and PKA in the model group was reduced compared to that of the control group, and compound 6a could reverse this phenomenon. Molecular docking was performed to investigate the interactions of the studied compound 6a with 5-HT1AR on the molecular level.

Abstract Certain metabolites in the tumor microenvironment (TME) can alter innate immunity. Here, it is shown how phosphomevalonate kinase (PMVK) allows hepatocellular carcinoma (HCC) cells to overcome the anti‐tumor immunity mediated by CD8+ T cells. In HCCs, depletion of PMVK is required to facilitate CD8+ T cell activation and their subsequent suppression of tumor growth. Mechanistically, PMVK phosphorylates and stabilizes glutamate decarboxylase 1 (GAD1), thus increasing the synthesis of γ‐aminobutyric acid (GABA), which normally functions as a neurotransmitter. However, PMVK also recruits acetyl‐CoA acetyltransferase 1 (ACAT1) and allows it to convert GABA, to 4‐acetaminobutyric acid (4‐Ac‐GABA), which is released into the TME. There, 4‐Ac‐GABA activates the GABAA receptor (GABAAR) on CD8+ T cells, which inhibits AKT1 signaling. This in turn suppresses CD8+ T cell activation, intratumoral infiltration, and the anti‐tumor response. Inhibiting PMVK or GABAAR in HCC mouse models overcomes resistance to anti‐PD‐1 immune checkpoint therapy. These findings reveal non‐canonical and cooperative functions among the key metabolic enzymes PMVK, GAD1, and ACAT1 that reprogram glutamine metabolism to synthesize a potent CD8+ T cell inhibitor 4‐Ac‐GABA. Blocking 4‐Ac‐GABA signaling in CD8+ T cells, particularly when combined with immune checkpoint inhibition, potentially represents a new and potent form of immunotherapy.

IntroductionCurrently, there are few investigations on the effect of a synthetic exogenous quorum sensing (QS) agonist on the bioleaching rate of Acidithiobacillus thiooxidans (A. thiooxidans).MethodsWe created AHL (N-acyl-homoserine lactone) analogues and investigated their effects on A. thiooxidans biofilm formation, adsorption kinetics, bioleaching, and mechanism.ResultsThe findings revealed that N-(3-thiolactone)- dodecylamine (Y3) significantly increased the biofilm formation of A. thiooxidans in 96-well plates and sulfur sheets. Adsorption tests revealed that Y3 increased the adhesion rate, adsorption constant, and adsorption efficiency. Bioleaching tests indicated that Y3 boosted bioleaching efficiency, with Ni2+ and Cu2+ bioleaching rates increasing by 49.13% and 33.03%, respectively. Transcriptomic analysis revealed that Y3 increased genes associated with QS pathways and biofilm formation, particularly afeI, which was dramatically elevated 42 times.DiscussionThe study laid the groundwork for a better understanding of the mechanics of A. thiooxidans biofilm formation, which could help improve the potential application of A. thiooxidans in bioleaching.

BackgroundTuberculous meningitis (TBM) with adults Epstein-Barr (EB) virus encephalitis is a very rare infectious disease, with a high mortality and disability. Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) is highly diagnostic. We report on a case of severe meningoencephalitis caused by co-infection with mycobacterium tuberculosis and EB virus. Brain MRI indicated a parenchyma lesion in the brain. mNGS of CSF indicated Mycobacterium tuberculosis and EB virus amplification, positive serum EB virus IgG antibodies, and improved symptoms after anti-tuberculosis and antiviral treatment. A re-examination of the brain MRI revealed that the significantly absorption of the lesions.Case reportA 49-year-old male patient presented with a chief complaint of headache and fever with consciousness disturbance. The brain magnetic resonance imaging showed a lesions in the right parenchymal brain with uneven enhancement, accompanied by significantly increased intracranial pressure, elevated CSF cell count and protein levels, as well as notably decreased glucose and chloride levels. mNGS of CSF showed the coexistence of Mycobacterium tuberculosis and EBV. The patient was diagnosed as TBM with EBV encephalitis. The patient’s symptoms gradually improved with the active administration of anti-tuberculosis combined with antiviral agents, the use of hormones to reduce inflammatory reaction, dehydration to lower intracranial pressure, and intrathecal injection. Subsequent follow-up brain magnetic resonance imaging indicated significant absorption of the lesions, along with a marked decrease in CSF count and protein levels, as well as obvious increase in glucose and chloride levels.ConclusionTBM associated with adult EBV encephalitis is extremely rare. The disease’s early stages are severe and have a high fatality rate. A prompt and accurate diagnosis is particularly important. NGS of CSF is of great value for early diagnosis.

Abstract Tuberculosis (TB) remains the second leading cause of death from a single infectious agent and long-term medication could lead to antituberculosis drug-induced liver injury (ATB-DILI). We established a prospective longitudinal cohort of ATB-DILI with multiple timepoint blood sampling and used untargeted metabolomics to analyze the metabolic profiles of 107 plasma samples from healthy controls and newly diagnosed TB patients who either developed ATB-DILI within 2 months of anti-TB treatment (ATB-DILI subjects) or completed their treatment without any adverse drug reaction (ATB-Ctrl subjects). The untargeted metabolome revealed that 77 metabolites (of 895 total) were significantly changed with ATB-DILI progression. Among them, levels of multiple fatty acids and bile acids significantly increased over time in ATB-DILI subjects. Meanwhile, metabolites of the same class were highly correlated with each other and pathway analysis indicated both fatty acids metabolism and bile acids metabolism were up-regulated with ATB-DILI progression. The targeted metabolome further validated that 5 fatty acids had prediction capability at the early stage of the disease and 6 bile acids had a better diagnostic performance when ATB-DILI occurred. These findings provide evidence indicating that fatty acids metabolism and bile acids metabolism play a vital role during ATB-DILI progression. Our report adds a dynamic perspective better to understand the pathological process of ATB-DILI in clinical settings.

Faced with the increasingly complicated electromagnetic environment, the joint design of radar and communication system has been an effective solution to save spectrum resources and reduce the complexity of system hardware. By introducing index modulation, we design a joint radar-communication system based on the frequency diverse array (FDA) based multiple-input-multiple-output (MIMO) radar. Different from the conventional phased-array (PA) radar and MIMO radar array, the FDA-MIMO radar can generate range-angle-dependent beampattern, which enables the distinctive signal processing methods. In this paper, we proceed the investigation on performance analysis of the proposed joint system scheme by firstly establishing the three-dimension (3D) signal model for the radar subsystem, based on which the achievable radar resolution in range, angle and Doppler dimension can be estimated. Since the beampattern of FDA-MIMO radar is range-dependent, the joint system can achieve interference suppression against the false targets in radar mainlobe. For communication subsystem, a communication security enhancement approach is proposed, followed by the derivation of theoretical symbol error rate (SER) upper bound. The numerical results demonstrate the effectiveness and superiority compared with the other dual-function systems based on conventional multi-antenna arrays.

A method for identifying six estrogen preparations by thin-layer chromatography combined with Raman imaging microscopy (TLC-RIM) was established. An appropriate pretreatment method was adopted to extract and purify the six estrogen preparations. After that, each estrogen extraction solution was spotted on a thin-layer chromatography plate. Estriol (E3), estradiol (E2), estradiol valerate (EV), estradiol benzoate (EB), nilestriol (CEE), and ethinylestradiol (EE2) were separated by TLC, and their Rf value and localization were determined under a UV lamp at 254 nm, followed by the in situ enrichment of the drug component. Using a 532 nm laser as the light source, the Raman scattering spectrum of the component was directly collected by micro-Raman imaging. The Rf values after TLC separation of the six estrogens and their Raman spectra can, respectively, reflect differences in polarity and structure, and they are not affected by the excipients of preparation. The detection limits of the six estrogens are 0.636, 1.00, 0.687, 0.497, 0.649, and 0.626 mg/mL. Based on the intensity of the minimum characteristic peak, the stability results within 40 min showed that the RSD of each substance is 1.34, 2.06, 1.65, 3.99, 1.16, and 2.71%, respectively. This method has strong specificity, good stability, and high sensitivity, and it can provide a new reference for improving the identification standards of estrogen preparations.

Compute‐in‐memory (CIM) is a pioneering approach using parallel data processing to eliminate traditional data transmission bottlenecks for faster, energy‐efficient data handling. Crossbar arrays with two‐terminal devices such as memristors and phase‐change memory are commonly employed in CIM, but they encounter challenges such as leakage current and increased power usage. Three‐terminal transistor arrays have potential solutions, yet large‐scale electrolyte‐gated transistors (EGTs) demonstrations are uncommon due to compatibility issues with existing photolithography processes. Herein, a 20 × 20 EGTs array is designed using indium‐gallium‐zinc‐oxide as the semiconductor channel and polyacrylonitrile (PAN) doped with C2F6LiNO4S2 as the electrolyte. Each transistor unit in the array can serve as a synapse, exhibiting a large conductance range, low energy consumption (6.984 fJ) for read–write operations, excellent repeatability, and quasilinear update characteristics. It has been confirmed that the EGTs array not only enables precise device programming but also virtually eliminates signal interference between neighboring devices during the programming process. Using 54 transistors in the EGTs array, unsupervised learning with a winner‐takes‐all neural network is successfully demonstrated. After 50 training iterations, the neural network achieves perfect 100% accuracy in classifying test‐set letters. The work demonstrates the potential of EGTs for constructing large‐scale integration synaptic array toward efficient computing architectures.

The surface symmetry of the substrate plays an important role in the epitaxial high-quality growth of 2D materials; however, in-depth and in situ studies on these materials during growth are still limited due to the lack of effective in situ monitoring approaches. In this work, taking the growth of MoSe2 as an example, the distinct growth processes on Al2O3 (112¯0) and Al2O3 (0001) are revealed by parallel monitoring using in situ reflectance anisotropy spectroscopy (RAS) and differential reflectance spectroscopy (DRS), respectively, highlighting the dominant role of the surface symmetry. In our previous study, we found that the RAS signal of MoSe2 grown on Al2O3 (112¯0) initially increased and decreased ultimately to the magnitude of bare Al2O3 (112¯0) when the first layer of MoSe2 was fully merged, which is herein verified by the complementary DRS measurement that is directly related to the film coverage. Consequently, the changing rate of reflectance anisotropy (RA) intensity at 2.5 eV is well matched with the dynamic changes in differential reflectance (DR) intensity. Moreover, the surface-dominated uniform orientation of MoSe2 islands at various stages determined by RAS was further investigated by low-energy electron diffraction (LEED) and atomic force microscopy (AFM). By contrast, the RAS signal of MoSe2 grown on Al2O3 (0001) remains at zero during the whole growth, implying that the discontinuous MoSe2 islands have no preferential orientations. This work demonstrates that the combination of in situ RAS and DRS can provide valuable insights into the growth of unidirectional aligned islands and help optimize the fabrication process for single-crystal transition metal dichalcogenide (TMDC) monolayers.

Ulcerative colitis (UC) is a chronic and recurrent inflammatory disease of the gastrointestinal tract. This study aimed to determine the effect of cathelicidin-related antimicrobial peptide (Cramp) on dextran sulfate sodium (DSS)-induced acute experimental colitis in mice and to investigate the underlying mechanisms. Acute UC was induced in C57BL/6 mice with 3% DSS for 7 days, 4 mg/kg b.w. synthetic Cramp peptide was administrated once daily starting on day 4 of the experimental period. Mice were evaluated for body weight, colon length, colon histopathology, and inflammatory cytokines in colon tissue. Using 16 s rRNA sequencing, the composition structure of gut microbiota was characterized. Metabolomic profiling of the serum was performed. The results showed that DSS treatment significantly induced intestinal damage as reflected by disease activity index, histopathological features, and colon length, while Cramp treatment significantly prevented these trends. Meanwhile, Cramp treatment decreased the levels of inflammatory cytokines in both serum and colonic tissue on DSS-induced colitis. It was also observed that DSS damaged the integrity of the intestinal epithelial barrier, whereas Cramp also played a protective role by attenuating these deteriorated effects. Furthermore, Cramp treatment reversed the oxidative stress by increasing the antioxidant enzymes of GSH-PX and decreasing the oxidant content of MDA. Notably, compared to the DSS group, Cramp treatment significantly elevated the abundance of Verrucomicrobiota at the phylum level. Furthermore, at the genus level, Parasutterella and Mucispirllum abundance was increased significantly in response to Cramp treatment, although Roseburia and Enterorhabdus reduced remarkably. Metabolic pathway analysis of serum metabolomics showed that Cramp intervention can regulate various metabolic pathways such as α-linolenic acid, taurine and hypotaurine, sphingolipid, and arachidonic acid metabolism. The study concluded that Cramp significantly ameliorated DSS-induced colonic injury, colonic inflammation, and intestinal barrier dysfunction in mice. The underlying mechanism is closely related to the metabolic alterations derived from gut microbiota.

Abstract The artificial synapse array with an electrolyte‐gated transistor (EGT) as an array unit presents considerable potential for neuromorphic computation. However, the integration of EGTs faces the drawback of the conflict between the polymer electrolytes and photo‐lithography. This study presents a scheme based on a lateral‐gate structure to realize high‐density integration of EGTs and proposes the integration of 100 × 100 EGTs into a 2.5 × 2.5 cm2 glass, with a unit density of up to 1600 devices cm−2. Furthermore, an electrolyte framework is developed to enhance the array performance, with ionic conductivity of up to 2.87 × 10−3 S cm−1 owing to the porosity of zeolitic imidazolate frameworks‐67. The artificial synapse array realizes image processing functions, and exhibits high performance and homogeneity. The handwriting recognition accuracy of a representative device reaches 92.80%, with the standard deviation of all the devices being limited to 9.69%. The integrated array and its high performance demonstrate the feasibility of the scheme and provide a solid reference for the integration of EGTs.

Drought at the flower and pod stage, which is the most moisture-sensitive stage of soybean development, is the main cause of yield loss in soybean. Nitrogen is a vital nutrient for soybeans. The objective of this study was to assess the potential of post-drought nitrogen fertilization at the soybean (Heihe 45) pod stage to (1) reduce pod shedding and increase yield, and (2) elucidate the mechanisms by which nitrogen fertilization regulates soybean growth under drought stress. The pot experiment was designed with two moisture levels and three nitrogen levels, resulting in a total of six treatments. The results show that nitrogen reduces cellular oxidation by regulating key enzymes of sucrose metabolism, such as sucrose synthase and sucrose phosphate synthase; and regulates cellulase to reduce shedding and mitigate drought. Comparison of low and high nitrogen conditions under drought conditions showed that the number of flowers and pods in soybean increased by 30% and 32.94%, respectively, malondialdehyde content decreased by 24%, cellulase activity in flowers and pods decreased by 15.07% and 12.31%, respectively, and yields increased by 29.98% under high nitrogen conditions. The high nitrogen treatment performed optimally and the differences between treatments reached the significant level.

Orthogonal frequency-division multiplexing (OFDM) chirp waveforms are an attractive candidate to be a dual-function signal scheme for the joint radar and communication systems. OFDM chirp signals can not only be employed to transmit communication data through classic phase modulation, but also can perform radar detection by applying linear frequency modulation for subcarriers. However, the performance of the OFDM chirp communication system under the phase noise environment still remains uninvestigated. This paper tries to discuss the influence of phase noise on OFDM chirp communication systems and proposes effective phase noise estimation and compensation methods. We find that the phase noise effect on OFDM chirp communication systems consists of a common phase error (CPE) and an inter-carrier interference (ICI). If not compensated, the performance of the dual-function systems can be seriously degraded. In particular, an exact expression for the signal-plus-interference to noise ratio (SINR) for the OFDM chirp communication system is derived and some critical parameters are analyzed to exhibit the phase noise effects on system performance. Moreover, two low-complexity estimation approaches, maximum likelihood (ML) and linear minimum mean square error (LMMSE), as well as two compensation approaches, the de-correlation and cancellation algorithms, are respectively utilized to eliminate the phase noise impairment. Finally, the phase noise effects and the effectiveness of the compensation approach are verified by extensive numerical results.

IntroductionAcute pancreatitis is a common gastrointestinal disease. The mortality of patients affected by severe acute pancreatitis (SAP) remains high. It is unclear whether high-dose intravenous vitamin C (HDIVC) therapy could improve the prognosis of these patients. The current prospective, randomized, double-blinded, placebo-controlled study will explore the effect of high-dose intravenous vitamin C therapy on the prognosis in patients with moderately severe and severe acute pancreatitis.Methods and designA total of 418 participants with moderately severe and severe acute pancreatitis who meet the eligible criteria will be randomly assigned in a 1:1 ratio to receive treatment with HDIVC (200 mg/kg/24 h) or placebo (saline) for a period of 7 days. The primary outcome is 28-day mortality in these patients. The secondary outcomes include organ functions and interventions, laboratory tests, healthcare, and 90-day mortality.Ethics and disseminationThis protocol was approved by the institutional ethics board of the Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Registration Number: 2019-90). The report of the study will be published in peer-reviewed journals and presented at conferences, both nationally and internationally.Clinical trial registrationChinese Clinical Trial Registry (ChiCTR1900022022). Version 1.5.

Ossified intracranial meningiomas (OIM) and ossified spinal meningiomas (OSM) are rare neoplasms of mesenchymal origin that predominantly manifest in the spinal cord and infrequently in the cranial region, accounting for ~0. 7–5.5% of all meningiomas. It is extremely rare to have multiple intracranial and spinal lesions accompanied by ossification. Herein, we report this rare case for the first time. A 34-year-old woman presented with paresthesia and limb weakness in the right lower limb and gradually worsened. Approximately half a year later, she could only walk with crutches. Magnetic resonance imaging of the brain and spinal cord showed multiple meningiomas, and histopathological examination confirmed multiple OIM and OSM (WHO grade 1). Multiple OIM and OSM are extremely rare with diverse imaging features, and it is easily confused with other tumors. Histopathological examination is the final diagnostic method.

Abstract Background The gut microbiome plays a pivotal role in the progression of sepsis. However, the specific mechanism of gut microbiota and its metabolites involved in the process of sepsis remains elusive, which limits its translational application. Method In this study, we used a combination of the microbiome and untargeted metabolomics to analyze stool samples from patients with sepsis enrolled at admission, then microbiota, metabolites, and potential signaling pathways that might play important roles in disease outcome were screened out. Finally, the above results were validated by the microbiome and transcriptomics analysis in an animal model of sepsis. Results Patients with sepsis showed destruction of symbiotic flora and elevated abundance of Enterococcus, which were validated in animal experiments. Additionally, patients with a high burden of Bacteroides, especially B. vulgatus, had higher Acute Physiology and Chronic Health Evaluation II scores and longer stays in the intensive care unit. The intestinal transcriptome in CLP rats illustrated that Enterococcus and Bacteroides had divergent profiles of correlation with differentially expressed genes, indicating distinctly different roles for these bacteria in sepsis. Furthermore, patients with sepsis exhibited disturbances in gut amino acid metabolism compared with healthy controls; namely, tryptophan metabolism was tightly related to an altered microbiota and the severity of sepsis. Conclusion Alterations in microbial and metabolic features in the gut corresponded with the progression of sepsis. Our findings may help to predict the clinical outcome of patients in the early stage of sepsis and provide a translational basis for exploring new therapies.

Abstract The metabolic pathways through which p53 functions as a potent tumor suppressor are incompletely understood. Here we report that, by associating with the Vitamin D receptor (VDR), p53 induces numerous genes encoding enzymes for peroxisomal fatty acid β-oxidation (FAO). This leads to increased cytosolic acetyl-CoA levels and acetylation of the enzyme 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC), which catalyzes the last two steps in the purine biosynthetic pathway. This acetylation step, mediated by lysine acetyltransferase 2B (KAT2B), occurs at ATIC Lys 266, dramatically inhibits ATIC activity, and inversely correlates with colorectal cancer (CRC) tumor growth in vitro and in vivo, and acetylation of ATIC is downregulated in human CRC samples. p53-deficient CRCs with high levels of ATIC is more susceptible to ATIC inhibition. Collectively, these findings link p53 to peroxisomal FAO, purine biosynthesis, and CRC pathogenesis in a manner that is regulated by the levels of ATIC acetylation.

The index modulation based on multiple-antenna architecture is a prospective information embedding approach for the joint radar-communication system (JRCS). Current investigations mainly focus on the spatial and frequency index modulation applied in phased array (PA) radar and multiple-input multiple-output (MIMO) radar. In this article, we design an information embedding strategy by combining phase modulation and frequency index modulation for random frequency diverse array (RFDA) based on MIMO radar. The devised system can perform joint range and angle estimation in radar operation, which is currently not achievable in dual-function systems based on PA and MIMO radar. Considering the time-variance of the transmit waveform, we propose a multichannel receiver for the joint system. For radar, the impact of the random frequency assignment on the transmit-receive virtual beampattern and Cramér-Rao bounds (CRBs) of range and angle are analyzed. For communication, a maximum ratio combining (MRC) assisted ML detector is introduced to improve the accuracy of the information decoding. Extensive numerical results are presented to verify the feasibility and effectiveness of the proposed system scheme.

Abstract Background Propofol and sevoflurane are two commonly used perioperative anesthetics. Some studies have found that these anesthetic drugs affect tumorigenesis. Previous studies have mostly focused on in vitro experiments, and the specimens collected were mainly peripheral body fluids, lacking direct evidence of the impact of anesthetic drugs on human tissues. This study aimed to elucidate the effects of propofol and sevoflurane on lung cancer using next-generation sequencing through an in vivo experiment. Methods Patients were randomly assigned to a group receiving either propofol or sevoflurane during surgery. Then, the patients’ tumor and paired normal samples were collected and sequenced by next-generation sequencing. Differentially expressed genes (DEG) were analyzed by two statistical models, followed by cluster analysis, PCA, Gene Ontology, and KEGG pathway analysis. Candidate genes were confirmed by qRT–PCR. Results The demographic data of the two study groups were not statistically significant. Through single-factor model analysis, 810 DEG in the propofol group and 508 DEG in the sevoflurane group were obtained. To better reflect the differential effects between propofol and sevoflurane while reducing the false-positive DEG, we used multifactor model analysis, which resulted in 124 DEG. In PCA and cluster analysis, four groups (propofol cancer group, propofol normal group, sevoflurane cancer group, sevoflurane normal group) were separated adequately, indicating the accuracy of the analysis. We chose seven significant pathways (cellular response to interleukin-1, chemokine-mediated signaling pathway, chemokine signaling pathway, cytokine–cytokine receptor interaction, inflammatory response, immune response, and TNF signaling pathway) for downstream analysis. Based on the pathway analysis, three candidate genes (CXCR1, CXCL8, and TNFAIP3) were chosen, and their qRT–PCR results were consistent with the sequencing results. Conclusions Through RNA-seq analysis, the effects of propofol and sevoflurane during lung cancer resection were different, mainly in inflammatory-related pathways, which might be possibly by targeting CXCL8. Trial registration Trial registry number was ChiCTR1900026213 .

Vip3Aa, secreted by Bacillus thuringiensis, is effective at controlling major agricultural pests such as Spodoptera frugiperda. However, to control Vip3Aa resistance evolved in the field by different lepidoptera species, an in–depth study of sequence––structure––activity relationships is necessary to design new Vip3Aa variants. In this study, the four specific loops (β4–β5 loop, β9–β10 loop, β12–β13 loop, and β14–β15 loop) in domain III were selected and four loop mutants were constructed by replacing all residues in each specific loop with alanine. We obtained soluble proteins for three of the loop mutants, excluding the β9–β10 loop. These loop mutants have been characterized by toxicity bioassays against S. frugiperda, proteolytic processing, and receptor binding. These results indicate that the β4–β5 loop and β14–β15 loop are involved in receptor binding and Vip3Aa toxicity. Based on this, we constructed numerous mutants and obtained three single mutants (Vip3Aa–S366T, Vip3Aa–S366L, and Vip3Aa–R501A) that exhibited significantly increased toxicity of 2.61–fold, 3.39–fold, and 2.51–fold, respectively. Compared to Vip3Aa, the receptor affinity of Vip3Aa–S366T and Vip3Aa–S366L was significantly enhanced. Furthermore, we also analyzed and aligned the three–dimensional structures of the mutants and Vip3Aa. In summary, these results indicate that the loops in domain III have the potential to be targeted to enhance the insecticidal toxicity of the Vip3Aa protein.

Multiple nitrate transporter (NRT) genes exist in the genome of bread wheat, and it is of great importance to identify the elite NRT genes for N-efficient wheat cultivar breeding. A candidate gene association study (CGAS) of six N use efficiency (NUE) related traits (grain N concentration (GNC), straw N concentration (SNC), grain yield (GY), grain N accumulation (GNA), shoot total N accumulation (STN) and N harvest index (NHI)) was performed based on SNPs in 46 NRT2 genes using a panel composed of 286 wheat cultivars. CGAS identified TaNRT2.1-6B as an elite NRT gene that is significantly associated with four (NHI, SNC, GNA and GY) of the six NUE-related traits simultaneously. TaNRT2.1-6B is located on the plasma membrane and acts as a dual-affinity NRT. The overexpression of TaNRT2.1-6B increased the N influx and root growth of wheat, whereas gene silence lines resulted in the opposite effects. The overexpression of TaNRT2.1-6B also improved GY and N accumulation of wheat under either limited or sufficient N conditions. The data provide the TaNRT2.1-6B gene and the two associated SNP markers as promising powerful tools for breeding wheat cultivars with high N uptake ability and NUE.

Abstract Background The outbreak of SARS-CoV-2 at the end of 2019 sounded the alarm for early inspection on acute respiratory infection (ARI). However, diagnosis pathway of ARI has still not reached a consensus and its impact on prognosis needs to be further explored. Methods ESAR is a multicenter, open-label, randomized controlled, non-inferiority clinical trial on evaluating the diagnosis performance and its impact on prognosis of ARI between mNGS and multiplex PCR. Enrolled patients will be divided into two groups with a ratio of 1:1. Group I will be directly tested by mNGS. Group II will firstly receive multiplex PCR, then mNGS in patients with severe infection if multiplex PCR is negative or inconsistent with clinical manifestations. All patients will be followed up every 7 days for 28 days. The primary endpoint is time to initiate targeted treatment. Secondary endpoints include incidence of significant events (oxygen inhalation, mechanical ventilation, etc.), clinical remission rate, and hospitalization length. A total of 440 participants will be enrolled in both groups. Discussion ESAR compares the efficacy of different diagnostic strategies and their impact on treatment outcomes in ARI, which is of great significance to make precise diagnosis, balance clinical resources and demands, and ultimately optimize clinical diagnosis pathways and treatment strategies. Trial registration Clinicaltrial.gov, NCT04955756, Registered on July 9th 2021.

Abstract Background Phyllosphere microbes play important roles in host plant performance and fitness. Recent studies have suggested that tropical and temperate forests harbor diverse phyllosphere bacterial and fungal communities and their assembly is driven by host species identity and plant traits. However, no study has yet examined how seasonality (e.g. dry vs. wet seasons) influences phyllosphere microbial community assembly in natural forests. In addition, in subtropical forests characterized as the transitional zonal vegetation type from tropical to temperate forests, how tree phyllosphere microbial communities are assembled remains unknown. In this study, we quantified bacterial and fungal community structure and diversity on the leaves of 45 tree species with varying phylogenetic identities and importance values within a 20-ha lower subtropical evergreen broad-leaved forest plot in dry and wet seasons. We explored if and how the microbial community assembly varies with host species identity, plant traits and seasonality. Results Phyllosphere microbial communities in the subtropical forest are more abundant and diverse than those in tropical and temperate forests, and the tree species share a “core microbiome” in either bacteria or fungi. Variations in phyllosphere bacterial and fungal community assembly are explained more by host species identity than by seasonality. There is a strong clustering of the phyllosphere microbial assemblage amongst trees by seasonality, and the seasonality effects are more pronounced on bacterial than fungal community assembly. Host traits have different effects on community compositions and diversities of both bacteria and fungi, and among them calcium concentration and importance value are the most powerful explaining variables for bacteria and fungi, respectively. There are significant evolutionary associations between host species and phyllosphere microbiome. Conclusions Our results suggest that subtropical tree phyllosphere microbial communities vary with host species identity, plant traits and seasonality. Host species identity, compared to seasonality, has greater effects on phyllosphere microbial community assembly, and such effects differ between bacterial and fungal communities. These findings advance our understanding of the patterns and drivers of phyllosphere microbial community assembly in zonal forests at a global scale.

Edible insects are a highly nutritious source of protein and are enjoyed by people all over the world. Insects contain various other nutrients and beneficial compounds, such as lipids, vitamins and minerals, chitin, phenolic compounds, and antimicrobial peptides, which contribute to good health. The practice of insect farming is far more resource-efficient compared to traditional agriculture and animal husbandry, requiring less land, energy, and water, and resulting in a significantly lower carbon footprint. In fact, insects are 12 to 25 times more efficient than animals in converting low-protein feed into protein. When it comes to protein production per unit area, insect farming only requires about one-eighth of the land needed for beef production. Moreover, insect farming generates minimal waste, as insects can consume food and biomass that would otherwise go to waste, contributing to a circular economy that promotes resource recycling and reuse. Insects can be fed with agricultural waste, such as unused plant stems and food scraps. Additionally, the excrement produced by insects can be used as fertilizer for crops, completing the circular chain. Despite the undeniable sustainability and nutritional benefits of consuming insects, widespread acceptance of incorporating insects into our daily diets still has a long way to go. This paper provides a comprehensive overview of the nutritional value of edible insects, the development of farming and processing technologies, and the problems faced in the marketing of edible insect products and insect foods to improve the reference for how people choose edible insects.

Previously, we identified a highly conserved, γ-shaped RNA element (γRE) from satellite RNAs of cucumber mosaic virus (CMV), and we determined γRE to be structurally required for satRNA survival and the inhibition of CMV replication. It remains unknown how γRE biologically functions. In this work, pull-down assays were used to screen candidates of host factors from Nicotiana benthamiana plants using biotin-labeled γRE as bait. Nine host factors were found to interact specifically with γRE. Then, all of these host factors were down-regulated individually in N. benthamiana plants via tobacco rattle virus-induced gene silencing and tested with infection by GFP-expressing CMV (CMV-gfp) and the isolate T1 of satRNA (sat-T1). Out of nine candidates, three host factors, namely histone H3, GTPase Ran3, and eukaryotic translation initiation factor 4A, were extremely important for infection by CMV-gfp and sat-T1. Moreover, we found that cytosolic glyceraldehyde-3-phosphate dehydrogenase 2 contributed to the replication of CMV and sat-T1, but also negatively regulated CMV 2b activity. Collectively, our work provides essential clues for uncovering the mechanism by which satRNAs inhibit CMV replication.

Triboelectric nanogenerators have shown promising potential towards self-powered wearable electronics and devices. Here, authors introduce topological insulators to enrich the current triboelectric family of materials and sensing technologies.

Cognitive control is of great interest to researchers and practitioners. The concurrent association between family socioeconomic status (SES) and adolescent cognitive control is well-documented. However, little is known about whether and how SES relates to individual differences in the development of adolescent cognitive control. The current four-year longitudinal investigation (N = 167, 13–14 years at Wave 1) used multi-source interference task performance (reaction time in interference correct trials minus neutral correct trials) and corresponding neural activities (blood oxygen level dependent contrast of interference versus neutral conditions) as measures of cognitive control. SES and parenting behaviors (warmth, monitoring) were measured through surveys. We examined direct and indirect effects of earlier SES on the development of cognitive control via parenting behaviors; the moderating effect of parenting also was explored. Results of latent growth modeling (LGM) revealed significant interactive effects between SES and parenting predicting behavioral and neural measures of cognitive control. Lower family SES was associated with poorer cognitive performance when coupled with low parental warmth. In contrast, higher family SES was associated with greater improvement in performance, as well as a higher intercept and steeper decrease in frontoparietal activation over time, when coupled with high parental monitoring. These findings extend prior cross-sectional evidence to show the moderating effect of the parenting environment on the potential effects of SES on developmental changes in adolescent cognitive control.

Probiotics gained significant attention for their potential to improve gut health and enhance productivity in animals, including poultry. This comprehensive study focused on the genetic analysis of Lactiplantibacillus plantarum 18 (LP18) to understand its survival and colonization characteristics in the gastrointestinal tract. LP18 was supplemented in the late-stage diet of laying hens to investigate its impact on growth performance, egg quality, and lipid metabolism. The complete genome sequence of LP18 was determined, consisting of 3,275,044 base pairs with a GC content of 44.42% and two circular plasmids. Genomic analysis revealed genes associated with adaptability, adhesion, and gastrointestinal safety. LP18 supplementation significantly improved the daily laying rate (p < 0.05) during the late-production phase and showed noteworthy advancements in egg quality, including egg shape index (p < 0.05), egg albumen height (p < 0.01), Haugh unit (p < 0.01), and eggshell strength (p < 0.05), with notable improvements in eggshell ultrastructure. Additionally, LP18 supplementation resulted in a significant reduction in serum lipid content, including LDL (p < 0.01), FFA (p < 0.05), and Gly (p < 0.05). These findings provide valuable insights into the genomic characteristics of LP18 and the genes that support its survival and colonization in the gastrointestinal tract. Importantly, this study highlights the potential of LP18 as a probiotic candidate to enhance productivity, optimize egg quality, and modulate lipid metabolism in poultry production.

PEEK is being used increasingly often in seals, bushings, bearings, and other moving parts due to its excellent mechanical and tribological properties. Herein, PEEK-based composites were prepared using PI as the organic filler and h-BN and nano-SiO2 particles as the inorganic fillers. There was significant improvement in the tribological properties of PEEK at conditions above the glass transition temperature; the coefficient of friction of +20P/4B/4Si was stabilized at 0.06 at 200 °C and the wear rate was reduced by 60% compared to PEEK. The role played by the thermal conductivity of h-BN and the promotion of friction transfer film by nano-SiO2 in improving the tribological properties of PEEK is illustrated. The modified composites exhibited stable mechanical and tribological properties over a wide temperature range, which is instructive for instrumentation and testing applications in harsh environments.

Abstract The worldwide pandemic of coronavirus disease 2019 (COVID-19) presents us with a serious public health crisis. To combat the virus and slow its spread, wider testing is essential. There is a need for more sensitive, specific, and convenient detection methods of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Advanced detection can greatly improve the ability and accuracy of the clinical diagnosis of COVID-19, which is conducive to the early suitable treatment and supports precise prophylaxis. In this article, we combine and present the latest laboratory diagnostic technologies and methods for SARS-CoV-2 to identify the technical characteristics, considerations, biosafety requirements, common problems with testing and interpretation of results, and coping strategies of commonly used testing methods. We highlight the gaps in current diagnostic capacity and propose potential solutions to provide cutting-edge technical support to achieve a more precise diagnosis, treatment, and prevention of COVID-19 and to overcome the difficulties with the normalization of epidemic prevention and control.

The booming wearable market and recent advances in material science has led to the rapid development of the various wearable sensors, actuators, and devices that can be worn, embedded in fabric, accessorized, or tattooed directly onto the skin. Wearable actuators, a subcategory of wearable technology, have attracted enormous interest from researchers in various disciplines and many wearable actuators and devices have been developed in the past few decades to assist and improve people’s everyday lives. In this paper, we review the actuation mechanisms, structures, applications, and limitations of recently developed wearable actuators including pneumatic and hydraulic actuators, shape memory alloys and polymers, thermal and hygroscopic materials, dielectric elastomers, ionic and conducting polymers, piezoelectric actuators, electromagnetic actuators, liquid crystal elastomers, etc. Examples of recent applications such as wearable soft robots, haptic devices, and personal thermal regulation textiles are highlighted. Finally, we point out the current bottleneck and suggest the prospective future research directions for wearable actuators.

BackgroundSepsis is an inflammatory syndrome with life-threatening organ dysfunction and high mortality. In the recent 10 years, high-dose intravenous injection of vitamin C, the first-line antioxidant of humans, has received highlighted attention in the field of critical care. The study aims to examine the efficacy and safety of high-dose intravenous injection of vitamin C in the treatment of sepsis.Methods and designHere, we are conducting a prospective, multi-centered, double-blinded, randomized, and placebo-controlled superiority study named High-Dose Vitamin C on Sepsis (HDVCOS). A total of 620 participants diagnosed with sepsis in four participating sites across China that satisfy the eligibility criteria will be randomized at a ratio of 1:1 to receive treatment with a high-dose intravenous injection of vitamin C (200 mg/kg/24 h) or placebo (saline) for 4 days. The primary outcome is 28 days of mortality. The secondary outcomes include the incidence of organ failure, Sequential Organ Failure Assessment (SOFA) score change, organ support, the relationship between plasma vitamin C concentration and outcomes, and adverse events.ConclusionThe findings of this study will provide potential evidence for high-dose intravenous injection of vitamin C in the treatment of sepsis.Clinical trial registration[http://www.chictr.org.cn/showprojen.aspx?proj=29851], identifier [ChiCTR1800017633].

Abstract Van der Waals (vdW) heterostructures—in which layered materials are purposely selected to assemble with each other—allow unusual properties and different phenomena to be combined and multifunctional electronics to be created, opening a new chapter for the spread of internet‐of‐things applications. Here, an O2‐ultrasensitive MoTe2 material and an O2‐insensitive SnS2 material are integrated to form a vdW heterostructure, allowing the realization of charge‐polarity control for multioperation‐mode transistors through a simple and effective rapid thermal annealing strategy under dry‐air and vacuum conditions. The charge‐polarity control (i.e., doping and de‐doping processes), which arises owing to the interaction between O2 adsorption/desorption and tellurium defects at the MoTe2 surface, means that the MoTe2/SnS2 heterostructure transistors can reversibly change between unipolar, ambipolar, and anti‐ambipolar transfer characteristics. Based on the dynamic control of the charge‐polarity properties, an inverter, output polarity controllable amplifier, p‐n diode, and ternary‐state logics (NMIN and NMAX gates) are demonstrated, which inspire the development of reversibly multifunctional devices and indicates the potential of 2D materials.

Background To develop a highly discriminative machine learning model for the prediction of intensive care unit admission (>24h) using the easily available preoperative information from electronic health records. An accurate prediction model for ICU admission after surgery is of great importance for surgical risk assessment and appropriate utilization of ICU resources. Method Data were collected retrospectively from a large hospital, comprising 135,442 adult patients who underwent surgery except for cardiac surgery between 1 January 2014, and 31 July 2018 in China. Multiple existing predictive machine learning algorithms were explored to construct the prediction model, including logistic regression, random forest, adaptive boosting, and gradient boosting machine. Four secondary analyses were conducted to improve the interpretability of the results. Results A total of 2702 (2.0%) patients were admitted to the intensive care unit postoperatively. The gradient boosting machine model attained the highest area under the receiver operating characteristic curve of 0.90. The machine learning models predicted intensive care unit admission better than the American Society of Anesthesiologists Physical Status (area under the receiver operating characteristic curve: 0.68). The gradient boosting machine recognized several features as highly significant predictors for postoperatively intensive care unit admission. By applying subgroup analysis and secondary analysis, we found that patients with operations on the digestive, respiratory, and vascular systems had higher probabilities for intensive care unit admission. Conclusion Compared with conventional American Society of Anesthesiologists Physical Status and logistic regression model, the gradient boosting machine could improve the performance in the prediction of intensive care unit admission. Machine learning models could be used to improve the discrimination and identify the need for intensive care unit admission after surgery in elective noncardiac surgical patients, which could help manage the surgical risk.

Abstract Recently, researchers have focused on optoelectronics based on two-dimensional van der Waals materials to realize multifunctional memory and neuron applications. Layered indium selenide (InSe) semiconductors satisfy various requirements as photosensitive channel materials, and enable the realization of intriguing optoelectronic applications. Herein, we demonstrate InSe photonic devices with different trends of output currents rooted in the carrier capture/release events under various gate voltages. Furthermore, we reported an increasing/flattening/decreasing synaptic weight change index (∆W n ) via a modulated gate electric field, which we use to imitate medicine-acting metaplasticity with effective/stable/ineffective features analogous to the synaptic weight change in the nervous system of the human brain. Finally, we take advantage of the low-frequency noise (LFN) measurements and the energy-band explanation to verify the rationality of carrier capture-assisted optoelectronics applied to neural simulation at the device level. Utilizing optoelectronics to simulate essential biomedical neurobehaviors, we experimentally demonstrate the feasibility and meaningfulness of combining electronic engineering with biomedical neurology.

Anxiety- and depression-like behavior following chemotherapy treatment occurs in cancer patients with high probability and no specific therapeutics are available for treatment and prevention of this complication. Here, tilapia skin peptides (TSP), a novel enzymatically hydrolyzed bioactive peptide mixture, obtained from tilapia (Oreochromis mossambicus) scraps, were studied on cyclophosphamide (CP)-induced anxiety- and depression-like behavior in mice. Mice were received intraperitoneal injection of CP for 2 weeks, while TSP was administered for 4 weeks. After the end of the animal experiment, behavioral, biochemical, and molecular tests were carried out. The mice decreased preference for sugar water, increased immobility time in the forced swimming and tail suspension test, and decreased travel distance in the open field test in the Model group, compared with the Control group. Abnormal changes in behavioral tests were significantly improved after the TSP treatment. Additionally, abnormalities on superoxide dismutase, malondialdehyde, glutathione peroxidase were rescued by administration of 1000 mg/kg/d TSP in mice than that of the Model group. TSP has normalized the expression of Iba-1 and the levels of TNF-α and IL-1β in the hippocampus of mice, which indicated that TSP could observably ameliorate neuroinflammatory response in the hippocampus of mice. TSP ameliorated the apoptosis of hippocampal neurons of CA1 and CA3 regions in the TSP group vs. the Model group. The number of doublecortin positive cells was drastically increased by administering 1000 mg/kg/d TSP in mice vs. the Model group. Furthermore, TSP reversed the Nrf2/HO-1 signaling pathway, BDNF/TrkB/CREB signaling pathway, and reduced the Bcl-2/Bax/caspase-3 apoptosis pathway. In conclusion, TSP could restore CP-induced anxiety- and depression-like behavior via improving oxidative stress, neuroinflammation, neuron apoptosis, and neurogenesis in mice hippocampus.

Developing efficient memory and artificial synaptic systems based on environmentally sensitive van der Waals materials remains a challenge. Here, the authors present a native oxidation-inspired InSe field-effect transistor that benefits from a boosted charge trapping behavior under ambient conditions.

Abstract It is currently uncertain to what extent genetic transformations of strategic crops (targeting diverse traits) have improved their N use efficiency (NUE), and what the key factors affecting their NUE are. Based on data collected from 130 publications, the effect sizes of genetic transformations and the key factors influencing NUE for three major cereal crops (rice, maize, and wheat), were investigated using a meta-analysis approach. Genetic transformations increased yield, shoot biomass, N uptake efficiency (NUpE), and partial factor productivity of N (PFPN) in the crops, but decreased shoot NUE (SNUE) and grain NUE (GNUE). Transporter genes improved yield and NUE parameters more efficiently, than did the other gene types. The effect sizes for some NUE parameters varied according to crop species and experimental conditions but did not differ between the overexpression and ectopic expression methods. Most effect sizes did not correlate with gene overexpression levels. These results indicate a promising potential of genetic transformations approaches for improving certain NUE parameters.

Abstract Objective Stage I‐II uterine papillary serous carcinoma (UPSC) has aggressive biological behavior and leads to poor prognosis. However, clinicopathologic risk factors to predict cancer‐specific survival of patients with stage I‐II UPSC were still unclear. This study was undertaken to develop a prediction model of survival in patients with early‐stage UPSC. Methods Using Surveillance, Epidemiology, and End Results (SEER) database, 964 patients were identified with International Federation of Gynecology and Obstetrics (FIGO) stage I‐II UPSC who underwent at least hysterectomy between 2004 and 2015. By considering competing risk events for survival outcomes, we used proportional subdistribution hazards regression to compare cancer‐specific death (CSD) for all patients. Based on the results of univariate and multivariate analysis, the variables were selected to construct a predictive model; and the prediction results of the model were visualized using a nomogram to predict the cancer‐specific survival and the response to adjuvant chemotherapy and radiotherapy of stage I‐II UPSC patients. Results The median age of the cohort was 67 years. One hundred and sixty five patients (17.1%) died of UPSC (CSD), while 8.6% of the patients died from other causes (non‐CSD). On multivariate analysis, age ≥ 67 (HR = 1.45, P = .021), tumor size ≥ 2 cm (HR = 1.81, P = .014) and >10 regional nodes removed (HR = 0.52, P = .002) were significantly associated with cumulative incidence of CSD. In the age ≥67 cohort, FIGO stage IB‐II was a risk factor for CSD (HR = 1.83, P = .036), and >10 lymph nodes removed was a protective factor (HR = 0.50, P = .01). Both adjuvant chemotherapy combined with radiotherapy and adjuvant chemotherapy alone decreased CSD of patients with stage I‐II UPSC older than 67 years (HR = 0.47, P = .022; HR = 0.52, P = .024, respectively). The prediction model had great risk stratification ability as the high‐risk group had higher cumulative incidence of CSD than the low‐risk group (P

Previous research focused on the qualitative discussion of the correlation between surgical time and mortality in acute pancreatitis (AP). Recommendations for surgical timing of necrotizing pancreatitis are delayed as far as possible, without recommendations for individuals. The aim of this article is to predict timing of surgical intervention in necrotizing pancreatitis with recurrent neural network (RNN). Time series data in AP were retrospectively extracted from a hospital in China (n = 15,813) to develop model, and the Cerner Health Facts database in the United States (n = 142,650) was used to externally validate. The developed model, time-aware Phased-Decay long short-term memory (LSTM), was used to predict timing of surgical intervention and critical clinical features in necrotizing pancreatitis based on laboratory tests, compared to other machine learning models. Area under the ROC curve (AUC) of RNN-based models was more than 0.70. The AUC of time-aware Phased-Decay LSTM (0.75) with more explanatory was similar to that (0.76) of Phased-Decay LSTM to predict surgical timing. The developed model visualized the specific surgical process and laboratory indicators changes for the patients with AP from the onset to discharge. Different clinical features had different contribution modes with time to the specific surgical event in AP. Heart function contributed the most to the prediction of surgical intervention at the onset and in the first week. Our developed model could monitor the specific surgical process from the onset of AP to discharge and extract the contribution modes of clinical features with time in necrotizing pancreatitis.

Salmonella pullorum causes typical “Bacillary White Diarrhea” and loss of appetite in chicks, which leads to the death of chicks in severe cases; thus, it is still a critical issue in China. Antibiotics are conventional medicines used for Salmonella infections; however, due to the extensive long-term use and even abuse of antibiotics, drug resistance becomes increasingly severe, making treating pullorum disease more difficult. Most of the endolysins are hydrolytic enzymes produced by bacteriophages to cleave the host’s cell wall during the final stage of the lytic cycle. A virulent bacteriophage, YSP2, of Salmonella was isolated in a previous study. A Pichia pastoris expression strain that can express the Salmonella bacteriophage endolysin was constructed efficiently, and the Gram-negative bacteriophage endolysin, LySP2, was obtained in this study. Compared with the parental phage YSP2, which can only lyse Salmonella, LySP2 can lyse Salmonella and Escherichia. The survival rate of Salmonella-infected chicks treated with LySP2 can reach up to 70% and reduce Salmonella abundance in the liver and intestine. The treatment group showed that LySP2 significantly improved the health of infected chicks and alleviated organ damage caused by Salmonella infection. In this study, the Salmonella bacteriophage endolysin was expressed efficiently by Pichia pastoris, and the endolysin LySP2 showed good potential for the treatment of pullorum disease caused by Salmonella pullorum.

This study was conducted to investigate oropharyngeal microbiota alterations during the progression of coronavirus disease 2019 (COVID-19) by analyzing these alterations during the infection and clearance processes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The diagnosis of COVID-19 was confirmed by using positive SARS-CoV-2 quantitative reverse transcription polymerase chain reaction (RT-qPCR). The alterations in abundance, diversity, and potential function of the oropharyngeal microbiome were identified using metatranscriptomic sequencing analyses of oropharyngeal swab specimens from 47 patients with COVID-19 (within a week after diagnosis and within two months after recovery from COVID-19) and 40 healthy individuals. As a result, in the infection process of SARS-CoV-2, compared to the healthy individuals, the relative abundances of Prevotella, Aspergillus, and Epstein–Barr virus were elevated; the alpha diversity was decreased; the beta diversity was disordered; the relative abundance of Gram-negative bacteria was increased; and the relative abundance of Gram-positive bacteria was decreased. After the clearance of SARS-CoV-2, compared to the healthy individuals and patients with COVID-19, the above disordered alterations persisted in the patients who had recovered from COVID-19 and did not return to the normal level observed in the healthy individuals. Additionally, the expressions of several antibiotic resistance genes (especially multi-drug resistance, glycopeptide, and tetracycline) in the patients with COVID-19 were higher than those in the healthy individuals. After SARS-CoV-2 was cleared, the expressions of these genes in the patients who had recovered from COVID-19 were lower than those in the patients with COVID-19, and they were different from those in the healthy individuals. In conclusion, our findings provide evidence that potential secondary infections with oropharyngeal bacteria, fungi, and viruses in patients who have recovered from COVID-19 should not be ignored; this evidence also highlights the clinical significance of the oropharyngeal microbiome in the early prevention of potential secondary infections of COVID-19 and suggests that it is imperative to choose appropriate antibiotics for subsequent bacterial secondary infection in patients with COVID-19.

ABSTRACT: The genotype VII Newcastle disease virus (NDV) vaccine has begun to replace the traditional genotype II NDV vaccine and is widely used in the commercial poultry of China. However, the effect of homologous and heterogeneous anti-NDV serum on the evolution of prevalent NDV is unknown. To understand the effect of genotype II and VII anti-NDV serum on the evolution of genotype VII NDV strains, ZJ1 (waterfowl origin) and CH/SD/2008/128 (ND128; chicken origin) were used for serial passage of 30 generations in DF-1 cells without anti-NDV serum or with genotype II and VII anti-NDV serum independently. The F and HN genes of the 2 viruses were amplified for the 10th, 20th, and 30th generations of each serial passage group and compared with their respective original viruses. We found that there was only one mutation at position 248 in the F gene of ZJ1 due to the serum pressure of genotype VII anti-NDV. Similarly, mutations at residue 527 of the F gene, and position 9 and 319 of the HN gene of ND128 were noted in both anti-NDV serum groups. The results show that the nonsynonymous (NS)-to-synonymous (S) ratio of the F gene of ZJ1 virus was 1.6, and for the HN gene, it was 2.5 in the anti-II serum group. In the anti-VII serum group, the NS/S ratio for the F gene was 2.1, and for the HN gene, it was 2.5. The NS/S ratio of the F gene of the ND128 virus was 0.8, and for the HN gene, it was 3 in the anti-II serum group. Furthermore, the NS/S ratio of the F gene was 0.8, and the HN gene was 2.3 in the anti-VII group. Taken together, our findings highlight that there was no significant difference in the variation of protective antigens in genotype VII NDV under the selection pressure of homologous and heterogeneous genotype NDV inactivated vaccines.

Objective: Previous studies discussing phenotypic and temporal heterogeneity of knee osteoarthritis (KOA) separately have fatal limitations that either clustering patients with similar severity or assuming all knees have a single common progression pattern, which are unreliable. This study tried to uncover more reliable information on phenotypic and temporal heterogeneity of KOA.Design: Data were from Osteoarthritis Initiative database. Six hundred and seventy-eight unilateral knees that have greater Kellgren and Lawrence (KL) grade than the contralateral knees at baseline and in all follow-up 48 months were included. Measurements of biomarkers at baseline were chosen. Subtype and Stage Inference model (SuStaIn) was applied as a subtype-progression model to identify subtypes, subtype biomarker progress sequences and stages of KOA.Results: This study identified three subtypes which account for 15, 61, and 24% of knees, respectively. Each subtype has distinct subtype biomarker progress sequence. For knees with KL grade 0/1, 2, 3, and 4, they have different distributions on stage and 26, 53, 89, and 95% of them are strongly assigned to subtypes. When assessing whether a knee has KL (grade ≥ 2), subtypes and stages from subtypes-progression model (SuStaIn) are significantly better fitting than those from subtypes-only (mixture of Gaussians) (likelihood ratio = 105.59, p = 2.2 × 10−16) or stages-only (SuStaIn where setting c = 1) (likelihood ratio = 58.04, p = 2.57 × 10−14) model. Stages in subtypes-progression model has greater β than stages-only model. Subtypes from subtypes-progression model have no statistical significance.Conclusions: For subtypes-progression model, stages contain more complete temporal information and subtypes are closer to real OA subtypes.

Background: Predicting the risk of progression to severe coronavirus disease 2019 (COVID-19) could facilitate personalized diagnosis and treatment options, thus optimizing the use of medical resources.Methods: In this prospective study, 206 patients with COVID-19 were enrolled from regional medical institutions between December 20, 2019, and April 10, 2020. We collated a range of data to derive and validate a predictive model for COVID-19 progression, including demographics, clinical characteristics, laboratory findings, and cytokine levels. Variation analysis, along with the least absolute shrinkage and selection operator (LASSO) and Boruta algorithms, was used for modeling. The performance of the derived models was evaluated by specificity, sensitivity, area under the receiver operating characteristic (ROC) curve (AUC), Akaike information criterion (AIC), calibration plots, decision curve analysis (DCA), and Hosmer–Lemeshow test.Results: We used the LASSO algorithm and logistic regression to develop a model that can accurately predict the risk of progression to severe COVID-19. The model incorporated alanine aminotransferase (ALT), interleukin (IL)-6, expectoration, fatigue, lymphocyte ratio (LYMR), aspartate transaminase (AST), and creatinine (CREA). The model yielded a satisfactory predictive performance with an AUC of 0.9104 and 0.8792 in the derivation and validation cohorts, respectively. The final model was then used to create a nomogram that was packaged into an open-source and predictive calculator for clinical use. The model is freely available online at https://severeconid-19predction.shinyapps.io/SHINY/.Conclusion: In this study, we developed an open-source and free predictive calculator for COVID-19 progression based on ALT, IL-6, expectoration, fatigue, LYMR, AST, and CREA. The validated model can effectively predict progression to severe COVID-19, thus providing an efficient option for early and personalized management and the allocation of appropriate medical resources.

Background: Coronavirus disease 2019 (COVID-19) pandemic is continuing to impact multiple countries worldwide and effective treatment options are still being developed. In this study, we investigate the potential of high-dose intravenous vitamin C (HDIVC) in the prevention of moderate COVID-19 disease aggravation.Methods: In this retrospective before-after case-matched clinical study, we compare the outcome and clinical courses of patients with moderate COVID-19 patients who were treated with an HDIVC protocol (intravenous injection of vitamin C, 100 mg/kg/day, 1 g/h, for 7 days from admission) during a one-month period (between March 18 and april 18, 2020, HDIVC group) with a control group treated without the HDIVC protocol during the preceding two months (January 18 to March 18, 2020). Patients in the two groups were matched in a 1:1 ratio according to age and gender.Results: The HDIVC and control groups each comprised 55 patients. For the primary outcomes, there was a significant difference in the number of patients that evolved from moderate to severe type between the two groups (HDIVC: 4/55 vs. control: 12/55, relative risk [RR] = 0.28 [0.08, 0.93], P = 0.03). Compared to the control group, there was a shorter duration of systemic inflammatory response syndrome (SIRS) (P = 0.0004) during the first week and lower SIRS occurrence (2/21 vs 10/22, P = 0.0086) on Day 7 (6–7 days after admission). In addition, HDIVC group had lower C-reactive protein levels (P = 0.005) and higher number of CD4+ T cells from Day 0 (on admission) to Day 7 (P = 0.04).” The levels of coagulation indicators, including activated partial thromboplastin time and D-dimer were also improved in the HDIVC compared to the control group on Day 7.Conclusion: HDIVC may be beneficial in limiting disease aggravation in the early stage of COVID-19 pneumonia, which may be related to its improvements on the inflammatory response, immune function and coagulation function. Further randomized controlled trials are required to augment these findings.

Objective: To explore the influence by not performing an oral glucose tolerance test (OGTT) in Han Chinese over 40 years. Design: Overall, 6682 participants were included in the prospective cohort study and were followed up for 3 years. Methods: Fasting plasma glucose (FPG), 2-h post-load plasma glucose (2h-PG), FPG and 2h-PG (OGTT), and HbA1c testing using World Health Organization (WHO) or American Diabetes Association (ADA) criteria were employed for strategy analysis. Results: The prevalence of diabetes is 12.4% (95% CI: 11.6–13.3), while the prevalence of prediabetes is 34.1% (95% CI: 32.9–35.3) and 56.5% (95% CI: 55.2–57.8) using WHO and ADA criteria, respectively. 2h-PG determined more diabetes individuals than FPG and HbA1c. The testing cost per true positive case of OGTT is close to FPG and less than 2h-PG or HbA1c. FPG, 2h-PG and HbA1c strategies would increase costs from complications for false-positive (FP) or false-negative (FN) results compared with OGTT. Moreover, the least individuals identified as normal by OGTT at baseline developed (pre)diabetes, and the most prediabetes individuals identified by HbA1c or FPG using ADA criteria developed diabetes. Conclusions: The prevalence of isolated impaired glucose tolerance and isolated 2-h post-load diabetes were high, and the majority of individuals with (pre)diabetes were undetected in Chinese Han population. Not performing an OGTT results in underdiagnosis, inadequate developing risk assessment and probable cost increases of (pre)diabetes in Han Chinese over 40 years and great consideration should be given to OGTT in detecting (pre)diabetes in this population. Further population-based prospective cohort study of longer-term effects is necessary to investigate the risk assessment and cost of (pre)diabetes.

Abstract Copper ferrites are emerging transition metal oxides that have potential applications in energy storage devices. However, it still lacks in-depth designing of copper ferrites based anode architectures with enhanced electroactivity for lithium-ion batteries. Here, we report a facile synthesis technology of copper ferrites anchored on reduced graphene oxide (CuFeO2@rGO and Cu/CuFe2O4@rGO) as the high-performance electrodes. In the resulting configuration, reduced graphene offers continuous conductive channels for electron/ion transfer and high specific surface area to accommodate the volume expansion of copper ferrites. Consequently, the sheet-on-sheet CuFeO2@rGO electrode exhibits a high reversible capacity (587 mAh g−1 after 100 cycles at 200 mA g−1). In particular, Cu/CuFe2O4@rGO hybrid, which combines the advantages of nano-copper and reduced graphene, manifests a significant enhancement in lithium storage properties. It reveals superior rate capability (723 mAh g−1 at 800 mA g−1; 560 mAh g−1 at 3200 mA g−1) and robust cycling capability (1102 mAh g−1 after 250 cycles at 800 mA g−1). This unique structure design provides a strategy for the development of multivalent metal oxides in lithium storage device applications.