Subtle changes in crosslinking drive diverse anomalous transport characteristics in actin-microtubule networks.

Anomalous diffusion in crowded and complex environments is widely studied due to its importance in intracellular transport, fluid rheology and materials engineering. Specifically, diffusion through the cytoskeleton, a network comprised of semiflexible actin filaments and rigid microtubules that interact both sterically and via crosslinking, plays a principal role in viral infection, vesicle transport and targeted drug delivery. Here, we elucidate the impact of crosslinking on particle diffusion in composites of actin and microtubules with actin-actin, microtubule-microtubule and actin-microtubule crosslinking. We analyze a suite of transport metrics by coupling single-particle tracking and differential dynamic microscopy. Using these complementary techniques, we find that particles display non-Gaussian and non-ergodic subdiffusion that is markedly enhanced by cytoskeletal crosslinking, which we attribute to suppressed microtubule mobility. However, the extent to which transport deviates from normal Brownian diffusion depends strongly on the crosslinking motif - with actin-microtubule crosslinking inducing the most pronounced anomalous characteristics. Our results reveal that subtle changes to actin-microtubule interactions can have complex impacts on particle diffusion in cytoskeleton composites, and suggest that a combination of reduced filament mobility and more variance in actin mobilities leads to more strongly anomalous particle transport.

Leishmanicidal Effects of Piperlongumine (Piplartine) and Its Putative Metabolites.

Piperlongumine is an amide alkaloid found in Piperaceae species that shows a broad spectrum of biological properties, including antitumor and antiparasitic activities. Herein, the leishmanicidal effect of piperlongumine and its derivatives produced by a biomimetic model using metalloporphyrins was investigated. The results showed that IC50 values of piperlongumine in promastigote forms of Leishmania infantum and Leishmania amazonensis were 7.9 and 3.3 µM, respectively. The IC50 value of piperlongumine in the intracellular amastigote form of L. amazonensis was 0.4 µM, with a selectivity index of 25. The piperlongumine biomimetic derivatives, Ma and Mb, also showed leishmanicidal effects. We also carried out an in vitro metabolic degradation study showing that Ma is the most stable piperlongumine derivative in rat liver microsome incubations. The results presented here indicate that piperlongumine is a potential leishmanicidal candidate and support the biomimetic approach for development of new antileishmanial derivatives.

K-complexes, spindles, and ERPs as impulse responses: unification via neural field theory.

To interrelate K-complexes, spindles, evoked response potentials (ERPs), and spontaneous electroencephalography (EEG) using neural field theory (NFT), physiology-based NFT of the corticothalamic system is used to model cortical excitatory and inhibitory populations and thalamic relay and reticular nuclei. The impulse response function of the model is used to predict the responses to impulses, which are compared with transient waveforms in sleep studies. Fits to empirical data then allow underlying brain physiology to be inferred and compared with other waves. Spontaneous K-complexes, spindles, and other transient waveforms can be reproduced using NFT by treating them as evoked responses to impulsive stimuli with brain parameters appropriate to spontaneous EEG in sleep stage 2. Using this approach, spontaneous K-complexes and sleep spindles can be analyzed using the same single theory as previously been used to account for waking ERPs and other EEG phenomena. As a result, NFT can explain a wide variety of transient waveforms that have only been phenomenologically classified to date. This enables noninvasive fitting to be used to infer underlying physiological parameters. This physiology-based model reproduces the time series of different transient EEG waveforms; it has previously reproduced experimental EEG spectra, and waking ERPs, and many other observations, thereby unifying transient sleep waveforms with these phenomena.

In Vitro Inhibition of Human CYP450s 1A2, 2C9, 3A4/5, 2D6 and 2E1 by Grandisin.

Grandisin, a lignan isolated from many species of plants, such as Virola surinamensis, is a potential drug candidate due to its biological properties, highlighted by its antitumor and trypanocidal activities. In this study, the inhibitory effects of grandisin on the activities of human cytochrome P450 enzymes were investigated by using human liver microsomes. Results showed that grandisin is a competitive inhibitor of CYP2C9 and a competitive and mechanism-based inhibitor of CYP3A4/5. The apparent Ki value for CYP2C9 was 50.60 µM and those for CYP3A4/5 were 48.71 µM and 31.25 µM using two different probe substrates, nifedipine and midazolam, respectively. The apparent KI, kinact, and kinact/KI ratio for the mechanism-based inhibition of CYP3A4/5 were 6.40 µM, 0.037 min-1, and 5.78 mL ·â€Šmin-1 µmol-1, respectively, by examining nifedipine oxidation, and 31.53 µM, 0.049 min-1, and 1.55 mL ·â€Šmin-1 µmol-1, respectively, by examining midazolam 1'-hydroxylation. These apparent kinact/KI values were comparable to or even higher than those for several therapeutic drugs that act as mechanism-based inhibitors of CYP3A4/5. CYP1A2 and CYP2D6 activities, in turn, were not substantially inhibited by grandisin (IC50 > 200 µM and 100 µM, respectively). In contrast, from a concentration of 4 µM, grandisin significantly stimulated CYP2E1 activity. These results improve the prediction of grandisin-drug interactions, suggesting that the risk of interactions with drugs metabolized by CYP3A4/5 and CYP2E1 cannot be overlooked.

In vitro metabolism of monensin A: microbial and human liver microsomes models.

1. Monensin A, an important antibiotic ionophore that is primarily employed to treat coccidiosis, selectively complexes and transports sodium cations across lipid membranes and displays a variety of biological properties. 2. In this study, we evaluated the fungi Cunninghamella echinulata var. elegans ATCC 8688A, Cunninghamella elegans NRRL 1393 ATCC 10028B and human hepatic microsomes as CYP-P450 models to investigate the in vitro metabolism of monensin A and compare the products with the metabolites produced in vivo. 3. Mass spectrometry analysis of the products from these model systems revealed the formation of three metabolites: 3-O-demethyl monensin A, 12-hydroxy monensin A and 12-hydroxy-3-O-demethyl monensin A. We identified these products by tandem mass spectrometry and through comparison with the in vivo metabolites. 4. This analysis demonstrated that the model systems produce the same metabolites found in in vivo studies, thus they could be used to predict the metabolism of monensin A. Furthermore, we verified that liquid chromatography coupled to mass spectrometry is a powerful tool to study the in vitro metabolism of drugs, because it allows the successful identifications of several derivatives from different metabolic models.

Positive sexuality and its impact on overall well-being.

Historically, the issue of sexual health has been largely considered with respect to the associated negative health outcomes. The dangers of sexual activity such as sexually transmitted infections (STIs), HIV/AIDS, unintended pregnancy, sexual coercion, and sexual violence have dominated the attention of those working in the field. Over the last 20 years, and particularly in the last decade, an increasing number of people from a variety disciplines that address issues of sexual health have developed a new discourse concerning the positive aspects of sexuality. This review of the literature explores this emerging discourse. The results indicate that sexual health, physical health, mental health, and overall well-being are all positively associated with sexual satisfaction, sexual self-esteem, and sexual pleasure. The beneficial effects of sexual satisfaction should be integrated into programs that seek to improve these diverse health outcomes through service delivery, prevention, and sexuality education.

Patterns of individual compliance with anthelmintic treatment for soil-transmitted helminth infections in southern Ethiopia over six rounds of community-wide mass drug administration.

BACKGROUND: The mainstay of soil-transmitted helminth (STH) control is repeated mass drug administration (MDA) of anthelmintics to endemic populations. Individual longitudinal compliance treatment patterns are important for identifying pockets of infected individuals who remain untreated and serve as infection reservoirs. METHODS: The Geshiyaro Project censused the study population in Wolaita, Ethiopia at baseline in 2018. Individual longitudinal compliance was recorded for six rounds of community-wide MDA (cMDA). The probability distribution of treatment frequency was analysed by age and gender stratifications. Probabilities of transmission interruption for different compliance patterns were calculated using an individual-based stochastic model of Ascaris lumbricoides transmission. RESULTS: The never-treated (0.42%) population was smaller than expected from a random positive binomial distribution. The observed compliance frequency was well described by the beta-binomial distribution. Preschool-age children (odds ratio [OR] 10.1 [95% confidence interval {CI} 6.63 to 15.4]) had the highest never-treated proportion of the age groups. Conversely, school-age children (SAC) and adults (OR 1.03 [95% CI 0.98 to 1.09]) had the highest always-treated proportion of the age groups. CONCLUSIONS: The study reports the largest dataset of individual longitudinal compliance to cMDA for STH control. Clear pattens are shown in the age-dependent distribution of individual compliance behaviour. The impact of compliance on the probability of elimination is significant, highlighting the importance of recording the full frequency distribution, not just the never-treated proportion.

Topological digestion drives time-varying rheology of entangled DNA fluids.

Understanding and controlling the rheology of polymeric complex fluids that are pushed out-of-equilibrium is a fundamental problem in both industry and biology. For example, to package, repair, and replicate DNA, cells use enzymes to constantly manipulate DNA topology, length, and structure. Inspired by this feat, here we engineer and study DNA-based complex fluids that undergo enzymatically-driven topological and architectural alterations via restriction endonuclease (RE) reactions. We show that these systems display time-dependent rheological properties that depend on the concentrations and properties of the comprising DNA and REs. Through time-resolved microrheology experiments and Brownian Dynamics simulations, we show that conversion of supercoiled to linear DNA topology leads to a monotonic increase in viscosity. On the other hand, the viscosity of entangled linear DNA undergoing fragmentation displays a universal decrease that we rationalise using living polymer theory. Finally, to showcase the tunability of these behaviours, we design a DNA fluid that exhibits a time-dependent increase, followed by a temporally-gated decrease, of its viscosity. Our results present a class of polymeric fluids that leverage naturally occurring enzymes to drive diverse time-varying rheology by performing architectural alterations to the constituents.

Enantioselective fungal biotransformation of risperidone in liquid culture medium by capillary electrophoresis and hollow fiber liquid-phase microextraction.

Knowing that microbial transformations of compounds play vital roles in the preparation of new derivatives with biological activities, risperidone and its chiral metabolites were determined by capillary electrophoresis and hollow fiber liquid-phase microextraction after a fungal biotransformation study in liquid culture medium. The analytes were extracted from 1 mL liquid culture medium into 1-octanol impregnated in the pores of the hollow fiber, and into an acid acceptor solution inside the polypropylene hollow fiber. The electrophoretic separations were carried out in 100 mmol/L sodium phosphate buffer pH 3.0 containing 2.0% w/v sulfated-α-CD and carboxymethyl-ß-CD 0.5% w/v with a constant voltage of -10 kV. The method was linear over the concentration range of 100-5000 ng/mL for risperidone and 50-5000 ng/mL for each metabolite enantiomer. Within-day and between-day assay precisions and accuracies for all the analytes were studied at three concentration levels, and the values of relative standard deviation and relative error were lower than 15%. The developed method was applied in a pilot biotransformation study employing risperidone as the substrate and the filamentous fungus Mucor rouxii. This study showed that the filamentous fungus was able to metabolize risperidone enantioselectively into its chiral active metabolite, (-)-9-hydroxyrisperidone.

The maintenance of strain structure in populations of recombining infectious agents.

Using mathematical models that combine population genetic and epidemiological processes, we resolve the paradox that many important pathogens appear to persist as discrete strains despite the constant exchange of genetic material. We show that dominant polymorphic determinants (that is, those that elicit the most effective immune responses) will be organized into nonoverlapping combinations as a result of selection by the host immune system, thereby defining a set of discrete independently transmitted strains. By analysing 222 isolates of Neisseria meningitidis, we show that two highly polymorphic epitopes of the outer membrane protein PorA exist in nonoverlapping combinations as predicted by this general framework. The model indicates that dominant polymorphic determinants will be in linkage disequilibrium, despite frequent genetic exchange, even though they may be encoded by several unlinked genes. This suggests that the detection of nonrandom associations between epitope regions can be employed as a novel strategem for identifying dominant polymorphic antigens.

Dynamic transmission models and economic evaluations of pneumococcal conjugate vaccines: a quality appraisal and limitations.

BACKGROUND: Of over 90 serotypes of Streptococcus pneumoniae, only seven were included in the first pneumococcal conjugate vaccine (PCV). While PCV reduced the disease incidence, in part because of a herd immunity effect, a replacement effect was observed whereby disease was increasingly caused by serotypes not included in the vaccine. Dynamic transmission models can account for these effects to describe post-vaccination scenarios, whereas economic evaluations can enable decision-makers to compare vaccines of increasing valency for implementation. AIM: The aim of this review was to examine epidemiological and economic models and their assumptions for their potential contributions to future research and immunisation policy. SOURCES: Pubmed, Scopus, Ovid, ISI Web of Knowledge, Centre of Reviews and Dissemination (CRD) databases were searched. CONTENT: Twenty-three dynamic transmission models and 21 economic models were retrieved and reviewed. Published models employed various templates, revealing several key uncertainties regarding the biology and epidemiology of pneumococcal infection. While models suggested that PCVs will reduce the burden of disease, the extent to which they are predicted to do so depended on various assumptions regarding features of pneumococcal infection and epidemiology that governed PCV cost-effectiveness as well. Such features include the duration of protection and competitive interactions between serotypes, which are unclear at present, but which directly relate to herd immunity and serotype replacement. IMPLICATIONS: Economic evaluations are not typically based on transmission dynamic models and hence omit indirect herd immunity effects. The two tools could be used in conjunction to inform decision-makers on vaccine implementation, but so far there have been few attempts to build economic evaluations on transmission dynamic models, and none in this field. Future directions for research could include studies to evaluate key parameters for the models involving herd immunity, serotype competition and the natural history of infection.

Mathematical studies of parasitic infection and immunity.

The techniques that underpin modern molecular biology have been rapidly adopted by those interested in the major parasitic infections of humans. The parasitological literature is full of reports of genes and their amino acid sequences, of molecules, of cell membrane receptors and channels, and of the fine details of the immunological responses mounted by the host to combat infection. Much less enthusiasm has been shown for the mathematical techniques that facilitate the analysis and interpretation of dynamical processes such as transmission, evolution, and the interplay between parasite population growth and immunological responses within the host. Molecular techniques provide enormous opportunities for description, but ultimately, understanding biological systems with the precision that physicists and engineers aspire to in their own fields will require quantitative description of the many rate processes that dictate both an observed pattern and the dynamics of its change.

Directly transmitted infections diseases: control by vaccination.

Mathematical models for the dynamics of directly transmitted viral and bacterial infections are guides to the understanding of observed patterns in the age specific incidence of some common childhood diseases of humans, before and after the advent of vaccination programs. For those infections that show recurrent epidemic behavior, the interepidemic period can be related to parameters characterizing the infection (such as latent and infectious periods and the average age of first infection); this relation agrees with the data of a variety of childhood diseases. Criteria for the eradication of a disease are given, in terms of the proportion of the population to be vaccinated and the age-specific vaccination schedule. These criteria are compared with a detailed analysis of the vaccination programs against measles and whooping cough in Britain, and estimates are made of the levels of protection that would be needed to eradicate these diseases.

Predisposition to hookworm infection in humans.

Frequency distributions of parasitic helminths within human communities are invariably highly aggregated, the majority of worms occurring in relatively small fractions of the host populations. It has been suggested that the heavily infected individuals are predisposed to this state, not by chance, but by as yet undefined genetic, ecological, behavioral, or social factors. Analyses of individual post-treatment patterns of hookworm reinfection among 112 villagers in an endemic area of West Bengal provide quantitative evidence of predisposition to heavy infection. This observation has implications for the design of control programs based on chemotherapy because of the potential economic advantage of selective or targeted treatment as opposed to mass or blanket treatment.

Infectious diseases and population cycles of forest insects.

The regulation of natural populations of invertebrate hosts by viral, bacterial, protozoan, or helminth infections is discussed, using models that combine elements of conventional epidemiology (where the host population is assumed constant) with dynamic elements drawn from predator-prey studies; the apparent absence of acquired immunity in invertebrates simplifies the analysis. Highly pathogenic infections, with long-lived infective stages, tend to produce cyclic behavior in their host populations. The models give an explanation of the 9- to 10-year population cycles of the larch bud moth (Zeiraphera diniana) in the European Alps and suggest that microsporidian protozoan and baculovirus infections may be responsible for the 5- to 12-year population cycles observed in many temperate forest insects.

The foot-and-mouth epidemic in Great Britain: pattern of spread and impact of interventions.

We present an analysis of the current foot-and-mouth disease epidemic in Great Britain over the first 2 months of the spread of the virus. The net transmission potential of the pathogen and the increasing impact of control measures are estimated over the course of the epidemic to date. These results are used to parameterize a mathematical model of disease transmission that captures the differing spatial contact patterns between farms before and after the imposition of movement restrictions. The model is used to make predictions of future incidence and to simulate the impact of additional control strategies. Hastening the slaughter of animals with suspected infection is predicted to slow the epidemic, but more drastic action, such as "ring" culling or vaccination around infection foci, is necessary for more rapid control. Culling is predicted to be more effective than vaccination.

Antigenic diversity and the transmission dynamics of Plasmodium falciparum.

The average age of humans at their first infection with Plasmodium falciparum is typically less than 1 year in most endemic areas. This has been interpreted as evidence of the high transmissibility of the parasite, with the implication that control of malaria will require high levels of coverage with a potential vaccine. This interpretation is challenged by mathematical models that demonstrate that the long period required to develop immunity to malaria permits a high risk (or low average age) of infection even when parasite transmissibility is low. Patterns of seroconversion to five antigenically distinct isolates of P. falciparum in a highly malarious area of Papua New Guinea indicate that each is only mildly transmissible and that malaria, as a construct of several such independently transmitted strains, has a basic reproductive rate (or transmissibility) that is an order of magnitude lower than other estimates.

Antigenic diversity thresholds and the development of AIDS.

Longitudinal studies of patients infected with HIV-1 reveal a long and variable incubation period between infection and the development of AIDS. Data from a small number of infected patients show temporal changes in the number of genetically distinct strains of the virus throughout the incubation period, with a slow but steady rise in diversity during the progression to disease. A mathematical model of the dynamic interaction between viral diversity and the human immune system suggests the existence of an antigen diversity threshold, below which the immune system is able to regulate viral population growth but above which the virus population induces the collapse of the CD4+ lymphocyte population. The model suggests that antigenic diversity is the cause, not a consequence, of immunodeficiency disease. The model is compared with available data, and is used to assess how the timing of the application of chemotherapy or immunotherapy influences the rate of progress to disease.

Cytogenetic Biomarkers of Radiation Exposure.

Biological monitoring of radiation exposure relies heavily on the quantification of chromosome aberrations such as dicentrics and reciprocal translocations in the peripheral blood lymphocytes of exposed and potentially exposed subjects. The differences in the spatial deposition of energy and the quality of damage initially induced between individual low- and high-linear energy transfer (LET) radiation tracks are known to impact dramatically on the type and complexity of chromosome aberration induced. Over the years, researchers have proposed numerous cytogenetic markers and signatures based on these differences with the aim of biologically discriminating exposure to radiation of varying qualities. Complex chromosome aberrations are a broad classification of aberration types that are known to be characteristically induced after low doses of high-LET. The mechanistic basis for complex aberration formation and the potential applicability of these complex aberration products as LET-specific biomarkers are considered.

Combining hippocampal volume metrics to better understand Alzheimer's disease progression in at-risk individuals.

To date nearly all clinical trials of Alzheimer's disease (AD) therapies have failed. These failures are, at least in part, attributable to poor endpoint choice and to inadequate recruitment criteria. Recently, focus has shifted to targeting at-risk populations in the preclinical stages of AD thus improved predictive markers for identifying individuals likely to progress to AD are crucial to help inform the sample of individuals to be recruited into clinical trials. We focus on hippocampal volume (HV) and assess the added benefit of combining HV and rate of hippocampal atrophy over time in relation to disease progression. Following the cross-validation of previously published estimates of the predictive value of HV, we consider a series of combinations of HV metrics and show that a combination of HV and rate of hippocampal atrophy characterises disease progression better than either measure individually. Furthermore, we demonstrate that the risk of disease progression associated with HV metrics does not differ significantly between clinical states. HV and rate of hippocampal atrophy should therefore be used in tandem when describing AD progression in at-risk individuals. Analyses also suggest that the effects of HV metrics are constant across the continuum of the early stages of the disease.