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Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.

Essential genes are commonly assumed to function in basic cellular processes and to change slowly. However, it remains unclear whether all essential genes are similarly conserved or if their evolutionary rates can be accelerated by specific factors. To address these questions, we replaced 86 essential genes of Saccharomyces cerevisiae with orthologues from four other species that diverged from S. cerevisiae about 50, 100, 270 and 420 Myr ago. We identify a group of fast-evolving genes that often encode subunits of large protein complexes, including anaphase-promoting complex/cyclosome (APC/C). Incompatibility of fast-evolving genes is rescued by simultaneously replacing interacting components, suggesting it is caused by protein co-evolution. Detailed investigation of APC/C further revealed that co-evolution involves not only primary interacting proteins but also secondary ones, suggesting the evolutionary impact of epistasis. Multiple intermolecular interactions in protein complexes may provide a microenvironment facilitating rapid evolution of their subunits.

To comprehensively assess osteoporosis in the lumbar spine, a compositional MR imaging technique is proposed to quantify proton fractions for all the water components as well as fat in lumbar vertebrae measured by a combination of a 3D short repetition time adiabatic inversion recovery prepared ultrashort echo time (STAIR-UTE) MRI and IDEAL-IQ.A total of 182 participants underwent MRI, quantitative CT, and DXA. Lumbar collagen-bound water proton fraction (CBWPF), free water proton fraction (FWPF), total water proton fraction (TWPF), bone mineral density (BMD), and T-score were calculated in three vertebrae (L2-L4) for each subject. The correlations of the CBWPF, FWPF, and TWPF with BMD and T-score were investigated respectively. A comprehensive diagnostic model combining all the water components and clinical characteristics was established. The performances of all the water components and the comprehensive diagnostic model to discriminate between normal, osteopenia, and osteoporosis cohorts were also evaluated using receiver operator characteristic (ROC).The CBWPF showed strong correlations with BMD (r = 0.85, p0.001) and T-score (r = 0.72, p0.001), while the FWPF and TWPF showed moderate correlations with BMD (r = 0.65 and 0.68, p0.001) and T-score (r = 0.47 and 0.49, p0.001). The high area under the curve values obtained from ROC analysis demonstrated that CBWPF, FWPF, and TWPF have the potential to differentiate the normal, osteopenia, and osteoporosis cohorts. At the same time, the comprehensive diagnostic model shows the best performance.The compositional MRI technique, which quantifies CBWPF, FWPF, and TWPF in trabecular bone, is promising in the assessment of bone quality.• Compositional MR imaging technique is able to quantify proton fractions for all the water components (i.e., collagen-bound water proton fraction (CBWPF), free water proton fraction (FWPF), and total water proton fraction (TWPF)) in the human lumbar spine. • The biomarkers derived from the compositional MR imaging technique showed moderate to high correlations with bone mineral density (BMD) and T-score and showed good performance in distinguishing people with different bone mass. • The comprehensive diagnostic model incorporating CBWPF, FWPF, TWPF, and clinical characteristics showed the highest clinical diagnostic capability for the assessment of osteoporosis.

This study aimed to investigate the associations between overall lifestyles and HRQoL, as well as the variations in age, sex, education level, and income.A total of 23,402 participants from the Henan rural cohort were included. The healthy lifestyle score (HLS) consists of five lifestyle factors: smoking, alcohol drinking, physical activity, diet, and body mass index. HRQoL was assessed by the EQ-5D-5L questionnaire. The general linear model and Tobit regression model were utilized to assess the associations of HLS with visual analogue score (VAS) and utility index.Compared with participants with an HLS of 0-2, the corresponding regression coefficients (β) and 95% confidence intervals (CI) of participants with an HLS of 3, 4, and 5 for VAS score were 1.09 (0.59, 1.59), 1.92 (1.38, 2.46), and 2.60 (1.83, 3.37); the corresponding β and 95% CI for utility index were 0.02 (0.01, 0.03), 0.05 (0.03, 0.06), and 0.06 (0.04, 0.07). Notably, these positive associations were greater among the elderly, female, and those with lower education level and average monthly income (p for interaction 0.05). For instance, the corresponding β and 95% CI of individuals with an HLS of 5 for utility index in average monthly income 500 RMB, 500-999 RMB, and ≥ 1000 RMB groups were 0.08 (0.05, 0.11), 0.06 (0.03, 0.09), and 0.02 (- 0.00, 0.05).Engaging in healthier lifestyle habits was associated with a higher level of HRQoL, especially in the elderly, females, and those with low education level and average monthly income.

This meta-analysis aimed at exploring the impact of opioid-free anesthesia (OFA) on pain score and opioid consumption in patients undergoing bariatric surgery (BS). Literature search identified eight eligible trials. Forest plot revealed a significantly lower pain score (mean difference (MD) = - 0.96, p = 0.0002; 318 patients), but not morphine consumption (MD = - 5.85 mg, p = 0.1; 318 patients) at postoperative 24 h in patients with OFA than in those without. Pooled analysis also showed a lower pain score (p = 0.002), morphine consumption (p = 0.0003) in the postanesthetic care unit, and risk of postoperative nausea/vomiting (p = 0.0003) in the OFA group compared to the controls. In conclusion, this meta-analysis demonstrated that opioid-free anesthesia improved pain outcomes immediately and at 24 h after surgery without a beneficial impact on opioid consumption at postoperative 24 h. KEY POINTS: • Roles of opioid-free anesthesia (OFA) in bariatric surgery (BS) were investigated. • Outcomes included postoperative pain score, opioid use, and nausea/vomiting risk. • OFA was associated with lower 24-h pain score but not opioid consumption. • Lower pain score and opioid consumption were noted in the postanesthetic care unit. • OFA correlated with a lower risk of postoperative nausea/vomiting.

To improve the efficiency and accuracy of single-event effect (SEE) research at the Heavy Ion Research Facility at Lanzhou, Hi’Beam-SEE must precisely localize the position at which each heavy ion hitting the integrated circuit (IC) causes SEE. In this study, we propose a fast multi-track location (FML) method based on deep learning to locate the position of each particle track with high speed and accuracy. FML can process a vast amount of data supplied by Hi’Beam-SEE online, revealing sensitive areas in real time. FML is a slot-based object-centric encoder–decoder structure in which each slot can learn the location information of each track in the image. To make the method more accurate for real data, we designed an algorithm to generate a simulated dataset with a distribution similar to that of the real data, which was then used to train the model. Extensive comparison experiments demonstrated that the FML method, which has the best performance on simulated datasets, has high accuracy on real datasets as well. In particular, FML can reach 238 fps and a standard error of 1.6237 μm. This study discusses the design and performance of FML.

Green seaweed, as the most abundant species of macroseaweeds, is an important marine biological resource. It is a rich source of several amino acids, fatty acids, and dietary fibers, as well as polysaccharides, polyphenols, pigments, and other active substances, which have crucial roles in various biological processes such as antioxidant activity, immunoregulation, and anti-inflammatory response. In recent years, attention to marine resources has accelerated the exploration and utilization of green seaweeds for greater economic value. This paper elaborates on the main nutrients and active substances present in different green seaweeds and provides a review of their biological activities and their applications for high-value utilization. Graphical abstract

Epigenetic modifications are involved in the remodeling of the tumor microenvironment (TME) and the regulation of immune response. Nonetheless, the role of histone H4 methylation (H4M) modification in the TME and immune regulation of hepatocellular carcinoma (HCC) is unknown. As a result, the purpose of this research is to discover H4M-mediated modification patterns and their effects on TME and immunologic characteristics in HCC. A total of 2305 samples were enrolled from 13 different cohorts. With the help of consensus clustering analysis, three distinct H4M modification patterns were identified. The cell-infiltrating characteristics of TME under these three patterns were highly consistent with their enriched biological processes and clinical outcome. The H4Mscore was then created using principal component analysis algorithm to quantify the H4M modification pattern of each individual tumor and was systematically correlated with representative tumor characteristics. We found that analyzing H4M modification patterns within individual tumors could predict TME infiltration, homologous recombination deficiency (HRD), intratumor heterogeneity, proliferation activity, mRNA stemness index, and prognosis. The group with a low H4Mscore had an inflamed TME phenotype and a better immunotherapy response, as well as a better survival outcome. The prognostic value of H4Mscore was validated in three internal cohorts and five external cohorts, respectively. In external immunotherapy cohorts, the low H4Mscore was also linked to an enhanced response to anti-PD-1/L1 and anti-CTLA4 immunotherapy and a better prognosis. This study revealed that H4M modification played an important role in forming TME diversity and complexity. Evaluating the H4M modification pattern of individual tumors could help us learn more about TME and develop more effective immunotherapy strategies.

To investigate the outcomes of the modified radial tongue-shaped flap following stepwise surgery release for treating Benson type I camptodactyly of the 5th digit. A retrospective analysis involving patients with Benson type I camptodactyly of the 5th digit was performed. A total of 8 patients with 12 affected digits were included. Extent of surgical release depended on the degree of soft tissue contracture. Skin release, subcutaneous fascial release, and flexor digitorum superficialis tenotomy were performed in all 12 digits, sliding volar plate release in 2 digits, and intrinsic tendon transfer in 1 digit. The mean total passive motion of proximal interphalangeal joint significantly increased from 32.5° ± 16° to 86.3° ± 20.4°, while mean total active motion significantly increased from 22° ± 10.5° to 73.8° ± 27.5° (P

Exposure to a single metal has been reported to damage renal function in humans. However, information regarding the association between multiple-metal exposure and markers for early renal impairment in different sexes among the young adult Taiwanese population is scarce. We assessed the association between exposure to arsenic (As), cadmium (Cd), and lead (Pb), and early renal impairment markers using urinary microalbumin (MA), β2-microglobulin (β2MG), and N-acetyl-beta-D-glucosaminidase (NAG) by analyzing 157 young adults aged 20‒29 years, in Taiwan. Inductively coupled plasma mass spectrometry was used to determine urinary As, Cd, and Pb levels. Regression models were applied to different sex groups. The results showed that after adjusting for potential confounding factors and each metal, urinary Cd levels were significantly positively associated with urinary MA (β = 0.523, 95% CI: 0.147-0.899) and β2MG (β = 1.502, 95% CI: 0.635-2.370) in males. However, the urinary Cd level was significantly positively associated with only urinary NAG (β = 0.161, 95% CI: 0.027-0.296) in females. This study thus indicates that the effect of exposure to metals (especially Cd) on early renal impairment among young adults in Taiwan is sex-specific. Our study results could contribute toward developing early intervention programs for decreasing the incidence of renal dysfunction. Further studies are warranted to confirm our findings and clarify the potential mechanisms involved.

Connecting genes to their cis-regulatory elements has been enabled by genome-wide mapping of chromatin interactions using proximity ligation in ChIA-PET, Hi-C, and their derivatives. However, these methods require millions of input cells for high-quality data and thus are unsuitable for many studies when only limited cells are available. Conversely, epigenomic profiling via transposase digestion in ATAC-seq requires only hundreds to thousands of cells to robustly map open chromatin associated with transcription activity, but it cannot directly connect active genes to their distal enhancers. Here, we combine proximity ligation in ChIA-PET and transposase accessibility in ATAC-seq into ChIATAC to efficiently map interactions between open chromatin loci in low numbers of input cells. We validate ChIATAC in Drosophila cells and optimize it for mapping 3D epigenomes in human cells robustly. Applying ChIATAC to primary human T cells, we reveal mechanisms that topologically regulate transcriptional programs during T cell activation.

Background Impaired renal function is frequently observed in patients with heart failure and reduced ejection fraction (HFrEF). The differential effect of sacubitril/valsartan and angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEIs/ARBs) on the clinical and renal outcomes in patients with HFrEF and chronic kidney disease (CKD) remains unknown. Aims This study aimed to explore the differential effect of sacubitril/valsartan and ACEI/ARB on the clinical and renal outcomes as well as renal function over a 12-month follow-up period in HFrEF patients with and without CKD. Methods Patients with HfrEF (LVEF ≤35%) and NYHA class ≥II were enrolled from the Chang Gung Research Database between 2017 and 2020. Baseline characteristics were compared between patients prescribed sacubitril/valsartan and ACEI/ARB. After propensity score matching, the following clinical and renal outcomes were compared between the two groups in patients with and without CKD over a 12-month follow-up period: acute kidney injury (AKI), emergent dialysis/renal death, HF hospitalization, cardiovascular mortality, and all-cause mortality. Results This study enrolled 3735 HFrEF patients with a mean left ventricular EF of 27.56 ± 5.86%, who had been prescribed sacubitril/valsartan (N = 1708) or ACEI/ARB (N = 2027). After propensity score matching, the clinical and renal outcomes did not differ between the sacubitril/valsartan and ACEI/ARB groups in patients without CKD. In patients with CKD, the ACEI/ARB group had a significantly higher incidence of all-cause mortality than the sacubitril/valsartan group (14.89% vs. 10.50%; hazard ratio 1.46; 95% confidence interval 1.06–2.00; p = 0.02), and the incidence of AKI, HF hospitalization, and CV mortality did not differ between the two groups. Conclusions Sacubitril/valsartan had a lower all-cause mortality compared to ACEI/ARB in symptomatic HFrEF patients with CKD. Further prospective randomized studies are warranted to confirm our findings.

Previous studies have shown that calcium (Ca), magnesium (Mg), and Ca/Mg ratio are associated with inflammation and metabolic disorders, but their relationship with non-alcoholic fatty liver disease (NAFLD) is unclear. Thus, we aimed to explore the association between Ca, Mg, Ca/Mg ratio, and NAFLD in Chinese adults. We conducted a case-control study based on the Kailuan Cohort in China, including 1816 cases and 1111 gender- and age-matched controls. Dose-response relationships between blood Ca, Mg, Ca/Mg ratio, and NAFLD were evaluated using restricted cubic splines. Odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated by logistic regression models. A negative association between blood Ca (overall association P0.001 and linear association P0.001) and NAFLD as well as Ca/Mg ratio (overall association P = 0.002 and linear association P = 0.024) and NAFLD was observed. Compared with the highest quartile, the adjusted OR (95% CI) for the lowest quartile of Ca and Ca/Mg ratio was 2.116 (1.679-2.667) and 1.358 (1.076-1.713), respectively. A U-shaped relationship was found for blood Mg and NAFLD, with the highest OR of 1.685 in the lowest quartile group when using the second quartile as a reference. Additionally, we observed the interaction between alanine aminotransferase and blood Ca (P = 0.024), total cholesterol (P = 0.017), low-density lipoprotein-cholesterol (P = 0.013), and blood Mg, as well as total cholesterol and Ca/Mg ratio (P = 0.014). Lower blood Ca and Ca/Mg ratio were significantly associated with the risk of NAFLD. Liver function or lipid metabolism parameters may modify their association, suggesting an individualized prevention strategy for NAFLD.

For centuries, herbal medicines have been used to treat humans and animals. Veterinary medicines are well-regulated; inspectors monitor milk and associated dairy products to screen for unacceptable contaminants. However, few scholars have discussed how the by-products of veterinary herbal medicine can be found in food products. In this paper, we applied nontargeted profiling of the UHPLC–ESI–TOF platform to screen possible by-products originating from veterinary herbal medicine in commercial milk samples. These tentatively identified alkaloids showed high consistency with the plant extract of Holarrhena antidysenterica (L.) Wall. ex A. DC., which indicated the possibility that dairy farmers had used plants from genus Holarrhena as veterinary herbal medicine. This is the first report showing the presence of by-products originating from veterinary herbal medicine in commercial milk. This finding could help authorities to evaluate the use of veterinary herbal medicine in farm animals.

We establish various bounds on the solutions to a Stein equation for Poisson approximation in the Wasserstein distance with nonlinear transportation costs. The proofs are a refinement of those in Barbour and Xia (Bernoulli 12:943–954, 2006) using the results in Liu and Ma (Ann Inst H Poincare Probab Stat 45:58–69, 2009). As a corollary, we obtain an estimate of Poisson approximation error measured in the $$L^2$$ -Wasserstein distance.

Death receptor 5 (DR5) is overexpressed in many tumors. Combination of the anti-DR5 antibody with radionuclides such as lutetium-177 (177Lu) could enhance apoptosis and decrease the possibility of drug-induced resistance. In this study, a humanized anti-DR5 monoclonal antibody CTB006 was labeled with zirconium-89 (89Zr) and 177Lu to improve its efficiency for diagnosis and radiotherapy, respectively. The radiolabeled antibodies showed high tumor uptake in colon205 xenografts according to the results of micro-PET imaging and biodistribution. The 177Lu-DOTA-CTB006 could inhibit tumor growth significantly.

Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients1. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses2,3. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells4,5 and lower therapeutic efficacy6, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial7. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8+ T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8+ T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential. H9T, an engineered IL-2 partial agonist, promotes the expansion of T cells while maintaining a stem-cell-like state, leading to improved efficacy of adoptive cell therapy in mouse models of melanoma and acute lymphoblastic leukaemia.

Human communication is a new method that uses human body biological tissue as the transmission medium for short-distance communication. Because static human communication characteristics have been studied more, this paper proposed and verified a dynamic human body communication channel model in the Human Body Communication band, and the dynamic channel characteristics of 35 kinds of human body continuous postures were analyzed. The results of using five typical communication links on the dynamic human body model show that the average power delay is following a second order exponential decay. The Akaike information criterion was used to determine the cumulative probability density function distribution of the first path delay, interval delay and delay spread. The channel characteristics of two-person standing side-by-side communication were studied to extend the application of human communication technology, and the two human models touch each other through their arms. The forward and backward motion of the noncontact arm along the human body surface has different effects on the path loss of the communication link with the chest as the transmitter and the arm as the transmitter. To evaluate the safety of human body communication technology on the human body, the frequency domain finite differential analysis method was used to analyze the distribution of the electromagnetic field. The absorption rate is the quantification of the electromagnetic energy absorbed by the human body, and the absorptivity of 35 postures demonstrated that human communication technology is not harmful to the human body.

Gigantopithecus blacki was a giant hominid that inhabited densely forested environments of Southeast Asia during the Pleistocene epoch1. Its evolutionary relationships to other great ape species, and the divergence of these species during the Middle and Late Miocene epoch (16-5.3 million years ago), remain unclear2,3. Hypotheses regarding the relationships between Gigantopithecus and extinct and extant hominids are wide ranging but difficult to substantiate because of its highly derived dentognathic morphology, the absence of cranial and post-cranial remains1,3-6, and the lack of independent molecular validation. We retrieved dental enamel proteome sequences from a 1.9-million-year-old G. blacki molar found in Chuifeng Cave, China7,8. The thermal age of these protein sequences is approximately five times greater than that of any previously published mammalian proteome or genome. We demonstrate that Gigantopithecus is a sister clade to orangutans (genus Pongo) with a common ancestor about 12-10 million years ago, implying that the divergence of Gigantopithecus from Pongo forms part of the Miocene radiation of great apes. In addition, we hypothesize that the expression of alpha-2-HS-glycoprotein, which has not been previously observed in enamel proteomes, had a role in the biomineralization of the thick enamel crowns that characterize the large molars in Gigantopithecus9,10. The survival of an Early Pleistocene dental enamel proteome in the subtropics further expands the scope of palaeoproteomic analysis into geographical areas and time periods previously considered incompatible with the preservation of substantial amounts of genetic information. E.C. and F.W. are supported by VILLUM FONDEN (17649) and by the European Commission through a Marie Skłodowska-Curie (MSCA) Individual Fellowship (795569). T.M.-B. is supported by BFU2017-86471-P (MINECO/FEDER, UE), NIHM grant U01 MH106874, Howard Hughes International Early Career grant, Obra Social ‘La Caixa’ and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880). E.C., J.C., J.V.O., D.S. and P.G. are supported by the Marie Skłodowska-Curie European Training Network (ETN) TEMPERA, a project funded by the European Union’s EU Framework Program for Research and Innovation Horizon 2020 under grant agreement no. 722606. M.J.C. and M.M. are supported by the Danish National Research Foundation award PROTEIOS (DNRF128). Work at the Novo Nordisk Foundation Center for Protein Research is funded in part by a donation from the Novo Nordisk Foundation (NNF14CC0001). Research at Chuifeng Cave is made possible by support from the National Natural Science Foundation of China (41572023) and by a grant from the Bagui Scholar of Guangxi. M.K. was supported by a Deutsche Forschungsgemeinschaft (DFG) fellowship (KU 3467/1-1) and the Postdoctoral Junior Leader Fellowship Programme from ‘la Caixa’ Banking Foundation (LCF/BQ/PR19/11700002). M.E.A. is supported by the Independent Research Fund Denmark (7027-00147B). We thank E. Willerslev for critical reading of the manuscript, scientific support and guidance.

Background Several biomarkers have been proposed to predict the occurrence of acute kidney injury (AKI); however, their efficacy varies between different trials. The aim of this study was to compare the predictive performance of different candidate biomarkers for AKI. Methods In this systematic review, we searched PubMed, Medline, Embase, and the Cochrane Library for papers published up to August 15, 2022. We selected all studies of adults (> 18 years) that reported the predictive performance of damage biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP)), inflammatory biomarker (interleukin-18 (IL-18)), and stress biomarker (tissue inhibitor of metalloproteinases-2 × insulin-like growth factor-binding protein-7 (TIMP-2 × IGFBP-7)) for the occurrence of AKI. We performed pairwise meta-analyses to calculate odds ratios (ORs) and 95% confidence intervals (CIs) individually. Hierarchical summary receiver operating characteristic curves (HSROCs) were used to summarize the pooled test performance, and the Grading of Recommendations, Assessment, Development and Evaluations criteria were used to appraise the quality of evidence. Results We identified 242 published relevant studies from 1,803 screened abstracts, of which 110 studies with 38,725 patients were included in this meta-analysis. Urinary NGAL/creatinine (diagnostic odds ratio [DOR] 16.2, 95% CI 10.1–25.9), urinary NGAL (DOR 13.8, 95% CI 10.2–18.8), and serum NGAL (DOR 12.6, 95% CI 9.3–17.3) had the best diagnostic accuracy for the risk of AKI. In subgroup analyses, urinary NGAL, urinary NGAL/creatinine, and serum NGAL had better diagnostic accuracy for AKI than urinary IL-18 in non-critically ill patients. However, all of the biomarkers had similar diagnostic accuracy in critically ill patients. In the setting of medical and non-sepsis patients, urinary NGAL had better predictive performance than urinary IL-18, urinary L-FABP, and urinary TIMP-2 × IGFBP-7: 0.3. In the surgical patients, urinary NGAL/creatinine and urinary KIM-1 had the best diagnostic accuracy. The HSROC values of urinary NGAL/creatinine, urinary NGAL, and serum NGAL were 91.4%, 85.2%, and 84.7%, respectively. Conclusions Biomarkers containing NGAL had the best predictive accuracy for the occurrence of AKI, regardless of whether or not the values were adjusted by urinary creatinine, and especially in medically treated patients. However, the predictive performance of urinary NGAL was limited in surgical patients, and urinary NGAL/creatinine seemed to be the most accurate biomarkers in these patients. All of the biomarkers had similar predictive performance in critically ill patients. Trial registrationCRD42020207883, October 06, 2020.

Background Vitamin K antagonists and different direct oral anticoagulants (DOACs) have different renal clearance rates. However, the impact of different stages of chronic renal impairment on the efficacy and safety of warfarin, dabigatran, rivaroxaban, apixaban, and edoxaban in atrial fibrillation (AF) patients remains unclear. Methods This study enrolled AF patients from the Chang Gung Research Database. The study endpoints included thromboembolic events, major/fatal bleeding, gastrointestinal (GI) bleeding and intracranial hemorrhage (ICH). The risks of time to study endpoints between groups were compared using a Cox proportional hazards regression model with adjustment. Results This study enrolled 3525 patients with moderate renal impairment (30 ≤ creatinine clearance (CrCl) Conclusion There did not appear to be major differences in bleeding or thromboembolic risk compared to warfarin in AF patients across a range of degree of renal failure when appropriate dose reductions of the DOACs are made.

TGF-β signaling is necessary for CD8+ T cell differentiation into tissue resident memory T cells (TRM). Although higher frequency of CD8+ TRM cells in the tumor microenvironment is associated with better prognosis, TGF-β−blockade typically improves rather than worsens outcomes. Here we show that in a mouse melanoma model, in the tumor-draining lymph nodes (TDLN) rather than in the tumors themselves, stem-like CD8+ T cells differentiate into TRMs in a TGF-β and tumor antigen dependent manner. Following vaccination against a melanoma-specific epitope, most tumour-specific CD8+ T cells are maintained in a stem-like state, but a proportion of cells lost TRM status and differentiate into CX3CR1+ effector CD8+ T cells in the TDLN, which are subsequently migrating into the tumours. Disruption of TGF-β signaling changes the dynamics of these developmental processes, with the net result of improving effector CD8+ T cell migration into the tumours. In summary, TDLN stem-like T cells transiently switch from a TGF-β-dependent TRM differentiation program to an anti-tumor migratory effector development upon vaccination, which transition can be facilitated by targeted TGF-β blockade.

Seaweed has emerged as one of the most promising resources due to its remarkable adaptability, short development period, and resource sustainability. It is an effective breakthrough to alleviate future resource crises. Algal resources have reached a high stage of growth in the past years due to the increased output and demand for seaweed worldwide. Several aspects global seaweed farming production and processing over the last 20 years are reviewed, such as the latest situation and approaches of seaweed farming. Research progress and production trend of various seaweed application are discussed. Besides, the challenges faced by seaweed farming and processing are also analyzed, and the related countermeasures are proposed, which can provide advice for seaweed farming and processing. The primary products, extraction and application, or waste utilization of seaweed would bring greater benefits with the continuous development and improvement of applications in various fields. Graphical Abstract

Mounting studies have demonstrated that RAB3GAP1 expression is modified in brain diseases with multiple neurobiological functions and processes and acts as a potentially significant target. However, the cellular and molecular events arising from RAB3GAP1 dysexpression are still incompletely understood. In this work, underexpression and overexpression of RAB3GAP1 were first induced into cultured mouse cortical neurons by transfection with lentivirus plasmids. Then we globally explored the effects of RAB3GAP1 dysexpression on the proteome of the neurons through the use of isobaric tag for relative and absolute quantitation (iTRAQ)-based quantitative proteomics with bioinformatics. A total of 364 proteins in the RAB3GAP1-underexpression group and 314 proteins in the RAB3GAP1-overexpression group were identified to be differentially expressed. Subsequent bioinformatics analysis indicated that the proteome functional expression profiles induced by RAB3GAP1 underexpression and overexpression were different, suggesting the potential differences in biological processes and cellular effects. Subsequent intergroup cross-comparison revealed some candidate target proteins regulated directly by RAB3GAP1. Further parallel reaction monitoring (PRM) analysis illustrated that Sub1, Ssrp1, and Top1 proteins might serve as new potentially important linkers in the RAB3GAP1-mediated autophagy pathway in the cortical neurons. Collectively, the current proteomics data furnished new valuable insights to better understand the regulatory molecular mechanism of neuronal RAB3GAP1.

Two novel adsorbents of thiol- and amino-functionalized GO grafted onto LDH (LDH@GO-NH2 and LDH@GO-SH) were synthesized and contrasted for adsorption properties for Cu(II) and Cd(II). Characterization experiments illustrated that thiol group (-SH) and amino group (-NH2) were existed onto LDH@GO-NH2 and LDH@GO-SH. Adsorption isotherm results showed that the adsorption processes were satisfactorily fitted by both Langmuir and Freundlich models. The maximum adsorption capacity of Cd(II) on LDH@GO-SH at 308 K was 102.77 mg/g, which was about triple that of LDH@GO-NH2. The enhancement in adsorption capacity was due to the cooperative effect of LDH and GO-SH. The kinetic experimental data for LDH@GO-NH2 and LDH@GO-SH were found to be in good agreement with pseudo-second-order model. The thermodynamic parameters calculated from the temperature dependent adsorption isotherms indicated that the adsorption was a spontaneous and endothermic process. The possible adsorption mechanisms comprising formation of precipitation, isomorphic substitution of Mg(II), and formation of complexation with amino-groups and thiol-groups were proposed. Desorption experiments put into evidence that the LDH@GO-NH2 and LDH@GO-SH may be promising suitable candidates for the remediation of metal ions from aqueous solutions in real work in the near future.

A significant shift in meal pattern with frequent eating out was closely associated with multiple chronic outcomes, but with limited evidence on hyperuricemia. We aimed to explore the associations between eating out and serum uric acid (SUA) as well as hyperuricemia. A total of 29,597 participants were recruited from the Henan Rural Cohort Study. A validated food frequency questionnaire (FFQ) was used to collect dietary data, including the frequency of eating out. Linear regression models were used to examine the association of eating-out frequency with SUA and BMI. Logistic regression and restricted cubic spline were performed to assess the association and dose–response relationship between eating-out frequency and hyperuricemia. The mediation effect of BMI between eating out and the risk of hyperuricemia was evaluated. Eating out was significantly associated with higher SUA levels in the total population and males (P

Developing durable, low-cost water electrolysis catalysts plays a critical role in solving clean energy problems. Herein, we synthesized Ni/Co9S8@CNT micro flower comprising Ni/Co9S8 mesoporous nanosheets and carbon nanotubes (CNT). HRTEM images indicate that the Ni/Co9S8@CNT micro flower contains abundant Ni/Co9S8 heterojunctions. The band structure and coupling effect of the Ni/Co9S8 heterostructure optimizes the transfer of electrons, thus the synergistic hybrid effectively improves conductivity and electrocatalytic performance. Therefore, Ni/Co9S8@CNT shows good evolution reaction (OER) and hydrogen evolution reaction (HER) performance in an alkaline environment. Specifically, at a current density of 10 mA cm−2, the overpotential of OER is 289 mV, and the overpotential of HER is 228 mV. The Tafel slope is 69 mV dec−1. In addition, Ni/Co9S8@CNT in alkaline electrolyte only loses 10% of its activity after working for 10 h at a current density of 10 mA cm−2. These results indicate that composite materials composed of transition metal sulfides and highly conductive carbon materials are a good choice for low-cost electrocatalysts. Synthesize the heterojunction of metal Ni and Co9S8 and anchor it on the CNT to improve the performance of OER and HER.

This paper examines the level of model fidelity required to support design phases in the urban solar planning process. The two modelling features crucial to the fidelity of the photovoltaic (PV) yield prediction on urban surfaces are (1) a level of fidelity for modelling urban shading and solar reflection and (2) a level of fidelity for modelling PV system operation. The paper compares three different models for predicting urban shading and reflection and two different PV models for predicting PV system operation. The relevance of the model fidelities is investigated through a case study of an urban area in Wuhan, China under three decision-making contexts: setting a solar target, place-making, and economic assessment for urban-scale distributed PV integration. Predictions for the decision-makings are generated using the selected models through computational simulation under the same annual weather profile. The results show that the relatively less accurate canyon-based method tends to overpredict with 57 buildings identified as suitable for PV installation for walls in the studied urban area; the more accurate vector-based model predicts only 14 suitable buildings. The results predicted with additional consideration of dynamic PV system operation exhibit differences from those predicted by the static PV system model, with a difference of roughly 13 buildings on average within each payback-time category. The differences are noticeable but can be regarded as incremental for urban-scale economic assessment compared with the significant difference due to the fidelity level of modelling urban shading and reflection.

Background Lung cancer is the leading cause of malignancy-related mortality and lung adenocarcinoma accounts for about 40% of lung malignancies. The aim of this study was to investigate the associations of intraflagellar transport protein 20 (IFT20) and Golgi matrix protein 130 (GM130) expression with clinicopathological features and survival in patients with lung adenocarcinoma. Methods The expressions of IFT20 and GM130 protein in cancerous and matched adjacent lung tissues of 235 patients with lung adenocarcinoma were assessed by tissue microarray and immunohistochemistry, which were indicated by the mean optical density (IOD/area), the rate of positive staining cells and staining intensity score. The correlation between IFT20 and GM130 protein was assessed by Spearman’s rank correlation. Associations of IFT20 and GM130 protein expression with clinicopathological features of patients were analyzed by multivariate logistic regression models. The survival analysis of patients was performed by Cox proportional hazard regression models. Results With adjustment for multiple potential confounders, each one-point increase in IFT20 protein staining intensity score was significantly associated with 32% and 29% reduced risk for TNM stage in II ~ IV and lymphatic metastasis of patients, respectively (P 7 cm by 29% and 38% for lung adenocarcinoma patients, respectively (P 7 cm or distant metastasis by 54% and 65%, respectively (P Conclusion IFT20 and GM130 protein expressions were negatively associated with tumor differentiated types, size, TNM stage and lymphatic metastasis of lung adenocarcinoma. Both IFT20 and GM130 proteins have some protective effects on the survival of lung adenocarcinoma patients with specific clinicopathological features.

Background Stroke is a leading cause of death and functional impairment in older people. To assess the prospective association between fasting blood glucose-to-glycated hemoglobin ratio and all-cause mortality and poor prognosis in stroke patients. Methods A total of 971 Chinese inpatients with acute stroke (mean age of 65.7) were consecutively enrolled in the prospective clinical study and followed up for 12 months after discharge. Stress hyperglycemia was measured using the ratio of fasting blood glucose (FBG, mmol/L)/glycated hemoglobin (HbA1c, %). The primary outcome was all-cause mortality, and secondary outcomes were poor prognosis defined as infectious complications, a National Institutes of Health Stroke Scale (NIHSS) score ≥ 6, a Barthel Index score ≤ 60, or a modified Rankin Scale (mRS) score of 3–6, presented as multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) across the quartiles of the FBG/HbA1c ratio. Results There were 35 (4.1%) all-cause deaths at 3 months and 85 (11.4%) at 12 months. The inpatients with the highest quartile of the FBG/HbA1c ratio had a higher risk of all-cause death at 3 months (adjusted OR: 5.16, 95% CI: 1.03–25.74) and at 12 months (adjusted OR: 2.59, 95% CI: 1.14–5.89)) and a higher risk of infectious complications (adjusted OR 2.37, 95% CI 1.27–4.43) and dysfunction (adjusted OR 1.79, 95% CI 1.06–3.01) during hospitalization than inpatients with the lowest quartile. Conclusions Stress hyperglycemia, measured by the FBG/HbA1c ratio, was associated with an increased risk of adverse outcomes, including all-cause death, infectious complications, and dysfunction after stroke.

LianhuaQingwen capsule, prepared from an herbal combination, is officially recommended as treatment for COVID-19 in China. Of the serial pharmacokinetic investigations we designed to facilitate identifying LianhuaQingwen compounds that are likely to be therapeutically important, the current investigation focused on the component Glycyrrhiza uralensis roots (Gancao). Besides its function in COVID-19 treatment, Gancao is able to induce pseudoaldosteronism by inhibiting renal 11β-HSD2. Systemic and colon-luminal exposure to Gancao compounds were characterized in volunteers receiving LianhuaQingwen and by in vitro metabolism studies. Access of Gancao compounds to 11β-HSD2 was characterized using human/rat, in vitro transport, and plasma protein binding studies, while 11β-HSD2 inhibition was assessed using human kidney microsomes. LianhuaQingwen contained a total of 41 Gancao constituents (0.01–8.56 μmol/day). Although glycyrrhizin ( 1 ), licorice saponin G2 ( 2 ), and liquiritin/liquiritin apioside ( 21 / 22 ) were the major Gancao constituents in LianhuaQingwen, their poor intestinal absorption and access to colonic microbiota resulted in significant levels of their respective deglycosylated metabolites glycyrrhetic acid ( 8 ), 24-hydroxyglycyrrhetic acid ( M2 D ; a new Gancao metabolite), and liquiritigenin ( 27 ) in human plasma and feces after dosing. These circulating metabolites were glucuronized/sulfated in the liver and then excreted into bile. Hepatic oxidation of 8 also yielded M2 D . Circulating 8 and M2 D , having good membrane permeability, could access (via passive tubular reabsorption) and inhibit renal 11β-HSD2. Collectively, 1 and 2 were metabolically activated to the pseudoaldosterogenic compounds 8 and M2 D . This investigation, together with such investigations of other components, has implications for precisely defining therapeutic benefit of LianhuaQingwen and conditions for its safe use.

Selective laser melting (SLM) is one of the widely used metal additive manufacturing techniques. While SLM is able to produce high-quality products, the parameter selection process can be very complicated, especially for magnetic materials in that the iron loss and permeability properties must also be considered, which renders the parameter selecting process more complicated. This research explores the parameter selection process of magnetic material for SLM, which integrates machine and evolutionary algorithms to accurately predict magnetic characteristics, such as iron loss and permeability, and generates suggestions for the process parameters according to practical demands.

High-flow nasal oxygen (HFNO) has been used in “tubeless” shared-airway surgeries but whether HFNO increased the fire hazard is yet to be examined. We used a physical model for simulation to explore fire safety through a series of ignition trials. An HFNO device was attached to a 3D-printed nose with nostrils connected to a degutted raw chicken. The HFNO device was set at twenty combinations of different oxygen concentration and gas flow rate. An electrocautery and diode laser were applied separately to a fat cube in the cavity of the chicken. Ten 30 s trials of continuous energy source application were conducted. An additional trial of continuous energy application was conducted if no ignition was observed for all the ten trials. A total of eight short flashes were observed in one hundred electrocautery tests; however, no continuous fire was observed among them. There were thirty-six events of ignition in one hundred trials with laser, twelve of which turned into violent self-sustained fires. The factors found to be related to a significantly increased chance of ignition included laser application, lower gas flow, and higher FiO2. The native tissue and smoke can ignite and turn into violent self-sustained fires under HFNO and continuous laser strikes, even in the absence of combustible materials. The results suggest that airway surgeries must be performed safely with HFNO if only a short intermittent laser is used in low FiO2.

A numerical method consisting of an off-line part and an on-line part for optimal control problems is proposed in this paper. In the off-line part, the state space is discretized into a Cartesian grid structure and then define a graph over all grid points by connecting two points if the Euclidean norm between them is closer than a positive number called adjacent radius, the minimum cost between them is estimated using difference method and stored in a matrix. After that the matrix is updated by a shortest path algorithm and a matrix holding the information of the shortest paths between any two grid points is generated. In the on-line part, the optimal control vector at each time step can be generated by reading data from the matrix according to the current state and target state and doing some simple calculations. Since there is no need to do a lot of calculation in the on-line part, this method can satisfy the real-time requirements in some engineering control problems. We prove that the solution of the proposed method converge to the analytical solution when the adjacent radius and the grid size tend to zero and the grid size tend is a higher order infinitesimal of the adjacent radius. At the end of this paper, some numerical examples are taken to illustrate the effectiveness of the proposed method.

Patients with cancer are at increased risk of severe infections. From a cohort including 3060 patients with confirmed COVID-19, 109 (3.4%) cancer patients were included in this study. Among them, 23 (21.1%) patients died in the hospital. Cancer patients, especially those with hematological malignancies (41.6%), urinary carcinoma (35.7%), malignancies of the digestive system (33.3%), gynecological malignancies (20%), and lung cancer (14.3%), had a much higher mortality than patients without cancer. A total of 19 (17.4%) cancer patients were infected in the hospital. The clinical characteristics of deceased cancer patients were compared with those of recovered cancer patients. Multivariate Cox regression analysis indicated that a Nutritional Risk Screening (NRS2002) score ⩾ 3 (adjusted hazard ratio (HR) 11.00; 95% confidence interval (CI) 4.60–26.32; P < 0.001), high-risk type (adjusted HR 18.81; 95% CI 4.21–83.93; P < 0.001), tumor stage IV (adjusted HR 4.26; 95% CI 2.34–7.75; P < 0.001), and recent adjuvant therapy (< 1 month) (adjusted HR 3.16; 95% CI 1.75–5.70; P < 0.01) were independent risk factors for in-hospital death after adjusting for age, comorbidities, D-dimer, and lymphocyte count. In conclusion, cancer patients showed a higher risk of COVID-19 infection with a poorer prognosis than patients without cancer. Cancer patients with high-risk tumor, NRS2002 score ⩾ 3, advanced tumor stage, and recent adjuvant therapy (< 1 month) may have high risk of mortality. Electronic Supplementary Material Supplementary material is available in the online version of this article at 10.1007/s11684-021-0845-6 and is accessible for authorized users.

In this article, the nanoparticles of CoFe2O4 and FeS2/FeCoS2 have been generated by direct oxidation and sulfurization of Fe–Co precursor and used as counter electrode (CE) material for dye-sensitized solar cells (DSSCs). Compared with CoFe2O4, FeS2/FeCoS2 nanoparticles have superior electrical conductivity and catalytic activity. Furthermore, the introduction of reduced graphene oxide (RGO) improved the performance of FeS2/FeCoS2. By attaching FeS2/FeCoS2 nanoparticles to the surface of RGO, it alleviated the agglomeration of nanoparticles effectively. Meanwhile, the catalytic activity and electrical conductivity of FeS2/FeCoS2@RGO in DSSC are greatly improved. With increasing contact area, the penetration rate of the electrolyte is accelerated, which results in a faster reaction rate of tri-iodide that can be significantly accelerated. We explain the modification of FeS2/FeCoS2 nanoparticles by RGO through the morphology characterization and electrochemical performance test. The DSSCs assembled by FeS2/FeCoS2@RGO achieved a choiceness power conversion efficiency (PCE) of 7.84%, which is higher than those of CoFe2O4 nanoparticles (3.71%), FeS2/FeCoS2 nanoparticles (7.05%), and platinum (Pt) (7.54%).