Activation of pyruvate kinase as therapeutic option for rare hemolytic anemias:Shedding new light on an old enzyme

Novel developments in therapies for various hereditary hemolytic anemias reflect the pivotal role of pyruvate kinase (PK), a key enzyme of glycolysis, in red blood cell (RBC) health. Without PK catalyzing one of the final steps of the Embden-Meyerhof pathway, there is no net yield of adenosine triphosphate (ATP) during glycolysis, the sole source of energy production required for proper RBC function and survival. In hereditary hemolytic anemias, RBC health is compromised and therefore lifespan is shortened. Although our knowledge on glycolysis in general and PK function in particular is solid, recent advances in genetic, molecular, biochemical, and metabolic aspects of hereditary anemias have improved our understanding of these diseases. These advances provide a rationale for targeting PK as therapeutic option in hereditary hemolytic anemias other than PK deficiency. This review summarizes the knowledge, rationale, (pre)clinical trials, and future advances of PK activators for this important group of rare diseases.</p

Insourcen, outsourcen of backsourcen? Het geval van de Brusselse gewestelijke administratie

Sinds de jaren 1980 zijn bedrijven en openbare besturen geneigd zich op hun kernactiviteiten te focussen en taken als IT, beveiliging, catering en schoonmaak uit te besteden. De jongste jaren zien we echter een omkering van deze tendens in vele organisaties, die sommige van deze activiteiten opnieuw intern gaan uitvoeren. Een proces dat we “backsourcing” noemen. Het doel van dit artikel is om te onderzoeken in welke mate activiteiten werden uitbesteed in de Brusselse gewestelijke besturen, wat de impact daarvan is op de betrokken medewerkers en organisaties en hoe de belanghebbenden staan tegenover een eventuele backsourcing van laaggekwalificeerde banen. In het kader van een multidisciplinair project van BSI voor Talent.Brussels hebben onze bevindingen aangetoond dat beslissingen over in- en outsourcing complex en multidimensionaal zijn en dat ze niet enkel gebaseerd mogen zijn op kostenoverwegingen.Since the 1980s, there has been a trend for businesses and public administrations to focus on their core activities, outsourcing tasks such as IT, security, catering and cleaning services. However, in recent years, many organisations have been reversing the trend by insourcing, or “backsourcing”, some of these activities. The aim of this article is to study the extent to which activities have been outsourced in the Brussels regional administrations, its impact on workers and organisations involved, and the attitudes of stakeholders towards a possible re-internalisation of low-skilled jobs. Based on a multidisciplinary BSI project for Talent.Brussels, our findings show that decisions about outsourcing and insourcing are complex and multidimensional, and that they should not be based solely on monetary cost considerations. Since the 1980s, there has been a trend for businesses and public administrations to focus on their core activities, outsourcing tasks such as IT, security, catering and cleaning services. However, in recent years, many organisations have been reversing the trend by insourcing, or “backsourcing”, some of these activities. The aim of this article is to study the extent to which activities have been outsourced in the Brussels regional administrations, its impact on workers and organisations involved, and the attitudes of stakeholders towards a possible re-internalisation of low-skilled jobs. Based on a multidisciplinary BSI project for Talent.Brussels, our findings show that decisions about outsourcing and insourcing are complex and multidimensional, and that they should not be based solely on monetary cost considerations.À partir des années 1980, les entreprises et les administrations publiques ont eu tendance à externaliser des tâches, notamment les services informatiques, de sécurité, de restauration et de nettoyage, afin de se concentrer sur leurs activités principales. Cependant, ces dernières années, de nombreuses organisations ont inversé cette tendance en internalisant ou réinternalisant (« backsourcing ») certaines des tâches en question. Le présent article vise à examiner le degré d’externalisation des activités dans les administrations régionales bruxelloises, l’incidence du phénomène sur les travailleurs et les organismes concernés, ainsi que le regard porté par les parties prenantes sur l’éventualité d’une réinternalisation d’emplois peu qualifiés. Nos constatations, qui s’appuient sur un projet pluridisciplinaire mené par le BSI pour talent.brussels, font apparaître que les décisions en matière d’externalisation et d’internalisation sont complexes et multidimensionnelles, et ne devraient pas se fonder uniquement sur des considérations pécuniaires

Externalisation, internalisation ou réinternalisation ? Le cas de l’administration régionale bruxelloise

À partir des années 1980, les entreprises et les administrations publiques ont eu tendance à externaliser des tâches, notamment les services informatiques, de sécurité, de restauration et de nettoyage, afin de se concentrer sur leurs activités principales. Cependant, ces dernières années, de nombreuses organisations ont inversé cette tendance en internalisant ou réinternalisant (« backsourcing ») certaines des tâches en question. Le présent article vise à examiner le degré d’externalisation des activités dans les administrations régionales bruxelloises, l’incidence du phénomène sur les travailleurs et les organismes concernés, ainsi que le regard porté par les parties prenantes sur l’éventualité d’une réinternalisation d’emplois peu qualifiés. Nos constatations, qui s’appuient sur un projet pluridisciplinaire mené par le BSI pour talent.brussels, font apparaître que les décisions en matière d’externalisation et d’internalisation sont complexes et multidimensionnelles, et ne devraient pas se fonder uniquement sur des considérations pécuniaires.Sinds de jaren 1980 zijn bedrijven en openbare besturen geneigd zich op hun kernactiviteiten te focussen en taken als IT, beveiliging, catering en schoonmaak uit te besteden. De jongste jaren zien we echter een omkering van deze tendens in vele organisaties, die sommige van deze activiteiten opnieuw intern gaan uitvoeren. Een proces dat we “backsourcing” noemen. Het doel van dit artikel is om te onderzoeken in welke mate activiteiten werden uitbesteed in de Brusselse gewestelijke besturen, wat de impact daarvan is op de betrokken medewerkers en organisaties en hoe de belanghebbenden staan tegenover een eventuele backsourcing van laaggekwalificeerde banen. In het kader van een multidisciplinair project van BSI voor Talent.Brussels hebben onze bevindingen aangetoond dat beslissingen over in- en outsourcing complex en multidimensionaal zijn en dat ze niet enkel gebaseerd mogen zijn op kostenoverwegingen.Since the 1980s, there has been a trend for businesses and public administrations to focus on their core activities, outsourcing tasks such as IT, security, catering and cleaning services. However, in recent years, many organisations have been reversing the trend by insourcing, or “backsourcing”, some of these activities. The aim of this article is to study the extent to which activities have been outsourced in the Brussels regional administrations, its impact on workers and organisations involved, and the attitudes of stakeholders towards a possible re-internalisation of low-skilled jobs. Based on a multidisciplinary BSI project for Talent.Brussels, our findings show that decisions about outsourcing and insourcing are complex and multidimensional, and that they should not be based solely on monetary cost considerations

International criteria for electrocardiographic interpretation in athletes: Consensus statement.

Sudden cardiac death (SCD) is the leading cause of mortality in athletes during sport. A variety of mostly hereditary, structural or electrical cardiac disorders are associated with SCD in young athletes, the majority of which can be identified or suggested by abnormalities on a resting 12-lead electrocardiogram (ECG). Whether used for diagnostic or screening purposes, physicians responsible for the cardiovascular care of athletes should be knowledgeable and competent in ECG interpretation in athletes. However, in most countries a shortage of physician expertise limits wider application of the ECG in the care of the athlete. A critical need exists for physician education in modern ECG interpretation that distinguishes normal physiological adaptations in athletes from distinctly abnormal findings suggestive of underlying pathology. Since the original 2010 European Society of Cardiology recommendations for ECG interpretation in athletes, ECG standards have evolved quickly, advanced by a growing body of scientific data and investigations that both examine proposed criteria sets and establish new evidence to guide refinements. On 26-27 February 2015, an international group of experts in sports cardiology, inherited cardiac disease, and sports medicine convened in Seattle, Washington (USA), to update contemporary standards for ECG interpretation in athletes. The objective of the meeting was to define and revise ECG interpretation standards based on new and emerging research and to develop a clear guide to the proper evaluation of ECG abnormalities in athletes. This statement represents an international consensus for ECG interpretation in athletes and provides expert opinion-based recommendations linking specific ECG abnormalities and the secondary evaluation for conditions associated with SCD

Flooding Greatly Affects the Diversity of Arbuscular Mycorrhizal Fungi Communities in the Roots of Wetland Plants

The communities of arbuscular mycorrhizal fungi (AMF) colonizing the roots of three mangrove species were characterized along a tidal gradient in a mangrove swamp. A fragment, designated SSU-ITS-LSU, including part of the small subunit (SSU), the entire internal transcribed spacer (ITS) and part of the large subunit (LSU) of rDNA from samples of AMF-colonized roots was amplified, cloned and sequenced using AMF-specific primers. Similar levels of AMF diversity to those observed in terrestrial ecosystems were detected in the roots, indicating that the communities of AMF in wetland ecosystems are not necessarily low in diversity. In total, 761 Glomeromycota sequences were obtained, which grouped, according to phylogenetic analysis using the SSU-ITS-LSU fragment, into 23 phylotypes, 22 of which belonged to Glomeraceae and one to Acaulosporaceae. The results indicate that flooding plays an important role in AMF diversity, and its effects appear to depend on the degree (duration) of flooding. Both host species and tide level affected community structure of AMF, indicating the presence of habitat and host species preferences

Sprouty Proteins Inhibit Receptor-mediated Activation of Phosphatidylinositol-specific Phospholipase C

PLCγ03B3 binds Spry1 and Spry2. Overexpression of Spry decreased PLCγ03B3 activity and IP3 and DAG production, whereas Spry-deficient cells yielded more IP3. Spry overexpression inhibited T-cell receptor signaling and Spry1 null T-cells hyperproliferated with TCR ligation. Through action of PLCγ03B3, Spry may influence signaling through multiple receptors

Nutrition and the ageing brain: moving towards clinical applications

The global increases in life expectancy and population have resulted in a growing ageing population and with it a growing number of people living with age-related neurodegenerative conditions and dementia, shifting focus towards methods of prevention, with lifestyle approaches such as nutrition representing a promising avenue for further development. This overview summarises the main themes discussed during the 3 Symposium on "Nutrition for the Ageing Brain: Moving Towards Clinical Applications" held in Madrid in August 2018, enlarged with the current state of knowledge on how nutrition influences healthy ageing and gives recommendations regarding how the critical field of nutrition and neurodegeneration research should move forward into the future. Specific nutrients are discussed as well as the impact of multi-nutrient and whole diet approaches, showing particular promise to combatting the growing burden of age-related cognitive decline. The emergence of new avenues for exploring the role of diet in healthy ageing, such as the impact of the gut microbiome and development of new techniques (imaging measures of brain metabolism, metabolomics, biomarkers) are enabling researchers to approach finding answers to these questions. But the translation of these findings into clinical and public health contexts remains an obstacle due to significant shortcomings in nutrition research or pressure on the scientific community to communicate recommendations to the general public in a convincing and accessible way. Some promising programs exist but further investigation to improve our understanding of the mechanisms by which nutrition can improve brain health across the human lifespan is still required

Nutrition and the ageing brain: Moving towards clinical applications

The global increases in life expectancy and population have resulted in a growing ageing population and with it a growing number of people living with age-related neurodegenerative conditions and dementia, shifting focus towards methods of prevention, with lifestyle approaches such as nutrition representing a promising avenue for further development.This overview summarises the main themes discussed during the 3rd Symposium on “Nutrition for the Ageing Brain: Moving Towards Clinical Applications” held in Madrid in August 2018, enlarged with the current state of knowledge on how nutrition influences healthy ageing and gives recommendations regarding how the critical field of nutrition and neurodegeneration research should move forward into the future.Specific nutrients are discussed as well as the impact of multi-nutrient and whole diet approaches, showing particular promise to combatting the growing burden of age-related cognitive decline. The emergence of new avenues for exploring the role of diet in healthy ageing, such as the impact of the gut microbiome and development of new techniques (imaging measures of brain metabolism, metabolomics, biomarkers) are enabling researchers to approach finding answers to these questions. But the translation of these findings into clinical and public health contexts remains an obstacle due to significant shortcomings in nutrition research or pressure on the scientific community to communicate recommendations to the general public in a convincing and accessible way. Some promising programs exist but further investigation to improve our understanding of the mechanisms by which nutrition can improve brain health across the human lifespan is still required.</p

Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals

Sudden cardiac death (SCD) continues to be one of the leading causes of mortality worldwide, with an annual incidence estimated at 250,000–300,000 in the United States and with the vast majority occurring in the setting of coronary disease. We performed a genome-wide association meta-analysis in 1,283 SCD cases and >20,000 control individuals of European ancestry from 5 studies, with follow-up genotyping in up to 3,119 SCD cases and 11,146 controls from 11 European ancestry studies, and identify the BAZ2B locus as associated with SCD (P = 1.8×10−10). The risk allele, while ancestral, has a frequency of ∼1.4%, suggesting strong negative selection and increases risk for SCD by 1.92–fold per allele (95% CI 1.57–2.34). We also tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P = 0.006)

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

BACKGROUND: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. METHODS: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. RESULTS: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (P&lt;5×10-8) near NOS1AP, KCNQ1, and KLF12, and 1 missense variant in KCNE1(p.Asp85Asn) at the suggestive threshold (P&lt;10-6). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation (h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (rg=0.40; P=3.2×10-3). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (P&lt;10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (P&lt;0.005). CONCLUSIONS: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.</p