Search

Lack of Factor VIII (FVIII) concentrates is one of limiting factors for Hemophilia A prophylaxis in resource-limited countries. Rondaptivon pegol (BT200) is a pegylated aptamer and has been shown to elevate the level of von Willebrand Factor (VWF) and FVIII in previous studies. A population pharmacokinetic model for BT200 was built and linked to the kinetic models of VWF and FVIII based on reasonable assumptions. The developed PK/PD model for BT200 described the observed kinetic of BT200, VWF, and FVIII in healthy volunteers and patients with mild-to-moderate hemophilia A from two clinical trials. The developed model was evaluated using an external dataset in patients with severe hemophilia A taking recombinant FVIII products. The developed and evaluated PK/PD model was able to describe and predict concentration–time profiles of BT200, VWF, and FVIII in healthy volunteers and patients with hemophilia A. Concentration–time profiles of FVIII were then predicted following coadministration of plasma-derived FVIII concentrate and BT200 under various dosing scenarios in virtual patients with severe hemophilia A. Plasma-derived products, that contain VWF, are more accessible in low-resource countries as compared to their recombinant counterparts. The predicted time above 1 and 3 IU/dL FVIII in one week was compared between scenarios in the absence and presence of BT200. A combination dose of 6 mg BT200 once weekly plus 10 IU/kg plasma-derived FVIII twice weekly maintained similar coverage to a 30 IU/kg FVIII thrice weekly dose in absence of BT200, representing only 22% of the FVIII dose per week. [ABSTRACT FROM AUTHOR]

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. The naked mole-rat exhibits extreme longevity, resistance to hypoxia and absence of cardiovascular disease. Here, Faulkes et al. identify mechanisms behind these traits by comparing cardiac metabolomes and transcriptomes of naked more-rats to other African mole-rat genera and evolutionary divergent mammals. [ABSTRACT FROM AUTHOR]

Animals are increasingly challenged to respond to novel or rapidly changing habitats due to urbanization and/or displacement outside their native range by humans. Behavioral differences, such as increased boldness (i.e., propensity for risk-taking), are often observed in animals persisting in novel environments; however, in many cases, it is unclear how these differences arise (e.g., through developmental plasticity or evolution) or when they arise (i.e., at what age or developmental stage). In the Guttural Toad (Sclerophrys gutturalis), adult urban toads from both native and invasive ranges are bolder than conspecifics in natural habitats. Here, we reared Guttural Toad tadpoles in a common garden experiment, and tested for innate differences in boldness across their development and between individuals whose parents and lineage came from rural-native, urban-native, and urban-invasive localities (i.e., origin populations). Tadpoles did not differ in their boldness or in how their boldness changed over ontogeny based on their origin populations. In general, tadpoles typically became less bold as they aged, irrespective of origin population. Our findings indicate that differences in boldness in free-living adult Guttural Toads are not innate in the tadpole stage and we discuss three possible mechanisms driving phenotypic divergence in adult boldness for the focus of future research: habitat-dependent developmental effects on tadpole behavior, decoupled evolution between the tadpole and adult stage, and/or behavioral flexibility, learning, or acclimatization during the adult stage. Significance statement: To determine if animals can persist in urban areas or become invasive outside their native ranges, it is important to understand how they adapt to life in the city. Our study investigates if differences in boldness that have been found in adult Guttural Toads (Sclerophrys gutturalis) represent heritable differences that can also be found in early life stages by rearing tadpoles from eggs in a common garden experiment. We did not find any differences in boldness among tadpoles from rural-native, urban-native, and urban-invasive origin populations. Our findings suggest that differences in boldness are not innate and/or that boldness is a behavioral trait that is decoupled between the tadpole and the adult stage. [ABSTRACT FROM AUTHOR]

Purpose: This prospective, observational first in human study evaluated the safety and effectiveness of WRAPSODYTM Cell-impermeable Endoprosthesis (Merit Medical Systems, Inc.) in the treatment of arteriovenous fistula and arteriovenous graft access circuit stenosis. Materials and Methods: Investigators conducted a prospective analysis of 46 patients with access circuit stenosis from three centres. Treatment sites included the peripheral outflow veins (e.g. cephalic arch, basilic vein swing point; 16 fistula and 10 graft patients); the graft-vein anastomosis (9 patients); and the central veins (up to, but not including the SVC; 11 patients). Primary outcome measures included 30-day freedom from access circuit-related safety events and 30-day target lesion primary patency. Secondary outcome measures included procedural success; device- and procedure-related adverse events; target lesion primary patency; access circuit primary patency; and secondary patency. In-person follow-up was scheduled at 1, 3, 6, and 12 months. An independent data monitoring/clinical event committee adjudicated all reinterventions and device/procedure-relatedness for adverse events. Results: All initial procedures were successful. All but one patient was free from safety events through the first 30 days (97.8% (45/46)). This event was not device-related. Over the remainder of the study, one adverse event was adjudicated as possibly device-related. Six- and 12-month target lesion primary patency rates were 97.7% (42/43) and 84.6.% (33/39), respectively. Six- and 12-month access circuit primary patency rates were 84.4% (38/45) and 65.9% (29/44), respectively. Conclusion: Results suggest that the study device is safe and effective for treatment of stenoses in the peripheral and central veins of arteriovenous access circuits. Level of Evidence: Level 2b, cohort study. [ABSTRACT FROM AUTHOR]

Purpose: Stenoses in mature arteriovenous fistulas (AVFs) are common and can negatively impact on the quality of haemodialysis, the longevity of the AVF and lead to debilitating symptoms. Multiple treatment options exist; however, management can vary between different centres. We aimed to establish multidisciplinary consensus on the optimal stepwise application of interventions based on evidence and consensus.Methods: A modified Delphi process was conducted with 13 participants from hospitals across the UK, all of whom have high-volume dialysis access practice.Results: The usual intervention to rectify de novo stenoses of mature AVFs is fistuloplasty, although surgery for inflow segment stenoses is also clinically acceptable. Appropriate first-line interventions include plain old balloon angioplasty or high-pressure balloon angioplasty; if these fail during the fistuloplasty, consider upsizing the balloon, prolonged balloon inflation or using alternative interventions, such as cutting or scoring balloons and ultra-high-pressure balloons. Alternative or subsequent interventions vary by anatomical site and may require additional multidisciplinary team input. For a stenoses recurring between 3 and 12 months, it is appropriate to consider interventions used de novo, but with a lower threshold for using drug-coated balloons (DCBs) in all regions and for using stent grafts in all regions but inflow segment. Recurrence after 12 months should be treated as a de novo lesion, with DCBs considered if they have been used successfully during previous interventions.Conclusions: These recommendations aim to provide a practical guide to multidisciplinary teams in order to optimise the use of multiple interventions for rectifying AVF stenoses and provide unified evidence-based practice guidelines. [ABSTRACT FROM AUTHOR]

Many biological invasions occur within and between urban areas. If native species adapted to anthropogenically altered habitats are subsequently moved from an urban area in their native range to one within a novel region, then their urban-specialized phenotypes may provide them an advantage via prior adaptation. Here we examine if urban-derived behavioral traits are present within native guttural toad, Sclerophrys gutturalis, populations (Durban, South Africa) and investigate whether these localized phenotypes persisted within their invasive populations in Mauritius and Réunion. In our study, we measured boldness and exploration in populations along the toad's invasion route and found that toads were significantly bolder in urban populations, within both native and invasive ranges. This suggests boldness increased when toads transitioned to urban living in their native range and these heightened levels of boldness were maintained within invaded urban areas. This provides evidence that a bolder phenotype was a prior adaptation that likely increased guttural toad's invasion success. Interestingly, toad boldness returned to pre-urbanization levels within invasive populations that spread into natural areas, replicated on both islands. Exploration, on the other hand, was not increased above pre-urbanization, or pre-invasion, levels for any of the populations, and was lower in toads from Mauritius. Overall, our findings suggest that increased boldness is favored in urban habitats and that urban-derived behavioral traits may provide individuals an advantage when invading new urban landscapes. Significance statement: Species adapting to anthropogenic landscapes have the ability to increase their invasive potential if the altered phenotypes they accrue can provide them advantages once they are transported outside their native range. Our study examined differences in behavioral traits, boldness, and exploration, along the invasion route of guttural toads, Sclerophrys gutturalis, between natural and urban sites from their native origin populations around Durban, South Africa, to their invasive populations in Mauritius and Réunion. We determined that populations were bolder in urban areas in their native range and that this increased boldness persisted in the other anthropogenic habitats within their invasive ranges, but reverted back to natural-native levels within populations that had spread into natural areas on both islands. Our findings support the growing trend that anthropogenically altered landscapes favor bolder individuals, as well as the assertion that urban-derived traits may bolster a species' ability to establish and spread within novel landscapes. [ABSTRACT FROM AUTHOR]

Urban wildlife faces a novel set of challenges resulting in selective pressure that can lead to population-level changes. We studied Australian water dragons (Intellagama lesueurii) from urban and natural populations to test if urban populations differed in body size, shape, and performance capacity. If urban-derived morphology has arisen through selection, we predicted distinct morphological differences between wild dragons from urban and natural areas in both adult and hatchling life-stages. Urban hatchlings were morphologically distinct (shorter body lengths and longer limbs) from natural populations, while urban adult males continued this trend but only for body size (shorter body lengths). We then experimentally reared hatchlings originating from urban and natural populations within urban- and natural-style enclosures (2 × 2 factorial design) for a year to determine if differences in morphology and performance capacity (sprint speed, endurance, and clinging ability) were related to either the individual's origin population or developmental environment. Yearlings reared in urban-style enclosures, irrespective of population origin, had smaller body sizes compared to those from natural-style enclosures, suggesting developmental environment was affecting their morphology. Despite this difference in body size, yearling dragon performance capacity was not significantly different between treatments. Overall, this study provides evidence of a complex relationship driving urban-divergent morphology – whereby urban dragons emerge as smaller hatchlings with longer limbs (innate traits) and are then further influenced by the urban environments that they develop in (phenotypic plasticity); however, and potentially owing to behavioral, ecological, and demographical differences, these changes appear to be sex-specific. [ABSTRACT FROM AUTHOR]

Nutritional studies often require precise control of nutrients via dilution of artificial diets with indigestible material, but such studies in bees are limited. Common diluents like cellulose typically result in total mortality of bee larvae, making quantitative studies difficult. We investigated potential alternative dietary dilution agents, sporopollenin (pollen exines) and agar. We reared Osmia bicornis larvae on pollen diluted with these substances, alongside undiluted controls. Sporopollenin neither prevented nor improved survival, suggesting it is a suitable diluent. Agar appeared marginally to increase survival and its suitability requires further research. Both substances reduced cocoon weight, and sporopollenin also prolonged development, suggesting processing costs. Determining the physiological mechanisms driving these responses requires further work. Our findings should facilitate studies involving nutritional manipulations for solitary bees. [ABSTRACT FROM AUTHOR]

The effect of conventional anti-platelet agents is limited in secondary stroke prevention, and their effects are blunted under high shear stress in the presence of increased levels of circulating von Willebrand factor (VWF). VWF is critically involved in thrombus formation at sites of stenotic extracranial/intracranial arteries. A third generation anti-VWF aptamer (BT200) has been generated which could be useful for secondary stroke prevention. To characterize the effects of BT200 in blood of patients with large artery atherosclerosis stroke (LAA). Blood samples were obtained from 33 patients with acute stroke or transient ischemic attack to measure inhibition of VWF activity and VWF-dependent platelet function. Patients who received clopidogrel or dual antiplatelet therapy did not differ in VWF dependent platelet function tests from aspirin treated patients. Of 18 patients receiving clopidogrel with or without aspirin, only 3 had a prolonged collagen adenosine diphosphate closure time, and none of the patients had ristocetin induced aggregation in the target range. BT200 concentration-dependently reduced median VWF activity from 178 to < 3%, ristocetin induced platelet aggregation from 40U to < 10U and prolonged collagen adenosine diphosphate closure times from 93 s to > 300 s. Baseline VWF activity correlated (r = 0.86, p < 0.001) with concentrations needed to reduce VWF activity to < 20% of normal, indicating that BT200 acts in a target concentration-dependent manner. Together with a long half-life supporting once weekly administration, the safety and tolerability observed in an ongoing phase I trial, and the existence of a reversal agent, BT200 is an interesting drug candidate. [ABSTRACT FROM AUTHOR]

Von Willebrand factor (VWF) plays a major role in arterial thrombosis. Antiplatelet drugs induce only a moderate relative risk reduction after atherothrombosis, and their inhibitory effects are compromised under high shear rates when VWF levels are increased. Therefore, we investigated the ex vivo effects of a third-generation anti-VWF aptamer (BT200) before/after stimulated VWF release. We studied the concentration-effect curves BT200 had on VWF activity, platelet plug formation under high shear rates (PFA), and ristocetin-induced platelet aggregation (Multiplate) before and after desmopressin or endotoxin infusions in healthy volunteers. VWF levels increased > 2.5-fold after desmopressin or endotoxin infusion (p < 0.001) and both agents elevated circulating VWF activity. At baseline, 0.51 µg/ml BT200 reduced VWF activity to 20% of normal, but 2.5-fold higher BT200 levels were required after desmopressin administration (p < 0.001). Similarly, twofold higher BT200 concentrations were needed after endotoxin infusion compared to baseline (p < 0.011). BT200 levels of 0.49 µg/ml prolonged collagen-ADP closure times to > 300 s at baseline, whereas 1.35 µg/ml BT200 were needed 2 h after desmopressin infusion. Similarly, twofold higher BT200 concentrations were necessary to inhibit ristocetin induced aggregation after desmopressin infusion compared to baseline (p < 0.001). Both stimuli elevated plasma VWF levels in a manner representative of thrombotic or pro-inflammatory conditions such as arterial thrombosis. Even under these conditions, BT200 potently inhibited VWF activity and VWF-dependent platelet function, but higher BT200 concentrations were required for comparable effects relative to the unstimulated state. [ABSTRACT FROM AUTHOR]

The adaptive nature of invasive species facilitates their survival in conditions that differ markedly from their native range. Behavioral changes in invasive populations are poorly explored but offer a wide potential when combined with physiological traits. For amphibians invading xeric habitats, finding water is important to function optimally and avoid dehydration. The water-finding hypothesis postulates that survival can be enhanced through the increased behavioral ability to find water. We tested the water-finding hypothesis in guttural toads (Sclerophrys gutturalis) from their native range and an invasive population. Additionally, we tested if artificially elevated corticosterone levels, which increase during dehydration, affect behavioral traits linked to water balance. In a labyrinth experiment, we observed the toads' ability to find water in different hydration states (100%, 90%, and 80%). We found that individuals from the invasive population took longer to engage in water-searching behavior and spent more time close to the water source after finding it. Toads from the invasive population were also more active, and at 90% hydration, their attempts to find water increased. Moreover, artificially increasing corticosterone in fully hydrated invasive toads increased water-finding success. Our experiments demonstrated that invasive toads show water-conservation behaviors that can optimize water balance and might facilitate survival in an invaded xeric environment. Additionally, we suggest a link between elevated corticosterone levels and water-finding success. Our results lend support to the importance of behavior in successful invasions and the modulation of water-finding behavior by corticosterone. Significant statement: Invasion success is associated with behavioral and physiological adaptations of invasive species. For anuran species invading xeric habitats, the ability to find water is an important behavioral trait. Using a labyrinth experiment and toads (Sclerophrys gutturalis) dehydrated at different levels, we observed that individuals invading a hydric challenging habitat showed advantageous water-conservation behaviors (e.g., taking longer to engage in water-searching behavior and spent more time close to the water source after finding it) compared to toads from the native range. Transdermal treatment with corticosterone, a hormone that increases its plasma concentrations under dehydration, increased success of finding water in 100% hydrated animals. Our results indicate that, compared to the native population, invasive toads display water-conservation behaviors that might improve survival rates in a novel xeric environment and that experimental corticosterone elevation modulates this water-finding behavior. [ABSTRACT FROM AUTHOR]

Recombinant protein therapeutics, vaccines, and plasma products have a long record of safety. However, the use of cell culture to produce recombinant proteins is still susceptible to contamination with viruses. These contaminations cost millions of dollars to recover from, can lead to patients not receiving therapies, and are very rare, which makes learning from past events difficult. A consortium of biotech companies, together with the Massachusetts Institute of Technology, has convened to collect data on these events. This industry-wide study provides insights into the most common viral contaminants, the source of those contaminants, the cell lines affected, corrective actions, as well as the impact of such events. These results have implications for the safe and effective production of not just current products, but also emerging cell and gene therapies which have shown much therapeutic promise. The Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) provides a comprehensive and forward-looking overview of industry's experience with viral contamination of cell cultures used to produce recombinant proteins. [ABSTRACT FROM AUTHOR]

Next generation sequencing technologies have accelerated the rate at which whole genome sequencing (WGS) data is acquired. The sheer volume of data generated by WGS requires computational annotation to define potential coding regions and chromosomal features. The accuracy of genomic annotation is thus limited by the power of the computational algorithm and the sequence coverage provided by the raw data. Sequencing of the New Zealand White (NZW) rabbit has been performed to a 7× depth of coverage, leaving large gaps in coverage and potential errors within the draft assembly. In the present study, we have resequenced the collagen type I, alpha 1 ( Col1A1) gene of Oryctolagus cuniculus (n = 8). We have characterized the full length cDNA, identified splicing errors within the reference sequence, and identified single nucleotide polymorphisms within the gene. These data underscore the need for a higher resolution assembly of the rabbit genome to advance research in this important large animal model. [ABSTRACT FROM AUTHOR]

The diverse selection pressures driving the evolution of sexual size dimorphism (SSD) have long been debated. Whilst the balance between fecundity selection and sexual selection has received much attention, explanations based on sex-specific ecology have proven harder to test. In ectotherms, females are typically larger than males, and this is frequently thought to be because size constrains female fecundity more than it constrains male mating success. However, SSD could additionally reflect maternal care strategies. Under this hypothesis, females are relatively larger where reproduction requires greater maximum maternal effort-for example where mothers transport heavy provisions to the nests. To test this hypothesis, we focussed on digger wasps (Hymenoptera: Ammophilini), a relatively homogeneous group in which only females provision offspring. In some species, a single large prey item, up to ten times the mother's weight, must be carried to each burrow on foot; other species provide many small prey, each flown individually to the nest. We found more pronounced female-biased SSD in species where females carry single, heavy prey. More generally, SSD was negatively correlated with the numbers of prey provided per offspring. Females provisioning multiple small items had longer wings and thoraxes, probably because smaller prey are carried in flight. Despite much theorising, few empirical studies have tested how sex-biased parental care can affect SSD. Our study reveals that such costs can be associated with the evolution of dimorphism, and this should be investigated in other clades where parental care costs differ between sexes and species. [ABSTRACT FROM AUTHOR]

Pollinating insects are vital to the survival of many primary producers in terrestrial ecosystems, as up to 80-85 % of the world's flowering plants require pollinators for reproduction. Over the last few decades however, numerous pollinating insect populations have declined substantially. The causes of these declines are multifaceted and synergistic, and include pesticides, herbicides, monoculture, urbanization, disease, parasites, and climate change. Here, we present evidence for a generally understudied yet potentially significant source of pollinator mortality, collisions with vehicles. Negative impacts from roads have been observed for the majority of vertebrate groups but studies of the effects on invertebrates have remained largely absent from the scientific literature. We documented road mortality of pollinating insects along a 2 km stretch of highway in Ontario, Canada and used our findings to extrapolate expected levels of road mortality across a number of landscape scales. Our extrapolations demonstrate the potential for loss of hundreds of thousands (on our studied highway) to hundreds of billions (generalised across North America) of Lepidopterans, Hymenopterans and pollinating Dipterans each summer. Our projections of such high levels of annual road mortality highlight the need for research to assess whether the mortality levels observed are contributing to the substantial declines of pollinating insects occurring on a global scale, thus putting the ecological functioning of natural areas and agricultural productivity in jeopardy. [ABSTRACT FROM AUTHOR]

The article presents abstracts on topics including neurotropic human alpha herpes viruses, anatomy of maxillary sinus, and neuroanatomy of larynx.

Wireless sensor networks (WSNs) offer an attractive solution to many environmental, security, and process monitoring problems. However, one barrier to their fuller adoption is the need to supply electrical power over extended periods of time without the need for dedicated wiring. Energy harvesting provides a potential solution to this problem in many applications. This paper reviews the characteristics and energy requirements of typical sensor network nodes, assesses a range of potential ambient energy sources, and outlines the characteristics of a wide range of energy conversion devices. It then proposes a method to compare these diverse sources and conversion mechanisms in terms of their normalised power density. [ABSTRACT FROM AUTHOR]

The human major histocompatibility complex (MHC) is contained within about 4 Mb on the short arm of chromosome 6 and is recognised as the most variable region in the human genome. The primary aim of the MHC Haplotype Project was to provide a comprehensively annotated reference sequence of a single, human leukocyte antigen-homozygous MHC haplotype and to use it as a basis against which variations could be assessed from seven other similarly homozygous cell lines, representative of the most common MHC haplotypes in the European population. Comparison of the haplotype sequences, including four haplotypes not previously analysed, resulted in the identification of >44,000 variations, both substitutions and indels (insertions and deletions), which have been submitted to the dbSNP database. The gene annotation uncovered haplotype-specific differences and confirmed the presence of more than 300 loci, including over 160 protein-coding genes. Combined analysis of the variation and annotation datasets revealed 122 gene loci with coding substitutions of which 97 were non-synonymous. The haplotype (A3-B7-DR15; PGF cell line) designated as the new MHC reference sequence, has been incorporated into the human genome assembly (NCBI35 and subsequent builds), and constitutes the largest single-haplotype sequence of the human genome to date. The extensive variation and annotation data derived from the analysis of seven further haplotypes have been made publicly available and provide a framework and resource for future association studies of all MHC-associated diseases and transplant medicine. [ABSTRACT FROM AUTHOR]

Lentiviral vectors have received much attention in recent years due to their ability to efficiently transduce non-dividing cells. Of the lentiviruses HIV-2 and SIV offer several unique benefits as the basis for lentiviral vector design. HIV-1, HIV-2 and SIV remain the only known primate lentiviruses, and consequently are among the most extensively studied viruses known. Substantial effort has been devoted towards identifying the pathogenic determinants of the primate lentiviruses and towards understanding their replication within primates. Of the primate lentiviruses, the pathogenicity and rates of transmission of HIV-2 and SIV fall far below that of HIV-1, potentially providing vectors based upon HIV-2/SIV with a greater degree of biosafety. Last, and perhaps most importantly, HIV-2 and SIV are viruses which may be studied within non-human primate models susceptible to AIDS-like disease, making vectors based upon these viruses accessible to substantial preclinical evaluation. We approach this Chapter presenting information regarding the basic biology of HIV-2 and SIV and conclude by pointing to how unique features of HIV-2 and SIV are well suited to vector design, hoping to leave the reader with a greater appreciation of the potential these viruses offer within the field of gene transfer applications. [ABSTRACT FROM AUTHOR]

The SCL gene encodes a highly conserved bHLH transcription factor with a pivotal role in hemopoiesis and vasculogenesis. We have sequenced and analyzed 320 kb of genomic DNA composing the SCL loci from human, mouse, and chicken. Long-range sequence comparisons demonstrated multiple peaks of human/mouse homology, a subset of which corresponded precisely with known SCL enhancers. Comparisons between mammalian and chicken sequences identified some, but not all, SCL enhancers. Moreover, one peak of human/mouse homology (+23 region), which did not correspond to a known enhancer, showed significant homology to an analogous region of the chicken SCL locus. A transgenic Xenopus reporter assay was established and demonstrated that the +23 region contained a new neural enhancer. This combination of long-range comparative sequence analysis with a high-throughput transgenic bioassay provides a powerful strategy for identifying and characterizing developmentally important enhancers. [ABSTRACT FROM AUTHOR]

The article questions the validity and reliability of evidence provided by J.N. Pruitt and C.J. Goodnight to support their claims of group selection causing genetic changes over generations in spiders. Topics include Pruitt and Goodnight's failure to evaluate individual-level selection in comparison to group selection in the spiders, inconsistencies in the years of measurement and the resource sites used, and their failure to consider changes within generations such as colony size.

Presents a specific program for continuous improvement toward instructional excellence in classroom teaching which is based on total quality management. Quality defined by customer; Top leadership responsibility; Systematic analysis of work processes; Continuous effort conducted throughout the organization.

Polycythemia vera (PV) is an acquired clonal disorder characterized by increased production of mature red cells and growth of erythroid colonies in the absence of erythropoietin. Mutation of the erythropoietin receptor has been demonstrated to cause familial polycythemia, but no mutations have been found in PV. Moreover, both erythroid and myeloid progenitors from patients with PV have been reported to be hypersensitive to a number of different growth factors. Attention has therefore focused on post-receptor signal transduction pathways. The SHP-1 gene is an especially attractive candidate gene. Firstly, SHP-1 binds to and negatively regulates signalling from the erythropoietin receptor and is likely to regulate other cytokine receptors in a similar manner. Secondly, absence of SHP-1 protein in the motheaten mouse is accompanied by increased sensitivity of hematopoietic progenitors to a number of cytokines including erythropoietin. Thirdly, familial or sporadic polycythemia in man may result from mutations of the SHP-1 binding domain of the erythropoietin receptor. We have therefore searched for mutations of the SHP-1 gene in genomic DNA from patients with PV. In this disease the majority of peripheral blood lymphocytes are not part of the malignant clone and a variable proportion of myeloid cells may arise from normal progenitors. We have therefore chosen to study DNA from purified peripheral blood granulocytes obtained from nine women in whom the granulocytes were clonally derived. Southern analysis was used to show that the gene was not rearranged and densitometry confirmed the presence of two copies of the gene in each DNA sample. Sequencing of the entire coding region and all splice junctions revealed no mutations. Hematopoietic transcription factor binding sites in the SHP-1 promoter region were intact and the methylation status of the two SHP-1 promoters in PV patients was identical to that in three normal controls. Finally, we showed that levels of... [ABSTRACT FROM AUTHOR]

Although the topic of rural crime has received relatively little attention in traditional criminal justice research, the more specialized subtopic of rural criminal investigation has received even less. As criminological research and public attention begin to focus upon rural crime due to its rapid growth, rural police agencies will need to assess their investigative attitudes and resources in an effort to reduce accelerating crime rates. This paper surveyed the attitudes of 52 rural sheriffs in an effort to gather information necessary to assess needs and attitudes unique to the rural investigation. [ABSTRACT FROM AUTHOR]

A straightforward and reliable method to determine densities of molten salts at high temperatures was de-veloped by Janz and Lorenz several years ago. This method was followed in order to determine the density of the LiF/LiS eutectic over the temperature range of 1176 to 1355 K in which the eutectic is liquid. The rel-ative lack of data for this eutectic is surprising given its potential usefulness in the study of advanced batteries'31 and electrowinning of metals from molten sulfides. The method is based on the fact that a solid piece of metal of known volume suspended from a pan balance into a molten salt will weigh less than if it were sus-pended in air at the same temperature. This difference in weight measured in grams will be equal to the buoyant force of the liquid at that temperature. The density of the salt bath can then readily be determined by dividing this difference by the volume of the solid piece of metal that is immersed in the bath. The procedure can be re-peated to give density values over a range of temperatures. [ABSTRACT FROM AUTHOR]

Urban environments are novel landscapes that markedly alter animal behavior. Divergence in behavior in response to urbanization may provide advantages in navigation, exploiting resources, and surviving under a novel suite of selective pressures. Relatively few studies, however, have identified population-level behavioral changes in response to urbanization that are not confounded by rearing environment and prior experience (e.g., an urban upbringing). To address this, we used the Australian water dragon (Intellagama lesueurii) to test whether populations under varying levels of urbanization (urban, semi-natural, and natural populations) differ in their innate behavioral traits; acquired either heritably or due to population-specific maternal effects. Eggs were collected from wild mothers and hatched in the lab. Hatchlings were then reared in the lab under standardized conditions (a common-garden experiment). We then assayed individual behavioral traits (boldness, exploration, and neophilia) five times across their first year of development. We compared behavioral traits, as well as their expression (repeatability), between urban, semi-natural, and natural populations. Neophilia and explorative behavior was similar among all populations. However, dragons from semi-natural populations were significantly bolder than those from natural populations. Urban dragons were also bolder than dragons from natural populations, although this trend was not significant because of high variance in boldness. Dragons from semi-natural and urban populations had similar boldness scores, suggesting a potentially biologically relevant difference in boldness between them and natural populations. We also saw some differences in the consistency of the expression of behavior. Boldness in individuals from urban environments was also the only repeatable trait. Overall, our study suggests that boldness is an innate, urban-derived divergent behavioral trait that likely contributes to the success of these lizards in anthropogenically altered environments. Significance statement: Lizards from human-modified areas are innately bolder than ones from natural habitats. To determine this, we raised lizards from eggs collected from urban, semi-natural, and natural populations in a standardized environment, removing the effects of prior experience and developmental environment, and examined their behavioral traits over time. The difference we found in boldness was related to their origin population, rather than being shaped through experience, suggesting this trait may be heritable and is being selected for in anthropogenic landscapes. Our study addresses an important gap in studies of urban behavioral ecology by examining behavioral differences among replicated, differently urbanized, sites after experimentally accounting for both rearing environment and prior experience. [ABSTRACT FROM AUTHOR]

Esophageal adenocarcinoma (EAC) incidence is increasing while 5-year survival rates remain less than 15%. A lack of experimental models has hampered progress. We have generated clinically annotated EAC organoid cultures that recapitulate the morphology, genomic, and transcriptomic landscape of the primary tumor including point mutations, copy number alterations, and mutational signatures. Karyotyping of organoid cultures has confirmed polyclonality reflecting the clonal architecture of the primary tumor. Furthermore, subclones underwent clonal selection associated with driver gene status. Medium throughput drug sensitivity testing demonstrates the potential of targeting receptor tyrosine kinases and downstream mediators. EAC organoid cultures provide a pre-clinical tool for studies of clonal evolution and precision therapeutics. Esophageal adenocarcinoma (EAC) has a poor 5-year survival rate and lacks robust preclinical models for use in research. Here, the authors show that newly derived organoids recapitulate the transcriptomic, genetic, and morphological landscape of the primary EAC tumors and provide a platform to test drug sensitivity and study tumor clonality. [ABSTRACT FROM AUTHOR]

Abstract: Innate antipredator responses are integral for survival in many species, particularly those which lack parental care. Antipredator responses include both active (fight or flight) and passive behaviours (immobility). As the success of antipredator responses directly relates to survival and fitness, investigating the drivers that explain variance in these traits is key to understanding how predation shapes the instinctive behaviour of animals. We quantified innate antipredator behaviour of hatchling Australian water dragons (Intellagama lesueurii) immediately after hatching using a model snake to simulate a series of attacks, and scored their behaviour using a fight or flight index. Then we explored which factors were related to dragon antipredator behaviour, such as habitat disturbance, origin population, morphology, and parental genetic effects and phenotype (clutch effects). We developed multiple hypotheses and used model selection to determine which factors drive variation in hatchling antipredator behaviour. Clutch effects explained a significant proportion of variation in innate antipredator responses, suggesting a heritable component. We also found an effect of body size on innate antipredator behaviour: larger hatchlings were more prone to flight behaviour (e.g. short-distance runs and long-distance sprinting), while smaller individuals were more prone to standing their ground and being aggressive (e.g. throat puffing, mouth gaping, biting). Clutch effects also explained a significant proportion of the variance in dragon body size. Our study provides evidence that the innate antipredator responses of water dragons are heritable in origin (directly through clutch effects, and indirectly through body size) and not associated with particular populations or habitat types. We suggest future research examine the survival implications of these responses.Significance statement: The action an animal takes in response to a predator is a life or death decision, and can be required immediately after birth. These innate antipredator behaviours may be genetically linked, and enable individuals to emerge into their environment with the necessary behaviour to promote survival. We examined what factors drive hatchling lizards to exhibit different innate antipredator behaviour. Our study found that body size affected their innate behaviour: larger hatchlings were more prone to flee and smaller hatchlings were more likely to fight. Interestingly, parental genetics and phenotype (clutch effects) also significantly explained the variation in innate antipredator behaviour, which supports the hypothesis that these behaviours are heritable. Understanding what drives variation is a cornerstone of evolutionary biology, and our findings raise questions about how selection acts on antipredator behaviour and the degree to which they are plastic. [ABSTRACT FROM AUTHOR]

Comments on the book 'Beginning Perl for Bioinformatics,' by James Tisdall. Language for text manipulation and report generation; Object-oriented programming techniques.

Sports-related concussions and repetitive subconcussive exposure are increasingly recognized as potential dangers to paediatric populations, but much remains unknown about the short-term and longterm consequences of these events, including potential cognitive impairment and risk of later-life dementia. This Expert Consensus Document is the result of a 1-day meeting convened by Safe Kids Worldwide, the Alzheimer's Drug Discovery Foundation, and the Andrews Institute for Orthopaedics and Sports Medicine. The goal is to highlight knowledge gaps and areas of critically needed research in the areas of concussion science, dementia, genetics, diagnostic and prognostic biomarkers, neuroimaging, sports injury surveillance, and information sharing. For each of these areas, we propose clear and achievable paths to improve the understanding, treatment and prevention of youth sports-related concussions. [ABSTRACT FROM AUTHOR]