Pedro Beltran-Alvarez

Hull York Medical School

Climate adaptation is caused by multiple mechanisms, including evolution of regulatory promoter sequences under broad environmental pressures, however, little is known about these processes in response to climate pressures in animals. Here, we examined spatial and temporal evolution of climate-related gene promoters in an insular species, the Weste...

Better understanding how organisms respond to their abiotic environment, especially at the biochemical level, is critical in predicting population trajectories under climate change. In this study, we measured constitutive stress biomarkers and protein post-translational modifications associated with oxidative stress in Gallotia galloti, an insular...

Climate change increases the frequency and duration of heat events. Negative effects of heat stress may be exacerbated through the action of social metabolites between aquatic animals. Whilst early life stages are vulnerable to stress-induced damage, they deploy cellular mechanisms to protect cells against mutagens such as ultraviolet rays (UV). Li...

AIMS • Assess/evaluate transcriptomic changes in GBM, maintained on a microfluidics system, in response to treatment with arginine methylation inhibitor GSK3368715, currently in clinical trials, to identify novel therapeutic strategies, synergising with personalised patient care and precision medicine • Investigate molecular differences between hea...

Heat alters biology from molecular to ecological levels, but may also have unknown indirect effects. This includes the concept that animals exposed to abiotic stress can induce stress in naive receivers. Here, we provide a comprehensive picture of the molecular signatures of this process, by integrating multiomic and phenotypic data. In individual...

Arginine methylation is a post-translational modification that consists of the transfer of one or two methyl (CH3) groups to arginine residues in proteins. Several types of arginine methylation occur, namely monomethylation, symmetric dimethylation and asymmetric dimethylation, which are catalysed by different protein arginine methyltransferases (P...

AIMS The first aim was to measure the changes in the levels of 105 cytokines potentially released by GBM tissue maintained on-chip. The second aim was to compare the cytokine profiles from control GBM tissue and tissue treated with anti-GBM drugs {temozolomide (TMZ) at 1 and 10μM both with 1μM arginine methylation inhibitors}. METHOD Intra-operati...

AIMS Assess/evaluate apoptosis in GBM samples maintained on a microfluidics system in response to GSK3368715 and other PRMT inhibitors, currently in clinical trials, with the ultimate goal of synergising with personalised patient care and precision medicine. Investigate the effect of treating GBM biopsies on-chip with PRMT inhibitors at the molecul...

Heat alters biology from molecular to ecological levels, but may also have unknown indirect effects. This includes the novel concept that animals exposed to abiotic stress can induce stress in naive receivers. Here, we provide a comprehensive picture of the molecular signatures of this process, by integrating multi-omic and phenotypic data. In indi...

Chromobox 2 (CBX2) is a chromatin-binding component of polycomb repressive complex 1, which causes gene silencing. CBX2 expression is elevated in triple-negative breast cancer (TNBC), for which there are few therapeutic options. Here, we aimed to investigate the functional role of CBX2 in TNBC. CBX2 knockdown in TNBC models reduced cell numbers, wh...

Cardiovascular disease is the major cause of death worldwide. Extensive cardiovascular biomarkers are available using blood tests but very few, if any, investigations have described non-invasive tests for cardiovascular biomarkers based on readily available hair samples. Here we show, first, that human hair proteins are post-translationally modifie...

Understanding the genomic basis of adaptation to different abiotic environments is important in the context of climate change and resulting short‐term environmental fluctuations. Using functional and comparative genomics approaches, we here investigated whether signatures of genomic adaptation to a set of environmental parameters are concentrated i...

Aquatic organisms must cope with both rising and rapidly changing temperatures. These thermal changes can affect numerous traits, from molecular to ecological scales. Biotic stressors are already known to induce the release of chemical cues which trigger behavioural responses in other individuals. In this study, we infer whether fluctuating tempera...

Aquatic organisms must cope with both rising and rapidly changing temperatures. These environmental changes can affect numerous traits, from molecular to ecological scales. Biotic stressors can induce the release of chemical cues which trigger behavioural responses in other individuals. In this study, we infer whether abiotic stressors, such as flu...

Despite intense research efforts, our pharmaceutical repertoire against high-grade brain tumours has not been able to increase patient survival for a decade and life expectancy remains at less than 16 months after diagnosis, on average. Inhibitors of protein arginine methyltransferases (PRMTs) have been developed and investigated over the past 15 y...

Background Glioblastoma is a deadly disease with a median survival of 15 months after treatment. While maximal safe surgical resection and adjuvant chemoradiotherapy continues to be the mainstay of treatment, glioblastoma demostrates a remarkably heterogeneous molecular profile, and there is a drive to discover further chemotherapeutic targets that...

Understanding the genomic basis of adaptation to different abiotic environments is important for understanding organismal responses to current short-term environmental fluctuations. Using functional and comparative genomics approaches, we here investigated whether genomic adaptation to a set of environmental parameters is contingent across vertebra...

Background: The inhibitory subunit of cardiac troponin (cTnI) is a gold standard cardiac biomarker and also an essential protein in cardiomyocyte excitation-contraction coupling. The interactions of cTnI with other proteins are fine-tuned by post-translational modification of cTnI. Mutations in cTnI can lead to hypertrophic cardiomyopathy. Method...

Plakophilin 2, an armadillo protein, is a constituent of the desmosomal protein complex. Its function is very important in the maintenance of the integrity of tissues exposed to mechanical stress, such as the cardiac tissues. Mutations in the PKP2 gene complex has been implicated in the development of (Arrhythmogenic Cardiomyopathy (ACM), a conditi...

Glioblastomas (GBM) are the most common grade 4 brain tumours; patients have very poor prognosis with an average survival of 15 months after diagnosis. Novel research lines have begun to explore aberrant protein arginine methylation (ArgMe) as a possible therapeutic target in GBM and ArgMe inhibitors are currently in clinical trials. Enzymes known...

Obesity leading to hyperlipidaemia and atherosclerosis is recognised to induce morphological and metabolic changes in many tissues. However, hyperlipidaemia can occur in the absence of obesity. The impact of the latter scenario on skeletal muscle and liver is not understood sufficiently. In this regard, we used the Apolipoprotein E-deficient (ApoE-...

The cardiac voltage-gated sodium channel (gene: SCN5A, protein: NaV1.5) is responsible for the sodium current that initiates the cardiomyocyte action potential. Research into the mechanisms of SCN5A gene expression has gained momentum over the last few years. We have recently described the transcriptional regulation of SCN5A by GATA4 transcription...

Aberrant expression of the sodium channel gene (SCN5A) has been proposed to disrupt cardiac action potential and cause human cardiac arrhythmias, but the mechanisms of SCN5A gene regulation and dysregulation still remain largely unexplored. To gain insight into the transcriptional regulatory networks of SCN5A, we surveyed the promoter and first int...

Purpose: Arginine methylation (ArgMe) is one of the most ubiquitous post-translational modifications, and hundreds of proteins undergo ArgMe in e.g. brain. However, the scope of ArgMe in many tissues, including the heart, is currently under explored. Here, we aimed to 1) identify proteins undergoing ArgMe in human organs, and 2) expose the relevan...

Arginine methylation (ArgMe) is a post-translational modification that consists on the addition of methyl groups to the target Arg in proteins. Recent studies have identified hundreds of proteins undergoing ArgMe in tissues such as brain. However, only a handful of non-histone proteins are known to undergo ArgMe in the heart. Rationale: Ongoing res...

Voltage-gated sodium channels are essential proteins in brain physiology, as they generate the sodium currents that initiate neuronal action potentials. Voltage-gated sodium channels expression, localisation and function are regulated by a range of transcriptional and post-translational mechanisms. Here, we review our understanding of regulation of...

Voltage-gated sodium channels are essential proteins in brain physiology, as they generate the sodium currents that initiate neuronal action potentials. Volt - age-gated sodium channels expression, localisation and function are regulated by a range of transcriptional and post-translational mechanisms. Here, we review our under - standing of reg...

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. Objectives: We sought to identify the genetic cause of CPVT in this family, to preventively treat and clin...

Arginine methylation is a novel post-translational modification within the voltage-gated ion channel superfamily, including the cardiac sodium channel, NaV1.5. We show that NaV1.5 R513 methylation decreases S516 phosphorylation rate by 4 orders of magnitude, the first evidence of protein kinase A inhibition by arginine methylation. Reciprocally, S5...

The α subunit of the cardiac voltage-gated sodium channel, NaV1.5, provides the rapid sodium inward current that initiates cardiomyocyte action potentials. Here, we analyzed for the first time the post-translational modifications of NaV1.5 purified from end-stage heart failure human cardiac tissue. We identified R526 methylation as the major post-t...

Brugada Syndrome (BrS) is a life-threating arrhythmogenic disease associated with a high risk of Sudden Cardiac Death. Genetic alterations in SCN5A, which encodes the alpha subunit of the cardiac voltage-gated sodium channel (Nav1.5), are the most common cause of BrS. Nav1.5 channel is responsible for the rapid influx of sodium ions that initiate t...

Long QT Syndrome (LQTS) is a rare inherited cardiac disorder with a high risk of sudden cardiac death in a structurally normal heart. To date, pathogenic mutations have been described as responsible for approximately 70-75% of LQTS patients, mainly in ion channel genes. Mutations in genes encoding the sodium channel α subunit or other regulatory pr...

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiac disease characterized by fibrofatty replacement of the right ventricular myocardium, which may cause ventricular arrhythmias and sudden cardiac death (SCD). Mutations in genes encoding desmosome proteins have been associated with ARVC: plakophilin-2 (PKP2), desmoplakin (DSP),...

The α-subunit of the cardiac voltage-gated sodium channel (NaV1.5) plays a central role in cardiomyocyte excitability. We have recently reported that NaV1.5 is post-translationally modified by arginine methylation. Here, we aimed to identify the enzymes that methylate NaV1.5, and to describe the role of arginine methylation on NaV1.5 function. Our...

Brugada Syndrome (BrS) is a familial disease associated with sudden cardiac death. A 20-25% of BrS patients carry genetic defects that cause loss-of-function of the voltage-gated cardiac sodium channel. Thus 70-75% of patients remain without a genetic diagnosis. In this work we identified a novel missense mutation (p.Asp211Gly) in the sodium β2 sub...

Brugada syndrome (BrS) is a life-threatening, inherited arrhythmogenic syndrome associated with autosomal dominant mutations in SCN5A, the gene encoding the cardiac Na(+) channel alpha subunit (Na(v)1.5). The aim of this work was to characterize the functional alterations caused by a novel SCN5A mutation, I890T, and thus establish whether this muta...

Reported SCN5A mutations related to Brugada Syndrome in pore regions of Nav1.5. The table contains all missense and nonsense mutations reported in the Human Gene Mutation Database (HGMD) Professional (version 2012.1 from 30/03/2012) [21] and in the repository of genetic data on the inherited arrhythmogenic diseases [61]. The mutation sites and amin...

I890 is a highy conserved aminoacid among vertebrates. Sequence alignment of voltage-gated sodium channel α-subunit family members of different species. Human Nav1.5 I890 and its homologues are marked with a dark box. Identical amimoacids are highlighted in grey. Similar aminoacids are included inside light boxes. (TIF)

The α subunit of the cardiac sodium channel (Na(v)1.5) is an essential protein in the initial depolarization phase of the cardiomyocyte action potential. Post-translational modifications such as phosphorylation are known to regulate Na(v)1.5 function. Here, we used a proteomic approach for the study of the post-translational modifications of Na(v)1...

Proteing-metabolite networks are central to biological systems, but are incompletely understood. Here, we report a screen to catalog proteing-lipid interactions in yeast. We used arrays of 56 metabolites to measure lipid-binding fingerprints of 172 proteins, including 91 with predicted lipid-binding domains. We identified 530 proteing-lipid associa...

Sudden cardiac death is a major contributor to mortality in industrialized nations; in fact, it is the cause of more deaths than acquired immune deficiency syndrome, lung and breast cancer, and stroke together. Frequently, the autopsy becomes the principal diagnostic tool because macroscopic and microscopic analyses reveal the underlying cause of d...

The genome of Mycoplasma pneumoniae is among the smallest found in self-replicating organisms. To study the basic principles of bacterial proteome organization, we used tandem affinity purification–mass spectrometry (TAP-MS) in a proteome-wide screen. The analysis revealed 62 homomultimeric and 116 heteromultimeric soluble protein complexes, of whi...

Interactions between the acyl carrier protein (ACP) and ketoacylsynthase (KS) components of the actinorhodin polyketide synthase have been investigated using kinetic assays. These indicate that for three different quantifiable interactions (acceleration of self-malonylation, initiation and extension) mutations of E47 and E53 residues located on ACP...

The actinorhodin (act) minimal polyketide synthase (PKS) from Streptomyces coelicolor consists of three proteins: an acyl carrier protein (ACP) and two beta-ketoacyl ACP synthase components known as KSalpha and KSbeta. The act minimal PKS catalyzes at least 18 separate reactions which can be divided into loading, initiation, extension, and cyclizat...

Norsolorinic acid synthase (NSAS) is a type I iterative polyketide synthase that occurs in the filamentous fungus Aspergillus parasiticus. PCR was used to clone fragments of NSAS corresponding to the acyl carrier protein (ACP), acyl transferase (AT) and beta-ketoacyl-ACP synthase (KS) catalytic domains. Expression of these gene fragments in Escheri...

In order to evaluate the environmental quality of Portland cement, an analysis of the total concentration of the 15 minor elements considered in the Dutch Building Materials Decree (DBMD): antimony, arsenic, barium, cadmium, chromium, cobalt, copper, mercury, lead, molybdenum, nickel, selenium, tin, vanadium and zinc has been carried out. The total...