Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy.

The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-ß superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.

The sinister story of a gauche deliverer and his corrie-fisted tribesmen: Ehud and the left-handed artillery.

Bias against left-handers is well-documented and seen in the etymology of "left" and "right" in most languages. The subject of this study, Ehud, lived between the exodus of the Hebrew slaves from Egypt and the establishment of the Israelite kingdom (c1200-1000 BC), at the transition between the Late Bronze Age and Iron Age 1. His left-handedness was crucial to his deliverance of the proto-nation from tyranny, recorded in Judges in the Hebrew Bible. The description of Ehud as left-handed ('itter yad-yεmînô) is used once more in the Hebrew Bible, also in Judges, to describe the artillery of Ehud's tribe. The words apparently mean "bound/restricted in the right hand", sometimes interpreted as "ambidextrous". This is unlikely: ambidexterity is uncommon. The artillery used the sling with either hand, but Ehud used his left (sεm'ol) hand to draw his sword. sεm'ol, used throughout the Hebrew Bible, means left, without bias or derogatory implications. We suggest that 'itter yad-yεmînô was a right-handed bias towards left-handed people, but Ehud's left-handed victory was recognized as significant. Significant enough that (a) the language changed and the biased description was dropped in favour of simple description, and (b) the army changed with the development of left-handed slingers (artillery).

"Old" and "new" contaminants and their management: learning from the past, looking to the future.

Within the 50 year lifetime of the Society for Environmental Geochemistry and Health (SEGH), we have seen a number of contaminants transfer from being the wonder chemical of their day through to becoming current contaminants of concern. This is also true for a variety of emerging contaminants such as plastic microbeads, pharmaceutical residues, and fire retardant chemicals, amongst others. This thought piece discusses the risk associated with a range of these emerging contaminants, their global nature, how existing models and frameworks can be applied to deal with their impacts, and research and management gaps and challenges.

Parasitic nematodes of the genus Syphacia Seurat, 1916 infecting Cricetidae in the British Isles: the enigmatic status of Syphacia nigeriana.

Oxyurid nematodes (Syphacia spp.) from bank (Myodes glareolus) and field/common (Microtus spp.) voles, from disparate geographical sites in the British Isles, were examined morphologically and genetically. The genetic signatures of 118 new isolates are provided, based primarily on the rDNA internal transcribed spacers (ITS1-5.8S-ITS2) region and for representative isolates also on the small subunit 18S rDNA region and cytochrome c oxidase subunit 1 (cox-1) gene locus. Genetic data on worms recovered from Microtus spp. from the European mainland and from other rodent genera from the Palaearctic, North America and West Africa are also included. We test historical hypotheses indicating that S. nigeriana is a generalist species, infecting a range of different rodent genera. Our results establish that S. nigeriana is a parasite of both bank and field voles in the British Isles. An identical genotype was also recorded from Hubert's multimammate mouse (Mastomys huberti) from Senegal, but Mastomys spp. from West Africa were additionally parasitized by a related, although genetically distinct Syphacia species. We found no evidence for S. petrusewiczi in voles from the British Isles but isolates from Russia and North America were genetically distinct and formed their own separate deep branch in maximum likelihood molecular phylogenetic trees.

Tracking sleep in the field: sleep quality and sleep behaviours of elite track and field athletes during preparation and competition.

Elite athletes are susceptible to inadequate sleep, which may peak during competition and be exacerbated by poor sleep behaviours. This study sought to characterise and compare the sleep quality and sleep behaviours of elite track and field athletes during preparation and major competitions. Forty elite international track and field athletes (50% female, aged 25.1 ± 3.9 years) completed the Athlete Sleep Screening Questionnaire and the Athlete Sleep Behaviour Questionnaire on three separate occasions: during habitual training, during a pre-meet training camp and during a major international competition. Overall, 62.5% of athletes reported at least mild sleep difficulty during competition. Athletes reported higher sleep difficulty and poorer sleep behaviour during major competitions and the pre-meet training camp compared to habitual training (P = .001-.025). No significant differences were observed between the training camp and major competition. Global sleep behaviour scores were underpinned by unique characteristics at each timepoint. Sleep behaviour (R2 = .330, P = .017), injury status (R2 = .253, P = .003) and major championship experience (R2 = .113, P = .034) were associated with sleep difficulty during competition. Sleep quality and behaviours vary according to stage of the track and field season, providing a foundation for targeted intervention.

Immunoglobulin gene analysis as a tool for investigating human immune responses.

The human immunoglobulin repertoire is a hugely diverse set of sequences that are formed by processes of gene rearrangement, heavy and light chain gene assortment, class switching and somatic hypermutation. Early B cell development produces diverse IgM and IgD B cell receptors on the B cell surface, resulting in a repertoire that can bind many foreign antigens but which has had self-reactive B cells removed. Later antigen-dependent development processes adjust the antigen affinity of the receptor by somatic hypermutation. The effector mechanism of the antibody is also adjusted, by switching the class of the antibody from IgM to one of seven other classes depending on the required function. There are many instances in human biology where positive and negative selection forces can act to shape the immunoglobulin repertoire and therefore repertoire analysis can provide useful information on infection control, vaccination efficacy, autoimmune diseases, and cancer. It can also be used to identify antigen-specific sequences that may be of use in therapeutics. The juxtaposition of lymphocyte development and numerical evaluation of immune repertoires has resulted in the growth of a new sub-speciality in immunology where immunologists and computer scientists/physicists collaborate to assess immune repertoires and develop models of immune action.

Science and agriculture: promoting beneficial symbiosis.

While fundamental research into key mechanisms and interactions is important, the practical investigations that scientists also undertake have additional considerations, since the results are applicable in the real world but need disseminating in a way that reaches the intended audience. Worldwide, rapid population growth produces multiple pressures on land, meaning agriculture must become more efficient and productive. Other pressures on farmers are also increasing: to meet environmental quality standards, to follow legislation about application of chemical products, to remain financially viable against uncertain markets, and more. Applied research addresses specific aspects, but often reports do not describe local contexts or are too restricted, lacking details that enable an understanding of their wider application. We illustrate from our experience within UK agriculture, with a particular focus on soil, the identification of current shortcomings in many research publications; provide examples of good practice; and make suggestions for how scientists can help agriculturalists use their work to address the global issues currently faced. Specifically, we recommend that communication between science and agricultural communities is nurtured, to improve mutual understanding and facilitate two-way flow of ideas. In scientific publications, provision of as much contextual information as possible, and consideration for climatic/temporal/location influences, will enable investigations and results to be used for maximum practical effect and should increase citations.

Environmental and human iodine and selenium status: lessons from Gilgit-Baltistan, North-East Pakistan.

Iodine and selenium deficiencies are common worldwide. We assessed the iodine and selenium status of Gilgit-Baltistan, Pakistan. We determined the elemental composition (ICP-MS) of locally grown crops (n = 281), drinking water (n = 82), urine (n = 451) and salt (n = 76), correcting urinary analytes for hydration (creatinine, specific gravity). We estimated dietary iodine, selenium and salt intake. Median iodine and selenium concentrations were 11.5 (IQR 6.01, 23.2) and 8.81 (IQR 4.03, 27.6) µg/kg in crops and 0.24 (IQR 0.12, 0.72) and 0.27 (IQR 0.11, 0.46) µg/L in water, respectively. Median iodised salt iodine was 4.16 (IQR 2.99, 10.8) mg/kg. Population mean salt intake was 13.0 g/day. Population median urinary iodine (uncorrected 78 µg/L, specific gravity-corrected 83 µg/L) was below WHO guidelines; creatinine-corrected median was 114 µg/L but was unreliable. Daily selenium intake (from urinary selenium concentration) was below the EAR in the majority (46-90%) of individuals. Iodine and selenium concentrations in all crops were low, but no health-related environmental standards exist. Iodine concentration in iodised salt was below WHO-recommended minimum. Estimated population average salt intake was above WHO-recommended daily intake. Locally available food and drinking water together provide an estimated 49% and 72% of EAR for iodine (95 µg/day) and selenium (45 µg/day), respectively. Low environmental and dietary iodine and selenium place Gilgit-Baltistan residents at risk of iodine deficiency disorders despite using iodised salt. Specific gravity correction of urine analysis for hydration is more consistent than using creatinine. Health-relevant environmental standards for iodine and selenium are needed.

Mining is bad for health: a voyage of discovery.

Mining continues to be a dangerous activity, whether large-scale industrial mining or small-scale artisanal mining. Not only are there accidents, but exposure to dust and toxins, along with stress from the working environment or managerial pressures, give rise to a range of diseases that affect miners. I look at mining and health from various personal perspectives: that of the ordinary man (much of life depends on mined elements in the house, car and phone); as a member of the Society for Environmental Geochemistry and Health (environmental contamination and degradation leads to ill health in nearby communities); as a public health doctor (mining health is affected by many factors, usually acting in a mix, ranging from individual inheritance-genetic makeup, sex, age; personal choices-diet, lifestyle; living conditions-employment, war; social support-family, local community; environmental conditions-education, work; to national and international constraints-trade, economy, natural world); as a volunteer (mining health costs are not restricted to miners or industry but borne by everyone who partakes of mining benefits-all of us); and as a lay preacher (the current global economy concentrates on profit at the expense of the health of miners). Partnership working by academics with communities, government and industry should develop evidence-based solutions. Employment, health, economic stability and environmental protection need not be mutually exclusive. We all need to act.

Parasitic nematodes of the genus Syphacia Seurat, 1916 infecting Muridae in the British Isles, and the peculiar case of Syphacia frederici.

Syphacia stroma (von Linstow, 1884) Morgan, 1932 and Syphacia frederici Roman, 1945 are oxyurid nematodes that parasitize two murid rodents, Apodemus sylvaticus and Apodemus flavicollis, on the European mainland. Only S. stroma has been recorded previously in Apodemus spp. from the British Isles. Despite the paucity of earlier reports, we identified S. frederici in four disparate British sites, two in Nottinghamshire, one each in Berkshire and Anglesey, Wales. Identification was based on their site in the host (caecum and not small intestine), on key morphological criteria that differentiate this species from S. stroma (in particular the tail of female worms) and by sequencing two genetic loci (cytochrome C oxidase 1 gene and a section of ribosomal DNA). Sequences derived from both genetic loci of putative British S. frederici isolates formed a tight clade with sequences from continental worms known to be S. frederici, clearly distinguishing these isolates from S. stroma which formed a tight clade of its own, distinct from clades representative of Syphacia obvelata from Mus and S. muris from Rattus. The data in this paper therefore constitute the first record of S. frederici from British wood mice, and confirm the status of this species as distinct from both S. obvelata and S. stroma.

Seeking evidence of multidisciplinarity in environmental geochemistry and health: an analysis of arsenic in drinking water research.

A multidisciplinary approach to research affords the opportunity of objectivity, creation of new knowledge and potentially a more generally acceptable solution to problems that informed the research in the first place. It increasingly features in national programmes supporting basic and applied research, but for over 40 years, has been the arena for many research teams in environmental geochemistry and health. This study explores the nature of multidisciplinary research in the earth and health sciences using a sample selected from co-authored articles reporting research on arsenic (As) in drinking water from 1979 to 2013. A total of 889 relevant articles were sourced using the online version of the science citation index-expanded (SCI-expanded). The articles were classified according to author affiliation and later by author discipline/research interests using the Revised Field of Science and Technology Frascati manual DSTI/EAS/STP/NESTI (2006) 19/FINAL and a decision algorithm. Few articles were published on the topic until 2000. More articles were published across all affiliations in the last 10 years of the review period (2004-2013) than in the first 10 years (1979-1988). Only 84 (~9%) articles fell within the "earth and health" only and "earth, health and other" categories when classification was undertaken by author affiliation alone. This suggests that level of collaboration between earth and health scientists in arsenic in drinking water research may be very low. By refining the classification further using author discipline/research interests, only 28 of the 84 articles appear to be co-authored by earth and health scientists alongside professionals in other fields. More than half of these 28 articles involved descriptive non-experimental, observational study designs, limited in direct causal hypotheses and mechanistic investigation. If collaborative research is to lead to the increased multidisciplinary research, early interaction should be encouraged between students from different disciplines. In order to achieve multidisciplinarity in practise, it is imperative that scientific communities and research agencies do more to encourage interaction and integration between researchers from different disciplines. This must develop from educational institutions seeing opportunities to improve graduate skills in an increasingly diverse research landscape.

Characterization of Diabetogenic CD8+ T Cells: IMMUNE THERAPY WITH METABOLIC BLOCKADE.

Type 1 diabetes mellitus is caused by the killing of insulin-producing ß cells by CD8+T cells. The disease progression, which is chronic, does not follow a course like responses to conventional antigens such as viruses, but accelerates as glucose tolerance deteriorates. To identify the unique features of the autoimmune effectors that may explain this behavior, we analyzed diabetogenic CD8+ T cells that recognize a peptide from the diabetes antigen IGRP (NRP-V7-reactive) in prediabetic NOD mice and compared them to others that shared their phenotype (CD44(+)CD62L(lo)PD-1(+)CXCR3(+)) but negative for diabetes antigen tetramers and to LCMV (lymphocytic choriomeningitis)-reactive CD8+ T cells. There was an increase in the frequency of the NRP-V7-reactive cells coinciding with the time of glucose intolerance. The T cells persisted in hyperglycemic NOD mice maintained with an insulin pellet despite destruction of ß cells. We compared gene expression in the three groups of cells compared with the other two subsets of cells, and the NRP-V7-reactive cells exhibited gene expression of memory precursor effector cells. They had reduced cellular proliferation and were less dependent on oxidative phosphorylation. When prediabetic NOD mice were treated with 2-deoxyglucose to block aerobic glycolysis, there was a reduction in the diabetes antigen versus other cells of similar phenotype and loss of lymphoid cells infiltrating the islets. In addition, treatment of NOD mice with 2-deoxyglucose resulted in improved ß cell granularity. These findings identify a link between metabolic disturbances and autoreactive T cells that promotes development of autoimmune diabetes.

Achieving attainable outcomes from good science in an untidy world: case studies in land and air pollution.

While scientific understanding of environmental issues develops through careful observation, experiment and modelling, the application of such advances in the day to day world is much less clean and tidy. Merseyside in northwest England has an industrial heritage from the earliest days of the industrial revolution. Indeed, the chemical industry was borne here. Land contamination issues are rife, as are problems with air quality. Through the examination of one case study for each topic, the practicalities of applied science are explored. An integrated, multidisciplinary response to pollution needs more than a scientific risk assessment. The needs of the various groups (from public to government) involved in the situations must be considered, as well as wider, relevant contexts (from history to European legislation), before a truly integrated response can be generated. However, no such situation exists in isolation and the introduction of environmental investigations and the exploration of suitable, integrated responses will alter the situation in unexpected ways, which must be considered carefully and incorporated in a rolling fashion to enable solutions to continue to be applicable and relevant to the problem being faced. This integrated approach has been tested over many years in Merseyside and found to be a robust approach to ever-changing problems that are well described by the management term, "wicked problems".

Identification of cis-regulatory variation influencing protein abundance levels in human plasma.

Proteins are central to almost all cellular processes, and dysregulation of expression and function is associated with a range of disorders. A number of studies in human have recently shown that genetic factors significantly contribute gene expression variation. In contrast, very little is known about the genetic basis of variation in protein abundance in man. Here, we assayed the abundance levels of proteins in plasma from 96 elderly Europeans using a new aptamer-based proteomic technology and performed genome-wide local (cis-) regulatory association analysis to identify protein quantitative trait loci (pQTL). We detected robust cis-associations for 60 proteins at a false discovery rate of 5%. The most highly significant single nucleotide polymorphism detected was rs7021589 (false discovery rate, 2.5 × 10(-12)), mapped within the gene coding sequence of Tenascin C (TNC). Importantly, we identified evidence of cis-regulatory variation for 20 previously disease-associated genes encoding protein, including variants with strong evidence of disease association show significant association with protein abundance levels. These results demonstrate that common genetic variants contribute to the differences in protein abundance levels in human plasma. Identification of pQTLs will significantly enhance our ability to discover and comprehend the biological and functional consequences of loci identified from genome-wide association study of complex traits. This is the first large-scale genetic association study of proteins in plasma measured using a novel, highly multiplexed slow off-rate modified aptamer (SOMAmer) proteomic platform.