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Background: Current management practices and outcomes in weaning from invasive mechanical ventilation are poorly understood. We aimed to describe the epidemiology, management, timings, risk for failure, and outcomes of weaning in patients requiring at least 2 days of invasive mechanical ventilation. Methods: WEAN SAFE was an international, multicentre, prospective, observational cohort study done in 481 intensive care units in 50 countries. Eligible participants were older than 16 years, admitted to a participating intensive care unit, and receiving mechanical ventilation for 2 calendar days or longer. We defined weaning initiation as the first attempt to separate a patient from the ventilator, successful weaning as no reintubation or death within 7 days of extubation, and weaning eligibility criteria based on positive end-expiratory pressure, fractional concentration of oxygen in inspired air, and vasopressors. The primary outcome was the proportion of patients successfully weaned at 90 days. Key secondary outcomes included weaning duration, timing of weaning events, factors associated with weaning delay and weaning failure, and hospital outcomes. This study is registered with ClinicalTrials.gov, NCT03255109. Findings: Between Oct 4, 2017, and June 25, 2018, 10 232 patients were screened for eligibility, of whom 5869 were enrolled. 4523 (77·1%) patients underwent at least one separation attempt and 3817 (65·0%) patients were successfully weaned from ventilation at day 90. 237 (4·0%) patients were transferred before any separation attempt, 153 (2·6%) were transferred after at least one separation attempt and not successfully weaned, and 1662 (28·3%) died while invasively ventilated. The median time from fulfilling weaning eligibility criteria to first separation attempt was 1 day (IQR 0–4), and 1013 (22·4%) patients had a delay in initiating first separation of 5 or more days. Of the 4523 (77·1%) patients with separation attempts, 2927 (64·7%) had a short wean (≤1 day), 457 (10·1%) had intermediate weaning (2–6 days), 433 (9·6%) required prolonged weaning (≥7 days), and 706 (15·6%) had weaning failure. Higher sedation scores were independently associated with delayed initiation of weaning. Delayed initiation of weaning and higher sedation scores were independently associated with weaning failure. 1742 (31·8%) of 5479 patients died in the intensive care unit and 2095 (38·3%) of 5465 patients died in hospital. Interpretation: In critically ill patients receiving at least 2 days of invasive mechanical ventilation, only 65% were weaned at 90 days. A better understanding of factors that delay the weaning process, such as delays in weaning initiation or excessive sedation levels, might improve weaning success rates. Funding: European Society of Intensive Care Medicine, European Respiratory Society.

Exercise promotes health in people with diabetes. Weight-bearing activities increase the risk of foot ulcers. Air-pressure shoes may relieve high plantar pressure. Nevertheless, no study has investigated whether air-pressure shoes affect the plantar foot. A repeated measures study design, with five healthy subjects were tested with three inner air pressures (80, 160, and 240 mmHg) and 20 minutes of walking to examine their effects on peak plantar pressure (PPP). PPP after walking was measured from the forefoot in the big toe (T1), first metatarsal head (M1), and second metatarsal head (M2). We used a one-way ANOVA to analyze the results. We found that after walking for 20 min, inner air pressure significantly affected plantar pressure in the M1 and M2 (P = 0.008 and 0.006, respectively). Regarding the inner air pressure effect, there was a significant difference in the M1 head between 80 and 240 mmHg (274.2 ± 35.6 kPa vs. 689.4 ± 106.3 kPa, P = 0.002) at 20 minutes of walking duration. Moreover, there was a significant difference in the M2 head between 80 mmHg and 240 mmHg (250.6 ± 30.1 kPa vs. 572.4 ± 87.3 kPa, P = 0.002) and 160 and 240 mmHg (396.6 ± 35.3.7 kPa vs. 572.4 ± 87.3 kPa, P = 0.050). This finding is significant because the higher inner air pressure shoes can increase plantar pressure compared to 80 mmHg inner air pressure. This study suggests that individuals who are at high risk of developing foot ulcers should wear shoes with an inner air insole (80 mmHg).

Pyrimidine nucleosides (PN) are abundant in mammalian milk and mainly involved in glycogen deposition and lipid metabolism. To investigate the effects of maternal supplementation with pyrimidine nucleoside on glucose, fatty acids (FAs), and amino acids (AAs) metabolism in neonatal piglets. Forty pregnant sows were randomly assigned into the control (CON) group (fed a basal diet

N-Carbamoyl-aspartic acid (NCA) is a critical precursor for de novo biosynthesis of pyrimidine nucleotides. To investigate the cumulative effects of maternal supplementation with NCA on the productive performance, serum metabolites and intestinal microbiota of sows, 40 pregnant sows (∼day 80) were assigned into two groups: (1) the control (CON) and (2) treatment (NCA, 50 g tResults showed that piglets from the NCA group had heavier birth weight than those in the CON group (P 0.05). In addition, maternal supplementation with NCA decreased the backfat loss of sows during lactation (P 0.05). Furthermore,16S-rRNA sequencing results revealed that maternal NCA supplementation decreased the abundance of Cellulosilyticum, Fournierella, Anaerovibrio, and Oribacterium genera of sows during late pregnancy (P 0.05). Similarly, on the 14th day of lactation, maternal supplementation with NCA reduced the diversity of fecal microbes of sows as evidenced by significantly lower observed species, Chao1, and Ace indexes, and decreased the abundance of Lachnospire, Faecalibacterium, and Anaerovorax genera, while enriched the abundance of Catenisphaera (P 0.05). Untargeted metabolomics showed that a total of 48 differentially abundant biomarkers were identified, which were mainly involved in metabolic pathways of arginine/proline metabolism, phenylalanine/tyrosine metabolism, and fatty acid biosynthesis, etc. CONCLUSION: Overall, the results indicated that NCA supplementation regulated intestinal microbial composition of sows and serum differential metabolites related to arginine, proline, phenylalanine, tyrosine, and fatty acids metabolism that may contribute to regulating the backfat loss of sows, and the birth weight and diarrhea rate of piglets. © 2022 Society of Chemical Industry.

Xinyu Fan,1,2,* Jiachen Shi,1,* Ye Liu,3 Mengqiu Zhang,1 Min Lu,1,2 Ding Qu1,2 1Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China; 2Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, People’s Republic of China; 3The Second Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Min Lu, Jiangsu Province Academy of Traditional Chinese Medicine, 100 Shizi Street, Hongshan Road Nanjing 210028, People’s Republic of China, Email lmxlsr6666@163.com Ding Qu, Jiangsu Province Academy of Traditional Chinese Medicine, 100 Shizi Street, Hongshan Road, Nanjing, 210028, People’s Republic of China, Email quding1985@hotmail.comBackground: Berberine (BR) shows promise as a candidate for treating irritable bowel syndrome with diarrhea (IBS-D). However, the undesired physicochemical properties and poor oral absorption limit its clinical translation. A ketogenic diet (KD) can induce intestinal overexpression of cannabidiol (CB) receptors, which may offer a potential target for IBS-D-specific delivery of BR.Methods: The microemulsions loaded with BR and decorated with cannabidiol (CBD/BR-MEs) were developed through a one-step emulsion method. The pharmaceutical behaviors of the CBD/BR-MEs were measured using dynamic light scattering and high-performance liquid chromatography. The efficacy of the anti-IBS-D therapy was evaluated by assessing fecal water content, Bristol score, and AWR score. The intestinal permeability were assessed through immunofluorescent staining of CB1 and ZO-1, respectively. The signaling of CREB/BDNF/c-Fos was also studied along with immunofluorescent and immunohistochemical examination of brain sections.Results: The CBD/BR-MEs, which had a particle size of approximately 30 nm and a surface density of 2% (wt%) CBD, achieved greater than 80% (wt%) encapsulation efficiency of BR. The pharmacokinetics performance of CBD/BR-MEs was significantly improved in the KD-fed IBS-D rats than the standard diet-fed ones, which is highly related to intestinal expression of CB1 receptors. The treatment with CBD/BR-MEs and KD exhibited evident comprehensive advantages over the other groups in terms of anti-IBS-D efficacy. CBD/BR-MEs and KD synergistically decreased intestinal permeability. Moreover, the treatment with CBD/BR-MEs and KD not only blocked the CREB/BDNF/c-Fos signaling in the brain but also decreased the levels of neurotrophic factors, neurotransmitters, and inflammatory cytokines in the serum of IBS-D model rats.Conclusion: Such a design represents the first attempt at IBS-D-targeted drug delivery for improved oral absorption and efficacy through KD-induced target exposure, which holds promising potential for the treatment of IBS-D.Keywords: irritable bowel syndrome-diarrhea, berberine, microemulsion, ketogenic diet, CB1 receptors

It is the first step for understanding how RNA structure folds from base sequences that to know how its secondary structure is formed. Traditional energy-based algorithms are short of precision, particularly for non-nested sequences, while learning-based algorithms face challenges in obtaining high-quality training data. Recently, quantum annealer has rapidly predicted the folding of the secondary structure, highlighting that quantum computing is a promising solution to this problem. However, gate model algorithms for universal quantum computing are not available. In this paper, gate-based quantum algorithms will be presented, which are highly flexible and can be applied to various physical devices. Mapped all possible secondary structure to the state of a quadratic Hamiltonian, the whole folding process is described as a quadratic unconstrained binary optimization model. Then the model can be solved through quantum approximation optimization algorithm. We demonstrate the performance with both numerical simulation and experimental realization. Throughout our benchmark dataset, simulation results suggest that our quantum approach is comparable in accuracy to classical methods. For non-nested sequences, our quantum approach outperforms classical energy-based methods. Experimental results also indicate our method is robust in current noisy devices. It is the first instance of universal quantum algorithms being employed to tackle RNA folding problems, and our work provides a valuable model for utilizing universal quantum computers in solving RNA folding problems., 19 pages, 7 figures

ObjectiveThe goal of the present study was to investigate gender differences in disability-free life expectancy (DFLE) and DFLE/LE ratio among older adults in China; portray changing trend from 2010 to 2020; and discuss the implications for public policies.MethodsMortality data and disability rate data were derived from the Sixth China Population Census in 2010 and the Seventh China Population Census in 2020. The study assessed disability status of older adults based on self-assessment health in the above censuses. Life table and Sullivan method were used to estimate LE, DFLE, and DFLE/LE ratio by gender.ResultsDFLE increased from 19.33 to 21.78 years for 60-year-old males, while from 21.94 to 24.80 years for 60-year-old females, from 2010 to 2020, respectively. DFLE/LE ratio was 96.40% for 60-year-old males and 94.86% for 60-year-old females in 2010, while DFLE/LE ratio was 96.63% for 60-year-old males and 95.44% for 60-year-old females in 2020, respectively. In terms of gender differences in DFLE/LE ratio, men aged 60 are 1.19 percentage points higher than women at the same age; men aged 70 are 1.71 percentage points higher than women; men aged 80 are 2.87 percentage points higher than women.ConclusionFrom 2010 to 2020, the DFLE of China’s male and female older adults increased simultaneously with the increase of LE, and the DFLE/LE ratio also increased. However, the DFLE/LE ratio of female older adults is lower than that of male at the same age, and this gender difference is narrowing over the decade but has not yet been eliminated, especially the health disadvantage of female older adults among the oldest old age group (age 80 and above) is more prominent.

PurposeVitamin D deficiency is frequent in patients with multiple myeloma (MM), however, its prognostic relevance in MM was rather inconclusive. We first investigated the association of vitamin D deficiency with abnormal bone and lipid metabolism in newly diagnosed multiple myeloma (NDMM), and next assessed the impact of serum ratio of vitamin D to carboxy-terminal telopeptide of type I collagen (β-CTX) on progression-free survival (PFS) and overall free survival (OS) in patients with NDMM.MethodsThe data of 431 consecutive patients with NDMM at Beijing Jishuitan Hospital from September 2013 to December 2022 were collected and retrospectively reviewed through our electronic medical record system. The measurement of 25-hydroxyvitamin D in the blood is an indicator of an individual’s overall vitamin D status.ResultsThe serum levels of vitamin D were negatively correlated with β-CTX in NDMM patients. Of note, positive correlation between vitamin D and cholesterol levels in the serum was found in this study. The cohort (n = 431) was divided into two groups based on the serum ratio of vitamin D to β-CTX. Compared to the group with a higher vitamin D to β-CTX ratio, the group with a lower vitamin D to β-CTX ratio (n = 257, 60%) exhibited hypocholesterolemia, inferior PFS and OS, along with increased cases of ISS stage-III and R-ISS stage-III, a higher number of plasma cells in the bone marrow, and elevated serum calcium levels. Consistent with this, multivariate analysis confirmed that the vitamin D to β-CTX ratio was an independent unfavorable indicator for survival in NDMM patients.ConclusionOur data demonstrated the ratio of vitamin D to β-CTX in the serum is a unique biomarker for NDMM patients to identify the high-risk cases with poor prognosis, which is superior to vitamin D itself for predicting PFS and OS in NDMM. Also, it is worth mentioning that our data on the connection between vitamin D deficiency and hypocholesterolemia might help clarify novel mechanistic aspects of myeloma development.

This study presents a comprehensive approach that addresses the challenges of scientometric analysis in the rapidly evolving field of Artificial Intelligence (AI). By combining search terms related to AI with the advanced language processing capabilities of generative pre-trained transformers (GPT), we developed a highly accurate method for identifying and analyzing AI-related articles in the Web of Science (WoS) database. Our multi-step approach included filtering articles based on WoS citation topics, category, keyword screening, and GPT classification. We evaluated the effectiveness of our method through precision and recall calculations, finding that our combined approach captured around 94% of AI-related articles in the entire WoS corpus with a precision of 90%. Following this, we analyzed the publication volume trends, revealing a continuous growth pattern from 2013 to 2022 and an increasing degree of interdisciplinarity. We conducted citation analysis on the top countries and institutions and identified common research themes using keyword analysis and GPT. This study demonstrates the potential of our approach to facilitate accurate scientometric analysis, by providing insights into the growth, interdisciplinary nature, and key players in the field., 29 pages, 10 figures, 5 tables

Figure S1 shows the expression of RNF8 in different pathological types of lung cancers tissues. Figure S2 shows the overexpression of RNF8-C406S cannot improve the migration potential of A549 cells.

Many ectomycorrhizal (ECM) fungi produce commercially valuable edible sporocarps. However, the effects of nitrogen (N) application on ECM fungal sporocarp formation remain poorly understood. In this study, we investigated the effect of application of various N concentrations (0, 5, 25, 50, 100, and 200 mg/L) on the growth of Laccaria japonica mycelia in vitro for 1 month. The results showed that L. japonica mycelial biomass was highest in the 50 mg/L treatment and was significantly inhibited at N concentrations higher than 200 mg/L. Next, we investigated the effects of N application on mycorrhizal colonization and sporocarp formation in L. japonica colonizing Pinus densiflora seedlings in pots. The seedlings were watered with nutrient solutions containing 0, 5, 25, 50, or 100 mg N/L. The biomass, photosynthetic rate, and mycorrhizal colonization rates of the seedlings were measured at 45 days (first appearance of primordia), 65 days (sporocarp appearance on the substrate surface), and 4 months after seedlings were transplanted. The numbers of primordia and sporocarps were recorded during the experimental period. Total carbon (C) and N content were determined in seedlings at 4 months after transplantation, and in L. japonica sporocarps. Both mycelial growth and sporocarp production reached their maximum at an N application concentration of 50 mg/L, suggesting that the most suitable N concentration for ECM fungal sporocarp formation can easily be estimated in vitro during mycelial growth. This finding may help determine the most suitable N conditions for increasing edible ECM fungus sporocarp production in natural forests.

A bispecific monoclonal antibody (BsMAb) that can simultaneously recognize aflatoxin B1 (AFB1) and amantadine (AMD) was prepared. Quantum dot nanobead immunochromatographic assay (QB-ICA) based on the BsMAb was developed for the simultaneous detection of AFB1 and AMD in four feed samples (suckling pig feed, piglet feed, sow feed, and compound feed for laying ducks). Under optimal experimental conditions, the LOD values of QB-ICA for AFB1 in four feed samples were 0.188, 0.221, 0.233, and 0.306 μg/kg, respectively. The LOD values of QB-ICA for AMD in the same feed samples were 0.125, 0.187, 0.076, and 0.191 μg/kg, respectively. The recovery rates of QB-ICA for AFB1 and AMD ranged from 91.55% to 150.87% and from 91.62% to 138.42%, respectively. The variation coefficients were all less than 15%. The proposed QB-ICA had high reliability and specificity for the simultaneous detection of AFB1 and AMD, providing a platform for simultaneous detection of hazardous substances.

Purpose: Recent evidence indicates that small noncoding RNA molecules, known as microRNAs (miRNAs), are involved in cancer initiation and progression. We hypothesized that genetic variations in miRNAs and miRNA target sites could be associated with the efficacy of androgen-deprivation therapy (ADT) in men with prostate cancer.Experimental Design: We systematically evaluated 61 common single nucleotide polymorphisms (SNPs) inside miRNAs and miRNA target sites in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT were assessed by Kaplan–Meier analysis and Cox regression model.Results: Four, seven, and four SNPs were significantly associated with disease progression, PCSM, and ACM, respectively, after ADT in univariate analysis. KIF3C rs6728684, CDON rs3737336, and IFI30 rs1045747 genotypes remained as significant predictors for disease progression; KIF3C rs6728684, PALLD rs1071738, GABRA1 rs998754, and SYT9 rs4351800 remained as significant predictors for PCSM; and SYT9 rs4351800 remained as a significant predictor for ACM in multivariate models that included clinicopathologic predictors. Moreover, strong combined genotype effects on disease progression and PCSM were also observed. Patients with a greater number of unfavorable genotypes had a shorter time to progression and worse prostate cancer-specific survival during ADT (P for trend < 0.001).Conclusion: SNPs inside miRNAs and miRNA target sites have a potential value to improve outcome prediction in prostate cancer patients receiving ADT. Clin Cancer Res; 17(4); 1–9. ©2010 AACR.

Supplementary Table S1.

Background: Thalassemia presents a higher incidence in southern China. The objective of this study is to analyze the genotype distribution of thalassemia in Yangjiang, a western city of Guangdong Province in China.Methods: The genotypes of suspected cases with thalassemia were tested by PCR and reverse dot blot (RDB). Unidentified rare thalassemia genotypes of the samples were further ascertained by PCR and direct DNA sequencing.Results: Among 22467 suspected cases with thalassemia, 7658 cases were found with thalassemia genotypes using our PCR-RDB kit. Among these 7658 cases, 5313 cases were found with α-thalassemia (α-thal) alone, --SEA/αα was the most common genotype, accounting for 61.75% of α-thal genotypes, and the following mutations were found: α3.7/αα, -α4.2/αα, αCSα/αα, αWSα/αα, and αQSα/αα. A total of 2032 cases were found with β-thalassemia (β-thal) alone. βCD41-42/βN, βIVS−II−654/βN, and β−28/βN accounted for 80.9% of all β-thal genotypes, and the following genotypes were found: βCD17/βN, βCD71-72/βN, and βE/βN. Compound heterozygotes of β-thal and β-thalassemia homozygotes were identified in 11 and five cases, respectively, in this study. α-thal combined with β-thal was identified in 313 cases, showing 57 genotype combinations of the coincidence of both Hb disorders; one extreme patient had a genotype of --SEA/αWSα and βCD41-42/β−28. In addition, four rare α-mutations (--THAI, HKαα, Hb Q-Thailand, and CD31 AGG>AAG) and six rare β-mutations (CD39 CAG>TAG, IVS-Ⅱ-2 (−T), −90(C>T), Chinese Gγ+(Aγδβ)0, CD104 (-G), and CD19 A>G) were also found in this study population.Conclusion: This study provided detailed genotypes of thalassemia in Yangjiang of western Guangdong Province in China and reflected the complexity of genotypes in this high-prevalence region, and this would be valuable for diagnosis and counseling for thalassemia in this area.

Additional file 1: Table S1. The classification and number among different species used in OBPs, CSPs and GRs in the phylogenetic trees. OBPs and CSPs in non-coleoptera species were not used in the phylogenetic analyses. The number of GR in non-coleoptera species of annotated proteins in those genomes were marked in green, in the transcriptome data was marked in bule. The italic numbers were used to structure the GR tree. Table S2. Primers for qRT-PCR of chemosensory genes in P. versicolora. Table S3. The Blastx match of P. versicolora candidate CSP and OBP genes. The new genes compared to previous reports were marked with bule color. Table S4. The Blastx match of P. versicolora candidate GR, IR, OR and SNMP genes. The new genes compared to previous reports were marked with bule color. Fig. S1. Distribution of unigene size of transcriptome assembly from third instar larvae head in P. versicolora. Fig. S2. Gene ontology (GO) classification of transcriptome unigenes from third instar larvae head in P. versicolora. Figure S3. Phylogenetic analysis of the IRs. The P. versicolora genes are shown in blue. The values at the branch nodes represent bootstrap values based on 1000 replicates. Figure S4. The Venn diagrams of chemosensory genes in P. versicolora from the transcriptome of antennae, forelegs and larvae. Figure S5. Phylogenetic analysis of the ORs. The P. versicolora genes are shown in blue. Pver, P. versicolora; Harm, Helicoverpa armigera; Cbow, Colaphellus bowringi. The values at the branch nodes represent bootstrap values based on 1000 replicates. File S1. The amino acid sequences of Plagiodera versicolora putative chemosensory genes.

Additional file 1: Search strategies.

Additional file 1: Figure S1. ACLY is upregulated by SEC63 in response to ER stress in HCC cells. A The heatmaps displaying the differentially expressed ARGs from TCGA-LIHC, ICGC-LIRI-JP, and GSE101728 cohorts. B The expression level of the indicated genes was analyzed in the indicated cohorts. C The overall survival curve of the HCC patients with different ACLY mRNA levels from ICGC was analyzed by Kaplan-Meier analyses. D Triple immunofluorescene (IF) staining for ACLY (red), SEC63 (green), and nuclei (DAPI, blue) was performed in Huh7 and HepG2 cells. Scale bar, 10 μm. E GST pulldown assay with purified fragments as indicated. Figure S2. SEC63 is phosphorylated at T537 after ER stress. A Western blot analysis of SEC63 in cell lysates of Huh7 cells treated as indicated. B Relative SEC63 expression levels in HepG2 and Huh7 cells were determined by immunofluorescence assay using Leica LAS X confocal software (n = 100). C The predication analysis of SEC63 localization by COMPARTMENTS. D Cell fraction was performed and western blot was employed for analyzing the indicated protein. E Dot blot analysis was performed for validating T537-p antibody. F Cell lysates from Huh7 cells were subjected to Co-IP using the indicated antibody. G Cell fraction was performed and the indicated proteins were determined by western blot. Figure S3. SEC63 increases the stability of ACLY. A Total RNA extracted from the Huh7 cells treated with TM (5 μg/mL) or TG (1 μM) were subjected to RT-qPCR as indicated. B HepG2 and Huh7 cells were treated with TM (5 μg/mL) or TG (1 μM) and immunofluorescence was performed. Scale bar, 10 μm. Figure S4. SEC63 is associated with prognosis of HCC patients. A The mRNA level of SEC63 was analyzed as indicated. B The overall survival curve of the HCC patients with different SEC63 mRNA levels from ICGC database was analyzed by Kaplan-Meier analyses. C The overall survival and disease-free survival curves of HCC patients were plotted against the SEC63 and/or ACLY mRNA levels based on the prognosis data of TCGA-LIHC database using the Kaplan-Meier method. The difference between the survival curves was analyzed using the log-rank test. D Overall survival curve of HCC patients was plotted against the SEC63 and/or ACLY mRNA levels based on the prognosis data of ICGC database using the Kaplan-Meier method. The difference between the survival curves was analyzed using the log-rank test. Figure S5. SEC63 promotes HCC cell metastasis relying on ACLY. A HepG2 or Huh7 stable cell lines with overexpression of SEC63 were generated. Western blot was performed for analyzing the expression level of SEC63. B Huh7 or PLC/PRF/5 stable cell lines with knockdown of SEC63 were generated. The knockdown effect was determined by western blot. C-F The cells were treated as indicated and cell proliferation was assessed by MTT assay. G Migration assay or invasion assay was performed as indicated. Migration or invasion rate was further quantified (n = 3). H Wound healing assay was performed as indicated. Wound closure rate was quantified (n = 3). I Western blot analysis of the indicated proteins in 12 individual paired HCC tissues used in Figure 4I. Figure S6. SEC63 modulates ACLY-related metabolic and epigenetic reprogramming. A The cellular acetyl-CoA level was evaluated in the indicated cells (n = 4). B The cellular free fatty acids, cholesterol level, and triglyceride levels were evaluated in the indicated cells (n = 4). C The potential interacting proteins of SEC63 related to ER stress were identified by liquid chromatography-tandem mass spectrometry. D Huh7 cells were transfected as indicated. Then, total RNA was extracted and RT-qPCR was performed using the SNAI1 primers (n = 3). E The ctrl cells or ACLY-depleted cells were treated with WM1119. Western blot was performed for the indicated proteins. F The correlation analyses were analyzed as indicated using TCGA HCC dataset. G The overall survival or disease-free survival curves were analyzed as indicated using TCGA HCC dataset. H The overall survival curve was plotted as indicated using ICGC dataset. Table S1. Correlation of SEC63/ACLY expression with clinicopathologic status in 139 cases of patients with HCC. Table S2. Reagents and antibodies. Table S3. shRNA sequence. Table S4. Primer used for RT-qPCR.

Fungi, as eukaryotic organisms, contain two genomes, the mitochondrial genome and the nuclear genome, in their cells. How the two genomes evolve and correlate to each other is debated. Herein, taking the gourmet pine mushroom Tricholoma matsutake as an example, we performed comparative mitogenomic analysis using samples collected from diverse locations and compared the evolution of the two genomes. The T. matsutake mitogenome encodes 49 genes and is rich of repetitive and non-coding DNAs. Six genes were invaded by up to 11 group I introns, with one cox1 intron cox1P372 showing presence/absence dynamics among different samples. Bioinformatic analyses suggested limited or no evidence of mitochondrial heteroplasmy. Interestingly, hundreds of mitochondrial DNA fragments were found in the nuclear genome, with several larger than 500 nt confirmed by PCR assays and read count comparisons, indicating clear evidence of transfer of mitochondrial DNA into the nuclear genome. Nuclear DNA of T. matsutake showed a higher mutation rate than mitochondrial DNA. Furthermore, we found evidence of incongruence between phylogenetic trees derived from mitogenome and nuclear DNA sequences. Together, our results reveal the dynamic genome evolution of the gourmet pine mushroom.

Established herein is a radical-mediated C-H alkylation of enamides with cyclopropanols. An environmentally benign catalytic system with iron salt and air is used to permit the oxidative coupling process. The protocol demonstrates a broad substrate scope, allowing the stereoselective synthesis of alkylated enamides. The value of this strategy is further reflected by late-stage diversification of complex cyclopropanol-containing molecules and downstream transformations. Mechanistic studies reveal the dual role of iron salt in the reaction.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of solid tumors, associated with a high prevalence of cachexia (~80%). PDAC-derived cachexia (PDAC-CC) is a systemic disease involving the complex interplay between the tumor and multiple organs. The endocrine organ–like tumor (EOLT) hypothesis may explain the systemic crosstalk underlying the deleterious homeostatic shifts that occur in PDAC-CC. Several studies have reported a markedly heterogeneous collection of cachectic mediators, signaling mechanisms, and metabolic pathways, including exocrine pancreatic insufficiency, hormonal disturbance, pro-inflammatory cytokine storm, digestive and tumor-derived factors, and PDAC progression. The complexities of PDAC-CC necessitate a careful review of recent literature summarizing cachectic mediators, corresponding metabolic functions, and the collateral impacts on wasting organs. The EOLT hypothesis suggests that metabolites, genetic instability, and epigenetic changes (microRNAs) are involved in cachexia development. Both tumors and host tissues can secrete multiple cachectic factors (beyond only inflammatory mediators). Some regulatory molecules, metabolites, and microRNAs are tissue-specific, resulting in insufficient energy production to support tumor/cachexia development. Due to these complexities, changes in a single factor can trigger bi-directional feedback circuits that exacerbate PDAC and result in the development of irreversible cachexia. We provide an integrated review based on 267 papers and 20 clinical trials from PubMed and ClinicalTrials.gov database proposed under the EOLT hypothesis that may provide a fundamental understanding of cachexia development and response to current treatments.

Background RNF8 is an E3 ligase identified as a critical DNA damage-responsive protein. Recently, multiple reports have shown that RNF8 could be used as an important therapeutic target for cancer chemo/radiotherapy. However, the understanding of RNF8 remains limited due to the lack of its interactome reference map and comprehensive analysis of RNF8 in diverse cancers, which underscores the need to map the interactome of RNF8 via high-throughput methods. Results A two-way identification method based on LC–MS was designed for the identification of the RNF8 interactome with high-specificity. By in silico analysis and in vitro validation, we identified a new reference map of the RNF8 interactome network containing many new targets, such as YBX1, DNMT1, and HDCA1, new biological functions and the gene-disease associations of RNF8. Our results revealed a close relationship between RNF8 and neurodegenerative diseases or tumor-infiltrating immune cells using bulk RNA-seq and scRNA-seq datasets. As a proof of concept of our interactome map, we validated the direct binding between RNF8 and YBX1 and showed that RNF8 catalyzed the ubiquitination of YBX1. These results demonstrated that RNF8 might be a crucial regulator of YBX1. Conclusions Our work provides a unique framework for researchers and clinicians who seek to better explore or understand RNF8-regulated biological functions in cancers. This study will hopefully facilitate the rational design and further development of anti-RNF8 therapy in cancers. Graphical abstract

Bone metastasis is one of the leading causes of cancer-related death and remains incurable in spite of great efforts. Bone-targeted nanoparticle-based drug carriers can overcome the difficulties in delivering therapeutic agents to metastatic bone and endowing them with a stimuli-responsive feature for controllable drug release can further maximize their therapeutic outcome. In light of hypoxic microenvironment of bone metastasis, we herein reported a bone-targeted and hypoxia-responsive polymeric micelle system for effective treatment of bone metastatic prostate cancer. The micelles were self-assembled from a polyethylene glycol and poly-l-lysine based copolymer using alendronate as a bone-targeted moiety and azobenzene as a hypoxia-responsive linker, showing a high affinity to metastatic bone and a high sensitivity in responding to hypoxia in vitro. In vivo studies further showed that after a selective accumulation in metastatic bone, the micelles could respond to hypoxic bone metastasis for rapid drug release to an effective therapeutic dosage. As a result, the micelles could suppress tumor growth in bone and inhibit bone destruction by inhibiting osteoclast activity and promoting osteoblast activity, achieving an enhanced therapeutic outcome with relieved bone pain and prolonged survival time. Bone-targeted and hypoxia-responsive nanocarriers therefore represent a promising advancement for treating bone metastasis. To our best knowledge, it might be the first example of the application of hypoxia-responsive nanocarriers in treating bone metastasis.

The synthesis of highly luminescent colloidal CsSnX3 (X = halogen) perovskite nanocrystals (NCs) remains a long-standing challenge due to the lack of a fundamental understanding of how to rationally suppress the formation of structural defects that significantly influence the radiative carrier recombination processes. Here, we develop a theory-guided, general synthetic concept for highly luminescent CsSnX3 NCs. Guided by density functional theory calculations and molecular dynamics simulations, we predict that, although there is an opposing trend in the chemical potential-dependent formation energies of various defects, highly luminescent CsSnI3 NCs with narrow emission could be obtained through decreasing the density of tin vacancies. We then develop a colloidal synthesis strategy that allows for rational fine-tuning of the reactant ratio in a wide range but still leads to the formation of CsSnI3 NCs. By judiciously adopting a tin-rich reaction condition, we obtain narrow-band-emissive CsSnI3 NCs with a record emission quantum yield of 18.4%, which is over 50 times larger than those previously reported. Systematic surface-state characterizations reveal that these NCs possess a Cs/I-lean surface and are capped with a low density of organic ligands, making them an excellent candidate for optoelectronic devices without any postsynthesis ligand management. We showcase the generalizability of our concept by further demonstrating the synthesis of highly luminescent CsSnI2.5Br0.5 and CsSnI2.25Br0.75 NCs. Our findings not only highlight the value of computation in guiding the synthesis of high-quality colloidal perovskite NCs but also could stimulate intense efforts on tin-based perovskite NCs and accelerate their potential applications in a range of high-performance optoelectronic devices.

BackgroundTo explore the geographical pattern and temporal trend of autism spectrum disorders (ASD) epidemiology from 1990 to 2019, and perform a bibliometric analysis of risk factors for ASD.MethodsIn this study, ASD epidemiology was estimated with prevalence, incidence, and disability-adjusted life-years (DALYs) of 204 countries and territories by sex, location, and sociodemographic index (SDI). Age-standardized rate (ASR) and estimated annual percentage change (EAPC) were used to quantify ASD temporal trends. Besides, the study performed a bibliometric analysis of ASD risk factors since 1990. Publications published were downloaded from the Web of Science Core Collection database, and were analyzed using CiteSpace.ResultsGlobally, there were estimated 28.3 million ASD prevalent cases (ASR, 369.4 per 100,000 populations), 603,790 incident cases (ASR, 9.3 per 100,000 populations) and 4.3 million DALYs (ASR, 56.3 per 100,000 populations) in 2019. Increases of autism spectrum disorders were noted in prevalent cases (39.3%), incidence (0.1%), and DALYs (38.7%) from 1990 to 2019. Age-standardized rates and EAPC showed stable trend worldwide over time. A total of 3,991 articles were retrieved from Web of Science, of which 3,590 were obtained for analysis after removing duplicate literatures. “Rehabilitation”, “Genetics & Heredity”, “Nanoscience & Nanotechnology”, “Biochemistry & Molecular biology”, “Psychology”, “Neurosciences”, and “Environmental Sciences” were the hotspots and frontier disciplines of ASD risk factors.ConclusionsDisease burden and risk factors of autism spectrum disorders remain global public health challenge since 1990 according to the GBD epidemiological estimates and bibliometric analysis. The findings help policy makers formulate public health policies concerning prevention targeted for risk factors, early diagnosis and life-long healthcare service of ASD. Increasing knowledge concerning the public awareness of risk factors is also warranted to address global ASD problem.

To observe the effect of moxibustion on the regulation of nuclear factor-kappa B (NF-κB) and inflammatory factors by multiple microRNAs (miRNAs) in rats with diarrhea-predominant irritable bowel syndrome (IBS-D), and to explore the anti-inflammatory mechanism of moxibustion on IBS-D.Twelve of 52 newborn rats were randomly selected into a normal group. The remaining rats were made into IBS-D model. A total of 36 rats with successful model were randomly divided into a model group, a medication group and a moxibustion group, 12 rats in each group. The rats in the medication group were intraperitoneally injected with pyrrolidine dithiocarbamate (PDTC). The rats in the moxibustion group were treated with moxibustion at "Tianshu" (ST 25) and "Shangjuxu" (ST 37) for 20 min each time. All the intervention was given once a day for 7 days. Before and after modeling as well as after intervention, the body mass, loose stool rate and the minimum volume threshold of abdominal withdrawal reflex (AWR) were measured. After intervention, the contents of serum tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-8 were detected by ELISA method; the morphology of colon tissues was observed by HE staining, and the expressions of miR-155, miR-125b, miR-29b, miR-31, miR-18a and NF-κB p65 mRNA in colon tissues were detected by real-time PCR. The expressions of NF-κB p65, TNF-α, IL-1β and IL-8 protein in colon tissues were detected by immunofluorescence.After modeling, the body mass and the minimum volume threshold of AWR in the model group were lower than those in the normal group (The anti-inflammatory mechanism of moxibustion at "Tianshu" (ST 25) and "Shangjuxu" (ST 37) for IBS-D rats may be related to regulating multiple miRNAs to inhibit NF-κB signal pathway and reduce the expression of inflammatory factors.

In the eukaryotic cellular milieu, proteins are continuously synthesized and degraded effectively via endogenous protein degradation machineries such as the ubiquitin-proteasome and lysosome pathways. By reengineering and repurposing these natural protein regulatory mechanisms, the targeted protein degradation (TPD) strategies are presenting biologists with powerful tools to manipulate the abundance of proteins of interest directly, precisely, and reversibly at the post-translational level. In recent years, TPD is gaining massive attention and is recognized as a paradigm shift both in basic research, application-oriented synthetic biology, and pioneering clinical work. In this review, we summarize the updated information, especially the engineering efforts and developmental route, of current state-of-the-art TPD technology such as Trim-Away, LYTACs, and AUTACs. Besides, the general design principle, benefits, problems, and opportunities to be addressed were further analyzed, with the aim of providing guidelines for exploration, discovery, and further application of novel TPD tools in the future.

Afzelia africana, Entada africana, and Pterocarpus erinaceus are economically important tropical tree species in Africa. In this study, we performed morphological and molecular analyses to examine the mycorrhizal status of these species in their natural habitat in Benin, West Africa. Fine roots were examined using trypan blue staining. Putative arbuscular mycorrhizal fungi (AMF) were identified by extracting root DNA and sequencing the large subunit region of ribosomal DNA. Operational taxonomic units (OTUs) were positioned on a consensus phylogenetic tree produced using maximum likelihood and neighbor-joining models. Morphological analyses revealed vesicles, arbuscules, and inter- and intracellular hyphae in roots of all three tree species. Molecular analyses revealed 39 AMF OTUs, among which 18 were from roots of E. africana, 15 from P. erinaceus, and 9 from A. africana. These OTUs belonged to Glomus, Nanoglomus, Rhizoglomus, Sclerocystis, Septoglomus, and Scutellospora; two unidentified species belonged to the family Glomeraceae. This is the first study to report AMF in roots of A. africana, E. africana, and P. erinaceus in Benin, and opens new avenues for future studies.

Sugammadex has several pharmacological advantages over neostigmine, including faster reversal of neuromuscular blockade and fewer adverse effects. However, the economic impact of sugammadex remains controversial due to the considerable heterogeneity of study designs and clinical settings in previous studies. In a post-hoc analysis of a randomized controlled trial, we evaluated patients who underwent elective surgeries and general anesthesia with endotracheal intubation in a medical center in Taiwan between March 2020 and August 2020. Patients were divided into either the sugammadex or neostigmine group based on the neuromuscular blocking drug used. Propensity score matching was used to balance the baseline patient characteristics between the two groups. The patient’s recovery from anesthesia and the putative cost-effectiveness of sugammadex versus neostigmine was assessed. Derived cost-effectiveness using personnel costs in the operating room and the post-anesthesia care unit was estimated using multiple linear regression models. A total of 2587 and 1784 patients were included before and after matching, respectively. Time to endotracheal extubation was significantly shorter in the sugammadex group (mean 6.0 ± standard deviation 5.3 min) compared with the neostigmine group (6.6 ± 6.3 min; p = 0.0032). In addition, the incidence of bradycardia was significantly lower in the sugammadex group (10.2%) compared with the neostigmine group (16.9%; p < 0.001). However, the total costs were significantly lower in the neostigmine group (50.6 ± 21.4 United States dollars) compared with the sugammadex group (212.0 ± 49.5 United States dollars). Despite improving postoperative recovery, the benefits of sugammadex did not outweigh its higher costs compared with neostigmine, possibly due to the low costs of labor in Taiwan’s healthcare system.

The development of high performance and low-cost catalyst is very important to remove tar during biomass gasification. Solid waste coal gangue ash (CGA), which mainly contains SiO2, Al2O3, Fe2O3 and CaO, was selected as support for Ni-based catalyst. The prepared low-cost catalysts were characterized suitably by XRD, BET, TPR, SEM, TG and Raman techniques. Toluene was selected as typical biomass tar model compounds to test the catalyst performance and compared with traditional catalysts Ni/Al2O3 and Ni/SiO2. Ni/CGA-1d exhibited the highest catalytic performance with the toluene conversion and H2 yield accounting for 91.5% and 58.2% respectively, at 800 °C. It was showed that the performance of Ni/CGA-1d was higher than traditional catalysts Ni/Al2O3 and Ni/SiO2, and comparable with other polymetallic reforming catalysts. Due to the good resistance of carbon deposition, the Ni/CGA-1d catalyst also performed better catalytic activity stability. The ability should be attributing to the existence of some metal elements such as Fe, Mg, K, Ca et al. in coal gangue ash support.

Islet β cell death has been proved to contribute to diabetes. Studies suggest that the activation of nuclear factor κB (NF-κB)-inducing kinase (NIK) is involved in the β cell dysfunction encountered in obesity. However, the pathological significance of NIK activation in diabetes remains largely unknown. Here, we report that β cell-specific overexpression of NIK (β-NIK-OE) results in spontaneous diabetes in male mice at a young age (≥10 weeks of age), which is likely due to insulin deficiency, β cell death, and insulitis. Importantly, inhibiting the kinase activation of NIK by the small molecule B022 prevents NIK- or H(2)O(2)-induced β cell death and also reduces streptozotocin (STZ)-induced β cell death while ameliorating hyperglycemia, suggesting that the kinase activity of NIK is essential in inducing islet inflammation, β cell death, and diabetes. In all, this study not only uncovers a role of NIK in β cell failure but also provides a potential therapeutic target for the treatment of diabetes.

RNF8 (ring finger protein 8), a RING finger E3 ligase best characterized for its role in DNA repair and sperm formation via ubiquitination, has been found to promote tumor metastasis in breast cancer recently. However, whether RNF8 also plays a role in other types of cancer, especially in lung cancer, remains unknown. We show here that RNF8 expression levels are markedly increased in human lung cancer tissues and negatively correlated with the survival time of patients. Overexpression of RNF8 promotes the EMT process and migration ability of lung cancer cells, while knockdown of RNF8 demonstrates the opposite effects. In addition, overexpression of RNF8 activates the PI3K/Akt signaling pathway, knockdown of RNF8 by siRNA inhibits this activation, and pharmacologic inhibition of PI3K/Akt in RNF8-overexpressing cells also reduces the expression of EMT markers and the ability of migration. Furthermore, RNF8 is found to directly interact with Slug and promoted the K63-Ub of Slug, and knockdown of Slug disrupts RNF8-dependent EMT in A549 cells, whereas overexpression of Slug rescues RNF8-dependent MET in H1299 cells, and depletion of RNF8 expression by shRNA inhibits metastasis of lung cancer cells in vivo. Taken together, these results indicate that RNF8 is a key regulator of EMT process in lung cancer and suggest that inhibition of RNF8 could be a useful strategy for lung cancer treatment. Implications: This study provides a new mechanistic insight into the novel role of RNF8 and identifies RNF8 as a potential new therapeutic target for the treatment of lung cancer.

The exploration of high-value-added materials using inorganic solid waste is a very important contribution to sustainable development. Coal gangue ash (CGA) as a solid waste was chosen as catalyst support. Five low-cost catalysts modified by different promoters (Co, Ce, Fe, Mn, and Mo) were prepared using a co-impregnation method. The toluene steam reforming tests were carried out at 800 °C under S/C = 2 (steam-to-carbon mole ratio). Catalyst characteristics were evaluated using X-ray diffraction (XRD), the Brunauer-Emmett-Teller (BET) method, temperature-programmed reduction (TPR), and Raman spectroscopy. The results showed that most promoters could interact with a Ni active compound and enhance the toluene conversion and H2 yield. The Mo-Ni/CGA-1d (1d means the acid pretreatment time) catalyst performed the best catalytic activity, and corresponding toluene conversion and H2 yield was equal to 92.6 and 62.3%, respectively, and it should be due to the formation of Mo-Ni alloy. Meanwhile, the Mo-Ni/CGA-1d catalyst exhibited higher stability during the runtime of 300 min compared with the Mn-Ni/CGA-1d catalyst, which can be attributed to the formation of the Mo2C structure with high-carbon-resistance ability. This is perhaps because the dissociation of CO2 or H2O on the Mo2C structure surface is beneficial to the production of free oxygen species, which can accelerate the removal of carbon deposition on the catalyst surface.

BackgroundRNF8 was an E3 ligase identified as a critical DNA damage-responsive protein. Recently, massive reports showed that RNF8 could be used as an important therapeutic target for cancer chemo/radiotherapy. However, the in-depth understanding of RNF8 remains limited for the lack of its interactome reference map and comprehensive analysis in divergent cancers, which underscore the need to identify the interactome of RNF8 via high-throughput methods. ResultsA two-way identification method based on LC-MS was designed for the identification of RNF8 interactome with high-specificity. By in silico analysis and in vitro validation, we identified a new reference map of RNF8 interactome network containing substantial new targets, such as YBX1, DNMT1, and HDCA1, new biological functions and the gene-disease associations of RNF8. Our results implied a close relationship between RNF8 and neurodegenerative diseases or tumor-infiltrating immune cells using bulk RNA-seq and scRNA-seq datasets. As a proof of concept of our interactome map, we validated the direct binding between RNF8 and YBX1, and showed that RNF8 catalyzed the ubiquitination of YBX. These results demonstrated that RNF8 might be a crucial regulator of YBX1.ConclusionsOur work provides a unique framework for researchers and clinicians who seek to better explore or understand RNF8-regulated biological functions in cancers. This study hopefully will facilitate rational design and further development of anti-RNF8 therapy in cancers.

TheCEACAM5gene product [carcinoembryonic antigen (CEA)] is an attractive target for colorectal cancer because of its high expression in virtually all colorectal tumors and limited expression in most healthy adult tissues. However, highly active CEA-directed investigational therapeutics have been reported to be toxic, causing severe colitis because CEA is expressed on normal gut epithelial cells. Here, we developed a strategy to address this toxicity problem: the Tmod dual-signal integrator. CEA Tmod cells use two receptors: a chimeric antigen receptor (CAR) activated by CEA and a leukocyte Ig-like receptor 1 (LIR-1)–based inhibitory receptor triggered by human leukocyte antigen (HLA)-A*02. CEA Tmod cells exploit instances of HLA heterozygous gene loss in tumors to protect the patient from on-target, off-tumor toxicity. CEA Tmod cells potently killed CEA-expressing tumor cells in vitro and in vivo. But in contrast to a traditional CEA-specific T cell receptor transgenic T cell, Tmod cells were highly selective for tumor cells even when mixed with HLA-A*02–expressing cells. These data support further development of the CEA Tmod construct as a therapeutic candidate for colorectal cancer.

Accurate prognostic stratification of patients can provide guidance for personalized therapy. Many prognostic models for acute myeloid leukemia (AML) have been reported, but most have considerable inaccuracies due to contained variables with insufficient capacity of predicting survival and lack of adequate verification. Here, 235 genes strongly related to survival in AML were systematically identified through univariate Cox regression analysis of eight independent AML datasets. Pathway enrichment analysis of these 235 genes revealed that the IL-2/STAT5 signaling pathway was the most highly enriched. Through Cox proportional-hazards regression model and stepwise algorithm, we constructed a six-gene STAT5-associated signature based on the most robustly survival-related genes related to the IL-2/STAT5 signaling pathway. Good prognostic performance was observed in the training cohort (GSE37642-GPL96), and the signature was validated in seven other validation cohorts. As an independent prognostic factor, the STAT5-associated signature was positively correlated with patient age and ELN2017 risk levels. An integrated score based on these three prognostic factors had higher prognostic accuracy than the ELN2017 risk category. Characterization of immune cell infiltration indicated that impaired B-cell adaptive immunity, immunosuppressive effects, serious infection, and weakened anti-inflammatory function tended to accompany high-risk patients. Analysis of in-house clinical samples revealed that the STAT5-assocaited signature risk scores of AML patients were significantly higher than those of healthy people. Five chemotherapeutic drugs that were effective in these high-risk patients were screened in silico. Among the five drugs, MS.275, a known HDAC inhibitor, selectively suppressed the proliferation of cancer cells with high STAT5 phosphorylation levels in vitro. Taken together, the data indicate that the STAT5-associated signature is a reliable prognostic model that can be used to optimize prognostic stratification and guide personalized AML treatments.