A Single-Cell Landscape of Human Liver Transplantation Reveals a Pathogenic Immune Niche Associated with Early Allograft Dysfunction

Liver transplantation(LT)is the standard therapy for individuals afflicted with end-stage liver disease.Despite notable advancements in LT technology,the incidence of early allograft dysfunction(EAD)remains a critical concern,exacerbating the current organ shortage and detrimentally affecting the prognosis of recipients.Unfortunately,the perplexing hepatic heterogeneity has impeded characterization of the cellular traits and molecular events that contribute to EAD.Herein,we constructed a pioneering single-cell transcriptomic landscape of human transplanted livers derived from non-EAD and EAD patients,with 12 liver samples collected from 7 donors during the cold perfusion and portal reperfusion stages.Comparison of the 75231 cells of non-EAD and EAD patients revealed an EAD-associated immune niche comprising mucosal-associated invariant T cells,granzyme B^(+)(GZMB^(+))granzyme K^(+)(GZMK^(+))natural killer cells,and S100 calcium binding protein A12^(+)(S100A12^(+))neutrophils.Moreover,we verified this immune niche and its association with EAD occurrence in two independent cohorts.Our findings elucidate the cellular characteristics of transplanted livers and the EAD-associated pathogenic immune niche at the single-cell level,thus,offering valuable insights into EAD onset.

Cellular Chemical Field and Cellular Homeostasis

1.Introduction Cell structure and function are controlled by a complex regulatory networking process,in which molecular adaptation and interaction are essential to maintain cellular homeostasis following dynamic multi-omics rules and multi-systematic changes.This complex chemical process is an important mechanism for stabilizing the cell microenvironment.

Efficacy and safety of acupuncture in treating low back and pelvic girdle pain during pregnancy:a systematic review and meta-analysis of randomized controlled trials

Objectives:Low back and pelvic girdle pain(LBPGP)is common during pregnancy.Acupuncture is an effective and safe therapy for pain relief.However,further evidence is required to confirm the efficacy and safety of acupuncture in treating LBPGP during pregnancy.This study aimed to systematically review and investigate the clinical efficacy and safety of acupuncture for the treatment of pregnancy-related LBPGP.Methods:The PubMed,EMBASE,Cochrane Library,CNKI,VIP,and WanFang databases were searched from January 2000 to August 2023.Only the randomized controlled trials(RCTs)involving pregnant women between 16 and 34 weeks of gestation diagnosed with LBPGP were included in the study.A meta-analysis was conducted and pooled risk ratios(RRs)or mean differences(MDs)with 95%confidence intervals(CIs)were compared.Results:Meta-analysis included 12 RCTs involving 1,641 participants.Eleven trials compared acupuncture alone or acupuncture combined with standard care(SC),of which three trials also used non-penetrating or placebo acupuncture as the control group.One trial compared acupuncture alone with non-penetrating acupuncture.Compared with SC,acupuncture combined with SC group significantly decreased visual analog scale score(mean difference(MD)=−2.83,95%CI=−3.41 to−2.26,P<0.00001),cesarean section rate(RR=0.69,95%CI=0.49–0.97,P=0.03),preterm birth rate(RR=0.42,95%CI=0.27–0.65,P<0.0001),labor duration(MD=−1.97,95%CI=−2.73 to−1.20,P<0.0001),and Oswestry disability index score(MD=−9.14,95%CI=−15.68 to−2.42,P=0.008).In addition,acupuncture combined with SC significantly improved 12-Items Short Form Health Survey of physical component summaries(SF12-PCS).No significant differences were observed in the spontaneous delivery rate,newborn weight,drowsiness,and 12-Items Short Form Health Survey of mental component summaries(SF12-MCS)between the two groups.Adverse events such as needle pain and needle bleeding were aggravated in both the SC and acupuncture treatment groups but none were associated with acupuncture during or after the treatment period.Conclusions:Meta-analysis showed that acupuncture combined with SC had better efficacy than SC alone and could be a potential therapy for LBPGP during pregnancy.The safety results imply that acupuncture caused few adverse reactions;however,more evidence is required for further confirmation.

Single-cell RNA sequencing reveals the dynamics of hepatic non-parenchymal cells in autoprotection against acetaminophen-induced hepatotoxicity

Gaining a better understanding of autoprotection against drug-induced liver injury(DILI)may provide new strategies for its prevention and therapy.However,little is known about the underlying mechanisms of this phenomenon.We used single-cell RNA sequencing to characterize the dynamics and functions of hepatic non-parenchymal cells(NPCs)in autoprotection against DILI,using acetaminophen(APAP)as a model drug.Autoprotection was modeled through pretreatment with a mildly hepatotoxic dose of APAP in mice,followed by a higher dose in a secondary challenge.NPC subsets and dynamic changes were identified in the APAP(hepatotoxicity-sensitive)and APAP-resistant(hepatotoxicity-resistant)groups.A chemokine(C-C motif)ligand 2^(+)endothelial cell subset almost disappeared in the APAP-resistant group,and an R-spondin 3^(+)endothelial cell subset promoted hepatocyte proliferation and played an important role in APAP autoprotection.Moreover,the dendritic cell subset DC-3 may protect the liver from APAP hepatotoxicity by inducing low reactivity and suppressing the autoimmune response and occurrence of inflammation.DC-3 cells also promoted angiogenesis through crosstalk with endothelial cells via vascular endothelial growth factor-associated ligand-receptor pairs and facilitated liver tissue repair in the APAP-resistant group.In addition,the natural killer cell subsets NK-3 and NK-4 and the Sca-1^(-)CD62L^(+)natural killer T cell subset may promote autoprotection through interferon-γ-dependent pathways.Furthermore,macrophage and neutrophil subpopulations with anti-inflammatory phenotypes promoted tolerance to APAP hepatotoxicity.Overall,this study reveals the dynamics of NPCs in the resistance to APAP hepatotoxicity and provides novel insights into the mechanism of autoprotection against DILI at a high resolution.

High-throughput transcriptional profiling of perturbations by Panax ginseng saponins and Panax notoginseng saponins using TCM-seq

Panax ginseng(PG)and Panax notoginseng(PN)are highly valuable Chinese medicines(CM).Although both CMs have similar active constituents,their clinical applications are clearly different.Over the past decade,RNA sequencing(RNA-seq)analysis has been employed to investigate the molecular mechanisms of extracts or monomers.However,owing to the limited number of samples in standard RNA-seq,few studies have systematically compared the effects of PG and PN spanning multiple conditions at the transcriptomic level.Here,we developed an approach that simultaneously profiles transcriptome changes for multiplexed samples using RNA-seq(TCM-seq),a high-throughput,low-cost workflow to molecularly evaluate CM perturbations.A species-mixing experiment was conducted to illustrate the accuracy of sample multiplexing in TCM-seq.Transcriptomes from repeated samples were used to verify the robustness of TCM-seq.We then focused on the primary active components,Panax notoginseng saponins(PNS)and Panax ginseng saponins(PGS)extracted from PN and PG,respectively.We also characterized the transcriptome changes of 10 cell lines,treated with four different doses of PNS and PGS,using TCM-seq to compare the differences in their perturbing effects on genes,functional pathways,gene modules,and molecular networks.The results of transcriptional data analysis showed that the transcriptional patterns of various cell lines were significantly distinct.PGS exhibited a stronger regulatory effect on genes involved in cardiovascular disease,whereas PNS resulted in a greater coagulation effect on vascular endothelial cells.This study proposes a paradigm to comprehensively explore the differences in mechanisms of action between CMs based on transcriptome readouts.

Preface for Special Issue: Single-Cell and Spatially Resolved Omics

In this special issue,we are excited to present a collection of articles focusing on the emerging and rapidly evolving field of singlecell and spatially resolved omics,including epigenomics,transcriptomics,proteomics,and metabolomics.In recent years,the developmentofadvanced,high-throughput technologiessand computational methods has enabled researchers to study individual cells at an unprecedented resolution,shedding light on their heterogeneity and the complex interplay between their various molecular components.The detailed exploration of these aspects is crucial not only for a better understanding of the fundamental biology underlying cell function and organization but also for identifying novel therapeutic targets and strategies in various disease contexts.

Preface for Special Issue:Single-Cell and Spatially Resolved Omics

We are delighted to present you this special issue,which consists of a collection of articles focusing on the novel and rapidly evolving field of single-cell and spatially resolved omics.This encompasses epigenomics,transcriptomics,proteomics,and metabolomics.Recent technological advances,coupled with computational techniques,have advanced the scope of this discipline to allow the investigation of individual cells down to an unprecedented level of detail.Researchers can now explore the cellular heterogeneity and the intricate interplay among its multiple molecular elements comprehensively.

Safety Research in Traditional Chinese Medicine: Methods, Applications, and Outlook

Traditional Chinese medicine (TCM) is a medical system that has collected and summarized abundant clinical experience over its long history of more than 2000 years. However, the frequent occurrence of TCM-induced adverse reactions has hindered the modernization and internationalization of TCM, while attracting increasing attention from around the world. Unlike chemical drugs and biological agents, the difficulties involved in research on the toxicity and safety of TCM mainly include the complexity of its components and the unpredictability of drug–body interactions. Much of TCM, which has overall therapeutic effects, has the typical mechanisms of multiple components, multiple pathways, and multiple targets. While considering the gradualness and unpredictability of TCM toxicity, the ambiguity of toxicants and safe dosage, and individual differences during long-term TCM administration, we have systematically established key techniques for the toxicity assessment of TCM. These techniques mainly include TCM toxicity discovery in an early phase, based on a combination of drug toxicology genomics and metabolomics;methods to identify dose–toxicity relationships in TCM;and integrated techniques for the exploration of TCM interactions, such as fast-screening tests based on drug-metabolizing enzymes and receptor pathways. In particular, we have developed a new technical system for TCM safety evaluation using molecular toxicology, which has been validated well in research on TCM compatibility contraindication, quality control, and allergen discovery. The application of this key technical platform is introduced here in detail. This application includes model organisms, toxicant biomarkers, a magnetic suspension technique, and the application of network toxicology and computational toxicology in research on the toxicity of Fructus toosendan, Semen cassiae, Polygonum multiflorum, and Fructus psoraleae.

An ultra-robust fingerprinting method for quality assessment of traditional Chinese medicine using multiple reaction monitoring mass spectrometry

Chromatographic fingerprinting has been perceived as an essential tool for assessing quality and chemical equivalence of traditional Chinese medicine.However,this pattern-oriented approach still has some weak points in terms of chemical coverage and robustness.In this work,we proposed a multiple reaction monitoring(MRM)-based fingerprinting method in which approximately 100 constituents were simultaneously detected for quality assessment.The derivative MRM approach was employed to rapidly design MRM transitions independent of chemical standards,based on which the large-scale fingerprinting method was efficiently established.This approach was exemplified on QiShenYiQi Pill(QSYQ),a traditional Chinese medicine-derived drug product,and its robustness was systematically evaluated by four indices:clustering analysis by principal component analysis,similarity analysis by the congruence coefficient,the number of separated peaks,and the peak area proportion of separated peaks.Compared with conventional ultraviolet-based fingerprints,the MRM fingerprints provided not only better discriminatory capacity for the tested normal/abnormal QSYQ samples,but also higher robustness under different chromatographic conditions(i.e.,flow rate,apparent pH,column temperature,and column).The result also showed for such large-scale fingerprints including a large number of peaks,the angle cosine measure after min-max normalization was more suitable for setting a decision criterion than the unnormalized algorithm.This proof-of-concept application gives evidence that combining MRM technique with proper similarity analysis metrices can provide a highly sensitive,robust and comprehensive analytical approach for quality assessment of traditional Chinese medicine.

Neuroprotective effects of Ginkgo biloba dropping pills in Parkinson's disease

Parkinson's disease(PD) is the second most common neurodegenerative disease in the world;however,it lacks effective and safe treatments. Ginkgo biloba dropping pill(GBDP), a unique Chinese G. biloba leaf extract preparation, exhibits antioxidant and neuroprotective effects and has a potential as an alternative therapy for PD. Thus, the aims of this study were to evaluate the effects of GBDP in in vitro and in vivo PD models and to compare the chemical constituents and pharmacological activities of GBDP and the G. biloba extract EGb 761. Using liquid chromatography tandem-mass spectrometry, 46 GBDP constituents were identified. Principal component analysis identified differences in the chemical profiles of GBDP and EGb 761. A quantitative analysis of 12 constituents showed that GBDP had higher levels of several flavonoids and terpene trilactones than EGb 761, whereas EGb 761 had higher levels of organic acids.Moreover, we found that GBDP prevented 6-hydroxydopamine-induced dopaminergic neuron loss in zebrafish and improved cognitive impairment and neuronal damage in methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice. Although similar effects were observed after EGb 761 treatment,the neuroprotective effects were greater after GBDP treatment on several endpoints. In addition, in vitro results suggested that the Akt/GSK3β pathway may be involved in the neuroprotective effects of GBDP.These findings demonstrated that GBDP have potential neuroprotective effects in the treatment of PD.

The effect of extrusion conditions on the properties and textures of AZ31B alloy

The effect of extrusion conditions on the tensile properties and texture of AZ31B alloy has been investigated by means of optical microscopy(OM),scanning electron microscopy(SEM),electron backscattered diffraction(EBSD)and tensile tests.It is found that the ultimate tensile strength(UTS),the yield strength(YS)and elongation(EN)of the extruded AZ31B alloy are more significantly influenced by extrusion velocities in contrast with temperature.Although the extrusion conditions are different,the {1102}<0101> texture is the chief texture in the AZ31B after extrusion.Moreover,the extrusion textures become scattered with increasing the temperatures at the same extrusion velocity.As the extrusion velocity is raised at the same temperature,the orientation density of textures increases and the separated textures become relatively concentrated.This leads to the changes of tensile properties at different extrusion conditions.©2017 Production and hosting by Elsevier B.V.on behalf of Chongqing University.

Spatial pattern and driving factors of biomass carbon density for natural and planted coniferous forests in mountainous terrain,eastern Loess Plateau of China

Background:Understanding the spatial pattern and driving factors of forest carbon density in mountainous terrain is of great importance for monitoring forest carbon in support of sustainable forest management for mitigating climate change.Methods:We collected the forest inventory data in 2015 in Shanxi Province,eastern Loess Plateau of China,to explore the spatial pattern and driving factors of biomass carbon density(BCD)for natural and planted coniferous forests using Anselin Local Moran’s I,Local Getis-Ord G*and semivariogram analyses,and multi-group structural equation modeling,respectively.Results:The result of spatial pattern of BCDs for natural forests showed that the BCD was generally higher in the north but lower in the south of Shanxi.The spatial pattern for planted forests was substantially different from that for natural forests.The results of multi-group SEM suggested that elevation(or temperature as the alternative factor of elevation)and stand age were important driving factors of BCD for these two forest types.Compared with other factors,the effects of latitude and elevation on BCD showed much greater difference between these two forest types.The difference in indirect effect of latitude(mainly through affecting elevation and stand age)between natural and planted forests was to some extent a reflection of the difference between the spatial patterns of BCDs for natural and planted forests in Shanxi.Conclusions:The natural coniferous forests had a higher biomass carbon density,a stronger spatial dependency of biomass carbon density relative to planted coniferous forests in Shanxi.Elevation was the most important driving factor,and the effect on biomass carbon density was stronger for natural than planted coniferous forests.Besides,latitude presented only indirect effect on it for the two forest types.

Multimodal integrated strategy for the discovery and identification of quality markers in traditional Chinese medicine

With the modernization and internationalization of traditional Chinese medicine(TCM),the requirement for quality control has increased.The quality marker(Q-marker)is an important standard in this field and has been implemented with remarkable success in recent years.However,the establishment of Qmarkers remains fragmented and the process lacks systematicity,resulting in inconsistent quality control and insufficient correlation with clinical efficacy and safety of TCM.This review introduces four multimodal integrated approaches that contribute to the discovery of more comprehensive and accurate Qmarkers,thus aiding in the establishment of new quality control patterns based on the characteristics and principles of TCM.These include the whole-process quality control strategy,chemical-activity-based screening method,efficacy,safety,and consistent combination strategy,and TCM theory-guided approach.Furthermore,methodologies and representative examples of these strategies are described,and important future directions and questions in this field are also proposed.

Measurement of the sea surface using a GPS towing-body in Wanshan area

Wanshan area has been chosen to be the specified field to calibrate and validate(Cal/Val)the HY-2 altimeter and its follow-on satellites.In March 2018,an experiment has been conducted to determine the sea surface height(SSH)under the HY-2 A ground track(Pass No.203).A GPS towing-body(GPS-TB)was designed to measure the SSH covering an area of about 6 km×28 km wide centered on the HY-2 A altimeter satellite ground track.Three GPS reference stations,one tide gauge and a GPS buoy were placed in the research area,in order to process and resolve the kinematic solution and check the precision of the GPS-TB respectively.All the GPS data were calculated by the GAMIT/GLOBK software and TRACK module.The sea surface was determined by the GPS-TB solution and the tide gauge placed on Zhiwan Island.Then the sea surface of this area was interpolated by Arc GIS10.2 with ordinary Kriging method.The results showed that the precision of the GPS-TB is about 1.10 cm compared with the tide gauge placed nearby,which has an equivalent precision with the GPS buoy.The interpolated sea surface has a bias of–1.5–4.0 cm with standard deviation of 0.2–2.4 cm compared with the checking line.The gradient of the measured sea surface is about 1.62 cm/km along the HY-2 orbit which shows a good agreement compared with the CLS11 mean sea surface(MSS).In the Cal/Val of satellites,the sea surface between the tide gauge/GPS buoy and the footprint of altimeter can be improved by this work.

Determination of inhibitory activity of Salvia miltiorrhiza extracts on xanthine oxidase with a paper-based analytical device

A novel paper-based analytical device(PAD)was prepared and applied to determine the xanthine oxidase(XOD)inhibitory activity of Salvia miltiorrhiza extracts(SME).First,polycaprolactone was 3D printed on filter paper and heated to form hydrophobic barriers.Then the modified paper was cut according to the specific design.Necessary reagents including XOD for the colorimetric assay were immobilized on two separate pieces of paper.By simply adding phosphate buffer,the reaction was performed on the double-layer PAD.Quantitative results were obtained by analyzing the color intensity with the specialized device system(consisting of a smartphone,a detection box and sandwich plates).The 3Dprinted detection box was small,with a size of 9.0 cm×7.0 cm×11.5 cm.Color component G performed well in terms of linearity and detection limits and thus was identified as the index.The reaction conditions were optimized using a definitive screening design.Moreover,a 10%glycerol solution was found to be a suitable stabilizer.When the stabilizer was added,the activity of XOD could be maintained for at least 15 days under 4℃ or-20℃ storage conditions.The inhibitory activity of SME was investigated and compared to that of allopurinol.The results obtained with the PAD showed agreement with those obtained with the microplate method.In conclusion,the proposed PAD method is simple,accurate and has a potential for point-of-care testing.It also holds promise for use in rapid quality testing of medicinal herbs,intermediate products,and preparations of traditional Chinese medicines.

Preliminary calibration results for Jason-3 and Sentinel-3 altimeters in the Wanshan Islands

We present preliminary calibration results for Jason-3 and Sentinel-3A altimeters that we set up in the Wanshan Islands in Guandong Province,China.Two campaigns were carried out in 2018,from March 8 to April 16 and from November 3 to December 11,2018.Three GPS reference stations and tide gauges were established on the islands of Zhiwan,Dangan,and Wailingding during the campaigns.The in-situ sea surface height(SSH)of the altimeter footprint was determined using the tide gauge.The tidal and geoid connection between the tide gauge locations and the altimeter footprints were computed with the NAO.99Jb tidal prediction system and the EGM 2008 geoid,respectively.The data of the tide gauges were defi ned using the GPS buoy and GPS reference stations during the campaigns.The results show that the waveform of the altimeters was slightly contaminated by the small islands.The bias associated with Jason-3 and Sentinel-3A amounted to approximately+20.7±49.7 mm and+30.1±39.4 mm,respectively,which agreed well with the results from other in-situ calibration fi elds.This indicates that the Wanshan area was very suitable as an in-situ calibration/validation fi eld.The wet zenith delay(WZD)determined from the Microwave Radiometer(MWR)and the GPS measurements diff ered from each other for the Jason-3 and Sentinel-3A by−6.6±7.4 mm and 0±6.8 mm,respectively.

Carbon quantum dot preparation and application to detecting active ingredients in traditional Chinese medicine

Carbon quantum dots(CQDs)are fluorescent carbon nanomaterials that have been applied to biology,medicine,and optoelectronics,owing to their significant advantages such as simple synthesis methods,low cost,and widely available sources of raw synthesis materials.This review summarizes CQD preparation methods,which include hydrothermal and microwave-assisted synthesis methods,as well as separation methods such as centrifugation,dialysis,and filtration.Additionally,we review the application of CQDs in the detection of active ingredients,primarily phenolic compounds,in traditional Chinese medicine.We also discuss the quenching mechanism of CQD fluorescence using the active ingredients of traditional Chinese medicine.Limitations such as insufficient test selectivity,weak fluorescence intensity,and an unclear quantitative relationship between preparation methods and properties should be resolved for the efficient use of CQDs to detect active ingredients in Chinese medicine.

Generation of Intense Sub-10 fs Pulses at 385 nm

We demonstrated the generation and characterization of 9.7 fs,180 J pulses centered at 385 nm via the frequency doubling of few-cycle near-infrared pulses.Both moderate conversion efficiency(9.5%)and broad phase matching bandwidth(20 nm)were achieved by shaping the spectra of the fundamental pulses.The strong intensity dependence of second-order harmonic generation and well controlled material dispersion ensured the inexistence of satellite pulses,which was confirmed by the self-diffraction frequency resolved optical gating measurement.

Laser capture microdissection for biomedical research: towards high-throughput, multi-omics, and single-cell resolution

Spatial omics technologies have become powerful methods to provide valuable insights into cells and tissues within a complex context,significantly enhancing our understanding of the intricate and multifaceted biological system.With an increasing focus on spatial heterogeneity,there is a growing need for unbiased,spatially resolved omics technologies.Laser capture microdissection(LCM)is a cutting-edge method for acquiring spatial information that can quickly collect regions of interest(ROIs)from heterogeneous tissues,with resolutions ranging from single cells to cell populations.Thus,LCM has been widely used for studying the cellular and molecular mechanisms of diseases.This review focuses on the differences among four types of commonly used LCM technologies and their applications in omics and disease research.Key attributes of application cases are also highlighted,such as throughput and spatial resolution.In addition,we comprehensively discuss the existing challenges and the great potential of LCM in biomedical research,disease diagnosis,and targeted therapy from the perspective of high-throughput,multi-omics,and single-cell resolution.

Effects of Plant Growth-Promoting Rhizobacteria and N Source on Plant Growth and N and P Uptake by Tomato Grown on Calcareous Soils

Introducing specific microorganisms into the soil ecological system is an important strategy for improving nutrient use efficiency.Two pot experiments were conducted in the greenhouse from December 3, 2012 to January 25, 2013(Experiment 1) and March 11 to April 23, 2013(Experiment 2) to evaluate the effect of nitrogen(N) source and inoculation with plant growth-promoting rhizobacteria(PGPR) on plant growth and N and phosphorus(P) uptake in tomato(Lycopersicon esculentum Mill.) grown on calcareous soils from South Florida, USA.Treatments included urea, controlled release urea(a controlled release fertilizer, CRF) each at low and high N rates and with or without inoculation of PGPR.A mixture of PGPR strains Bacillus amyloliquefaciens IN937 a and Bacillus pumilus T4 was applied to the soil during growing periods of tomato.Treatments with PGPR inoculation increased plant height compared to treatments without PGPR in both experiments.Inoculation with PGPR increased shoot dry weight and shoot N uptake for the same N rate and N source.In both experiments, only at high N rate, CRF and urea treatments with PGPR had significantly(P < 0.05)greater shoot biomass than those without PGPR.Only at high N rate, CRF treatment with PGPR significantly increased shoot N uptake by 39.0% and 10.3% compared to that without PGPR in Experiments 1 and 2, respectively.Meanwhile, presence of PGPR in the soil increased shoot P uptake for all treatments in Experiment 1 and for most treatments in Experiment 2.In Experiment 1, only at low N rate, CRF treatment with PGPR significantly increased shoot P uptake compared with that without PGPR.In Experiment2, a significant increase in shoot P uptake by inoculation of PGPR was only observed in CRF treatment at high N rate.Results from this study indicate that inoculation with PGPR may increase plant growth and N and P uptake by tomato grown on calcareous soils.However, the effect of PGPR varied and was influenced by many factors such as N source, N rate, and soil fertility.Further investigations are warranted to confirm the effect of PGPR under different soil conditions.