查看更多>>摘要：Prostate cancer(PCa)is a common malignant tumor with high morbidity and mortality worldwide.The prostate cancer stem cell(PCSC)model provides novel insights into the pathogenesis of PCa and its therapeutic response.However,the roles and molecular mechanisms of specific genes in mediating fate decisions of PCSCs and carcinogenesis of PCa remain to be elusive.In this study,we have explored the expression,function,and mechanism of AZGP1P2,a pseudogene of AZGP1,in regulating the stemness and apoptosis of PCSCs and treatment resistance of docetaxel in castration-resistant prostate cancer(CRPC).We revealed that AZGP1P2 was downregulated in CRPC cell lines and PCSCs,while it was positively associated with progression-free interval.Upregulation of the AZGP1P2 enhanced the sensitivity of docetaxel treatment in CRPCs via inhibiting their stemness.RNA pull-down associated with mass spectrometry analysis,co-immunoprecipitation assay,and RNA immunoprecipitation assay demonstrated that AZGP1P2 could bind to UBA1 and RBM15 as a"writer"of methyltransferase to form a compound.UBA1,an E1 ubiquitin-activating enzyme,contributed to RBM15 protein degradation via ubiquitination modification.Methylated RNA immunoprecipitation assay displayed that RBM15 controlled the mRNA decay of TPM1 in m6A methylation.Furthermore,a xenograft mouse model and patient-derived organoids showed that the therapeutic effect of docetaxel in CRPC was increased by AZGP1P2 in vivo.Collectively,these results imply that AZGP1P2 mediates the stemness and apoptosis of PCSCs and promotes docetaxel therapeutic effect by suppressing tumor growth and metastasis via UBA1/RBM15-mediated TPM1 mRNA decay in CRPC.
查看更多>>摘要：Rheumatoid arthritis(RA)is a chronic inflammatory autoimmune disease accompanied by persistent multiarticular synovitis and cartilage degradation.The present clinical treatments are limited to disease-modifying anti-rheumatic drugs(DMARDs)and aims to relieve pain and control the inflammation of RA.Despite considerable advances in the research of RA,the employment of current clinical procedure is enormous,hindered by systemic side effect,frequent administration,tolerance from long-lasting administration,and high costs.Emerging immunoengineering-based strategies,such as multiple immune-active nanotechnologies via mechanism-based immunology approaches,have been developed to improve specific targeting and to reduce adverse reactions for RA treatments.Here,we review recent studies in immunoengineering for the treatment of RA.The prospect of future immunoengineering treatment for RA has also been discussed.
查看更多>>摘要：While genetic factors were associated with over 30％of colorectal cancer(CRC)patients,mutations in CRC-susceptibility genes were identified in only 5％to 10％of these patients.Besides,previous studies on hereditary CRC were largely designed to analyze germline mutations in patients with single genetic high-risk factor,which limited understanding of the association between genotype and phenotypes.From January 2015 to December 2018,we retrospectively enrolled 2,181 patients from 8,270 consecutive CRC cases,covering 5 categories of genetic high-risk factors.Leukocyte genomic DNA was analyzed for germline mutations in cancer predisposition genes.The germline mutations under each category were detected and analyzed in association with CRC susceptibility,clinical phenotypes,and prognoses.A total of 462 pathogenic variants were detected in 19.3％of enrolled CRC patients.Mismatch repair gene mutation was identified in 9.1％of patients,most prevalent across all high-risk groups.Homologous recombination(HR)gene mutations were detected in 6.5％of cases,penetrated in early-onset and extra-colonic cancer risk groups.Mutations in HR genes,including BARD1,RAD50,and ATM,were found to increase CRC risk with odds ratios of 2.8-,3.1-,and 3.1-fold,respectively.CRC patients with distinct germline mutations manifested heterogeneous phenotypes in clinicopathology and long-term prognoses.Thus,germline mutation screenings should be performed for CRC patients with any of those genetic risk factors.This study also reveals that HR gene mutations may be another major driver for increased CRC risk.
查看更多>>摘要：Electrochemiluminescence(ECL)has established itself as an excellent transduction technique in biosensing and light-emitting device,while conventional ECL mechanism depending on spontaneous emission of luminophores lacks reversibility and tunable emission characters,limiting the universality of ECL technique in the fields of fundamental research and clinical applications.Here,we report the first observation of stimulated emission route in ECL and thus establish a reversible tuning ECL microscopy for single-cell imaging.This microscopy uses a focused red-shifted beam to transfer spontaneous ECL into stimulated ECL,which enables selective and reversible tuning of ECL emission from homogeneous solution,single particles,and single cells.After excluding other possible competitive routes,the stimulated ECL emission route is confirmed by a dual-objective system in which the suppressed spontaneous ECL is accompanied by the enhanced stimulated ECL.By incorporating a commercial donut-shaped beam,the sharpness of single-cell matrix adhesion is improved 2 to 3 times compared with the counterpart in confocal ECL mode.The successful establishment of this stimulated emission ECL will greatly advance the development of light-emitting device and super-resolution ECL microscopy.
查看更多>>摘要：Gene transcription often occurs in discrete bursts,and it can be difficult to deduce the underlying regulatory mechanisms for transcriptional bursting with limited experimental data.Here,we categorize numerous states of single eukaryotic genes and identify 6 essential transcriptional events,each comprising a series of state transitions;transcriptional bursting is characterized as a sequence of 4 events,capable of being organized in various configurations,in addition to the beginning and ending events.By associating transcriptional kinetics with mean durations and recurrence probabilities of the events,we unravel how transcriptional bursting is modulated by various regulators including transcription factors.Through analytical derivation and numerical simulation,this study reveals key state transitions contributing to transcriptional sensitivity and specificity,typical characteristics of burst profiles,global constraints on intrinsic transcriptional noise,major regulatory modes in individual genes and across the genome,and requirements for fast gene induction upon stimulation.It is illustrated how biochemical reactions on different time scales are modulated to separately shape the durations and ordering of the events.Our results suggest that transcriptional patterns are essentially controlled by a shared set of transcriptional events occurring under specific promoter architectures and regulatory modes,the number of which is actually limited.
查看更多>>摘要：Great efforts have been devoted to the study of photo-responsive adsorption,but its current methodology largely depends on the well-defined photochromic units and their photo-driven molecular deformation.Here,a methodology to fabricate nondeforming photo-responsive sorbents is successfully exploited.With C60-fullerene doping in metalloporphyrin metal-organic frameworks(PCN-M,M=Fe,Co,or Ni)and intensively interacting with the metalloporphyrin sites,effective charge-transfer can be achieved over the metalloporphyrin-C60 architectures once excited by the light at 350 to 780 nm.The electron density distribution and the resultant adsorption activity are thus changed by excited states,which are also stable enough to meet the timescale of microscopic adsorption equilibrium.The charge-transfer over Co(Ⅱ)-porphyrin-C60 is proved to be more efficient than the Fe(Ⅱ)-and Ni(Ⅱ)-porphyrin-C60 sites,as well as than all the metalloporphyrin sites,so the CO2 adsorption capacity(CAC;at 0 ℃ and 1 bar)over the C60-doped PCN-Co can be largely improved from 2.05 mmol g-1 in the darkness to 2.69 mmol g-1 with light,increased by 31％,in contrast to photo-irresponsive CAC over all C60-undoped PCN-M sorbents and only the photo-loss CAC over C60.
查看更多>>摘要：Proteins secreted by Gram-negative bacteria are tightly linked to the virulence and adaptability of these microbes to environmental changes.Accurate identification of such secreted proteins can facilitate the investigations of infections and diseases caused by these bacterial pathogens.However,current bioinformatic methods for predicting bacterial secreted substrate proteins have limited computational efficiency and application scope on a genome-wide scale.Here,we propose a novel deep-learning-based framework-DeepSecE-for the simultaneous inference of multiple distinct groups of secreted proteins produced by Gram-negative bacteria.DeepSecE remarkably improves their classification from nonsecreted proteins using a pretrained protein language model and transformer,achieving a macro-average accuracy of 0.883 on 5-fold cross-validation.Performance benchmarking suggests that DeepSecE achieves competitive performance with the state-of-the-art binary predictors specialized for individual types of secreted substrates.The attention mechanism corroborates salient patterns and motifs at the N or C termini of the protein sequences.Using this pipeline,we further investigate the genome-wide prediction of novel secreted proteins and their taxonomic distribution across～1,000 Gram-negative bacterial genomes.The present analysis demonstrates that DeepSecE has major potential for the discovery of disease-associated secreted proteins in a diverse range of Gram-negative bacteria.An online web server of DeepSecE is also publicly available to predict and explore various secreted substrate proteins via the input of bacterial genome sequences.
查看更多>>摘要：The limitations of autologous bone grafts necessitate the development of advanced biomimetic biomaterials for efficient cranial defect restoration.The cranial bones are typical flat bones with sandwich structures,consisting of a diploe in the middle region and 2 outer compact tables.In this study,we originally developed 2 types of flat-bone-mimetic β-tricalcium phosphate bioceramic scaffolds(Gyr-Comp and Gyr-Tub)by high-precision vat-photopolymerization-based 3-dimensional printing.Both scaffolds had 2 outer layers and an inner layer with gyroid pores mimicking the diploe structure.The outer layers of Gyr-Comp scaffolds simulated the low porosity of outer tables,while those of Gyr-Tub scaffolds mimicked the tubular pore structure in the tables of flat bones.The Gyr-Comp and Gyr-Tub scaffolds possessed higher compressive strength and noticeably promoted in vitro cell proliferation,osteogenic differentiation,and angiogenic activities compared with conventional scaffolds with cross-hatch structures.After implantation into rabbit cranial defects for 12 weeks,Gyr-Tub achieved the best repairing effects by accelerating the generation of bone tissues and blood vessels.This work provides an advanced strategy to prepare biomimetic biomaterials that fit the structural and functional needs of efficacious bone regeneration.
查看更多>>摘要：Early-life stress can lead to sustained alterations in regional resting-state brain functions,but the underlying molecular mechanism remains unclear.Stress can also induce sustained changes in epigenetic modifications across brain regions,which are not limited to a few genes;rather,they often tend to produce global levels of change.The functional implication of these changes also remains to be elucidated.We hypothesize that global epigenetic changes may partly modulate the resting-state functions of brain regions to influence behavior.To test this hypothesis,we used an adolescent social stress(ASS)model in mice and examined the relationship between epigenetic modifications and regional resting-state brain activity using resting-state functional magnetic resonance imaging(rs-fMRI).The results showed that,compared to the control mice,the stressed mice showed increased anxiety and social avoidance behaviors and greater levels of dimethylation of histone H3 at lysine 9(H3K9me2)in the medial prefrontal cortex(mPFC).In addition,the resting-state activity represented by the amplitude of low-frequency fluctuation(ALFF)was significantly lower in the mPFC of stressed mice.To verify the relationship of H3K9me2 and ALFF,the specific inhibition of H3Kme2 was performed by using the drug UNC0642,which reversed the anxiety behavior induced by ASS and significantly increase the ALFF value of mPFC in both normal and ASS animals.Our study is the first to report an association between histone modifications and rs-fMRI findings,providing a new perspective for understańding of the significance of regional brain epigenetic changes and a possible molecular explanation for rs-fMRI findings.
查看更多>>摘要：Non-Hermitian systems associated with exceptional points(EPs)are expected to demonstrate a giant response enhancement for various sensors.The widely investigated enhancement mechanism based on diverging from an EP should destroy the EP and further limits its applications for multiple sensing scenarios in a time sequence.To break the above limit,here,we proposed a new enhanced sensing mechanism based on shifting an EP.Different from the mechanism of diverging from an EP,our scheme is an EP nondemolition and the giant enhancement of response is acquired by a slight shift of the EP along the parameter axis induced by perturbation.The new sensing mechanism can promise the most effective response enhancement for all sensors in the case of multiple sensing in a time sequence.To verify our sensing mechanism,we construct a mass sensor and a gyroscope with concrete physical implementations.Our work will deepen the understanding of EP-based sensing and inspire designing various high-sensitivity sensors in different physical systems.
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