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\" With a government plagued by systemic ills and deep ideological divides, democracy, as we know it, is in jeopardy. Yet, ironically, voter apathy remains prevalent and evidence suggests standard civic education has done little to instill a sense of civic duty in the American public. While some are waiting for change to come from within, trying to influence already polarized voters, or counting down the days until the \"next election,\" leading child and adolescent development experts Daniel Hart and James Youniss are looking to another solution: America's youth. In Renewing Democracy in Young America, Hart and Youniss examine the widening generation gap, the concentration of wealth in pockets of the US, and the polarized political climate, and they arrive at a compelling solution to some of the most hotly contested issues of our time. The future of democracy depends on the American people seeing citizenship as a long-term psychological identity, and thus it is critical that youth have the opportunity to act as citizens during the time of their identity formation. Proposing that 16- and 17-year-olds be able to vote in municipal elections and suggesting that schools create science-based, community-oriented environmental engagement programs, the authors expound that by engaging youth through direct citizen-participatory experiences, we can successfully create active and committed citizens. Political scientists, media commentators, and citizens alike agree that democratic processes are broken across the nation, but we cannot stop at simply showing that our political system is dysfunctional. Refreshingly lucid and unabashedly hopeful, Renewing Democracy in Young America is an impeccably timed call to action. \"-- Provided by publisher.

In this study, 20% of patients with Covid-19 had a prolonged activated partial-thromboplastin time. In 90% of these cases, the cause was lupus anticoagulant, with no associated bleeding. Patients with Covid-19 are susceptible to thromboses. The presence of a prolonged aPTT should, in general, not be considered a contraindication to anticoagulation.

The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we describe the development of a long-term feeder-free, chemically defined culture system for distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5 + basal cells. AT2 organoids were able to differentiate into AT1 cells, and basal cell organoids developed lumens lined with differentiated club and ciliated cells. Single-cell analysis of KRT5 + cells in basal organoids revealed a distinct population of ITGA6 + ITGB4 + mitotic cells, whose offspring further segregated into a TNFRSF12A hi subfraction that comprised about ten per cent of KRT5 + basal cells. This subpopulation formed clusters within terminal bronchioles and exhibited enriched clonogenic organoid growth activity. We created distal lung organoids with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection of AT2 and basal cultures with SARS-CoV-2 and identifying club cells as a target population. This long-term, feeder-free culture of human distal lung organoids, coupled with single-cell analysis, identifies functional heterogeneity among basal cells and establishes a facile in vitro organoid model of human distal lung infections, including COVID-19-associated pneumonia. A long-term culture method for organoids derived from single adult human lung cells is used to identify progenitor cells and study SARS-CoV-2 infection.

Haemophilia A and B are rare congenital, recessive X-linked disorders caused by lack or deficiency of clotting factor VIII (FVIII) or IX (FIX), respectively. The severity of the disease depends on the reduction of levels of FVIII or FIX, which are determined by the type of the causative mutation in the genes encoding the factors (F8 and F9, respectively). The hallmark clinical characteristic, especially in untreated severe forms, is bleeding (spontaneous or after trauma) into major joints such as ankles, knees and elbows, which can result in the development of arthropathy. Intracranial bleeds and bleeds into internal organs may be life-threatening. The median life expectancy was ~30 years until the 1960s, but improved understanding of the disorder and development of efficacious therapy based on prophylactic replacement of the missing factor has caused a paradigm shift, and today individuals with haemophilia can look forward to a virtually normal life expectancy and quality of life. Nevertheless, the potential development of inhibitory antibodies to infused factor is still a major hurdle to overcome in a substantial proportion of patients. Finally, gene therapy for both types of haemophilia has progressed remarkably and could soon become a reality.Haemophilia is a recessive, X-linked, genetic disease caused by mutations in the gene encoding coagulation factor VIII (in haemophilia A) or IX (in haemophilia B). Individuals living with haemophilia are susceptible to bleeding events that can occur spontaneously or as a result of injury.

An AAV5 vector containing the factor IX Padua allele was administered to 54 men with hemophilia B. Factor IX expression increased to approximately 39% of normal, and the annualized bleeding rate was decreased to 1.5.

haemophilia is an inherited bleeding disorder caused by a deficiency in one of the blood coagulation factors. For people affected by severe haemophilia, the deficiency can cause spontaneous internal bleeding. Most young people with severe haemophilia in the UK follow a preventative treatment regimen (prophylaxis) consisting of several intravenous injections of factor concentrate each week. There is good evidence that prophylaxis reduces bleeds whilst also improving quality of life. However, levels of adherence among young people with haemophilia reported in the existing literature vary widely and are predominately based on estimations made by healthcare professionals and parents. Additionally, drivers of (non)adherence among young people specifically have not been evidenced. to assess self-reported adherence among young people with haemophilia, provide evidence of psychosocial predictors of adherence, and to establish the associations between non-adherence and number of bleeds and hospital visits. 91 participants were recruited during outpatient appointments in 13 haemophilia centres across England and Wales, and invited to complete a questionnaire assessing self-reported adherence (VERITAS-Pro), Haemophilia-related pain and impact of pain, Illness Perceptions, Beliefs about Medications, Self-efficacy, Outcome expectations, Positive and Negative Affect, and Social support. Number of hospital visits and bleeds during the previous six months were collected from medical files. Of 78 participants with complete data, just 18% had scores indicating non-adherence. Psychosocial predictors differed between intentional (skipping) and un-intentional (forgetting) non-adherence. Overall, however, better adherence was reported where participants perceived the need for prophylaxis was greater than their concern over taking it as well as having a positive expectancy of its effectiveness, good social support and a stronger emotional reaction to having haemophilia. The findings indicate that adherence is generally good, and that assessing illness and treatment beliefs, social support and outcome expectations may play a valuable role in identifying which individuals are at risk of non-adherence. Interventions aimed at improving adherence should particularly consider improving social support, reducing patients' concerns about prophylaxis, increasing their belief in the necessity of prophylaxis, and increasing positive outcome expectations.

The life-long inhibitor risk in non-severe hemophilia A has been an important clinical and research focus in recent years. Non-severe hemophilia A is most commonly caused by point mutation, missense genotypes, of which over 500 variants are described. The immunogenic potential of just a single amino acid change within a complex 2,332 amino acid protein is an important reminder of the challenges of protein replacement therapies in diverse, global populations. Although some genotypes have been identified as \"high risk\" mutations in non-severe hemophilia A (e.g., R593C), this is likely, in part at least, a reporting bias and oversimplification of the underlying immunological mechanism. Bioinformatic approaches offer a strategy to dissect the contribution of genotype in the context of the wider HLA diversity through which antigenic peptides will necessarily be presented. Extensive modeling of all permutations of FVIII-derived fifteen-mer peptides straddling all reported genotype positions demonstrate the likely heterogeneity of peptide binding affinity to different HLA II grooves. For the majority of genotypes it is evident that inhibitor risk prediction is dependent on the combination of genotype and available HLA II. Only a minority of FVIII-derived peptides are predicted to bind to all candidate HLA molecules. predictions still over call the risk of inhibitor occurrence, suggestive of mechanisms of \"protection\" against clinically meaningful inhibitor events. The structural homology between FVIII and FV provides an attractive mechanism by which some genotypes may be afforded co-incidental tolerance through homology of FV and FVIII primary amino sequence. strategies enable the extension of this hypothesis to analyse the extent to which co-incidental cross-matching exists between FVIII-derived primary peptide sequences and any other protein in the entire human proteome and thus potential central tolerance. This review of complimentary , and clinical epidemiology data documents incremental insights into immunological mechanism of inhibitor occurrence in non-severe hemophilia A over the last decade. However, complex questions remain about antigenic processing and presentation to truly understand and predict an individual person with hemophilia risk of inhibitor occurrence.

The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57/BL6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.

Naked mole-rats are among the most hypoxia-tolerant mammals. During hypoxia, their body temperature (Tb) decreases via unknown mechanisms to conserve energy. In small mammals, non-shivering thermogenesis in brown adipose tissue (BAT) is critical to Tb regulation; therefore, we hypothesize that hypoxia decreases naked mole-rat BAT thermogenesis. To test this, we measure changes in Tb during normoxia and hypoxia (7% O2; 1–3 h). We report that interscapular thermogenesis is high in normoxia but ceases during hypoxia, and Tb decreases. Furthermore, in BAT from animals treated in hypoxia, UCP1 and mitochondrial complexes I-V protein expression rapidly decrease, while mitochondria undergo fission, and apoptosis and mitophagy are inhibited. Finally, UCP1 expression decreases in hypoxia in three other social African mole-rat species, but not a solitary species. These findings suggest that the ability to rapidly down-regulate thermogenesis to conserve oxygen in hypoxia may have evolved preferentially in social species.