Multiple Hit Research Articles

Exploring the "Multiple-Hit Hypothesis" of Neurodegenerative Disease: Bacterial Infection Comes Up to Bat.

Despite major strides in personalized genomics, it remains poorly understood why neurodegenerative diseases occur in only a fraction of individuals with a genetic predisposition and conversely, why individuals with no genetic risk of a disorder develop one. Chronic diseases like Alzheimer's, Parkinson's, and Multiple sclerosis are speculated to result from a combination of genetic and environmental factors, a concept commonly referred to as the “multiple hit hypothesis.” A number of bacterial infections have been linked to increased risk of neurodegeneration, and in some cases, clearance of bacterial pathogens has been correlated with amelioration of central nervous system (CNS) deficits. Additionally, mutations in several genes known to contribute to CNS disorders like Parkinson's Disease have repeatedly been implicated in susceptibility to intracellular bacterial infection. Recent data has begun to demonstrate roles for these genes (PARK2, PINK1, and LRRK2) in modulating innate immune outcomes, suggesting that immune dysregulation may play an even more important role in neurodegeneration than previously appreciated. This review will broadly explore the connections between bacterial infection, immune dysregulation, and CNS disorders. Understanding this interplay and how bacterial pathogenesis contributes to the “multiple-hit hypothesis” of neurodegeneration will be crucial to develop therapeutics to effectively treat both neurodegeneration and infection.

Structural elucidation and molecular dynamics study targeting the viral surface glycoproteins against HIV-2 infection

Introduction: The acquired immunodeficiency syndrome (AIDS) is the culmination of the infection by the human immunodeficiency viruses upon destruction of CD4+ lymphocytes of the host [1]. The efficacy of the available antiretroviral drugs is very limited against HIV-2 and, most importantly, none of the current drugs effectively prevents entry into the cells. HIV envelope glycoproteins mediate binding to the receptor CD4 and co-receptors at the surface of the target cell, enabling fusion with the cell membrane and viral entry [2,3]. The discovery of multiple new hit compounds that can be used as useful starting points towards drug candidates for HIV-1 and HIV-2 therapy is the main goal of this work. The glycoproteins gp120 and gp125 are critical to the receptors recognition and internalization of viral material into the cell. The study aimed to assess if the modulation of the glycoproteins activity can lead to the disturbance of the entry viral mechanism. Materials and methods: Until now, it has been marked by the use of computational techniques to study the viral surface glycoproteins as potential drug targets against HIV-1 and HIV-2 infections. A 3D structure of HIV-2ROD gp125 was generated by homology modelling, using MOE2016 and MODELLER 9v19. Additionally, to disclose the importance of the main structural features and compare with experimental results, 3D-models of six V3 mutants were also generated using the C2V3C3 domain. Additionally, molecular dynamics is being performed, using Gromacs 2006.3, in order to better characterize this protein and disclose its the biological dynamic behaviour. The structures to use in molecular dynamic simulations were prepared using MOE 2016.0802 software and further exported as PDB files. Results: It is primordial to understand the structural behavior of these domains inserted in the main structure. These mutations revealed selectively impact in the behaviour of the protein. Structurally, the mutations studied leads to a loss of aromatic features, very important for the establishment of π-π interactions, which could induce a structural preference by a specific coreceptor. Discussion and conclusions: In the absence of a crystallographic structure of HIV-2 envelope gp125 comprising variable domains, computer aided modulation is crucial to identify structural features in the variable regions that correlate with HIV-2 tropism and susceptibility to neutralization, highly associated with the mutated residues. These new insights into the structure-function relationship will help in the design of better models and into the following of the design of new small molecules capable of use under the proposal presented inhibit the attachment and binding of HIV with host cells mediated by the envelope surface glycoproteins.

Exploring a potential mechanistic role of DNA methylation in the relationship between in utero and post-natal environmental exposures and risk of childhood acute lymphoblastic leukaemia.

The aetiology of childhood acute lymphoblastic leukaemia (ALL) is unclear. Genetic abnormalities have been identified in a number of ALL cases, although these alone are not sufficient for leukaemic transformation. Various in utero and post-natal environmental exposures have been suggested to alter risk of childhood ALL. DNA methylation patterns can be influenced by environmental exposures, and are reported to be altered in ALL, suggesting a potential mediating mechanism between environment and ALL disease risk. To investigate this, we used a 'meet in the middle' approach, investigating the overlap between exposure-associated and disease-associated methylation change. Genome-wide DNA methylation changes in response to possible ALL-risk exposures (i.e. breast feeding, infection history, day care attendance, maternal smoking, alcohol, caffeine, folic acid, iron and radiation exposure) were investigated in a sub-population of the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort using an epigenome-wide association study (EWAS) approach (n = 861-927), and compared to a list of ALL disease-associated methylation changes compiled from published data. Hypergeometric probability tests suggested that the number of directionally concordant gene methylation changes observed in ALL disease and in response to the following exposures; maternal radiation exposure (p = 0.001), alcohol intake (p = 0.006); sugary caffeinated drink intake during pregnancy (p = 0.045); and infant day care attendance (p = 0.003), were not due to chance. Data presented suggests that DNA methylation may be one mediating mechanism in the multiple hit pathway needed for ALL disease manifestation.

The multiple hit effect: Joint impact of adolescent oral contraceptive use and early adversity on the cortisol awakening response in healthy adult women

The multiple hit effect: Joint impact of adolescent oral contraceptive use and early adversity on the cortisol awakening response in healthy adult women

The Multiple Hit Hypothesis for Gulf War Illness: Self-Reported Chemical/Biological Weapons Exposure and Mild Traumatic Brain Injury.

The Gulf War Illness Consortium (GWIC) was designed to identify objective biomarkers of Gulf War Illness (GWI) in 1991 Gulf War veterans. The symptoms of GWI include fatigue, pain, cognitive problems, gastrointestinal, respiratory, and skin problems. Neurotoxicant exposures during deployment, such as pesticides, sarin, and pyridostigmine bromide pills have been identified as contributors to GWI. We have also found an association between mild traumatic brain injury (mTBI) and increased rates of GWI. However, the combined impact of these physical and chemical exposures has not yet been explored in GWI. The objective of this study was to examine both self-reported mTBI and exposure to chemical/biological weapons (CBW) as a multiple or two hit model for increased risk of GWI and other chronic health conditions. The study population included 125 Gulf War (GW) veterans from the Boston GWIC. Exposure to CBW was reported in 47.2% of the study population, and 35.2% reported sustaining a mTBI during the war. Results confirmed that those with both exposures (mTBI and CBW) had higher rates of comorbid chronic health conditions while rates of GWI were equivalent for mTBI and CBW or mTBI alone. The timing of exposure to mTBI was found to be strikingly different between those with GWI and those without it. Correspondingly, 42.3% of GWI cases reported experiencing a mTBI during military service while none of the controls did (p = 0.0002). Rates of mTBI before and after the war did not differ between the cases and controls. In addition, 54% of cases compared to 14.3% of controls (p = <0.001) reported being exposed to CBW during military service. The current study examined the relation of the separate and combined effects of exposure to mTBI and CBW in 1991 GW veterans. The findings from this study suggest that both exposure to mTBI and CBW are associated with the development of GWI and multiple chronic health conditions and that combined exposure appears to lead to higher risk of chronic health effects.

Network pharmacology-based identification of major component of Angelica sinensis and its action mechanism for the treatment of acute myocardial infarction.

Background: To decipher the mechanisms of Angelica sinensis for the treatment of acute myocardial infarction (AMI) using network pharmacology analysis. Methods: Databases were searched for the information on constituents, targets, and diseases. Cytoscape software was used to construct the constituent–target–disease network and screen the major targets, which were annotated with the DAVID (Database for Annotation, Visualization and Integrated Discovery) tool. The cardioprotective effects of Angelica sinensis polysaccharide (ASP), a major component of A. sinensis, were validated both in H9c2 cells subjected to simulated ischemia by oxygen and glucose deprivation and in rats with AMI by ligation of the left anterior coronary artery. Results: We identified 228 major targets against AMI injury for A. sinensis, which regulated multiple pathways and hit multiple targets involved in several biological processes. ASP significantly decreased endoplasmic reticulum (ER) stress-induced cell death both in vitro and in vivo. In ischemia injury rats, ASP treatment reduced infarct size and preserved heart function. ASP enhanced activating transcription factor 6 (ATF6) activity, which improved ER-protein folding capacity. ASP activated the expression of p-AMP-activated protein kinase (p-AMPK) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). Additionally, ASP attenuated levels of proinflammatory cytokines and maintained a balance in the oxidant/antioxidant levels after AMI. Conclusion: In silico analysis revealed the associations between A. sinensis and AMI through multiple targets and several key signaling pathways. Experimental data indicate that ASP protects the heart against ischemic injury by activating ATF6 to ameliorate the detrimental ER stress. ASP’s effects could be mediated via the activation of AMPK-PGC1α pathway.

Osteonecrosis of the femoral head: genetic basis.

Genetic factors and hereditary forms of osteonecrosis of the femoral head (ONFH) have been elucidated through genetic association studies. The significance of these cases is that they suggest an alternative hypothesis to the development of the disease. This review presents a summary of single nucleotide polymorphisms (SNPs) and other genetic mutation variations found in association with ONFH, including our recent identification of a novel mutation in the transient receptor potential vanilloid 4 (TRPV4) gene in association with inherited ONFH. The purpose of this review is to consolidate and categorize genetic linkages according to physiological pathways. A systematic review of literature from PubMed and Google Scholar was undertaken with a focus on genetic linkages and hereditary case studies of the disease. Recent genetic analysis studies published after 2007 were the focus of genetic linkages in non-hereditary cases. The summary of these genetic findings identifies biological processes believed to be involved in the development of ONFH, which include circulation, steroid metabolism, immunity, and the regulation of bone formation. Taken together, these associations may lead to new pathways of bone repair and remodeling while opening new avenues for therapeutic targets. Knowledge of genetic variations could help identify individuals considered to be at higher risk of developing ONFH and prevent the multiple hit effect.

Cancer follows chromosome missegregation when all endogenous repair mechanisms fail

Almost all solid tumors consist of aneuploid cells with highly abnormal chromosome numbers. Such cancer cells could very well originate from chromosome missegregation which is a disturbingly common phenomenon, happening in 0.01 to 4 percent of cell divisions. Missegregated cells are aneuploid, typically lacking a chromosome or having one in surplus. Missegregated cells have mutation in the gene dose of the perhaps a thousand genes on a chromosome in one step. After missegregation cell division cannot be done right, as at least one daughter cell has a faulty chromosome number. At division in cells with surplus chromosomes the number will tend to increase due to mismatch in the division machinery. The organism has a number of repair mechanisms in place to prevent potential damage of accumulating aneuploidy. The first is the roll-back of the cell division itself, leading to tetraploidy or sometimes two nuclei in one cell; another is the prevention of further divisions. A very important one is induction of apoptosis, the cellular suicide. A special case is the elimination of the nucleus itself in the formation of red blood cells. Many aneuploid cells are probably eliminated by the immune system. A hypothetical mechanism would be the prevention of metastasis. Missegregation increases with age when the chromosomes lose their protective telomere ends at the Hayflick limit after about 50 divisions, and the unraveled chromosomes fuse and break. For cancer to develop all of these repair mechanisms must fail. The hypothesis offers a straightforward rationale for the multiple hit hypothesis of cancer development.

Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: From "two hit theory" to "multiple hit model".

Nonalcoholic fatty liver disease (NAFLD) has become the dominant form of chronic liver disease in children and adolescents with the increasing prevalence of obesity worldwide. NAFLD represents a wide spectrum of conditions, ranging from fatty liver - which generally follows a benign, non-progressive clinical course - to non-alcoholic steatohepatitis, a subset of NAFLD that may progress to cirrhosis and end-stage liver disease or liver carcinoma. The underlying pathophysiological mechanism of “pediatric” NAFLD remains unclear, although it is strongly associated with obesity and insulin resistance. In this review we provide a general overview on the current understanding of NAFLD in children and adolescents, which underpins practice, enabling early diagnosis and appropriate therapeutic intervention for this life-threatening liver disease.

Multiple hit infection and autoimmunity: the dysbiotic microbiota-ACPA connection in rheumatoid arthritis.

This review highlights the most recent data obtained in this field and provides clues toward the better understanding of the close interplay between microbiota and host, leading to autoimmune diseases. A well-described model of microbiota/host interaction of relevance to autoimmunity is linking anti-citrullinated peptide antibody positive rheumatoid arthritis and alterations of microbiota largely concentrating on Porphyromonas gingivalis and more recently of Aggregatibacter actinomycetemcomitans and Prevotella copri. The perception of the classical link between microbial infection and development of autoimmune disease has evolved to the more recent concept of the connection between the microbiome/dysbiosis and breaking of immunological tolerance.

A combination of analysis techniques for efficient track reconstruction of high multiplicity events in silicon detectors

A novel combination of established data analysis techniques for reconstructing all charged-particle tracks in high energy collisions is proposed. It uses all information available in a collision event while keeping competing choices open as long as possible. Suitable track candidates are selected by transforming measured hits to a binned, three- or four-dimensional, track parameter space. It is accomplished by the use of templates taking advantage of the translational and rotational symmetries of the detectors. Track candidates and their corresponding hits, the nodes, form a usually highly connected network, a bipartite graph, where we allow for multiple hit to track assignments, edges. The graph is cut into very many minigraphs by removing a few of its vulnerable components, edged and nodes. Finally the hits are distributed among the track candidates by exploring a deterministic decision tree. A depth-limited search is performed maximising the number of hits on tracks, and minimising the sum of track-fit $\chi^2$. Simplified models of LHC silicon trackers, as well as the relevant physics processes, are employed to study the performance (efficiency, purity, timing) of the proposed method in the case of single or many simultaneous proton-proton collisions (high pileup), and for single heavy-ion collisions at the highest available energies.

T cells directed against different myelin antigen epitopes cooperate to induce autoimmune encephalomyelitis in mice

Abstract Multiple Sclerosis (MS) is the most common demyelinating autoimmune disease of the central nervous system (CNS). Important insights have emerged into the pathogenic mechanisms that drive the inflammatory events and demyelination in MS, however, much less is known about the events initiating this disease. The murine model of MS, experimental autoimmune encephalomyelitis (EAE), is usually induced through injection with a high dose of single immunodominant peptides found on the myelin sheath of the CNS. Low doses of single peptide do not induce EAE or result in very low disease incidence. In individual MS patients, autoimmune T cell-reactivity is usually directed against multiple myelin antigen epitopes and fluctuates significantly over the course of disease. Thus, we hypothesize that MS is triggered by the emergence of autoreactive T cells directed against multiple myelin epitopes, which together synergize to induce the disease. To test this concept in an animal model of EAE, we explored the effect of induction of EAE using combinations of low dose peptides akin to a “multiple hit” mechanism implicated in other disease conditions. We found that EAE can be induced through the immunization of mice with a combination of low dose myelin peptides from different myelin proteins, which individually are suboptimal to induce disease. The disease observed after multi-peptide immunization is comparable or more severe than with optimal doses of peptide traditionally used to induce EAE. This research provides new insights into the potential mechanisms underlying the induction of MS and could lead to novel approaches for immunotherapy.

Characterization of Hit Compounds Identified from High-throughput Screening for their Effect on Blood–brain Barrier Integrity and Amyloid-β Clearance: In Vitro and In Vivo Studies

In Alzheimer’s disease (AD) the blood–brain barrier (BBB) is compromised, thus therapeutic targeting of the BBB to enhance its integrity and function could be a unique approach to treat, slow or hold the progression of AD. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that increase the integrity of a cell-based BBB model. Results from primary screen identified multiple hit compounds that enhanced the monolayer integrity. Herein, further characterization of selected hit compounds, namely 8-bromoguanosine cyclic monophosphate, JW74, 1,10-phenanthroline monohydrate, SB216763 and α-tocopherol was performed. Compounds were subjected to concentration-dependent studies to determine their EC50 and potency to enhance the cell-based model integrity by the Lucifer Yellow permeability and amyloid-beta (Aβ) transport across the monolayer. The compounds demonstrated different EC50s to enhance the monolayer integrity ranging from 0.4 to 12.8 µM, and different effect on enhancing Aβ transport with highest transport observed for α-tocopherol (2.2-fold increase). Such effects were associated with increased levels of tight junction proteins such as claudin-5 and/or ZO-1, and Aβ major transport proteins LRP1 and P-glycoprotein. In vivo studies for α-tocopherol were performed in AD mouse model; consistent with the in vitro results α-tocopherol significantly increased BBB integrity measured by IgG extravasation, and reduced brain Aβ levels. In conclusion, findings support our developed cell-based BBB model as a functional predictive in vivo tool to select hit compounds, and suggest that enhancing BBB tightness and function has the potential to reduce Aβ pathology associated with AD.

Is Parkinson's Disease a Neurodevelopmental Disorder and Will Brain Organoids Help Us to Understand It?

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. The incidence of PD cases increases with age, accordingly classically PD is considered to be an age-associated neurodegenerative disease. In this review, the hypothesis that PD is actually a neurodevelopmental disorder that is compensated for a long time will be discussed. However, patients who suffer from PD typically do not show symptoms early in their lives. This implies that, if the hypothesis that PD has a significant neurodevelopmental component is correct, the developmental defects are compensated for a long time. Furthermore, these developmental defects might not causally lead to the disease but increase the susceptibility for disease onset after a "second hit." In this logic, deregulated developmental processes might represent the "first hit." Even a minor developmental defect could lead to a reduced compensatory capacity or reduced fault tolerance of the entire system. In such a case of an already imbalanced system one or more additional hits could perturb the entire system sufficiently to bring it out of balance and lead to the pathology and symptoms which we classify as PD. However, if the developmental hypothesis and the "multiple hit" hypothesis are correct, an early diagnosis of these developmental defects might allow the start of a therapy for at-risk individuals before disease pathology becomes severe and before symptoms occur. Modern stem cell technologies, including the generation of personalized brain organoids, might play an important role in these strategies.

Endoplasmic reticulum stress response in nonalcoholic fatty liver disease

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased over the past few decades due to a rise in the incidence of Type 2 diabetes and obesity. Sedentary lifestyle coupled with exorbitant consumption of high-caloric diet has been associated with root cause of the epidemic increase in chronic liver diseases. NAFLD is a chronic liver disease which encompasses a spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), further leading to irreversible liver cirrhosis. A “multiple hit working model” is a recognized theory that explains the development and progression of NASH, the advanced stage of NAFLD. According to this model, initial hit leads to the development of steatosis, which makes the liver vulnerable to following hits induced by inflammatory cytokines, endotoxins, lipid peroxidation, oxidative stress, endoplasmic reticulum (ER) stress, saturated fatty acid deposition, and/or hepatic organelle dysfunction. These hits eventually result in hepatic fibrosis, inflammation, and apoptosis, which are considered the key features of NASH. Accumulation of hepatic fats leads to the activation of various pathways, including unfolded protein response, which is associated with intracellular stress and inflammation. ER plays a crucial role in restoring cellular homeostasis by directing either through the refolding of misfolded proteins or employing several alternative mechanisms such as ER-associated degradation. ER stress response also causes insulin resistance and inflammation and in the worst cases, culminates in severe liver damage and hepatic cell death, all of which are central to the pathogenesis of NASH. This review sheds some light on recent findings of ER stress response and oxidative stress in the progression of NAFLD.

Exploring the multiple-hit hypothesis of preterm white matter damage using diffusion MRI.

BackgroundPreterm infants are at high risk of diffuse white matter injury and adverse neurodevelopmental outcome. The multiple hit hypothesis suggests that the risk of white matter injury increases with cumulative exposure to multiple perinatal risk factors. Our aim was to test this hypothesis in a large cohort of preterm infants using diffusion weighted magnetic resonance imaging (dMRI).MethodsWe studied 491 infants (52% male) without focal destructive brain lesions born at < 34 weeks, who underwent structural and dMRI at a specialist Neonatal Imaging Centre. The median (range) gestational age (GA) at birth was 30+ 1 (23+ 2–33+ 5) weeks and median postmenstrual age at scan was 42+ 1 (38–45) weeks. dMRI data were analyzed using tract based spatial statistics and the relationship between dMRI measures in white matter and individual perinatal risk factors was assessed. We tested the hypothesis that increased exposure to perinatal risk factors was associated with lower fractional anisotropy (FA), and higher radial, axial and mean diffusivity (RD, AD, MD) in white matter. Neurodevelopmental performance was investigated using the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III) in a subset of 381 infants at 20 months corrected age. We tested the hypothesis that lower FA and higher RD, AD and MD in white matter were associated with poorer neurodevelopmental performance.ResultsIdentified risk factors for diffuse white matter injury were lower GA at birth, fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition, necrotizing enterocolitis and male sex. Clinical chorioamnionitis and patent ductus arteriosus were not associated with white matter injury. Multivariate analysis demonstrated that fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition were independently associated with lower FA values. Exposure to cumulative risk factors was associated with reduced white matter FA and FA values at term equivalent age were associated with subsequent neurodevelopmental performance.ConclusionThis study suggests multiple perinatal risk factors have an independent association with diffuse white matter injury at term equivalent age and exposure to multiple perinatal risk factors exacerbates dMRI defined, clinically significant white matter injury. Our findings support the multiple hit hypothesis for preterm white matter injury.

Effect of maternal immune activation and sex on electrophysiological features related to Schizophrenia

Maternal immune activation (MIA) in response to gestational infection is a risk factor for the development of schizophrenia in offspring. Previous studies have shown that MIA in rats or mice, induced by the non-infectious viral mimic Poly(I:C), produces a wide-range of schizophrenia-like behavioural alterations in the offspring. The current study investigated the impact of MIA on two electrophysiological features altered in schizophrenia, gamma activity and mismatch negativity (MMN). Pregnant Wistar rats were exposed to either Poly(I:C) (MIA) or saline during late gestation (gestational day 19). Reliable ASSRs were found from 40 to 80 Hz. No significant treatment or sex effects were found for ASSRs. MMN responses were found and female animals had higher overall responses than males early in the MMN waveform, a novel finding. However, no significant treatment effects were found for any MMN component. A multiple hit model of MIA, or a two-hit model of a variety of risk factors might be employed in the future to produce more observable alterations. Our novel findings of sex differences suggest that animal research should consistently include both sexes to improve the validity of current models of schizophrenia.

Pathophysiology of Pain: Why Does Chronic Pain Hurt? The Multiple Hit Theory

Acute pain hurts and most often is the result of tissue injury. Chronic pain also hurts. Although those who suffer from chronic pain also tend to associate the onset with an injury, illness, or surgical procedure; the root cause is far more complex. Chronic pain most often does not follow dermatomal distributions associated with any injury, disease or surgical procedure. And more often than not, chronic pain sufferers also suffer from various forms of depression and/or anxiety. The process of central sensitization resulting from tissue injury has been elucidated, as has many of the molecular changes within the brain that perpetuate chronic pain. Genetics, epigenetics, environmental stressors, and emotional stressors all play roles to varying degrees in the development of the chronic pain state. This article explores how synaptic memories form in the brain as a result of both physical and emotional traumas (multiple hits) resulting in progression to chronic pain, because of failure of the brain’s descending modulatory mechanisms to prevent or control “the pain.” This review contains 15 figures, and 178 references. Key words: Epigenetics, memory, central sensitization, chronic pain

Evolution of Daily Gene Co-expression Patterns from Algae to Plants.

Daily rhythms play a key role in transcriptome regulation in plants and microalgae orchestrating responses that, among other processes, anticipate light transitions that are essential for their metabolism and development. The recent accumulation of genome-wide transcriptomic data generated under alternating light:dark periods from plants and microalgae has made possible integrative and comparative analysis that could contribute to shed light on the evolution of daily rhythms in the green lineage. In this work, RNA-seq and microarray data generated over 24 h periods in different light regimes from the eudicot Arabidopsis thaliana and the microalgae Chlamydomonas reinhardtii and Ostreococcus tauri have been integrated and analyzed using gene co-expression networks. This analysis revealed a reduction in the size of the daily rhythmic transcriptome from around 90% in Ostreococcus, being heavily influenced by light transitions, to around 40% in Arabidopsis, where a certain independence from light transitions can be observed. A novel Multiple Bidirectional Best Hit (MBBH) algorithm was applied to associate single genes with a family of potential orthologues from evolutionary distant species. Gene duplication, amplification and divergence of rhythmic expression profiles seems to have played a central role in the evolution of gene families in the green lineage such as Pseudo Response Regulators (PRRs), CONSTANS-Likes (COLs), and DNA-binding with One Finger (DOFs). Gene clustering and functional enrichment have been used to identify groups of genes with similar rhythmic gene expression patterns. The comparison of gene clusters between species based on potential orthologous relationships has unveiled a low to moderate level of conservation of daily rhythmic expression patterns. However, a strikingly high conservation was found for the gene clusters exhibiting their highest and/or lowest expression value during the light transitions.

Incorporating interaction networks into the determination of functionally related hit genes in genomic experiments with Markov random fields.

MotivationIncorporating gene interaction data into the identification of ‘hit’ genes in genomic experiments is a well-established approach leveraging the ‘guilt by association’ assumption to obtain a network based hit list of functionally related genes. We aim to develop a method to allow for multivariate gene scores and multiple hit labels in order to extend the analysis of genomic screening data within such an approach.ResultsWe propose a Markov random field-based method to achieve our aim and show that the particular advantages of our method compared with those currently used lead to new insights in previously analysed data as well as for our own motivating data. Our method additionally achieves the best performance in an independent simulation experiment. The real data applications we consider comprise of a survival analysis and differential expression experiment and a cell-based RNA interference functional screen.Availability and implementationWe provide all of the data and code related to the results in the paper.Supplementary information Supplementary data are available at Bioinformatics online.