Enteropathway: the metabolic pathway database for the human gut microbiota.

The human gut microbiota produces diverse, extensive metabolites that have the potential to affect host physiology. Despite significant efforts to identify metabolic pathways for producing these microbial metabolites, a comprehensive metabolic pathway database for the human gut microbiota is still lacking. Here, we present Enteropathway, a metabolic pathway database that integrates 3269 compounds, 3677 reactions, and 876 modules that were obtained from 1012 manually curated scientific literature. Notably, 698 modules of these modules are new entries and cannot be found in any other databases. The database is accessible from a web application (https://enteropathway.org) that offers a metabolic diagram for graphical visualization of metabolic pathways, a customization interface, and an enrichment analysis feature for highlighting enriched modules on the metabolic diagram. Overall, Enteropathway is a comprehensive reference database that can complement widely used databases, and a tool for visual and statistical analysis in human gut microbiota studies and was designed to help researchers pinpoint new insights into the complex interplay between microbiota and host metabolism.

Mouse Model of Parkinson's Disease with Bilateral Dorsal Striatum Lesion with 6-Hydroxydopamine Exhibits Cognitive Apathy-like Behavior.

Among the symptoms of Parkinson's disease (PD), apathy comprises a set of behavioral, affective, and cognitive features that can be classified into several subtypes. However, the pathophysiology and brain regions that are involved in these different apathy subtypes are still poorly characterized. We examined which subtype of apathy is elicited in a mouse model of PD with 6-hydroxydopamine (6-OHDA) lesions and the behavioral symptoms that are exhibited. Male C57/BL6J mice were allocated to sham (n = 8) and 6-OHDA (n = 13) groups and locally injected with saline or 4 µg 6-OHDA bilaterally in the dorsal striatum. We then conducted motor performance tests and apathy-related behavioral experiments. We then pathologically evaluated tyrosine hydroxylase (TH) immunostaining. The 6-OHDA group exhibited significant impairments in motor function. In the behavioral tests of apathy, significant differences were observed between the sham and 6-OHDA groups in the hole-board test and novelty-suppressed feeding test. The 6-OHDA group exhibited impairments in inanimate novel object preference, whereas social preference was maintained in the three-chamber test. The number of TH+ pixels in the caudate putamen and substantia nigra compacta was significantly reduced in the 6-OHDA group. The present mouse model of PD predominantly showed dorsal striatum dopaminergic neuronal loss and a decrease in novelty seeking as a symptom that is related to the cognitive apathy component.

Heterozygous and homozygous gene knockout of the 5-HT1B receptor have different effects on methamphetamine-induced behavioral sensitization.

The psychostimulant drug methamphetamine (METH) causes euphoria in humans and locomotor hyperactivity in rodents by acting on the mesolimbic dopamine (DA) pathway and has severe abuse and addiction liability. Behavioral sensitization, an increased behavioral response to a drug with repeated administration, can persist for many months after the last administration. Research has shown that the serotonin 1B (5-HT1B) receptor plays a critical role in the development and maintenance of drug addiction, as well as other addictive behaviors. This study examined the role of 5-HT1B receptors in METH-induced locomotor sensitization using 5-HT1B knockout (KO) mice. To clarify the action of METH in 5-HT1B KO mice the effects of METH on extracellular levels of DA (DAec) and 5-HT (5-HTec) in the caudate putamen (CPu) and the nucleus accumbens (NAc) were examined. Locomotor sensitization and extracellular monoamine levels were determined in wild-type mice (5-HT1B +/+), heterozygous 5-HT1B receptor KO (5-HT1B +/-) mice and homozygous 5-HT1B receptor KO mice (5-HT1B -/-). Behavioral sensitization to METH was enhanced in 5-HT1B -/- mice compared to 5-HT1B +/+ mice but was attenuated in 5-HT1B +/- mice compared to 5-HT1B +/+ and 5-HT1B -/- mice. In vivo, microdialysis demonstrated that acute administration of METH increases DAec levels in the CPu and NAc of 5-HT1B KO mice compared to saline groups. In 5-HT1B +/- mice, METH increased 5-HTec levels in the CPu, and DAec levels in the NAc were higher than in others.5-HT1B receptors play an important role in regulating METH-induced behavioral sensitization.

Role for µ-opioid receptor in antidepressant effects of δ-opioid receptor agonist KNT-127.

Previous pharmacological data have shown the possible existence of functional interactions between µ- (MOP), κ- (KOP), and δ-opioid receptors (DOP) in pain and mood disorders. We previously reported that MOP knockout (KO) mice exhibit a lower stress response compared with wildtype (WT) mice. Moreover, DOP agonists have been shown to exert antidepressant-like effects in numerous animal models. In the present study, the tail suspension test (TST) and forced swim test (FST) were used to examine the roles of MOP and DOP in behavioral despair. MOP-KO mice and WT mice were treated with KNT-127 (10 mg/kg), a selective DOP agonist. The results indicated a significant decrease in immobility time in the KNT-127 group compared with the saline group in all genotypes in both tests. In the saline groups, immobility time significantly decreased in MOP-KO mice compared with WT mice in both tests. In female MOP-KO mice, KNT-127 significantly decreased immobility time in the TST compared with WT mice. In male MOP-KO mice, however, no genotypic differences were found in the TST after either KNT-127 or saline treatment. Thus, at least in the FST and TST, the activation of DOP and absence of MOP had additive effects in reducing measures of behavioral despair, suggesting that effects on this behavior by DOP activation occur independently of MOP.

Overexpression of tyrosine hydroxylase in dopaminergic neurons increased sensitivity to methamphetamine.

Drug abuse is one of the great social problems in the world and a major healthcare challenge. It is supposed that sensitivity and reactivity to abuse drugs may vary from person to person, while its molecular basis is largely unknown. Dopaminergic neurons are deeply involved in addiction, and tyrosine hydroxylase (TH) catalyzes the first and rate-limiting step of the biosynthesis of dopamine (DA). We investigated the effects of increased TH expression on the metabolism of DA and reactivity to methamphetamine (METH), a drug of abuse, in mice. Wild-type TH (WT-TH) or the S40E mutant of TH (S40E-TH), which is an active form of TH mimicking phosphorylated TH at the 40th serine, was expressed in midbrain dopaminergic neurons using an adeno-associated virus (AAV) vector. The biochemical analysis showed that the turnover rates of DA in the nerve terminals were increased by the expression of WT-TH and S40E-TH, while there were few changes in the DA contents. Next, we administered METH to TH-overexpressing mice. We found that the S40E-TH-expressing mice responded to lower doses of METH than the control mice and WT-TH mice. The stereotyped behaviors appeared first in S40E-TH mice and then in WT-TH and control mice in this order. These data showed that the TH activity and expression level differentially affect DA metabolism in the nerve terminals from that in the cell bodies and that the TH activity and expression level are one of the determining factors for sensitivity and reactivity to METH. We suggest that TH may be a drug target for ameliorating sensitivity to drugs of abuse.

DIRECT ASSIMILATION OF ATMOSPHERIC CARBON BY IMMATURE APPLE FRUITS.

Although fruit development primarily depends on photoassimilation by leaves, immature green fruits can also directly assimilate atmospheric CO2. To elucidate the process of C accumulation due to direct assimilation by fruit, we conducted a 13CO2 exposure experiment in an orchard in late June with immature 'Fuji' apples (Malus domestica). Four fruits from three trees were enclosed in transparent plastic bags and exposed to 13CO2 using an in-situ exposure system. Fruits were collected prior to and immediately following exposure in early July, late September and mid-November, and 13C concentrations in the peduncle, skin, flesh and core (including seeds) were measured. The higher assimilated 13C concentrations measured following exposure indicated that the fruits directly assimilated atmospheric 13C. The 13C concentration in fruit skin was higher immediately after exposure and in early July compared with that prior to exposure. In late September and mid-November, 13C concentrations were close to natural levels.

EXPERIMENTAL EVALUATION OF DISTRIBUTION OF 14C PHOTOASSIMILATED INTO CARBOHYDRATES IN DIFFERENT GROWTH STAGES OF FRUIT-BEARING APPLE SHOOTS USING A 13CO2 IN-SITU EXPOSURE SYSTEM.

In this study, we aimed to investigate the photoassimilation process of 14CO2 into agricultural plants through determining the photoassimilated carbohydrate-13C in each part (leaves, current branch and fruit) of the fruit-bearing apple shoots exposed to 13CO2 in different growth stages (early and late fruit development stages). The carbohydrate content was assessed as soluble (ethanol-extracted fraction) and other (HCl-extracted and residual fractions) components. The total (i.e. sum of the three fractions) bulk carbohydrate concentrations in all parts of the shoots were statistically similar between different growth stages. The changes in the concentration of 13C-labeled soluble carbohydrate (i.e. ethanol-extracted fraction) to the total content between different growth stages were statistically unclear among all parts of the shoot. These results suggest that the distribution ratio of photoassimilated 13C in soluble and other components in the apple shoot was thereabout constantly independent of the growth stages.

DEVELOPMENT OF IN-SITU SYSTEMS FOR 13CO2 EXPOSURE AND DETERMINATION OF 13C NET ASSIMILATION RATE OF FRUIT-BEARING SHOOTS AND WHOLE TREE AND CHAMBER FOR PRECISION 13CO2 EXPOSURE OF YOUNG POTTED TREES.

14C is the most important radionuclide for assessing exposure dose around the Rokkasho nuclear fuel reprocessing plant, Aomori Prefecture, Japan. A simplified model with ample margins has been used so far for the assessment of the dose derived from 14C. Realistic dose estimate of 14C using more realistic model is necessary for safety. Apple production is an important core industry in Aomori Prefecture. To construct the dynamic model for apple, using 13C as a tracer to substitute for 14C, we collected data on 13C abundance in organs including fruit after 13CO2 exposure at various fruit growth stages. We developed 13CO2 exposure systems for three intact fruit-bearing shoots (1), whole mature tree (2) and young potted trees (3). Systems (1) and (2) also can determine net amounts of carbon and 13C photoassimilated. System (3) is capable of precise feedback control of 13CO2 and 12CO2 concentrations based on on-time determination.

TogoID: an exploratory ID converter to bridge biological datasets.

MOTIVATION: Understanding life cannot be accomplished without making full use of biological data, which are scattered across databases of diverse categories in life sciences. To connect such data seamlessly, identifier (ID) conversion plays a key role. However, existing ID conversion services have disadvantages, such as covering only a limited range of biological categories of databases, not keeping up with the updates of the original databases and outputs being hard to interpret in the context of biological relations, especially when converting IDs in multiple steps. RESULTS: TogoID is an ID conversion service implementing unique features with an intuitive web interface and an application programming interface (API) for programmatic access. TogoID currently supports 65 datasets covering various biological categories. TogoID users can perform exploratory multistep conversions to find a path among IDs. To guide the interpretation of biological meanings in the conversions, we crafted an ontology that defines the semantics of the dataset relations. AVAILABILITY AND IMPLEMENTATION: The TogoID service is freely available on the TogoID website (https://togoid.dbcls.jp/) and the API is also provided to allow programmatic access. To encourage developers to add new dataset pairs, the system stores the configurations of pairs at the GitHub repository (https://github.com/togoid/togoid-config) and accepts the request of additional pairs. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Improvement in Dacryoendoscopic Visibility after Image Processing Using Comb-Removal and Image-Sharpening Algorithms.

Recently, a minimally invasive treatment for lacrimal passage diseases was developed using dacryoendoscopy. Good visibility of the lacrimal passage is important for examination and treatment. This study aimed to investigate whether image processing can improve the dacryoendoscopic visibility using comb-removal and image-sharpening algorithms. We processed 20 dacryoendoscopic images (original images) using comb-removal and image-sharpening algorithms. Overall, 40 images (20 original and 20 post-processing) were randomly presented to the evaluators, who scored each image on a 10-point scale. The scores of the original and post-processing images were compared statistically. Additionally, in vitro experiments were performed using a test chart to examine whether image processing could improve the dacryoendoscopic visibility in a turbid fluid. The visual score (estimate ± standard error) of the images significantly improved from 3.52 ± 0.26 (original images) to 5.77 ± 0.28 (post-processing images; p < 0.001, linear mixed-effects model). The in vitro experiments revealed that the contrast and resolution of images in the turbid fluid improved after image processing. Image processing with our comb-removal and image-sharpening algorithms improved dacryoendoscopic visibility. The techniques used in this study are applicable for real-time processing and can be easily introduced in clinical practice.

In situ experimental exposure of fruit-bearing shoots of apple trees to 13CO2 and construction of a dynamic transfer model of carbon.

Evaluating the transfer and metabolism of carbon (C) in apple fruit is key to estimating the potential accumulation of atmospheric 14C in fruit near and around nuclear facilities. We developed a dynamic compartment model for apple fruit-bearing shoots, assuming that the shoots are a simple unit of source and sink for photoassimilates. Fruit-bearing shoots of Malus domestica "Fuji" at different fruit growth stages were exposed to 13CO2in situ, followed by sampling at 72 h after exposure or at harvest. The 13C/(13C+12C) mole ratio in fruits, leaves, and current branch were measured to construct a five-compartment model of 13C (fruit, each fast and slow component of leaves, and current branch). The C inventories in the compartments were presented in accordance with the measured growth curves of C in the organs. The model simulated the 13C dynamics in plant tissues well. Simulation results of photoassimilate distribution using the model indicated that the retention of photoassimilated C at the harvest depended on the growth rate of C in the organs at the exposure.

Stereopsis and retinal microstructures following macular hole surgery.

The aim of this prospective study was to evaluate the changes in stereopsis in patients who underwent vitrectomy for macular hole (MH) and assess the relationship between stereopsis and retinal microstructures. Fifty-two patients who underwent successful vitrectomy for unilateral MH and 20 control participants were recruited. We examined stereopsis using the Titmus Stereo Test (TST) and TNO stereotest (TNO), optical coherence tomography, and best-corrected visual acuity measurements, preoperatively, and at 3, 6, and 12 months postoperatively. As a result, preoperative and postoperative 3, 6, and 12-month values of stereopsis assessed by TST (log) were 2.7, 2.2, 2.2, and 2.2, respectively. TNO (log) were 2.8, 2.5, 2.4, and 2.4, respectively. Stereopsis in MH after surgery was significantly worse than that in normal participants (p < 0.001). Preoperative TST significantly correlated with MH size and defect length of external limiting membrane (ELM). Postoperative TST demonstrated significant correlation with the preoperative ELM defect length, and postoperative TNO was associated with the preoperative interdigitation zone defect length. Vitrectomy for MH significantly improved stereopsis, although not to normal levels. The ELM defect lengths, which approximately correspond to TST circles, are prognostic factors for postoperative stereopsis by TST. The interdigitation zone defect length, similar in size to the TNO index, is a prognostic factor for postoperative stereopsis by TNO.

BioHackathon 2015: Semantics of data for life sciences and reproducible research.

We report on the activities of the 2015 edition of the BioHackathon, an annual event that brings together researchers and developers from around the world to develop tools and technologies that promote the reusability of biological data. We discuss issues surrounding the representation, publication, integration, mining and reuse of biological data and metadata across a wide range of biomedical data types of relevance for the life sciences, including chemistry, genotypes and phenotypes, orthology and phylogeny, proteomics, genomics, glycomics, and metabolomics. We describe our progress to address ongoing challenges to the reusability and reproducibility of research results, and identify outstanding issues that continue to impede the progress of bioinformatics research. We share our perspective on the state of the art, continued challenges, and goals for future research and development for the life sciences Semantic Web.

Vision-related parameters that affect stereopsis in patients with macular hole.

This study evaluated stereopsis and other visual functions in patients with idiopathic macular hole (MH), and sought to identify vision-related parameters that affect stereopsis. In this prospective, consecutive, comparative study, 39 eyes of 39 patients with unilateral idiopathic MH were included. At baseline and at 6 months after MH surgery, we evaluated stereopsis, with the Titmus stereo test (TST) and TNO stereotest (TNO), best-corrected visual acuity (BCVA), letter contrast sensitivity, severity of metamorphopsia, as assessed using M-CHARTS, and extent of aniseikonia, by the new aniseikonia test. Preoperative stereopsis (log) in patients with MH were 2.72 ± 0.53 (range 1.9-4.1) in the TST and 2.82 ± 0.65 (range 1.8-3.9) in the TNO. Preoperative TST was significantly correlated with letter contrast sensitivity (p < 0.05), but not with the other visual functions. TNO showed significant correlation with letter contrast sensitivity (p < 0.05) and aniseikonia (p < 0.005). Preoperative TNO was associated with aniseikonia by multivariate analysis (p < 0.005). MH surgery significantly improved stereopsis, BCVA, letter contrast sensitivity, metamorphopsia, and aniseikonia. Postoperative TST and TNO was significantly associated with BCVA by multivariate analysis. Deterioration of stereopsis in MH patients is associated with contrast sensitivity and the degree of aniseikonia.

Targeted enzyme gene re-positioning: A computational approach for discovering alternative bacterial enzymes for the synthesis of plant-specific secondary metabolites.

Plant-biosynthesised secondary metabolites are unique sources of pharmaceuticals, food additives, and flavourings, among other industrial uses. However, industrial production of these metabolites is difficult because of their structural complexity, dangerousness and unfriendliness to natural environment, so the development of new methods to synthesise them is required. In this study, we developed a novel approach to identifying alternative bacterial enzyme to produce plant-biosynthesised secondary metabolites. Based on the similarity of enzymatic reactions, we searched for candidate bacterial genes encoding enzymes that could potentially replace the enzymes in plant-specific secondary metabolism reactions that are contained in the KEGG database (enzyme re-positioning). As a result, we discovered candidate bacterial alternative enzyme genes for 447 plant-specific secondary metabolic reaction. To validate our approach, we focused on the ability of an enzyme from Streptomyces coelicolor strain A3(2) strain to convert valencene to the grapefruit metabolite nootkatone, and confirmed its enzymatic activity by gas chromatography-mass spectrometry. This enzyme re-positioning approach may offer an entirely new way of screening enzymes that cannot be achieved by most of other conventional methods, and it is applicable to various other metabolites and may enable microbial production of compounds that are currently difficult to produce industrially.

Surgical Outcomes of Vitrectomy for Macular Hole Retinal Detachment in Highly Myopic Eyes: A Multicenter Study.

PURPOSE: To investigate surgical outcomes of macular hole retinal detachment (MHRD) in highly myopic eyes. DESIGN: Multicenter, retrospective case study. PARTICIPANTS: One hundred ten eyes with retinal detachment resulting from macular hole (MH) were evaluated. METHODS: The medical records of consecutive patients who underwent vitrectomy between January 2010 and December 2015, inclusive, to treat MHRD in 10 hospitals of the Japan Clinical Retinal Study Team were reviewed. MAIN OUTCOME MEASURES: Retinal reattachment rate and MH closure rate after the initial surgery. RESULTS: One hundred ten eyes of 110 patients were studied. The retina was reattached in 85% of eyes and MH was closed in 52% of eyes after the initial surgery. Eyes with gas tamponade achieved higher reattachment rate than those with silicone oil tamponade. CONCLUSIONS: The gas tamponade group achieved better retinal reattachment rate than silicone oil tamponade group. Gas tamponade could be the first choice for MHRD.

Repeated methamphetamine treatment increases spine density in the nucleus accumbens of serotonin transporter knockout mice.

AIM: Repeated psychostimulant drug treatment, including methamphetamine, in rodents readily produces behavioral sensitization, which reflects altered brain function caused by repeated drug exposure. Dendritic remodeling of medium spiny neurons in the nucleus accumbens is thought to be an essential mechanism underlying behavioral sensitization. We recently showed that chronic methamphetamine treatment did not produce behavioral sensitization in serotonin transporter knockout mice. METHODS: In this study, we report the spine density of medium spiny neurons in the nucleus accumbens after repeated methamphetamine injection to examine morphological alterations in serotonin transporter knockout mice. RESULTS: Golgi-COX staining clearly showed that the spine density of medium spiny neurons in the nucleus accumbens increased following repeated methamphetamine treatment in both wild-type and serotonin transporter knockout mice. CONCLUSIONS: Our results suggested that augmented serotonergic neurotransmission produced by serotonin transporter deletion prevents the development of behavioral sensitization in a manner that is independent of dendritic remodeling in the nucleus accumbens.

TogoGenome/TogoStanza: modularized Semantic Web genome database.

TogoGenome is a genome database that is purely based on the Semantic Web technology, which enables the integration of heterogeneous data and flexible semantic searches. All the information is stored as Resource Description Framework (RDF) data, and the reporting web pages are generated on the fly using SPARQL Protocol and RDF Query Language (SPARQL) queries. TogoGenome provides a semantic-faceted search system by gene functional annotation, taxonomy, phenotypes and environment based on the relevant ontologies. TogoGenome also serves as an interface to conduct semantic comparative genomics by which a user can observe pan-organism or organism-specific genes based on the functional aspect of gene annotations and the combinations of organisms from different taxa. The TogoGenome database exhibits a modularized structure, and each module in the report pages is separately served as TogoStanza, which is a generic framework for rendering an information block as IFRAME/Web Components, which can, unlike several other monolithic databases, also be reused to construct other databases. TogoGenome and TogoStanza have been under development since 2012 and are freely available along with their source codes on the GitHub repositories at https://github.com/togogenome/ and https://github.com/togostanza/, respectively, under the MIT license.

The jPOST environment: an integrated proteomics data repository and database.

Rapid progress is being made in mass spectrometry (MS)-based proteomics, yielding an increasing number of larger datasets with higher quality and higher throughput. To integrate proteomics datasets generated from various projects and institutions, we launched a project named jPOST (Japan ProteOme STandard Repository/Database, https://jpostdb.org/) in 2015. Its proteomics data repository, jPOSTrepo, began operations in 2016 and has accepted more than 10 TB of MS-based proteomics datasets in the past two years. In addition, we have developed a new proteomics database named jPOSTdb in which the published raw datasets in jPOSTrepo are reanalyzed using standardized protocol. jPOSTdb provides viewers showing the frequency of detected post-translational modifications, the co-occurrence of phosphorylation sites on a peptide and peptide sharing among proteoforms. jPOSTdb also provides basic statistical analysis tools to compare proteomics datasets.

MAPLE 2.3.0: an improved system for evaluating the functionomes of genomes and metagenomes.

MAPLE is an automated system for inferring the potential comprehensive functions harbored by genomes and metagenomes. To reduce runtime in MAPLE analyzing the massive amino acid datasets of over 1 million sequences, we improved it by adapting the KEGG automatic annotation server to use GHOSTX and verified no substantial difference in the MAPLE results between the original and new implementations.