Spliceosome-mediated decay (SMD) regulates expression of nonintronic genes in budding yeast

We uncovered a novel role for the spliceosome in regulating mRNA expression levels that involves splicing coupled to RNA decay, which we refer to as spliceosome-mediated decay (SMD). Our transcriptome-wide studies identified numerous transcripts that are not known to have introns but are spliced by the spliceosome at canonical splice sites in Saccharomyces cerevisiae. Products of SMD are primarily degraded by the nuclear RNA surveillance machinery. We demonstrate that SMD can significantly down-regulate mRNA levels; splicing at canonical splice sites in the bromodomain factor 2 (BDF2) transcript reduced transcript levels roughly threefold by generating unstable products that are rapidly degraded by the nuclear surveillance machinery. Regulation of BDF2 mRNA levels by SMD requires Bdf1, a functionally redundant Bdf2 paralog that plays a role in recruiting the spliceosome to the BDF2 mRNA. Interestingly, mutating BDF2 5' splice site and branch point consensus sequences partially suppresses the bdf1Δ temperature-sensitive phenotype, suggesting that maintaining proper levels of Bdf2 via SMD is biologically important. We propose that the spliceosome can also repress protein-coding gene expression by promoting nuclear turnover of spliced RNA products and provide an insight for coordinated regulation of Bdf1 and Bdf2 levels in the cell

Adapting Medical Guidelines to Be Patient-centered Using a Patient-driven Process for Individuals With Sickle Cell Disease and Their Caregivers

Background: Evidence-based guidelines for sickle cell disease (SCD) health maintenance and management have been developed for primary health care providers, but not for individuals with SCD. To improve the quality of care delivered to individuals with SCD and their caregivers, the main purposes of this study were to: (1) understand the desire for patient-centered guidelines among the SCD community; and (2) adapt guideline material to be patient-centered using community-engagement strategies involving health care providers, community -based organizations, and individuals with the disease. Methods: From May–December 2016, a volunteer sample of 107 individuals with SCD and their caregivers gave feedback at community forums (n = 64) and community listening sessions (n = 43) about technology use for health information and desire for SCD-related guidelines. A team of community research partners consisting of community stakeholders, individuals living with SCD, and providers and researchers (experts) in SCD at nine institutions adapted guidelines to be patient-centered based on the following criteria: (1) understandable, (2) actionable, and (3) useful. Results: In community forums (n = 64), almost all participants (91%) wanted direct access to the content of the guidelines. Participants wanted guidelines in more than one format including paper (73%) and mobile devices (79%). Guidelines were adapted to be patient-centered. After multiple iterations of feedback, 100% of participants said the guidelines were understandable, most (88%) said they were actionable, and everyone (100%) would use these adapted guidelines to discuss their medical care with their health care providers. Conclusions: Individuals with SCD and their caregivers want access to guidelines through multiple channels, including technology. Guidelines written for health care providers can be adapted to be patient-centered using Community-engaged research involving providers and patients. These patient-centered guidelines provide a framework for patients to discuss their medical care with their health care providers

Correlated response to selection for litter size environmental variability in rabbits' resilience

[EN] Resilience is the ability of an animal to return soon to its initial productivity after facing diverse environmental challenges. This trait is directly related to animal welfare and it plays a key role in fluctuations of livestock productivity. A divergent selection experiment for environmental variance of litter size has been performed successfully in rabbits over ten generations. The objective of this study was to analyse resilience indicators of stress and disease in the divergent lines of this experiment. The high line showed a lower survival rate at birth than the low line (-4.1%). After correcting by litter size, the difference was -3.2%. Involuntary culling rate was higher in the high than in the low line (+12.4%). Before vaccination against viral haemorrhagic disease or myxomatosis, concentration of lymphocytes, C-reactive protein (CRP), complement C3, serum bilirubin, triglycerides and cholesterol were higher in the high line than in the low line (difference between lines +4.5%, +5.6 mu g/ml, +4.6 mg/ml, +7.9 mmol/l, +0.3 mmol/l and +0.4 mmol/l). Immunological and biochemical responses to the two vaccines were similar. After vaccination, the percentage of lymphocytes and CRP concentration were higher in the low line than in the high one (difference between lines +4.0% and +13.1 mu g/ml). The low line also showed a higher increment in bilirubin and triglycerides than the high line (+14.2 v. +8.7 mmol/l for bilirubin and +0.11 v. +0.01 mmol/l for triglycerides); these results would agree with the protective role of bilirubin and triglycerides against the larger inflammatory response found in this line. In relation to stress, the high line had higher basal concentration of cortisol than the low line (+0.2ng/ml); the difference between lines increased more than threefold after the injection of ACTH 1 to 24, the increase being greater in the high line (+0.9 ng/ml) than in the low line (+0.4 ng/ml). Selection for divergent environmental variability of litter size leads to dams with different culling rate for reproductive causes and different kits' neonatal survival. These associations suggest that the observed fitness differences are related to differences in the inflammatory response and the corticotrope response to stress, which are two important components of physiological adaptation to environmental aggressions.This study is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) with the Projects AGL2014-55921, C2-1-P and C2-2-P, and AGL2017-86083, C2-1-P and C2-2-P.Argente, M.; Garcia, M.; Zbynovska, K.; Petruska, P.; Capcarova, M.; Blasco Mateu, A. (2019). Correlated response to selection for litter size environmental variability in rabbits' resilience. Animal. 13(10):2348-2355. https://doi.org/10.1017/S1751731119000302S234823551310Glaser, R., & Kiecolt-Glaser, J. K. (2005). Stress-induced immune dysfunction: implications for health. Nature Reviews Immunology, 5(3), 243-251. doi:10.1038/nri1571Markanday, A. (2015). Acute Phase Reactants in Infections: Evidence-Based Review and a Guide for Clinicians. Open Forum Infectious Diseases, 2(3). doi:10.1093/ofid/ofv098Rauw, W. ., Kanis, E., Noordhuizen-Stassen, E. ., & Grommers, F. . (1998). Undesirable side effects of selection for high production efficiency in farm animals: a review. Livestock Production Science, 56(1), 15-33. doi:10.1016/s0301-6226(98)00147-xPiles, M., García, M. L., Rafel, O., Ramon, J., & Baselga, M. (2006). Genetics of litter size in three maternal lines of rabbits: Repeatability versus multiple-trait models. 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Genetics of adaptation in domestic farm animals: A review. Livestock Science, 132(1-3), 1-12. doi:10.1016/j.livsci.2010.05.003García, M. L., Blasco, A., & Argente, M. J. (2016). Embryologic changes in rabbit lines selected for litter size variability. Theriogenology, 86(5), 1247-1250. doi:10.1016/j.theriogenology.2016.04.065Feingold KR and Grunfeld C 2015. The effect of inflammation and infection on lipids and lipoproteins. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R, Singer F and Vinik A. Endotext, South Dartmouth, MA, USA. Retrieved on 7 June 2018 from https://www.ncbi.nlm.nih.gov/books/NBK326741/.Minemura, M. (2014). Liver involvement in systemic infection. World Journal of Hepatology, 6(9), 632. doi:10.4254/wjh.v6.i9.632Knap, P. W. (2005). Breeding robust pigs. Australian Journal of Experimental Agriculture, 45(8), 763. doi:10.1071/ea05041Barcia, A. M., & Harris, H. W. (2005). Triglyceride-Rich Lipoproteins as Agents of Innate Immunity. Clinical Infectious Diseases, 41(Supplement_7), S498-S503. doi:10.1086/432005Webster, J. I., Tonelli, L., & Sternberg, E. M. (2002). NEUROENDOCRINEREGULATION OFIMMUNITY. Annual Review of Immunology, 20(1), 125-163. doi:10.1146/annurev.immunol.20.082401.104914Fortun-Lamothe, L. (2006). Energy balance and reproductive performance in rabbit does. Animal Reproduction Science, 93(1-2), 1-15. doi:10.1016/j.anireprosci.2005.06.009Cabezas, S., Blas, J., Marchant, T. A., & Moreno, S. (2007). Physiological stress levels predict survival probabilities in wild rabbits. Hormones and Behavior, 51(3), 313-320. doi:10.1016/j.yhbeh.2006.11.004De Nardo, D., Labzin, L. I., Kono, H., Seki, R., Schmidt, S. V., Beyer, M., … Latz, E. (2013). High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3. Nature Immunology, 15(2), 152-160. doi:10.1038/ni.2784BURKUŠ, J., KAČMAROVÁ, M., KUBANDOVÁ, J., KOKOŠOVÁ, N., FABIANOVÁ, K., FABIAN, D., … ČIKOŠ, Š. (2015). Stress exposure during the preimplantation period affects blastocyst lineages and offspring development. Journal of Reproduction and Development, 61(4), 325-331. doi:10.1262/jrd.2015-012Posthouwer, D., Voorbij, H. A. M., Grobbee, D. E., Numans, M. E., & van der Bom, J. G. (2004). Influenza and pneumococcal vaccination as a model to assess C-reactive protein response to mild inflammation. Vaccine, 23(3), 362-365. doi:10.1016/j.vaccine.2004.05.035Ibáñez-Escriche, N., Sorensen, D., Waagepetersen, R., & Blasco, A. (2008). Selection for Environmental Variation: A Statistical Analysis and Power Calculations to Detect Response. Genetics, 180(4), 2209-2226. doi:10.1534/genetics.108.091678Colditz, I. G., & Hine, B. C. (2016). Resilience in farm animals: biology, management, breeding and implications for animal welfare. 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Addressing Recruitment Challenges in the Engage-HU Trial in Young Children with Sickle Cell Disease

Background: Sickle cell disease (SCD) is a genetic disorder that causes significant medical and neurologic morbidity in children. Hydroxyurea (HU) is the primary medication used to prevent these complications. National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend offering HU to children as young as 9 months of age with SCD (HbSS or HbSB0 thalassemia) using a shared decision-making approach. Although HU has proven efficacious it remains underutilized and caregivers report that they are not always actively involved in the decision to initiate this therapy. Reasons for limited HU uptake likely include lack of clinician knowledge and training and negative caregiver perceptions. Thus, we developed the Engage-HU trial as a novel approach to address HU utilization barriers. A critical consideration for this trial was that SCD primarily affects individuals of African and Hispanic/Latino descent. In these minority populations, intervention trials are sometimes terminated early because of recruitment difficulties related to mistrust of research, caregiver burden, and transportation issues. As such, the Engage-HU trial design included best-practice strategies for recruiting people of color in research. This study describes these strategies, the initial recruitment plan, preliminary recruitment outcomes and strategies, and our procedural adaptations. Study Design and Methods: Engage-HU is a randomized control trial (NCT03442114) to assess how clinicians can engage caregivers in a shared discussion that considers their values and preferences and includes evidence that supports HU. Engage-HU compares two dissemination methods for clinicians to facilitate shared decision-making with caregivers of young children with SCD: 1) the American Society of Hematology Pocket Guide, and 2) the HU Shared-Decision Making (H-SDM) Toolkit. The study aims to recruit 174 caregivers and evaluate the effectiveness of the dissemination methods on patient-centered outcomes (caregiver confidence in decision-making and perceptions of experiencing shared decision-making) as well as HU uptake and child health outcomes. Eligible children are aged 0 to 5 years, candidates for HU, and their caregiver has not made a decision about HU in the past 3 months. The trial is being conducted at 9 sites in the United States and uses a stepped-wedge design. Data will be analyzed based on the intent-to-treat principle. All participants will remain in the arm of the study to which they were randomized, regardless of whether or not they receive the assigned dissemination method. The primary endpoints are caregiver decisional uncertainty and caregiver perception of shared decision-making measured using validated tools. Data will be analyzed using a linear mixed effects regression model with a robust variance estimator and maximum likelihood estimation with observations clustered within site. The Engage-HU trial includes adaptations to increase recruitment such as tailored messaging, a relational recruitment approach, streamlined data collection, and a Stakeholder Advisory Committee. However, even with these adaptations, the first 6-months of the trial yielded lower than anticipated recruitment. Rather than terminate the trial or accept low enrollment, the research team implemented a series of recruitment strategies to address barriers including helping to improve research coordinator knowledge of the study purpose and adjusting no-show and follow-up procedures (e.g., calls to families after missed appointments and reminder calls before appointments). Site clinicians and clinic staff were provided with additional training so they could give more context about Engage-HU to caregivers and the study principal investigator led monthly "all coordinator" calls to provide support by sharing updates and experiences about successful recruitment. Implementation of these strategies resulted in triple the number of enrollments over the next 7-months compared to the previous 6-months (Table 1). Our goal in sharing this information is to provide lessons learned that can be implemented in future trials with the systematically underserved SCD population. It is also anticipated that methods described here may also inform clinical approaches to better engage caregivers of young children around critical clinical conversations, such as initiating medications like HU. Disclosures King: Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; RiverVest: Consultancy; Novimmune: Research Funding; Celgene: Consultancy; Tioma Therapuetics: Consultancy; Amphivena Therapeutics: Research Funding; WUGEN: Current equity holder in private company; Cell Works: Consultancy; Incyte: Consultancy. Smith-Whitley:Prime: Other: Education material; Celgene: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Neumayr:Emmaus: Consultancy; Bayer: Consultancy; CTD Holdings: Consultancy; Pfizer: Consultancy; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Micelle: Other: Site principal investigator; GBT: Other: Site principal investigator; PCORI: Other: site principal investigator; Novartis: Other: co-investigator; Bluebird Bio: Other: co-investigator; Sangamo Therapeutics: Other; Silarus: Other; Celgene: Other; La Jolla Pharmaceuticals: Other; Forma: Other; Imara: Other; National Heart, Lung, and Blood Institute: Other; Health Resources and Services Administration: Other; Centers for Disease Control and Prevention: Other; Seattle Children's Research: Other. Yates:Novartis: Research Funding. Thompson:Novartis: Consultancy, Honoraria, Research Funding; CRISPR/Vertex: Research Funding; BMS: Consultancy, Research Funding; Baxalta: Research Funding; Biomarin: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. </jats:sec

Interleukin-10 polymorphisms in Spanish IgA deficiency patients: a case-control and family study

BACKGROUND: IgA deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. Genetic and environmental factors are suspected to be involved in the development of the disease. Interleukin-10 (IL-10) is a cytokine with stimulatory activity on immunoglobulin production and it may be an important regulator in IgAD pathogenesis. The IL-10 gene contains several single nucleotide polymorphisms (SNPs) and two polymorphic microsatellites located in the 5'-flanking region. Our aim was to ascertain if any of these polymorphic markers are associated or linked to IgAD in Spanish patients. METHODS: We genotyped 278 patients with IgAD and 573 ethnically matched controls for the microsatellites IL-10R and IL-10G and for three single nucleotide polymorphisms at positions -1082, -819 and -592 in the proximal promoter of the gene. We also included in this study the parents of 194 patients in order to study the IL-10 haplotypes transmitted and not transmitted to the affected offspring. RESULTS: The only allele where a significant difference was observed in the comparison between IgA deficiency patients and controls was the IL-10G12 allele (OR = 1.58 and p = 0.021). However, this p value could not withstand a Bonferroni correction. None of the IL-10R or promoter SNP alleles was found at a different frequency when patients were compared with controls. CONCLUSION: Our data do not show any significant difference in IL-10 polymorphism frequencies between control and IgAD patient samples. Their haplotype distribution among patients and controls was also equivalent and therefore these microsatellites and SNPs do not seem to influence IgAD susceptibility

Vitamin A deficiency and inflammatory markers among preschool children in the Republic of the Marshall Islands

BACKGROUND: The exclusion of individuals with elevated acute phase proteins has been advocated in order to improve prevalence estimates of vitamin A deficiency in surveys, but it is unclear whether this will lead to sampling bias. The purpose of the study was to determine whether the exclusion of individuals with elevated acute phase proteins is associated with sampling bias and to characterize inflammation in children with night blindness. METHODS: In a survey in the Republic of the Marshall Islands involving 281 children, aged 1–5 years, serum retinol, C-reactive protein (CRP), and α(1)-acid glycoprotein (AGP) were measured. RESULTS: Of 281 children, 24 (8.5%) had night blindness and 165 (58.7%) had serum retinol <0.70 μmol/L. Of 248 children with AGP and CRP measurements, 123 (49.6%) had elevated acute phase proteins (CRP >5 mg/L and/or AGP >1000 mg/L). Among children with and without night blindness, the proportion with serum retinol <0.70 μmol/L was 79.2% and 56.8% (P = 0.03) and with anemia was 58.3% and 35.7% (P = 0.029), respectively. The proportion of children with serum retinol <0.70 μmol/L was 52.0% after excluding children with elevated acute phase proteins. Among children with and without elevated acute phase proteins, mean age was 2.8 vs 3.2 years (P = 0.016), the proportion of boys was 43.1% vs. 54.3% (P = 0.075), with no hospitalizations in the last year was 11.0% vs 23.6% (P = 0.024), and with anemia was 43.8% vs 31.7% (P = 0.05), respectively. CONCLUSIONS: Exclusion of children with inflammation in this survey of vitamin A deficiency does not improve prevalence estimates for vitamin A deficiency and instead leads to sampling bias for variables such as age, gender, anemia, and hospitalization history

Human Pentraxin 3 Binds to the Complement Regulator C4b-Binding Protein

The long pentraxin 3 (PTX3) is a soluble recognition molecule with multiple functions including innate immune defense against certain microbes and the clearance of apoptotic cells. PTX3 interacts with recognition molecules of the classical and lectin complement pathways and thus initiates complement activation. In addition, binding of PTX3 to the alternative complement pathway regulator factor H was shown. Here, we show that PTX3 binds to the classical and lectin pathway regulator C4b-binding protein (C4BP). A PTX3-binding site was identified within short consensus repeats 1–3 of the C4BP α-chain. PTX3 did not interfere with the cofactor activity of C4BP in the fluid phase and C4BP maintained its complement regulatory activity when bound to PTX3 on surfaces. While C4BP and factor H did not compete for PTX3 binding, the interaction of C4BP with PTX3 was inhibited by C1q and by L-ficolin. PTX3 bound to human fibroblast- and endothelial cell-derived extracellular matrices and recruited functionally active C4BP to these surfaces. Whereas PTX3 enhanced the activation of the classical/lectin pathway and caused enhanced C3 deposition on extracellular matrix, deposition of terminal pathway components and the generation of the inflammatory mediator C5a were not increased. Furthermore, PTX3 enhanced the binding of C4BP to late apoptotic cells, which resulted in an increased rate of inactivation of cell surface bound C4b and a reduction in the deposition of C5b-9. Thus, in addition to complement activators, PTX3 interacts with complement inhibitors including C4BP. This balanced interaction on extracellular matrix and on apoptotic cells may prevent excessive local complement activation that would otherwise lead to inflammation and host tissue damage

Genome-wide association study of bronchopulmonary dysplasia : a potential role for variants near the CRP gene

Bronchopulmonary dysplasia (BPD), the main consequence of prematurity, has a significant heritability, but little is known about predisposing genes. The aim of this study was to identify gene loci predisposing infants to BPD. The initial genome-wide association study (GWAS) included 174 Finnish preterm infants of gestational age 24-30 weeks. Thereafter, the most promising single-nucleotide polymorphisms (SNPs) associated with BPD were genotyped in both Finnish (n = 555) and non-Finnish (n = 388) replication cohorts. Finally, plasma CRP levels from the first week of life and the risk of BPD were assessed. SNP rs11265269, flanking the CRP gene, showed the strongest signal in GWAS (odds ratio [ OR] 3.2, p = 3.4 x 10(-6)). This association was nominally replicated in Finnish and French African populations. A number of other SNPs in the CRP region, including rs3093059, had nominal associations with BPD. During the first week of life the elevated plasma levels of CRP predicted the risk of BPD (OR 3.4, p = 2.9 x 10(-4)) and the SNP rs3093059 associated nominally with plasma CRP levels. Finally, SNP rs11265269 was identified as a risk factor of BPD (OR 1.8, p = 5.3 x 10(-5)), independently of the robust antenatal risk factors. As such, in BPD, a potential role for variants near CRP gene is proposed.Peer reviewe

Genomic view of the evolution of the complement system

The recent accumulation of genomic information of many representative animals has made it possible to trace the evolution of the complement system based on the presence or absence of each complement gene in the analyzed genomes. Genome information from a few mammals, chicken, clawed frog, a few bony fish, sea squirt, fruit fly, nematoda and sea anemone indicate that bony fish and higher vertebrates share practically the same set of complement genes. This suggests that most of the gene duplications that played an essential role in establishing the mammalian complement system had occurred by the time of the teleost/mammalian divergence around 500 million years ago (MYA). Members of most complement gene families are also present in ascidians, although they do not show a one-to-one correspondence to their counterparts in higher vertebrates, indicating that the gene duplications of each gene family occurred independently in vertebrates and ascidians. The C3 and factor B genes, but probably not the other complement genes, are present in the genome of the cnidaria and some protostomes, indicating that the origin of the central part of the complement system was established more than 1,000 MYA

Gradient Descent Optimization in Gene Regulatory Pathways

BACKGROUND: Gene Regulatory Networks (GRNs) have become a major focus of interest in recent years. Elucidating the architecture and dynamics of large scale gene regulatory networks is an important goal in systems biology. The knowledge of the gene regulatory networks further gives insights about gene regulatory pathways. This information leads to many potential applications in medicine and molecular biology, examples of which are identification of metabolic pathways, complex genetic diseases, drug discovery and toxicology analysis. High-throughput technologies allow studying various aspects of gene regulatory networks on a genome-wide scale and we will discuss recent advances as well as limitations and future challenges for gene network modeling. Novel approaches are needed to both infer the causal genes and generate hypothesis on the underlying regulatory mechanisms. METHODOLOGY: In the present article, we introduce a new method for identifying a set of optimal gene regulatory pathways by using structural equations as a tool for modeling gene regulatory networks. The method, first of all, generates data on reaction flows in a pathway. A set of constraints is formulated incorporating weighting coefficients. Finally the gene regulatory pathways are obtained through optimization of an objective function with respect to these weighting coefficients. The effectiveness of the present method is successfully tested on ten gene regulatory networks existing in the literature. A comparative study with the existing extreme pathway analysis also forms a part of this investigation. The results compare favorably with earlier experimental results. The validated pathways point to a combination of previously documented and novel findings. CONCLUSIONS: We show that our method can correctly identify the causal genes and effectively output experimentally verified pathways. The present method has been successful in deriving the optimal regulatory pathways for all the regulatory networks considered. The biological significance and applicability of the optimal pathways has also been discussed. Finally the usefulness of the present method on genetic engineering is depicted with an example