novoPathFinder: a webserver of designing novel-pathway with integrating GEM-model

To increase the number of value-added chemicals that can be produced by metabolic engineering and synthetic biology, constructing metabolic space with novel reactions/pathways is crucial. However, with the large number of reactions that existed in the metabolic space and complicated metabolisms within hosts, identifying novel pathways linking two molecules or heterologous pathways when engineering a host to produce a target molecule is an arduous task. Hence, we built a user-friendly web server, novoPathFinder, which has several features: (i) enumerate novel pathways between two specified molecules without considering hosts; (ii) construct heterologous pathways with known or putative reactions for producing target molecule within Escherichia coli or yeast without giving precursor; (iii) estimate novel pathways with considering several categories, including enzyme promiscuity, Synthetic Complex Score (SCScore) and LD50 of intermediates, overall stoichiometric conversions, pathway length, theoretical yields and thermodynamic feasibility. According to the results, novoPathFinder is more capable to recover experimentally validated pathways when comparing other rule-based web server tools. Besides, more efficient pathways with novel reactions could also be retrieved for further experimental exploration. novoPathFinder is available at http://design.rxnfinder.org/novopathfinder/

MCF2Chem: A manually curated knowledge base of biosynthetic compound production

Abstract Background Microbes have been used as cell factories to synthesize various chemical compounds. Recent advances in synthetic biological technologies have accelerated the increase in the number and capacity of microbial cell factories; the variety and number of synthetic compounds produced via these cell factories have also grown substantially. However, no database is available that provides detailed information on the microbial cell factories and the synthesized compounds. Results In this study, we established MCF2Chem, a manually curated knowledge base on the production of biosynthetic compounds using microbial cell factories. It contains 8888 items of production records related to 1231 compounds that were synthesizable by 590 microbial cell factories, including the production data of compounds (titer, yield, productivity, and content), strain culture information (culture medium, carbon source/precursor/substrate), fermentation information (mode, vessel, scale, and condition), and other information (e.g., strain modification method). The database contains statistical analyses data of compounds and microbial species. The data statistics of MCF2Chem showed that bacteria accounted for 60% of the species and that “fatty acids”, “terpenoids”, and “shikimates and phenylpropanoids” accounted for the top three chemical products. Escherichia coli, Saccharomyces cerevisiae, Yarrowia lipolytica, and Corynebacterium glutamicum synthesized 78% of these chemical compounds. Furthermore, we constructed a system to recommend microbial cell factories suitable for synthesizing target compounds and vice versa by combining MCF2Chem data, additional strain- and compound-related data, the phylogenetic relationships between strains, and compound similarities. Conclusions MCF2Chem provides a user-friendly interface for querying, browsing, and visualizing detailed statistical information on microbial cell factories and their synthesizable compounds. It is publicly available at https://mcf.lifesynther.com . This database may serve as a useful resource for synthetic biologists

RDBridge: a knowledge graph of rare diseases based on large-scale text mining

Motivation: Despite low prevalence, rare diseases affect 300 million people worldwide. Research on pathogenesis and drug development lags due to limited commercial potential, insufficient epidemiological data, and a dearth of publications. The unique characteristics of rare diseases, including limited annotated data, intricate processes for extracting pertinent entity relationships, and difficulties in standardizing data, represent challenges for text mining. Results: We developed a rare disease data acquisition framework using text mining and knowledge graphs and constructed the most comprehensive rare disease knowledge graph to date, Rare Disease Bridge (RDBridge). RDBridge offers search functions for genes, potential drugs, pathways, literature, and medical imaging data that will support mechanistic research, drug development, diagnosis, and treatment for rare diseases. Availability and implementation: RDBridge is freely available at http://rdb.lifesynther.com/.ISSN:1367-4803ISSN:1460-205

Identification and characterization of the glucose dual-affinity transport system in Neurospora crassa: pleiotropic roles in nutrient transport, signaling, and carbon catabolite repression

Abstract Background The glucose dual-affinity transport system (low- and high-affinity) is a conserved strategy used by microorganisms to cope with natural fluctuations in nutrient availability in the environment. The glucose-sensing and uptake processes are believed to be tightly associated with cellulase expression regulation in cellulolytic fungi. However, both the identities and functions of the major molecular components of this evolutionarily conserved system in filamentous fungi remain elusive. Here, we systematically identified and characterized the components of the glucose dual-affinity transport system in the model fungus Neurospora crassa . Results Using RNA sequencing coupled with functional transport analyses, we assigned GLT-1 ( K m \ua0=\ua018.42\ua0\ub1\ua03.38\ua0mM) and HGT-1/-2 ( K m \ua0=\ua016.13\ua0\ub1\ua00.95 and 98.97\ua0\ub1\ua022.02\ua0\ub5M) to the low- and high-affinity glucose transport systems, respectively. The high-affinity transporters hgt - 1/ - 2 complemented a moderate growth defect under high glucose when glt - 1 was deleted. Simultaneous deletion of hgt - 1/ - 2 led to extensive derepression of genes for plant cell wall deconstruction in cells grown on cellulose. The suppression by HGT-1/-2 was connected to both carbon catabolite repression (CCR) and the cyclic adenosine monophosphate-protein kinase A pathway. Alteration of a residue conserved across taxa in hexose transporters resulted in a loss of glucose-transporting function, whereas CCR signal transduction was retained, indicating dual functions for HGT-1/-2 as \u201ctransceptors.\u201d Conclusions In this study, GLT-1 and HGT-1/-2 were identified as the key components of the glucose dual-affinity transport system, which plays diverse roles in glucose transport and carbon metabolism. Given the wide conservation of the glucose dual-affinity transport system across fungal species, the identification of its components and their pleiotropic roles in this study shed important new light on the molecular basis of nutrient transport, signaling, and plant cell wall degradation in fungi

The Putative Cellodextrin Transporter-like Protein CLP1 Is Involved in Cellulase Induction inNeurospora crassa

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Parallel Evolution of Chromatin Structure Underlying Metabolic Adaptation

Parallel evolution occurs when a similar trait emerges in independent evolutionary lineages. Although changes in protein coding and gene transcription have been investigated as underlying mechanisms for parallel evolution, parallel changes in chromatin structure have never been reported. Here, Saccharomyces cerevisiae and a distantly related yeast species, Dekkera bruxellensis, are investigated because both species have independently evolved the capacity of aerobic fermentation. By profiling and comparing genome sequences, transcriptomic landscapes, and chromatin structures, we revealed that parallel changes in nucleosome occupancy in the promoter regions of mitochondria-localized genes led to concerted suppression of mitochondrial functions by glucose, which can explain the metabolic convergence in these two independent yeast species. Further investigation indicated that similar mutational processes in the promoter regions of these genes in the two independent evolutionary lineages underlay the parallel changes in chromatin structure. Our results indicate that, despite several hundred million years of separation, parallel changes in chromatin structure, can be an important adaptation mechanism for different organisms. Due to the important role of chromatin structure changes in regulating gene expression and organism phenotypes, the novel mechanism revealed in this study could be a general phenomenon contributing to parallel adaptation in nature

Exploring the Spatial and Temporal Distribution of Frigate Tuna (<i>Auxis thazard</i>) Habitat in the South China Sea in Spring and Summer during 2015–2019 Using Fishery and Remote Sensing Data

Frigate tuna Auxis thazard fishery is considered a potential marine resource in the open South China Sea (SCS). However, little is known about the spatial and temporal distribution of its habitat, and how this may respond to environmental changes. Using fish survey and remote sensing data from 2015–2019, we applied generalized additive models to identify relationships between environmental factors and the distribution of A. thazard in the SCS. To examine seasonal patterns in the habitat of A. thazard in the SCS, we generated a habitat suitability index model using environmental factors screened by generalized additive models. Results showed that A. thazard migrates from south to north in the SCS, and its suitable habitat is patchily distributed. Significant environmental factors affecting the habitat of A. thazard distribution were different in different seasons; we demonstrated A. thazard to be sensitive to Chl-a in spring (optimum 0.155, optimal range ~0.1252–0.1840), and in summer to be sensitive to SST (optimum 30.405, optimal range ~29.789–31.021) and SSH (optimum 0.741, optimal range ~0.618–0.864). Suitable habitat in spring occurs mainly in northeastern areas, while in summer it occurs mainly around the southeastern Nansha Islands. Compared with that in spring, the area of suitable habitat increases in summer, as does the habitat suitability index of the entire sea area. These results improve our understanding of environmental factors that affect the distribution of A. thazard habitat in the SCS, and provide a scientific basis for the development and management of A. thazard resources

SynBioTools: a one-stop facility for searching and selecting synthetic biology tools

Abstract Background The rapid development of synthetic biology relies heavily on the use of databases and computational tools, which are also developing rapidly. While many tool registries have been created to facilitate tool retrieval, sharing, and reuse, no relatively comprehensive tool registry or catalog addresses all aspects of synthetic biology. Results We constructed SynBioTools, a comprehensive collection of synthetic biology databases, computational tools, and experimental methods, as a one-stop facility for searching and selecting synthetic biology tools. SynBioTools includes databases, computational tools, and methods extracted from reviews via SCIentific Table Extraction, a scientific table-extraction tool that we built. Approximately 57% of the resources that we located and included in SynBioTools are not mentioned in bio.tools, the dominant tool registry. To improve users’ understanding of the tools and to enable them to make better choices, the tools are grouped into nine modules (each with subdivisions) based on their potential biosynthetic applications. Detailed comparisons of similar tools in every classification are included. The URLs, descriptions, source references, and the number of citations of the tools are also integrated into the system. Conclusions SynBioTools is freely available at https://synbiotools.lifesynther.com/ . It provides end-users and developers with a useful resource of categorized synthetic biology databases, tools, and methods to facilitate tool retrieval and selection

Evidence of a Critical Role for Cellodextrin Transporte 2 (CDT-2) in Both Cellulose and Hemicellulose Degradation and Utilization in <i>Neurospora crassa</i>

<div><p>CDT-1 and CDT-2 are two cellodextrin transporters discovered in the filamentous fungus <i>Neurospora crassa</i>. Previous studies focused on characterizing the role of these transporters in only a few conditions, including cellulose degradation, and the function of these two transporters is not yet completely understood. In this study, we show that deletion of <i>cdt-2</i>, but not <i>cdt-1</i>, results in growth defects not only on Avicel but also on xylan. <i>cdt-2</i> can be highly induced by xylan, and this mutant has a xylodextrin consumption defect. Transcriptomic analysis of the <i>cdt-2</i> deletion strain on Avicel and xylan showed that major cellulase and hemicellulase genes were significantly down-regulated in the <i>cdt-2</i> deletion strain and artificial over expression of <i>cdt-2</i> in <i>N. crassa</i> increased cellulase and hemicellulase production. Together, these data clearly show that CDT-2 plays a critical role in hemicellulose sensing and utilization. This is the first time a sugar transporter has been assigned a function in the hemicellulose degradation pathway. Furthermore, we found that the transcription factor XLR-1 is the major regulator of <i>cdt-2</i>, while <i>cdt-1</i> is primarily regulated by CLR-1. These results deepen our understanding of the functions of both cellodextrin transporters, particularly for CDT-2. Our study also provides novel insight into the mechanisms for hemicellulose sensing and utilization in <i>N. crassa</i>, and may be applicable to other cellulolytic filamentous fungi.</p></div

Xylobiose and xylotriose consumption by WT, Δ<i>cdt-2</i> and Pc-<i>cdt-2</i>.

<p>All strains were grown in liquid MM media for 16% xylan or 0.5% sucrose. Ten milliliters of mycelia were collected and incubated with 90 µM of either xylobiose or xylotriose for 15 min. The mean and deviation represent three independent measurements. *<i>P</i><0.05 (two sided student’s t-test).</p