bluuebunny/crossref_metadata_2025 huggingface dataset:
Significant East Asian Affinity of the Sichuan Hui Genomic Structure Suggests the Predominance of the Cultural Diffusion Model in the Genetic Formation Process
Authors: Liu Yan , Yang Junbao , Li Yingxiang , Tang Renkuan , Yuan Didi , Wang Yicheng , Wang Peixin , Deng Shudan , Zeng Simei , Li Hongliang , Chen Gang , Zou Xing , Wang Mengge , He Guanglin
Published: June 2021

The ancestral origin and genomic history of Chinese Hui people remain to be explored due to the paucity of genome-wide data. Some evidence argues that an eastward migration of Central Asians gave rise to modern Hui people, which is referred to as thedemic diffusion hypothesis; other evidence favors thecultural diffusion hypothesis, which posits that East Asians adopted Muslim culture to form the modern culturally distinct populations. However, the extent to which the observed genetic structure of the Huis was mediated by the movement of people or the assimilation of Muslim culture also remains highly contentious. Analyses of over 700 K SNPs in 109 western Chinese individuals (49 Sichuan Huis and 60 geographically close Nanchong Hans) together with the available ancient and modern Eurasian sequences allowed us to fully explore the genomic makeup and origin of Hui and neighboring Han populations. The results from PCA, ADMIXTURE, and allele-sharing-basedf-statistics revealed a strong genomic affinity between Sichuan Huis and Neolithic-to-modern Northern East Asians, which suggested a massive gene influx from East Asians into the Sichuan Hui people. Three-way admixture models in theqpWave/qpAdmanalyses further revealed a small stream of gene influx from western Eurasians into the Sichuan Hui people, which was further directly confirmed via the admixture event from the temporally distinct Western sources to Sichuan Hui people in theqpGraph-based phylogenetic model, suggesting the key role of the cultural diffusion model in the genetic formation of the Sichuan Huis. ALDER-based admixture date estimation showed that this observed western Eurasian admixture signal was introduced into the Sichuan Huis during the historic periods, which was concordant with the extensive western–eastern communication along the Silk Road and historically documented Huis' migration history. In summary, although significant cultural differentiation exists between Hui people and their neighbors, our genomic analysis showed their strong genetic affinity with modern and ancient Northern East Asians. Our results support the hypothesis that the Sichuan Huis arose from a mixture of minor western Eurasian ancestry and predominant East Asian ancestry.
Predicting the Risk Genes of Autism Spectrum Disorders
Authors: Lin Yenching , Yerukala Sathipati Srinivasulu , Ho Shinn-Ying
Published: June 2021

Autism spectrum disorder (ASD) refers to a wide spectrum of neurodevelopmental disorders that emerge during infancy and continue throughout a lifespan. Although substantial efforts have been made to develop therapeutic approaches, core symptoms persist lifelong in ASD patients. Identifying the brain temporospatial regions where the risk genes are expressed in ASD patients may help to improve the therapeutic strategies. Accordingly, this work aims to predict the risk genes of ASD and identify the temporospatial regions of the brain structures at different developmental time points for exploring the specificity of ASD gene expression in the brain that would help in possible ASD detection in the future. A dataset consisting of 13 developmental stages ranging from 8 weeks post-conception to 8 years from 26 brain structures was retrieved from the BrainSpan atlas. This work proposes a support vector machine–based risk gene prediction method ASD-Risk to distinguish the risk genes of ASD and non-ASD genes. ASD-Risk used an optimal feature selection algorithm called inheritable bi-objective combinatorial genetic algorithm to identify the brain temporospatial regions for prediction of the risk genes of ASD. ASD-Risk achieved a 10-fold cross-validation accuracy, sensitivity, specificity, area under a receiver operating characteristic curve, and a test accuracy of 81.83%, 0.84, 0.79, 0.84, and 72.27%, respectively. We prioritized the temporospatial features according to their contribution to the prediction accuracy. The top identified temporospatial regions of the brain for risk gene prediction included the posteroventral parietal cortex at 13 post-conception weeks feature. The identified temporospatial features would help to explore the risk genes that are specifically expressed in different brain regions of ASD patients.
Challenges, Strategies, and Perspectives for Reference-Independent Longitudinal Multi-Omic Microbiome Studies
Authors: Martínez Arbas Susana , Busi Susheel Bhanu , Queirós Pedro , de Nies Laura , Herold Malte , May Patrick , Wilmes Paul , Muller Emilie E. L. , Narayanasamy Shaman
Published: June 2021

In recent years, multi-omic studies have enabled resolving community structure and interrogating community function of microbial communities. Simultaneous generation of metagenomic, metatranscriptomic, metaproteomic, and (meta) metabolomic data is more feasible than ever before, thus enabling in-depth assessment of community structure, function, and phenotype, thus resulting in a multitude of multi-omic microbiome datasets and the development of innovative methods to integrate and interrogate those multi-omic datasets. Specifically, the application of reference-independent approaches provides opportunities in identifying novel organisms and functions. At present, most of these large-scale multi-omic datasets stem from spatial sampling (e.g., water/soil microbiomes at several depths, microbiomes in/on different parts of the human anatomy) or case-control studies (e.g., cohorts of human microbiomes). We believe that longitudinal multi-omic microbiome datasets are the logical next step in microbiome studies due to their characteristic advantages in providing a better understanding of community dynamics, including: observation of trends, inference of causality, and ultimately, prediction of community behavior. Furthermore, the acquisition of complementary host-derived omics, environmental measurements, and suitable metadata will further enhance the aforementioned advantages of longitudinal data, which will serve as the basis to resolve drivers of community structure and function to understand the biotic and abiotic factors governing communities and specific populations. Carefully setup future experiments hold great potential to further unveil ecological mechanisms to evolution, microbe-microbe interactions, or microbe-host interactions. In this article, we discuss the challenges, emerging strategies, and best-practices applicable to longitudinal microbiome studies ranging from sampling, biomolecular extraction, systematic multi-omic measurements, reference-independent data integration, modeling, and validation.
Genetics of Ankylosing Spondylitis—Focusing on the Ethnic Difference Between East Asia and Europe
Authors: Wu Xin , Wang Geng , Zhang Luding , Xu Huji
Published: June 2021

Ankylosing spondylitis (AS) is a common, highly heritable inflammatory arthritis affecting the mainly axial joints in both East Asia and Europe. To date, the pathogenesis of AS is still unknown, although we know that genetics play a vital role in it. The HLA-B27 allele is found in over 85% of AS patients. However, strong evidence suggests that other major histocompatibility complex (MHC) and non-MHC genes are also involved in the pathogenesis. In addition, current data showed that there were significant differences in both genomics and metagenomics among the different ethnic populations. The investigation of the key role of the microbiome in AS pathogenesis also highlighted the host–microbiome genetic interactions. Here, we systematically review current AS genetic research data and further compare genetic differences, especially between East Asian and European groups, which may highlight the challenge in future genetic studies.
The Genetics of Adverse Drug Outcomes in Type 2 Diabetes: A Systematic Review
Authors: Baye Assefa M. , Fanta Teferi G. , Siddiqui Moneeza K. , Dawed Adem Y.
Published: June 2021

Background: Adverse drug reactions (ADR) are a major clinical problem accounting for significant hospital admission rates, morbidity, mortality, and health care costs. One-third of people with diabetes experience at least one ADR. However, there is notable interindividual heterogeneity resulting in patient harm and unnecessary medical costs. Genomics is at the forefront of research to understand interindividual variability, and there are many genotype-drug response associations in diabetes with inconsistent findings. Here, we conducted a systematic review to comprehensively examine and synthesize the effect of genetic polymorphisms on the incidence of ADRs of oral glucose-lowering drugs in people with type 2 diabetes.

Methods: A literature search was made to identify articles that included specific results of research on genetic polymorphism and adverse effects associated with oral glucose-lowering drugs. The electronic search was carried out on 3rd October 2020, through Cochrane Library, PubMed, and Web of Science using keywords and MeSH terms.

Result: Eighteen articles consisting of 10, 383 subjects were included in this review. Carriers of reduced-function alleles of organic cation transporter 1 (OCT 1, encoded by SLC22A1) or reduced expression alleles of plasma membrane monoamine transporter (PMAT, encoded by SLC29A4) or serotonin transporter (SERT, encoded by SLC6A4) were associated with increased incidence of metformin-related gastrointestinal (GI) adverse effects. These effects were shown to exacerbate by concomitant treatment with gut transporter inhibiting drugs. The CYP2C9 alleles, *2 (rs1799853C>T) and *3 (rs1057910A>C) that are predictive of low enzyme activity were more common in subjects who experienced hypoglycemia after treatment with sulfonylureas. However, there was no significant association between sulfonylurea-related hypoglycemia and genetic variants in the ATP-binding cassette transporter sub-family C member 8 (ABCC8)/Potassium Inwardly Rectifying Channel Subfamily J Member 11 (KCNJ11). Compared to the wild type, the low enzyme activity C allele at CYP2C8*3 (rs1057910A>C) was associated with less weight gain whereas the C allele at rs6123045 in the NFATC2 gene was significantly associated with edema from rosiglitazone treatment.

Conclusion: In spite of limited studies investigating genetics and ADR in diabetes, some convincing results are emerging. Genetic variants in genes encoding drug transporters and metabolizing enzymes are implicated in metformin-related GI adverse effects, and sulfonylurea-induced hypoglycemia, respectively. Further studies to investigate newer antidiabetic drugs such as DPP-4i, GLP-1RA, and SGLT2i are warranted. In addition, pharmacogenetic studies that account for race and ethnic differences are required.
A Combined RNA Signature Predicts Recurrence Risk of Stage I-IIIA Lung Squamous Cell Carcinoma
Authors: Sun Li , Li Juan , Li Xiaomeng , Yang Xuemei , Zhang Shujun , Wang Xue , Wang Nan , Xu Kanghong , Jiang Xinquan , Zhang Yi
Published: June 2021

Objective

Recurrence remains the main cause of the poor prognosis in stage I-IIIA lung squamous cell carcinoma (LUSC) after surgical resection. In the present study, we aimed to identify the long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) related to the recurrence of stage I-IIIA LUSC. Moreover, we constructed a risk assessment model to predict the recurrence of LUSC patients.

Methods

RNA sequencing data (including miRNAs, lncRNAs, and mRNAs) and relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) database. The differentially expressed lncRNAs, miRNAs, and mRNAs were identified using the “DESeq2” package of the R language. Univariate Cox proportional hazards regression analysis and Kaplan-Meier curve were used to identify recurrence-related genes. Stepwise multivariate Cox regression analysis was carried out to establish a risk model for predicting recurrence in the training cohort. Moreover, Kaplan-Meier curves and receiver operating characteristic (ROC) curves were adopted to examine the predictive performance of the signature in the training cohort, validation cohort, and entire cohort.

Results

Based on the TCGA database, we analyzed the differentially expressed genes (DEGs) among 27 patients with recurrent stage I-IIIA LUSC and 134 patients with non-recurrent stage I-IIIA LUSC, and identified 431 lncRNAs, 36 miRNAs, and 746 mRNAs with different expression levels. Out of these DEGs, the optimal combination of DEGs was finally determined, and a nine-joint RNA molecular signature was constructed for clinical prediction of recurrence, including LINC02683, AC244517.5, LINC02418, LINC01322, AC011468.3, hsa-mir-6825, AC020637.1, AC027117.2, and SERPINB12. The ROC curve proved that the model had good predictive performance in predicting recurrence. The area under the curve (AUC) of the prognostic model for recurrence-free survival (RFS) was 0.989 at 3 years and 0.958 at 5 years (in the training set). The combined RNA signature also revealed good predictive performance in predicting the recurrence in the validation cohort and entire cohort.

Conclusions

In the present study, we constructed a nine-joint RNA molecular signature for recurrence prediction of stage I-IIIA LUSC. Collectively, our findings provided new and valuable clinical evidence for predicting the recurrence and targeted treatment of stage I-IIIA LUSC.
Genomic Landscape of Head and Neck Squamous Cell Carcinoma Across Different Anatomic Sites in Chinese Population
Authors: Ju Yunhe , Wu Xingrao , Wang Huizhen , Li Bin , Long Qing , Zhang Dadong , Chen Hao , Xiao Nianqing , Li Fugen , Zhang Shiwen , Yang Shenggang
Published: June 2021

Background

The characteristics of head and neck squamous cell carcinoma (HNSCC) across different anatomic sites in the Chinese population have not been studied. To determine the genomic abnormalities underlying HNSCC across different anatomic sites, the alterations of selected cancer-related genes were evaluated.

Methods

Genomic DNA samples obtained from formalin-fixed, paraffin-embedded tissues were analyzed using targeted sequencing in a panel of 383 cancer-related genes to determine the genomic alterations.

Results

A total of 317 formalin-fixed, paraffin-embedded HNSCC specimens were collected, and a total of 2,156 protein-coding mutations, including 1,864 single nucleotide variants and 292 insertions and deletions, were identified across more than six different anatomic sites. Mutation loads were distinct across the anatomic sites. Larynx carcinoma was found with the highest mutation loads, whereas nasopharynx carcinoma showed the lowest mutation loads. A total of 1,110 gains and 775 losses were identified in the 317 specimens. Patients who had at least one clinically actionable alteration (levels 1–4 in OncoKB) were identified. One patient had an actionable alteration with level 1 evidence in OncoKB, TEX10-NTRK2 fusion, who may benefit from larotrectinib or entrectinib treatment.

Conclusion

The genomic profiling of HNSCC using targeted sequencing can identify rational therapeutic candidate genes suitable for the treatment of the HNSCCs.
De novo Transcriptome Sequencing Coupled With Co-expression Analysis Reveal the Transcriptional Regulation of Key Genes Involved in the Formation of Active Ingredients in Peucedanum praeruptorum Dunn Under Bolting Period
Authors: Song Cheng , Li Xiaoli , Jia Bin , Liu Li , Ou Jinmei , Han Bangxing
Published: June 2021

Peucedanum praeruptorum Dunn is a perennial and one-off flowering plant of the Peucedanum genus in Umbelliferae. The cultivated P. praeruptorum Dunn usually grows nutritionally in the first year and then moves into the reproductive growth in the second year. The lignification of the roots caused by bolting leads to the quality decline of crude materials. Since most of the previous studies have dealt with coumarin biosynthesis and identification of functional genes in P. praeruptorum, the scientific connotation of the inability that the bolted P. praeruptorum cannot be used medically is still unclear. Here, we employed a transcriptome sequencing combined with coexpression analysis to unearth the regulation mechanism of key genes related to coumarin synthesis in pre- and postbolting period, and to explore the mechanisms underlying the effects of bolting on the formation and transport of coumarins between the annual and biennial plants. Six cDNA libraries were constructed, and the transcripts were sequenced and assembled by Illumina Hiseq platform. A total of 336,505 unigenes were obtained from 824,129 non-redundant spliced transcripts. Unigenes (114,488) were annotated to the NCBI nr database, 119,017 and 10,475 unigenes were aligned to Gene Ontology (GO) functional groups and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, respectively. Differential expression analysis screened out a series of upregulated and downregulated genes related to the phenylpropanoid pathway. The heatmap clustering showed that the similar expression patterns were both observed in groups C vs. D and groups C vs. F. The WGCNA-based coexpression was performed to elucidate the module and trait relationship to unearth important genes related to the bolting process. Seven pivotal modules on the KEGG functional annotations suggested these genes were mainly enriched in the process of plant–pathogen interaction, plant hormone signal transduction, MAPK signaling pathway, α-linolenic acid metabolism, circadian rhythm, and phenylpropanoid pathway. Further analysis provided clues that the key genes of the phenylpropanoid pathway, the ABC transporters, the apoptosis-related and circadian rhythm regulatory genes may play pivotal roles in regulating bolting signaling, biosynthesis, and transportation of coumarins.
Immune Response to Therapeutic Staphylococcal Bacteriophages in Mammals: Kinetics of Induction, Immunogenic Structural Proteins, Natural and Induced Antibodies
Authors: Kaźmierczak Zuzanna , Majewska Joanna , Miernikiewicz Paulina , Międzybrodzki Ryszard , Nowak Sylwia , Harhala Marek , Lecion Dorota , Kęska Weronika , Owczarek Barbara , Ciekot Jarosław , Drab Marek , Kędzierski Paweł , Mazurkiewicz-Kania Marta , Górski Andrzej , Dąbrowska Krystyna
Published: June 2021

Bacteriophages are able to affect the human immune system. Phage-specific antibodies are considered as major factors shaping phage pharmacokinetics and bioavailability. So far, general knowledge of phage antigenicity nevertheless remains extremely limited. Here we present comparative studies of immunogenicity in two therapeutic bacteriophages, A3R and 676Z, active againstStaphylococcus aureus, routinely applied in patients at the Phage Therapy Unit, Poland. Comparison of the overall ability of whole phages to induce specific antibodies in a murine model revealed typical kinetics of IgM and IgG induction by these two phages. In further studies we identified the location of four phage proteins in the virions, with the focus on the external capsid head (Mcp) or tail sheath (TmpH) or an unidentified precise location (ORF059 and ORF096), and we confirmed their role as structural proteins of these viruses. Next, we compared the immune response elicited by these proteins after phage administration in mice. Similar to that in T4 phage, Mcp was the major element of the capsid that induced specific antibodies. Studies of protein-specific sera revealed that antibodies specific to ORF096 were able to neutralize antibacterial activity of the phages. In humans (population level), none of the studied proteins plays a particular role in the induction of specific antibodies; thus none potentially affects in a particular way the effectiveness of A3R and 676Z. Also in patients subjected to phage therapy, we did not observe increased specific immune responses to the investigated proteins.
TLR2 Regulates Mast Cell IL-6 and IL-13 Production During Listeria monocytogenes Infection
Authors: Soria-Castro Rodolfo , Alfaro-Doblado Ángel R. , Rodríguez-López Gloria , Campillo-Navarro Marcia , Meneses-Preza Yatsiri G. , Galán-Salinas Adrian , Alvarez-Jimenez Violeta , Yam-Puc Juan C. , Munguía-Fuentes Rosario , Domínguez-Flores Adriana , Estrada-Parra Sergio , Pérez-Tapia Sonia M. , Chávez-Blanco Alma D. , Chacón-Salinas Rommel
Published: June 2021

Listeria monocytogenes (L.m) is efficiently controlled by several cells of the innate immunity, including the Mast Cell (MC). MC is activated by L.m inducing its degranulation, cytokine production and microbicidal mechanisms. TLR2 is required for the optimal control of L.m infection by different cells of the immune system. However, little is known about the MC receptors involved in recognizing this bacterium and whether these interactions mediate MC activation. In this study, we analyzed whether TLR2 is involved in mediating different MC activation responses during L.m infection. We found that despite MC were infected with L.m, they were able to clear the bacterial load. In addition, MC degranulated and produced ROS, TNF-α, IL-1β, IL-6, IL-13 and MCP-1 in response to bacterial infection. Interestingly, L.m induced the activation of signaling proteins: ERK, p38 and NF-κB. When TLR2 was blocked, L.m endocytosis, bactericidal activity, ROS production and mast cell degranulation were not affected. Interestingly, only IL-6 and IL-13 production were affected when TLR2 was inhibited in response to L.m infection. Furthermore, p38 activation depended on TLR2, but not ERK or NF-κB activation. These results indicate that TLR2 mediates only some MC activation pathways during L.m infection, mainly those related to IL-6 and IL-13 production.
Neutrophil Extracellular Traps Induce the Epithelial-Mesenchymal Transition: Implications in Post-COVID-19 Fibrosis
Authors: Pandolfi Laura , Bozzini Sara , Frangipane Vanessa , Percivalle Elena , De Luigi Ada , Violatto Martina Bruna , Lopez Gianluca , Gabanti Elisa , Carsana Luca , D’Amato Maura , Morosini Monica , De Amici Mara , Nebuloni Manuela , Fossali Tommaso , Colombo Riccardo , Saracino Laura , Codullo Veronica , Gnecchi Massimiliano , Bigini Paolo , Baldanti Fausto , Lilleri Daniele , Meloni Federica
Published: June 2021

The release of neutrophil extracellular traps (NETs), a process termed NETosis, avoids pathogen spread but may cause tissue injury. NETs have been found in severe COVID-19 patients, but their role in disease development is still unknown. The aim of this study is to assess the capacity of NETs to drive epithelial-mesenchymal transition (EMT) of lung epithelial cells and to analyze the involvement of NETs in COVID-19. Bronchoalveolar lavage fluid of severe COVID-19 patients showed high concentration of NETs that correlates with neutrophils count; moreover, the analysis of lung tissues of COVID-19 deceased patients showed a subset of alveolar reactive pneumocytes with a co-expression of epithelial marker and a mesenchymal marker, confirming the induction of EMT mechanism after severe SARS-CoV2 infection. By airway in vitro models, cultivating A549 or 16HBE at air-liquid interface, adding alveolar macrophages (AM), neutrophils and SARS-CoV2, we demonstrated that to trigger a complete EMT expression pattern are necessary the induction of NETosis by SARS-CoV2 and the secretion of AM factors (TGF-β, IL8 and IL1β). All our results highlight the possible mechanism that can induce lung fibrosis after SARS-CoV2 infection.
Genetic Analysis of Tryptophan Metabolism Genes in Sporadic Amyotrophic Lateral Sclerosis
Authors: Fifita Jennifer A. , Chan Moi Fat Sandrine , McCann Emily P. , Williams Kelly L. , Twine Natalie A. , Bauer Denis C. , Rowe Dominic B. , Pamphlett Roger , Kiernan Matthew C. , Tan Vanessa X. , Blair Ian P. , Guillemin Gilles J.
Published: June 2021

The essential amino acid tryptophan (TRP) is the initiating metabolite of the kynurenine pathway (KP), which can be upregulated by inflammatory conditions in cells. Neuroinflammation-triggered activation of the KP and excessive production of the KP metabolite quinolinic acid are common features of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). In addition to its role in the KP, genes involved in TRP metabolism, including its incorporation into proteins, and synthesis of the neurotransmitter serotonin, have also been genetically and functionally linked to these diseases. ALS is a late onset neurodegenerative disease that is classified as familial or sporadic, depending on the presence or absence of a family history of the disease. Heritability estimates support a genetic basis for all ALS, including the sporadic form of the disease. However, the genetic basis of sporadic ALS (SALS) is complex, with the presence of multiple gene variants acting to increase disease susceptibility and is further complicated by interaction with potential environmental factors. We aimed to determine the genetic contribution of 18 genes involved in TRP metabolism, including protein synthesis, serotonin synthesis and the KP, by interrogating whole-genome sequencing data from 614 Australian sporadic ALS cases. Five genes in the KP (AFMID, CCBL1, GOT2, KYNU, HAAO) were found to have either novel protein-altering variants, and/or a burden of rare protein-altering variants in SALS cases compared to controls. Four genes involved in TRP metabolism for protein synthesis (WARS) and serotonin synthesis (TPH1, TPH2, MAOA) were also found to carry novel variants and/or gene burden. These variants may represent ALS risk factors that act to alter the KP and lead to neuroinflammation. These findings provide further evidence for the role of TRP metabolism, the KP and neuroinflammation in ALS disease pathobiology.
Genome-Wide Characterization of the Nuclear Receptor Gene Family in Macrostomum lignano Imply Its Evolutionary Diversification
Authors: Cheng Yunying , Chen Jinlin , Mukhtar Irum , Chen Jianming
Published: June 2021

Nuclear receptors (NRs), a series of key transcription factors that are mostly activated by endogenous ligands or environmental xenobiotics, are reportedly good phylogenetic markers of animal genome evolution. As the early diverging class of bilaterians, however, a comprehensive view of the NR family in a marine free-living flatworm Macrostomum lignano and comparative information in flatworms are still lacking, which is of significance to address the evolutionary diversification of the NR family and imply the adaptive evolution in the early diverging Bilateria. Herein, a total of 51, 26, and 23 putative NR genes were identified in M. lignano, Sparganum proliferum, and Clonorchis sinensis, respectively, which were classified into eight subfamilies, implying an extensive expansion of the NR family in M. lignano. It is presumed that the extensive expansion was mainly attributed to the M. lignano-specific hidden polyploidy, segmental, and tandem duplication events. The duplicated NR pairs in M. lignano and the NR orthologs in flatworms all experienced the purifying selection. Phylogenetic analyses indicated the presence of NR3-like genes in M. lignano, which is first reported in flatworms. Intron loss and reduced intron size were mainly contributed to the structural divergence of NR genes in flatworms. The combined data provide indispensable information for a better understanding of the complexity and the adaptive evolution of the NR gene family in metazoans.
Next-Generation Sequencing of Cell-Free DNA Extracted From Pleural Effusion Supernatant: Applications and Challenges
Authors: Patel Ami , Hissong Erika , Rosado Lucelina , Burkhardt Robert , Cong Lin , Alperstein Susan A. , Siddiqui Momin T. , Park Hyeon Jin , Song Wei , Velu Priya D. , Rennert Hanna , Heymann Jonas J.
Published: June 2021

Cell-free DNA (cfDNA) extracted from diverse specimen types has emerged as a high quality substrate for molecular tumor profiling. Analytical and pre-analytical challenges in the utilization of cfDNA extracted from pleural effusion supernatant (PES) are herein characterized in patients with metastatic non-small cell lung carcinoma (NSCLC). Pleural effusion specimens containing metastatic NSCLC were collected prospectively. After ThinPrep® (TP) and cell block (CB) preparation, DNA was extracted from residual PES and analyzed by gel electrophoresis for quality and quantity. Libraries were prepared and sequenced with a targeted next-generation sequencing (NGS) platform and panel clinically validated for plasma specimens. Results were compared with DNA extracted from corresponding FFPE samples that were sequenced using institutional targeted NGS assays clinically validated for solid tumor FFPE samples. Tumor (TC) and overall cellularity (OC) were evaluated. Fourteen specimens were collected from 13 patients. Median specimen volume was 180 mL (range, 35–1,400 mL). Median TC and OC on TP slides and CB sections were comparable. Median extracted DNA concentration was 7.4 ng/μL (range, 0.1–58.0 ng/μL), with >5 ng/μL DNA extracted from 10/14 specimens (71%). Mutations were identified in 10/14 specimens, including 1/3 specimens with median molecular coverage <1,000 reads. The minimal detected allelic fraction was 0.6%. NGS was falsely negative for the presence of one driver mutation. No correlation was identified between sample volume or OC, quality or quantity of extracted DNA, or mutation detection. Despite analytical and pre-analytical challenges, PES represents a robust source of DNA for NGS.
Viral Biomarkers for Hepatitis B Virus-Related Hepatocellular Carcinoma Occurrence and Recurrence
Authors: Liu Yuanyuan , Veeraraghavan Vaishnavi , Pinkerton Monica , Fu Jianjun , Douglas Mark W. , George Jacob , Tu Thomas
Published: June 2021

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the fourth leading cause of cancer-related death. The most common risk factor for developing HCC is chronic infection with hepatitis B virus (HBV). Early stages of HBV-related HCC (HBV-HCC) are generally asymptomatic. Moreover, while serum alpha-fetoprotein (AFP) and abdominal ultrasound are widely used to screen for HCC, they have poor sensitivity. Thus, HBV-HCC is frequently diagnosed at an advanced stage, in which there are limited treatment options and high mortality rates. Serum biomarkers with high sensitivity and specificity are crucial for earlier diagnosis of HCC and improving survival rates. As viral–host interactions are key determinants of pathogenesis, viral biomarkers may add greater diagnostic power for HCC than host biomarkers alone. In this review, we summarize recent research on using virus-derived biomarkers for predicting HCC occurrence and recurrence; including circulating viral DNA, RNA transcripts, and viral proteins. Combining these viral biomarkers with AFP and abdominal ultrasound could improve sensitivity and specificity of early diagnosis, increasing the survival of patients with HBV-HCC. In the future, as the mechanisms that drive HBV-HCC to become clearer, new biomarkers may be identified which can further improve early diagnosis of HBV-HCC.
Comparative Genomic Insights Into the Taxonomic Classification, Diversity, and Secondary Metabolic Potentials of Kitasatospora, a Genus Closely Related to Streptomyces
Authors: Li Yisong , Wang Meng , Sun Zhong-Zhi , Xie Bin-Bin
Published: June 2021

While the genusStreptomyces(familyStreptomycetaceae) has been studied as a model for bacterial secondary metabolism and genetics, its close relatives have been less studied. The genusKitasatosporais the second largest genus in the familyStreptomycetaceae. However, its taxonomic position within the family remains under debate and the secondary metabolic potential remains largely unclear. Here, we performed systematic comparative genomic and phylogenomic analyses ofKitasatospora.Firstly, the three genera within the familyStreptomycetaceae(Kitasatospora, Streptomyces, andStreptacidiphilus) showed common genomic features, including high G + C contents, high secondary metabolic potentials, and high recombination frequencies. Secondly, phylogenomic and comparative genomic analyses revealed phylogenetic distinctions and genome content differences among these three genera, supportingKitasatosporaas a separate genus within the family. Lastly, the pan-genome analysis revealed extensive genetic diversity within the genusKitasatospora, while functional annotation and genome content comparison suggested genomic differentiation among lineages. This study provided new insights into genomic characteristics of the genusKitasatospora, and also uncovered its previously underestimated and complex secondary metabolism.
Temporal Integration of Text Transcripts and Acoustic Features for Alzheimer's Diagnosis Based on Spontaneous Speech
Authors: Martinc Matej , Haider Fasih , Pollak Senja , Luz Saturnino
Published: June 2021

Background:Advances in machine learning (ML) technology have opened new avenues for detection and monitoring of cognitive decline. In this study, a multimodal approach to Alzheimer's dementia detection based on the patient's spontaneous speech is presented. This approach was tested on a standard, publicly available Alzheimer's speech dataset for comparability. The data comprise voice samples from 156 participants (1:1 ratio of Alzheimer's to control), matched by age and gender.

Materials and Methods:A recently developed Active Data Representation (ADR) technique for voice processing was employed as a framework for fusion of acoustic and textual features at sentence and word level. Temporal aspects of textual features were investigated in conjunction with acoustic features in order to shed light on the temporal interplay between paralinguistic (acoustic) and linguistic (textual) aspects of Alzheimer's speech. Combinations between several configurations of ADR features and more traditional bag-of-n-grams approaches were used in an ensemble of classifiers built and evaluated on a standardised dataset containing recorded speech of scene descriptions and textual transcripts.

Results:Employing only semantic bag-of-n-grams features, an accuracy of 89.58% was achieved in distinguishing between Alzheimer's patients and healthy controls. Adding temporal and structural information by combining bag-of-n-grams features with ADR audio/textual features, the accuracy could be improved to 91.67% on the test set. An accuracy of 93.75% was achieved through late fusion of the three best feature configurations, which corresponds to a 4.7% improvement over the best result reported in the literature for this dataset.

Conclusion:The proposed combination of ADR audio and textual features is capable of successfully modelling temporal aspects of the data. The machine learning approach toward dementia detection achieves best performance when ADR features are combined with strong semantic bag-of-n-grams features. This combination leads to state-of-the-art performance on the AD classification task.
Mind-Body Exercise Modulates Locus Coeruleus and Ventral Tegmental Area Functional Connectivity in Individuals With Mild Cognitive Impairment
Authors: Liu Jiao , Tao Jing , Xia Rui , Li Moyi , Huang Maomao , Li Shuzhen , Chen Xiangli , Wilson Georgia , Park Joe , Zheng Guohua , Chen Lidian , Kong Jian
Published: June 2021

Mild cognitive impairment (MCI) is a common global health problem. Recently, the potential of mind-body intervention for MCI has drawn the interest of investigators. This study aims to comparatively explore the modulation effect of Baduanjin, a popular mind-body exercise, and physical exercise on the cognitive function, as well as the norepinephrine and dopamine systems using the resting state functional connectivity (rsFC) method in patients with MCI. 69 patients were randomized to the Baduanjin, brisk walking, or healthy education control group for 6 months. The Montreal Cognitive Assessment (MoCA) and magnetic resonance imaging (MRI) scans were applied at baseline and at the end of the experiment. Results showed that (1) compared to the brisk walking, the Baduanjin significantly increased MoCA scores; (2) Baduanjin significantly increased the right locus coeruleus (LC) and left ventral tegmental area (VTA) rsFC with the right insula and right amygdala compared to that of the control group; and the right anterior cingulate cortex (ACC) compared to that of the brisk walking group; (3) the increased right LC-right insula rsFC and right LC-right ACC rsFC were significantly associated with the corresponding MoCA score after 6-months of intervention; (4) both exercise groups experienced an increased effective connectivity from the right ACC to the left VTA compared to the control group; and (5) Baduanjin group experienced an increase in gray matter volume in the right ACC compared to the control group. Our results suggest that Baduanjin can significantly modulate intrinsic functional connectivity and the influence of the norepinephrine (LC) and dopamine (VTA) systems. These findings may shed light on the mechanisms of mind-body intervention and aid the development of new treatments for MCI.
Head Injury Exposure in Veterans Presenting to Memory Disorders Clinic: An Observational Study of Clinical Characteristics and Relationship of Event-Related Potentials and Imaging Markers
Authors: Turk Katherine W. , Marin Anna , Schiloski Kylie A. , Vives-Rodriguez Ana L. , Uppal Prayerna , Suh Cheongmin , Dwyer Brigid , Palumbo Rocco , Budson Andrew E.
Published: June 2021

Objective: Traumatic brain injury (TBI) and repetitive head impacts (RHI) related to blasts or contact sports are commonly reported among military service members. However, the clinical implications of remote TBI and RHI in veterans remains a challenge when evaluating older veterans at risk of neurodegenerative conditions including Alzheimer's disease (AD) and Chronic Traumatic Encephalopathy (CTE). This study aimed to test the hypothesis that veterans in a memory disorders clinic with remote head injury would be more likely to have neurodegenerative clinical diagnoses, increased rates of amyloid PET positivity, higher prevalence of cavum septum pellucidi/vergae, and alterations in event-related potential (ERP) middle latency auditory evoked potentials (MLAEPs) and long latency ERP responses compared to those without head injuries.

Methods: Older veterans aged 50–100 were recruited from a memory disorders clinic at VA Boston Healthcare system with a history of head injury (n = 72) and without head injury history (n = 52). Patients were classified as reporting prior head injury including TBI and/or RHI exposure based on self-report and chart review. Participants underwent MRI to determine presence/absence of cavum and an ERP auditory oddball protocol.

Results: The head injury group was equally likely to have a positive amyloid PET compared to the non-head injury group. Additionally, the head injury group were less likely to have a diagnosis of a neurodegenerative condition than those without head injury. P200 target amplitude and MLAEP amplitudes for standard and target tones were decreased in the head injury group compared to the non-head injury group while P3b amplitude did not differ.

Conclusions: Veterans with reported remote head injury evaluated in a memory disorders clinic were not more likely to have a neurodegenerative diagnosis or imaging markers of neurodegeneration than those without head injury. Decreased P200 target and MLAEP target and standard tone amplitudes in the head injury group may be relevant as potential diagnostic markers of remote head injury.
Behavioural Features of Cerebral Visual Impairment Are Common in Children With Down Syndrome
Authors: Wilton Gemma J. , Woodhouse Rhodri , Vinuela-Navarro Valldeflors , England Rachel , Woodhouse J. Margaret
Published: June 2021

It is widely recognised that children with Down syndrome have a broad range and a high prevalence of visual deficits and it has been suggested that those with Down syndrome are more likely to exhibit visual perception deficits indicative of cerebral visual impairment. This exploratory study aims to determine the prevalence of behavioural features suggestive of cerebral visual impairment (CVI) occurring with Down syndrome and whether the visual problems can be ascribed to optometric factors. A cohort of 226 families of children with Down syndrome (trisomy 21), aged 4–17, were invited to participate in a validated question inventory, to recognise visual perception issues. The clinical records of the participants were then reviewed retrospectively. A five-question screening instrument was used to indicate suspected CVI. The majority of the 81 families who responded to the questionnaire reported some level of visual perceptual difficulty in their child. Among this cohort, the prevalence of suspected CVI as indicated by the screening questionnaire was 38%. Only ametropia was found to have a significant association with suspected CVI, although this increased the correct prediction of suspected CVI outcome by only a small amount. Results suggest that children with Down syndrome are more likely to experience problems consistent with cerebral visual impairment, and that these may originate from a similar brain dysfunction to that which contributes to high levels of ametropia and failure to emmetropise. It is important that behavioural features of CVI are recognised in children with Down syndrome, further investigations initiated and appropriate management applied.
A Novel Inflammatory-Nutritional Prognostic Scoring System for Stage III Gastric Cancer Patients With Radical Gastrectomy Followed by Adjuvant Chemotherapy
Authors: Wang Nan , Xi Wenqi , Lu Sheng , Jiang Jinling , Wang Chao , Zhu Zhenglun , Yan Chao , Liu Jing , Zhang Jun
Published: June 2021

Purpose

The present study was designed to explore the prognostic value of preoperative inflammatory and nutritional biomarkers in stage III gastric cancer (GC) patients with adjuvant chemotherapy and to develop a novel scoring system called the inflammatory-nutritional prognostic score (INPS).

Methods

A total of 513 patients with pathological stage III GC undergoing radical gastrectomy followed by adjuvant chemotherapy from 2010 to 2017 were enrolled in the study. Clinicopathological characteristics and blood test parameters of individual patients were collected. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used for feature selection to construct INPS. Survival curves were generated using the Kaplan-Meier method with log-rank tests. The nomogram was generated based on the result of the multivariate analysis using Cox’s proportional hazards model. The model was assessed by the concordance index (C-index) and was internally validated by bootstraps.

Results

According to the results of Lasso Cox regression and K-M survival curves, INPS was determined as follows: a low body mass index (BMI) (<23 kg/m2), a low prealbumin (<180 mg/L), a high neutrophil-lymphocyte ratio (NLR) (≥2.7), a high platelet-lymphocyte ratio (PLR) (≥209.4), a low lymphocyte-monocyte ratio (LMR) (<2.8), and a low prognostic nutritional index (PNI) (<45.1); each were scored as 1, and the remaining values were scored as 0. The individual scores were then summed up to construct the INPS and further divided into 4 groups: Low Risk (INPS 0); Low-medium Risk (INPS 1); High-medium Risk (INPS 2-4); and High Risk (INPS 5-6). In multivariate analysis, INPS was an independent predictor of overall survival (OS) in stage III GC, with the 5-year OS rates of 70.8%, 57.4%, 41.5%, and 30.6%, respectively. The nomogram based on INPS and other independent predictors (gender, pT stage, pN stage, lymphovascular invasion, and CEA level) showed good predicting performance with a C-index of 0.707, which was superior to the TNM stage alone (C-index 0.645, p=0.008) and was internally validated with the corrected C-index of 0.693.

Conclusion

Preoperative INPS was an independent prognostic factor of stage III GC patients with radical surgery followed by adjuvant chemotherapy. The nomogram based on INPS may serve as a simple and potential model in risk stratification and guiding treatment strategies in clinical practice.
siRNAs Targeting Mouse-Specific lncRNA AA388235 Induce Human Tumor Cell Pyroptosis/Apoptosis
Authors: Chen Yan-Ru , Feng Wan-Ying , Cheng Yuan-Xiong , Zhu Hao , Liu Hong-Juan , Gao Yi , Zhou Wei-Jie
Published: June 2021

Species-specific lncRNAs significantly determine species-specific functions through various ways, such as epigenetic regulation. However, there has been no study focusing on the role of species-specific lncRNAs in other species yet. Here, we found that siRNAs targeting mouse-specific lncRNA AA388235 could significantly induce death of human tumor cells, although it has no effect on mouse tumor cells and normal human cells. The mechanism studies showed that these siRNAs could activate the response of human tumor cells to exogenous nucleic acids, induce pyroptosis and apoptosis in the presence of GSDME, but induce apoptosis in the absence of GSDME. They also significantly inhibited the growth of human tumor cells in vivo. 17 siRNAs were designed for seven more mouse-specific lncRNAs selected randomly, among which 12 siRNAs targeting five lncRNAs induced death in human tumor cell. Our study not only demonstrates that the siRNAs designed for knocking down mouse-specific lncRNA AA388235 can be potential tumor therapeutic drugs, but also suggests that non-human species-specific lncRNAs are a huge potential library that can be used to design siRNAs for tumor treatment. Large-scale screening based on this is promising.
Different Patient Subgroup Different Maintenance, Proteasome Inhibitors or Immunomodulators Maintenance for Newly Diagnosed Multiple Myeloma: A 7-Year Single-Center Data in China
Authors: Han Xiaoyan , Jin Chunxiang , Zheng Gaofeng , He Donghua , Zhao Yi , Li Yi , Wu Wenjun , Zheng Weiyan , Wei Guoqing , Zhang Enfan , Huang He , He Jingsong , Cai Zhen
Published: June 2021

Introduction

We analyzed different patient subgroups to determine optimal maintenance therapy in newly diagnosed multiple myeloma (NDMM) patients.

Methods

A total of 226 NDMM patients in our center were included in the study. The characteristics, survival, and adverse reactions were compared among patients who received maintenance therapy or not, and patients who received proteasome inhibitors (PIs) or immunomodulators (IMiDs) maintenance. The survival of different maintenance durations of bortezomib-based regimens was also analyzed.

Results

The maintenance therapy not only upgraded more patient responses (34.3 vs 13.3%, P = 0.006), but also significantly prolonged their progression-free survival (PFS) (median PFS: 41.1 vs 10.5 months, P < 0.001) and overall survival (OS) (median OS: not reached vs 38.6 months, P < 0.001). Compared with IMiDs, the PFS (median PFS: 43.7 vs 38.5 months, P = 0.034) and OS (median OS: not reached vs 78.5 months, P = 0.041) were both enhanced by PIs maintenance. Patients younger than 65 years who received PIs had a significantly prolonged OS (P = 0.032). Patients achieving only a partial response (PR) after induction and consolidation therapy had significantly longer PFS and OS after PIs maintenance compared to IMiDs (P = 0.007, 0.002). High-risk patients (ISS 2–3, DS 2–3, and RISS 2–3) given PIs maintenance benefit from a prolonged PFS (P = 0.002, 0.02, 0.06) and OS (P = 0.059, 0.047, 0.044, respectively) compared with IMiDs therapy. OS was significantly prolonged in patients who received ≥ 12 months of bortezomib-based maintenance therapy compared to those who were treated for < 12 months (P < 0.001), but no difference was observed in OS between patients who received 12 to 24 or ≥ 24 months of bortezomib-based maintenance therapy (P = 0.292).

Conclusion

PIs maintenance was superior to IMiDs in overall PFS and OS. The beneficial effect was most evident in patients achieving PR after induction and consolidation therapy, and in high-risk patients. Moreover, younger patients also benefited from PIs maintenance with an increased OS. A bortezomib-based maintenance therapy duration of 12 to 24 months after induction and consolidation therapy produced satisfactory OS.