Curing hemoglobinopathies : challenges and advances of conventional and new gene therapy approaches

Inherited hemoglobin disorders, including beta-thalassemia (BT) and sickle-cell disease (SCD), are the most common monogenic diseases worldwide, with a global carrier frequency of over 5%.1 With migration, they are becoming more common worldwide, making their management and care an increasing concern for health care systems. BT is characterized by an imbalance in the \u3b1/\u3b2-globin chain ratio, ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hemopoietic expansion.1 Globally, there are over 25,000 births each year with transfusion-dependent thalassemia (TDT). The currently available treatment for TDT is lifelong transfusions and iron chelation therapy or allogenic bone marrow transplantation as a curative option. SCD affects 300 million people worldwide2 and severely impacts the quality of life of patients who experience unpredictable, recurrent acute and chronic severe pain, stroke, infections, pulmonary disease, kidney disease, retinopathy, and other complications. While survival has been dramatically extended, quality of life is markedly reduced by disease- and treatment-associated morbidity. The development of safe, tissue-specific and efficient vectors, and efficient gene-editing technologies has led to the development of several gene therapy trials for BT and SCD. However, the complexity of the approach presents its hurdles. Fundamental factors at play include the requirement for myeloablation on a patient with benign disease, the age of the patient, and the consequent bone marrow microenvironment. A successful path from proof-of-concept studies to commercialization must render gene therapy a sustainable and accessible approach for a large number of patients. Furthermore, the cost of these therapies is a considerable challenge for the health care system. While new promising therapeutic options are emerging,3,4 and many others are on the pipeline,5 gene therapy can potentially cure patients. We herein provide an overview of the most recent, likely potentially curative therapies for hemoglobinopathies and a summary of the challenges that these approaches entail

Mixing Chiral Polytopes

An abstract polytope of rank n is said to be chiral if its automorphism group has two orbits on the flags, such that adjacent flags belong to distinct orbits. Examples of chiral polytopes have been difficult to find. A "mixing" construction lets us combine polytopes to build new regular and chiral polytopes. By using the chirality group of a polytope, we are able to give simple criteria for when the mix of two polytopes is chiral

Comprehensive analysis of the start-up period of a full-scale drinking water biofilter provides guidance for optimization

The use of biofilters to produce drinking water from anaerobic groundwater is widespread in some European countries. A major disadvantage of biofilters is the long start-up period required for virgin filter medium to become fully functional. Although individual aspects of biofilter start-up have previously been investigated, no comprehensive study in full scale using inherent inoculation has previously been documented. A thorough investigation of a full-scale drinking water biofilter was carried out over 10 weeks of start-up. The many spatial and temporal changes taking place during start-up were documented using a holistic approach. In addition to collection of many samples over time (frequency) and space (filter depth), this study entailed the use of multiple sample media (water, backwash water and filter media) and multiple types of analyses (physical, chemical and microbiological). The decrease in filter effluent concentrations of individual substances to compliance levels followed a specific order that was shown to coincide with the spatiotemporal development of bacteria on the filter media. Due to the abiotic nature of the iron removal process, iron disappears at the earliest in the start-up period followed by substances that require growth of microorganisms. Ammonium disappears next, with nitrite appearing briefly near the end of ammonium removal, followed by manganese. The thorough overall picture obtained by these efforts provides guidance for optimization and monitoring of the start-up. Guidance for optimization includes shortening the start-up by focusing on kick-starting the ammonium removal; limiting the monitoring burden (at-line measurements of ammonium in finished water supplemented with manual manganese measurements when ammonium removal is complete); and improving filter design by isolating the removal processes in separate, smaller filters.</p

A Narrative Review about Prosocial and Antisocial Behavior in Childhood: The Relationship with Shame and Moral Development

We conducted a literature review aimed at identifying the origins of shame as well as its effects on moral development, especially in terms of behavioral outcomes, and we reflected on the practical implications of our findings. We explored the role of shame in moral development through cultural differences and parental influences, collecting evidence of psychopathological consequences of primary moral emotion dysregulation. These studies showed a dichotomous feature of shame, as a prosocial behavior enhancer in morally relevant situations and, simultaneously, a risk factor for aggressive and antisocial behaviors on other occasions. Dysregulated shame leads to maladaptive interpersonal behaviors, which could evolve towards psychopathological paths. Therefore, an integrated intervention is recommended in children with emotional/behavioral problems

Promoting health-enhancing physical activity in Europe: Surveillance, policy development and implementation 2015-2018

In the European Union (EU), the low levels of health-enhancing physical activity (HEPA) and high levels of sedentary behaviour are a concerning public health issue common to all Member States. In 2013, the Council of the EU recognized the need for more data related to HEPA to support policymaking across the region and proposed a monitoring framework that included 23 indicators covering different themes relevant to HEPA promotion in the EU context. In 2014, the EU Physical Activity Focal Points Network was established to support the implementation of the monitoring framework and in 2015 and 2018 surveys were conducted to collect epidemiological and policy information related to HEPA for each Member State. This paper aims to provide an update on the status of HEPA policies and surveillance in the EU and describe the changes that have occurred since 2015. In 2018, all countries had implemented more than 10 indicators, 8/28 had implemented 20 or more indicators, and only one country had completed all 23 indicators. From 2015 to 2018, 19 indicators improved, one remained unchanged, and three regressed. From the country perspective, 17 improved the number of accomplished indicators, five maintained the indicators, and five worsened the number of indicators. Overall, there has been a clear increase in the number of countries implementing HEPA policies and strategies across the different sectors, although some heterogeneity between Members Sates was still observed. Implementation of regional physical activity strategies and the establishment of the EU-wide monitoring framework appears to have had an overall positive impact on HEPA policy development and implementation.This study was funded by the European Commission Directorate-General for Education and Culture

Effect of cold rolling on pitting resistance in duplex stainless steels

Duplex Stainless Steels (DSS) are biphasic austeno-ferritic steels in which the best combination of mechanicaland corrosion-resistance properties is achieved for almost equal volume fractions of the phases. These steelsare classifi ed according to their pitting corrosion resistance, assessed by the PREN index (Pitting ResistanceEquivalent Number) which, although qualitatively, is widely employed as comparison. The present work isaimed to study the pitting resistance of four DSS grades (SAF 2101, 2304, 2205 and 2507) in the as-receivedconditions and after cold rolling at various thickness reductions (from 15% to 85%), to highlight the effects ofcold working on the corrosion behaviour. The materials were potentiodynamically tested in artifi cial seawater(pH 7) and the corresponding Critical Pitting Temperatures (CPT) were determined. Cold deformation mainlyaffected the Lean DSS grades, whereas the high-alloyed DSS were stable, even after heavy deformations.These differences can be attributed not only to composition but also to the onset of diffusionless phasetransformations induced by cold working, which make the materials more prone to corrosive attacks

Trattamenti di ricottura dell’acciaio inossidabile duplex 2205 dopo deformazione plastica

Le buone caratteristiche meccaniche e le elevate proprietà di resistenza a corrosione spiegano il vasto utilizzodegli inossidabili duplex in ambito chimico, petrolchimico e strutturale i duplex sono, però soggetti aprecipitazione di fasi secondarie, che ne degradano le proprietà, negli intervalli di temperatura 500-1000°C.In questo lavoro si è analizzata l’influenza del trattamento isotermico nell’intervallo 850-900°C sulletrasformazioni di fase per l’acciaio 2205 deformato a freddo.La lega è stata sottoposta a deformazioni a freddo con una riduzione di spessore del 5%, 10%, 15%; in seguitoa trattamenti termici presenta precipitazione di fasi deleterie ? e ?. Si è analizzata l’evoluzione dellaprecipitazione in funzione del grado di deformazione e del tempo di trattamento, mediante microscopia otticaed elettronica. Mediante software d’analisi d’immagine è stata realizzata la quantificazione delle fasiprecipitate. I risultati ottenuti hanno rivelato che il materiale deformato a freddo è molto più sensibile allaprecipitazione di fasi secondarie rispetto al materiale allo stato solubilizzato ed al conseguente infragilimentodopo brevi soste nell’intervallo di temperatura critico per la precipitazione

WHO European Childhood Obesity Surveillance Initiative: associations between sleep duration, screen time and food consumption frequencies

BACKGROUND: Both sleep duration and screen time have been suggested to affect children's diet, although in different directions and presumably through different pathways. The present cross-sectional study aimed to simultaneously investigate the associations between sleep duration, screen time and food consumption frequencies in children. METHODS: The analysis was based on 10 453 children aged 6-9 years from five European countries that participated in the World Health Organization European Childhood Obesity Surveillance Initiative. Logistic multilevel models were used to assess associations of parent-reported screen time as well as sleep duration (exposure variables) with consumption frequencies of 16 food items (outcome variables). All models were adjusted for age, sex, outdoor play time, maximum educational level of parents and sleep duration or screen time, depending on the exposure under investigation. RESULTS: One additional hour of screen time was associated with increased consumption frequencies of 'soft drinks containing sugar' (1.28 [1.19;1.39]; odds ratio and 99% confidence interval), 'diet/light soft drinks' (1.21 [1.14;1.29]), 'flavoured milk' (1.18 [1.08;1.28]), 'candy bars or chocolate' (1.31 [1.22;1.40]), 'biscuits, cakes, doughnuts or pies' (1.22 [1.14;1.30]), 'potato chips (crisps), corn chips, popcorn or peanuts' (1.32 [1.20;1.45]), 'pizza, French fries (chips), hamburgers'(1.30 [1.18;1.43]) and with a reduced consumption frequency of 'vegetables (excluding potatoes)' (0.89 [0.83;0.95]) and 'fresh fruits' (0.91 [0.86;0.97]). Conversely, one additional hour of sleep duration was found to be associated with increased consumption frequencies of 'fresh fruits' (1.11 [1.04;1.18]) and 'vegetables (excluding potatoes)' (1.14 [1.07;1.23]). CONCLUSION: The results suggest a potential relation between high screen time exposure and increased consumption frequencies of foods high in fat, free sugar or salt whereas long sleep duration may favourably be related to children's food choices. Both screen time and sleep duration are modifiable behaviours that may be tackled in childhood obesity prevention efforts

Percutaneous nephrolithotomy in the transplant kidney - a prospective 20 year multicentre experience

Introduction & Objectives: Percutaneous nephrolithotomy (PCNL) in transplanted kidneys presents unique endourological challenges. By pooling the collective experience of three centres, each combining high volume transplant and high volume endourology practices, we aim to accurately and reliably demonstrate the safety and feasibility of this technique

Benchmarking recombinant Pichia pastoris for 3-hydroxypropionic acid production from glycerol

The use of the methylotrophic yeast Pichia pastoris (Komagataella phaffi) to produce heterologous proteins has been largely reported. However, investigations addressing the potential of this yeast to produce bulk chemicals are still scarce. In this study, we have studied the use of P. pastoris as a cell factory to produce the commodity chemical 3-hydroxypropionic acid (3-HP) from glycerol. 3-HP is a chemical platform which can be converted into acrylic acid and to other alternatives to petroleum-based products. To this end, the mcr gene from Chloroflexus aurantiacus was introduced into P. pastoris. This single modification allowed the production of 3-HP from glycerol through the malonyl-CoA pathway. Further enzyme and metabolic engineering modifications aimed at increasing cofactor and metabolic precursors availability allowed a 14-fold increase in the production of 3-HP compared to the initial strain. The best strain (PpHP6) was tested in a fed-batch culture, achieving a final concentration of 3-HP of 24.75 g l−1, a product yield of 0.13 g g−1 and a volumetric productivity of 0.54 g l−1 h−1, which, to our knowledge, is the highest volumetric productivity reported in yeast. These results benchmark P. pastoris as a promising platform to produce bulk chemicals for the revalorization of crude glycerol and, in particular, to produce 3-HP