A cabazitaxel liposome for increased solubility, enhanced antitumor effect and reduced systemic toxicity

The potential side effects of cabazitaxel(CBZ)in the field of cancer treatment have become a great limitation to its further clinical application.Liposomal delivery is a well-established approach to increase the therapeutic index of hydrophobic drugs.In this study,a PEGmodified liposome was developed for efficiently encapsulating CBZ,thus enhancing its specific tumor inhibition effect and reducing the systemic toxicity.It was found that the loading efficiency of CBZ into the liposome could be improved with the increase of lipophilic materials,as it could be over 80%under the weight ratio of 20:1(total lipid:CBZ).The diameter of CBZ loaded liposome(CBZ@Lipo)was^100 nm.And the liposome suspending in aqueous medium was stable at 4°C for at least one month,according to the change of its size distribution.The killing ability of CBZ@Lipo to cancer cells was significantly lower comparing to that of CBZ solution,which could be attributed to the slow release of CBZ from the liposomes.However,CBZ@Lipo could induce an obvious apoptosis of the cancer cells at low concentration.Furthermore,CBZ@Lipo exhibited an expressively enhanced tumor growth inhibition effect comparing to CBZ solution.More importantly,CBZ@Lipo showed an obviously higher biosafety proved by lower hemolysis probability,stable body weight of mice during the whole experiment and no obvious lesion in histology analysis.Our work provided a useful reference of the formulation of CBZ,which had potential for greater clinical application.

Analysis of Performance Stability and Clinical Efficacy of OBERS - 3000 Hemodialysis Machine

Objective To explore the method of safety and efficacy validation of hemodialysis machine,and observe the clinical efficacy of OBERS-3000 multifunctional hemodialysis machine.Methods Randomized,open,two-phase crossover and positive control design,a total of 72 patients from two hospitals were included.OBERS-3000 multifunctional hemodialysis machine was the test machine,and the Fresenius 4008 series hemodialysis machine was as the control machine,indicators of blood routine test,serum electrolytes,liver and kidney function test,blood gas analysis,CRP were compared,body weight before and after hemodialysis,ultrafiltration volume were recorded,urea clearance index,urea reduction ratio were calculated.The XL90 conductivity meter was connected in series in the test machine,to monitor the temperature,conductance,venous pressure and arterial pressure during the dialysis in real time,and the measured value were compared with the machine monitoring value.Results Both of the test machine and the control machine could effectively eliminate creatinine,urea nitrogen and other uremic toxins,could continuously supply qualified dialysate,and precisely control the ultrafiltration volume.There were no significant differences in temperature,conductance,venous pressure and arterial pressure monitoring with the real time measured value by XL90 conductivity meter.Conclusions OBERS-3000 multifunctional hemodialysis machine can effectively eliminate uremic toxins,maintain electrolyte and acid-base balance,and can accurately display the monitoring parameters.

Reductive lipid nanoparticles loaded with vinorelbine inhibit chemotherapy-induced invasion of cancer cells by modulating ENPP2

Cancer is a predominant culprit behind worldwide death and accounts for up to 10 million deaths every year.Chemotherapy is the primary therapeutic method employed for cancer in clinical settings and is essential in controlling tumor progression.Despite the advances in this field,tumor invasion and metastasis during treatment remain a significant cause of treatment failure.Nevertheless,the underlying mechanisms involving such a disappointing phenomenon are still not fully elucidated.Vinorelbine(VNB)extends the lifespan of many cancer patients in the clinic as an emerging chemotherapy drug approved by Food and Drug Administration(FDA).However,VNB-induced tumor metastasis is still an intractable problem,which may be closely related to the abnormal oxidative stress generated during VNB-mediated treatment.Hence,the study aims to construct a reductive nanosystem loaded with VNB,called VNB-VNP,to improve cancer cure rates and reduce tumor metastasis.With the reductive component vitamin E,VNB-VNP can effectively reduce oxidative stress and significantly outperform free VNB in preventing tumor progression.The transcriptome analysis shows that VNB-VNP can alleviate the over-expression of ectonucleotide pyrophosphatase/phosphodiesterase 2(ENPP2),which may be the main reason why VNB-VNP can inhibit tumor invasion and metastasis.Overall,the research designs a new platform for VNB treatment,which demonstrates promising efficacy in inhibiting neoplastic progression and identifies a new mechanism associated with VNB-induced tumor metastasis,which may offer several valuable references for enhancing chemotherapy efficacy in clinical anti-tumor therapy.

Application of bioactive hydrogels combined with dental pulp stem cells for the repair of large gap peripheral nerve injuries

Due to the limitations in autogenous nerve grafting or Schwann cell transplantation,large gap peripheral nerve injuries require a bridging strategy supported by nerve conduit.Cell based therapies provide a novel treatment for peripheral nerve injuries.In this study,we first experimented an optimal scaffold material synthesis protocol,from where we selected the 10%GFD formula(10%GelMA hydrogel,recombinant human basic fibroblast growth factor and dental pulp stem cells(DPSCs))to fill a cellulose/soy protein isolate composite membrane(CSM)tube to construct a third generation of nerve regeneration conduit,CSM-GFD.Then this CSM-GFD conduit was applied to repair a 15-mm long defect of sciatic nerve in a rat model.After 12 week post implant surgery,at histologic level,we found CSM-GFD conduit could regenerate nerve tissue like neuron and Schwann like nerve cells and myelinated nerve fibers.At physical level,CSM-GFD achieved functional recovery assessed by a sciatic functional index study.In both levels,CSM-GFD performed like what gold standard,the nerve autograft,could do.Further,we unveiled that almost all newly formed nerve tissue at defect site was originated from the direct differentiation of exogeneous DPSCs in CSM-GFD.In conclusion,we claimed that this third-generation nerve regeneration conduit,CSM-GFD,could be a promising tissue engineering approach to replace the conventional nerve autograft to treat the large gap defect in peripheral nerve injuries.

Comprehensive strategy of conduit guidance combined with VEGF producing Schwann cells accelerates peripheral nerve repair

Peripheral nerve regeneration requires stepwise and well-organized establishment of microenvironment.Since local delivery of VEGF-A in peripheral nerve repair is expected to promote angiogenesis in the microenvironment and Schwann cells(SCs)play critical role in nerve repair,combination of VEGF and Schwann cells may lead to efficient peripheral nerve regeneration.VEGF-A overexpressing Schwann cells were established and loaded into the inner wall of hydroxyethyl cellulose/soy protein isolate/polyaniline sponge(HSPS)conduits.When HSPS is mechanically distorted,it still has high durability of strain strength,thus,can accommodate unexpected strain of nerve tissues in motion.A 10 mm nerve defect rat model was used to test the repair performance of the HSPS-SC(VEGF)conduits,meanwhile the HSPS,HSPS-SC,HSPS-VEGF conduits and autografts were worked as controls.The immunofluorescent co-staining of GFP/VEGF-A,Ki67 and MBP showed that the VEGF-A overexpressing Schwann cells could promote the proliferation,migration and differentiation of Schwann cells as the VEGF-A was secreted from the VEGF-A overexpressing Schwann cells.The nerve repair performance of the multifunctional and flexible conduits was examined though rat behavioristics,electrophysiology,nerve innervation to gastrocnemius muscle(GM),toluidine blue(TB)staining,transmission electron microscopy(TEM)and NF200/S100 double staining in the regenerated nerve.The results displayed that the effects on the repair of peripheral nerves in HSPS-SC(VEGF)group was the best among the conduits groups and closed to autografts.HSPS-SC(VEGF)group exhibited notably increased CD31+endothelial cells and activation of VEGFR2/ERK signaling pathway in the regenerated nerve tissues,which probably contributed to the improved nerve regeneration.Altogether,the comprehensive strategy including VEGF overexpressing Schwann cells-mediated and HSPS conduit-guided peripheral nerve repair provides a new avenue for nerve tissue engineering.

Nitrogen content diagnosis of apple trees canopies using hyperspectral reflectance combined with PLS variable extraction and extreme learning machine

Nitrogen(N)is an important mineral element in apple production.Rapid estimation of apple tree N status is helpful for achieving precise N management.The objective of this work was to explore partial least squares(PLS)regression in dimensional reduction of spectral data and build the diagnostic model.The spectral reflectance data were collected from Fuji apple trees with 4 levels of N fertilizer treatment in the Loess Plateau in 2018 and 2019 using an ASD portable spectroradiometer,and leaf total N content was obtained at the same time.The raw spectra were pretreated using Savitzky-Golay(SG)smoothing and a combination of SG and first-order derivative(SG_FD)or second-order derivative(SG_SD).The samples were divided into a calibration dataset and a prediction dataset using SPXY.Based on 4 factors of PLS regression,including latent variables(LVs),X-loading,variable importance in projection(VIP)and regression coefficients(RC),the 6 methods(LVs,X-loading,VIP_01,VIP_02,RC_01 and RC_02)were derived and used for variable extraction,based on which PLS model and ELM model were established.The results indicated that the spectral data processed by SG_FD had the highest signal-to-noise ratio and was selected for subsequent analysis.The amounts of variables extracted by LVs,X-loading,VIP_01,VIP_02,RC_01 and RC_02 were 6,11,18,305,26 and 88,respectively.The method of extracting variables with an RC threshold based on the minimum RMSEP(RC_02)could effectively avoid the omission of effective information.The RC_02 method was recommended for related research which required accurate wavelength information as a variable.The variable extraction method based on LVs generated an ELM model with a simple structure.The prediction results showed that the ELM model outperformed the PLS model.The PLS(LVs)_ELM model was the best;R2P,RMSEP and RPD were 0.837,2.393 and 2.220,respectively.

Phenotypic similarities in pigs with SOX10^(c.321dupC)and SOX10^(c.325A>T)mutations implied the correlation of SOX10 haploinsufficiency with Waardenburg syndrome

SOX10 is a causative gene of Waardenburg syndrome(WS)that is a rare genetic disorder characterized by hearing loss and pigment disturbance.More than 100 mutations of SOX10 have been found in patients with Type 2 WS(WS2),Type 4 WS(WS4),and more complex syndromes.However,no mutation hotspot has been detected in SOX10,and most cases are sporadic,making it difficult to establish a correlation between the high phenotypic and genetic variability.In this study,a duplication of the 321th cytosine(c.321dupC)was introduced into SOX10 in pigs,which induced premature termination of the translation of SOX10(p.K108QfsX45).The premature stop codon in Exon 3 triggered the degradation of mutant mRNA through nonsense-mediated mRNA decay.However,SOX10^(c.321dupC) induced a highly similar phenotype of WS2 with heterogeneous inner ear malformation compared with its adjacent missense mutation SOX10^(c.325A>T).In addition,a site-saturation mutation analysis of the SOX10 N-terminal nuclear localization signal(n-NLS),where these two mutations located,revealed the correlation between SOX10 haploinsufficiency and WS by an in vitro reporter assay.The analysis combining the in vitro assay with clinical cases may provide a clue to clinical diagnoses.

A high-resolution cell atlas of the domestic pig lung and an online platform for exploring lung single-cell data

The genetically engineered pig is regarded as an optimal source of organ transplantation for humans and an excellent model for human disease research,given its comparable physiology to human beings.A myriad of single-cell RNA sequencing(sc RNA-seq)data on humans has been reported,but such data on pigs are scarce.Here,we apply sc RNA-seq technology to study the cellular heterogeneity of 3-month-old pig lungs,generating the single-cell atlas of 13,580 cells covering 16 major cell types.Based on these data,we systematically characterize the similarities and differences in the cellular cross-talk and expression patterns of respiratory virus receptors in each cell type of pig lungs compared with human lungs.Furthermore,we analyze pig lung xenotransplantation barriers and reported the cell-type expression patterns of 10 genes associated with pig-to-human immunobiological incompatibility and coagulation dysregulation.We also investigate the conserved transcription factors(TFs)and their candidate target genes and constructed five conserved TF regulatory networks in the main cell types shared by pig and human lungs.Finally,we present a comprehensive and openly accessible online platform,Scdb Lung.Our sc RNA-seq atlas of the domestic pig lung and Scdb Lung database can guide pig lung research and clinical applicability.

Single-cell brain atlas of Parkinson's disease mouse model

Parkinson's disease(PD)is a neurodegenerative disease,leading to the impairment of movement execution.PD pathogenesis has been largely investigated,either limited to bulk transcriptomic levels or at certain cell types,which failed to capture the cellular heterogeneity and intrinsic interplays among distinct cell types.Here,we report the application of single-nucleus RNA-seq on midbrain,striatum,and cerebellum of theα-syn-A53 T mouse,a well-established PD mouse model,and matched controls,generating the first single cell transcriptomic atlas for the PD model mouse brain composed of 46,174 individual cells.Additionally,we comprehensively depicte the dysfunctions in PD pathology,covering the elevation of NF-k B activity,the alteration of ion channel components,the perturbation of protein homeostasis network,and the dysregulation of glutamatergic signaling.Notably,we identify a variety of cell types closely associated with PD risk genes.Taken together,our study provides valuable resources to systematically dissect the molecular mechanism of PD pathogenesis at the single-cell resolution,which facilitates the development of novel approaches for diagnosis and therapies against PD.

Vehicle adaptive cruise control design with optimal switching between throttle and brake

For vehicle adaptive cruise control （ACC） systems, the switching performance between throttle and brake determines the driving comfort, fuel consumption and service lives of vehicle mechanical components. In this paper, an ACC algorithm with the optimal switching control between throttle and brake is designed in model predictive control （MPC） framework. By introducing the binary integer variables, the dynamics of throttle and brake are integrated in one model expression for the controller design. Then the ACC algorithm is designed to satisfy not only safe car following, but also the optimal switching between throttle and brake, which leads to an online mixed integer quadratic programming solved by the nested two-loop method. The simulation results show that the proposed ACC algorithm meets the requirements of safe car following, outperforms the traditional algorithms by performing smoother responses, reducing the switching times between throttle and brake, and therefore improves driving comfort and fuel efficiency significantly.

Single-cell atlas of domestic pig cerebral cortex and hypothalamus

The brain of the domestic pig(Sus scrofa domesticus)has drawn considerable attention due to its high similarities to that of humans.However,the cellular compositions of the pig brain(PB)remain elusive.Here we investigated the single-nucleus transcriptomic profiles of five regions of the PB(frontal lobe,parietal lobe,temporal lobe,occipital lobe,and hypothalamus)and identified 21 cell subpopulations.The cross-species comparison of mouse and pig hypothalamus revealed the shared and specific gene expression patterns at the single-cell resolution.Furthermore,we identified cell types and molecular pathways closely associated with neurological disorders,bridging the gap between gene mutations and pathogenesis.We reported,to our knowledge,the first single-cell atlas of domestic pig cerebral cortex and hypothalamus combined with a comprehensive analysis across species,providing extensive resources for future research regarding neural science,evolutionary developmental biology,and regenerative medicine.

Viral receptor profiles of masked palm civet revealed by single-cell transcriptomics

Civets are small mammals belonging to the family Viverridae.The masked palm civets(Paguma larvata)served as an intermediate host in the bat-to-human transmission of severe acute respiratory syndrome coronavirus(SARS-Co V)in 2003(Guan et al.,2003).Because of their unique role in the SARS outbreak,civets were suspected as a potential intermediate host of SARS-Co V-2.

Corrigendum to‘Application of bioactive hydrogels combined with dental pulp stem cells for the repair of large gap peripheral nerve injuries’[Bioactive Mater.6(3)(2021)638-654]

The authors regret that the author(A.H.)was removed as an agreement could not be reached between the two affiliations of the author.The authors would like to apologise for any inconvenience caused.