A search for protein biomarkers links olfactory signal transduction to social immunity.

BACKGROUND: The Western honey bee (Apis mellifera L.) is a critical component of human agriculture through its pollination activities. For years, beekeepers have controlled deadly pathogens such as Paenibacillus larvae, Nosema spp. and Varroa destructor with antibiotics and pesticides but widespread chemical resistance is appearing and most beekeepers would prefer to eliminate or reduce the use of in-hive chemicals. While such treatments are likely to still be needed, an alternate management strategy is to identify and select bees with heritable traits that allow them to resist mites and diseases. Breeding such bees is difficult as the tests involved to identify disease-resistance are complicated, time-consuming, expensive and can misidentify desirable genotypes. Additionally, we do not yet fully understand the mechanisms behind social immunity. Here we have set out to discover the molecular mechanism behind hygienic behavior (HB), a trait known to confer disease resistance in bees. RESULTS: After confirming that HB could be selectively bred for, we correlated measurements of this behavior with protein expression over a period of three years, at two geographically distinct sites, using several hundred bee colonies. By correlating the expression patterns of individual proteins with HB scores, we identified seven putative biomarkers of HB that survived stringent control for multiple hypothesis testing. Intriguingly, these proteins were all involved in semiochemical sensing (odorant binding proteins), nerve signal transmission or signal decay, indicative of the series of events required to respond to an olfactory signal from dead or diseased larvae. We then used recombinant versions of two odorant-binding proteins to identify the classes of ligands that these proteins might be helping bees detect. CONCLUSIONS: Our data suggest that neurosensory detection of odors emitted by dead or diseased larvae is the likely mechanism behind a complex and important social immunity behavior that allows bees to co-exist with pathogens.

HapX positively and negatively regulates the transcriptional response to iron deprivation in Cryptococcus neoformans.

The fungal pathogen Cryptococcus neoformans is a major cause of illness in immunocompromised individuals such as AIDS patients. The ability of the fungus to acquire nutrients during proliferation in host tissue and the ability to elaborate a polysaccharide capsule are critical determinants of disease outcome. We previously showed that the GATA factor, Cir1, is a major regulator both of the iron uptake functions needed for growth in host tissue and the key virulence factors such as capsule, melanin and growth at 37°C. We are interested in further defining the mechanisms of iron acquisition from inorganic and host-derived iron sources with the goal of understanding the nutritional adaptation of C. neoformans to the host environment. In this study, we investigated the roles of the HAP3 and HAPX genes in iron utilization and virulence. As in other fungi, the C. neoformans Hap proteins negatively influence the expression of genes encoding respiratory and TCA cycle functions under low-iron conditions. However, we also found that HapX plays both positive and negative roles in the regulation of gene expression, including a positive regulatory role in siderophore transporter expression. In addition, HapX also positively regulated the expression of the CIR1 transcript. This situation is in contrast to the negative regulation by HapX of genes encoding GATA iron regulatory factors in Aspergillus nidulans and Schizosaccharomyces pombe. Although both hapX and hap3 mutants were defective in heme utilization in culture, only HapX made a contribution to virulence, and loss of HapX in a strain lacking the high-affinity iron uptake system did not cause further attenuation of disease. Therefore, HapX appears to have a minimal role during infection of mammalian hosts and instead may be an important regulator of environmental iron uptake functions. Overall, these results indicated that C. neoformans employs multiple strategies for iron acquisition during infection.

Rapid behavior-based identification of neuroactive small molecules in the zebrafish.

Neuroactive small molecules are indispensable tools for treating mental illnesses and dissecting nervous system function. However, it has been difficult to discover novel neuroactive drugs. Here, we describe a high-throughput, behavior-based approach to neuroactive small molecule discovery in the zebrafish. We used automated screening assays to evaluate thousands of chemical compounds and found that diverse classes of neuroactive molecules caused distinct patterns of behavior. These 'behavioral barcodes' can be used to rapidly identify new psychotropic chemicals and to predict their molecular targets. For example, we identified new acetylcholinesterase and monoamine oxidase inhibitors using phenotypic comparisons and computational techniques. By combining high-throughput screening technologies with behavioral phenotyping in vivo, behavior-based chemical screens can accelerate the pace of neuroactive drug discovery and provide small-molecule tools for understanding vertebrate behavior.

Neutralizing antibodies to interferon beta-1b multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial.

BACKGROUND: The frequency and impact of neutralizing antibodies (NAbs) to interferon beta-1b (IFNß-1b) on clinical and radiographic outcomes is controversial. OBJECTIVE: To assess NAb impact in the BEYOND study. METHODS: 2244 patients were randomized (2:2:1) to receive IFNß-1b, either 250 or 500 µg, or glatiramer acetate, 20 mg, and observed for 2-3.5 years. NAb titers were determined every 6 months. A titer ≥20 NU/ml was considered NAb positive. Efficacy was compared between NAb-positive and NAb-negative patients, using comprehensive statistical analyses, taking into account the delayed appearance of NAbs, the time-dependent changes in the relapse rate, spontaneous reversions to NAb-negative status, NAb-titer level, and also adjusting for baseline factors. RESULTS: In the IFNß-1b 250 µg group, NAb-positive titers were detected (≥ once) in 319 patients (37.0%); of these, 112 (35.1%) reverted to NAb-negative status. In the IFNß-1b 500 µg group, 340 patients (40.7%) became NAb-positive and 119 (35.0%) reverted to NAb-negative status. In both IFNß groups, especially the 250 µg arm, NAb-positive status was not associated with a convincing impact on any clinical outcome measure by any statistical analysis. By contrast, in both IFNß groups, NAbs were associated with a very consistent deleterious impact on most MRI outcomes. CONCLUSION: There was a notable dissociation between the impact of NAbs on MRI and clinical outcomes. On MRI measures, the impact was consistent and convincing, whereas on clinical measures a negative impact of NAbs was not found. The basis for this clinico-radiographic paradox is unknown but it suggests that the relationship between NAbs and the therapeutic effects of IFNß-1b is complex.

Photoreactions of cyclic sulfite esters: Evidence for diradical intermediates.

The photochemistry of a phenyl and 1,2-diphenyl substituted sulfite ester is reported. The performance of photoreactions under relatively mild reaction conditions enables the detection of products that have not been observed in previous studies. It is concluded that, complementary to the initially proposed carbene intermediates, diradicals may also be considered.

Common errors in the execution of preoperative templating for primary total hip arthroplasty.

We reviewed 75 primary total hip arthroplasty preoperative and postoperative radiographs and recorded limb length discrepancy, change in femoral offset, acetabular position, neck cut, and femoral component positioning. Interobturator line, as a technique to measure preoperative limb length discrepancy, had the least amount of variance when compared with interteardrop and intertuberosity lines (Levene test, P = .0527). The most common error in execution of preoperative templating was excessive limb lengthening (mean, 3.52 mm), primarily due to inferior acetabular cup positioning (Pearson correlation coefficient, P = .036). Incomplete medialization of the acetabular component contributed the most to offset discrepancy. The most common errors in the execution of preoperative templating resulted in excessive limb lengthening and increased offset. Identifying these errors can lead to more accurate templating techniques and improved intraoperative execution.

Ex vivo comparison of three surgical techniques to stabilize canine cranial cruciate ligament deficient stifles.

OBJECTIVE: To quantify and compare canine stifle stability after 3 stabilization techniques. STUDY DESIGN: Randomized controlled study. SAMPLE POPULATION: Adult canine cadaveric pelvic limbs. METHODS: Total craniocaudal (CrCa) tibial translation quantified in stifles with the cranial cruciate ligament (CrCL) intact, transected, and stabilized with 1 of 3 techniques: (1) hamstring graft (HG); (2) modified retinacular imbrication (MRIT); (3) anatometric fascia lata translocation (AFLT). Tibial translation was quantified from radiographs generated during application of cranial and caudal forces to the tibia. After removal of all soft tissues except periarticular ligaments and fixation, CrCa tibial translation, as before, and medial-lateral rotation, via torsional loading, was quantified with an active motion analysis system. Total tibial translation was evaluated for effect of technique and cruciate status using mixed effect linear model with significance considered at P-value <.05. RESULTS: CrCa translation was not significantly different across stabilization techniques with CrCLs intact, transected, or after stabilization. Poststabilization translation was significantly less than posttransection for all techniques. Compared with the intact CrCL, CrCa translation poststabilization after HG was significantly greater whereas poststabilization after MRIT and AFLT was not significantly different. Tibial rotation exceeded instrumentation limits in 62.5% HG limbs, 20% MRIT limbs, and 60% AFLT limbs. CONCLUSIONS: All 3 stifle stabilization techniques confer comparable CrCa translational stability after CrCL disruption with that provided by the MRIT and AFLT techniques comparable to the intact CrCL. CLINICAL RELEVANCE: The extra- and intracapsular techniques evaluated in this study reduced CrCa tibial translation in CrCL deficient stifles to varying amounts.

Quantitative iTRAQ proteome and comparative transcriptome analysis of elicitor-induced Norway spruce (Picea abies) cells reveals elements of calcium signaling in the early conifer defense response.

Long-lived conifer trees depend on both constitutive and induced defenses for resistance against a myriad of potential pathogens and herbivores. In species of spruce (Picea spp.), several of the late events of pathogen-, insect-, or elicitor-induced defense responses have previously been characterized at the anatomical, biochemical, transcriptome, and proteome levels in stems and needles. However, accurately measuring the early events of induced cellular responses in a conifer is technically challenging due to limitations in the precise timing of induction and tissue sampling from intact trees following insect or fungal treatment. In the present study, we used the advantages of Norway spruce (Picea abies) cell suspensions combined with chitosan elicitation to investigate the early proteome response in a conifer. A combination of iTRAQ labeling and a new design of iterative sample analysis employing data-dependent exclusion lists were used for proteome analysis. This approach improved the coverage of the spruce proteome beyond that achieved in any prior study in a conifer system. Comparison of elicitor-induced proteome and transcriptome responses in Norway spruce cells consistently identified features associated with calcium-mediated signaling and response to oxidative stress that have not previously been observed in the response of intact trees to fungal attack.

Predicting the regenerative capacity of conifer somatic embryogenic cultures by metabolomics.

Somatic embryogenesis in gymnosperms is an effective approach to clonally propagating germplasm. However, embryogenic cultures frequently lose regenerative capacity. The interactions between metabolic composition, physiological state, genotype and embryogenic capacity in Pinus taeda (loblolly pine) somatic embryogenic cultures were explored using metabolomics. A stepwise modelling procedure, using the Bayesian information criterion, generated a 47 metabolite predictive model that could explain culture productivity. The model performed extremely well in cross-validation, achieving a correlation coefficient of 0.98 between actual and predicted mature embryo production. The metabolic composition and structure of the model implied that variation in culture regenerative capacity was closely linked to the physiological transition of cultures from the proliferation phase to the maturation phase of development. The propensity of cultures to advance into this transition appears to relate to nutrient uptake and allocation in vivo, and to be associated with the tolerance and response of cultures to stress, during the proliferation phase.

Iron regulation of the major virulence factors in the AIDS-associated pathogen Cryptococcus neoformans.

Iron overload is known to exacerbate many infectious diseases, and conversely, iron withholding is an important defense strategy for mammalian hosts. Iron is a critical cue for Cryptococcus neoformans because the fungus senses iron to regulate elaboration of the polysaccharide capsule that is the major virulence factor during infection. Excess iron exacerbates experimental cryptococcosis and the prevalence of this disease in Sub-Saharan Africa has been associated with nutritional and genetic aspects of iron loading in the background of the HIV/AIDS epidemic. We demonstrate that the iron-responsive transcription factor Cir1 in Cr. neoformans controls the regulon of genes for iron acquisition such that cir1 mutants are "blind" to changes in external iron levels. Cir1 also controls the known major virulence factors of the pathogen including the capsule, the formation of the anti-oxidant melanin in the cell wall, and the ability to grow at host body temperature. Thus, the fungus is remarkably tuned to perceive iron as part of the disease process, as confirmed by the avirulence of the cir1 mutant; this characteristic of the pathogen may provide opportunities for antifungal treatment.

Magnetic resonance spectroscopy evidence for declining gliosis in MS patients treated with ocrelizumab versus interferon beta-1a.

BACKGROUND: Magnetic resonance spectroscopy quantitatively monitors biomarkers of neuron-myelin coupling (N-acetylaspartate (NAA)), and inflammation (total creatine (tCr), total choline (tCho), myo-inositol (mI)) in the brain. OBJECTIVE: This study aims to investigate how ocrelizumab and interferon beta-1a differentially affects imaging biomarkers of neuronal-myelin coupling and inflammation in patients with relapsing multiple sclerosis (MS). METHODS: Forty patients with relapsing MS randomized to either treatment were scanned at 3T at baseline and weeks 24, 48, and 96 follow-up. Twenty-four healthy controls were scanned at weeks 0, 48, and 96. NAA, tCr, tCho, mI, and NAA/tCr were measured in a single large supra-ventricular voxel. RESULTS: There was a time × treatment interaction in NAA/tCr (p = 0.04), primarily driven by opposing tCr trends between treatment groups after 48 weeks of treatment. Patients treated with ocrelizumab showed a possible decline in mI after week 48 week, and stable tCr and tCho levels. Conversely, the interferon beta-1a treated group showed possible increases in mI, tCr, and tCho over 96 weeks. CONCLUSIONS: Results from this exploratory study suggest that over 2 years, ocrelizumab reduces gliosis compared with interferon beta-1a, demonstrated by declining ml, and stable tCr and tCho. Ocrelizumab may improve the physiologic milieu by decreasing neurotoxic factors that are generated by inflammatory processes.

The transcriptional response of hybrid poplar (Populus trichocarpa x P. deltoides) to infection by Melampsora medusae leaf rust involves induction of flavonoid pathway genes leading to the accumulation of proanthocyanidins.

The transcriptional response of hybrid poplar (Populus trichocarpa x P. deltoides) to poplar leaf rust (Melampsora medusae) infection was studied using the Populus 15.5K cDNA microarray. Pronounced changes in the transcriptome were observed, with approximately 20% of genes on the array showing either induction or repression of transcription within the 9-day infection timecourse. A small number of pathogen-defense genes encoding PR-1, chitinases, and other pathogenesis-related proteins were consistently upregulated throughout the experimental period, but most genes were affected only at individual timepoints. The largest number of changes in gene expression was observed late in the infection at 6 to 9 days postinoculation (dpi). At these timepoints, genes encoding enzymes required for proanthocyanidin (condensed tannin) synthesis were upregulated dramatically. Phytochemical analysis confirmed that, late in the infection, proanthocyanidin levels increased in infected leaves. Strongly M. medusae-repressed genes at 9 dpi included previously characterized wound- and herbivore-induced defense genes, which suggests antagonism between the tree responses to insect feeding and M. medusae infection. In this highly compatible plant-pathogen interaction, we postulate that the biotrophic pathogen evades detection and suppresses early host responses.

Peptide biomarkers used for the selective breeding of a complex polygenic trait in honey bees.

We present a novel way to select for highly polygenic traits. For millennia, humans have used observable phenotypes to selectively breed stronger or more productive livestock and crops. Selection on genotype, using single-nucleotide polymorphisms (SNPs) and genome profiling, is also now applied broadly in livestock breeding programs; however, selection on protein/peptide or mRNA expression markers has not yet been proven useful. Here we demonstrate the utility of protein markers to select for disease-resistant hygienic behavior in the European honey bee (Apis mellifera L.). Robust, mechanistically-linked protein expression markers, by integrating cis- and trans- effects from many genomic loci, may overcome limitations of genomic markers to allow for selection. After three generations of selection, the resulting marker-selected stock outperformed an unselected benchmark stock in terms of hygienic behavior, and had improved survival when challenged with a bacterial disease or a parasitic mite, similar to bees selected using a phenotype-based assessment for this trait. This is the first demonstration of the efficacy of protein markers for industrial selective breeding in any agricultural species, plant or animal.

Elimination of acute hepatitis B among adolescents after one decade of an immunization program targeting Grade 6 students.

BACKGROUND: British Columbia introduced a preadolescent hepatitis B (HB) immunization program in 1992. This study documents trends in the reported rate of acute HB disease since 1992 and examines factors bearing on the rate of infection throughout the period of program implementation. METHODS: All Grade 6 students were eligible for immunization. Vaccine uptake was reported annually for every school. Acute HB infections were reported by physicians and by biomedical laboratories. Year-to-year trends were analyzed overall and by age group using the electronic public health information system and S-plus. Likelihood ratio tests were used to establish whether a variable was associated with the rate of acute HB in a given cohort. Poisson regression was applied to determine which variables were independently associated with the rate of acute HB. RESULTS: Immunization coverage ranged between 90 and 93% for each year between 1993 and 2001. The overall rate of reported acute HB declined from 7 per 100,000 to just more than 2 per 100,000, whereas that in 12- to 21-year-olds declined from 1.7 to 0 per 100,000 over this one decade period. In the final Poisson regression model, the rate of acute HB infection was significantly associated with year, urban region and lower vaccine uptake. There was an interaction between region and vaccine uptake such that higher vaccine uptake appeared more protective in rural than in urban regions. CONCLUSIONS: Acute HB has been eliminated in the immunized adolescent cohort. A higher carrier rate in urban regions most likely explains the apparent difference in program effectiveness between urban and rural regions.

Viscosity dependence of the denitrogenation quantum yield in azoalkane photolysis: experimental evidence for reversible formation of the diazenyl diradical.

[reaction: see text] Experimental evidence is reported for the reversible formation of the singlet diazenyl diradical ((1)DZ), photolytically generated from the structurally elaborate DBH-type azoalkane. Reversiblity of the (1)DZ formation manifests itself through the decrease of the photodenitrogenation quantum yield over a ca. 40-fold viscosity variation (from 0.5 to 19.3 cP). This viscosity behavior is interpreted in terms of frictional effects on the competitive reaction modes of the diazenyl diradical.

Vitamin D as an early predictor of multiple sclerosis activity and progression.

IMPORTANCE: It remains unclear whether vitamin D insufficiency, which is common in individuals with multiple sclerosis (MS), has an adverse effect on MS outcomes. OBJECTIVES: To determine whether serum concentrations of 25-hydroxyvitamin D (25[OH]D), a marker of vitamin D status, predict disease activity and prognosis in patients with a first event suggestive of MS (clinically isolated syndrome). DESIGN, SETTING, AND PARTICIPANTS: The Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment study was a randomized trial originally designed to evaluate the impact of early vs delayed interferon beta-1b treatment in patients with clinically isolated syndrome. Serum 25(OH)D concentrations were measured at baseline and 6, 12, and 24 months. A total of 465 of the 468 patients randomized had at least 1 25(OH)D measurement, and 334 patients had them at both the 6- and 12-month (seasonally asynchronous) measurements. Patients were followed up for 5 years clinically and by magnetic resonance imaging. MAIN OUTCOMES AND MEASURES: New active lesions, increased T2 lesion volume, and brain volume on magnetic resonance imaging, as well as MS relapses and disability (Expanded Disability Status Scale score). RESULTS: Higher 25(OH)D levels predicted reduced MS activity and a slower rate of progression. A 50-nmol/L (20-ng/mL) increment in average serum 25(OH)D levels within the first 12 months predicted a 57% lower rate of new active lesions (P < .001), 57% lower relapse rate (P = .03), 25% lower yearly increase in T2 lesion volume (P < .001), and 0.41% lower yearly loss in brain volume (P = .07) from months 12 to 60. Similar associations were found between 25(OH)D measured up to 12 months and MS activity or progression from months 24 to 60. In analyses using dichotomous 25(OH)D levels, values greater than or equal to 50 nmol/L (20 ng/mL) at up to 12 months predicted lower disability (Expanded Disability Status Scale score, -0.17; P = .004) during the subsequent 4 years. CONCLUSIONS AND RELEVANCE: Among patients with MS mainly treated with interferon beta-1b, low 25(OH)D levels early in the disease course are a strong risk factor for long-term MS activity and progression.

Correlation of proteome-wide changes with social immunity behaviors provides insight into resistance to the parasitic mite, Varroa destructor, in the honey bee (Apis mellifera).

BACKGROUND: Disease is a major factor driving the evolution of many organisms. In honey bees, selection for social behavioral responses is the primary adaptive process facilitating disease resistance. One such process, hygienic behavior, enables bees to resist multiple diseases, including the damaging parasitic mite Varroa destructor. The genetic elements and biochemical factors that drive the expression of these adaptations are currently unknown. Proteomics provides a tool to identify proteins that control behavioral processes, and these proteins can be used as biomarkers to aid identification of disease tolerant colonies. RESULTS: We sampled a large cohort of commercial queen lineages, recording overall mite infestation, hygiene, and the specific hygienic response to V. destructor. We performed proteome-wide correlation analyses in larval integument and adult antennae, identifying several proteins highly predictive of behavior and reduced hive infestation. In the larva, response to wounding was identified as a key adaptive process leading to reduced infestation, and chitin biosynthesis and immune responses appear to represent important disease resistant adaptations. The speed of hygienic behavior may be underpinned by changes in the antenna proteome, and chemosensory and neurological processes could also provide specificity for detection of V. destructor in antennae. CONCLUSIONS: Our results provide, for the first time, some insight into how complex behavioural adaptations manifest in the proteome of honey bees. The most important biochemical correlations provide clues as to the underlying molecular mechanisms of social and innate immunity of honey bees. Such changes are indicative of potential divergence in processes controlling the hive-worker maturation.

Application of linear discriminant analysis in performance evaluation of extractable nuclear antigen immunoassay systems in the screening and diagnosis of systemic autoimmune rheumatic diseases.

This study applied a linear discriminant analysis model to evaluate the performance of 2 types of commercially available extractable nuclear antigen (ENA) immunoassays for the screening and diagnosis of systemic autoimmune rheumatic diseases (SARDs) in a large tertiary hospital reference laboratory: (1) an enzyme-linked immunosorbent assay (ELISA) and (2) a multiplex bead-based immunoassay (MPBI). The results of the study showed both ENA immunoassays had comparable sensitivity for the detection of SARDs compared with the antinuclear antigen immunofluorescence (ANA-IF) method (ANA-IF: 85.6%, ENA-ELISA: 91.5%, ENA-MPBI: 83.1%, pairwise comparisons with ANA-IF: P > .05). However, both ENA immunoassays offered improved specificity compared with the ANA-IF (ANA-IF: 24.2%; ENA-ELISA: 39.8%; ENA-MPBI: 53.1%; pairwise comparison with ANA-IF: P < .001). The use of a more specific screening immunoassay with comparable sensitivity to ANA-IF is important in a tertiary hospital with high prevalence of non-SARD immune diseases. Diagnostic performance of the ENA/dsDNA components by the MPBI and ELISA methods did not differ significantly (area under the curve [AUC], 81.0% vs 83.0%, respectively, P > .05), but the key ENA/dsDNA variables contributing to the discriminating power of the assays for the diagnosis of specific SARDs were reagent/method dependent.

A yeast phenomic model for the gene interaction network modulating CFTR-ΔF508 protein biogenesis.

BACKGROUND: The overall influence of gene interaction in human disease is unknown. In cystic fibrosis (CF) a single allele of the cystic fibrosis transmembrane conductance regulator (CFTR-[increment]F508) accounts for most of the disease. In cell models, CFTR-[increment]F508 exhibits defective protein biogenesis and degradation rather than proper trafficking to the plasma membrane where CFTR normally functions. Numerous genes function in the biogenesis of CFTR and influence the fate of CFTR-[increment]F508. However it is not known whether genetic variation in such genes contributes to disease severity in patients. Nor is there an easy way to study how numerous gene interactions involving CFTR-[increment]F would manifest phenotypically. METHODS: To gain insight into the function and evolutionary conservation of a gene interaction network that regulates biogenesis of a misfolded ABC-transporter, we employed yeast genetics to develop a "phenomic" model, in which the CFTR-[increment]F508-equivalent residue of a yeast homolog is mutated (Yor1-[increment]F670), and where the genome is scanned quantitatively for interaction. We first confirmed that Yor1-[increment]F undergoes protein misfolding and has reduced half-life, analogous to CFTR-[increment]F. Gene interaction was then assessed quantitatively by growth curves for all ~5000 double mutants, based on alteration in the dose response to growth inhibition by oligomycin, a toxin extruded from the cell at the plasma membrane by Yor1. RESULTS: From a comparative genomic perspective, yeast gene interaction influencing Yor1-[increment]F biogenesis was representative of human homologs previously found to modulate processing of CFTR-[increment]F in mammalian cells. Additional evolutionarily conserved pathways were implicated by the study, and a [increment]F-specific pro-biogenesis function of the recently discovered ER Membrane Complex (EMC) was evident from the yeast screen. This novel function was validated biochemically by siRNA of an EMC ortholog in a human cell line expressing CFTR-[increment]F508. The precision and accuracy of quantitative high throughput cell array phenotyping (Q-HTCP), which captures tens of thousands of growth curves simultaneously, provided powerful resolution to measure gene interaction on a phenomic scale, based on discrete cell proliferation parameters. CONCLUSION: We propose phenomic analysis of Yor1-[increment]F as a model for investigating gene interaction networks that can modulate cystic fibrosis disease severity. Although the clinical relevance of the Yor1-[increment]F gene interaction network for cystic fibrosis remains to be defined, the model appears to be informative with respect to human cell models of CFTR-[increment]F. Moreover, the general strategy of yeast phenomics can be employed in a systematic manner to model gene interaction for other diseases relating to pathologies that result from protein misfolding or potentially any disease involving evolutionarily conserved genetic pathways.