G-quadruplex DNA motifs in the malaria parasite Plasmodium falciparum and their potential as novel antimalarial drug targets

G-quadruplexes are DNA or RNA secondary structures that can be formed from guanine-rich nucleic acids. These four-stranded structures, composed of stacked quartets of guanine bases, can be highly stable and have been demonstrated to occur in vivo in the DNA of human cells and other systems, where they play important biological roles, influencing processes such as telomere maintenance, DNA replication and transcription, or, in the case of RNA G-quadruplexes, RNA translation and processing. We report for the first time that DNA G-quadruplexes can be detected in the nuclei of the malaria parasite Plasmodium falciparum, which has one of the most A/T-biased genomes sequenced and therefore possesses few guanine-rich sequences with the potential to form G-quadruplexes. We show that despite this paucity of putative G-quadruplex-forming sequences, P. falciparum parasites are sensitive to several G-quadruplex-stabilizing drugs, including quarfloxin, which previously reached phase 2 clinical trials as an anticancer drug. Quarfloxin has a rapid initial rate of kill and is active against ring stages as well as replicative stages of intraerythrocytic development. We show that several G-quadruplex-stabilizing drugs, including quarfloxin, can suppress the transcription of a G-quadruplex-containing reporter gene in P. falciparum but that quarfloxin does not appear to disrupt the transcription of rRNAs, which was proposed as its mode of action in both human cells and trypanosomes. These data suggest that quarfloxin has potential for repositioning as an antimalarial with a novel mode of action. Furthermore, G-quadruplex biology in P. falciparum may present a target for development of other new antimalarial drugs

Development and validation of a risk calculator for major mood disorders among the offspring of bipolar parents using information collected in routine clinical practice.

Family history is a significant risk factor for bipolar disorders (BD), but the magnitude of risk varies considerably between individuals within and across families. Accurate risk estimation may increase motivation to reduce modifiable risk exposures and identify individuals appropriate for monitoring over the peak risk period. Our objective was to develop and independently replicate an individual risk calculator for bipolar spectrum disorders among the offspring of BD parents using data collected in routine clinical practice. Data from the longitudinal Canadian High-Risk Offspring cohort study collected from 1996 to 2020 informed the development of a 5 and 10-year risk calculator using parametric time-to-event models with a cure fraction and a generalized gamma distribution. The calculator was then externally validated using data from the Lausanne-Geneva High-Risk Offspring cohort study collected from 1996 to 2020. A time-varying C-index by age in years was used to estimate the probability that the model correctly classified risk. Bias corrected estimates and 95% confidence limits were derived using a jackknife resampling approach. The primary outcome was age of onset of a major mood disorder. The risk calculator was most accurate at classifying risk in mid to late adolescence in the Canadian cohort (n = 285), and a similar pattern was replicated in the Swiss cohort (n = 128). Specifically, the time-varying C-index indicated that there was approximately a 70% chance that the model would correctly predict which of two 15-year-olds would be more likely to develop the outcome in the future. External validation within a smaller Swiss cohort showed mixed results. Findings suggest that this model may be a useful clinical tool in routine practice for improved individualized risk estimation of bipolar spectrum disorders among the adolescent offspring of a BD parent; however, risk estimation in younger high-risk offspring is less accurate, perhaps reflecting the evolving nature of psychopathology in early childhood. Based on external validation with a Swiss cohort, the risk calculator may not be as predictive in more heterogenous high-risk populations. The Canadian High-Risk Study has been funded by consecutive operating grants from the Canadian Institutes for Health Research, currently CIHR PJT Grant 152796 he Lausanne-Geneva high-risk study was and is supported by five grants from the Swiss National Foundation (#3200-040,677, #32003B-105,969, #32003B-118,326, #3200-049,746 and #3200-061,974), three grants from the Swiss National Foundation for the National Centres of Competence in Research project "The Synaptic Bases of Mental Diseases" (#125,759, #158,776, and #51NF40 - 185,897), and a grant from GlaxoSmithKline Clinical Genetics

Arithmetically Cohen-Macaulay Bundles on complete intersection varieties of sufficiently high multidegree

Recently it has been proved that any arithmetically Cohen-Macaulay (ACM) bundle of rank two on a general, smooth hypersurface of degree at least three and dimension at least four is a sum of line bundles. When the dimension of the hypersurface is three, a similar result is true provided the degree of the hypersurface is at least six. We extend these results to complete intersection subvarieties by proving that any ACM bundle of rank two on a general, smooth complete intersection subvariety of sufficiently high multi-degree and dimension at least four splits. We also obtain partial results in the case of threefolds.Comment: 15 page

No downregulation of immune function during breeding in two year-round breeding bird species in an equatorial East African environment

Some equatorial environments exhibit substantial within-location variation in environmental conditions throughout the year and yet have year-round breeding birds. This implies that breeding in such systems are potentially unrelated to the variable environmental conditions. By breeding not being influenced by environmental conditions, we become sure that any differences in immune function between breeding and non-breeding birds do not result from environmental variation, therefore allowing for exclusion of the confounding effect of variation in environmental conditions. This create a unique opportunity to test if immune function is down-regulated during reproduction compared to non-breeding periods. We compared the immune function of sympatric male and female chick-feeding and non-breeding red-capped Calandrella cinerea and rufous-naped larks Mirafra africana in equatorial East Africa. These closely-related species occupy different niches and have different breeding strategies in the same grassland habitat. Red-capped larks prefer areas with short grass or almost bare ground, and breed during low rainfall periods. Rufous-naped larks prefer areas of tall grass and scattered shrubs and breed during high rainfall. We measured the following immune indices: nitric oxide, haptoglobin, agglutination and lysis, and measured total monthly rain, monthly average minimum (T-min) and maximum (T-max) temperatures. Contrary to our predictions, we found no down-regulation of immune function during breeding; breeding birds had higher nitric oxide than non-breeding ones in both species, while the other three immune indices did not differ between breeding phases. Red-capped larks had higher nitric oxide concentrations than Rufous-naped larks, which in turn had higher haptoglobin levels than red-capped larks. T-max was higher during breeding than during non-breeding for red-capped larks only, suggesting potential confounding effect of T-max on the comparison of immune function between breeding and non-breeding birds for this species. Overall, we conclude that in the two year-round breeding equatorial larks, immune function is not down-regulated during breeding

Why and how to apply Weber's Law to coevolution and mimicry

Abstract: In mimicry systems, receivers discriminate between the stimuli of models and mimics. Weber's Law of proportional processing states that receiver discrimination is based on proportional, not absolute, differences between stimuli. Weber's Law operates in a variety of taxa and modalities, yet it has largely been ignored in the context of mimicry, despite its potential relevance to whether receivers can discriminate models from mimics. Specifically, Weber's Law implies that for a given difference in stimulus magnitude between a model and mimic, as stimulus magnitudes increase, the mimic will be less discriminable from their model. This implies that mimics should benefit when stimulus magnitudes are high, and that high stimulus magnitudes will reduce selection for mimetic fidelity. Whether models benefit from high stimulus magnitudes depends on whether mimicry is honest or deceptive. We present four testable predictions about evolutionary trajectories of models and mimics based on this logic. We then provide a framework for testing whether receiver discrimination adheres to Weber's Law and illustrate it using coevolutionary examples and case studies from avian brood parasitism. We conclude that, when studying mimicry systems, researchers should consider whether receiver perception conforms to Weber's Law, because it could drive stimulus evolution in counterintuitive directions

Fabrication and characterization of dual function nanoscale pH-scanning ion conductance microscopy (SICM) probes for high resolution pH mapping

The easy fabrication and use of nanoscale dual function pH-scanning ion conductance microscopy (SICM) probes is reported. These probes incorporate an iridium oxide coated carbon electrode for pH measurement and an SICM barrel for distance control, enabling simultaneous pH and topography mapping. These pH-SICM probes were fabricated rapidly from laser pulled theta quartz pipets, with the pH electrode prepared by in situ carbon filling of one of the barrels by the pyrolytic decomposition of butane, followed by electrodeposition of a thin layer of hydrous iridium oxide. The other barrel was filled with an electrolyte solution and Ag/AgCl electrode as part of a conductance cell for SICM. The fabricated probes, with pH and SICM sensing elements typically on the 100 nm scale, were characterized by scanning electron microscopy, energy-dispersive X-ray spectroscopy, and various electrochemical measurements. They showed a linear super-Nernstian pH response over a range of pH (pH 2–10). The capability of the pH-SICM probe was demonstrated by detecting both pH and topographical changes during the dissolution of a calcite microcrystal in aqueous solution. This system illustrates the quantitative nature of pH-SICM imaging, because the dissolution process changes the crystal height and interfacial pH (compared to bulk), and each is sensitive to the rate. Both measurements reveal similar dissolution rates, which are in agreement with previously reported literature values measured by classical bulk methods

Using contractual incentives in district nursing in the English NHS: results from a qualitative study

© 2018 The author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Since 2008, health policy in England has been focusing increasingly on improving quality in healthcare services. To ensure quality improvements in community nursing, providers are required to meet several quality targets, including an incentive scheme known as Commissioning for Quality and Innovation (CQUIN). This paper reports on a study of how financial incentives are used in district nursing, an area of care which is particularly difficult to measure and monitor

Ontologies, Mental Disorders and Prototypes

As it emerged from philosophical analyses and cognitive research, most concepts exhibit typicality effects, and resist to the efforts of defining them in terms of necessary and sufficient conditions. This holds also in the case of many medical concepts. This is a problem for the design of computer science ontologies, since knowledge representation formalisms commonly adopted in this field do not allow for the representation of concepts in terms of typical traits. However, the need of representing concepts in terms of typical traits concerns almost every domain of real world knowledge, including medical domains. In particular, in this article we take into account the domain of mental disorders, starting from the DSM-5 descriptions of some specific mental disorders. On this respect, we favor a hybrid approach to the representation of psychiatric concepts, in which ontology oriented formalisms are combined to a geometric representation of knowledge based on conceptual spaces

A program of nurse algorithm-guided care for adult patients with acute minor illnesses in primary care

Background: Attention to patients with acute minor-illnesses requesting same-day consultation represents a major burden in primary care. The workload is assumed by general practitioners in many countries. A number of reports suggest that care to these patients may be provided, at in least in part, by nurses. However, there is scarce information with respect to the applicability of a program of nurse management for adult patients with acute minor-illnesses in large areas. The aim of this study is to assess the effectiveness of a program of nurse algorithm-guided care for adult patients with acute minor illnesses requesting same-day consultation in primary care in a largely populated area. Methods: A cross-sectional study of all adult patients seeking same day consultation for 16 common acute minor illnesses in a large geographical area with 284 primary care practices. Patients were included in a program of nurse case management using management algorithms. The main outcome measure was case resolution, defined as completion of the algorithm by the nurse without need of referral of the patient to the general practitioner. The secondary outcome measure was return to consultation, defined as requirement of new consultation for the same reason as the first one, in primary care within a 7-day period. Results: During a two year period (April 2009-April 2011), a total of 1,209,669 consultations were performed in the program. Case resolution was achieved by nurses in 62.5% of consultations. The remaining cases were referred to a general practitioner. Resolution rates ranged from 94.2% in patients with burns to 42% in patients with upper respiratory symptoms. None of the 16 minor illnesses had a resolution rate below 40%. Return to consultation during a 7-day period was low, only 4.6%. Conclusions: A program of algorithms-guided care is effective for nurse case management of patients requesting same day consultation for minor illnesses in primary care

Eggshell composition and surface properties of avian brood-parasitic species compared with non-parasitic species

The eggs of avian obligate brood-parasitic species have multiple adaptations to deceive hosts and optimize development in host nests. While the structure and composition of the eggshell in all birds is essential for embryo growth and protection from external threats, parasitic eggs may face specific challenges such as high microbial loads, rapid laying and ejection by the host parents. We set out to assess whether eggshells of avian brood-parasitic species have either (i) specialized structural properties, to meet the demands of a brood-parasitic strategy or (ii) similar structural properties to eggs of their hosts, due to the similar nest environment. We measured the surface topography (roughness), wettability (how well surfaces repel water) and calcium content of eggshells of a phylogenetically and geographically diverse range of brood-parasitic species (representing four of the seven independent lineages of avian brood-parasitic species), their hosts and close relatives of the parasites. These components of the eggshell structure have been demonstrated previously to influence such factors as the risk of microbial infection and overall shell strength. Within a phylogenetically controlled framework, we found no overall significant differences in eggshell roughness, wettability and calcium content between (i) parasitic and non-parasitic species, or (ii) parasitic species and their hosts. Both the wettability and calcium content of the eggs from brood-parasitic species were not more similar to those of their hosts' eggs than expected by chance. By contrast, the mean surface roughness of the eggs of brood-parasitic species was more similar to that of their hosts’ eggs than expected by chance, suggesting brood-parasitic species may have evolved to lay eggs that match the host nest environment for this trait. The lack of significant overall differences between parasitic and non-parasitic species, including hosts, in the traits we measured, suggests that phylogenetic signal, as well as general adaptations to the nest environment and for embryo development, outweigh any influence of a parasitic lifestyle on these eggshell properties