bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting enzyme targets for cancer drugs by profiling human Metabolic reactions in NCI-60 cell lines
Authors: Li Limin , Zhou Xiaobo , Ching Wai-Ki , Wang Ping
Published: December 2019

Background

Drugs can influence the whole metabolic system by targeting enzymes which catalyze metabolic reactions. The existence of interactions between drugs and metabolic reactions suggests a potential way to discover drug targets.

Results

In this paper, we present a computational method to predict new targets for approved anti-cancer drugs by exploring drug-reaction interactions. We construct a Drug-Reaction Network to provide a global view of drug-reaction interactions and drug-pathway interactions. The recent reconstruction of the human metabolic network and development of flux analysis approaches make it possible to predict each metabolic reaction's cell line-specific flux state based on the cell line-specific gene expressions. We first profile each reaction by its flux states in NCI-60 cancer cell lines, and then propose a kernel k-nearest neighbor model to predict related metabolic reactions and enzyme targets for approved cancer drugs. We also integrate the target structure data with reaction flux profiles to predict drug targets and the area under curves can reach 0.92.

Conclusions

The cross validations using the methods with and without metabolic network indicate that the former method is significantly better than the latter. Further experiments show the synergism of reaction flux profiles and target structure for drug target prediction. It also implies the significant contribution of metabolic network to predict drug targets. Finally, we apply our method to predict new reactions and possible enzyme targets for cancer drugs.
Three-Level Prediction of Protein Function by Combining Profile-Sequence Search, Profile-Profile Search, and Domain Co-Occurrence Networks
Authors: Wang Zheng , Cao Renzhi , Cheng Jianlin
Published: December 2019

Predicting protein function from sequence is useful for biochemical experiment design, mutagenesis analysis, protein engineering, protein design, biological pathway analysis, drug design, disease diagnosis, and genome annotation as a vast number of protein sequences with unknown function are routinely being generated by DNA, RNA and protein sequencing in the genomic era. However, despite significant progresses in the last several years, the accuracy of protein function prediction still needs to be improved in order to be used effectively in practice, particularly when little or no homology exists between a target protein and proteins with annotated function. Here, we developed a method that integrated profile-sequence alignment, profile-profile alignment, and Domain Co-Occurrence Networks (DCN) to predict protein function at different levels of complexity, ranging from obvious homology, to remote homology, to no homology. We tested the method blindingly in the 2011 Critical Assessment of Function Annotation (CAFA). Our experiments demonstrated that our three-level prediction method effectively increased the recall of function prediction while maintaining a reasonable precision. Particularly, our method can predict function terms defined by the Gene Ontology more accurately than three standard baseline methods in most situations, handle multi-domain proteins naturally, and make ab initio function prediction when no homology exists. These results show that our approach can combine complementary strengths of most widely used BLAST-based function prediction methods, rarely used in function prediction but more sensitive profile-profile comparison-based homology detection methods, and non-homology-based domain co-occurrence networks, to effectively extend the power of function prediction from high homology, to low homology, to no homology (ab initio cases).
Prediction of conformational epitopes with the use of a knowledge-based energy function and geometrically related neighboring residue characteristics
Authors: Lo Ying-Tsang , Pai Tun-Wen , Wu Wei-Kuo , Chang Hao-Teng
Published: December 2019

Background

A conformational epitope (CE) in an antigentic protein is composed of amino acid residues that are spatially near each other on the antigen's surface but are separated in sequence; CEs bind their complementary paratopes in B-cell receptors and/or antibodies. CE predication is used during vaccine design and in immuno-biological experiments. Here, we develop a novel system, CE-KEG, which predicts CEs based on knowledge-based energy and geometrical neighboring residue contents. The workflow applied grid-based mathematical morphological algorithms to efficiently detect the surface atoms of the antigens. After extracting surface residues, we ranked CE candidate residues first according to their local average energy distributions. Then, the frequencies at which geometrically related neighboring residue combinations in the potential CEs occurred were incorporated into our workflow, and the weighted combinations of the average energies and neighboring residue frequencies were used to assess the sensitivity, accuracy, and efficiency of our prediction workflow.

Results

We prepared a database containing 247 antigen structures and a second database containing the 163 non-redundant antigen structures in the first database to test our workflow. Our predictive workflow performed better than did algorithms found in the literature in terms of accuracy and efficiency. For the non-redundant dataset tested, our workflow achieved an average of 47.8% sensitivity, 84.3% specificity, and 80.7% accuracy according to a 10-fold cross-validation mechanism, and the performance was evaluated under providing top three predicted CE candidates for each antigen.

Conclusions

Our method combines an energy profile for surface residues with the frequency that each geometrically related amino acid residue pair occurs to identify possible CEs in antigens. This combination of these features facilitates improved identification for immuno-biological studies and synthetic vaccine design. CE-KEG is available at http://cekeg.cs.ntou.edu.tw.
Quasi-cellular systems: stochastic simulation analysis at nanoscale range
Authors: Calviello Lorenzo , Stano Pasquale , Mavelli Fabio , Luisi Pier Luigi , Marangoni Roberto
Published: December 2019

Background

The wet-lab synthesis of the simplest forms of life (minimal cells) is a challenging aspect in modern synthetic biology. Quasi-cellular systems able to produce proteins directly from DNA can be obtained by encapsulating the cell-free transcription/translation system PURESYSTEM™(PS) in liposomes. It is possible to detect the intra-vesicle protein production using DNA encoding for GFP and monitoring the fluorescence emission over time. The entrapment of solutes in small-volume liposomes is a fundamental open problem. Stochastic simulation is a valuable tool in the study of biochemical reaction at nanoscale range. QDC (Quick Direct-Method Controlled), a stochastic simulation software based on the well-known Gillespie's SSA algorithm, was used. A suitable model formally describing the PS reactions network was developed, to predict, from inner species concentrations (very difficult to measure in small-volumes), the resulting fluorescence signal (experimentally observable).

Results

Thanks to suitable features specific of QDC, we successfully formalized the dynamical coupling between the transcription and translation processes that occurs in the real PS, thus bypassing the concurrent-only environment of Gillespie's algorithm. Simulations were firstly performed for large liposomes (2.67µm of diameter) entrapping the PS to synthetize GFP. By varying the initial concentrations of the three main classes of molecules involved in the PS (DNA, enzymes, consumables), we were able to stochastically simulate the time-course of GFP-production. The sigmoid fit of the GFP-production curves allowed us to extract three quantitative parameters which are significantly dependent on the various initial states. Then we extended this study for small-volume liposomes (575 nm of diameter), where it is more complex to infer the intra-vesicle composition, due to the expected anomalous entrapment phenomena. We identified almost two extreme states that are forecasted to give rise to significantly different experimental observables.

Conclusions

The present work is the first one describing in the detail the stochastic behavior of the PS. Thanks to our results, an experimental approach is now possible, aimed at recording the GFP production kinetics in very small micro-emulsion droplets or liposomes, and inferring, by using the simulation as a reverse-engineering procedure, the internal solutes distribution, and shed light on the still unknown forces driving the entrapment phenomenon.
A nonparametric Bayesian approach for clustering bisulfate-based DNA methylation profiles
Authors: Zhang Lin , Meng Jia , Liu Hui , Huang Yufei
Published: December 2019

Background

DNA methylation occurs in the context of a CpG dinucleotide. It is an important epigenetic modification, which can be inherited through cell division. The two major types of methylation include hypomethylation and hypermethylation. Unique methylation patterns have been shown to exist in diseases including various types of cancer. DNA methylation analysis promises to become a powerful tool in cancer diagnosis, treatment and prognostication. Large-scale methylation arrays are now available for studying methylation genome-wide. The Illumina methylation platform simultaneously measures cytosine methylation at more than 1500 CpG sites associated with over 800 cancer-related genes. Cluster analysis is often used to identify DNA methylation subgroups for prognosis and diagnosis. However, due to the unique non-Gaussian characteristics, traditional clustering methods may not be appropriate for DNA and methylation data, and the determination of optimal cluster number is still problematic.

Method

A Dirichlet process beta mixture model (DPBMM) is proposed that models the DNA methylation expressions as an infinite number of beta mixture distribution. The model allows automatic learning of the relevant parameters such as the cluster mixing proportion, the parameters of beta distribution for each cluster, and especially the number of potential clusters. Since the model is high dimensional and analytically intractable, we proposed a Gibbs sampling "no-gaps" solution for computing the posterior distributions, hence the estimates of the parameters.

Result

The proposed algorithm was tested on simulated data as well as methylation data from 55 Glioblastoma multiform (GBM) brain tissue samples. To reduce the computational burden due to the high data dimensionality, a dimension reduction method is adopted. The two GBM clusters yielded by DPBMM are based on data of different number of loci (P-value < 0.1), while hierarchical clustering cannot yield statistically significant clusters.
The parasite specific substitution matrices improve the annotation of apicomplexan proteins
Authors: Ali Jamshaid , Thummala Shashi Rekha , Ranjan Akash
Published: December 2019

Background

A number of apicomplexan genomes have been sequenced successfully in recent years and this would help in understanding the biology of apicomplexan parasites. The members of the phylum Apicomplexa are important protozoan parasites (Plasmodium, Toxoplasma and Cryptosporidium etc) that cause some of the deadly diseases in humans and animals. In our earlier studies, we have shown that the standard BLOSUM matrices are not suitable for compositionally biased apicomplexan proteins. So we developed a novel series (SMAT and PfFSmat60) of substitution matrices which performed better in comparison to standard BLOSUM matrices and developed ApicoAlign, a sequence search and alignment tool for apicomplexan proteins. In this study, we demonstrate the higher specificity of these matrices and make an attempt to improve the annotation of apicomplexan kinases and proteases.

Results

The ROC curves proved that SMAT80 performs best for apicomplexan proteins followed by compositionally adjusted BLOSUM62 (PSI-BLAST searches), BLOSUM90 and BLOSUM62 matrices in terms of detecting true positives. The poor E-values and/or bit scores given by SMAT80 matrix for the experimentally identified coccidia-specific oocyst wall proteins against hematozoan (non-coccidian) parasites further supported the higher specificity of the same. SMAT80 uniquely detected (missed by BLOSUM) orthologs for 1374 apicomplexan hypothetical proteins against SwissProt database and predicted 70 kinases and 17 proteases. Further analysis confirmed the conservation of functional residues of kinase domain in one of the SMAT80 detected kinases. Similarly, one of the SMAT80 detected proteases was predicted to be a rhomboid protease.

Conclusions

The parasite specific substitution matrices have higher specificity for apicomplexan proteins and are helpful in detecting the orthologs missed by BLOSUM matrices and thereby improve the annotation of apicomplexan proteins which are hypothetical or with unknown function.
Investigating the relationship of DNA methylation with mutation rate and allele frequency in the human genome
Authors: Xia Junfeng , Han Leng , Zhao Zhongming
Published: December 2019

Background

DNA methylation, which mainly occurs at CpG dinucleotides, is a dynamic epigenetic regulation mechanism in most eukaryotic genomes. It is already known that methylated CpG dinucleotides can lead to a high rate of C to T mutation at these sites. However, less is known about whether and how the methylation level causes a different mutation rate, especially at the single-base resolution.

Results

In this study, we used genome-wide single-base resolution methylation data to perform a comprehensive analysis of the mutation rate of methylated cytosines from human embryonic stem cell. Through the analysis of the density of single nucleotide polymorphisms, we first confirmed that the mutation rate in methylated CpG sites is greater than that in unmethylated CpG sites. Then, we showed that among methylated CpG sites, the mutation rate is markedly increased in low-intermediately (20-40% methylation level) to intermediately methylated CpG sites (40-60% methylation level) of the human genome. This mutation pattern was observed regardless of DNA strand direction and the sequence coverage over the site on which the methylation level was calculated. Moreover, this highly non-random mutation pattern was found more apparent in intergenic and intronic regions than in promoter regions and CpG islands. Our investigation suggested this pattern appears primarily in autosomes rather than sex chromosomes. Further analysis based on human-chimpanzee divergence confirmed these observations. Finally, we observed a significant correlation between the methylation level and cytosine allele frequency.

Conclusions

Our results showed a high mutation rate in low-intermediately to intermediately methylated CpG sites at different scales, from the categorized genomic region, whole chromosome, to the whole genome level, thereby providing the first supporting evidence of mutation rate variation at human methylated CpG sites using the genome-wide sing-base resolution methylation data.
Steps to ensure accuracy in genotype and SNP calling from Illumina sequencing data
Authors: Liu Qi , Guo Yan , Li Jiang , Long Jirong , Zhang Bing , Shyr Yu
Published: December 2019

Background

Accurate calling of SNPs and genotypes from next-generation sequencing data is an essential prerequisite for most human genetics studies. A number of computational steps are required or recommended when translating the raw sequencing data into the final calls. However, whether each step does contribute to the performance of variant calling and how it affects the accuracy still remain unclear, making it difficult to select and arrange appropriate steps to derive high quality variants from different sequencing data. In this study, we made a systematic assessment of the relative contribution of each step to the accuracy of variant calling from Illumina DNA sequencing data.

Results

We found that the read preprocessing step did not improve the accuracy of variant calling, contrary to the general expectation. Although trimming off low-quality tails helped align more reads, it introduced lots of false positives. The ability of markup duplication, local realignment and recalibration, to help eliminate false positive variants depended on the sequencing depth. Rearranging these steps did not affect the results. The relative performance of three popular multi-sample SNP callers, SAMtools, GATK, and GlfMultiples, also varied with the sequencing depth.

Conclusions

Our findings clarify the necessity and effectiveness of computational steps for improving the accuracy of SNP and genotype calls from Illumina sequencing data and can serve as a general guideline for choosing SNP calling strategies for data with different coverage.
Delayed neuronal cell death in brainstem after transient brainstem ischemia in gerbils
Authors: Cao Fang , Hata Ryuji , Zhu Pengxiang , Takeda Shoichiro , Yoshida Tadashi , Hakuba Nobuhiro , Sakanaka Masahiro , Gyo Kiyofumi
Published: December 2019

Background

Because of the lack of reproducible brainstem ischemia models in rodents, the temporal profile of ischemic lesions in the brainstem after transient brainstem ischemia has not been evaluated intensively. Previously, we produced a reproducible brainstem ischemia model of Mongolian gerbils. Here, we showed the temporal profile of ischemic lesions after transient brainstem ischemia.

Results

Brainstem ischemia was produced by occlusion of the bilateral vertebral arteries just before their entry into the transverse foramina of the cervical vertebrae of Mongolian gerbils. Animals were subjected to brainstem ischemia for 15 min, and then reperfused for 0 d (just after ischemia), 1 d, 3 d and 7 d (n = 4 in each group). Sham-operated animals (n = 4) were used as control. After deep anesthesia, the gerbils were perfused with fixative for immunohistochemical investigation. Ischemic lesions were detected by immunostaining for microtubule-associated protein 2 (MAP2). Just after 15-min brainstem ischemia, ischemic lesions were detected in the lateral vestibular nucleus and the ventral part of the spinal trigeminal nucleus, and these ischemic lesions disappeared one day after reperfusion in all animals examined. However, 3 days and 7 days after reperfusion, ischemic lesions appeared again and clusters of ionized calcium-binding adapter molecule-1(IBA-1)-positive cells were detected in the same areas in all animals.

Conclusion

These results suggest that delayed neuronal cell death took place in the brainstem after transient brainstem ischemia in gerbils.
Effects of aluminum on nucleoli in root tip cells and selected physiological and biochemical characters in Allium cepa var. agrogarumL
Authors: Qin Rong , Jiao Yunqiu , Zhang Shanshan , Jiang Wusheng , Liu Donghua
Published: December 2019

Background

Increased Al concentration causes reduction of mitotic activity, induction of nucleolar alteration, increase of the production of ROS and alteration of several antioxidant enzyme activities in plant cells. Allium cepa is an excellent plant and a useful biomarker for environmental monitoring. Limited information is available about the effects of Al on nucleoli, antioxidant enzyme system, contents of MDA and soluble protein in A. cepa. Therefore, we carried out the investigation in order to better understand the effects of Al on the growth, nucleoli in root tip cells and selected physiological and biochemical characters.

Results

The results showed that the root growth exposed to 50 μM Al was inhibited significantly. 50 μM Al could induce some particles of argyrophilic proteins scattered in the nuclei and extruded from the nucleoli into the cytoplasm. The nucleolus did not disaggregate normally and still remained its characteristic structure during metaphase. Nucleolar reconstruction was inhibited. 50 μM Al induced high activities of SOD and POD in leaves and roots significantly (P < 0.05) when compared with control, whereas the level of CAT was low significantly (P < 0.05). At 50 μM Al the content of MDA in leaves was high significantly (P < 0.05) at 9th day and in roots increased (P < 0.05) with prolonging the treatment time during 6-12 days. The soluble protein content in leaves treated with 50 μM Al was high significantly (P < 0.05) at 6th day and increased with prolonging the treatment time.

Conclusions

We suggest that variations in nucleoli and the alterations of antioxidant enzyme activities, MDA and soluble protein contents in Allium cepa can serve as useful biomarkers, which can provide valuable information for monitoring and forecasting effects of exposure to Al in real scenarios conditions. Among the antioxidant enzymes SOD and POD appear to play a key role in the antioxidant defense mechanism under Al toxicity condition. Data from MDA concentration show that Al indirectly produces superoxide radicals, resulting in increased lipid peroxidative products and oxidative stress.
Tumour suppressor function of MDA-7/IL-24 in human breast cancer
Authors: Patani Neill , Douglas-Jones Anthony , Mansel Robert , Jiang Wen , Mokbel Kefah
Published: December 2019

Introduction

Melanoma differentiation associated gene-7 (MDA-7), also known as interleukin (IL)-24, is a tumour suppressor gene associated with differentiation, growth and apoptosis. However, the mechanisms underlying its anti-neoplastic activity, tumour-specificity and efficacy across a spectrum of human cancers have yet to be fully elucidated. In this study, the biological impact of MDA-7 on the behavior of breast cancer (BC) cells is evaluated. Furthermore, mRNA expression of MDA-7 is assessed in a cohort of women with BC and correlated with established pathological parameters and clinical outcome.

Methods

The human BC cell line MDA MB-231 was used to evaluate the in-vitro impact of recombinant human (rh)-MDA-7 on cell growth and motility, using a growth assay, wounding assay and electric cell impedance sensing (ECIS). Localisation of MDA-7 in mammary tissues was assessed with standard immuno-histochemical methodology. BC tissues (n = 127) and normal tissues (n = 33) underwent RNA extraction and reverse transcription, MDA-7 transcript levels were determined using real-time quantitative PCR. Transcript levels were analyzed against tumour size, grade, oestrogen receptor (ER) status, nodal involvement, TNM stage, Nottingham Prognostic Index (NPI) and clinical outcome over a 10 year follow-up period.

Results

Exposure to rh-MDA-7 significantly reduced wound closure rates for human BC cells in-vitro. The ECIS model demonstrated a significantly reduced motility and migration following rh-MDA-7 treatment (p = 0.024). Exposure to rh-MDA-7 was only found to exert a marginal effect on growth. Immuno-histochemical staining of human breast tissues revealed substantially greater MDA-7 positivity in normal compared to cancer cells. Significantly lower MDA-7 transcript levels were identified in those predicted to have a poorer prognosis by the NPI (p = 0.049) and those with node positive tumours. Significantly lower expression was also noted in tumours from patients who died of BC compared to those who remained disease free (p = 0.035). Low levels of MDA-7 were significantly correlated with a shorter disease free survival (mean = 121.7 vs. 140.4 months, p = 0.0287) on Kaplan-Meier survival analysis.

Conclusion

MDA-7 significantly inhibits the motility and migration of human BC cells in-vitro. MDA-7 expression is substantially reduced in malignant breast tissue and low transcript levels are significantly associated with unfavourable pathological parameters, including nodal positivity; and adverse clinical outcomes including poor prognosis and shorter disease free survival. MDA-7 offers utility as a prognostic marker and potential for future therapeutic strategies.
Validating an infrared thermal switch as a novel access technology
Authors: Memarian Negar , Venetsanopoulos Anastasios N , Chau Tom
Published: December 2019

Background

Recently, a novel single-switch access technology based on infrared thermography was proposed. The technology exploits the temperature differences between the inside and surrounding areas of the mouth as a switch trigger, thereby allowing voluntary switch activation upon mouth opening. However, for this technology to be clinically viable, it must be validated against a gold standard switch, such as a chin switch, that taps into the same voluntary motion.

Methods

In this study, we report an experiment designed to gauge the concurrent validity of the infrared thermal switch. Ten able-bodied adults participated in a series of 3 test sessions where they simultaneously used both an infrared thermal and conventional chin switch to perform multiple trials of a number identification task with visual, auditory and audiovisual stimuli. Participants also provided qualitative feedback about switch use. User performance with the two switches was quantified using an efficiency measure based on mutual information.

Results

User performance (p = 0.16) and response time (p = 0.25) with the infrared thermal switch were comparable to those of the gold standard. Users reported preference for the infrared thermal switch given its non-contact nature and robustness to changes in user posture.

Conclusions

Thermal infrared access technology appears to be a valid single switch alternative for individuals with disabilities who retain voluntary mouth opening and closing.
IGFBP-rP1, a potential molecule associated with colon cancer differentiation
Authors: Ruan Wenjing , Zhu Shuzhen , Wang Haibing , Xu Fangying , Deng Hong , Ma Yu , Lai Maode
Published: December 2019

Background

In our previous studies, we have demonstrated that insulin-like growth factor binding protein-related protein1 (IGFBP-rP1) played its potential tumor suppressor role in colon cancer cells through apoptosis and senescence induction. In this study, we will further uncover the role of IGFBP-rP1 in colon cancer differentiation and a possible mechanism by revealing responsible genes.

Results

In normal colon epithelium, immunohistochemistry staining detected a gradient IGFBP-rP1 expression along the axis of the crypt. IGFBP-rP1 strongly expressed in the differentiated cells at the surface of the colon epithelium, while weakly expressed at the crypt base. In colon cancer tissues, the expression of IGFBP-rP1 correlated positively with the differentiation status. IGFBP-rP1 strongly expressed in low grade colorectal carcinoma and weakly expressed in high grade colorectal carcinoma. In vitro, transfection of PcDNA3.1(IGFBP-rP1) into RKO, SW620 and CW2 cells induced a more pronounced anterior-posterior polarity morphology, accompanied by upregulation with alkaline phosphatase (AKP) activity. Upregulation of carcino-embryonic antigen (CEA) was also observed in SW620 and CW2 transfectants. The addition of IGFBP-rP1 protein into the medium could mimic most but not all effects of IGFBP-rP1 cDNA transfection. Seventy-eight reproducibly differentially expressed genes were detected in PcDNA3.1(IGFBP-rP1)-RKO transfectants, using Affymetrix 133 plus 2.0 expression chip platform. Directed Acyclic Graph (DAG) of the enriched GO categories demonstrated that differential expression of the enzyme regulator activity genes together with cytoskeleton and actin binding genes were significant. IGFBP-rP1 could upreguate Transgelin (TAGLN), downregulate SRY (sex determining region Y)-box 9(campomelic dysplasia, autosomal sex-reversal) (SOX9), insulin receptor substrate 1(IRS1), cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B), amphiregulin(schwannoma-derived growth factor) (AREG) and immediate early response 5-like(IER5L) in RKO, SW620 and CW2 colon cancer cells, verified by Real time Reverse Transcription Polymerase Chain Reaction (rtRT-PCR). During sodium butyrate-induced Caco2 cell differentiation, IGFBP-rP1 was upregulated and the expression showed significant correlation with the AKP activity. The downregulation of IRS1 and SOX9 were also induced by sodium butyrate.

Conclusion

IGFBP-rP1 was a potential key molecule associated with colon cancer differentiation. Downregulation of IRS1 and SOX9 may the possible key downstream genes involved in the process.
Characterization of a new simian immunodeficiency virus strain in a naturally infected Pan troglodytes troglodyteschimpanzee with AIDS related symptoms
Authors: Etienne Lucie , Nerrienet Eric , LeBreton Matthew , Bibila Godwin Tafon , Foupouapouognigni Yacouba , Rousset Dominique , Nana Ahmadou , Djoko Cyrille F , Tamoufe Ubald , Aghokeng Avelin F , Mpoudi-Ngole Eitel , Delaporte Eric , Peeters Martine , Wolfe Nathan D , Ayouba Ahidjo
Published: December 2019

Background

Data on the evolution of natural SIV infection in chimpanzees (SIVcpz) and on the impact of SIV on local ape populations are only available for Eastern African chimpanzee subspecies (Pan troglodytes schweinfurthii), and no data exist for Central chimpanzees (Pan troglodytes troglodytes), the natural reservoir of the ancestors of HIV-1 in humans. Here, we report a case of naturally-acquired SIVcpz infection in a P.t.troglodytes chimpanzee with clinical and biological data and analysis of viral evolution over the course of infection.

Results

A male chimpanzee (Cam155), 1.5 years, was seized in southern Cameroon in November 2003 and screened SIV positive during quarantine. Clinical follow-up and biological analyses have been performed for 7 years and showed a significant decline of CD4 counts (1,380 cells/mm3 in 2004 vs 287 in 2009), a severe thrombocytopenia (130,000 cells/mm3 in 2004 vs 5,000 cells/mm3 in 2009), a weight loss of 21.8% from August 2009 to January 2010 (16 to 12.5 kg) and frequent periods of infections with diverse pathogens.

DNA from PBMC, leftover from clinical follow-up samples collected in 2004 and 2009, was used to amplify overlapping fragments and sequence two full-length SIVcpzPtt-Cam155 genomes. SIVcpzPtt-Cam155 was phylogenetically related to other SIVcpzPtt from Cameroon (SIVcpzPtt-Cam13) and Gabon (SIVcpzPtt-Gab1). Ten molecular clones 5 years apart, spanning the V1V4 gp120 env region (1,100 bp), were obtained. Analyses of the env region showed positive selection (dN-dS >0), intra-host length variation and extensive amino acid diversity between clones, greater in 2009. Over 5 years, N-glycosylation site frequency significantly increased (p < 0.0001).

Conclusions

Here, we describe for the first time the clinical history and viral evolution of a naturally SIV infected P.t.troglodytes chimpanzee. The findings show an increasing viral diversity over time and suggest clinical progression to an AIDS-like disease, showing that SIVcpz can be pathogenic in its host, as previously described in P.t.schweinfurthii. Although studying the impact of SIV infection in wild apes is difficult, efforts should be made to better characterize the pathogenicity of the ancestors of HIV-1 in their natural host and to find out whether SIV infection also plays a role in ape population decline.
Sequence analysis of the Epstein-Barr virus (EBV) BRLF1 gene in nasopharyngeal and gastric carcinomas
Authors: Jia Yuping , Wang Yun , Chao Yan , Jing Yongzheng , Sun Zhifu , Luo Bing
Published: December 2019

Background

Epstein-Barr virus (EBV) has a biphasic infection cycle consisting of a latent and a lytic replicative phase. The product of immediate-early gene BRLF1, Rta, is able to disrupt the latency phase in epithelial cells and certain B-cell lines. The protein Rta is a frequent target of the EBV-induced cytotoxic T cell response. In spite of our good understanding of this protein, little is known for the gene polymorphism of BRLF1.

Results

BRLF1 gene was successfully amplified in 34 EBV-associated gastric carcinomas (EBVaGCs), 57 nasopharyngeal carcinomas (NPCs) and 28 throat washings (TWs) samples from healthy donors followed by PCR-direct sequencing. Fourteen loci were found to be affected by amino acid changes, 17 loci by silent nucleotide changes. According to the phylogenetic tree, 5 distinct subtypes of BRLF1 were identified, and 2 subtypes BR1-A and BR1-C were detected in 42.9% (51/119), 42.0% (50/119) of samples, respectively. The distribution of these 2 subtypes among 3 types of specimens was significantly different. The subtype BR1-A preferentially existed in healthy donors, while BR1-C was seen more in biopsies of NPC. A silent mutation A/G was detected in all the isolates. Among 3 functional domains, the dimerization domain of Rta showed a stably conserved sequence, while DNA binding and transactivation domains were detected to have multiple mutations. Three of 16 CTL epitopes, NAA, QKE and ERP, were affected by amino acid changes. Epitope ERP was relatively conserved; epitopes NAA and QKE harbored more mutations.

Conclusions

This first detailed investigation of sequence variations in BRLF1 gene has identified 5 distinct subtypes. Two subtypes BR1-A and BR1-C are the dominant genotypes of BRLF1. The subtype BR1-C is more frequent in NPCs, while BR1-A preferentially presents in healthy donors. BR1-C may be associated with the tumorigenesis of NPC.
CT-guided iodine-125 seed permanent implantation for recurrent head and neck cancers
Authors: Jiang Yu L , Meng Na , Wang Jun J , Jiang Ping , Yuan Hui SH , Liu Chen , Qu Ang , Yang Rui J
Published: December 2019

Background

To investigate the feasibility, and safety of 125I seed permanent implantation for recurrent head and neck carcinoma under CT-guidance.

Results

A retrospective study on 14 patients with recurrent head and neck cancers undergone 125I seed implantation with different seed activities. The post-plan showed that the actuarial D90 of 125I seeds ranged from 90 to 218 Gy (median, 157.5 Gy). The follow-up was 3 to 60 months (median, 13 months). The median local control was 18 months (95% CI, 6.1-29.9 months), and the 1-, 2-, 3-, and 5- year local controls were 52%, 39%, 39%, and 39%, respectively. The 1-, 2-, 3-, and 5- survival rates were 65%, 39%, 39% and 39%, respectively, with a median survival time of 20 months (95% CI, 8.7-31.3 months). Of all patients, 28.6% (4/14) died of local recurrence, 7.1% (1/14) died of metastases, one patient died of hepatocirrhosis, and 8 patients are still alive to the date of data analysis.

Conclusion

CT-guided 125I seed implantation is feasible and safe as a salvage or palliative treatment for patients with recurrent head and neck cancers.
BioBin: a bioinformatics tool for automating the binning of rare variants using publicly available biological knowledge
Authors: Moore Carrie B , Wallace John R , Frase Alex T , Pendergrass Sarah A , Ritchie Marylyn D
Published: December 2019

Background

With the recent decreasing cost of genome sequence data, there has been increasing interest in rare variants and methods to detect their association to disease. We developed BioBin, a flexible collapsing method inspired by biological knowledge that can be used to automate the binning of low frequency variants for association testing. We also built the Library of Knowledge Integration (LOKI), a repository of data assembled from public databases, which contains resources such as: dbSNP and gene Entrez database information from the National Center for Biotechnology (NCBI), pathway information from Gene Ontology (GO), Protein families database (Pfam), Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome, NetPath - signal transduction pathways, Open Regulatory Annotation Database (ORegAnno), Biological General Repository for Interaction Datasets (BioGrid), Pharmacogenomics Knowledge Base (PharmGKB), Molecular INTeraction database (MINT), and evolutionary conserved regions (ECRs) from UCSC Genome Browser. The novelty of BioBin is access to comprehensive knowledge-guided multi-level binning. For example, bin boundaries can be formed using genomic locations from: functional regions, evolutionary conserved regions, genes, and/or pathways.

Methods

We tested BioBin using simulated data and 1000 Genomes Project low coverage data to test our method with simulated causative variants and a pairwise comparison of rare variant (MAF < 0.03) burden differences between Yoruba individuals (YRI) and individuals of European descent (CEU). Lastly, we analyzed the NHLBI GO Exome Sequencing Project Kabuki dataset, a congenital disorder affecting multiple organs and often intellectual disability, contrasted with Complete Genomics data as controls.

Results

The results from our simulation studies indicate type I error rate is controlled, however, power falls quickly for small sample sizes using variants with modest effect sizes. Using BioBin, we were able to find simulated variants in genes with less than 20 loci, but found the sensitivity to be much less in large bins. We also highlighted the scale of population stratification between two 1000 Genomes Project data, CEU and YRI populations. Lastly, we were able to apply BioBin to natural biological data from dbGaP and identify an interesting candidate gene for further study.

Conclusions

We have established that BioBin will be a very practical and flexible tool to analyze sequence data and potentially uncover novel associations between low frequency variants and complex disease.
Edaravone reduces oxidative stress and intestinal cell apoptosis after burn through up-regulating miR-320 expression
Authors: Ke Jiaxiang , Bian Xi , Liu Hu , Li Bei , Huo Ran
Published: December 2019

Background

Intestinal mucosa barrier dysfunction after burn injury is an important factor for causing mortality of burn patients. The current study established a burn model in rats and used a free radical scavenger edaravone (ED) to treat the rats, so as to investigate the effect of edaravone on intestinal mucosa barrier after burn injury.

Methods

Anesthetized rats were subjected to 40% total body surface area water burn immediately, followed by treatment with ED, scrambled antagomir, or antagomiR-320. Intestinal mucosa damage was observed by hematoxylin-eosin staining and graded by colon mucosal damage index (CMDI) score. The contents of total sulfhydryl (TSH), superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) were determined by spectrophotometry. Cell apoptosis, protein relative expression,and the in situ expressions of p-Akt and p-Bad were detected by flow cytometry, Western blotting and immunohistochemistry, respectively. The miR-320 expression was determined by quantitative real-time polymerase chain reaction.

Results

ED alleviated intestinal mucosal damage caused by burn injury, down-regulated the levels of MDA, cytochrome C, cleaved caspase-9 and cleaved caspase-3, but up-regulated the levels of TSH, SOD, CAT and Bcl-2. We also found that ED could reduce oxidative stress, inhibit cell apoptosis, increase the expressions of p-Akt, p-Bad and miR-320, and decrease PTEN expression. PTEN was predicted to be the target gene for miR-320, and cell apoptosis could be promoted by inhibiting miR-320 expression.

Conclusion

ED regulates Akt/Bad/Caspase signaling cascade to reduce apoptosis and oxidative stress through up-regulating miR-320 expression and down-regulating PTEN expression, thus protecting the intestinal mucosal barrier of rats from burn injury.
DeepSV: accurate calling of genomic deletions from high-throughput sequencing data using deep convolutional neural network
Authors: Cai Lei , Wu Yufeng , Gao Jingyang
Published: December 2019

Background

Calling genetic variations from sequence reads is an important problem in genomics. There are many existing methods for calling various types of variations. Recently, Google developed a method for calling single nucleotide polymorphisms (SNPs) based on deep learning. Their method visualizes sequence reads in the forms of images. These images are then used to train a deep neural network model, which is used to call SNPs. This raises a research question: can deep learning be used to call more complex genetic variations such as structural variations (SVs) from sequence data?

Results

In this paper, we extend this high-level approach to the problem of calling structural variations. We present DeepSV, an approach based on deep learning for calling long deletions from sequence reads. DeepSV is based on a novel method of visualizing sequence reads. The visualization is designed to capture multiple sources of information in the sequence data that are relevant to long deletions. DeepSV also implements techniques for working with noisy training data. DeepSV trains a model from the visualized sequence reads and calls deletions based on this model. We demonstrate that DeepSV outperforms existing methods in terms of accuracy and efficiency of deletion calling on the data from the 1000 Genomes Project.

Conclusions

Our work shows that deep learning can potentially lead to effective calling of different types of genetic variations that are complex than SNPs.
First evaluation of resistance to both a California OsHV-1 variant and a French OsHV-1 microvariant in Pacific oysters
Authors: Divilov Konstantin , Schoolfield Blaine , Morga Benjamin , Dégremont Lionel , Burge Colleen A. , Mancilla Cortez Daniel , Friedman Carolyn S. , Fleener Gary B. , Dumbauld Brett R. , Langdon Chris
Published: December 2019

Background

Variants of the Ostreid herpesvirus 1 (OsHV-1) cause high losses of Pacific oysters globally, including in Tomales Bay, California, USA. A suite of new variants, the OsHV-1 microvariants (μvars), cause very high mortalities of Pacific oysters in major oyster-growing regions outside of the United States. There are currently no known Pacific oysters in the United States that are resistant to OsHV-1 as resistance has yet to be evaluated in these oysters. As part of an effort to begin genetic selection for resistance to OsHV-1, 71 families from the Molluscan Broodstock Program, a US West Coast Pacific oyster breeding program, were screened for survival after exposure to OsHV-1 in Tomales Bay. They were also tested in a quarantine laboratory in France where they were exposed to a French OsHV-1 microvariant using a plate assay, with survival recorded from three to seven days post-infection.

Results

Significant heritability for survival were found for all time points in the plate assay and in the survival phenotype from a single mortality count in Tomales Bay. Genetic correlations between survival against the French OsHV-1 μvar in the plate assay and the Tomales Bay variant in the field trait were weak or non-significant.

Conclusions

Future breeding efforts will seek to validate the potential of genetic improvement for survival to OsHV-1 through selection using the Molluscan Broodstock Program oysters. The lack of a strong correlation in survival between OsHV-1 variants under this study’s exposure conditions may require independent selection pressure for survival to each variant in order to make simultaneous genetic gains in resistance.
Spectrum of heart diseases in children presenting to a paediatric cardiac echocardiography clinic in the Lake Zone of Tanzania: a 7 years overview
Authors: Zuechner Antke , Mhada Tumaini , Majani Naizihijwa G. , Sharau Godwin G. , Mahalu William , Freund Matthias W.
Published: December 2019

Background

Congenital heart diseases (CHD) are among the most common congenital malformations. It is estimated that the incidence of CHD is constant worldwide, but data are rare for most African countries including Tanzania. Even less data are available on the prevalence of acquired heart diseases (AHD) in African children. Rheumatic heart disease (RHD) is the leading cause of AHD and is remaining a public health concern in Sub-Saharan Africa affecting especially the younger population. Both, CHD and AHD contribute substantially to morbidity and mortality during infancy and childhood.

Methods

This hospital-based, retrospective review of the registry at the paediatric cardiac clinic of Bugando Medical Centre in the Lake Zone of Tanzania analysed the spectrum of heart diseases of paediatric patients during their first presentation by using simple descriptive statistics.

Results

Between September 2009 and August 2016, a total of 3982 patients received cardiac evaluation including echocardiography studies. 1830 (46.0%) pathologic findings were described, out of these 1371 (74.9%) patients had CHD, whereas 459 (25.1%) presented with AHD.

53.9% of the patients with CHD were female and the most common associated syndrome was Down syndrome in 12.8% of patients. In 807 patients (58.9%) diagnosis of CHD was established within the first year of life. The majority of patients (60.1%) were in need of surgical or interventional therapy at time of diagnosis and 6.3% of patients were judged inoperable at the time of first presentation. Nearly 50% of cases with AHD were RHDs followed by dilated cardiomyopathy and pulmonary hypertension without underlying CHD.

Conclusions

The spectrum of CHD and AHD from one centre in Tanzania is comparable to findings reported in other countries from the African continent. Echocardiography is a valuable diagnostic tool and the widespread use of it should be enhanced to diagnose heart diseases in a large number and reasonable time. Most patients present late and majority is in need of surgical or interventional treatment, which is still not readily available. Untreated heart diseases contribute substantially to morbidity and mortality during infancy and childhood. Adequate cardiac services should be established and strengthened.
Consent to data linkage in a large online epidemiological survey of 18–23 year old Australian women in 2012–13
Authors: Graves Anna , McLaughlin Deirdre , Leung Janni , Powers Jennifer
Published: December 2019

Background

Consent to link survey data with health-related administrative datasets is increasingly being sought but little is known about the influence of recruiting via online technologies on participants’ consents. The goal of this paper is to examine what factors (sociodemographic, recruitment, incentives, data linkage information, health) are associated with opt-in consent to link online survey data to administrative datasets (referred to as consent to data linkage).

Methods

The Australian Longitudinal Study on Women’s Health is a prospective study of factors affecting the health and well-being of women. We report on factors associated with opt-in consent to data linkage at the end of an online survey of a new cohort of 18–23 year old Australian women recruited in 2012–13. Classification and Regression Tree analysis with decision trees was used to predict consent.

Results

In this study 69% consented to data linkage. The provision of residential address by the individual, or not (as a measure of attitudes towards privacy), was the most important factor in classifying the data into similar groups of consenters (76% consenters versus 47% respectively). Thereafter, for those who did not provide their residential address, the incentives and data linkage information that was offered was the next most important factor, with incentive 2: limited-edition designer leggings and additional information about confidentiality showing increases in consent rates over Incentive 1: AUD50 gift voucher: 60% versus 37%.

Conclusions

In young Australian women, attitudes towards privacy was strongly associated with consenting to data linkage. Providing additional details about data confidentiality was successful in increasing consent and so was cohort appropriate incentives. Ensuring that prospective participants understand the consent and privacy protocols in place to protect their confidential information builds confidence in consenting to data linkage.