Immune recognition of protein antigens relies on the combined interaction of multiple antibody loops, which provide a fairly large footprint and constrain the size and shape of protein surfaces that ...can be targeted. Single protein loops can mediate extremely high-affinity binding, but it is unclear whether such a mechanism is available to antibodies. Here we report the isolation and characterization of an antibody called C05, which neutralizes strains from multiple subtypes of influenza A virus, including H1, H2 and H3. X-ray and electron microscopy structures show that C05 recognizes conserved elements of the receptor-binding site on the haemagglutinin surface glycoprotein. Recognition of the haemagglutinin receptor-binding site is dominated by a single heavy-chain complementarity-determining region 3 loop, with minor contacts from heavy-chain complementarity-determining region 1, and is sufficient to achieve nanomolar binding with a minimal footprint. Thus, binding predominantly with a single loop can allow antibodies to target small, conserved functional sites on otherwise hypervariable antigens.
Iron delivery to the developing brain is essential for energy and metabolic support needed for processes such as myelination and neuronal development. Iron deficiency, especially in the developing ...brain, can result in a number of long‐term neurological deficits that persist into adulthood. There is considerable debate that excess access to iron during development may result in iron overload in the brain and subsequently predispose individuals to age‐related neurodegenerative diseases. There is a significant gap in knowledge regarding how the brain acquires iron during development and how biological variables such as development, genetics, and sex impact brain iron status. In this study, we used a mouse model expressing a mutant form of the iron homeostatic regulator protein HFE, (Hfe H63D), the most common gene variant in Caucasians, to determine impact of the mutation on brain iron uptake. Iron uptake was assessed using 59Fe bound to either transferrin or H‐ferritin as the iron carrier proteins. We demonstrate that at postnatal day 22, mutant mice brains take up greater amounts of iron compared with wildtype. Moreover, we introduce H‐ferritin as a key protein in brain iron transport during development and identify a sex and genotype effect demonstrating female mutant mice take up more iron by transferrin, whereas male mutant mice take up more iron from H‐ferritin at PND22. Furthermore, we begin to elucidate the mechanism for uptake using immunohistochemistry to profile the regional distribution and temporal expression of transferrin receptor and T‐cell immunoglobulin and mucin domain 2, the latter is the receptor for H‐ferritin. These data demonstrate that sex and genotype have significant effects on iron uptake and that regional receptor expression may play a large role in the uptake patterns during development.
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Cover Image for this issue: doi: 10.1111/jnc.14731.
Iron delivery to the developing brain is a critical process that is needed for essential metabolic support in processes such as myelination. Iron deficiency can result in a number of long‐term neurological deficits that persist into adulthood. In this study, we examine sex and genotype as variables that impact iron uptake in the developing brain. Our data show critical differences in iron uptake by males and females of a mutant mouse model during development. We also begin to profile the receptors of transferrin and H‐ferritin during development. These data may have significant implications in the treatment of iron deficiency.
Cover Image for this issue: doi: 10.1111/jnc.14731.
Patients with chronic liver disease are often diagnosed during an index presentation to hospital with decompensated cirrhosis or liver-related events, and these presentations are associated with high ...mortality. However, there is often a long asymptomatic phase, in which there is an opportunity for earlier diagnosis and interventions to prevent progression to advanced disease. Therefore, strategies for early diagnosis and interventions (including behavioural changes and pharmacological treatments) that prevent patients progressing to cirrhosis and its associated complications probably have substantial benefits for patients and health-care services. Many community pathways have been generated. Some pathways focus on abnormal liver function tests as a starting point to diagnose liver disease. Other pathways target groups at greater risk of chronic liver disease-particularly people with harmful alcohol consumption, type 2 diabetes, and obesity. This systematic review summarises the existing strategies available for the early detection or risk stratification of liver disease, focusing primarily on alcohol-related liver disease and non-alcoholic fatty liver disease. Conducting randomised clinical trials that compare different strategies will be essential to elucidate which pathways are acceptable to patients, feasible, provide high diagnostic accuracy for the detection of liver disease, improve liver-related outcomes, and are most cost-effective at the population level.
Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as
, is poorly characterized, ...despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to
sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the
circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.
Genetic searches for tumor suppressors have recently linked small nucleolar RNA misregulations with tumorigenesis. In addition to their classically defined functions, several small nucleolar RNAs are ...now known to be processed into short microRNA-like fragments called small nucleolar RNA-derived RNAs. To determine if any small nucleolar RNA-derived RNAs contribute to breast malignancy, we recently performed a RNA-seq-based comparison of the small nucleolar RNA-derived RNAs of two breast cancer cell lines (MCF-7 and MDA-MB-231) and identified small nucleolar RNA-derived RNAs derived from 13 small nucleolar RNAs overexpressed in MDA-MB-231s. Importantly, we find that inhibiting the most differentially expressed of these small nucleolar RNA-derived RNAs (sdRNA-93) in MDA-MB-231 cells results primarily in a loss of invasiveness, whereas increased sdRNA-93 expression in either cell line conversely results in strikingly enhanced invasion. Excitingly, we recently determined sdRNA-93 expressions in small RNA-seq data corresponding to 116 patient tumors and normal breast controls, and while we find little sdRNA-93 expression in any of the controls and only sporadic expression in most subtypes, we find robust expression of sdRNA-93 in 92.8% of Luminal B Her2+tumors. Of note, our analyses also indicate that at least one of sdRNA-93's endogenous roles is to regulate the expression of Pipox, a sarcosine metabolism-related protein whose expression significantly correlates with distinct molecular subtypes of breast cancer. We find sdRNA-93 can regulate the Pipox 3'UTR via standard reporter assays and that manipulating endogenous sdRNA-93 levels inversely correlates with altered Pipox expression. In summary, our results strongly indicate that sdRNA-93 expression actively contributes to the malignant phenotype of breast cancer through participating in microRNA-like regulation.
Liver disease is a major cause of morbidity in the UK and one of the leading causes of death in 35–49 years.2 The national trainee collaborative, ToRcH-UK, involving 1168 patients with decompensated ...liver disease, across 104 acute trusts in UK, demonstrated 1 in 6 inpatients died during their admission.3 Over 70% of new liver disease presents acutely to hospital, many dying without the chance to change.4 The aim must be to reduce morbidity and mortality from liver disease. Even in NAFLD, historically considered a slowly progressing fibrotic process,10 trial data has demonstrated over a fifth of patients with nonalcoholic steatohepatitis and F3 fibrosis progressed to cirrhosis within 2 years.11 Furthermore, in studies that performed cost-effectiveness analyses, benefit over ‘standard of care’ was demonstrated.7 12 13 This was further supported by cost-comparison modelling of different strategies for detection fibrosis, supporting a two-step risk stratification model,14 now incorporated in international guidance.15 Early detection strategies need to be accompanied by public health strategy targeting liver disease to maximise their impact. ...detecting liver disease in the community is not solely the responsibility of primary care. Detection of liver disease by the opportunistic finding of abnormal liver blood tests is unsatisfactory and can lead to under diagnosis as well as overinvestigation of otherwise well individuals.Table 1 Arguments pro and con detecting patients at risk of liver disease in the community PRO CON UK liver disease morbidity and mortality is driven by preventable aetiologies No specific liver disease intervention for early disease Early recognition would allow for interventions to prevent these diseases Risk of harm (particularly quality of life) of a diagnosis in patients with limited risk of liver-related complications Community-based screening programmes are more likely to detect advanced fibrosis than standard of care and may be cost-effective Increased financial cost and an increase burden of work to an already stretched primary care service Early detection strategies have shown superiority in the detection of patients with advanced fibrosis compared with the use of opportunistic abnormal liver blood tests.
Non-alcoholic fatty liver disease (NAFLD) is a potentially serious liver disease that affects approximately one-quarter of the global adult population, causing a substantial burden of ill health with ...wide-ranging social and economic implications. It is a multisystem disease and is considered the hepatic component of metabolic syndrome. Unlike other highly prevalent conditions, NAFLD has received little attention from the global public health community. Health system and public health responses to NAFLD have been weak and fragmented, and, despite its pervasiveness, NAFLD is largely unknown outside hepatology and gastroenterology. There is only a nascent global public health movement addressing NAFLD, and the disease is absent from nearly all national and international strategies and policies for non-communicable diseases, including obesity. In this global Delphi study, a multidisciplinary group of experts developed consensus statements and recommendations, which a larger group of collaborators reviewed over three rounds until consensus was achieved. The resulting consensus statements and recommendations address a broad range of topics - from epidemiology, awareness, care and treatment to public health policies and leadership - that have general relevance for policy-makers, health-care practitioners, civil society groups, research institutions and affected populations. These recommendations should provide a strong foundation for a comprehensive public health response to NAFLD.
Linnets Linaria cannabina were caught in northern and eastern Scotland from winter 2003/04 to 2012/13, with the majority of catches in low-lying agricultural areas around the Moray Firth. Although ...most birds breeding around the Moray Firth were sedentary, birds from further north and west in Highland and Orkney undertook long-distance movements to wintering sites, mainly in the Moray Firth area. Within a winter, movements were short, mostly within 5 km of the original trapping site. There was little variation in the median distance moved as the winter progressed. In subsequent winters, there was a tendency for some birds to switch wintering areas, with significantly fewer being found within 5 km of the original catching site. Catches in northwest Sutherland in spring showed high site fidelity in subsequent summers. During the current study no Scottish birds were recovered abroad and the percentage of long distance movements was not significantly different from birds ringed in other areas of Britain and Ireland.
Capsule The breeding success of Lesser Spotted Woodpeckers Dendrocopos minor is now lower in England than previously reported and also lower than found in studies elsewhere in Europe.Aims To quantify ...the breeding success and identify the causes of nest failure. To test the hypotheses that breeding success is related to aspects of food limitation and parental care, and inclement weather during the nesting period, or to interactions with Great Spotted Woodpeckers.Methods Nests were monitored in three regions of England, recording survival and causes of failure. We measured aspects of food limitation and parental care, rainfall and Great Spotted Woodpecker interactions at nests, to explore whether there was any evidence that these factors were related to breeding success. We compared results to other studies from the UK and continental Europe.Results Nest survival was 52%. The average number of chicks produced from successful nests was 2.8. Chick-stage daily nest survival was positively related to provisioning rates, indicating that food supply may be limiting. The most common cause of nest failure was presumed starvation of chicks after the disappearance of an adult. Some females ceased visiting nests, leaving provisioning solely to the male. This behaviour has been reported elsewhere in Europe, but in the present study males were unable to compensate fully by increasing their provisioning rates, leading to poor nest survival. Provisioning rates and chick-stage daily nest survival were negatively associated with rainfall. Nest predation by Great Spotted Woodpeckers occurred but was a less frequent cause of failure. Aggressive interactions were recorded between the two woodpecker species but these were unrelated to breeding parameters.Conclusions Low breeding success is most probably related to food shortages in the breeding period. Simple population modelling using parameters from the present study and from published work shows that if the low productivity that we have observed is replicated throughout Britain, it would be sufficient to account for the observed population decline. However, the possibility that survival rates are also low cannot be ruled out.
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