Deciphering gastric inflammation-induced tumorigenesis through multi-omics data and AI methods

Gastric cancer(GC), the fifth most common cancer globally, remains the leading cause of cancer deaths worldwide. Inflammation-induced tumorigenesis is the predominant process in GC development;therefore, systematic research in this area should improve understanding of the biological mechanisms that initiate GC development and promote cancer hallmarks. Here, we summarize biological knowledge regarding gastric inflammation-induced tumorigenesis, and characterize the multi-omics data and systems biology methods for investigating GC development. Of note, we highlight pioneering studies in multi-omics data and state-of-the-art network-based algorithms used for dissecting the features of gastric inflammation-induced tumorigenesis, and we propose translational applications in early GC warning biomarkers and precise treatment strategies. This review offers integrative insights for GC research, with the goal of paving the way to novel paradigms for GC precision oncology and prevention.

Danlu Tongdu tablets treat lumbar spinal stenosis through reducing reactive oxygen species and apoptosis by regulating CDK2/CDK4/CDKN1A expression

Lumbar spinal stenosis is caused by the compression of the nerve root or cauda equina nerve by stenosis of the lumbar spinal canal or intervertebral foramen,and is manifested as chronic low back and leg pain.Danlu Tongdu(DLTD)tablets can relieve chronic pain caused by lumbar spinal stenosis,but the molecular mechanism remains largely unknown.In this study,the potential molecular mechanism of DLTD tablets in the treatment of lumbar spinal stenosis was first predicted by the network pharmacology method.Results showed that DLTD functions in regulating anti-oxidative,apoptosis,and inflammation signaling pathways.Furthermore,the flow cytometry results showed that DLTD tablets efficiently reduced reactive oxygen species content and inhibited rat neural stem cell apoptosis induced by hydrogen peroxide.DLTD also inhibited the mitochondrial membrane potential damage induced by hydrogen peroxide.Elisa analysis showed that DLTD induced cell cycle-related protein,CDK2 and CDK4,and reduced CDKN1A protein expression level.Taken together,our study provided new insights of DLTD in treating lumbar spinal stenosis through reducing reactive oxygen species content,decreasing apoptosis by inhibiting CDKN1A and promoting CDK2 and CDK4 expression levels.

Elastic Multiple Kernel Learning

(MKL ) 多重核学习被建议处理核熔化。MKL 听说线性联合几个核并且解决同时与联合的核联系的支持的向量机器(SVM ) 。MKL 的当前的框架鼓励核联合系数的稀少。核的重要部分什么时候是增进知识的，强迫稀少，趋于选择仅仅一些核并且可以忽略有用信息。在这份报纸，我们建议学习的有弹性的多重核(EMKL ) 完成适应的核熔化。EMKL 使用混合规则化功能损害稀少和非稀少。MKL 和 SVM 能被认为是 EMKL 的特殊情况。为 MKL 问题基于坡度降下算法，我们建议一个快算法解决 EMKL 问题。模拟数据集上的结果证明 EMKL 的表演有利地比作 MKL 和 SVM。我们进一步把 EMKL 用于基因集合分析并且得到有希望的结果。最后，我们学习比作另外的非稀少的 MKL 的 EMKL 的理论优点。

MiR-21 Mediates the Radiation Resistance of Glioblastoma Cells by Regulating PDCD4 and hMSH2

Summary： The purpose of this study was to investigate the molecular mechanism by which miR-21 and its target genes mediate radiation resistance of glioblastoma cells. Real-time PCR was employed to detect miR-21 expression in normal brain tissues, glioblastoma tissues and glioblastoma cell lines （A172, T98G and U87MG）. T98G cells were transfected with anti-miR-21 oligonucleotides, or plasmids con- taining PDCD4 or hMSH2 （PDCD4-pcDNA3 and hMSH2-pcDNA3）. The survival curve was obtained to investigate the sensitivity of T98G cells to radiation. Cell apoptosis was measured by using the Cas- pase-3/7 kit and cell cycle by flow cytometry. Western blotting was performed to detect the expression of hMSH2 and PDCD4 in miR-21-inhibiting T98G cells. The results showed that miR-21 expression in glioblastoma cells and tissues was conversely associated with the radiation sensitivity. Over-expression of miR-21 resulted in radiation resistance, while knockdown of miR-21 led to higher sensitivity of glioblastma cells to radiation. After miR-21 knockdown, the apoptosis of T98G cells was significantly increased and the G2 phase arrest was more significant. In addition, miR-21 knockdown increased the expression of endogenous PDCD4 and hMSH2, which contributed to the apoptosis and G2 arrest of T98G cells. The findings suggested that miR-21 may mediate the resistance of glioblastoma cells against radiation via its target genes PDCD4 and hMSH2. MiR-21 and its target genes may be used as potential molecular targets for clinical radiotherapy sensitization in the future.

Computational and Structural Investigation of Deleterious Functional SNPs in Breast Cancer BRCA2 Gene

In this work, we have analyzed the genetic variation that can alter the expression and the function in BRCA2 gene using computational methods. Out of the total 534 SNPs, 101 were found to be non synonymous (nsSNPs). Among the 7 SNPs in the untranslated region, 3 SNPs were found in 5′ and 4 SNPs were found in 3′ un-translated regions (UTR). Of the nsSNPs 20.7% were found to be damaging by both SIFT and PolyPhen server among the 101 nsSNPs investigated. UTR resource tool suggested that 2 SNPs in the 5′ UTR region and 4 SNPs in the 3′ UTR regions might change the protein expression levels. The mutation from asparagine to isoleucine at the position 3124 of the native protein of BRCA2 gene was most deleterious by both SIFT and PolyPhen servers. A structural analysis of this mutated protein and the native protein was made which had an RMSD value of 0.301 nm. Based on this work, we proposed that this most deleterious nsSNP with an SNPid rs28897759 is an important candidate for the cause of breast cancer by BRCA2 gene.

Systematic screening reveals synergistic interactions that overcome MAPK inhibitor resistance in cancer cells

Objective:Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor(MAPKi)resistance,which is one of the most common forms of resistance that has emerged in many types of cancers.Here,we aimed to systematically identify the genetic interactions underlying MAPKi resistance,and to further investigate the mechanisms that produce the genetic interactions that generate synergistic MAPKi resistance.Methods:We conducted a comprehensive pair-wise sgRNA-based high-throughput screening assay to identify synergistic interactions that sensitized cancer cells to MAPKi,and validated 3 genetic combinations through competitive growth,cell viability,and spheroid formation assays.We next conducted Kaplan-Meier survival analysis based on The Cancer Genome Atlas database and conducted immunohistochemistry to determine the clinical relevance of these synergistic combinations.We also investigated the MAPKi resistance mechanisms of these validated synergistic combinations by using co-immunoprecipitation,Western blot,qRTPCR,and immunofluorescence assays.Results:We constructed a systematic interaction network of MAPKi resistance and identified 3 novel synergistic combinations that effectively targeted MAPKi resistance(ITGB3+IGF1R,ITGB3+JNK,and HDGF+LGR5).We next analyzed their clinical relevance and the mechanisms by which they sensitized cancer cells to MAPKi exposure.Specifically,we discovered a novel protein complex,HDGF-LGR5,that adaptively responded to MAPKi to enhance cancer cell stemness,which was up-or downregulated by the inhibitors of ITGB3+JNK or ITGB3+IGF1R.Conclusions:Pair-wise sgRNA library screening provided systematic insights into elucidating MAPKi resistance in cancer cells.ITGB3-+IGF1R-targeting drugs(cilengitide+linsitinib)could be used as an effective therapy for suppressing the adaptive formation of the HDGF-LGR5 protein complex,which enhanced cancer stemness during MAPKi stress.

Phylogenetic Analysis of Drought Responsive ATMYB2 Proteins

Low temperature,drought and salinity aremajor adverse environmental factors that limitplant productivity.Understanding themechanisms by which plant perceive andtransduce these stress signals to initiate adaptiveresponses is essential for engineering stresstolerant plants. While studying the stressgenes,one of myb related genes,atmyb2。

Integrative molecular analysis of hepatocellular carcinoma by HCCDB

Objective:Hepatocellular carcinoma(HCC)is one of the most common and lethal cancer types.In the past decades,transcriptomic data have been accumulated vastly and applied widely in molecular classification and biomarker identification.As HCC is a highly heterogeneous disease.

Proteome profiling of spinal cord and dorsal root ganglia in rats with trinitrobenzene sulfonic acid-induced colitis

AIM: To investigate proteomic changes in spinal cord and dorsal root ganglia (DRG) of rats with trinitrobenzene sulfonic acid (TNBS)-induced colitis. METHODS: The colonic myeloperoxidase (MPO) activity and tumor necrosis factor-(TNF- ) level were determined. A two-dimensional electrophoresis (2-DE)-based proteomic technique was used to profile the global protein expression changes in the DRG and spinal cord of the rats with acute colitis induced by intracolonic injection of TNBS. RESULTS: TNBS group showed significantly elevated colonic MPO activity and increased TNF-level. The proteins derived from lumbosacral enlargement of the spinal cord and DRG were resolved by 2-DE; and 26 and 19 proteins that displayed significantly different expression levels in the DRG and spinal cord were identified respectively. Altered proteins were found to be involved in a number of biological functions, such as inflammation/immunity, cell signaling, redox regulation, sulfate transport and cellular metabolism. The over-expression of the protein similar to potassium channel tetramerisation domain containing protein 12 (Kctd 12) and low expression of proteasome subunit type-1 (psma) were validated by Western blotting analysis. CONCLUSION: TNBS-induced colitis has a profound impact on protein profiling in the nervous system. This result helps understand the neurological pathogenesis of inflammatory bowel disease.

Metabolite variation in hybrid corn grain from a large-scale multisite study

Metabolite composition is strongly affected by genotype,environment,and interactions between genotype and environment,although the extent of variation caused by these factors may depend upon the type of metabolite.To characterize the complexity of genotype,environment,and their interaction in hybrid seeds,50 genetically diverse non-genetically modified(GM) maize hybrids were grown in six geographically diverse locations in North America.Polar metabolites from 553 harvested corn grain samples were isolated and analyzed by gas chromatography–mass spectrometry and 45 metabolites detected in all samples were used to generate a data matrix for statistical analysis.There was moderate variation among biological replicates and across genotypes and test sites.The genotype effects were detected by univariate and Hierarchical clustering analyses(HCA) when environmental effects were excluded.Overall,environment exerted larger effects than genotype,and polar metabolite accumulation showed a geographic effect.We conclude that it is possible to increase seed polar metabolite content in hybrid corn by selection of appropriate inbred lines and growing regions.

Genetic characterization of Northeast Asian cattle based on sequence polymorphisms in the complete mitochondrial genome

In this study, we analyzed complete mtDNA sequences variation and genetic relationship among taurine, indicine and Bison groups. In total, 107 sequences from different breeds, 45 European (45 Italian), 16 Middle East Asian (seven Iranian and nine Iraqi), 41 Northeast Asian (34 Korean and seven Japanese), two Nellore (Bos indicus) and two American Bison bison (Ame. bison) were obtained from Gen-Bank database. One Korean Hanwoo (Bos taurus) sequence was generated using the SOLiDTM System. In total, 1370 polymorphic sites, representing 8.39% of the complete 107 mtDNA sequences (16,338 bp) were detected and of these, 1186 parsimony informative polymorphic sites were identified. Neighbor-joining tree indicated that Korean, Japanese, Iranian, Iraqi, and Italian cattle were closely related to one another, but are separated from B. Bison. The B. taurus mtDNA polymorphism was greater in the D-loop than in the other regions. The ATP8, ND3, ND5, and ND6 regions were also quite parsimony informative, similar to Cyt b. In addition, this study revealed a distinct genetic difference between Korean cattle and B. indicus.

Pathophysiological responses from human gut microbiome

The human gastrointestinal tract harbors a vast collection of symbiotic microorganisms-collectively termed as "gut microbiome". This microbiota has important effect in immune system and other host activities. Recent studies have suggested that alterations of the normal gut microbiota are associated with various human diseases and psychological disorders. The underlying cause, once proven, may provide novel insights into the importance of gut flora in human health. In this review, we give an attempt to describe how the alteration in the microbial community causes the development of certain widespread pathophysiological disorders; focusing on inflammatory bowel disease, colorectal cancer, obesity and autism. Proper knowledge about the hostmicrobiota interaction and linkage could be essential for the development of future personalized strategies of therapeutics.

Improved Clonal Propagation of <i>Alpinia calcarata</i>Rosc., a Commercially Important Medicinal Plant and Evaluation of Chemical Fidelity through Comparison of Volatile Compounds

An efficient and improved clonal propagation of Alpinia calcarata, a commercially important medicinal plant was established on Murashige and Skoog medium. The axillary shoot proliferation was achieved with maximum 5.2 ± 0.7 shoots in 92.8% of rhizome explants in medium with 2.0 mg/L 6-benzylamiopurine (BAP) and 0.2 mg/L indole-3-acetic acid (IAA). Axillary shoot buds (60%) upon subculture for 8 weeks in the same medium produced multiple shoot initials (12.1 ± 0.4) mediated with meristemoids (4.0 ± 0.5) and callus. A gradual reduction in the concentration of BAP or elimination of IAA was required for rapid induction of normal plants devoid of callus from propagules during subsequent subculture. Single clump of 3-4 multiple shoot initials during second subculture on medium with 1.0 mg/L BAP and 0.1 mg/L IAA yielded an average of 21 shoots which was best among different propagules tried. The shoot multiplication rate was further enhanced to 32 shoots when the similar propagules passed to third subculture on medium with 1.0 mg/L BAP alone. Clumps of multiple shoot initials upon subculture on medium with 1.0 mg/L BAP alone exhibited 10 fold multiplication rates. Use of liquid medium in culture bottles with polypropylene caps supported fast growth of the shoots and spontaneous root formation on 50% of the shoots. Shoots transferred to half-strength MS liquid medium with 0.2 mg/L of IAA and IBA was optimum for maximum roots (8.14 ± 1.34) in 100% shoots. The rooted plants were hardened in mist chamber showed 95% survival and well established in the field. The acclimatized plants showed rhizome formation after 4-6 weeks of growth under shade house. Volatile chemicals profile of the leaves, rhizome and root of the in vitro and conventionally propagated plants analyzed by gas chromatography-mass spectrometry were qualitatively and quantitatively similar. The analysis of growth characteristics of 36 month old in vitro and conventionally propagated plants showed a 50% increment of rhizome fresh biomass with prolific root and leaf growth in the former than the latter ones. The protocol described herein will have practical applications for the large scale production of uniform efficient plants for commercial cultivation of A. calcarata.

Associations of Single Nucleotide Polymorphisms in the Bovine <i>FADS</i>6 Gene with Fatty Acid Composition in Hanwoo (Korean Cattle)

The bovine fatty acid desaturase (FADS) gene cluster consists of FADS1, FADS2, FADS3, and FADS6, which acts as key enzymes in fatty acid metabolism. Of these, the genetics effects of variants in FADS1, FADS2 and FADS3 have been previously studied. However, the genetic effects of variants of FADS6 gene have not been studied. The aim of this study was to identify genetic variants in the bovine fatty acid desaturase 6 (FADS6) gene and study their association with fatty acid composition in Hanwoo cattle. Six genetic variants were observed, three each in intron 2 and exon 6 by DNA sequencing analyses. The association of genetic variants with fatty acid composition was evaluated in 90 Hanwoo steers. The variants were confirmed and the animals were genotyped by RFLP (Restriction Fragment Length Polymorphism) and AS-PCR (Allele Specific PCR) analyses. The analysis revealed that palmitoleic acid (C16:1n7) was associated with g.3391G > A, g.3660A > C and g.15657C > T, and stearic acid (C18:0) showed highly significant association with g.3660A > C segments. Both g.3391G > A, g.3660A > C also had strong additive and dominance effect for Palmitoleic acid, while g.3660A > C also had a strong dominance effect for stearic acid. These results could be useful for modulating fatty acid composition in beef and produce meat with higher monounsaturated fatty acid to saturated fatty acid ratio (MUFA/SFA), which had been shown to have positive health effect in humans.

Phylogenetic analysis and characterization of mitochondrial DNA for Korean native cattle

This study was aimed to preserve mitochondria from liver tissues of Korean native cattle (KNC) as genetic resources and to analyze phylogenetic relationships among cattle breeds using the whole sequences of mtDNA. Mitochondria of KNC has been isolated with the alkaline lysis procedure using1 gof liver tissues, and measurements showed numbers of cells (2.64 × 1010), concentration (114.6 ug/ml), proteins (0.278 ug/ml), and absorbance (0.029) in 260 nm. Mitochondrial DNAs (mtDNA) were extracted from the isolated mitochondria to determine whole sequences that can be used to estimate genetic distances among cattle breeds. Designing of primers based on the bovine mtDNA sequence was resulted in 16 primer sets covering the whole mtDNA regions. The analysis of 40 KNC mtDNA sequences revealed 69 polymorphic sites that were less than the average number of SNP (single nucleotide polymorphism) for other populations (82 sites) in this study. As expected, the highest observation of SNPs was found in the D-loop region, and a total of 29 SNPs were shared between cattle populations. The haplotype analysis, which used 13 SNPs located in D-loop, COX2, ND5, CYTB, and non coding regions, revealed that KNC showed clearly different haplotypes that may be used to distinguish KNC from other breeds as well as to characterize individual identifications. The phylogenetic analysis revealed that KNC showed a relatively close genetic distance with Japanese black cattle (JBC) comparing with other breeds. Estimations of the average nucleotide diversity (0.0008) and the ratio of transition/ transversion (0.1050) of KNC were placed somewhere in the middle of genetic diversity among cattle breeds. The identified genetic variants and results of phylogenetic analysis will help understanding the phylogenetic relationships of KNC and provide useful genetic information for further studies regarding SNPs in mtDNA regions.

Genetic characterization of <i>Burkholderia cepacia</i>strain from Northeast India: A potential bio-control agent

This paper reports the characterization of naturally occurring rhizobacteria from NE India for the control of wilt and damping-off diseases in French beans. French bean (Phaseolus vulgaris L.) is one of the most important food legumes for direct human consumption which was originated from South and Central America. In NE India wilt and damping-off in beans are serious diseases which are mainly caused by Fusarium spp and Rhizoctonia solani. Out of 625 bacterial isolates obtained from French bean growing fields of Manipur, 15 potential isolates were selected, whose inhibition zone width were more than 15 mm. Strain IBSD-LKBI exhibited strong antagonistic activity and can inhibit both the pathogens. Besides, this strain also produced extracellular hydrolytic enzymes (protease, chitinase, β-1, 3-glucanase), secondary metabolites (Siderophore, HCN). It also produces plant growth promoting hormone (IAA) and can solubilize organic phosphate. Burkholderia cepacia IBSD-LKBI exhibited the highest plant growth promotion and BCA. After 60 days of treatment, plant height, root length, fresh weight and % of disease suppression were significantly (P Burkholderia cepacia (98%). Multiple sequence alignment & phylogram with closely related sequence accessions using MEGA Software revealed this naturally occurring biocontrol bacteria belongs to Burkholderia cepacia complex genomovar I based on the Biolog identification system with 16S rDNA gene sequence analysis. This organism is one of the new reports from NE India for the control of wilt and damping-off diseases in French beans.

Towards additive manufacturing oriented geometric modeling using implicit functions

Surface-based geometric modeling has many advantages in terms of visualization and traditional subtractive manufacturing using computer-numerical-control cutting-machine tools.However,it is not an ideal solution for additive manufacturing because to digitally print a surface-represented geometric object using a certain additive manufacturing technology,the object has to be converted into a solid representation.However,converting a known surface-based geometric representation into a printable representation is essentially a redesign process,and this is especially the case,when its interior material structure needs to be considered.To specify a 3D geometric object that is ready to be digitally manufactured,its representation has to be in a certain volumetric form.In this research,we show how some of the difficulties experienced in additive manufacturing can be easily solved by using implicitly represented geometric objects.Like surface-based geometric representation is subtractive manufacturing-friendly,implicitly described geometric objects are additive manufacturing-friendly:implicit shapes are 3D printing ready.The implicit geometric representation allows to combine a geometric shape,material colors,an interior material structure,and other required attributes in one single description as a set of implicit functions,and no conversion is needed.In addition,as implicit objects are typically specified procedurally,very little data is used in their specifications,which makes them particularly useful for design and visualization with modern cloud-based mobile devices,which usually do not have very big storage spaces.Finally,implicit modeling is a design procedure that is parallel computing-friendly,as the design of a complex geometric object can be divided into a set of simple shape-designing tasks,owing to the availability of shape-preserving implicit blending operations.

NeoHunter:Flexible software for systematically detecting neoantigens from sequencing data

Complicated molecular alterations in tumors generate various mutant peptides.Some of these mutant peptides can be presented to the cell surface and then elicit immune responses,and such mutant peptides are called neoantigens.Accurate detection of neoantigens could help to design personalized cancer vaccines.Although some computational frameworks for neoantigen detection have been proposed,most of them can only detect SNV-and indel-derived neoantigens.In addition,current frameworks adopt oversimplified neoantigen prioritization strategies.These factors hinder the comprehensive and effective detection of neoantigens.We developed NeoHunter,flexible software to systematically detect and prioritize neoantigens from sequencing data in different formats.NeoHunter can detect not only SNV-and indel-derived neoantigens but also gene fusion-and aberrant splicing-derived neoantigens.NeoHunter supports both direct and indirect immunogenicity evaluation strategies to prioritize candidate neoantigens.These strategies utilize binding characteristics,existing biological big data,and T-cell receptor specificity to ensure accurate detection and prioritization.We applied NeoHunter to the TESLA dataset,cohorts of melanoma and non-small cell lung cancer patients.NeoHunter achieved high performance across the TESLA cancer patients and detected 79%(27 out of 34)of validated neoantigens in total.SNV-and indel-derived neoantigens accounted for 90%of the top 100 candidate neoantigens while neoantigens from aberrant splicing accounted for 9%.Gene fusion-derived neoantigens were detected in one patient.NeoHunter is a powerful tool to‘catch all’neoantigens and is available for free academic use on Github(XuegongLab/NeoHunter).

scEpiTools: a database to comprehensively interrogate analytic tools for single-cell epigenomic data

Recent advances in single-cell sequencing technologies provide significant implications for understanding cellular heterogeneity,developmental biology,and disease mechanisms.To fully exploit the potential of these data,numerous tools have been proposed for upstream and downstream analyses.In the the single-cell RNA sequencing(scRNA-seq)community,scRNA-tools(Zappia et al.,2018)was proposed to help researchers navigate the plethora of tools by category.Since its inception,scRNA-tools has been widely used and its updated version further reveals trends in the field with over 1000 collected tools(Zappia and Theis,2021),providing a valuable guidance in selecting tools for analyses.

Bioinformatics study indicates possible microRNA-regulated pathways in the differentiation of breast cancer

microRNAs (miRNAs) have been reported to be associated with the pathogenesis and progression of breast cancer.However,little is known about the pathways through which miRNAs regulate these processes,e.g.,the interaction between miRNAs and their target genes with regard to different pathological status of breast cancer,such as histological grades.This study investigated the possible roles of miRNAs in the differentiation of histological grades of breast cancer with a computational approach.Based on a microarray dataset,15 candidate miRNAs were identified,whose predicted target genes are enriched as differentially expressed between grade I and grade III breast tumors.Among them,9 key miRNAs focalize their target genes on 6 central signaling pathways.The SMAD7 protein,the main inhibitory protein in the TGF-β pathway,is predicted as a target of several miRNAs and is also regulated by several other pathways that are possibly targeted by miRNAs.It was hypothesized that miRNAs participate in the differentiation of breast cancer and the TGF-β pathway acts as a major implementary pathway on which several miRNAs take effect through multiple channels.The prediction power of the predicted miRNA target genes was validated on three independent datasets.The differential expression of three miRNAs was validated by real-time PCR on breast carcinoma samples of 10 patients.