MRI scans detect 'brain rust' in schizophrenia: Oxidative stress

"Using a new kind of MRI measurement, neuroscientists reported higher levels of oxidative stress in patients with schizophrenia, when compared both to healthy individuals and those with bipolar disorder."



'via Blog this'

Gamma frequency entrainment attenuates amyloid load and modifies microglia : Nature : Nature Research

Changes in gamma oscillations (20–50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer’s disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)1–40 and Aβ 1–42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ1–40 and Aβ1–42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer’s-disease-associated pathology."




Parkinson's Disease Linked to Microbiome | Caltech

Caltech scientists have discovered for the first time a functional link between bacteria in the intestines and Parkinson's disease (PD). The researchers show that changes in the composition of gut bacterial populations—or possibly gut bacteria themselves—are actively contributing to and may even cause the deterioration of motor skills that is the hallmark of this disease.
When gut bacteria break down dietary fiber, they produce molecules called short-chain fatty acids (SCFAs), such as acetate and butyrate. Previous research has shown that these molecules also can activate immune responses in the brain. Thus, Mazmanian's group hypothesized that an imbalance in the levels of SCFAs regulates brain inflammation and other symptoms of PD. Indeed, when germ-free mice were fed SCFAs, cells called microglia—which are immune cells residing in the brain—became activated. Such inflammatory processes can cause neurons to malfunction or even die. In fact, germ-free mice fed SCFAs now showed motor disabilities and alpha=synuclein aggregation in regions of the brain linked to PD.





Neonatal vitamin D status and risk of multiple sclerosis



Objective: As previous research has suggested that exposure to vitamin D insufficiency in utero may have relevance for the risk of multiple sclerosis (MS), we aimed to examine the direct association between level of neonatal vitamin D and risk of MS.

 Methods: We carried out a matched case-control study. Dried blood spots samples (DBSS) belonging to 521 patients with MS were identified in the Danish Newborn Screening Biobank. For every patient with MS, 1–2 controls with the same sex and birth date were retrieved from the Biobank (n = 972). Level of 25-hydroxyvitamin D (25[OH]D) in the DBSS was measured using liquid chromatography tandem mass spectroscopy. The association between different levels of 25(OH)D and risk of MS was evaluated by odds ratios (OR) calculated in conditional logistic regression models.

 Results: We observed that lower levels of 25(OH)D in neonates were associated with an increased risk of MS. In the analysis by quintiles, MS risk was highest among individuals in the bottom quintile (<20.7 nmol/L) and lowest among those in the top quintile of 25(OH)D (≥48.9 nmol/L), with an OR for top vs bottom of 0.53 (95% confidence interval [CI] 0.36–0.78). In the analysis treating 25(OH)D as a continuous variable, a 25 nmol/L increase in neonatal 25(OH)D resulted in a 30% reduced risk of MS (OR 0.70, 95% CI 0.57–0.84).

Conclusion: Low concentrations of neonatal vitamin D are associated with an increased risk of MS. In light of the high prevalence of vitamin D insufficiency among pregnant women, our observation may have importance for public health."



'via Blog this'

A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice : Nature Medicine : Nature Research

 Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition1, 2, 3, 4, 5, 6, 7. We previously demonstrated that administration of Akkermansia muciniphila to mice prevents the development of obesity and associated complications8. However, the underlying mechanisms of this protective effect remain unclear. Moreover, the sensitivity of A. muciniphila to oxygen and the presence of animal-derived compounds in its growth medium currently limit the development of translational approaches for human medicine9. We have addressed these issues here by showing that A. muciniphila retains its efficacy when grown on a synthetic medium compatible with human administration. Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. These improvements were notably associated with a modulation of the host urinary metabolomics profile and intestinal energy absorption. We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium. Finally, we showed that administration of live or pasteurized A. muciniphila grown on the synthetic medium is safe in humans. These findings provide support for the use of different preparations of A. muciniphila as therapeutic options to target human obesity and associated disorders.

'via Blog this'

Redefining the invertebrate RNA virosphere : Nature : Nature Research

"Current knowledge of RNA virus biodiversity is both biased and fragmentary, reflecting a focus on culturable or disease-causing agents. Here we profile the transcriptomes of over 220 invertebrate species sampled across nine animal phyla and report the discovery of 1,445 RNA viruses, including some that are sufficiently divergent to comprise new families. The identified viruses fill major gaps in the RNA virus phylogeny and reveal an evolutionary history that is characterized by both host switching and co-divergence. The invertebrate virome also reveals remarkable genomic flexibility that includes frequent recombination, lateral gene transfer among viruses and hosts, gene gain and loss, and complex genomic rearrangements. Together, these data present a view of the RNA virosphere that is more phylogenetically and genomically diverse than that depicted in current classification schemes and provide a more solid foundation for studies in virus ecology and evolution."



'via Blog this'

CerefolinNAC Therapy of Hyperhomocysteinemia Delays Cortical and White Matter Atrophy in Alzheimer's Disease and Cerebrovascular Disease. - PubMed - NCBI

We examined whether using a medical food therapy for hyperhomocysteinemia (HHcy) in patients with Alzheimer's disease (AD) or cognitive impairment due to cerebrovascular disease (CVD) with Cerefolin®/CerefolinNAC® (CFLN: L-methylfolate, methylcobalamin, and N-acetyl-cysteine) slowed regional brain atrophy. Thirty HHcy patients with AD and related disorders (ADRD) received CFLN (HHcy+CFLN: duration [μ ±  σ] = 18.6±16.1 months); a sub-sample of this group did not receive CFLN for varying periods of time (HHcy+NoCFLN: duration [μ ±  σ] = 12.6±5.6 months). Thirty-seven NoHHcy patients with ADRD did not receive CFLN (NoHHcy+NoCFLN: duration [μ ±  σ] = 13.3±17.7 months). No participant took supplemental B vitamins. Regional brain volumes were measured at baseline and end of study, and covariate-adjusted rates of hippocampal, cortical, and forebrain parenchymal (includes white matter) atrophy were predicted. The HHcy+CFLN group's hippocampal and cortical atrophy adjusted rates were 4.25 and 11.2 times slower than those of the NoHHcy+NoCFLN group (p < 0.024). The HHcy+CFLN group's forebrain parenchyma atrophy rate was significantly slower only for CVD; the rate of slowing was proportional to the degree of homocysteine lowering (p < 0.0001). CFLN was associated with significantly slowed hippocampal and cortical atrophy rates in ADRD patients with HHcy, and forebrain parenchymal atrophy rates in CVD patients with HHcy. The present results should be further validated.

Largest resource of human protein-protein interactions can help interpret genomic data

Human Interactome network visualized by Cytosc...
Human Interactome network visualized by Cytoscape 2.5. (Photo credit: Wikipedia 

An international research team has developed the largest database of protein-to-protein interaction networks, a resource that can illuminate how numerous disease-associated genes contribute to disease development and progression. Led by investigators at Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard, the team's report on its development of the network called InWeb_InBioMap (InWeb_IM) is receiving advance online publication in Nature Methods.  

A scored human protein–protein interaction network to catalyze genomic interpretation

The database is at Intomics


Early role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis : Nature Communications

 Multifactorial mechanisms underlying late-onset Alzheimer’s disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system’s integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions.



'via Blog this'

Aspartame may prevent, not promote, weight loss by blocking intestinal enzyme's activity: Study identifies possible mechanism behind sugar substitute's lack of effectiveness -- ScienceDaily

A team of Massachusetts General Hospital (MGH) investigators has found a possible mechanism explaining why use of the sugar substitute aspartame might not promote weight loss. In their report published online in Applied Physiology, Nutrition and Metabolism, the researchers show how the aspartame breakdown product phenylalanine interferes with the action of an enzyme previously shown to prevent metabolic syndrome -- a group of symptoms associated with type 2 diabetes and cardiovascular disease. They also showed that mice receiving aspartame in their drinking water gained more weight and developed other symptoms of metabolic syndrome than animals fed similar diets lacking aspartame.

Aspartame blocks a gut enzyme called intestinal alkaline phosphatase (IAP) that we previously showed can prevent obesity, diabetes and metabolic syndrome; so we think that aspartame might not work because, even as it is substituting for sugar, it blocks the beneficial aspects of IAP


Probiotic normalization of Candida albicans in schizophrenia: a randomized, placebo-controlled, longitudinal pilot study

The molecules and pathways of the gut-brain axis represent new targets for developing methods to diagnose and treat psychiatric disorders. Manipulation of the gut microbiome with probiotics may be a therapeutic strategy with the potential to relieve gastrointestinal (GI) comorbidities and improve psychiatric symptoms. Candida albicans and Saccharomyces cerevisiae, commensal yeast species, can be imbalanced in the unhealthy human microbiome, and these fungal exposures were previously found elevated in schizophrenia. In a longitudinal, double-blind, placebo-controlled, pilot investigation of 56 outpatients with schizophrenia, we examined the impact of probiotic treatment on yeast antibody levels, and the relationship between treatment and antibody levels on bowel discomfort and psychiatric symptoms. We found that probiotic treatment significantly reduced C. albicans antibodies over the 14-week study period in males, but not in females. Antibody levels of S. cerevisiae were not altered in either treatment group. The highest levels of bowel discomfort over time occurred in C. albicans-seropositive males receiving the placebo. We observed trends toward improvement in positive psychiatric symptoms in males treated with probiotics who were seronegative for C. albicans. Results from this pilot study hint at an association of C. albicans seropositivity with worse positive psychiatric symptoms, which was confirmed in a larger cohort of 384 males with schizophrenia. In conclusion, the administration of probiotics may help normalize C. albicans antibody levels and C. albicans-associated gut discomfort in many male individuals. Studies with larger sample sizes are warranted to address the role of probiotics in correcting C. albicans-associated psychiatric symptoms."



'via Blog this'

Understanding how genes and the environment interact — Science AAAS

We are all products of our environment. What we eat, the microbes and parasites to which we are exposed,
and even the environment of our predecessors all play a role in our ability to reproduce and live to a ripe old age. But how external factors like these interact with our genes to produce either health or pathology is generally not well understood.

Understanding how our changing environment affects us can help us generate models that will harness our surroundings for optimal health. This booklet offers a snapshot of our current knowledge of how genes and the environment interact.

Download a free copy now to discover more about how genes are influenced by the world around us.

Common food additive promotes colon cancer in mice

 In this study, the team fed mice with two very commonly used emulsifiers, polysorbate 80 and carboxymethylcellulose, at doses seeking to model the broad consumption of the numerous emulsifiers that are incorporated into the majority of processed foods. Researchers observed that consuming emulsifiers drastically changed the species composition of the gut microbiota in a manner that made it more pro-inflammatory, creating a niche favoring cancer induction and development. Alterations in bacterial species resulted in bacteria expressing more flagellin and lipopolysaccharide, which activate pro-inflammatory gene expression by the immune system.
When using a well established model of colorectal cancer, the researchers observed that dietary emulsifier consumption was sufficient to make the animals more susceptible to developing colonic tumors because this created and maintained a pro-inflammatory environment associated with an altered proliferation/apoptosis (cell death) balance. The researchers observed that enhanced tumor development was associated with an altered intestinal microbiota, characterized by an increased pro-inflammatory potential."

Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology : Nature Communications

Basal forebrain
Basal forebrain (Photo credit: Wikipedia)
There is considerable debate whether Alzheimer’s disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin.

Host/pathogen interactomes for 18 bacterial, viral, fungal and protozoan species

Host/pathogen interactomes for diverse viruses, fungi bacteria and protozoa together with KEGG pathways

  • Bacteria and spirochetes Borrelia Burgdorferi ; Chlamydia Pneumoniae ; Helicobacter pylori ; Porphyromonas Gingivalis 
  • Fungi Candida albicans; Cryptococcus Neoformans
  • Viruses  Bornavirus;  Dengue virus ;  Ebola virus; Epstein-Barr virus ; Ebola virus; Epstein-Barr virus; Hepatitis C virus; Herpes simplex (HSV-1); HERV-W; HIV-1; Human cytomegalovirus;  Influenza A virus
  • Protozoa
  • Toxoplasma Gondii; Trypanosoma Cruzi 






Activation of CB2 Receptor System Reverses Amyloid-Induced Memory Deficiency and Restores SOX2 Activity in a Transgenic Mouse Model of Alzheimer's Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive loss of memory and cognitive function. The brains of patients with AD are characterized by extensive deposits of extracellular aggregation of amyloid-beta peptides. These peptides form senile plaques and intracellular aggregation of hyperphosphorylated tau protein. In addition, amyloid fibrils activate the inflammatory pathway, characterized by the activated microglia and astrocytes seen in the brains of patients with AD.

Cannabinoid type 2 (CB2) agonists are neuroprotective and appear to play modulatory roles in neurodegenerative processes in AD. CB2 receptors are upregulated in reactive microglial cells in AD. This upregulation of CB2 receptors tends to attenuate the activation of early pro-inflammatory microglial signaling pathways associated with AD.

Sox2 (sex-determining region Y (SRY)-box 2) is a transcriptional factor that is essential for maintaining self-renewal/proliferation of undifferentiated embryonic stem cells (ESCs) and multipotency of neural stem cells (NSCs). Sox2 behaves as a protective factor during the development of Alzheimer’s disease.

We have studied the effect of 1-((3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl) piperidine (MDA7) a novel, blood brain barrier-permeant, and highly selective CB2 agonist that lacks psychoactivity on ameliorating the neuroinflammatory process, synaptic dysfunction, and cognitive impairment in the Tg-APPsw/PSEN1DE9 (APP/PS1) mouse model of AD. APP/PS1 mice are well suited for our investigations because they exhibit high production of Aβ peptides in the brain, accumulation of amyloid plaques, and demonstrate cognitive impairments. Senile plaques can be detected by thioflavin S or 3D6 as early as 4 months of age, and there is an overall increase in plaque burden with age. PAPP/PS1 mice displayed significantly impaired glutamatergic long-term potentiation (LTP) in the hippocampal CA1 neurons, indicating an impaired synaptic plasticity. LTP is an experimental phenomenon that takes place at excitatory glutamatergic synapses and is believed to play a central role in learning and memory.

At 3 mo of age, MDA7 14 mg/kg was administered intraperitoneally (i.p.) every other day for 5 mo. Another cohort of APP/PS1 received i.p. injections of the vehicle at alternate days for 5 mo. In the APP/PS1 transgenic mice, compared to wild type mice, treatment with MDA7 (i) ameliorated the expression of Iba1 (microglia marker), (ii) promoted amyloid-beta clearance in the hippocampal CA1, (iii) restored the expression of SOX2 (stem cell marker) in the hippocampal dentate gyrus, and (iv) restored synaptic plasticity, cognition and memory. Our findings suggest that MDA7 is an innovative therapeutic approach for Alzheimer’s disease.

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

The increasing incidence of autism suggests a major environmental influence. Epidemiology has implicated many candidates and genetics many susceptibility genes. Gene/environment interactions in autism were analysed using 206 autism susceptibility genes (ASG's) from the Autworks database to interrogate ∼1 million chemical/gene interactions in the comparative toxicogenomics database. Any bias towards ASG's was statistically determined for each chemical. Many suspect compounds identified in epidemiology, including tetrachlorodibenzodioxin, pesticides, particulate matter, benzo(a)pyrene, heavy metals, valproate, acetaminophen, SSRI's, cocaine, bisphenol A, phthalates, polyhalogenated biphenyls, flame retardants, diesel constituents, terbutaline and oxytocin, inter alia showed a significant degree of bias towards ASG's, as did relevant endogenous agents (retinoids, sex steroids, thyroxine, melatonin, folate, dopamine, serotonin). Numerous other suspected endocrine disruptors (over 100) selectively targeted ASG's including paraquat, atrazine and other pesticides not yet studied in autism and many compounds used in food, cosmetics or household products, including tretinoin, soy phytoestrogens, aspartame, titanium dioxide and sodium fluoride. Autism polymorphisms influence the sensitivity to some of these chemicals and these same genes play an important role in barrier function and control of respiratory cilia sweeping particulate matter from the airways. Pesticides, heavy metals and pollutants also disrupt barrier and/or ciliary function, which is regulated by sex steroids and by bitter/sweet taste receptors. Further epidemiological studies and neurodevelopmental and behavioural research is warranted to determine the relevance of a large number of suspect candidates whose addition to the environment, household, food and cosmetics might be fuelling the autism epidemic in a gene-dependent manner.

Gram-negative bacterial molecules associate with Alzheimer disease pathology. - PubMed - NCBI

OBJECTIVE:

We determined whether Gram-negative bacterial molecules are associated with Alzheimer disease (AD) neuropathology given that previous studies demonstrate Gram-negative Escherichia coli bacteria can form extracellular amyloid and Gram-negative bacteria have been reported as the predominant bacteria found in normal human brains.

METHODS:
Brain samples from gray and white matter were studied from patients with AD (n = 24) and age-matched controls (n = 18). Lipopolysaccharide (LPS) and E coli K99 pili protein were evaluated by Western blots and immunocytochemistry. Human brain samples were assessed for E coli DNA followed by DNA sequencing.

RESULTS:

LPS and E coli K99 were detected immunocytochemically in brain parenchyma and vessels in all AD and control brains. K99 levels measured using Western blots were greater in AD compared to control brains (p < 0.01) and K99 was localized to neuron-like cells in AD but not control brains. LPS levels were also greater in AD compared to control brain. LPS colocalized with Aβ1-40/42 in amyloid plaques and with Aβ1-40/42 around vessels in AD brains. DNA sequencing confirmed E coli DNA in human control and AD brains.
CONCLUSIONS:

E coli K99 and LPS levels were greater in AD compared to control brains. LPS colocalized with Aβ1-40/42 in amyloid plaques and around vessels in AD brain. The data show that Gram-negative bacterial molecules are associated with AD neuropathology. They are consistent with our LPS-ischemia-hypoxia rat model that produces myelin aggregates that colocalize with Aβ and resemble amyloid-like plaques."



'via Blog this'

Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis - The Lancet Diabetes & Endocrinology

Background
Endocrine-disrupting chemicals (EDCs) contribute to disease and dysfunction and incur high associated costs (>1% of the gross domestic product [GDP] in the European Union). Exposure to EDCs varies widely between the USA and Europe because of differences in regulations and, therefore, we aimed to quantify disease burdens and related economic costs to allow comparison.

Methods
We used existing models for assessing epidemiological and toxicological studies to reach consensus on probabilities of causation for 15 exposure–response relations between substances and disorders. We used Monte Carlo methods to produce realistic probability ranges for costs across the exposure–response relation, taking into account uncertainties. Estimates were made based on population and costs in the USA in 2010. Costs for the European Union were converted to US$ (€1=$1·33).

Findings
The disease costs of EDCs were much higher in the USA than in Europe ($340 billion [2·33% of GDP] vs $217 billion [1·28%]). The difference was driven mainly by intelligence quotient (IQ) points loss and intellectual disability due to polybrominated diphenyl ethers (11 million IQ points lost and 43 000 cases costing $266 billion in the USA vs 873 000 IQ points lost and 3290 cases costing $12·6 billion in the European Union). Accounting for probability of causation, in the European Union, organophosphate pesticides were the largest contributor to costs associated with EDC exposure ($121 billion), whereas in the USA costs due to pesticides were much lower ($42 billion).

 Interpretation
EDC exposure in the USA contributes to disease and dysfunction, with annual costs taking up more than 2% of the GDP. Differences from the European Union suggest the need for improved screening for chemical disruption to endocrine systems and proactive prevention."





'via Blog this'

The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. - PubMed

Genomics, epigenomics, transcriptomics, proteomics and metabolomics efforts rapidly generate a plethora of data on the activity and levels of biomolecules within mammalian cells. At the same time, curation projects that organize knowledge from the biomedical literature into online databases are expanding. Hence, there is a wealth of information about genes, proteins and their associations, with an urgent need for data integration to achieve better knowledge extraction and data reuse. For this purpose, we developed the Harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins from over 70 major online resources. We extracted, abstracted and organized data into ∼72 million functional associations between genes/proteins and their attributes. Such attributes could be physical relationships with other biomolecules, expression in cell lines and tissues, genetic associations with knockout mouse or human phenotypes, or changes in expression after drug treatment. We stored these associations in a relational database along with rich metadata for the genes/proteins, their attributes and the original resources. The freely available Harmonizome web portal provides a graphical user interface, a web service and a mobile app for querying, browsing and downloading all of the collected data. To demonstrate the utility of the Harmonizome, we computed and visualized gene-gene and attribute-attribute similarity networks, and through unsupervised clustering, identified many unexpected relationships by combining pairs of datasets such as the association between kinase perturbations and disease signatures. We also applied supervised machine learning methods to predict novel substrates for kinases, endogenous ligands for G-protein coupled receptors, mouse phenotypes for knockout genes, and classified unannotated transmembrane proteins for likelihood of being ion channels. The Harmonizome is a comprehensive resource of knowledge about genes and proteins, and as such, it enables researchers to discover novel relationships between biological entities, as well as form novel data-driven hypotheses for experimental validation.Database URL: