Precise assembly of complex beta sheet topologies from de novo designed building blocks.

Elife. 2015 Dec 09;4:

Authors: King IC, Gleixner J, Doyle L, Kuzin A, Hunt JF, Xiao R, Montelione GT, Stoddard BL, DiMaio F, Baker D

Abstract
Design of complex alpha-beta protein topologies poses a challenge because of the large number of alternative packing arrangements. A similar challenge presumably limited the emergence of large and complex protein topologies in evolution. Here, we demonstrate that protein topologies with six and seven-stranded beta sheets can be designed by insertion of one de novo designed beta sheet containing protein into another such that the two beta sheets are merged to form a single extended sheet, followed by amino acid sequence optimization at the newly formed strand-strand, strand-helix, and helix-helix interfaces. Crystal structures of two such designs closely match the computational design models. Searches for similar structures in the SCOP protein domain database yield only weak matches with different beta sheet connectivities. A similar beta sheet fusion mechanism may have contributed to the emergence of complex beta sheets during natural protein evolution.

PMID: 26650357 [PubMed - indexed for MEDLINE]

Rate and timing of cortical responses driven by separate sensory channels.

Elife. 2015 Dec 09;4:e10450

Authors: Saal HP, Harvey MA, Bensmaia SJ

Abstract
The sense of touch comprises multiple sensory channels that each conveys characteristic signals during interactions with objects. These neural signals must then be integrated in such a way that behaviorally relevant information about the objects is preserved. To understand the process of integration, we implement a simple computational model that describes how the responses of neurons in somatosensory cortex-recorded from awake, behaving monkeys-are shaped by the peripheral input, reconstructed using simulations of neuronal populations that reproduce natural spiking responses in the nerve with millisecond precision. First, we find that the strength of cortical responses is driven by one population of nerve fibers (rapidly adapting) whereas the timing of cortical responses is shaped by the other (Pacinian). Second, we show that input from these sensory channels is integrated in an optimal fashion that exploits the disparate response behaviors of different fiber types.

PMID: 26650354 [PubMed - indexed for MEDLINE]

Secretome identification of immune cell factors mediating metastatic cell homing.

Sci Rep. 2015 Dec 04;5:17566

Authors: Aguado BA, Wu JJ, Azarin SM, Nanavati D, Rao SS, Bushnell GG, Medicherla CB, Shea LD

Abstract
Metastatic cell homing is a complex process mediated in part by diffusible factors secreted from immune cells found at a pre-metastatic niche. We report on connecting secretomics and TRanscriptional Activity CEll aRray (TRACER) data to identify functional paracrine interactions between immune cells and metastatic cells as novel mediators of homing. Metastatic breast cancer mouse models were used to generate a diseased splenocyte conditioned media (D-SCM) containing immune cell secreted factors. MDA-MB-231 metastatic cell activity including cell invasion, migration, transendothelial migration, and proliferation were increased in D-SCM relative to control media. Our D-SCM secretome analysis yielded 144 secreted factor candidates that contribute to increased metastatic cell activity. The functional mediators of homing were identified using MetaCore software to determine interactions between the immune cell secretome and the TRACER-identified active transcription factors within metastatic cells. Among the 5 candidate homing factors identified, haptoglobin was selected and validated in vitro and in vivo as a key mediator of homing. Our studies demonstrate a novel systems biology approach to identify functional signaling factors associated with a cellular phenotype, which provides an enabling tool that complements large-scale protein identification provided by proteomics.

PMID: 26634905 [PubMed - indexed for MEDLINE]

EGF-dependent re-routing of vesicular recycling switches spontaneous phosphorylation suppression to EGFR signaling.

Elife. 2015 Nov 26;4:

Authors: Baumdick M, Brüggemann Y, Schmick M, Xouri G, Sabet O, Davis L, Chin JW, Bastiaens PI

Abstract
Autocatalytic activation of epidermal growth factor receptor (EGFR) coupled to dephosphorylating activity of protein tyrosine phosphatases (PTPs) ensures robust yet diverse responses to extracellular stimuli. The inevitable tradeoff of this plasticity is spontaneous receptor activation and spurious signaling. We show that a ligand-mediated switch in EGFR trafficking enables suppression of spontaneous activation while maintaining EGFR's capacity to transduce extracellular signals. Autocatalytic phosphorylation of tyrosine 845 on unliganded EGFR monomers is suppressed by vesicular recycling through perinuclear areas with high PTP1B activity. Ligand-binding results in phosphorylation of the c-Cbl docking tyrosine and ubiquitination of the receptor. This secondary signal relies on EGF-induced EGFR self-association and switches suppressive recycling to directional trafficking. The re-routing regulates EGFR signaling response by the transit-time to late endosomes where it is switched-off by high PTP1B activity. This ubiquitin-mediated switch in EGFR trafficking is a uniquely suited solution to suppress spontaneous activation while maintaining responsiveness to EGF.

PMID: 26609808 [PubMed - indexed for MEDLINE]

Endocrine resistance in breast cancer--An overview and update.

Mol Cell Endocrinol. 2015 Dec 15;418 Pt 3:220-34

Authors: Clarke R, Tyson JJ, Dixon JM

Abstract
Tumors that express detectable levels of the product of the ESR1 gene (estrogen receptor-α; ERα) represent the single largest molecular subtype of breast cancer. More women eventually die from ERα+ breast cancer than from either HER2+ disease (almost half of which also express ERα) and/or from triple negative breast cancer (ERα-negative, progesterone receptor-negative, and HER2-negative). Antiestrogens and aromatase inhibitors are largely indistinguishable from each other in their abilities to improve overall survival and almost 50% of ERα+ breast cancers will eventually fail one or more of these endocrine interventions. The precise reasons why these therapies fail in ERα+ breast cancer remain largely unknown. Pharmacogenetic explanations for Tamoxifen resistance are controversial. The role of ERα mutations in endocrine resistance remains unclear. Targeting the growth factors and oncogenes most strongly correlated with endocrine resistance has proven mostly disappointing in their abilities to improve overall survival substantially, particularly in the metastatic setting. Nonetheless, there are new concepts in endocrine resistance that integrate molecular signaling, cellular metabolism, and stress responses including endoplasmic reticulum stress and the unfolded protein response (UPR) that provide novel insights and suggest innovative therapeutic targets. Encouraging evidence that drug combinations with CDK4/CDK6 inhibitors can extend recurrence free survival may yet translate to improvements in overall survival. Whether the improvements seen with immunotherapy in other cancers can be achieved in breast cancer remains to be determined, particularly for ERα+ breast cancers. This review explores the basic mechanisms of resistance to endocrine therapies, concluding with some new insights from systems biology approaches further implicating autophagy and the UPR in detail, and a brief discussion of exciting new avenues and future prospects.

PMID: 26455641 [PubMed - indexed for MEDLINE]

Symptom clusters in women with breast cancer: an analysis of data from social media and a research study.

Qual Life Res. 2016 Mar;25(3):547-57

Authors: Marshall SA, Yang CC, Ping Q, Zhao M, Avis NE, Ip EH

Abstract
PURPOSE: User-generated content on social media sites, such as health-related online forums, offers researchers a tantalizing amount of information, but concerns regarding scientific application of such data remain. This paper compares and contrasts symptom cluster patterns derived from messages on a breast cancer forum with those from a symptom checklist completed by breast cancer survivors participating in a research study.
METHODS: Over 50,000 messages generated by 12,991 users of the breast cancer forum on MedHelp.org were transformed into a standard form and examined for the co-occurrence of 25 symptoms. The k-medoid clustering method was used to determine appropriate placement of symptoms within clusters. Findings were compared with a similar analysis of a symptom checklist administered to 653 breast cancer survivors participating in a research study.
RESULTS: The following clusters were identified using forum data: menopausal/psychological, pain/fatigue, gastrointestinal, and miscellaneous. Study data generated the clusters: menopausal, pain, fatigue/sleep/gastrointestinal, psychological, and increased weight/appetite. Although the clusters are somewhat different, many symptoms that clustered together in the social media analysis remained together in the analysis of the study participants. Density of connections between symptoms, as reflected by rates of co-occurrence and similarity, was higher in the study data.
CONCLUSIONS: The copious amount of data generated by social media outlets can augment findings from traditional data sources. When different sources of information are combined, areas of overlap and discrepancy can be detected, perhaps giving researchers a more accurate picture of reality. However, data derived from social media must be used carefully and with understanding of its limitations.

PMID: 26476836 [PubMed - indexed for MEDLINE]

Text analysis tools for identification of emerging topics and research gaps in conservation science.

Conserv Biol. 2015 Dec;29(6):1606-14

Authors: Westgate MJ, Barton PS, Pierson JC, Lindenmayer DB

Abstract
Keeping track of conceptual and methodological developments is a critical skill for research scientists, but this task is increasingly difficult due to the high rate of academic publication. As a crisis discipline, conservation science is particularly in need of tools that facilitate rapid yet insightful synthesis. We show how a common text-mining method (latent Dirichlet allocation, or topic modeling) and statistical tests familiar to ecologists (cluster analysis, regression, and network analysis) can be used to investigate trends and identify potential research gaps in the scientific literature. We tested these methods on the literature on ecological surrogates and indicators. Analysis of topic popularity within this corpus showed a strong emphasis on monitoring and management of fragmented ecosystems, while analysis of research gaps suggested a greater role for genetic surrogates and indicators. Our results show that automated text analysis methods need to be used with care, but can provide information that is complementary to that given by systematic reviews and meta-analyses, increasing scientists' capacity for research synthesis.

PMID: 26271213 [PubMed - indexed for MEDLINE]

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Pharmacogenomics of Prostaglandin and Leukotriene Receptors.

Front Pharmacol. 2016;7:316

Authors: Cornejo-García JA, Perkins JR, Jurado-Escobar R, García-Martín E, Agúndez JA, Viguera E, Pérez-Sánchez N, Blanca-López N

Abstract
Individual genetic background together with environmental effects are thought to be behind many human complex diseases. A number of genetic variants, mainly single nucleotide polymorphisms (SNPs), have been shown to be associated with various pathological and inflammatory conditions, representing potential therapeutic targets. Prostaglandins (PTGs) and leukotrienes (LTs) are eicosanoids derived from arachidonic acid and related polyunsaturated fatty acids that participate in both normal homeostasis and inflammatory conditions. These bioactive lipid mediators are synthesized through two major multistep enzymatic pathways: PTGs by cyclooxygenase and LTs by 5-lipoxygenase. The main physiological effects of PTGs include vasodilation and vascular leakage (PTGE2); mast cell maturation, eosinophil recruitment, and allergic responses (PTGD2); vascular and respiratory smooth muscle contraction (PTGF2), and inhibition of platelet aggregation (PTGI2). LTB4 is mainly involved in neutrophil recruitment, vascular leakage, and epithelial barrier function, whereas cysteinyl LTs (CysLTs) (LTC4, LTD4, and LTE4) induce bronchoconstriction and neutrophil extravasation, and also participate in vascular leakage. PTGs and LTs exert their biological functions by binding to cognate receptors, which belong to the seven transmembrane, G protein-coupled receptor superfamily. SNPs in genes encoding these receptors may influence their functionality and have a role in disease susceptibility and drug treatment response. In this review we summarize SNPs in PTGs and LTs receptors and their relevance in human diseases. We also provide information on gene expression. Finally, we speculate on future directions for this topic.

PMID: 27708579 [PubMed - in process]

Precision medicine: from pharmacogenomics to pharmacoproteomics.

Clin Proteomics. 2016;13:25

Authors: Chambliss AB, Chan DW

Abstract
Disease progression and drug response may vary significantly from patient to patient. Fortunately, the rapid development of high-throughput 'omics' technologies has allowed for the identification of potential biomarkers that may aid in the understanding of the heterogeneities in disease development and treatment outcomes. However, mechanistic gaps remain when the genome or the proteome are investigated independently in response to drug treatment. In this article, we discuss the current status of pharmacogenomics in precision medicine and highlight the needs for concordant analysis at the proteome and metabolome levels via the more recently-evolved fields of pharmacoproteomics, toxicoproteomics, and pharmacometabolomics. Integrated 'omics' investigations will be critical in piecing together targetable mechanisms of action for both drug development and monitoring of therapy in order to fully apply precision medicine to the clinic.

PMID: 27708556 [PubMed - in process]

Genetic factors affecting patient responses to pancreatic cancer treatment.

Ann Gastroenterol. 2016 Oct-Dec;29(4):466-476

Authors: Fotopoulos G, Syrigos K, Saif MW

Abstract
Cancer of the exocrine pancreas is a malignancy with a high lethal rate. Surgical resection is the only possible curative mode of treatment. Metastatic pancreatic cancer is incurable with modest results from the current treatment options. New genomic information could prove treatment efficacy. An independent review of PubMed and ScienceDirect databases was performed up to March 2016, using combinations of terms such pancreatic exocrine cancer, chemotherapy, genomic profile, pancreatic cancer pharmacogenomics, genomics, molecular pancreatic pathogenesis, and targeted therapy. Recent genetic studies have identified new markers and therapeutic targets. Our current knowledge of pancreatic cancer genetics must be further advanced to elucidate the molecular basis and pathogenesis of the disease, improve the accuracy of diagnosis, and guide tailor-made therapies.

PMID: 27708512 [PubMed - in process]

Cancer Gene Profiling for Response Prediction.

Methods Mol Biol. 2016;1381:163-79

Authors: Ghadimi BM, Jo P

Abstract
The revolution of genomic technologies, including gene expression profiling, high-resolution mapping of genomic imbalances, and next-generation sequencing, allows us to establish molecular portraits of cancer cells with unprecedented accuracy. This generates hope and justifies anticipation that disease diagnosis, prognosis, and the choice of treatment will be adapted to the individual needs of patients based on molecular evidence. Preoperative treatment strategies are now recommended for a variety of human cancers. Unfortunately, the response of individual tumors to a preoperative treatment is not uniform, and ranges from complete regression to resistance. This poses a considerable clinical dilemma, as patients with a priori resistant tumors could either be spared exposure to radiation or DNA-damaging drugs, i.e., could be referred to primary surgery, or dose-intensified protocols could be pursued. Because the response of an individual tumor as well as therapy-induced side effects represent the major limiting factors of current treatment strategies, identifying molecular markers of response or for treatment toxicity has become exceedingly important. However, complex phenotypes such as tumor responsiveness to multimodal treatments probably do not depend on the expression levels of just one or a few genes and proteins. Therefore, methods that allow comprehensive interrogation of genetic pathways and networks hold great promise in delivering such tumor-specific signatures, since expression levels of thousands of genes can be monitored simultaneously. Over the past few years, microarray technology has emerged as a central tool in addressing pertinent clinical questions, the answers to which are critical for the realization of a personalized genomic medicine, in which patients will be treated based on the biology of their tumor and their genetic profile (Quackenbush, N Engl J Med 354:2463-72, 2006; Jensen et al., Curr Opin Oncol 18:374-380, 2006; Bol and Ebner, Pharmacogenomics 7:227-235, 2006; Nevins and Potti, Nat Rev Genet 8:601-609, 2007).

PMID: 26667460 [PubMed - indexed for MEDLINE]

How can we improve on the already impressive results in pediatric ALL?

Hematology Am Soc Hematol Educ Program. 2015;2015:414-9

Authors: Thomas A

Abstract
The past 70 years have seen childhood acute lymphoblastic leukemia move from a fatal disease with a survival of barely 4 months to a curable disease in >85% of patients. It has become clear that as treatment has intensified, more children are cured but at the expense of increased toxicity which for some can cause significant long-term morbidity and even mortality. The drive in more recent years has been to identify sensitive markers of disease and response to treatment to allow a reduction in therapy in those who do not require it and more intensive treatment in those who do. Clinical characteristics have been used to stratify patients into different risk groups and this, coupled with following response at a molecular level, has done much to tailor treatment to the patient. Considerable research has been focused on the molecular characteristics of the leukemia itself to elucidate the biologic mechanisms underlying both the disease and the comparative or absolute resistance of some types of leukemia. These molecular markers can also act as targets for novel therapies, which require newer trial methodologies to prove their utility. There has been less focus on the biology of the patient but it is clear that some patients are more susceptible to adverse events and toxicities than others. Through the use of pharmacogenomics, modification to therapy may be appropriate in certain patients based on their genetic profile. As novel therapies become available, suitable controlled trials in children are essential for their safe use in this population and will ensure that children are not denied timely access to advances in treatment.

PMID: 26637751 [PubMed - indexed for MEDLINE]

Genetic Polymorphisms Analysis of Pharmacogenomic VIP Variants in Miao Ethnic Group of Southwest China.

Med Sci Monit. 2015 Dec 03;21:3769-76

Authors: Jin T, Aikemu A, Zhang M, Geng T, Feng T, Kang L, Luo ML

Abstract
BACKGROUND Genetic polymorphisms have a potential clinical role in determining both inter-individual and inter-ethnic differences in drug efficacy, but we have not found any pharmacogenomics information regarding minorities, such as the Miao ethnic group. Our study aimed to screen numbers of the Miao ethnic group for genotype frequencies of VIP variants and to determine differences between the Miao and other human populations worldwide. MATERIAL AND METHODS In this study, we genotyped 66 Very Important Pharmacogene (VIP) variants selected from PharmGKB in 98 unrelated, healthy Miao individuals from the Guizhou province and compared our data with 12 other populations, including 11 populations from the HapMap data set and Xi'an Han Chinese. RESULTS Using the χ2 test, we found that the allele frequencies of the VDR rs1544410 and VKORC1 (rs9934438) variants in the Miao population are quite different from that in other ethnic groups. Furthermore, we found that genotype frequencies of rs1801133 (MTHFR) in the 13 selected populations are significantly different. Population structure and F-statistics (Fst) analysis show that the genetic background of the Miao is relatively close to that of Chinese in metropolitan Denver, CO, USA (CHD). CONCLUSIONS Our results help complete the information provided by the pharmacogenomics database of the Miao ethnic group and provide a theoretical basis for safer drug administration, which may be useful for diagnosing and treating diseases in this population.

PMID: 26632549 [PubMed - indexed for MEDLINE]

Pharmacogenomics of estrogens on changes in carotid artery intima-medial thickness and coronary arterial calcification: Kronos Early Estrogen Prevention Study.

Physiol Genomics. 2016 Jan;48(1):33-41

Authors: Miller VM, Jenkins GD, Biernacka JM, Heit JA, Huggins GS, Hodis HN, Budoff MJ, Lobo RA, Taylor HS, Manson JE, Black DM, Naftolin F, Harman SM, de Andrade M

Abstract
Prior to the initiation of menopausal hormone treatment (MHT), genetic variations in the innate immunity pathway were found to be associated with carotid artery intima-medial thickness (CIMT) and coronary arterial calcification (CAC) in women (n = 606) enrolled in the Kronos Early Estrogen Prevention Study (KEEPS). Whether MHT might affect these associations is unknown. The association of treatment outcomes with variation in the same 764 candidate genes was evaluated in the same KEEPS participants 4 yr after randomization to either oral conjugated equine estrogens (0.45 mg/day), transdermal 17β-estradiol (50 μg/day), each with progesterone (200 mg/day) for 12 days each month, or placebo pills and patch. Twenty SNPs within the innate immunity pathway most related with CIMT after 4 yr were not among those associated with CIMT prior to MHT. In 403 women who completed the study in their assigned treatment group, single nucleotide polymorphisms (SNPs) within the innate immunity pathway were found to alter the treatment effect on 4 yr change in CIMT (i.e., significant interaction between treatment and genetic variation in the innate immunity pathway; P < 0.001). No SNPs by treatment effects were observed with changes of CAC >5 Agatston units after 4 yr. Results of this study suggest that hormonal status may interact with genetic variants to influence cardiovascular phenotypes, specifically, the pharmacogenomic effects within the innate immunity pathway for CIMT.

PMID: 26508701 [PubMed - indexed for MEDLINE]

Genetic diversity of variants involved in drug response and metabolism in Sri Lankan populations: implications for clinical implementation of pharmacogenomics.

Pharmacogenet Genomics. 2016 Jan;26(1):28-39

Authors: Chan SL, Samaranayake N, Ross CJ, Toh MT, Carleton B, Hayden MR, Teo YY, Dissanayake VH, Brunham LR

Abstract
BACKGROUND: Interpopulation differences in drug responses are well documented, and in some cases they correspond to differences in the frequency of associated genetic markers. Understanding the diversity of genetic markers associated with drug response across different global populations is essential to infer population rates of drug response or risk for adverse drug reactions, and to guide implementation of pharmacogenomic testing. Sri Lanka is a culturally and linguistically diverse nation, but little is known about the population genetics of the major Sri Lankan ethnic groups. The objective of this study was to investigate the diversity of pharmacogenomic variants in the major Sri Lankan ethnic groups.
METHODS: We examined the allelic diversity of more than 7000 variants in genes involved in drug biotransformation and response in the three major ethnic populations of Sri Lanka (Sinhalese, Sri Lankan Tamils, and Moors), and compared them with other South Asian, South East Asian, and European populations using Wright's Fixation Index, principal component analysis, and STRUCTURE analysis.
RESULTS: We observed overall high levels of similarity within the Sri Lankan populations (median FST=0.0034), and between Sri Lankan and other South Asian populations (median FST=0.0064). Notably, we observed substantial differentiation between Sri Lankan and European populations for important pharmacogenomic variants related to warfarin (VKORC1 rs9923231) and clopidogrel (CYP2C19 rs4986893) response.
CONCLUSION: These data expand our understanding of the population structure of Sri Lanka, provide a resource for pharmacogenomic research, and have implications for the clinical use of genetic testing of pharmacogenomic variants in these populations.

PMID: 26444257 [PubMed - indexed for MEDLINE]

Immunological Signatures after Bordetella pertussis Infection Demonstrate Importance of Pulmonary Innate Immune Cells.

PLoS One. 2016;11(10):e0164027

Authors: Raeven RH, Brummelman J, van der Maas L, Tilstra W, Pennings JL, Han WG, van Els CA, van Riet E, Kersten GF, Metz B

Abstract
Effective immunity against Bordetella pertussis is currently under discussion following the stacking evidence of pertussis resurgence in the vaccinated population. Natural immunity is more effective than vaccine-induced immunity indicating that knowledge on infection-induced responses may contribute to improve vaccination strategies. We applied a systems biology approach comprising microarray, flow cytometry and multiplex immunoassays to unravel the molecular and cellular signatures in unprotected mice and protected mice with infection-induced immunity, around a B. pertussis challenge. Pre-existing systemic memory Th1/Th17 cells, memory B-cells, and mucosal IgA specific for Ptx, Vag8, Fim2/3 were detected in the protected mice 56 days after an experimental infection. In addition, pre-existing high activity and reactivation of pulmonary innate cells such as alveolar macrophages, M-cells and goblet cells was detected. The pro-inflammatory responses in the lungs and serum, and neutrophil recruitment in the spleen upon an infectious challenge of unprotected mice were absent in protected mice. Instead, fast pulmonary immune responses in protected mice led to efficient bacterial clearance and harbored potential new gene markers that contribute to immunity against B. pertussis. These responses comprised of innate makers, such as Clca3, Retlna, Glycam1, Gp2, and Umod, next to adaptive markers, such as CCR6+ B-cells, CCR6+ Th17 cells and CXCR6+ T-cells as demonstrated by transcriptome analysis. In conclusion, besides effective Th1/Th17 and mucosal IgA responses, the primary infection-induced immunity benefits from activation of pulmonary resident innate immune cells, achieved by local pathogen-recognition. These molecular signatures of primary infection-induced immunity provided potential markers to improve vaccine-induced immunity against B. pertussis.

PMID: 27711188 [PubMed - in process]

Time Hierarchies and Model Reduction in Canonical Non-linear Models.

Front Genet. 2016;7:166

Authors: Löwe H, Kremling A, Marin-Sanguino A

Abstract
The time-scale hierarchies of a very general class of models in differential equations is analyzed. Classical methods for model reduction and time-scale analysis have been adapted to this formalism and a complementary method is proposed. A unified theoretical treatment shows how the structure of the system can be much better understood by inspection of two sets of singular values: one related to the stoichiometric structure of the system and another to its kinetics. The methods are exemplified first through a toy model, then a large synthetic network and finally with numeric simulations of three classical benchmark models of real biological systems.

PMID: 27708665 [PubMed - in process]

Plant sulfur and Big Data.

Plant Sci. 2015 Dec;241:1-10

Authors: Kopriva S, Calderwood A, Weckopp SC, Koprivova A

Abstract
Sulfur is an essential mineral nutrient for plants, therefore, the pathways of its uptake and assimilation have been extensively studied. Great progress has been made in elucidation of the individual genes and enzymes and their regulation. Sulfur assimilation has been intensively investigated by -omics technologies and has been target of several genome wide genetic approaches. This brought a significant step in our understanding of the regulation of the pathway and its integration in cellular metabolism. However, the large amount of information derived from other experiments not directly targeting sulfur has also brought new and exciting insights into processes affecting sulfur homeostasis. In this review we will integrate the findings of the targeted experiments with those that brought unintentional progress in sulfur research, and will discuss how to synthesize the large amount of information available in various repositories into a meaningful dissection of the regulation of a specific metabolic pathway. We then speculate how this might be used to further advance knowledge on control of sulfur metabolism and what are the main questions to be answered.

PMID: 26706053 [PubMed - indexed for MEDLINE]