BioCIDER: a Contextualisation InDEx for biological Resources discovery

Summary The vast, uncoordinated proliferation of bioinformatics resources (databases, software tools, training materials etc.) makes it difficult for users to find them. To facilitate their discovery, various services are being developed to collect such resources into registries. We have developed BioCIDER, which, rather like online shopping ‘recommendations’, provides a contextualization index to help identify biological resources relevant to the content of the sites in which it is embedded

Systematic identification of phenotypically enriched loci using a patient network of genomic disorders

Background Network medicine is a promising new discipline that combines systems biology approaches and network science to understand the complexity of pathological phenotypes. Given the growing availability of personalized genomic and phenotypic profiles, network models offer a robust integrative framework for the analysis of "omics" data, allowing the characterization of the molecular aetiology of pathological processes underpinning genetic diseases. Methods Here we make use of patient genomic data to exploit different network-based analyses to study genetic and phenotypic relationships between individuals. For this method, we analyzed a dataset of structural variants and phenotypes for 6,564 patients from the DECIPHER database, which encompasses one of the most comprehensive collections of pathogenic Copy Number Variations (CNVs) and their associated ontology-controlled phenotypes. We developed a computational strategy that identifies clusters of patients in a synthetic patient network according to their genetic overlap and phenotype enrichments. Results Many of these clusters of patients represent new genotype-phenotype associations, suggesting the identification of newly discovered phenotypically enriched loci (indicative of potential novel syndromes) that are currently absent from reference genomic disorder databases such as ClinVar, OMIM or DECIPHER itself. Conclusions We provide a high-resolution map of pathogenic phenotypes associated with their respective significant genomic regions and a new powerful tool for diagnosis of currently uncharacterized mutations leading to deleterious phenotypes and syndromes

Phenotype-loci associations in networks of patients with rare disorders: application to assist in the diagnosis of novel clinical cases

Copy number variations (CNVs) are genomic structural variations (deletions, duplications, or translocations) that represent the 4.8–9.5% of human genome variation in healthy individuals. In some cases, CNVs can also lead to disease, being the etiology of many known rare genetic/genomic disorders. Despite the last advances in genomic sequencing and diagnosis, the pathological effects of many rare genetic variations remain unresolved, largely due to the low number of patients available for these cases, making it difficult to identify consistent patterns of genotype–phenotype relationships. We aimed to improve the identification of statistically consistent genotype–phenotype relationships by integrating all the genetic and clinical data of thousands of patients with rare genomic disorders (obtained from the DECIPHER database) into a phenotype–patient–genotype tripartite network. Then we assessed how our network approach could help in the characterization and diagnosis of novel cases in clinical genetics. The systematic approach implemented in this work is able to better define the relationships between phenotypes and specific loci, by exploiting large-scale association networks of phenotypes and genotypes in thousands of rare disease patients. The application of the described methodology facilitated the diagnosis of novel clinical cases, ranking phenotypes by locus specificity and reporting putative new clinical features that may suggest additional clinical follow-ups. In this work, the proof of concept developed over a set of novel clinical cases demonstrates that this network-based methodology might help improve the precision of patient clinical records and the characterization of rare syndromes

Epigenetic regulation of Gfi1 in endocrine-related cancers: a role regulating tumor growth

Prostate and breast cancer constitute the most common cancers among men and women worldwide. The aging population is one of the main risk factors for prostate and breast cancer development and accumulating studies link aging with epigenetic changes. Growth factor independence-1 (Gfi1) is a transcriptional repressor with an important role in human malignancies, including leukemia, colorectal carcinoma, and lung cancer, but its role in prostate and breast cancer is unknown. We have found that Gfi1 epigenetic silencing is a common event in prostate and breast cancer. Gfi1 re-expression in prostate and breast cancer cell lines displaying Gfi1 epigenetic silencing decreases cell proliferation, reduced colony formation density, and tumor growth in nude mice xenografts. In addition, we found that Gfi1 repress alpha 1-anti-trypsin (AAT) and alpha 1-anti-chymotrypsin (ACT) expression, two genes with important functions in cancer development, suggesting that Gfi1 silencing promotes tumor growth by increasing AAT and ACT expression in our system. Finally, Gfi1 epigenetic silencing could be a promising biomarker for prostate cancer progression because it is associated with shorter disease-free survival. In conclusion, our findings strongly indicate that Gfi1 epigenetic silencing in prostate and breast cancer could be a crucial step in the development of these two-well characterized endocrine related tumors

Assessment of proline function in higher plants under extreme temperatures

Climate change and abiotic stress factors are key players in crop losses worldwide. Among which, extreme temperatures (heat and cold) disturb plant growth and development, reduce productivity and, in severe cases, lead to plant death. Plants have developed numerous strategies to mitigate the detrimental impact of temperature stress. Exposure to stress leads to the accumulation of various metabolites, e.g. sugars, sugar alcohols, organic acids and amino acids. Plants accumulate the amino acid ‘proline’ in response to several abiotic stresses, including temperature stress. Proline abundance may result from de novo synthesis, hydrolysis of proteins, reduced utilization or degradation. Proline also leads to stress tolerance by maintaining the osmotic balance (still controversial), cell turgidity and indirectly modulating metabolism of reactive oxygen species. Furthermore, the crosstalk of proline with other osmoprotectants and signalling molecules, e.g. glycine betaine, abscisic acid, nitric oxide, hydrogen sulfide, soluble sugars, helps to strengthen protective mechanisms in stressful environments. Development of less temperature-responsive cultivars can be achieved by manipulating the biosynthesis of proline through genetic engineering. This review presents an overview of plant responses to extreme temperatures and an outline of proline metabolism under such temperatures. The exogenous application of proline as a protective molecule under extreme temperatures is also presented. Proline crosstalk and interaction with other molecules is also discussed. Finally, the potential of genetic engineering of proline-related genes is explained to develop ‘temperature-smart’ plants. In short, exogenous application of proline and genetic engineering of proline genes promise ways forward for developing ‘temperature-smart’ future crop plants.Research of FJC is supported by a European Regional Development Fund co-financed grant from the Ministry of Economy and Competitiveness/Science and Innovation (PID2019-10103924GB-I00), Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020) (P18-FR-1359), Spain. This work was also supported by grants from Bill & Melinda Foundation (Tropical Legumes Project, OPP1114827), and Food Futures Institute of Murdoch University to RKV

Neuronal p38α mediates synaptic and cognitive dysfunction in an Alzheimer’s mouse model by controlling β-amyloid production.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a severe and progressive neuronal loss leading to cognitive dysfunctions. Previous reports, based on the use of chemical inhibitors, have connected the stress kinase p38α to neuroinflammation, neuronal death and synaptic dysfunction. To explore the specific role of neuronal p38α signalling in the appearance of pathological symptoms, we have generated mice that combine expression of the 5XFAD transgenes to induce AD symptoms with the downregulation of p38α only in neurons (5XFAD/p38α∆-N). We found that the neuronal-specific deletion of p38α improves the memory loss and long-term potentiation impairment induced by 5XFAD transgenes. Furthermore, 5XFAD/p38α∆-N mice display reduced amyloid-β accumulation, improved neurogenesis, and important changes in brain cytokine expression compared with 5XFAD mice. Our results implicate neuronal p38α signalling in the synaptic plasticity dysfunction and memory impairment observed in 5XFAD mice, by regulating both amyloid-β deposition in the brain and the relay of this accumulation to mount an inflammatory response, which leads to the cognitive deficits.post-print1848 K

The EGR2 gene is involved in axonal Charcot-Marie-Tooth disease

[EN] Background and purpose: A three-generation family affected by axonal Charcot-Marie-Tooth disease (CMT) was investigated with the aim of discovering genetic defects and to further characterize the phenotype. Methods: The clinical, nerve conduction studies and muscle magnetic resonance images of the patients were reviewed. A whole exome sequencing was performed and the changes were investigated by genetic studies, in silico analysis and luciferase reporter assays. Results: A novel c.1226G>A change (p.R409Q) in the EGR2 gene was identified. Patients presented with a typical, late-onset axonal CMT phenotype with variable severity that was confirmed in the ancillary tests. The in silico studies showed that the residue R409 is an evolutionary conserved amino acid. The p.R409Q mutation, which is predicted as probably damaging, would alter the conformation of the protein slightly and would cause a decrease of gene expression. Conclusions: This is the first report of an EGR2 mutation presenting as an axonal CMT phenotype with variable severity. This study broadens the phenotype of the EGR2-related neuropathies and suggests that the genetic testing of patients suffering from axonal CMT should include the EGR2 gene.This collaborative joint project is awarded by IRDiRC and funded by the Instituto de Salud Carlos III (ISCIII) - Subdireccion General de Evaluacion y Fomento de la Investigacion within the framework of the National R+D+I Plan (Grants IR11/TREAT-CMT, PI12/00946 and PI12/00453), co-funded with FEDER funds. C.E. has a "Miguel Servet' contract funded by the ISCIII and Centro de Investigacion Principe Felipe (CIPF) (Grant no. CPII14/00002). We are also grateful to Itziar Llopis for sample management.Sevilla, T.; Sivera, R.; Martínez-Rubio, D.; Lupo, V.; Chumillas, M.; Calpena-Corpas, E.; Dopazo, J.... (2015). The EGR2 gene is involved in axonal Charcot-Marie-Tooth disease. European Journal of Neurology. 22(12):1548-1555. https://doi.org/10.1111/ene.1278215481555221

Loss of S-nitrosoglutathione reductase disturbs phytohormone homeostasis and regulates shoot side branching and fruit growth in tomato

S-Nitrosoglutathione plays a central role in nitric oxide (NO) homeostasis, and S-nitrosoglutathione reductase (GSNOR) regulates the cellular levels of S-nitrosoglutathione across kingdoms. Here, we investigated the role of endogenous NO in shaping shoot architecture and controlling fruit set and growth in tomato (Solanum lycopersicum). SlGSNOR silencing promoted shoot side branching and led to reduced fruit size, negatively impacting fruit yield. Greatly intensified in slgsnor knockout plants, these phenotypical changes were virtually unaffected by SlGSNOR overexpression. Silencing or knocking out of SlGSNOR intensified protein tyrosine nitration and S-nitrosation and led to aberrant auxin production and signaling in leaf primordia and fruit-setting ovaries, besides restricting the shoot basipetal polar auxin transport stream. SlGSNOR deficiency triggered extensive transcriptional reprogramming at early fruit development, reducing pericarp cell proliferation due to restrictions on auxin, gibberellin, and cytokinin production and signaling. Abnormal chloroplast development and carbon metabolism were also detected in early-developing NO-overaccumulating fruits, possibly limiting energy supply and building blocks for fruit growth. These findings provide new insights into the mechanisms by which endogenous NO fine-tunes the delicate hormonal network controlling shoot architecture, fruit set, and post-anthesis fruit development, emphasizing the relevance of NO-auxin interaction for plant development and productivity.This work was supported by the São Paulo Research Foundation (FAPESP) (grants 16/02033-1, 16/01128-9 17/17935-3, 18/16389-8, 18/06436-9, 20/03720-8, 21/05714-8), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grants 422287/2018-0, 305012/2018-5), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES) – Finance Code 00

Multifaceted roles of nitric oxide in tomato fruit ripening: NO-induced metabolic rewiring and consequences for fruit quality traits

Nitric oxide (NO) has been implicated as part of the ripening regulatory network in fleshy fruits. However, very little is known about the simultaneous action of NO on the network of regulatory events and metabolic reactions behind ripening-related changes in fruit color, taste, aroma and nutritional value. Here, we performed an in-depth characterization of the concomitant changes in tomato (Solanum lycopersicum) fruit transcriptome and metabolome associated with the delayed-ripening phenotype caused by NO supplementation at the pre-climacteric stage. Approximately one-third of the fruit transcriptome was altered in response to NO, including a multilevel down-regulation of ripening regulatory genes, which in turn restricted the production and tissue sensitivity to ethylene. NO also repressed hydrogen peroxide-scavenging enzymes, intensifying nitro-oxidative stress and S-nitrosation and nitration events throughout ripening. Carotenoid, tocopherol, flavonoid and ascorbate biosynthesis were differentially affected by NO, resulting in overaccumulation of ascorbate (25%) and flavonoids (60%), and impaired lycopene production. In contrast, the biosynthesis of compounds related to tomato taste (sugars, organic acids, amino acids) and aroma (volatiles) was slightly affected by NO. Our findings indicate that NO triggers extensive transcriptional and metabolic rewiring at the early ripening stage, modifying tomato antioxidant composition with minimal impact on fruit taste and aroma.This work was supported by the São Paulo Research Foundation (FAPESP) (grants 2018/16389-8, 2016/04924-0, 2017/17935-3 and 2016/01128-9), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grants 422287/2018-0, 305012/2018-5, 303332/2019-0 and 300986/2018-1), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001. The research work of FJC and JMP is supported by a European Regional Development Fund cofinanced grant from the Ministry of Economy and Competitiveness (AGL2015-65104-P and PID2019-103924GB-I00), Spain