Domains of invasion organelle proteins from apicomplexan parasites are homologous with the Apple domains of blood coagulation factor XI and plasma pre-kallikrein and are members of the PAN module superfamily

AbstractMicronemes are specialised organelles, found in all apicomplexan parasites, which secrete molecules that are essential for parasite attachment to and invasion of host cells. Regions of several microneme proteins have sequence similarity to the Apple domains (A-domains) of blood coagulation factor XI (FXI) and plasma pre-kallikrein (PK). We have used mass spectrometry on a recombinant-expressed, putative A-domain from the microneme protein EtMIC5 from Eimeria tenella, to demonstrate that three intramolecular disulphide bridges are formed. These bridges are analogous to those that stabilise A-domains in FXI and PK. The data confirm that the apicomplexan domains are structural homologues of A-domains and are therefore novel members of the PAN module superfamily, which also includes the N-terminal domains of members of the plasminogen/hepatocyte growth factor family. The role of A-domains/PAN modules in apicomplexan parasites is not known, but their presence in the microneme suggests that they may be important for mediating protein–protein or protein–carbohydrate interactions during parasite attachment and host cell invasion

The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Databases: Important resources for haemostasis clinicians and researchers

Haemophilia published by John Wiley & Sons Ltd Introduction: Advances in genomic sequencing have facilitated the sequencing of genes associated with disorders of haemostasis. The identification of variants within genes and access to curated data incorporating structural, functional, evolutionary as well as phenotypic data has become increasingly important in order to ascribe pathogenicity. Aim: The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Database Project aims to provide a single port of entry to a web-accessible resource for variants in genes involved in clinical bleeding disorders. Results: New databases have evolved from previously developed single gene variant coagulation database projects, incorporating new data, new analysis tools and a new common database architecture with new interfaces and filters. These new databases currently present information about the genotype, phenotype (laboratory and clinical) and structural and functional effects of variants described in the genes of factor (F) VII (F7), FVIII (F8), FIX (F9) and von Willebrand factor (VWF). Conclusion: The project has improved the quality and quantity of information available to the haemostasis research and clinical communities, thereby enabling accurate classification of disease severity in order to make assessments of likely pathogenicity

Going places

Journeys. We all make them. Often they take us to exotic places. Sometimes they take us even further. They might take us through time. Or they might take us into a new way of life. There are times too, when we go all over the world and back again only to find that home is, after all, where it’s all happening. This book contains stories about many different types of journey. We hope you will enjoy travelling into it and finding a world that suits you

Inhibition of Thrombin Receptor Signaling on alpha-Smooth Muscle Actin(+) CD34(+) Progenitors Leads to Repair After Murine Immune Vascular Injury

OBJECTIVE: The goal of this study was to use mice expressing human tissue factor pathway inhibitor (TFPI) on α-smooth muscle actin (α-SMA)(+) cells as recipients of allogeneic aortas to gain insights into the cellular mechanisms of intimal hyperplasia (IH). METHODS AND RESULTS: BALB/c aortas (H-2(d)) transplanted into α-TFPI-transgenic (Tg) mice (H-2(b)) regenerated a quiescent endothelium in contrast to progressive IH seen in C57BL/6 wild-type (WT) mice even though both developed aggressive anti-H-2(d) alloresponses, indicating similar vascular injuries. Adoptively transferred Tg CD34(+) (but not CD34(-)) cells inhibited IH in WT recipients, indicating the phenotype of α-TFPI-Tg mice was due to these cells. Compared with syngeneic controls, endogenous CD34(+) cells were mobilized in significant numbers after allogeneic transplantation, the majority showing sustained expression of tissue factor and protease-activated receptor-1 (PAR-1). In WT, most were CD45(+) myeloid progenitors coexpressing CD31, vascular endothelial growth factor receptor-2 and E-selectin; 10% of these cells coexpressed α-SMA and were recruited to the neointima. In contrast, the α-SMA(+) human TFPI(+) CD34(+) cells recruited in Tg recipients were from a CD45(-) lineage. WT CD34(+) cells incubated with a PAR-1 antagonist or taken from PAR-1-deficient mice inhibited IH as Tg cells did. CONCLUSIONS: Specific inhibition of thrombin generation or PAR-1 signaling on α-SMA(+) CD34(+) cells inhibits IH and promotes regenerative repair despite ongoing immune-mediated damage

Targeted deletion of the mouse \u3ci\u3eMitoferrin1\u3c/i\u3e gene: from anemia to protoporphyria

Mitoferrin1 is 1 of 2 homologous mitochondrial iron transporters and is required for mitochondrial iron delivery in developing erythroid cells. We show that total deletion of Mfrn1 in embryos leads to embryonic lethality. Selective deletion of Mfrn1 in adult hematopoietic tissues leads to severe anemia because of a deficit in erythroblast formation. Deletion of Mfrn1 in hepatocytes has no phenotype or biochemical effect under normal conditions. In the presence of increased porphyrin synthesis, however, deletion of Mfrn1 in hepatocytes results in a decreased ability to convert protoporphyrin IX into heme, leading to protoporphyria, cholestasis, and bridging cirrhosis. Our results show that the activity of mitoferrin1 is required to manage an increase in heme synthesis. The data also show that alterations in heme synthesis within hepatocytes can lead to protoporphyria and hepatotoxicity

Threats from the air: damselfly predation on diverse prey taxa

To understand the diversity and strength of predation in natural communities, researchers must quantify the total amount of prey species in the diet of predators. Metabarcoding approaches have allowed widespread characterization of predator diets with high taxonomic resolution. To determine the wider impacts of predators, researchers should combine DNA techniques with estimates of population size of predators using mark–release–recapture (MRR) methods, and with accurate metrics of food consumption by individuals. Herein, we estimate the scale of predation exerted by four damselfly species on diverse prey taxa within a well‐defined 12‐ha study area, resolving the prey species of individual damselflies, to what extent the diets of predatory species overlap, and which fraction of the main prey populations are consumed. We identify the taxonomic composition of diets using DNA metabarcoding and quantify damselfly population sizes by MRR. We also use predator‐specific estimates of consumption rates, and independent data on prey emergence rates to estimate the collective predation pressure summed over all prey taxa and specific to their main prey (non‐biting midges or chironomids) of the four damselfly species. The four damselfly species collectively consumed a prey mass equivalent to roughly 870 (95% CL 410–1,800) g, over 2 months. Each individual consumed 29%–66% (95% CL 9.4–123) of its body weight during its relatively short life span (2.1–4.7 days; 95% CL 0.74–7.9) in the focal population. This predation pressure was widely distributed across the local invertebrate prey community, including 4 classes, 19 orders and c. 140 genera. Different predator species showed extensive overlap in diets, with an average of 30% of prey shared by at least two predator species. Of the available prey individuals in the widely consumed family Chironomidae, only a relatively small proportion (0.76%; 95% CL 0.35%–1.61%) were consumed. Our synthesis of population sizes, per‐capita consumption rates and taxonomic distribution of diets identifies damselflies as a comparatively minor predator group of aerial insects. As the next step, we should add estimates of predation by larger odonate species, and experimental removal of odonates, thereby establishing the full impact of odonate predation on prey communities.Peer reviewe

The EAHAD blood coagulation factor VII variant database

Hereditary blood coagulation factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder resulting from variants in the gene encoding FVII (F7 ). Integration of genetic variation with functional consequences on protein function is essential for the interpretation of the pathogenicity of novel variants. Here, we describe the integration of previous locus‐specific databases for F7 into a single curated database with enhanced features. The database provides access to in silico analyses that may be useful in the prediction of variant pathogenicity as well as cross‐species sequence alignments, structural information, and functional and clinical severity described for each variant, where appropriate. The variant data is shared with the F7 Leiden Open Variation Database. The updated database now includes 221 unique variants, representing gene variants identified in 728 individuals. Single nucleotide variants are the most common type (88%) with missense representing 74% of these variants. A number of variants are found with relatively high minor allele frequencies that are not pathogenic but contribute significantly to the likely pathogenicity of coinherited variants due to their effect on FVII plasma levels. This comprehensive collection of curated information significantly aids the assessment of pathogenicity

An online breathing and wellbeing programme (ENO Breathe) for people with persistent symptoms following COVID-19: a parallel-group, single-blind, randomised controlled trial

BACKGROUND: There are few evidence-based interventions for long COVID; however, holistic approaches supporting recovery are advocated. We assessed whether an online breathing and wellbeing programme improves health related quality-of-life (HRQoL) in people with persisting breathlessness following COVID-19. METHODS: We conducted a parallel-group, single-blind, randomised controlled trial in patients who had been referred from one of 51 UK-based collaborating long COVID clinics. Eligible participants were aged 18 years or older; were recovering from COVID-19 with ongoing breathlessness, with or without anxiety, at least 4 weeks after symptom onset; had internet access with an appropriate device; and were deemed clinically suitable for participation by one of the collaborating COVID-19 clinics. Following clinical assessment, potential participants were given a unique online portal code. Participants were randomly assigned (1:1) to either immediate participation in the English National Opera (ENO) Breathe programme or to usual care. Randomisation was done by the research team using computer-generated block randomisation lists, with block size 10. The researcher responsible for randomisation was masked to responses. Participants in the ENO Breathe group participated in a 6-week online breathing and wellbeing programme, developed for people with long COVID experiencing breathlessness, focusing on breathing retraining using singing techniques. Those in the deferred group received usual care until they exited the trial. The primary outcome, assessed in the intention-to-treat population, was change in HRQoL, assessed using the RAND 36-item short form survey instrument mental health composite (MHC) and physical health composite (PHC) scores. Secondary outcome measures were the chronic obstructive pulmonary disease assessment test score, visual analogue scales (VAS) for breathlessness, and scores on the dyspnoea-12, the generalised anxiety disorder 7-item scale, and the short form-6D. A thematic analysis exploring participant experience was also conducted using qualitative data from focus groups, survey responses, and email correspondence. This trial is registered with ClinicalTrials.gov, NCT04830033. FINDINGS: Between April 22 and May 25, 2021, 158 participants were recruited and randomly assigned. Of these, eight (5%) individuals were excluded and 150 participants were allocated to a treatment group (74 in the ENO Breathe group and 76 in the usual care group). Compared with usual care, ENO Breathe was associated with an improvement in MHC score (regression coefficient 2·42 [95% CI 0·03 to 4·80]; p=0·047), but not PHC score (0·60 [-1·33 to 2·52]; p=0·54). VAS for breathlessness (running) favoured ENO Breathe participation (-10·48 [-17·23 to -3·73]; p=0·0026). No other statistically significant between-group differences in secondary outcomes were observed. One minor self-limiting adverse event was reported by a participant in the ENO Breathe group who felt dizzy using a computer for extended periods. Thematic analysis of ENO Breathe participant experience identified three key themes: (1) improvements in symptoms; (2) feeling that the programme was complementary to standard care; and (3) the particular suitability of singing and music to address their needs. INTERPRETATION: Our findings suggest that an online breathing and wellbeing programme can improve the mental component of HRQoL and elements of breathlessness in people with persisting symptoms after COVID-19. Mind-body and music-based approaches, including practical, enjoyable, symptom-management techniques might have a role supporting recovery. FUNDING: Imperial College London

College campus smoking policies and programs and students' smoking behaviors

BACKGROUND: Although tobacco use in the United States has declined over the past 20 years, cigarette use among college students remains high. Additional research is thus needed to determine how university tobacco control policies and preventive education programs affect college students' smoking behaviors. METHODS: Approximately 13,000 undergraduate students at 12 universities or colleges in the state of Texas completed a web-based survey. College smoking policies were obtained from a survey of college administrators and from college websites. Logistic regression analyses were conducted to estimate the effects of individual smoking policies and programs on the odds of cigarette smoking. RESULTS: Of the individual programs, only having a preventive education program on campus was associated with lower odds of smoking. The existence of smoking cessation programs and designated smoking areas were associated with higher odds of smoking. Policies governing the sale and distribution of cigarettes were insignificantly associated with smoking. CONCLUSION: Rather than focusing on policies restricting cigarette sales and use, college administrators should consider implementing or expanding tobacco prevention and education programs to further reduce student smoking rates