Biology subjects

Ma, J.

Publications and source records attributed to Ma, J..

At least 433 records · Page 24Linked to original sources

bioRxiv2019

A novel QTL conferring Fusarium crown rot resistance located on chromosome arm 6HL in barley

Fusarium crown rot (FCR), caused primarily by Fusarium pseudograminearum, is a devastating disease for cereal production in semi-arid regions worldwide. To identify and characterize loci conferring FCR resistance, we assessed a landrace AWCS799 which is among the top lines identified from a screening. Genetic control of its resistance was investigated by generating and analysing two populations of recombinant inbred lines. One of the populations was used for QTL detection and the other for validation. A novel QTL, located on the long arm of chromosome 6H (designated as Qcrs.caf-6H), was consistently detected in each of the four trials conducted against the mapping population. The QTL explained up to 29.1% of the phenotypic variance and its effect was confirmed in the validation population. Significant interactions between this resistance locus and either plant height or heading date were not detected, further facilitating its manipulation in breeding programs. Key MessageThis study identified and validated a novel and large-effect QTL conferring Fusarium crown rot resistance on the long arm of chromosome 6HL in barley.

plant biology↗

bioRxiv2019

Loss of one Engrailed1 allele enhances induced α-synucleinopathy

BackgroundParkinsons disease (PD) is a synucleinopathy that has multiple neuropathological characteristics, with nigrostriatal dopamine system degeneration being a core feature. Current models of PD pathology typically fail to recapitulate several attributes of the pathogenic process and neuropathology. We aimed to define the effects of combining a mouse model exhibiting multiple PD-like changes with intrastriatal injections of -synuclein (-syn) pre-formed fibrils (PFFs) aggregates. We employed the heterozygous Engrailed 1 (En1+/-) mouse that features several pathophysiological hallmarks of clinical PD. Objective: To test the hypothesis that the neuropathological changes in the En1+/- mice will promote formation of -syn aggregates following intrastriatal injections of pathogenic human -syn PFFs. Methods: We unilaterally injected PFFs into the striata of 1 month-old En1+/- and control wild-type mice and euthanized animals at 3 months for post-mortem analysis. Results: Using immunohistochemistry and unbiased stereology, we established that PFF-injected En1+/- mice exhibited a near-threefold increase in pS129--syn-positive neurons in the substantia nigra compared to PFF-injected wild-type mice. The PFF-injected En1+/- mice also displayed significant increases in pS129--syn-positive neurons in the amygdala and ventral tegmental area; regions of known PD pathology with projections to the striatum. Additionally, we observed amplified pS129--syn-positive aggregation in En1+/- mice in multiple cortical regions. Conclusions: Following intrastriatal injection of PFFs, absence of an En1 allele leads to additional aggregation of pathological -syn, potentially due to En1-loss mediated nigrostriatal impairment. We propose that further development of this double-hit model could be predictive of pre-clinical therapeutic potential and success for PD than existing mouse models.

neuroscience↗

bioRxiv2019

Cryo-EM structures reveal a conformational change of SOPA1 during mitochondrial inner membrane fusion

Mammalian mitochondrial inner membrane fusion is mediated by OPA1(optic atrophy 1). Under physiological condition, OPA1 undergoes proteolytic processing to form a membrane-anchored long isoform (LOPA1) and a soluble short isoform (SOPA1). A combination of LOPA1 and SOPA1 are required for membrane fusion, however, the relevant mechanism is not well understood. In this study, we investigate the cryo-EM structures of SOPA1 coated liposome tube at nucleotide-free and GTP{gamma}S bound states. SOPA1 exhibits a general structure of dynamin family and can assemble onto membrane in a helical array with a building block of dimer and thus induce membrane tubulation. A predicted amphipathic helix is discovered to mediate the tubulation activity of SOPA1. The binding of GTP{gamma}S causes a conformational rotation between GTPase domain and stalk region, and then induces a rearrangement of the helical array and an expansion of the tube, which is opposite to the behavior of other dynamin proteins, suggesting a unique role of SOPA1 in the fusion of mitochondrial inner membrane.

biophysics↗

bioRxiv2019

Simplified Molecular Classification of Lung Adenocarcinomas Based on EGFR, KRAS, and TP53 Mutations

IntroductionGene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. To facilitate stratification of patients with this disease into similar molecular subtypes, we developed and validated a simple, mutually exclusive classification.\n\nMethodsMutational status of EGFR, KRAS, and TP53 was used to define six mutually exclusive molecular subtypes. A development cohort of 283 cytology specimens of lung adenocarcinoma was used to evaluate the associations between the proposed classification and clinicopathologic variables including demographic characteristics, smoking history, fluorescence in situ hybridization and molecular results. For validation and prognostic assessment, 63 of the 283 cytology specimens with available survival data were combined with a separate cohort of 428 surgical pathology specimens of lung adenocarcinoma.\n\nResultsThe proposed classification yielded significant associations between these molecular subtypes and clinical and prognostic features. We found better overall survival in patients who underwent surgery and had tumors enriched for EGFR mutations. Worse overall survival was associated with older age, stage IV disease, and tumors with comutations in KRAS and TP53. Interestingly, neither chemotherapy nor radiation therapy showed benefit to overall survival.\n\nConclusionsThe mutational status of EGFR, KRAS, and TP53 can be used to easily classify lung adenocarcinoma patients into six subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously.

cancer biology↗

bioRxiv2019

A molecular phylogeny of Schizothoracinae (Teleostei: Cypriniformes: Cyprinidae) based on 12 protein-coding mitochondrial genes and RAG1 gene analysis

The ever-increasing interest in the investigation of origin and speciation of schizothoracine fishes can be dated to 20th century. However, molecular phylogeny of Schizothoracinae and their phylogenetic relationships, as well as the divergence times still remain controversial. In this study, two DNA sets consisting of 12 protein-coding mitochondrial genes from 254 individuals and RAG1 gene from 106 individuals were used to reconstruct the phylogenetic relationships and calculate the divergence times among the subfamily schizothoracinae. Our results indicated that both of the data sets supported a non-monophyletic relationship due to involving of species of Barbinae. However, the phylogenetic relationships based on mtDNA genes were more reliable than that inferred from RAG1 gene. The highly specialized grade formed a monophyletic group, together with Ptychobarbus as a sister group of Diptychus and Gymnodiptychus, which was belonging to specialized grade, indicating that Ptychobarbus may be transition species to involve to highly specialized schizothoracianae. In addition, the primitive grade clustered with Percocypris pingi, a species of Barbinae. Based on mtDNA gene, the speciation time of Schizothoracinae was 66 Ma, and the divergence time of the primitive grade and Percocypris pingi was 64 Ma. The speciation times of the three grades Schizothoracinae were 57 Ma, 51 Ma and 43 Ma, respectively; and the divergence time of specialized and highly specialized grade was 46 Ma. The divergence times of three grades were not consistent with the three stages of uplift of Qinghai-Tibet Plateau, which is older than the times.

molecular biology↗

bioRxiv2019

Rice annexin OsANN4 interacting with OsCDPK24, reduces root aerenchyma formation by modulating H2O2 under ABA treatment

Plant annexins are calcium- and lipid-binding proteins that have multiple functions, and a significant amount of research on plant annexins has been reported in recent years. However, the functions of annexins in diverse biological processes in rice are largely unclear. Herein, we report that OsANN4, a calcium-binding rice annexin protein, is a substrate for OsCDPK24, and the OsANN4 phosphorylation site is the 13th serine, which is a key site for phosphorylation. Most strikingly, abscisic acid (ABA) promotes the interaction between OsANN4 and OsCDPK24. Moreover, knocking down OsANN4 by RNA interference resulted in visible and invisible phenotypes with exogenous ABA treatment, such as shorter shoots of seedlings, less lateral roots, earlier root aerenchyma formation and so on. The further analyzed results showed that decreased superoxide dismutase (SOD) and catalase (CAT) activity of the RNAi lines, which control H2O2 accumulation for redox homeostasis, and further promoted earlier aerenchyma formation of the root. These results suggest that a proposed molecular mechanism exists between OsANN4 and H2O2 production to response ABA.\n\nHighlightOsANN4 enhances SOD and CAT activities to scavenge H2O2 to alleviate the formation of aerenchyma under ABA treatment. OsCDPK24 interacts with and phosphorylates OsANN4, this interaction strengthened under ABA treatment.

plant biology↗

bioRxiv2019

Mitigating Data Scarcity in Protein Binding Prediction Using Meta-Learning

A plethora of biological functions are performed through various types of protein-peptide binding. Prime examples include the protein kinase phosphorylation on peptide substrates and the binding of major histocompatibility complex to neoantigens in the immune system. Understanding the specificity of protein-peptide interactions is critical for unraveling the architectures of functional pathways and the mechanisms of cellular processes in human cells. Despite mass-spectrometric techniques were developed for the identification of protein-peptide interactions, our understanding of the preferences of proteins on their binding peptides is still rudimentary. As a complementary direction, a line of computational prediction methods has been recently proposed to predict protein-peptide bindings which efficiently provide rich functional annotations on a large scale. To achieve a high prediction accuracy, these computational methods require a sufficient amount of data to build the prediction model. However, the number of experimentally verified protein-peptide bindings is often limited in real cases. For example, a majority of protein kinases have very few experimentally verified phosphorylation sites (e.g., less than 30 sites) in existing databases. These methods are thus limited to building accurate prediction models for only well-characterized proteins with a large volume of known binding peptides and cannot be extended to predict new binding peptides for less-studied proteins. In this paper, we introduce a generic framework to address this issue of data scarcity in protein binding prediction. We demonstrate the applicability of our framework in predicting kinase-specific phosphorylation sites. Our method uses an effective training strategy to build a prediction model with robust transferability. The model is able to predict the phosphorylation sites of a less-studied kinase, even if there is only a small number of phosphorylation sites known for this kinase. To achieve this, we train the model via a meta-learning phase followed by a few-shot learning phase. We demonstrate our framework has better transferability than state-of-the-art methods and is effective in utilizing limited data to accurately predict phosphorylation sites for less-characterized kinases. The implementation of our framework is available at https://github.com/luoyunan/MetaKinase.

bioinformatics↗

bioRxiv2019

Early-generated interneurons regulate neuronal circuit formation during early postnatal development

A small subset of interneurons that are generated earliest as pioneer neurons are the first cohort of neurons that enter the neocortex. However, it remains largely unclear whether these early-generated interneurons (EGIns) predominantly regulate neocortical circuit formation. Using inducible genetic fate mapping to selectively labeled EGIns and pseudo-random interneurons (pRIns), we found that EGIns exhibited more mature electrophysiological and morphological properties and higher synaptic connectivity than pRIns at early postnatal stages. In addition, when stimulating one cell, the proportion of EGIns that influence spontaneous network synchronization is significantly higher than that of pRIns. Importantly, toxin-mediated ablation of EGIns after birth significantly reduce spontaneous network synchronization and decrease inhibitory synaptic transmission during the first postnatal week. These results suggest that EGIns can shape developing networks and may contribute to the refinement of neuronal connectivity before the establishment of the adult neuronal circuit.

neuroscience↗

bioRxiv2018

HiCluster: A Robust Single-Cell Hi-C Clustering Method Based on Convolution and Random Walk

3D genome structure plays a pivotal role in gene regulation and cellular function. Single-cell analysis of genome architecture has been achieved using imaging and chromatin conformation capture methods such as Hi-C. To study variation in chromosome structure between different cell types, computational approaches are needed that can utilize sparse and heterogeneous single-cell Hi-C data. However, few methods exist that are able to accurately and efficiently cluster such data into constituent cell types. Here, we describe HiCluster, a single-cell clustering algorithm for Hi-C contact matrices that is based on imputations using linear convolution and random walk. Using both simulated and real data as benchmarks, HiCluster significantly improves clustering accuracy when applied to low coverage Hi-C datasets compared to existing methods. After imputation by HiCluster, structures similar to topologically associating domains (TADs) could be identified within single cells, and their consensus boundaries among cells were enriched at the TAD boundaries observed in bulk samples. In summary, HiCluster facilitates visualization and comparison of single-cell 3D genomes.\n\nAvailabilityhttps://github.com/zhoujt1994/HiCluster.git

bioinformatics↗

bioRxiv2018

Unification of miRNA and isomiR research: the mirGFF3 format and the mirtop API

BackgroundMicroRNAs (miRNAs) are small RNA molecules ([~]22 nucleotide long) involved in post-transcriptional gene regulation. Advances in high-throughput sequencing technologies led to the discovery of isomiRs, which are miRNA sequence variants. While many miRNA-seq analysis tools exist, a lack of consensus on miRNA/isomiR analyses exists, and the resulting diversity of output formats hinders accurate comparisons between tools and precludes data sharing and the development of common downstream analysis methods.\n\nFindingsTo overcome this situation, we present here a community-based project, miRTOP (miRNA Transcriptomic Open Project) working towards the optimization of miRNA analyses. The aim of miRTOP is to promote the development of downstream analysis tools that are compatible with any existing detection and quantification tool. Based on the existing GFF3 format, we first created a new standard format, mirGFF3, for the output of miRNA/isomiR detection and quantification results from small RNA-seq data. Additionally, we developed a command line Python tool, mirtop, to manage the mirGFF3 format. Currently, mirtop can convert into mirGFF3 the outputs of commonly used pipelines, such as seqbuster, miRge2.0, isomiR-SEA, sRNAbench, and Prost!, as well as BAM files. Its open architecture enables any tool or pipeline to output results in mirGFF3.\n\nConclusionsCollectively a comprehensive isomiR categorization system, along with the accompanying mirGFF3 and mirtop API provide a complete solution for the standardization of miRNA and isomiR analysis, enabling data sharing, reporting, comparative analyses, and benchmarking, while promoting the development of common miRNA methods focusing on downstream steps to miRNA detection, annotation, and quantification.

bioinformatics↗

bioRxiv2018

Revealing Hi-C subcompartments by imputing high-resolution inter-chromosomal chromatin interactions

The higher-order genome organization and its variation in different cellular conditions remains poorly understood. Recent high-resolution genome-wide mapping of chromatin interactions using Hi-C has revealed that chromosomes in the human genome are spatially segregated into distinct subcompartments. However, due to the requirement on sequencing coverage of the Hi-C data to define subcompartments, to date subcompartment annotation is only available in the GM12878 cell line, making it impractical to compare Hi-C subcompartment patterns across multiple cell types. Here we develop a new computational approach, named SO_SCPLOWNIPERC_SCPLOW, based on an autoencoder and multilayer perceptron classifier to infer subcompartments using typical Hi-C datasets with moderate coverage. We demonstrated that SO_SCPLOWNIPERC_SCPLOW can accurately reveal subcompartments based on Hi-C datasets with moderate coverage and can significantly outperform an existing method that uses numerous epigenomic datasets as input features in GM12878. We applied SO_SCPLOWNIPERC_SCPLOW to eight additional cell lines to identify the variation of Hi-C subcompartments across different cell types. SO_SCPLOWNIPERC_SCPLOW revealed that chromosomal regions with conserved and more dynamic subcompartment annotations across cell types have different patterns of functional genomic features. This work demonstrates that SO_SCPLOWNIPERC_SCPLOW is effective in identifying subcompartments without the need of high-coverage Hi-C data and has the potential to provide new insights into the spatial genome organization variation across different cell types.

bioinformatics↗

bioRxiv2018

Kinetic And Structural Parameters Governing Fic-Mediated Adenylylation/AMPylation of the Hsp70 chaperone, BiP/GRP78

Fic (filamentation induced by cAMP) proteins regulate diverse cell signaling events by post-translationally modifying their protein targets, predominantly by the addition of an AMP (adenosine monophosphate). This modification is called Fic-mediated Adenylylation or AMPylation. We previously reported that the human Fic protein, HYPE/FicD, is a novel regulator of the unfolded protein response (UPR) that maintains homeostasis in the endoplasmic reticulum (ER) in response to stress from misfolded proteins. Specifically, HYPE regulates UPR by adenylylating the ER chaperone, BiP/GRP78, which serves as a sentinel for UPR activation. Maintaining ER homeostasis is critical for determining cell fate, thus highlighting the importance of the HYPE-BiP interaction. Here, we study the kinetic and structural parameters that determine the HYPE-BiP interaction. By measuring the binding and kinetic efficiencies of HYPE in its activated (Adenylylation-competent) and wild type (de-AMPylation-competent) forms for BiP in its wild type and ATP-bound conformations, we determine that HYPE displays a nearly identical preference for the wild type and ATP-bound forms of BiP in vitro and preferentially de-AMPylates the wild type form of adenylylated BiP. We also show that AMPylation at BiPs Thr366 versus Thr518 sites differentially affect its ATPase activity, and that HYPE does not adenylylate UPR accessory proteins like J-protein ERdJ6. Using molecular docking models, we explain how HYPE is able to adenylylate Thr366 and Thr518 sites in vitro. While a physiological role for AMPylation at both the Thr366 and Thr518 sites has been reported, our molecular docking model supports Thr518 as the structurally preferred modification site. This is the first such analysis of the HYPE-BiP interaction and offers critical insights into substrate specificity and target recognition.

biochemistry↗

bioRxiv2018

Genomic analyses provide insights into genetic architecture of three-way crossbred pigs

BackgroundCrossbreeding is effective for improving performance in poultry and livestock, which is mainly attributed to heterosis. For pork production, a classic three-way crossbreeding system of Duroc x (Landrace x Yorkshire) (DLY) is widely used to produce terminal crossbred pigs with stable and prominent performance. Nonetheless, studies on the transmission of genetic information and gene expression pattern of DLY have been limited.\n\nFindingsWe analyzed population-scale SNPs based on 30 individuals from these three purebreds and identified 529.93 K SNPs of breed-of-origin of alleles. We also applied whole-genome sequencing of ten individuals from a DLY pig family as well as transcriptome of four representative tissues (adipose, skeletal muscle, heart, and liver) for six DLY individuals. Based on above, we identified a large number of high-confidence ASE genes, among which four ASE genes (KMO, PLIN4, POPDC3 and UGT1A6) were found to be shared over all DLY individuals.\n\nConclusionWe suggest DLY is a more effective strategy of three-way crossbreeding among these three purebreds from genetic aspect. We suppose the numerous breed-of-origin of alleles have close association with improved performance of crossbred individuals. ASE may also play important roles on DLY three-way crossbreeding system. Our findings are valuable for understanding the transmission of genetic information and the gene expression in DLY three-way crossbreeding and may be used to guide breeding and production of pigs in the future.

genomics↗

bioRxiv2018

The algae community in taxon Haptophyceae at the early bloom stage of Phaeocystis globosa in Northern Beibu Gulf in winter

Phaeocystis globosa (Order Phaeocystales, family Phaeocystaceae) caused significant impact on aquaculture farming, global climate change and industry. Since the year 2010, intensive red tides of P. globosa began to appear in Beibu Gulf, where previously free of harmful algal blooms, and posed great threats to the cooling systems of a nuclear power plant in 2014 and 2015. In order to discover the bloom mechanism, the community structure of marine microalgae, with a focus on Haptophyceae taxa, in winter in the northern Beibu Gulf near the Qinzhou Bay, Sanniang Bay (SNB) and Dafenjiang River Estuary (DRE), were explored via 18S ribosomal DNA analysis of the V4 region using the Illumina-Based Sequencing platform. The correlation between the relative abundance of five kinds of Haptophyceae algae and environmental factors of seawater were analyzed. The most abundant Haptophyceae-related OTU in terms of number of reads was identified as Phaeocystis and Chrysochromulina. The abundance for other Haptophyceae class was relatively low, such as Haptolina, Prymnesium and Isochrysis. Phaeocystis was present in all samples sites except S6, S11, S12, S14 and S15, and particularly abundant at S8, nearly 29 times more than the second most abundant site. Most notably, the results showed that Phaeocystis displayed highly positive linear correlation with the concentration of NO3--N (Pearson r=0.856, p<0.01). Linear regression analysis indicated that Phaeocystis was significantly linearly related to the NO3--N (R2=0.732; Y=-0.005 + 0.410*X, Y is the relative abundance of P.globosa, X is the concentration of NO3--N; F=38.227, P<0.05) and NO3--N has a significant positive effect on P.globosa (regression coefficient is 0.410, P=0.000). Moreover, the relative abundance of Phaeocystis was significant related to temperature of sea water (Pearson r=-0.882, p<0.01). Water temperature can explain the 77.8% change reason for the P.globosa (R2=0.778), and has a significant effect on P. globosa (Y=0.169-0.009*X, F=49.031, P<0.05), and the regression coefficient is -0.009 (P=0.000) which indicated a significant negative impact relationship between them. Our high throughput sequencing (HTS) based research illustrated how the P. globosa bloom generated and its relationship with NO3--N and temperature of sea water in northern Beibu Gulf for the first time, and bringing hope for solving this big problem.

ecology↗

bioRxiv2018

A simple method to co-purify genomic DNA, RNA, and proteins for functional studies

Understanding the regulation of gene expression, from the epigenetic modifications on genomes to posttranscriptional and translational controls, are critical for elucidating molecular mechanisms underlying distinct phenotypes in biology. With the rapid development of Multi-Omics analyses, it is desirable to minimize sample variations by using DNA, RNA, and proteins co-purified from the same samples. Currently, most of the co-purification protocols rely on Tri Reagent (Trizol as a common representative) and require protein precipitation and dissolving steps, which render difficulties in experimental handling and high-throughput analyses. Here, we established a simple and robust method to minimize the precipitation steps and yield ready-to-use RNA and protein in solutions. This method can be applied to samples in small quantity, such as protoplasts. We demonstrated that the protoplast system equipped with this method may facilitate studies on viroid biogenesis. Given the ease and the robustness of this new method, it will have broad applications for plant research and other disciplines in molecular biology.

plant biology↗

bioRxiv2018

Specific activation of HIV-1 from monocytic reservoir cells by bromodomain inhibitor in humanized mice in vivo

The combination antiretroviral therapy (cART) effectively suppresses HIV-1 infection and enables HIV-infected individuals to live long productive lives. However, the persistence of HIV-1 reservoir cells with latent or low-replicating HIV-1 in patients under cART make HIV-1 infection an incurable disease. Recent studies have focused on the development of strategies such as epigenetic modulators to activate and purge these reservoirs. Bromodomain inhibitors (BETi) are epigenetic modulating compounds able to activate viral transcription in HIV-1 latency cell lines in a positive transcription elongation factor b (P-TEFb)-dependent manner. Little is known about the efficacy of activating HIV-1 reservoir cells under cART by BETi in vivo. In this study, we seek to test the potential of a BETi (I-BET151) in activating HIV-1 reservoir cells under effective cART in humanized mice in vivo. We discover that I-BET151 efficiently activates HIV-1 transcription in monocytic cells, but not in CD4+ T cells, during suppressive cART in vivo. We further reveal that HIV-1 proviruses in monocytic cells are more sensitive to I-BET151 treatment than in T cells in vitro. Finally, we demonstrate that I-BET151-activated viral transcription in monocytic cells is dependent on both CDK2 and CDK9, whereas only CDK9 is involved in activation of HIV-1 by I-BET151 in T cells. Our findings indicate a role of myeloid cells in HIV-1 persistence, and highlights the limitation of measuring or targeting T cell reservoirs alone in terms of HIV-1 cure, as well as provides a potential strategy to reactivate monocytic reservoirs during cART.\n\nIMPORTANCEIt has been reported the low level of active P-TEFb critically contributes to the maintenance of HIV-1 latency or low-replication in HIV-1 reservoir cells under cART. Bromodomain inhibitors are used to activate HIV-1 replication in vitro but their effect on activation of the HIV-1 resevoirs with cART in vivo is not clear. We found that BETi (I-BET151) treatment reactivated HIV-1 gene expression in humanized mice during suppressive cART. Interestingly, I-BET151 preferentially reactivated HIV-1 gene expression in monocytic cells, but not in CD4 T cells. Furthermore, I-BET151 significantly increased HIV-1 transcription in monocytic cells, but not in latently infected CD4 T cells, via CDK2-dependent mechanisms. Our findings suggest that BETi can preferentially activate monocytic HIV-1 reservoir cells, and a combination of latency reversal agents targeting different cell types and pathways is needed to achieve reactivation of different HIV-1 reservoir cells during cART.

immunology↗

bioRxiv2018

Different subtypes of EGFR exon19 mutation can affect prognosis of patients with non-small cell lung adenocarcinoma

AimsIn this study, we determined whether different subtypes of epidermal growth factor receptor (EGFR) exon19 mutation are associated with the therapeutic effect of EGFR-tyrosine kinase inhibitors (TKIs) on advanced non-small cell lung adenocarcinoma.\n\nMethodsA total of 122 patients with stage III or IV non-small cell lung adenocarcinoma were retrospectively reviewed. Clinical characteristics of these patients, including progression-free survival (PFS) outcome for EGFR-TKI treatment, were analyzed.\n\nResultsAccording to the mutation pattern, we classified the in-frame deletions detected on EGFR Exon19 into three different types: codon deletion (CD), with a deletion of one or more original codons; codon substitution and skipping (CSS), with a deletion of one or two nucleotides but the residues could be translated into a new amino acid without changing following amino acid sequence; CD or CSS plus single nucleotide variant (SNV) (CD/CSS+SNV), exclude CD or CSS, theres another SNV nearby the deletion region. The clinical characteristics of three groups were analyzed and as a result, no significant difference was found. By comparing the average number of missing bases and amino acids of the three mutation subtypes, it could be discovered that the number of missing bases and amino acids of the three mutation subtypes is diverse, and group CSS> group CD> group CD/CSS+SNV. Finally, survival analysis was performed between three groups of patients. The median PFS of group CD, group CSS and group CD/CSS+SNV was 11 months, 9 months and 14 months respectively. There was a distinct difference in the PFS between group CSS and group CD/CSS+SNV (P=0.035<0.05), and the PFS of group CD/CSS+SNV was longer.\n\nConclusionsDifferent mutation subtypes of EGFR exon19 can predict the therapeutic effect of EGFR-TKIs on advanced non-small cell lung adenocarcinoma.

cancer biology↗

bioRxiv2018

Role of Cnot6l in maternal mRNA turnover

Removal of poly(A) tail is an important mechanism controlling eukaryotic mRNA turnover. The major eukaryotic deadenylase complex CCR4-NOT contains two deadenylase components, CCR4 and CAF1 for which mammalian CCR4 is encoded by Cnot6 or Cnot6l paralogs. We show that Cnot6l apparently supplies the majority of CCR4 in the maternal CCR4-NOT complex in mouse, hamster, and bovine oocytes. Deletion of Cnot6l yielded viable mice but Cnot6l-/- females exhibited ~40% smaller litter size. The main onset of the phenotype was post-zygotic: fertilized Cnot6l-/- eggs developed slower and arrested more frequently than Cnot6l+/- eggs suggesting that maternal CNOT6L is necessary for accurate oocyte-to-embryo transition (OET). Transcriptome analysis revealed major transcriptome changes in Cnot6l-/- ovulated eggs and 1-cell zygotes. In contrast, minimal transcriptome changes in preovulatory Cnot6l-/- oocytes were consistent with reported Cnot6l mRNA dormancy. A minimal overlap between transcripts sensitive to decapping inhibition and Cnot6l loss suggests that decapping and CNOT6L-mediated deadenylation selectively target distinct subsets of mRNAs during OET in mouse.

molecular biology↗