Deep learning has been widely used in the field of mammographic image classification owing to its superiority in automatic feature extraction.However,general deep learning models cannot achieve very satisfactory class...Deep learning has been widely used in the field of mammographic image classification owing to its superiority in automatic feature extraction.However,general deep learning models cannot achieve very satisfactory classification results on mammographic images because these models are not specifically designed for mammographic images and do not take the specific traits of these images into account.To exploit the essential discriminant information of mammographic images,we propose a novel classification method based on a convolutional neural network.Specifically,the proposed method designs two branches to extract the discriminative features from mammographic images from the mediolateral oblique and craniocaudal(CC)mammographic views.The features extracted from the two-view mammographic images contain complementary information that enables breast cancer to be more easily distinguished.Moreover,the attention block is introduced to capture the channel-wise information by adjusting the weight of each feature map,which is beneficial to emphasising the important features of mammographic images.Furthermore,we add a penalty term based on the fuzzy cluster algorithm to the cross-entropy function,which improves the generalisation ability of the classification model by maximising the interclass distance and minimising the intraclass distance of the samples.The experimental results on The Digital database for Screening Mammography INbreast and MIAS mammography databases illustrate that the proposed method achieves the best classification performance and is more robust than the compared state-ofthe-art classification methods.展开更多
Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the pr...Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.展开更多
Objective:bipolar cells(BCs)communicate with amacrine and ganglion cells of the retina via both transient and sustained neurotransmitter release in ribbon synapses.Reconstructing the published quantitative release dat...Objective:bipolar cells(BCs)communicate with amacrine and ganglion cells of the retina via both transient and sustained neurotransmitter release in ribbon synapses.Reconstructing the published quantitative release data from electrical soma stimulation(voltage clamp experiments)of rat rod BCs were used to develop two simple models to predict the number of released vesicles as time series.In the experiment,the currents coming to the All amacrine cell originating from releasing vesicles from the rod BC were recorded using paired-recordings in whole-cell voltage-clamp method.Method:one of the models is based directly on terminal transmembrane voltage,so-called ‘model’,whereas the temporally exacter modelCa includes changes of intracellular calcium concentrations at terminals.Result:the intracellular calcium concentration method replicates a 0.43 ms signal delay for the transient release to pulsatile stimulation as a consequence of calcium channel dynamics in the presynaptic membrane,while the modelV has no signal delay.Both models produce the quite similar results in low stimuli amplitudes.However,for large stimulation intensities that may be done during extracellular stimulations in retinal implants,the modelCa predicts that the reversal potential of calcium limits the number of transiently released vesicles.Adding sodium and potassium ion channels to the axon of the cell enable to study the impact of spikes on the transient release in BC ribbons.Conclusion:a spike elicited by somatic stimulation causes the rapid release of all vesicles that are available for transient release,while a non-spiking BC with a similar morphometry needs stronger stimuli for any transient vesicle release.During extracellular stimulation,there was almost no difference in transient release between the active and passive cells because in both cases the terminal membrane of the cell senses the same potentials originating from the microelectrode.An exception was found for long pulses when the spike has the possibility to generate a higher terminal voltage than the passive cell.Simulated periodic 5 Hz stimulation showed a reduced transient release of 3 vesicles per stimulus,which is a recovery effect.展开更多
病毒性传染病是威胁人类健康的重要因素,迫切需要新的治疗方法来降低由急性病毒感染如鼻病毒和登革热病毒以及慢性病毒感染如人类免疫缺陷病毒1和乙型肝炎病毒引起的发病率和死亡率.随着分子生物学技术的发展,靶向序列特异性的基因编辑...病毒性传染病是威胁人类健康的重要因素,迫切需要新的治疗方法来降低由急性病毒感染如鼻病毒和登革热病毒以及慢性病毒感染如人类免疫缺陷病毒1和乙型肝炎病毒引起的发病率和死亡率.随着分子生物学技术的发展,靶向序列特异性的基因编辑技术成为传染病治疗的有力工具.其中规律成簇间隔短回文重复序列(clustered regularly interspaced short palindromic repeats,CRISPR)-CRISPR相关蛋白9(CRISPR associated protein 9,Cas9)凭借其高效、简便、高特异性等特点被广泛应用于细胞系和动物模型中的传染病治疗,从而成为有前景的新型传染病治疗模式.目前,利用病毒和非病毒载体将Cas9以DNA、m RNA或蛋白质的形式递送到细胞中的可行性研究和评估CRISPR-Cas9体内适用性的临床试验已经在进行中.本篇综述中,我们将对CRISPR-Cas9的原理,其应用于传染病治疗的最新研究进展以及该技术面临的挑战和可预测性的解决方法等加以概述,并进一步展望其未来的发展方向.展开更多
The grey wolf （Canis lupus） is one of the most widely distributed terrestrial mammals, and its distribution and ecology in Europe and North America are largely well described. However, the distribution of grey wolve...The grey wolf （Canis lupus） is one of the most widely distributed terrestrial mammals, and its distribution and ecology in Europe and North America are largely well described. However, the distribution of grey wolves in southern China is still highly controversial. Several well-known western literatures stated that there were no grey wolves in southern China, while the presence of grey wolves across China has been indicated in A Guide to the Mammals of China, published by Princeton University Press. It is essential to solve this discrepancy since dogs may have originated from grey wolves in southern China. Therefore, we systematically investigated Chinese literatures about wild animal surveys and identified more than 100 articles and books that included information of the distribution of grey wolves in China. We also surveyed the collections of three Chinese natural museums and found 26 grey wolf skins specimens collected across China. Moreover, we investigated the fossil records in China and identified 25 archaeological sites with wolf remains including south China. In conclusion, with the comprehensive summary of Chinese literatures, museum specimens and fossil records, we demonstrate that grey wolves do distribute across all parts of the Chinese mainland, including the most southern parts.展开更多
Opportunistic bacteria in apical periodontitis (AP) may pose a risk for systemic dissemination.Mucosal-associated invariant T (MAIT) cells are innate-like T cells with a broad and potent antimicrobial activity importa...Opportunistic bacteria in apical periodontitis (AP) may pose a risk for systemic dissemination.Mucosal-associated invariant T (MAIT) cells are innate-like T cells with a broad and potent antimicrobial activity important for gut mucosal integrity.It was recently shown that MAIT cells are present in the oral mucosal tissue,but the involvement of MAIT cells in AP is unknown.Here,comparison of surgically resected AP and gingival tissues demonstrated that AP tissues express significantly higher levels of Vα7.2-Jα33,Vα7.2- Jα20,Vα7.2-Jα12,Cα and tumour necrosis factor (TNF),interferon (IFN)-γ and interleukin (IL)-17A transcripts,resembling a MAIT cell signature.Moreover,in AP tissues the MR1-restricted MAIT cells positive for MR1–5-OP-RU tetramer staining appeared to be of similar levels as in peripheral blood but consisted mainly of CD4^+ subset.Unlike gingival tissues,the AP microbiome was quantitatively impacted by factors like fistula and high patient age and had a prominent riboflavin-expressing bacterial feature.When merged in an integrated view,the examined immune and microbiome data in the sparse partial least squares discriminant analysis could identify bacterial relative abundances that negatively correlated with Vα7.2-Jα33,Cα,and IL-17A transcript expressions in AP,implying that MAIT cells could play a role in the local defence at the oral tissue barrier.In conclusion,we describe the presence of MAIT cells at the oral site where translocation of oral microbiota could take place.These findings have implications for understanding the immune sensing of polymicrobial-related oral diseases.展开更多
Objective: Cyclophosphamide is a conventional pro-drug used in Multiple Myeloma (MM) and other malignancies. The highly polymorphic CYP2B6 is suggested as a major contributor in cyclophosphamide bioactivation, and GST...Objective: Cyclophosphamide is a conventional pro-drug used in Multiple Myeloma (MM) and other malignancies. The highly polymorphic CYP2B6 is suggested as a major contributor in cyclophosphamide bioactivation, and GST enzymes are involved in detoxification. Polymorphisms of these enzymes may affect enzyme expression and function as well as treatment outcome. The aim of this study was to investigate the impact of the CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 SNP Ile105Val, and GSTM1 and GSTT1 null variants, on the outcome for cyclophosphamide treated MM patients, in order to find markers of value for individualised therapy. Methods: We used allele specific PCR and Pyrosequencing to investigate the impact of CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 Ile105Val, and GSTM1 and GSTT1 variants, on the outcome for 26 cyclophosphamide treated multiple myeloma patients. Results and Major Conclusion: The CYP2B6 785G carriers had significantly shorter progression free survival (p = 0.048*) and overall survival (p = 0.037*) with 785G/G patients having the worst outcome compared to patients carrying the wild type. A shorter progression free survival was also indicated in patients carrying both CYP2B6 516T & 785G (p = 0.068). These results indicate a predictive role of CYP2B6 SNPs, particularly A785G, in cyclophosphamide treatment.展开更多
NDFIP1 has been previously reported as a tumor suppressor in multiple solid tumors,but the function of NDFIP1 in NSCLC and the underlying mechanism are still unknown.Besides,the WW domain containing proteins can be re...NDFIP1 has been previously reported as a tumor suppressor in multiple solid tumors,but the function of NDFIP1 in NSCLC and the underlying mechanism are still unknown.Besides,the WW domain containing proteins can be recognized by NDFIP1,resulted in the loading of the target proteins into exosomes.However,whether WW domain-containing transcription regulator 1(WWTR1,also known as TAZ)can be packaged into exosomes by NDFIP1 and if so,whether the release of this oncogenic protein via exosomes has an effect on tumor development has not been investigated to any extent.Here,we first found that NDFIP1 was low expressed in NSCLC samples and cell lines,which is associated with shorter OS.Then,we confirmed the interaction between TAZ and NDFIP1,and the existence of TAZ in exosomes,which requires NDFIP1.Critically,knockout of NDFIP1 led to TAZ accumulation with no change in its mRNA level and degradation rate.And the cellular TAZ level could be altered by exosome secretion.Furthermore,NDFIP1 inhibited proliferation in vitro and in vivo,and silencing TAZ eliminated the increase of proliferation caused by NDFIP1 knockout.Moreover,TAZ was negatively correlated with NDFIP1 in subcutaneous xenograft model and clinical samples,and the serum exosomal TAZ level was lower in NSCLC patients.In summary,our data uncover a new tumor suppressor,NDFIP1 in NSCLC,and a new exosome-related regulatory mechanism of TAZ.展开更多
Information theory-based methods have been shown to be sensitive and specific for pre- dicting and quantifying the effects of non-coding mutations in Mendelian diseases. We present the Shannon pipeline software for ge...Information theory-based methods have been shown to be sensitive and specific for pre- dicting and quantifying the effects of non-coding mutations in Mendelian diseases. We present the Shannon pipeline software for genome-scale mutation analysis and provide evidence that the soft- ware predicts variants affecting mRNA splicing. Individual information contents （in bits） of refer- ence and variant splice sites are compared and significant differences are annotated and prioritized. The software has been implemented for CLC-Bio Genomics platform. Annotation indicates the context of novel mutations as well as common and rare SNPs with splicing effects. Potential natural and cryptic mRNA splicing variants are identified, and null mutations are distinguished from leaky mutations. Mutations and rare SNPs were predicted in genomes of three cancer cell lines （U2OS, U251 and A431）, which were supported by expression analyses. After filtering, tractable numbers of potentially deleterious variants are predicted by the software, suitable for further laboratory investigation. In these cell lines, novel functional variants comprised 6-17 inactivating mutations, 1 5 leaky mutations and 6-13 cryptic splicing mutations. Predicted effects were validated by RNA-seq analysis of the three aforementioned cancer cell lines, and expression microarray analysis of SNPs in HapMap cell lines.展开更多
In healthy individuals,the intestinal epithelium forms a tight barrier to prevent gut bacteria from reaching blood circulation.To study the effect of probiotics,dietary compounds and drugs on gut barrier formation and...In healthy individuals,the intestinal epithelium forms a tight barrier to prevent gut bacteria from reaching blood circulation.To study the effect of probiotics,dietary compounds and drugs on gut barrier formation and disruption,human gut epithelial and bacterial cells can be cocultured in an in vitro model called the human microbial crosstalk(HuMiX)gut-on-a-chip system.Here,we present the design,fabrication and integration of thin-film electrodes into the HuMiX platform to measure transepithelial electrical resistance(TEER)as a direct readout on barrier tightness in realtime.As various aspects of the HuMiX platform have already been set in their design,such as multiple compressible layers,uneven surfaces and nontransparent materials,a novel fabrication method was developed whereby thin-film metal electrodes were first deposited on flexible substrates and sequentially integrated with the HuMiX system via a transfer-tape approach.Moreover,to measure localized TEER along the cell culture chamber,we integrated multiple electrodes that were connected to an impedance analyzer via a multiplexer.We further developed a dynamic normalization method because the active measurement area depends on the measured TEER levels.The fabrication process and system setup can be applicable to other barrier-on-chip systems.As a proof-of-concept,we measured the barrier formation of a cancerous Caco-2 cell line in real-time,which was mapped at four spatially separated positions along the HuMiX culture area.展开更多
The role of the human intestinal tract in host–microbe interactions has been highlighted in recent years.Several 3-dimensional(3D)models have been developed to reproduce the physiological characteristics of the human...The role of the human intestinal tract in host–microbe interactions has been highlighted in recent years.Several 3-dimensional(3D)models have been developed to reproduce the physiological characteristics of the human gut and to investigate the function of the gut microbiota.One challenge for 3D models is to recapitulate the low oxygen concentrations in the intestinal lumen.Moreover,most earlier 3D culture systems used a membrane to physically separate bacteria from the intestinal epithelium,which has sometimes made the studies of bacteria adhering to or invading cells less feasible.We report the establishment of a 3D gut epithelium model and cultured it at high cell viability under an anaerobic condition.We further cocultured intestinal bacteria including both commensal and pathogen directly with epithelial cells in the established 3D model under the anaerobic condition.We subsequently compared the gene expression differences of aerobic and anaerobic conditions for cell and bacterial growth via dual RNA sequencing.Our study provides a physiologically relevant 3D gut epithelium model that mimics the anaerobic condition in the intestinal lumen and supplies a powerful system for future in-depth gut–microbe interactional investigations.展开更多
Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for om...Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for omics in LT.We reviewed the use of multiomics to elucidate the pathogenesis leading to LT and prognostication.Future directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in omics.Significant molecules were identified and summarized based on omics,with a focus on post-transplant liver fibrosis,early allograft dysfunction,tumor recurrence,and graft failure.We emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be established.We also outlined the ideal workflow for omics in LT.In step with advances in technology,the quality of omics data can be guaranteed using an improved algorithm at a lower price.Concerns should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.展开更多
The combination of flow elasticity and inertia has emerged as a viable tool for focusing and manipulating particles using microfluidics.Although there is considerable interest in the field of elasto-inertial microflui...The combination of flow elasticity and inertia has emerged as a viable tool for focusing and manipulating particles using microfluidics.Although there is considerable interest in the field of elasto-inertial microfluidics owing to its potential applications,research on particle focusing has been mostly limited to low Reynolds numbers(Re<1),and particle migration toward equilibrium positions has not been extensively examined.In this work,we thoroughly studied particle focusing on the dynamic range of flow rates and particle migration using straight microchannels with a single inlet high aspect ratio.We initially explored several parameters that had an impact on particle focusing,such as the particle size,channel dimensions,concentration of viscoelastic fluid,and flow rate.Our experimental work covered a wide range of dimensionless numbers(0.05<Reynolds number<85,1.5<Weissenberg number<3800,5<Elasticity number<470)using 3,5,7,and 10μm particles.Our results showed that the particle size played a dominant role,and by tuning the parameters,particle focusing could be achieved at Reynolds numbers ranging from 0.2(1μL/min)to 85(250μL/min).Furthermore,we numerically and experimentally studied particle migration and reported differential particle migration for high-resolution separations of 5μm,7μm and 10μm particles in a sheathless flow at a throughput of 150μL/min.Our work elucidates the complex particle transport in elasto-inertial flows and has great potential for the development of high-throughput and high-resolution particle separation for biomedical and environmental applications.展开更多
Dear Editor Mitochondria are multifunctional organelles of eukaryotic cells. Biogenesis and functionality of mitochondria require the import of more than 90% of its resident proteins after synthesis by cytosolic ribos...Dear Editor Mitochondria are multifunctional organelles of eukaryotic cells. Biogenesis and functionality of mitochondria require the import of more than 90% of its resident proteins after synthesis by cytosolic ribosomes.展开更多
Background:The presence of delayed treatment effects(DTE)is common in immuno-oncology trials.However,conventional trial designs often overlook the potential presence of DTE,which can result in an underestimation of th...Background:The presence of delayed treatment effects(DTE)is common in immuno-oncology trials.However,conventional trial designs often overlook the potential presence of DTE,which can result in an underestimation of the required sample size and loss of statistical power.Conversely,when there is actually no apparent delay in treatment effects,alternative trial designs for addressing DTE may lead to an over-estimation of sample size and unnecessary prolongation of the trial duration.To mitigate this challenge,we propose the use of a DTE predicting(DTEP)model to better guide immuno-oncology trial designs.Methods:The DTEP model was developed and validated using data from 147 pub-lished randomized immuno-oncology trials.The eligible trials were divided into a training set(approximately 75%of the trials)and a test set(approximately 25%).We employed linear discriminant analysis(LDA)to develop the DTEP model for pre-dicting the DTE status using baseline characteristics available at the trial design stage.The receiver operating characteristic(ROC)curve was utilized to assess the ability of the model to distinguish between trials with and without DTE.We further re-conducted the JUPITER-02 trial in a simulation setting,employing three design approaches to assess the potential benefits of utilizing the DTEP model.Results:Baseline characteristics available during the trial design stage,including cancer type,line of treatment,and experimental and control arm regimens were incorporated,and high accuracy in predicting the DTE status in both the training set(area under the operating characteristic curve(AUC),0.79;95%confidence interval(CI),0.71-0.88)and test set(AUC,0.78;95%CI,0.66-0.90)was achieved.Notably,the model successfully predicted the DTE status in two randomized trials among the test sets that were conducted by our team(ESCORT-1st(absence of DTE)and JUPITER-02(presence of DTE)).In silico re-conduct of the JUPITER-02 trial further showed that the statistical power would be markedly improved when trial designs were guided by the DTEP model.Conclusions:The DTEP model can significantly enhance the precision and effectiveness of immuno-oncology trial designs,thereby facilitating the discovery of effective im-munotherapeutics in a more streamlined and expedited manner.展开更多
Post-translational modifications(PTMs)of proteins play a crucial role in living organisms,altering the properties and functions of proteins.There are over 450 known PTMs involved in various life activities.LSD1(lysine...Post-translational modifications(PTMs)of proteins play a crucial role in living organisms,altering the properties and functions of proteins.There are over 450 known PTMs involved in various life activities.LSD1(lysine-specific demethylase 1)is the first identified histone demethylase that can remove monomethylation or dimethylation modifications from histone H3 lysine K4(H3K4)and histone H3 lysine K9(H3K9).This ability of LSD1 allows it to inhibit or activate transcription.LSD1 has been found to abnormally express at the protein level in various tumors, making it relevant to multiple diseases. As a PTM enzyme, LSD1 itself undergoes various PTMs, including phosphorylation, acetylation, ubiquitination, methylation, SUMOylation, and S-nitrosylation, influencing its activity and function. Dysregulation of thesePTMs has been implicated in a wide range of diseases, including cancer, metabolic disorders,neurological disorders, cardiovascular diseases, and bone diseases. Understanding the speciesof PTMs and functions regulated by various PTMs of LSD1 provides insights into its involvementin diverse physiological and pathological processes. In this review, we discuss the structuralcharacteristics of LSD1 and amino acid residues that affect its enzyme activity. We also summarize the potential PTMs that occur on LSD1 and their involvement in cellular processes.Furthermore, we describe human diseases associated with abnormal expression of LSD1. Thiscomprehensive analysis sheds light on the intricate interplay between PTMs and the functionsof LSD1, highlighting their significance in health and diseases.展开更多
Dear Editor Renal cell carcinoma(RCC)accounts for 2.2%of all cancers diagnosed and 1.8%of all cancer-related deaths. Clear cell RCC(ccRCC),an aggressive subtype,makes up about 70%of all RCCs and is often linked to poo...Dear Editor Renal cell carcinoma(RCC)accounts for 2.2%of all cancers diagnosed and 1.8%of all cancer-related deaths. Clear cell RCC(ccRCC),an aggressive subtype,makes up about 70%of all RCCs and is often linked to poor prognosis and familial syndromes like von Hippel-Lindau(VHL)disease. Most ccRCC cases are asymptomatic in early stages.Despite the immeasurable benefits of early cancer detection and the emergence of molecular biomarkers in precision medicine,specific markers for ccRCC remain scarce,where ccRCC heterogeneity poses challenges for developing new treatments.展开更多
G protein-coupled receptors(GPCRs)represent key drug targets,with approximately 30%-40%of all medications acting on these receptors.Recent advancements have uncovered the complexity of GPCR signaling,including biased ...G protein-coupled receptors(GPCRs)represent key drug targets,with approximately 30%-40%of all medications acting on these receptors.Recent advancements have uncovered the complexity of GPCR signaling,including biased signaling,which allows selective activation of specific intracellular pathways―primarily mediated by G proteins andß-arrestins.Among aminergic GPCRs,the serotonin 5-HT_(2A)receptor has garnered attention for its potential to generate therapeutic effects without adverse outcomes,such as hallucinations,through biased agonism.This review delivers a comprehensive overview of 5-HT_(2A)receptor-biased signaling and its significance in developing safer mental health therapeutics,particularly for depression and anxiety.We provide a critical evaluation of methodologies for assessing biased signaling,spanning from traditional radioligand binding assays to advanced biosensor technologies.Furthermore,we review structural studies and computational modeling that have identified key receptor residues modulating biased signaling.We also highlight novel biased ligands with selective pathway activation,presenting a promising avenue for developing targeted antidepressant therapies without psychedelic effects.Additionally,we explore the 5-HT_(2A)receptor’s role in memory processes and stress response regulation.Ultimately,advancing our understanding of 5-HT_(2A)receptor-biased signaling could drive the development of next-generation GPCR-targeted therapies,maximizing therapeutic efficacy while minimizing side effects in psychiatric treatment.展开更多
Proteome-wide Amino aCid and Elemental composition （PACE） analysis is a novel and informative way of interrogating the proteome. The PACE approach consists of in silico decompo- sition of proteins detected and quant...Proteome-wide Amino aCid and Elemental composition （PACE） analysis is a novel and informative way of interrogating the proteome. The PACE approach consists of in silico decompo- sition of proteins detected and quantified in a proteomics experiment into 20 amino acids and five elements （C, H, N, O and S）, with protein abundances converted to relative abundances of amino acids and elements. The method is robust and very sensitive; it provides statistically reliable differ- entiation between very similar proteomes. In addition, PACE provides novel insights into prote- ome-wide metabolic processes, occurring, e.g., during cell starvation. For instance, both Escherichia coli and Synechocystis down-regulate sulfur-rich proteins upon sulfur deprivation, but E. coli preferentially down-regulates cysteine-rich proteins while Synechocystis mainly down- regulates methionine-rich proteins. Due to its relative simplicity, flexibility, generality and wide applicability, PACE analysis has the potential of becoming a standard analytical tool in proteomics.展开更多
基金Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2019A1515110582Shenzhen Key Laboratory of Visual Object Detection and Recognition,Grant/Award Number:ZDSYS20190902093015527National Natural Science Foundation of China,Grant/Award Number:61876051。
文摘Deep learning has been widely used in the field of mammographic image classification owing to its superiority in automatic feature extraction.However,general deep learning models cannot achieve very satisfactory classification results on mammographic images because these models are not specifically designed for mammographic images and do not take the specific traits of these images into account.To exploit the essential discriminant information of mammographic images,we propose a novel classification method based on a convolutional neural network.Specifically,the proposed method designs two branches to extract the discriminative features from mammographic images from the mediolateral oblique and craniocaudal(CC)mammographic views.The features extracted from the two-view mammographic images contain complementary information that enables breast cancer to be more easily distinguished.Moreover,the attention block is introduced to capture the channel-wise information by adjusting the weight of each feature map,which is beneficial to emphasising the important features of mammographic images.Furthermore,we add a penalty term based on the fuzzy cluster algorithm to the cross-entropy function,which improves the generalisation ability of the classification model by maximising the interclass distance and minimising the intraclass distance of the samples.The experimental results on The Digital database for Screening Mammography INbreast and MIAS mammography databases illustrate that the proposed method achieves the best classification performance and is more robust than the compared state-ofthe-art classification methods.
基金supported by the GRF RGC&CRF,Hong Kong(Grant Nos.:475012 and C5045-20 EF)HMRF,Hong Kong(Grant No.:03141386)+3 种基金ITF,Hong Kong(Grant No.:ITS/209/12)UGC Direct Grant 2011,2012,2021.032HKOG Trust Fund 2011,2014,2019the National Natural Science Foundation of China(Grant Nos.:81974225 and 82201823)。
文摘Endometriosis is a common chronic gynecological disease with endometrial cell implantation outside the uterus.Angiogenesis is a major pathophysiology in endometriosis.Our previous studies have demonstrated that the prodrug of epigallocatechin gallate(ProEGCG)exhibits superior anti-endometriotic and anti-angiogenic effects compared to epigallocatechin gallate(EGCG).However,their direct binding targets and underlying mechanisms for the differential effects remain unknown.In this study,we demonstrated that oral ProEGCG can be effective in preventing and treating endometriosis.Additionally,1D and 2D Proteome Integral Solubility Alteration assay-based chemical proteomics identified metadherin(MTDH)and PX domain containing serine/threonine kinase-like(PXK)as novel binding targets of EGCG and ProEGCG,respectively.Computational simulation and BioLayer interferometry were used to confirm their binding affinity.Our results showed that MTDH-EGCG inhibited protein kinase B(Akt)-mediated angiogenesis,while PXK-ProEGCG inhibited epidermal growth factor(EGF)-mediated angiogenesis via the EGF/hypoxia-inducible factor(HIF-1a)/vascular endothelial growth factor(VEGF)pathway.In vitro and in vivo knockdown assays and microvascular network imaging further confirmed the involvement of these signaling pathways.Moreover,our study demonstrated that ProEGCG has superior therapeutic effects than EGCG by targeting distinct signal transduction pathways and may act as a novel antiangiogenic therapy for endometriosis.
基金HB was supported by the European Institute of Innovation and Technology Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 674901(switchboard).
文摘Objective:bipolar cells(BCs)communicate with amacrine and ganglion cells of the retina via both transient and sustained neurotransmitter release in ribbon synapses.Reconstructing the published quantitative release data from electrical soma stimulation(voltage clamp experiments)of rat rod BCs were used to develop two simple models to predict the number of released vesicles as time series.In the experiment,the currents coming to the All amacrine cell originating from releasing vesicles from the rod BC were recorded using paired-recordings in whole-cell voltage-clamp method.Method:one of the models is based directly on terminal transmembrane voltage,so-called ‘model’,whereas the temporally exacter modelCa includes changes of intracellular calcium concentrations at terminals.Result:the intracellular calcium concentration method replicates a 0.43 ms signal delay for the transient release to pulsatile stimulation as a consequence of calcium channel dynamics in the presynaptic membrane,while the modelV has no signal delay.Both models produce the quite similar results in low stimuli amplitudes.However,for large stimulation intensities that may be done during extracellular stimulations in retinal implants,the modelCa predicts that the reversal potential of calcium limits the number of transiently released vesicles.Adding sodium and potassium ion channels to the axon of the cell enable to study the impact of spikes on the transient release in BC ribbons.Conclusion:a spike elicited by somatic stimulation causes the rapid release of all vesicles that are available for transient release,while a non-spiking BC with a similar morphometry needs stronger stimuli for any transient vesicle release.During extracellular stimulation,there was almost no difference in transient release between the active and passive cells because in both cases the terminal membrane of the cell senses the same potentials originating from the microelectrode.An exception was found for long pulses when the spike has the possibility to generate a higher terminal voltage than the passive cell.Simulated periodic 5 Hz stimulation showed a reduced transient release of 3 vesicles per stimulus,which is a recovery effect.
文摘病毒性传染病是威胁人类健康的重要因素,迫切需要新的治疗方法来降低由急性病毒感染如鼻病毒和登革热病毒以及慢性病毒感染如人类免疫缺陷病毒1和乙型肝炎病毒引起的发病率和死亡率.随着分子生物学技术的发展,靶向序列特异性的基因编辑技术成为传染病治疗的有力工具.其中规律成簇间隔短回文重复序列(clustered regularly interspaced short palindromic repeats,CRISPR)-CRISPR相关蛋白9(CRISPR associated protein 9,Cas9)凭借其高效、简便、高特异性等特点被广泛应用于细胞系和动物模型中的传染病治疗,从而成为有前景的新型传染病治疗模式.目前,利用病毒和非病毒载体将Cas9以DNA、m RNA或蛋白质的形式递送到细胞中的可行性研究和评估CRISPR-Cas9体内适用性的临床试验已经在进行中.本篇综述中,我们将对CRISPR-Cas9的原理,其应用于传染病治疗的最新研究进展以及该技术面临的挑战和可预测性的解决方法等加以概述,并进一步展望其未来的发展方向.
基金supported by grants from the National Natural Science Foundation of China(91531303)the 973 program(2013CB835200 and 2013CB835202)+3 种基金the Breakthrough Project of Strategic Priority Program of the Chinese Academy of Sciences(XDB13000000)grants from the Carl Trygger Foundationthe Agria and Swedish Kennel Club research foundationsupported by the Youth Innovation Promotion Association,Chinese Academy of Sciences
文摘The grey wolf （Canis lupus） is one of the most widely distributed terrestrial mammals, and its distribution and ecology in Europe and North America are largely well described. However, the distribution of grey wolves in southern China is still highly controversial. Several well-known western literatures stated that there were no grey wolves in southern China, while the presence of grey wolves across China has been indicated in A Guide to the Mammals of China, published by Princeton University Press. It is essential to solve this discrepancy since dogs may have originated from grey wolves in southern China. Therefore, we systematically investigated Chinese literatures about wild animal surveys and identified more than 100 articles and books that included information of the distribution of grey wolves in China. We also surveyed the collections of three Chinese natural museums and found 26 grey wolf skins specimens collected across China. Moreover, we investigated the fossil records in China and identified 25 archaeological sites with wolf remains including south China. In conclusion, with the comprehensive summary of Chinese literatures, museum specimens and fossil records, we demonstrate that grey wolves do distribute across all parts of the Chinese mainland, including the most southern parts.
文摘Opportunistic bacteria in apical periodontitis (AP) may pose a risk for systemic dissemination.Mucosal-associated invariant T (MAIT) cells are innate-like T cells with a broad and potent antimicrobial activity important for gut mucosal integrity.It was recently shown that MAIT cells are present in the oral mucosal tissue,but the involvement of MAIT cells in AP is unknown.Here,comparison of surgically resected AP and gingival tissues demonstrated that AP tissues express significantly higher levels of Vα7.2-Jα33,Vα7.2- Jα20,Vα7.2-Jα12,Cα and tumour necrosis factor (TNF),interferon (IFN)-γ and interleukin (IL)-17A transcripts,resembling a MAIT cell signature.Moreover,in AP tissues the MR1-restricted MAIT cells positive for MR1–5-OP-RU tetramer staining appeared to be of similar levels as in peripheral blood but consisted mainly of CD4^+ subset.Unlike gingival tissues,the AP microbiome was quantitatively impacted by factors like fistula and high patient age and had a prominent riboflavin-expressing bacterial feature.When merged in an integrated view,the examined immune and microbiome data in the sparse partial least squares discriminant analysis could identify bacterial relative abundances that negatively correlated with Vα7.2-Jα33,Cα,and IL-17A transcript expressions in AP,implying that MAIT cells could play a role in the local defence at the oral tissue barrier.In conclusion,we describe the presence of MAIT cells at the oral site where translocation of oral microbiota could take place.These findings have implications for understanding the immune sensing of polymicrobial-related oral diseases.
基金supported by grants from The National Natural Science Foundation of China(81402850)the Special Scientific Research Project of Education Department of Shaanxi Provincial Government(17JK0669)~~
基金Swedish Cancer Society Swedish Research Council+2 种基金 Cancer So-ciety in Stockholm Karolinska Institutet County Council in Ostergotland
文摘Objective: Cyclophosphamide is a conventional pro-drug used in Multiple Myeloma (MM) and other malignancies. The highly polymorphic CYP2B6 is suggested as a major contributor in cyclophosphamide bioactivation, and GST enzymes are involved in detoxification. Polymorphisms of these enzymes may affect enzyme expression and function as well as treatment outcome. The aim of this study was to investigate the impact of the CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 SNP Ile105Val, and GSTM1 and GSTT1 null variants, on the outcome for cyclophosphamide treated MM patients, in order to find markers of value for individualised therapy. Methods: We used allele specific PCR and Pyrosequencing to investigate the impact of CYP2B6 SNPs G516T, A785G and C1459T, GSTP1 Ile105Val, and GSTM1 and GSTT1 variants, on the outcome for 26 cyclophosphamide treated multiple myeloma patients. Results and Major Conclusion: The CYP2B6 785G carriers had significantly shorter progression free survival (p = 0.048*) and overall survival (p = 0.037*) with 785G/G patients having the worst outcome compared to patients carrying the wild type. A shorter progression free survival was also indicated in patients carrying both CYP2B6 516T & 785G (p = 0.068). These results indicate a predictive role of CYP2B6 SNPs, particularly A785G, in cyclophosphamide treatment.
基金supported by grants from Science and Technology Commission of Shanghai Municipality(No.21ZR1433100)State Key Laboratory of Oncogenes and Related Genes(No.KF2122)+2 种基金National Natural Science Foundation of China(No.81773115)and Shanghai Jiao Tong University Interdisciplinary Research Funding(Nos.YG2022ZD016,YG2017MS52)approved by the Ethical Committee of the School of Biomedical Engineering,Shanghai Jiao Tong University(Nos.2019045,2020020).
文摘NDFIP1 has been previously reported as a tumor suppressor in multiple solid tumors,but the function of NDFIP1 in NSCLC and the underlying mechanism are still unknown.Besides,the WW domain containing proteins can be recognized by NDFIP1,resulted in the loading of the target proteins into exosomes.However,whether WW domain-containing transcription regulator 1(WWTR1,also known as TAZ)can be packaged into exosomes by NDFIP1 and if so,whether the release of this oncogenic protein via exosomes has an effect on tumor development has not been investigated to any extent.Here,we first found that NDFIP1 was low expressed in NSCLC samples and cell lines,which is associated with shorter OS.Then,we confirmed the interaction between TAZ and NDFIP1,and the existence of TAZ in exosomes,which requires NDFIP1.Critically,knockout of NDFIP1 led to TAZ accumulation with no change in its mRNA level and degradation rate.And the cellular TAZ level could be altered by exosome secretion.Furthermore,NDFIP1 inhibited proliferation in vitro and in vivo,and silencing TAZ eliminated the increase of proliferation caused by NDFIP1 knockout.Moreover,TAZ was negatively correlated with NDFIP1 in subcutaneous xenograft model and clinical samples,and the serum exosomal TAZ level was lower in NSCLC patients.In summary,our data uncover a new tumor suppressor,NDFIP1 in NSCLC,and a new exosome-related regulatory mechanism of TAZ.
基金support from Natural Sciences and Engineering Research Council (Discovery Grant 371758-2009) (PKR)Canadian Breast Cancer Foundation(PKR)+1 种基金Compute Canada (PKR),Canadian Foundation for Innovation,Canada Research Chairs,MITACS Accelerate(BCS)the Ontario Graduate Scholarship Programs (BCS) and Cytognomix Inc
文摘Information theory-based methods have been shown to be sensitive and specific for pre- dicting and quantifying the effects of non-coding mutations in Mendelian diseases. We present the Shannon pipeline software for genome-scale mutation analysis and provide evidence that the soft- ware predicts variants affecting mRNA splicing. Individual information contents （in bits） of refer- ence and variant splice sites are compared and significant differences are annotated and prioritized. The software has been implemented for CLC-Bio Genomics platform. Annotation indicates the context of novel mutations as well as common and rare SNPs with splicing effects. Potential natural and cryptic mRNA splicing variants are identified, and null mutations are distinguished from leaky mutations. Mutations and rare SNPs were predicted in genomes of three cancer cell lines （U2OS, U251 and A431）, which were supported by expression analyses. After filtering, tractable numbers of potentially deleterious variants are predicted by the software, suitable for further laboratory investigation. In these cell lines, novel functional variants comprised 6-17 inactivating mutations, 1 5 leaky mutations and 6-13 cryptic splicing mutations. Predicted effects were validated by RNA-seq analysis of the three aforementioned cancer cell lines, and expression microarray analysis of SNPs in HapMap cell lines.
基金funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie(grant agreement No.812954)the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation program(grant agreement No.757444 and grant agreement No.863664)+1 种基金funded by the Swedish Research Council(2019-00207)as a national research infrastructurefunding provided by Uppsala University.
文摘In healthy individuals,the intestinal epithelium forms a tight barrier to prevent gut bacteria from reaching blood circulation.To study the effect of probiotics,dietary compounds and drugs on gut barrier formation and disruption,human gut epithelial and bacterial cells can be cocultured in an in vitro model called the human microbial crosstalk(HuMiX)gut-on-a-chip system.Here,we present the design,fabrication and integration of thin-film electrodes into the HuMiX platform to measure transepithelial electrical resistance(TEER)as a direct readout on barrier tightness in realtime.As various aspects of the HuMiX platform have already been set in their design,such as multiple compressible layers,uneven surfaces and nontransparent materials,a novel fabrication method was developed whereby thin-film metal electrodes were first deposited on flexible substrates and sequentially integrated with the HuMiX system via a transfer-tape approach.Moreover,to measure localized TEER along the cell culture chamber,we integrated multiple electrodes that were connected to an impedance analyzer via a multiplexer.We further developed a dynamic normalization method because the active measurement area depends on the measured TEER levels.The fabrication process and system setup can be applicable to other barrier-on-chip systems.As a proof-of-concept,we measured the barrier formation of a cancerous Caco-2 cell line in real-time,which was mapped at four spatially separated positions along the HuMiX culture area.
基金the Swedish Research Council(2021-01683 and 2021-06112)the Swedish Foundation for Strategic Research(SSF)(ICA16-0050)+1 种基金Svenska Lakaresallskapet(SLS-784981 and SLS-960584)the Karolinska Institute Foundation.Y.S.Z.further acknowledges support by the Brigham Research Institute.
文摘The role of the human intestinal tract in host–microbe interactions has been highlighted in recent years.Several 3-dimensional(3D)models have been developed to reproduce the physiological characteristics of the human gut and to investigate the function of the gut microbiota.One challenge for 3D models is to recapitulate the low oxygen concentrations in the intestinal lumen.Moreover,most earlier 3D culture systems used a membrane to physically separate bacteria from the intestinal epithelium,which has sometimes made the studies of bacteria adhering to or invading cells less feasible.We report the establishment of a 3D gut epithelium model and cultured it at high cell viability under an anaerobic condition.We further cocultured intestinal bacteria including both commensal and pathogen directly with epithelial cells in the established 3D model under the anaerobic condition.We subsequently compared the gene expression differences of aerobic and anaerobic conditions for cell and bacterial growth via dual RNA sequencing.Our study provides a physiologically relevant 3D gut epithelium model that mimics the anaerobic condition in the intestinal lumen and supplies a powerful system for future in-depth gut–microbe interactional investigations.
基金supported by Innovative Research Groups of National Natural Science Foundation of China(81721091)Major Program of National Natural Science Foundation of China(91542205)+8 种基金National S&T Major Project(2017ZX 10203205)National Natural Science Foundation of China(81902813)Zhejiang International Science and Technology Cooperation Project(2016C04003)Zhejiang Provincial Natural Science Foundation of China(LY18H030002)Zhejiang Medical Association(grant no.2019ZYC-A81)International Youth Exchange Programme by China Association for Science and Technology(2019),Tianqing Liver Diseases Research Fund(TQGB20200114)Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(2021KY145)Organ Transplantation Overseas Training for Youth Talents from Shulan Excellent Talent Project,CSCO(Chinese Society Of Clinical Oncology)-Bayer Tumor Research Funding(Y-bayer202001/zb-0003)Open Fund of Key laboratory of High-Incidence-Tumor Prevention&Treatment(Guangxi Medical University)belonged to Ministry of Education.
文摘Omics data address key issues in liver transplantation(LT)as the most effective therapeutic means for end-stage liver disease.The purpose of this study was to review the current application and future direction for omics in LT.We reviewed the use of multiomics to elucidate the pathogenesis leading to LT and prognostication.Future directions with respect to the use of omics in LT are also described based on perspectives of surgeons with experience in omics.Significant molecules were identified and summarized based on omics,with a focus on post-transplant liver fibrosis,early allograft dysfunction,tumor recurrence,and graft failure.We emphasized the importance omics for clinicians who perform LTs and prioritized the directions that should be established.We also outlined the ideal workflow for omics in LT.In step with advances in technology,the quality of omics data can be guaranteed using an improved algorithm at a lower price.Concerns should be addressed on the translational value of omics for better therapeutic effects in patients undergoing LT.
基金funding from the European Union’s Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie Grant Agreement No.860775the European Union’s Framework Programme for Research and Innovation Horizon 2020 under the Marie Skłodowska-Curie Grant Agreement No.955605+1 种基金the Swedish Research Council(VR 2021-05861)supported by the European Research Council through project StG-852529(MUCUS)。
文摘The combination of flow elasticity and inertia has emerged as a viable tool for focusing and manipulating particles using microfluidics.Although there is considerable interest in the field of elasto-inertial microfluidics owing to its potential applications,research on particle focusing has been mostly limited to low Reynolds numbers(Re<1),and particle migration toward equilibrium positions has not been extensively examined.In this work,we thoroughly studied particle focusing on the dynamic range of flow rates and particle migration using straight microchannels with a single inlet high aspect ratio.We initially explored several parameters that had an impact on particle focusing,such as the particle size,channel dimensions,concentration of viscoelastic fluid,and flow rate.Our experimental work covered a wide range of dimensionless numbers(0.05<Reynolds number<85,1.5<Weissenberg number<3800,5<Elasticity number<470)using 3,5,7,and 10μm particles.Our results showed that the particle size played a dominant role,and by tuning the parameters,particle focusing could be achieved at Reynolds numbers ranging from 0.2(1μL/min)to 85(250μL/min).Furthermore,we numerically and experimentally studied particle migration and reported differential particle migration for high-resolution separations of 5μm,7μm and 10μm particles in a sheathless flow at a throughput of 150μL/min.Our work elucidates the complex particle transport in elasto-inertial flows and has great potential for the development of high-throughput and high-resolution particle separation for biomedical and environmental applications.
文摘Dear Editor Mitochondria are multifunctional organelles of eukaryotic cells. Biogenesis and functionality of mitochondria require the import of more than 90% of its resident proteins after synthesis by cytosolic ribosomes.
基金supported by the National Natural Science Foundation of China(82003269,82173128,81803327,81930065,and 81903406)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2019-I2M-5-036)the Young Faculty Development Project of Sun Yat-sen University(84000-31660002).
文摘Background:The presence of delayed treatment effects(DTE)is common in immuno-oncology trials.However,conventional trial designs often overlook the potential presence of DTE,which can result in an underestimation of the required sample size and loss of statistical power.Conversely,when there is actually no apparent delay in treatment effects,alternative trial designs for addressing DTE may lead to an over-estimation of sample size and unnecessary prolongation of the trial duration.To mitigate this challenge,we propose the use of a DTE predicting(DTEP)model to better guide immuno-oncology trial designs.Methods:The DTEP model was developed and validated using data from 147 pub-lished randomized immuno-oncology trials.The eligible trials were divided into a training set(approximately 75%of the trials)and a test set(approximately 25%).We employed linear discriminant analysis(LDA)to develop the DTEP model for pre-dicting the DTE status using baseline characteristics available at the trial design stage.The receiver operating characteristic(ROC)curve was utilized to assess the ability of the model to distinguish between trials with and without DTE.We further re-conducted the JUPITER-02 trial in a simulation setting,employing three design approaches to assess the potential benefits of utilizing the DTEP model.Results:Baseline characteristics available during the trial design stage,including cancer type,line of treatment,and experimental and control arm regimens were incorporated,and high accuracy in predicting the DTE status in both the training set(area under the operating characteristic curve(AUC),0.79;95%confidence interval(CI),0.71-0.88)and test set(AUC,0.78;95%CI,0.66-0.90)was achieved.Notably,the model successfully predicted the DTE status in two randomized trials among the test sets that were conducted by our team(ESCORT-1st(absence of DTE)and JUPITER-02(presence of DTE)).In silico re-conduct of the JUPITER-02 trial further showed that the statistical power would be markedly improved when trial designs were guided by the DTEP model.Conclusions:The DTEP model can significantly enhance the precision and effectiveness of immuno-oncology trial designs,thereby facilitating the discovery of effective im-munotherapeutics in a more streamlined and expedited manner.
基金supported by the Basic Research of Medical Science and Technique Foundation of Henan Province,China(No.SBGJ202301004 to X.B.C.)the Key Project of the High Education from the Education Department of Henan Province,China(No.22ZX008 to Y.C.Z.)+4 种基金the Youth Supporting Program from Henan Province,China(No.2021HYTP060 to Y.C.Z.)the Youth Supporting Program from Zhengzhou University(No.JC202044046 to Y.C.Z.)the Science and Technology Project of Henan Province,China(No.232102311179 to Y.G.)the National Natural Science Foundation of China(No.U21A20416,82020108030 to H.M.L,82103997 to B.W.)the China Postdoctoral Science Foundation(No.2021M692950 to B.W.,2021M702942 to L.J.Z.).
文摘Post-translational modifications(PTMs)of proteins play a crucial role in living organisms,altering the properties and functions of proteins.There are over 450 known PTMs involved in various life activities.LSD1(lysine-specific demethylase 1)is the first identified histone demethylase that can remove monomethylation or dimethylation modifications from histone H3 lysine K4(H3K4)and histone H3 lysine K9(H3K9).This ability of LSD1 allows it to inhibit or activate transcription.LSD1 has been found to abnormally express at the protein level in various tumors, making it relevant to multiple diseases. As a PTM enzyme, LSD1 itself undergoes various PTMs, including phosphorylation, acetylation, ubiquitination, methylation, SUMOylation, and S-nitrosylation, influencing its activity and function. Dysregulation of thesePTMs has been implicated in a wide range of diseases, including cancer, metabolic disorders,neurological disorders, cardiovascular diseases, and bone diseases. Understanding the speciesof PTMs and functions regulated by various PTMs of LSD1 provides insights into its involvementin diverse physiological and pathological processes. In this review, we discuss the structuralcharacteristics of LSD1 and amino acid residues that affect its enzyme activity. We also summarize the potential PTMs that occur on LSD1 and their involvement in cellular processes.Furthermore, we describe human diseases associated with abnormal expression of LSD1. Thiscomprehensive analysis sheds light on the intricate interplay between PTMs and the functionsof LSD1, highlighting their significance in health and diseases.
基金funded from ALF(RV 996277 and RV 993591)Cancerforskningsfonden i Norrland(LP24-2364)+5 种基金UmeåUniversity(982061),Swedish Cancer Society(23-2902-Pj-01-H)Swedish Research Council(2023-02370)the Kempe foundation,the Swedish Prostate Cancer Foundation and Erling Persson Foundation(2023-0148)funded by the Knut and Alice Wallenberg Foundation under the SciLifeLab and Wallenberg Data Driven Life Science Program(KAW 2020.0239)funded by Swedish Research Council(2020-02258)the Swedish Prostate Cancer Federation,Swedish Cancer Foundation(222166 Pj).
文摘Dear Editor Renal cell carcinoma(RCC)accounts for 2.2%of all cancers diagnosed and 1.8%of all cancer-related deaths. Clear cell RCC(ccRCC),an aggressive subtype,makes up about 70%of all RCCs and is often linked to poor prognosis and familial syndromes like von Hippel-Lindau(VHL)disease. Most ccRCC cases are asymptomatic in early stages.Despite the immeasurable benefits of early cancer detection and the emergence of molecular biomarkers in precision medicine,specific markers for ccRCC remain scarce,where ccRCC heterogeneity poses challenges for developing new treatments.
基金supported by a statutory funds grant from the Medical University of Lublin,Poland(grant number DS33),to Agnieszka A.Kaczor.
文摘G protein-coupled receptors(GPCRs)represent key drug targets,with approximately 30%-40%of all medications acting on these receptors.Recent advancements have uncovered the complexity of GPCR signaling,including biased signaling,which allows selective activation of specific intracellular pathways―primarily mediated by G proteins andß-arrestins.Among aminergic GPCRs,the serotonin 5-HT_(2A)receptor has garnered attention for its potential to generate therapeutic effects without adverse outcomes,such as hallucinations,through biased agonism.This review delivers a comprehensive overview of 5-HT_(2A)receptor-biased signaling and its significance in developing safer mental health therapeutics,particularly for depression and anxiety.We provide a critical evaluation of methodologies for assessing biased signaling,spanning from traditional radioligand binding assays to advanced biosensor technologies.Furthermore,we review structural studies and computational modeling that have identified key receptor residues modulating biased signaling.We also highlight novel biased ligands with selective pathway activation,presenting a promising avenue for developing targeted antidepressant therapies without psychedelic effects.Additionally,we explore the 5-HT_(2A)receptor’s role in memory processes and stress response regulation.Ultimately,advancing our understanding of 5-HT_(2A)receptor-biased signaling could drive the development of next-generation GPCR-targeted therapies,maximizing therapeutic efficacy while minimizing side effects in psychiatric treatment.
基金the Swedish Research Council(Grant No.2009-4103)
文摘Proteome-wide Amino aCid and Elemental composition （PACE） analysis is a novel and informative way of interrogating the proteome. The PACE approach consists of in silico decompo- sition of proteins detected and quantified in a proteomics experiment into 20 amino acids and five elements （C, H, N, O and S）, with protein abundances converted to relative abundances of amino acids and elements. The method is robust and very sensitive; it provides statistically reliable differ- entiation between very similar proteomes. In addition, PACE provides novel insights into prote- ome-wide metabolic processes, occurring, e.g., during cell starvation. For instance, both Escherichia coli and Synechocystis down-regulate sulfur-rich proteins upon sulfur deprivation, but E. coli preferentially down-regulates cysteine-rich proteins while Synechocystis mainly down- regulates methionine-rich proteins. Due to its relative simplicity, flexibility, generality and wide applicability, PACE analysis has the potential of becoming a standard analytical tool in proteomics.
