Biology subjects

Zhu, B.

Publications and source records attributed to Zhu, B..

180 records · Page 10Linked to original sources

bioRxiv2019

The lncRNAs Implicated in Redox Regulation in Ybx1 Deficient Zebrafish Larvae

Ybx1 has been demonstrated as a crucial gene in embryogenesis, reproduction as well as development in various vertebrates such as mouse and zebrafish. However, the underlying lncRNA-mediated mechanisms require deep investigation. Particularly, the importance of lncRNA to vertebrate development is controversial and questionable since many studies have yielded contradictory conclusions for the same lncRNAs. In the present study, in order to disclose the lncRNAs implicated in vertebrate development, a systematic transcriptome analysis is conducted based on the RNA sequencing data derived from ybx1 homozygous mutant zebrafish on day5 (day5_ybx1-/-) as well as wild type zebrafish on day5 and day6 (day5_ybx1+/+, day6_ybx1+/+). A high-confidence dataset of zebrafish lncRNAs is detected using a stepwise filtering pipeline. Differential expression analysis and co-expression network analysis reveal that several lncRNAs probably act on duox and noxo1a, the genes related to redox (reduction-oxidation reaction) processes which are triggered by ybx1 disruption. Validation by an experimental study on three selected lncRNAs indicates that knockdown of all selected lncRNAs leads to morphological deformation of larvae. In addition, our experiments effectively support the prediction of network analysis in many interaction patterns between the selected lncRNAs and the two redox genes (duox, noxo1a). In short, our study provides new insights into the function and mechanism of lncRNAs implicated in zebrafish embryonic development and demonstrates the importance of lncRNAs in vertebrate development.\n\nAuthor SummaryLncRNAs has been emerged as key regulatory layers because of their multiple functions in diverse biological processes and pathways. However, there is disagreement about the roles of lncRNAs in vertebrate development Some cases demonstrated that lncRNAs was important to development. Others showed that lncRNAs just have feeble functions in development. On the other hand, Ybx1 processing multi-functions has been well demonstrated as a key protein to most vertebrate in development. Hence, aimed at disclosure of key lncRNAs implicated in vertebrate development as well as their possible roles, we performed a systematic transcriptome analysis based on the deep RNA sequencing data of ybx1 homozygous mutant zebrafish and wild type zebrafish. Our analysis successfully revealed several lncRNAs probably target on the redox-related genes. Furthermore, our experiments validated the importance of these lncRNAs to zebrafish embryo development. This study is the first to utilize Ybx1 as breakpoint to identify key lncRNA related to vertebrate development and provides new insights into underlying mechanisms of lncRNAs in development.

developmental biology↗

bioRxiv2019

A Hidden Markov Modeling Approach forIdentifying Tumor Subclones in Next-GenerationSequencing Studies

Allele-specific copy number alteration (ASCNA) analysis is for identifying copy number abnormalities in tumor cells. Unlike normal cells, tumor cells are heterogeneous as a combination of dominant and minor subclones with distinct copy number profiles. Estimating the clonal proportion and identifying mainclone and subclone genotypes across the genome is important for understanding tumor progression. Several ASCNA tools have recently been developed, but they have been limited to the identification of subclone regions, and not the genotype of subclones. In this paper, we propose subHMM, a hidden Markov model-based approach that estimates both subclone region as well as region-specific subclone genotype and clonal proportion. We specify a hidden state variable representing the conglomeration of clonal genotype and subclone status. We propose a two-step algorithm for parameter estimation, where in the first step, a standard hidden Markov model with this conglomerated state variable is fit. Then, in the second step, region-specific estimates of the clonal proportions are obtained by maximizing region-specific pseudo-likelihoods. We apply subHMM to study renal cell carcinoma datasets in The Cancer Genome Atlas. In addition, we conduct simulation studies that show the good performance of the proposed approach. The R package is available online at https://dceg.cancer.gov/tools/analysis/subhmm. somatic copy number alteration; tumor heterogeneity; E-M algorithm; forward-backward algorithm.

cancer biology↗

bioRxiv2019

Transcriptome analysis of Xanthomonas oryzae pv. oryzicola exposed to H2O2 reveals horizontal gene transfer contributes to its oxidative stress response

Xanthomonas oryzae pv. oryzicola (Xoc) is the causal agent of bacterial leaf streak in rice. It is known as one of the most severe seed-born bacterial diseases of rice, molecular role governing its interaction with rice is mostly still unexplored. To successfully invade rice, the survival of the Xoc is mandotarory following generating a specific response to its hosts oxidative stress condition. However, the response network of Xoc is still unknown. To address this question, we performed a time-series RNA-seq analysis on the Xoc response to H2O2. Overall, our RNA sequence analysis of Xoc revealed a significant global gene expression profile when it exposed to H2O2. The response of key genes was also noted that soxR triggers and regulates the Xoc oxidative stress response in the early stage of infection, gene expression kinetics among the time-series samples, namely for TonB-dependent receptors and the suf and pst operons. Moreover, a hypothetical protein (XOC_2868) showed significant differential expression following its mutant endorsed RNA-seq findings by clearly displaying a greater H2O2 sensitivity and decreased pathogenicity than the wild-type. Gene location and phylogeny analysis strongly suggests that this gene may have been horizontally transferred from a Burkholderiaceae ancestor. Our study not only provides a first glance of Xocs global response against oxidative stress, but it also reveals the impact of horizontal gene transfer in the evolutionary history of Xoc.

microbiology↗

bioRxiv2019

Establishing reference samples for detection of somatic mutations and germline variants with NGS technologies

We characterized two reference samples for NGS technologies: a human triple-negative breast cancer cell line and a matched normal cell line. Leveraging several whole-genome sequencing (WGS) platforms, multiple sequencing replicates, and orthogonal mutation detection bioinformatics pipelines, we minimized the potential biases from sequencing technologies, assays, and informatics. Thus, our \"truth sets\" were defined using evidence from 21 repeats of WGS runs with coverages ranging from 50X to 100X (a total of 140 billion reads). These \"truth sets\" present many relevant variants/mutations including 193 COSMIC mutations and 9,016 germline variants from the ClinVar database, nonsense mutations in BRCA1/2 and missense mutations in TP53 and FGFR1. Independent validation in three orthogonal experiments demonstrated a successful stress test of the truth set. We expect these reference materials and \"truth sets\" to facilitate assay development, qualification, validation, and proficiency testing. In addition, our methods can be extended to establish new fully characterized reference samples for the community.

bioinformatics↗

bioRxiv2019

Host sex and genotype modify the gut microbiome response to helminth infection

The microbial community can be altered by direct/indirect interactions with parasites infecting host. Direct interactions can arise from physical/chemical contact with the parasite. Indirect interactions can involve parasite-induced changes in host immunity. If so, this would represent a case of genetic polymorphism in one species controlling an ecological interaction between other species. Here, we report a test of this expectation: we experimentally exposed Gasterosteus aculeatus to their naturally co-evolved parasite, Schistocephalus solidus. The host microbiome differed in response to parasite exposure, and between infected and uninfected fish. The microbial response to infection differed between host sexes, and also varied between variants at autosomal quantitative trait loci (QTL). These results indicate that host genotype regulates the indirect effect of infection on a vertebrate gut microbiome. Our results also raise the possibility that this sex-bias may be related to sex-specific microbial responses to the presence (or, absence) of helminthes. Therefore, helminth-based therapeutics as possible treatments for inflammatory bowel diseases might need to take account of these interactions, potentially requiring therapies tailored to host sex or genotype.

microbiology↗

bioRxiv2019

Subcellular localization of drug distribution by super-resolution ion beam imaging

Technologies that visualize multiple biomolecules at the nanometer scale in cells will enable deeper understanding of biological processes that proceed at the molecular scale. Current fluorescence-based methods for microscopy are constrained by a combination of spatial resolution limitations, limited parameters per experiment, and detector systems for the wide variety of biomolecules found in cells. We present here super-resolution ion beam imaging (srIBI), a secondary ion mass spectrometry approach capable of high-parameter imaging in 3D of targeted biological entities and exogenously added small molecules. Uniquely, the atomic constituents of the biomolecules themselves can often be used in our system as the "tag". We visualized the subcellular localization of the chemotherapy drug cisplatin simultaneously with localization of five other nuclear structures, with further carbon elemental mapping and secondary electron visualization, down to [~]30 nm lateral resolution. Cisplatin was preferentially enriched in nuclear speckles and excluded from closed-chromatin regions, indicative of a role for cisplatin in active regions of chromatin. These data highlight how multiplexed super-resolution techniques, such as srIBI, will enable studies of biomolecule distributions in biologically relevant subcellular microenvironments. One Sentence SummaryThree-dimensional multiplexed mass spectrometry-based imaging revealed the subcellular localization of proteins and small molecules at super-resolution.

systems biology↗

bioRxiv2019

12h-clock control of central dogma information flow by XBP1s

Our group recently discovered a cell-autonomous mammalian 12h-clock regulating physiological unfolded protein response. Xbp1s ablation impairs 12h-transcript oscillations in vitro, and we now show liver-specific deletion of XBP1s globally impaired murine 12h-transcriptome, but not the circadian rhythms in vivo. XBP1s-dependent 12h-transcriptome is enriched for transcription, mRNA processing, ribosome biogenesis, translation, and protein ER-Golgi processing/sorting in a temporal order consistent with the progressive molecular processing sequence described by the central dogma information flow (CEDIF). The 12h-rhythms of CEDIF are cell-autonomous and evolutionarily conserved in circatidal marine animals. Mechanistically, we found the motif stringency of promoter XBP1s binding sites, but not necessarily XBP1s expression, dictates its ability to drive 12h-rhythms of transcription and further identified GABP as putative novel transcriptional regulator of 12h-clock. We hypothesize the 12h-rhythms of CEDIF allows rush hours gene expression and processing, with the particular genes processed at each rush hour regulated by circadian and/or tissue specific pathways.

systems biology↗

bioRxiv2019

Introducing RpsA Point Mutation Δ438A or D123A into the Chromosome of M. tuberculosis Confirms its Role in Causing Resistance to Pyrazinamide

Pyrazinamide (PZA) is a unique frontiline drug for shortening tuberculosis treatment, but its mechanisms of action are elusive. We previously identified RpsA as a target of PZA and found an alanine deletion at position 438 ({Delta}438A) in RpsA associated with PZA resistance, but its role in PZA resistance is controversial. Here, we introduced RpsA mutation {Delta}438A or D123A into M. tuberculosis chromosome and demonstrated that the introduced RspA mutations are indeed responsible for PZA resistance.

microbiology↗

bioRxiv2019

Immune gene expression profiling reveals heterogeneity in luminal breast tumors

Disease heterogeneity of immune gene expression patterns of luminal breast cancer (BC) has not been well studied. We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 Asian luminal BC patients and identified three distinct immune subtypes. Tumors in one subtype exhibited signs of T-cell activation, lower ESR1/ESR2 expression ratio and higher expression of immune checkpoint genes, nonsynonymous mutation burden, APOBEC-signature mutations, and increasing body mass index compared to other luminal tumors. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in cases drawn from The Cancer Genome Atlas and a Korean breast cancer study. Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification.

genomics↗

bioRxiv2018

From copy number alterations to structural variants: the evolutionary cascade of papillary renal cell carcinomas

Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.

genomics↗

bioRxiv2018

Bacteroides fragilis defense against Cronobacter sakazakii -induced pathogenicity by regulating the intestinal epithelial barrier function and attenuating both apoptotic and pyroptotic cell death

Cronobacter sakazakii (CS), an important pathogen, is associated with the development of necrotizing enterocolitis (NEC), infant sepsis, and meningitis. Several randomized prospective clinical trials demonstrated that oral probiotics could decrease the incidence of NEC. Previously, we isolated and characterized a novel probiotic, B. fragilis strain ZY-312. However, it remains unclear how ZY-312 protects the host from the effects of CS infection. To understand the underlying mechanisms triggering the probiotic effects, we tested the hypothesis that there was a cross-talk between probiotics/probiotics-modulated microbiota and the local immune system, governed by the permeability of the intestinal mucosa using in vitro and in vivo models for the intestinal permeability. The probiotic effects of ZY-312 on intestinal epithelial cells were first examined, which revealed that ZY-312 inhibited CS invasion, CS-induced dual cell death (pyroptosis and apoptosis), and epithelial barrier dysfunction in vitro and in vivo. ZY-312 also decreased the expression of an inflammasome (NOD-like receptor family member pyrin domain-containing protein 3 (NLRP3), caspase-3, and serine protease caspase-1 in a neonatal rat model. Furthermore, ZY-312 significantly modulated the compositions of the intestinal bacterial communities, and decreased the relative abundances of Proteobacteria, Gamma proteobacteria, but increased the relative abundance of Bacteroides and Bacillus in neonatal rats. In conclusion, our findings have shown for the first time that the probiotic, B. fragilis ZY-312, suppresses CS-induced NEC by modulating the pro-inflammatory response and dual cell death (apoptosis and pyroptosis).\n\nAuthor summaryCronobacter sakazakii, a major necrotizing enterocolitis pathogen, is used as a model microorganism for the study of opportunistic bacteria in the pathogenesis of necrotizing enterocolitis. Here, we have now unequivocally demonstrated that both apoptotic and pyroptotic stimuli contribute to the pathogenesis of Cronobacter sakazakii -induced necrotizing enterocolitis. Previously, we isolated and characterized a novel probiotic, B. fragilis strain ZY-312. We found that the ZY-312 defense against Cronobacter sakazakii-induced necrotizing enterocolitis by inhibiting Cronobacter sakazakii invasion, epithelial barrier dysfunction, the expression of inflammatory cytokines and dual cell death (pyroptosis and apoptosis). This study demonstrates the utility of ZY-312 as a promising probiotic agent for the prevention and treatment of various intestinal diseases, including NEC.

microbiology↗

bioRxiv2018

hsegHMM: Hidden Markov Model-based Allele-specific Copy Number Alteration Analysis Accounting for Hypersegmentation

BackgroundSomatic copy number alternation (SCNA) is a common feature of the cancer genome and is associated with cancer etiology and prognosis. The allele-specific SCNA analysis of a tumor sample aims to identify the allele-specific copy numbers of both alleles, adjusting for the ploidy and the tumor purity. Next generation sequencing platforms produce abundant read counts at the base-pair resolution across the exome or whole genome which is susceptible to hypersegmentation, a phenomenon where numerous regions with very short length are falsely identified as SCNA.\n\nResultsWe propose hsegHMM, a hidden Markov model approach that accounts for hypersegmentation for allele-specific SCNA analysis. hsegHMM provides statistical inference of copy number profiles by using an effcient E-M algorithm procedure. Through simulation and application studies, we found that hsegHMM handles hypersegmentation effectively with a t-distribution as a part of the emission probability distribution structure and a carefully defined state space. We also compared hsegHMM with FACETS which is a current method for allele-specific SCNA analysis. For the application, we use a renal cell carcinoma sample from The Cancer Genome Atlas (TCGA) study.\n\nConclusionsWe demonstrate the robustness of hsegHMM to hypersegmentation. Furthermore, hsegHMM provides the quantification of uncertainty in identifying allele-specific SCNAs over the entire chromosomes. hsegHMM performs better than FACETS when read depth (coverage) is uneven across the genome.

bioinformatics↗

bioRxiv2017

Germline determinants of the somatic mutation landscape in 2,642 cancer genomes

Cancers develop through somatic mutagenesis, however germline genetic variation can markedly contribute to tumorigenesis via diverse mechanisms. We discovered and phased 88 million germline single nucleotide variants, short insertions/deletions, and large structural variants in whole genomes from 2,642 cancer patients, and employed this genomic resource to study genetic determinants of somatic mutagenesis across 39 cancer types. Our analyses implicate damaging germline variants in a variety of cancer predisposition and DNA damage response genes with specific somatic mutation patterns. Mutations in the MBD4 DNA glycosylase gene showed association with elevated C>T mutagenesis at CpG dinucleotides, a ubiquitous mutational process acting across tissues. Analysis of somatic structural variation exposed complex rearrangement patterns, involving cycles of templated insertions and tandem duplications, in BRCA1-deficient tumours. Genome-wide association analysis implicated common genetic variation at the APOBEC3 gene cluster with reduced basal levels of somatic mutagenesis attributable to APOBEC cytidine deaminases across cancer types. We further inferred over a hundred polymorphic L1/LINE elements with somatic retrotransposition activity in cancer. Our study highlights the major impact of rare and common germline variants on mutational landscapes in cancer.

genomics↗

bioRxiv2017

A set informative multiple autosomal markers for human identification: forensic research and population genetics analysis in a Chinese Xinjiang Hui group

In recent years, insertion/deletion (InDel) markers became a promising and useful supporting tool in forensic identification cases and biogeographic research field. In this study, 30 InDel loci were explored to reveal the genetic diversities and genetic relationships between Chinese Xinjiang Hui group and the 24 previously studied populations using varies methods such as forensic statistical parameter analysis, phylogenetic reconstruction, STRUCTURE analysis, multi-dimensional scaling, and principal component analysis. The observed heterozygosity and expected heterozygosity ranged from 0.1971 (HLD118) to 0.5092 (HLD 92), 0.2222 (HLD 114) to 0.5000 (HLD 6), respectively. Besides, after Bonferroni correction, no deviations from Hardy-Weinberg equilibrium tests were found at all 30 loci in Xinjiang Hui group. The cumulative probability of exclusion and combined discrimination power were 0.988849 and 0.99999999999378, respectively, which indicated that the 30 loci could be used as complementary genetic markers for paternity test and be qualified for personal identification in forensic cases. In this study, we found that Xinjiang Hui group had close relationships with most Chinese groups, especially Han populations, and all the results based on different genetic methods we used had a strong support for this finding. The 30 InDel loci has important significance in forensic identification research, in spite of this, for a better understanding of genetic background of the Chinese Xinjiang Hui group, molecular genetic genotyping at various genetic markers is necessary in future studies.\n\nSummary StatementWe report here, a promising Individual identification and population differentiation maker which could be used in forensic cases.

genetics↗

bioRxiv2017

A novel mathematical method for disclosing oscillations ingene transcription: a comparative study

Circadian rhythmicity, the 24-hour cycle responsive to light and dark, is determined by periodic oscillations in gene transcription. This phenomenon has broad ramifications in physiologic function. Recent work has disclosed more cycles in gene transcription, and to the uncovering of these we apply a novel signal processing methodology known as the pencil method and compare it to conventional parametric, nonparametric, and statistical methods. Methods: In order to assess periodicity of gene expression over time, we analyzed a database derived from livers of mice entrained to a 12-hour light/12-hour dark cycle. We also analyzed artificially generated signals to identify differences between the pencil decomposition and other alternative methods.\n\nResultsThe pencil decomposition revealed hitherto-unsuspected oscillations in gene transcription with 12-hour periodicity. The pencil method was robust in detecting the 24-hour circadian cycle that was known to exist, as well as confirming the existence of shorter-period oscillations. A key consequence of this approach is that orthogonality of the different oscillatory components can be demonstrated. thus indicating a biological independence of these oscillations, that has been subsequently confirmed empirically by knocking out the gene responsible for the 24-hour clock.\n\nConclusionSystem identification techniques can be applied to biological systems and can uncover important characteristics that may elude visual inspection of the data. Significance: The pencil method provides new insights on the essence of gene expression and discloses a wide variety of oscillations in addition to the well-studied circadian pattern. This insight opens the door to the study of novel mechanisms by which oscillatory gene expression signals exert their regulatory effect on cells to influence human diseases.

cell biology↗

bioRxiv2017

Sparse Tensor Decomposition For Haplotype Assembly Of Diploids And Polyploids

A framework that formulates haplotype assembly as sparse tensor decomposition is proposed. The problem is cast as that of decomposing a tensor having special structural constraints and missing a large fraction of its entries into a product of two factors, U and [Formula]; tensor [Formula] reveals haplotype information while U is a sparse matrix encoding the origin of erroneous sequencing reads. An algorithm, AltHap, which reconstructs haplotypes of either diploid or poly-ploid organisms by solving this decomposition problem is proposed. Starting from a judiciously selected initial point, AltHap alternates between two optimization tasks to recover U and [Formula] by relying on a modified gradient descent search that exploits salient structural properties of U and [Formula]. The performance and convergence properties of AltHap are theoretically analyzed and, in doing so, guarantees on the achievable minimum error correction scores and correct phasing rate are established. AltHap was tested in a number of different scenarios and was shown to compare favorably to state-of-the-art methods in applications to haplotype assembly of diploids, and significantly outperform existing techniques when applied to haplotype assembly of polyploids.

bioinformatics↗

bioRxiv2017

Kek-6: A Truncated Trk-Like Receptor For Drosophila Neurotrophin 2 Regulates Structural Synaptic Plasticity

Neurotrophism, structural plasticity, learning and long-term memory in mammals critically depend on neurotrophins binding Trk receptors to activate tyrosine kinase (TyrK) signalling, but Drosophila lacks full-length Trks, raising the question of how these processes occur in the fly. Paradoxically, truncated Trk isoforms lacking the TyrK predominate in the adult human brain, but whether they have neuronal functions independently of full-length Trks is unknown. Drosophila has TyrK-less Trk-family receptors, encoded by the kekkon (kek) genes, suggesting that evolutionarily conserved functions for this receptor class may exist. Here, we asked whether Keks function together with Drosophila neurotrophins (DNTs) at the larval glutamatergic neuromuscular junction (NMJ). Starting with an unbiased approach, we tested the evelen LRR and Ig-containing (LIG) proteins encoded in the Drosophila genome for expression in the central nervous system (CNS) and potential interaction with DNTs. Kek-6 was expressed in the CNS, could interact genetically with DNTs and could bind DNT2 both in signaling essays and in co-immunoprecipitations. There is promiscuity in ligand binding, as Kek-6 could also bind DNT1, and Kek-5 could also bind DNT2. In vivo, Kek-6 is found presynaptically in motoneurons, and binds DNT2 produced by the muscle, which functions as a retrograde factor at the NMJ. Kek-6 and DNT2 regulate NMJ growth, bouton formation and active zone homeostasis. Kek-6 does not antagonise the alternative DNT2 receptor Toll-6, but rather the two receptors contribute in distinct manners to NMJ structural plasticity. Using pull-down assays, we identified and validated CaMKII and VAP33A as intracellular partners of Kek-6, and show that together they regulate NMJ growth and active zone formation. These functions of Kek-6 could be evolutionarily conserved, raising the intriguing possibility that a novel mechanism of structural synaptic plasticity involving truncated Trk-family receptors independently of TyrK signaling may also operate in the human brain.\n\nAUTHOR SUMMARYA long-standing paradox had been to explain how brain structural plasticity, learning and long-term memory might occur in Drosophila in the absence of canonical Trk receptors for neurotrophin (NT) ligands. NTs link structure and function in the brain enabling adjustments in cell number, dendritic, axonal and synaptic patterns, in response to neuronal activity. These events are essential for brain development, learning and long-term memory, and are thought to depend on the tyrosine-kinase function of the NT Trk receptors. However, paradoxically, the most abundant Trk isoforms in the adult human brain lack the tyrosine kinase, and their neuronal function is unknown. Remarkably, Drosophila has kinase-less receptors of the Trk family encoded by the kekkon (kek) genes, suggesting that deep evolutionary functional conservation for this receptor class could be unveiled. Here, we show that Kek-6 is a receptor for Drosophila neurotrophin 2 (DNT2) that regulates structural synaptic plasticity via CaMKII and VAP33A, well-known factors regulating synaptic structure and plasticity, and vesicle release. Our findings suggest that in mammals truncated Trk-family receptors could also have synaptic functions in neurons independently of Tyrosine kinase signalling. This might reveal a novel mechanism of brain plasticity, with important implications for understanding also the human brain, in health and disease.

developmental biology↗

bioRxiv2017

Identification of drug candidates that enhance pyrazinamide activity from a clinical drug library

Tuberculosis (TB) remains a leading cause of morbidity and mortality globally despite the availability of the TB therapy. 1 The current TB therapy is lengthy and suboptimal, requiring a treatment time of at least 6 months for drug susceptible TB and 9-12 months (shorter Bangladesh regimen) or 18-24 months (regular regimen) for multi-drug-resistant tuberculosis (MDR-TB). 1 The lengthy therapy makes patient compliance difficult, which frequently leads to emergence of drug-resistant strains. The requirement for the prolonged treatment is thought to be due to dormant persister bacteria which are not effectively killed by the current TB drugs, except rifampin and pyrazinamide (PZA) which have higher activity against persisters. 2, 3 Therefore new therapies should address the problem of insufficient efficacy against M. tuberculosis persisters, which could cause relapse of clinical disease. 4 PZA is a critical frontline TB drug that kills persister bacteria 5 and shortens the TB treatment from 9-12 months to 6 months. 6, 7 Although several new TB drugs are showing promise in clinical studies, none can replace PZA as they all have to be used together with PZA. 7 Because of the essentiality of PZA and the high cost of developing new drugs, in this study, we explored the idea of identifying drugs that enhance the anti-persister activity of PZA as an economic alternative approach to developing new drugs for improved treatment by screening an clinical drug library against old M. tuberculosis cultures enriched with persisters.

microbiology↗