Lacticaseibacillus rhamnosus Fmb14 ameliorates hyperuricemia-induced hepatocyte pyroptosis via NLRP3 inflammasome cascade inhibition

Hyperuricemia is a high-risk factor for the development of gout and renal fibrosis,but the adverse effects of hyperuricemia on the liver have been seriously neglected.This research investigated the ameliorating effect of Lacticaseibacillus rhamnosus Fmb14 on hyperuricemia induced liver dysfunction both in vitro and in vivo.Cell free extracts of high dose L.rhamnosus Fmb14 treatment reduced the death rate of HepG2 cell lines from 24.1%to 14.9%by inhibiting NLRP3 recruitment,which was mainly activated by reactive oxygen species release and mitochondrial membrane potential disorder.In purine dietary induced hyperuricemia(PDIH)mice model,liver oedema and pyroptosis were ameliorated after L.rhamnosus Fmb14 administration through downregulating the expression levels of NLRP3,caspase-1 and gasdermin-D from 1.61 to 0.86,3.15 to 1.01 and 5.63 to 2.02,respectively.L.rhamnosus Fmb14 administration restored mitochondrial inner membrane protein(MPV17)and connexin 43 from 2.83 and 0.73 to 0.80 and 0.98 respectively in PDIH mice,indicating that dysbiosis of mitochondrial membrane potential was restored in liver.Intriguingly,PDIH pyroptosis stimulates the process of apoptosis,which leads to severe leakage of hepatocytes,and both of pyroptosis and apoptosis were decreased after L.rhamnosus Fmb14 treatment.Therefore,L.rhamnosus Fmb14 is a promising biological resource to maintain homeostasis of the liver in hyperuricemia and the prevention of subsequent complications.

Treadmill exercise improves hippocampal neural plasticity and relieves cognitive deficits in a mouse model of epilepsy

Epilepsy frequently leads to cognitive dysfunction and approaches to treatment remain limited.Although regular exercise effectively improves learning and memory functions across multiple neurological diseases,its application in patients with epilepsy remains controversial.Here,we adopted a 14-day treadmill-exercise paradigm in a pilocarpine injection-induced mouse model of epilepsy.Cognitive assays confirmed the improvement of object and spatial memory after endurance training,and electrophysiological studies revealed the maintenance of hippocampal plasticity as a result of physical exercise.Investigations of the mechanisms underlying this effect revealed that exercise protected parvalbumin interneurons,probably via the suppression of neuroinflammation and improved integrity of blood-brain barrier.In summary,this work identified a previously unknown mechanism through which exercise improves cognitive rehabilitation in epilepsy.

Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery

Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.

New indices to balanceα-diversity against tree size inequality

The number and composition of species in a community can be quantified withα-diversity indices,including species richness(R),Simpson’s index(D),and the Shannon-Wiener index(H΄).In forest communities,there are large variations in tree size among species and individu-als of the same species,which result in differences in eco-logical processes and ecosystem functions.However,tree size inequality(TSI)has been largely neglected in studies using the available diversity indices.The TSI in the diameter at breast height(DBH)data for each of 99920 m×20 m forest census quadrats was quantified using the Gini index(GI),a measure of the inequality of size distribution.The generalized performance equation was used to describe the rotated and right-shifted Lorenz curve of the cumulative proportion of DBH and the cumulative proportion of number of trees per quadrat.We also examined the relationships ofα-diversity indices with the GI using correlation tests.The generalized performance equation effectively described the rotated and right-shifted Lorenz curve of DBH distributions,with most root-mean-square errors(990 out of 999 quadrats)being<0.0030.There were significant positive correlations between each of threeα-diversity indices(i.e.,R,D,and H’)and the GI.Nevertheless,the total abundance of trees in each quadrat did not significantly influence the GI.This means that the TSI increased with increasing spe-cies diversity.Thus,two new indices are proposed that can balanceα-diversity against the extent of TSI in the com-munity:(1−GI)×D,and(1−GI)×H’.These new indices were significantly correlated with the original D and H΄,and did not increase the extent of variation within each group of indices.This study presents a useful tool for quantifying both species diversity and the variation in tree sizes in forest communities,especially in the face of cumulative species loss under global climate change.

Megafossils of Betulaceae from the Oligocene of Qaidam Basin and their paleoenvironmental and phytogeographic implications

Understanding the paleoenvironment and phytogeographical history of the Tibetan Plateau,China relies on discovering new plant fossils.The Qaidam Basin has long been regarded as an ideal‘field laboratory’to investigate the paleoclimate and paleobiological evolution of the northern Tibetan Plateau.However,fossil angiosperms from the Qaidam Basin are rare,and our knowledge of its paleovegetation is poor.Here,we report fossil leaves and fruits of Betulaceae found from the Oligocene Shangganchaigou Formation of northwestern Qaidam Basin(Huatugou area).Comparative morphological analysis led us to assign the fruits to the Betula subgenus Betula and the leaves to Carpinus grandis.These findings,together with other reported fossil plants from the same locality,reveal a close floristic linkage between the Qaidam Basin and Europe during the Oligocene.The northern pathway of this floristic exchange may have crossed through the Qaidam Basin during the late Paleogene.This floristic linkage may have been facilitated by the continuous narrowing of the Turgai Strait and stronger westerlies,which transported moisture and provided favorable climatic conditions.Indeed,fossil plants collected from the Qaidam Basin suggest that during the Oligocene this region had warm and humid deciduous broad-leaf forest,which differs from the region’s modern vegetation and indicates that the Qaidam Basin may have been a suitable region for these plants to flourish and spread during the Oligocene.

Untethered Micro/Nanorobots for Remote Sensing:Toward Intelligent Platform

Untethered micro/nanorobots that can wirelessly control their motion and deformation state have gained enormous interest in remote sensing applications due to their unique motion characteristics in various media and diverse functionalities.Researchers are developing micro/nanorobots as innovative tools to improve sensing performance and miniaturize sensing systems,enabling in situ detection of substances that traditional sensing methods struggle to achieve.Over the past decade of development,significant research progress has been made in designing sensing strategies based on micro/nanorobots,employing various coordinated control and sensing approaches.This review summarizes the latest developments on micro/nanorobots for remote sensing applications by utilizing the self-generated signals of the robots,robot behavior,microrobotic manipulation,and robot-environment interactions.Providing recent studies and relevant applications in remote sensing,we also discuss the challenges and future perspectives facing micro/nanorobots-based intelligent sensing platforms to achieve sensing in complex environments,translating lab research achievements into widespread real applications.

Identifying influential spreaders in social networks: A two-stage quantum-behaved particle swarm optimization with Lévy flight

The influence maximization problem aims to select a small set of influential nodes, termed a seed set, to maximize their influence coverage in social networks. Although the methods that are based on a greedy strategy can obtain good accuracy, they come at the cost of enormous computational time, and are therefore not applicable to practical scenarios in large-scale networks. In addition, the centrality heuristic algorithms that are based on network topology can be completed in relatively less time. However, they tend to fail to achieve satisfactory results because of drawbacks such as overlapped influence spread. In this work, we propose a discrete two-stage metaheuristic optimization combining quantum-behaved particle swarm optimization with Lévy flight to identify a set of the most influential spreaders. According to the framework,first, the particles in the population are tasked to conduct an exploration in the global solution space to eventually converge to an acceptable solution through the crossover and replacement operations. Second, the Lévy flight mechanism is used to perform a wandering walk on the optimal candidate solution in the population to exploit the potentially unidentified influential nodes in the network. Experiments on six real-world social networks show that the proposed algorithm achieves more satisfactory results when compared to other well-known algorithms.

Repressing iron overload ameliorates central poststroke pain via the Hdac2-Kv1.2 axis in a rat model of hemorrhagic stroke

Thalamic hemorrhage can lead to the development of central post-stroke pain.Changes in histone acetylation levels,which are regulated by histone deacetylases,affect the excitability of neurons surrounding the hemorrhagic area.However,the regulato ry mechanism of histone deacetylases in central post-stroke pain remains unclea r.Here,we show that iron overload leads to an increase in histone deacetylase 2expression in damaged ventral posterolateral nucleus neurons.Inhibiting this increase restored histone H3 acetylation in the Kcna2 promoter region of the voltage-dependent potassium(Kv)channel subunit gene in a rat model of central post-stroke pain,thereby increasing Kcna2expression and relieving central pain.However,in the absence of nerve injury,increasing histone deacetylase 2 expression decreased Kcna2expression,decreased Kv current,increased the excitability of neurons in the ventral posterolateral nucleus area,and led to neuropathic pain symptoms.Moreover,treatment with the iron chelator deferiprone effectively reduced iron overload in the ventral posterolateral nucleus after intracerebral hemorrhage,reversed histone deacetylase 2 upregulation and Kv1.2 downregulation,and alleviated mechanical hypersensitivity in central post-stroke pain rats.These results suggest that histone deacetylase 2 upregulation and Kv1.2 downregulation,mediated by iron overload,are important factors in central post-stroke pain pathogenesis and co uld se rve as new to rgets for central poststroke pain treatment.

Circulating RNA ZFR promotes hepatocellular carcinoma cell proliferation and epithelial-mesenchymal transition process through miR-624-3p/WEE1 axis

Background:Hepatocellular carcinoma(HCC),the most common type of primary liver cancer,is the fourth leading cause of cancer-related deaths worldwide.Previous evidence shows that the expression of circulating RNA ZFR(circZFR)is upregulated in HCC tissues.However,the molecular mechanism of circZFR in HCC is unclear.Methods:Quantitative reverse transcriptase polymerase chain reaction(qRT-PCR)was employed to detect the expression of circZFR,microRNA-624-3p(miR-624-3p)and WEE1 in HCC tissues and cells.RNase R assay and actinomycin D treatment assay were used to analyze the characteristics of circZFR.For functional analysis,the capacities of colony formation,cell proliferation,cell apoptosis,migration and invasion were assessed by colony formation assay,5-ethynyl-2-deoxyuridine(EdU)assay,flow cytometry assay and transwell assay.Western blot was used to examine the protein levels of WEE1 and epithelial-mesenchymal transition(EMT)-related proteins.The interactions between miR-624-3p and circZFR or WEE1 were validated by dual-luciferase reporter assay and RNA immunoprecipitation(RIP)assay.Xenograft models were established to determine the role of circZFR in vivo.Results:circZFR and WEE1 were upregulated,while miR-624-3p expression was reduced in HCC tissues and cells.circZFR could sponge miR-624-3p,and WEE1 was a downstream gene of miR-624-3p.Knockdown of circZFR significantly reduced the malignant behaviors of HCC and that co-transfection with miR624-3p inhibitor restored this change.Overexpression of WEE1 abolished the inhibitory effect of miR624-3p mimic on HCC cells.Mechanistically,circZFR acted as a competitive endogenous RNA(ceRNA)to regulate WEE1 expression by targeting miR-624-3p.Furthermore,in vivo studies have illustrated that circZFR knockdown inhibited tumor growth.Conclusions:circZFR knockdown reduced HCC cell proliferation,migration and invasion and promoted apoptosis by regulating the miR-624-3p/WEE1 axis,suggesting that the circZFR/miR-624-3p/WEE1 axis might be a potential target for HCC treatment.

Exploration of cyclooxygenase-2 inhibitory peptides from walnut dreg proteins based on in silico and in vitro analysis

Walnut dreg protein hydrolysates(WDPHs)exhibit a variety of biological activities,however,the cyclooxygenase-2(COX-2)inhibitory peptide of WDPHs remain unclear.The aim of this study was to rapidly screen for such peptides in WDPHs through a combination of in silico and in vitro analysis.In total,1262 peptide sequences were observed by nano liquid chromatography/tandem mass spectrometry(nano LC-MS/MS)and 4 novel COX-2 inhibitory peptides(AGFP,FPGA,LFPD,and VGFP)were identified.Enzyme kinetic data indicated that AGFP,FPGA,and LFPD displayed mixed-type COX-2 inhibition,whereas VGFP was a non-competitive inhibitor.This is mainly because the peptides form hydrogen bonds and hydrophobic interactions with residues in the COX-2 active site.These results demonstrate that computer analysis combined with in vitro evaluation allows for rapid screening of COX-2 inhibitory peptides in walnut protein dregs.

SLC6A14 promotes ulcerative colitis progression by facilitating NLRP3 inflammasome-mediated pyroptosis

BACKGROUND Ulcerative colitis(UC)is an inflammatory condition with frequent relapse and recurrence.Evidence suggests the involvement of SLC6A14 in UC pathogenesis,but the central regulator remains unknown.AIM To explore the role of SLC6A14 in UC-associated pyroptosis.METHODS Quantitative real-time polymerase chain reaction(qRT-PCR),immunoblotting,and immunohistochemical were used to assess SLC6A14 in human UC tissues.Lipopolysaccharide(LPS)was used to induce inflammation in FHC and NCM460 cells and model enteritis,and SLC6A14 levels were assessed.Pyroptosis markers were quantified using enzyme-linked immunosorbent assay,Western blotting,and qRT-PCR,and EdU incubation,CCK-8 assays and flow cytometry were used to examine proliferation and apoptosis.Mouse models of UC were used for verification.RESULTS SLC6A14 was increased and correlated with NLRP3 in UC tissues.LPS-induced FHC and NCM460 cells showed increased SLC6A14 levels.Reducing SLC6A14 increased cell proliferation and suppressed apoptosis.Reducing SLC6A14 decreased pyroptosis-associated proteins(ASC,IL-1β,IL-18,NLRP3).NLRP3 overexpression counteracted the effects of sh-SLC6A14 on LPS-induced FHC and NCM460 cell pyroptosis.SLC6A14 improved the mucosa in mice with dextran sulfate sodium-induced colitis.CONCLUSION SLC6A14 promotes UC pyroptosis by regulating NLRP3,suggesting the therapeutic potential of modulating the SLC6A14/NLRP3 axis.

TGF-β-regulated different iron metabolism processes in the development and cisplatin resistance of ovarian cancer

The impact of different iron metabolism processes(DIMP)on ovarian cancer remains unclear.In this study,we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ovarian cancer.cBioPortal was used to determine mutations in DIMP-associated genes in ovarian cancer.Kaplan-Meier plotter was used to examine the influence of DIMP on the prognosis of ovarian cancer.By analyzing 1669 serous ovarian cancer cases,we identified a range of mutations in iron metabolism genes,notably in those coding for the transferrin receptor(19%),melanotransferrin(19%),and ceruloplasmin(10%)in the iron import process,and glucose-6-phosphate isomerase(9%),hepcidin antimicrobial peptide(9%),metal regulatory transcription factor 1(8%),and bone morphogenetic protein 6(8%)in the iron regulation process.Compared to the unaltered group,the group with gene alterations exhibited a higher tumor mutation burden count(43 vs.54)and more advanced histologic grade(78.19%vs.87.90%).Compared to the normal ovarian counterparts,a reduction in expression was observed in 9 out of the 14 genes involved in iron utilization and 4 out of the 5 genes involved in iron export in ovarian cancer;in contrast,an increase in expression was observed in 2 out of the 3 genes involved in iron storage in ovarian cancer.Furthermore,in cisplatin-resistant cells compared to cisplatin-sensitive ones,the expression of all genes in iron storage and 13 out of 14 genes in iron import was decreased,while that of 8 out of the 10 genes in iron utilization was increased.In addition,survival curve analysis indicated that a higher expression in the majority of genes in the iron import process(12/21),or a reduced expression in most genes in the iron export process(4/5)correlated with poor progression-free survival.Additionally,TGF-βcould regulate the expression of most iron metabolism-associated genes;particularly,expression of genes involved in the iron storage process(2/2)was inhibited after TGF-β1 or TGF-β2 treatment.In conclusion,DIMP plays multifaceted roles in the initiation,chemo-resistance,and prognosis of ovarian cancer.Therapeutically targeting DIMP may pave the way for more tailored treatment approaches for ovarian cancer.

Applying Hybrid Clustering in Pulsar Candidate Sifting with Multi-modality for FAST Survey

Pulsar search is always the basis of pulsar navigation,gravitational wave detection and other research topics.Currently,the volume of pulsar candidates collected by the Five-hundred-meter Aperture Spherical radio Telescope(FAST)shows an explosive growth rate that has brought challenges for its pulsar candidate filtering system.Particularly,the multi-view heterogeneous data and class imbalance between true pulsars and non-pulsar candidates have negative effects on traditional single-modal supervised classification methods.In this study,a multi-modal and semi-supervised learning based on a pulsar candidate sifting algorithm is presented,which adopts a hybrid ensemble clustering scheme of density-based and partition-based methods combined with a feature-level fusion strategy for input data and a data partition strategy for parallelization.Experiments on both High Time Resolution Universe SurveyⅡ(HTRU2)and actual FAST observation data demonstrate that the proposed algorithm could excellently identify pulsars:On HTRU2,the precision and recall rates of its parallel mode reach0.981 and 0.988 respectively.On FAST data,those of its parallel mode reach 0.891 and 0.961,meanwhile,the running time also significantly decreases with the increment of parallel nodes within limits.Thus,we can conclude that our algorithm could be a feasible idea for large scale pulsar candidate sifting for FAST drift scan observation.

Distinct vibrational signatures and complex phase behavior in metallic oxygen

Evidence for metallization in dense oxygen has been reported for over 30 years[Desgreniers et al.,J.Phys.Chem.94,1117(1990)]at a now routinely accessible 95 GPa[Shimizu et al.,Nature 393,767(1998)].However,despite the longevity of this result and the technological advances since,the nature of the metallic phase remains poorly constrained[Akahama et al.,Phys.Rev.Lett.74,4690(1995);Goncharov et al.,Phys.Rev.B 68,224108(2003);Ma,Phys.Rev.B 76,064101(2007);and Weck et al.,Phys.Rev.Lett.102,255503(2009)].In this work,through Raman spectroscopy,we report the distinct vibrational characteristics of metallicζ-O_(2) from 85 to 225 GPa.In comparison with numerical simulations,wefind reasonable agreement with the candidate structure up to about 150 GPa.At higher pressures,the C2/mstructure is found to be unstable and incompatible with experimental observations.Alternative candidate structures,and Ci,with C2/m C2/conly two molecules in the primitive unit cell,are found to be stable and more compatible with measurements above 175 GPa,indicative of the dissociation of(O_(2))4 units.Further,we report and discuss a strong hysteresis and metastability with the precursory phaseϵ-O_(2).Thesefindings will reinvigorate experimental and theoretical work into the dense oxygen system,which will have importance for oxygen-bearing chemistry,prevalent in the deep Earth,as well as fundamental physics.

Utility of real-time 3D visualization system in the early stage of phacoemulsification training

●AIM:To determine the teaching effects of a real-time three dimensional(3D)visualization system in the operating room for early-stage phacoemulsification training.●METHODS:A total of 10 ophthalmology residents of the first-year postgraduate were included.All the residents were novices to cataract surgery.Real-time cataract surgical observations were performed using a custom-built 3D visualization system.The training lasted 4wk(32h)in all.A modified International Council of Ophthalmology’s Ophthalmology Surgical Competency Assessment Rubric(ICO-OSCAR)containing 4 specific steps of cataract surgery was applied.The self-assessment(self)and expert-assessment(expert)were performed through the microsurgical attempts in the wet lab for each participant.●RESULTS:Compared with pre-training assessments(self 3.2±0.8,expert 2.5±0.6),the overall mean scores of posttraining(self 5.2±0.4,expert 4.7±0.6)were significantly improved after real-time observation training of 3D visualization system(P<0.05).Scores of 4 surgical items were significantly improved both self and expert assessment after training(P<0.05).●CONCLUSION:The 3D observation training provides novice ophthalmic residents with a better understanding of intraocular microsurgical techniques.It is a useful tool to improve teaching efficiency of surgical education.

Diagnostic and prognostic role of LINC01767 in hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)is a primary contributor to cancer-related mortality on a global scale.However,the underlying molecular mechanisms are still poorly understood.Long noncoding RNAs are emerging markers for HCC diagnosis,prognosis,and therapeutic target.No study of LINC01767 in HCC was published.AIM To conduct a multi-omics analysis to explore the roles of LINC01767 in HCC for the first time.METHODS DESeq2 Package was used to analyze different gene expressions.Receiver operating characteristic curves assessed the diagnostic performance.Kaplan-Meier univariate and Cox multivariate analyses were used to perform survival analysis.The least absolute shrinkage and selection operator(LASSO)-Cox was used to identify the prediction model.Subsequent to the validation of LINC01767 expression in HCC fresh frozen tissues through quantitative real time polymerase chain reaction,next generation sequencing was performed following LINC01767 over expression(GSE243371),and Gene Ontology/Kyoto Encyclopedia of Genes and Genomes/Gene Set Enrichment Analysis/ingenuity pathway analysis was carried out.In vitro experiment in Huh7 cell was carried out.RESULTS LINC01767 was down-regulated in HCC with a log fold change=1.575 and was positively correlated with the cancer stemness.LINC01767 was a good diagnostic marker with area under the curve(AUC)[0.801,95% confidence interval(CI):0.751-0.852,P=0.0106]and an independent predictor for overall survival(OS)with hazard ratio=1.899(95%CI:1.01-3.58,P=0.048).LINC01767 nomogram model showed a satisfied performance.The top-ranked regulatory network analysis of LINC01767 showed the regulation of genes participating various pathways.LASSO regression identified the 9-genes model showing a more satisfied performance than 5-genes model to predict the OS with AUC>0.75.LINC01767 was down-expressed obviously in tumor than para-tumor tissues in our cohort as well as in cancer cell line;the over expression of LINC01767 inhibit cell proliferation and clone formation of Huh7 in vitro.CONCLUSION LINC01767 was an important tumor suppressor gene in HCC with good diagnostic and prognostic performance.

Regenerating gene 4 promotes chemoresistance of colorectal cancer by affecting lipid droplet synthesis and assembly

BACKGROUND Regenerating gene 4(REG4)has been proved to be carcinogenic in some cancers,but its manifestation and possible carcinogenic mechanisms in colorectal cancer(CRC)have not yet been elucidated.Our previous study found that the drug resistance of CRC cells may be closely linked to their fat metabolism.AIM To explore the role of REG4 in CRC and its association with lipid droplet formation and chemoresistance.METHODS We conducted a meta-analysis and bioinformatics and pathological analyses of REG4 expression in CRC.The effects of REG4 on the phenotypes and related protein expression were also investigated in CRC cells.We detected the impacts of REG4 on the chemoresistance and lipid droplet formation in CRC cells.Finally,we analyzed how REG4 regulated the transcription and proteasomal degradation of lipogenic enzymes in CRC cells.RESULTS Compared to normal mucosa,REG4 mRNA expression was high in CRC(P<0.05)but protein expression was low.An inverse correlation existed between lymph node and distant metastases,tumor-node-metastasis staging or short overall survival and REG4 mRNA overexpression(P<0.05),but vice versa for REG4 protein expression.REG4-related genes included:Chemokine activity;taste receptors;protein-DNA and DNA packing complexes;nucleosomes and chromatin;generation of second messenger molecules;programmed cell death signals;epigenetic regulation and DNA methylation;transcription repression and activation by DNA binding;insulin signaling pathway;sugar metabolism and transfer;and neurotransmitter receptors(P<0.05).REG4 exposure or overexpression promoted proliferation,antiapoptosis,migration,and invasion of DLD-1 cells in an autocrine or paracrine manner by activating the epidermal growth factor receptor-phosphoinositide 3-kinase-Akt-nuclear factor-κB pathway.REG4 was involved in chemoresistance not through de novo lipogenesis,but lipid droplet assembly.REG4 inhibited the transcription of acetyl-CoA carboxylase 1(ACC1)and ATP-citrate lyase(ACLY)by disassociating the complex formation of anti-acetyl(AC)-acetyl-histone 3-AC-histone 4-inhibitor of growth protein-5-si histone deacetylase;-sterol-regulatory element binding protein 1 in their promoters and induced proteasomal degradation of ACC1 or ACLY.CONCLUSION REG4 may be involved in chemoresistance through lipid droplet assembly.REG4 reduces expression of de novo lipid synthesis key enzymes by inhibiting transcription and promoting ubiquitination-mediated proteasomal degradation.

Construction of strong built-in electric field in binary metal sulfide heterojunction to propel high-loading lithium-sulfur batteries

The practical application of lithium-sulfur(Li-S)batteries is greatly hindered by soluble polysulfides shuttling and sluggish sulfur redox kinetics.Rational design of multifunctional hybrid materials with superior electronic conductivity and high electrocatalytic activity,e.g.,heterostructures,is a promising strategy to solve the above obstacles.Herein,a binary metal sulfide MnS-MoS_(2) heterojunction electrocatalyst is first designed for the construction of high-sulfur-loaded and durable Li-S batteries.The MnS-MoS_(2) p-n heterojunction shows a unique structure of MoS_(2) nanosheets decorated with ample MnS nanodots,which contributes to the formation of a strong built-in electric field at the two-phase interface.The MnS-MoS_(2) hybrid host shows strong soluble polysulfide affinity,enhanced electronic conductivity,and exceptional catalytic effect on sulfur reduction.Benefiting from the synergistic effect,the as-derived S/MnS-MoS_(2) cathode delivers a superb rate capability(643 m A h g^(-1)at 6 C)and a durable cyclability(0.048%decay per cycle over 1000 cycles).More impressively,an areal capacity of 9.9 m A h cm^(-2)can be achieved even under an extremely high sulfur loading of 14.7 mg cm^(-2)and a low electrolyte to sulfur ratio of 2.9μL mg^(-1).This work provides an in-depth understanding of the interfacial catalytic effect of binary metal compound heterojunctions on sulfur reaction kinetics.

Orthokeratology with increased compression factor in adolescent myopia control:a 2-year prospective randomized clinical trial

AIM:To explore the long-term efficacy,safety,and optical mechanism of orthokeratology with increased compression factor in adolescent myopia control.METHODS:A prospective,double-masked,and randomized clinical trial was performed from May 2016 to June 2020.Subjects aged between 8 and 16y,with myopia(-5.00 to-1.00 D),low astigmatism(≥-1.50 D)and anisometropia(≤1.00 D),were stratified into low(-2.75 to-1.00 D)and moderate(-5.00 to-3.00 D)myopia groups.Then they were randomly assigned to wear either increased compression factor(ICF;1.75 D)orthokeratology or conventional compression factor(CCF;0.75 D)orthokeratology.The data were recorded including axial length(AL),spherical equivalent(SE),best corrected visual acuity(BCVA),near visual acuity(NVA),corneal staining(using Efron grading scales),corneal hysteresis(CH),corneal resistance factor(CRF),higher-order aberrations(HOAs,expressed as root mean square,RMS_(h)),and subfoveal choroidal thickness(SFCh T)in the 2-year followup period.Pearson's correlation coefficient was conducted to analyze the association between the changes in AL and RMS_(h),SFCh T.RESULTS:At the 2-year visit,there were no statistical differences in all the parameters between the ICF group and the CCF group in low myopia subjects(P>0.05).For the moderate myopia subjects,the ICF group had shorter AL elongation(0.23±0.08 vs 0.30±0.11 mm,P=0.015),higher RMS_(h)(1.94±0.50 vs 1.65±0.51μm,P=0.041),and higher SFCh T(279.04±35.72 vs 254.08±29.60μm,P=0.008)than those in CCF group.The change in AL was negatively correlated with RMS_(h)(r=-0.687,P<0.001)and SFCh T(r=-0.464,P=0.013).CONCLUSION:ICF orthokeratology can control the progression of moderate myopia more effectively,which might be related to greater RMS_(h) and SFCh T.

A Deeper Understanding of the CO_(2)Emission Pathway Under China’s Carbon Emission Peak and Carbon Neutrality Goals

Achieving carbon neutrality is crucial in dealing with climate change and containing the increase in global temperature at below 1.5℃compared with preindustrial levels.During the general debate at the 75th session of the United Nations General Assembly in September 2020,President Xi Jinping announced that China would adopt more vigorous policies and measures against climate change.