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Poly (ADP-ribose) polymerase (PARP) is responsible for the synthesis of ADP-ribose polymers, which are involved in a wide range of cellular processes such as preservation of genome integrity, DNA damage signaling and repair, molecular switches between distinct cell death pathways, and cell cycle progression. Previously, we demonstrated that the only PARP present in T . cruzi migrates to the nucleus upon genotoxic stimulus. In this work, we identify the N-terminal domain as being sufficient for TcPARP nuclear localization and describe for the first time that TcPARP is enriched in the parasite’s nucleolus. We also describe that TcPARP is present in a thread-like structure that connects two dividing nuclei and co-localizes with nucleolar material and microtubules. Furthermore, ADP-ribose polymers could also be detected in this thread during mitosis. These findings represent a first approach to new potential TcPARP functions inside the nucleus and will help understand its role well beyond the largely described DNA damage response protein in trypanosomatids.

Background: Obesity may be associated with an increase in asthma and atopy in children. If so, the effect could be due to an effect of obesity on lung volume and thus airway hyperresponsiveness. Methods: Data from 5993 caucasian children aged 7–12 years from seven epidemiological studies performed in NSW were analysed. Subjects were included if data were available for height, weight, age, skin prick test results to a common panel of aeroallergens, and a measure of airway responsiveness. History of doctor diagnosed asthma, wheeze, cough, and medication use was obtained by questionnaire. Recent asthma was defined as a doctor diagnosis of asthma ever and wheeze in the last 12 months. Body mass index (BMI) percentiles, divided into quintiles per year age, were used as a measure of standardised weight. Dose response ratio (DRR) was used as a measure of airway responsiveness. Airway hyperresponsiveness was defined as a DRR of ⩾8.1. Adjusted odds ratios were obtained by logistic regression. Results: After adjusting for atopy, sex, age, smoking and family history, BMI was a significant risk factor for wheeze ever (OR = 1.06, p = 0.007) and cough (OR = 1.08, p = 0.001), but not for recent asthma (OR = 1.02, p = 0.43) or airway hyperresponsiveness (OR = 0.97 p = 0.17). In girls a higher BMI was significantly associated with higher prevalence of atopy (χ2 trend 7.9, p = 0.005), wheeze ever (χ2 trend 10.4, p = 0.001), and cough (χ2 trend 12.3, p<0.001). These were not significant in boys. Conclusions: Higher BMI is a risk factor for atopy, wheeze ever, and cough in girls only. Higher BMI is not a risk factor for asthma or airway hyperresponsiveness in either boys or girls.

Carcass decomposition largely depends on vertebrate scavengers. However, how behavioral differences between vertebrate scavenger species, the dominance of certain species, and the diversity of the vertebrate scavenger community affect the speed of carcass decomposition is poorly understood. As scavenging is an overlooked trophic interaction, studying the different functional roles of vertebrate species in the scavenging process increases our understanding about the effect of the vertebrate scavenger community on carcass decomposition. We used motion‐triggered infrared camera trap footages to profile the behavior and activity of vertebrate scavengers visiting carcasses in Dutch nature areas. We grouped vertebrate scavengers with similar functional roles. We found a clear distinction between occasional scavengers and more specialized scavengers, and we found wild boar (Sus scrofa) to be the dominant scavenger species in our study system. We showed that these groups are functionally different within the scavenger community. We found that overall vertebrate scavenger diversity was positively correlated with carcass decomposition speed. With these findings, our study contributes to the understanding about the different functional roles scavengers can have in ecological communities. We examined functional differences within the scavenger community and found groups of scavengers with similar roles. Wild boar (Sus scrofa) was determined to be the dominant scavenger in our system, accelerating the carcass decomposition speed.

BACKGROUND A study was undertaken to assess whether the recent increases in prevalence of both asthma and obesity are linked and to determine if obesity is a risk factor for diagnosed asthma, symptoms, use of asthma medication, or airway hyperresponsiveness. METHODS Data from 1971 white adults aged 17–73 years from three large epidemiological studies performed in NSW were pooled. Doctor diagnosis of asthma ever, history of wheeze, and medication use in the previous 12 months were obtained by questionnaire. Body mass index (BMI) in kg/m2 was used as a measure of obesity. Airway hyperresponsiveness (AHR) was defined as dose of <3.9 μmol histamine required to provoke a fall in forced expiratory volume in one second (FEV1) of 20% or more (PD20FEV1). Adjusted odds ratios (OR) were obtained by logistic regression. RESULTS After adjusting for atopy, age, sex, smoking history, and family history, severe obesity was a significant risk factor for recent asthma (OR 2.04, p=0.048), wheeze in the previous 12 months (OR 2.6, p=0.001), and medication use in the previous 12 months (OR 2.83, p=0.005), but not for AHR (OR 0.87, p=0.78). FEV1 and forced vital capacity (FVC) were significantly reduced in the group with severe obesity, but FEV1/FVC ratio, peak expiratory flow (PEF), and mid forced expiratory flow (FEF25–75) were not different from the group with normal BMI. The underweight group (BMI <18.5 kg/m2) had increased symptoms of shortness of breath, increased airway responsiveness, and reduced FEV1, FVC, PEF, and FEF25–75 with similar use of asthma medication as subjects in the normal weight range. CONCLUSIONS Although subjects with severe obesity reported more wheeze and shortness of breath which may suggest a diagnosis of asthma, their levels of atopy, airway hyperresponsiveness, and airway obstruction did not support the suggestion of a higher prevalence of asthma in this group. The underweight group appears to have more significant respiratory problems with a higher prevalence of symptoms, reduced lung function, and increased airway responsiveness without an increase in medication usage. This group needs further investigation.

Background: Obesity is associated with increased prevalence and incidence of asthma, but the mechanism is unknown. Obesity reduces lung volumes, which can increase airway responsiveness, and increases resistive and elastic work of breathing, which can increase dyspnea. Objective: To determine if the intensity of dyspnea due to airway narrowing or if airway responsiveness is increased in obese, non-asthmatic subjects. Subjects: Twenty-three obese (BMI (body mass index) ⩾30 kg m −2 ) and 26 non-obese (BMI <30 kg m −2 ) non-asthmatic subjects, aged between 18 and 70 years. Methods: High-dose methacholine challenge was used to determine the sensitivity and the maximal response to methacholine. Respiratory system resistance (Rrs) and reactance were measured, using the forced oscillation technique, as indicators of resistive and elastic loads during challenge. Perception of dyspnea was measured by the Borg score during challenge. Static lung volumes were measured by body plethysmography. Results: Static lung volumes were reduced in the obese subjects. There were no significant differences in the sensitivity or maximal response to methacholine between obese and non-obese subjects. The magnitude of change in Rrs was similar in both groups, but obese subjects had more negative reactance after challenge ( P =0.002) indicating a greater elastic load. The intensity of dyspnea was greater in obese subjects ( P =0.03). Conclusions: Obesity reduces lung volumes, but does not alter the sensitivity or maximal response to methacholine. However, obese subjects have enhanced perception of dyspnea, associated with greater apparent stiffness of the respiratory system, and may therefore be at greater risk of symptoms.

Background: Sahaja Yoga is a traditional system of meditation based on yogic principles which may be used for therapeutic purposes. A study was undertaken to assess the effectiveness of this therapy as an adjunctive tool in the management of asthma in adult patients who remained symptomatic on moderate to high doses of inhaled steroids. Methods: A parallel group, double blind, randomised controlled trial was conducted. Subjects were randomly allocated to Sahaja yoga and control intervention groups. Both the yoga and the control interventions required the subjects to attend a 2 hour session once a week for 4 months. Asthma related quality of life (AQLQ, range 0–4), Profile of Mood States (POMS), level of airway hyperresponsiveness to methacholine (AHR), and a diary card based combined asthma score (CAS, range 0–12) reflecting symptoms, bronchodilator usage, and peak expiratory flow rates were measured at the end of the treatment period and again 2 months later. Results: Twenty one of 30 subjects randomised to the yoga intervention and 26 of 29 subjects randomised to the control group were available for assessment at the end of treatment. The improvement in AHR at the end of treatment was 1.5 doubling doses (95% confidence interval (CI) 0.0 to 2.9, p=0.047) greater in the yoga intervention group than in the control group. Differences in AQLQ score (0.41, 95% CI –0.04 to 0.86) and CAS (0.9, 95% CI –0.9 to 2.7) were not significant (p>0.05). The AQLQ mood subscale did improve more in the yoga group than in the control group (difference 0.63, 95% CI 0.06 to 1.20), as did the summary POMS score (difference 18.4, 95% CI 0.2 to 36.5, p=0.05). There were no significant differences between the two groups at the 2 month follow up assessment. Conclusions: This randomised controlled trial has shown that the practice of Sahaja yoga does have limited beneficial effects on some objective and subjective measures of the impact of asthma. Further work is required to understand the mechanism underlying the observed effects and to establish whether elements of this intervention may be clinically valuable in patients with severe asthma.

Background/Objectives: Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, which currently affects around 8 million people worldwide. The therapeutic arsenal against T. cruzi is so far limited to only two approved drugs, benznidazole and nifurtimox, that have considerable side effects and limited efficacy in the chronic stage of the disease. Here, we have resorted to supervised phenotypic machine learning models to explore drug repurposing opportunities and identify potential new therapeutic solutions for Chagas disease. Methods: More than 100,000 bioactivity data points were retrieved from ChEMBL and carefully curated according to the data-centric machine learning paradigm. After curation, two datasets comprising 344 compounds tested against T. cruzi Y strain trypomastigotes and 785 compounds tested against Tulahuen strain amastigotes were obtained and used to infer ensemble learning models with excellent average and early enrichment metrics in retrospective screening experiments (AUROC > 0.96 and EF0.01 > 58). A prospective screening campaign was then performed on DrugBank and the Drug Repurposing Hub databases, submitting eight in silico hits for experimental confirmation. Results: Six of the in silico hits confirmed their predicted trypanocidal effects. Conclusions: We have built portable meta-classifiers capable of identifying small molecules with trypanocidal activity against amastigotes, the clinically most relevant stage of T. cruzi. The predictive ability of this meta-classifier was experimentally validated.

BackgroundHeterogeneous airway narrowing and closure are characteristics of asthma. However, they have never been quantified by direct measurements of parallel sister airways obtained from image data, and the anatomical basis of these processes remains unknown.MethodsSeven normal and nine asthmatic subjects underwent high-resolution CT, before and after methacholine challenge. Mean lumen areas of the entire airways were measured in 28 and 24 parallel sister airway pairs (a pair of airways arising from the same bifurcation) respectively (range 1.0–8.7 mm diameter). Heterogeneous narrowing was defined as the median difference in percentage narrowing between parallel sister airways. Forced oscillatory respiratory resistance (Rrs) and spirometry were measured before and after methacholine challenge conducted while supine.ResultsThe airways of asthmatics were smaller at baseline, and following bronchoconstriction there were similar decreases in FEV1, increases in Rrs and mean narrowing of airways for asthmatic and non-asthmatic groups. Non-asthmatics required higher doses of methacholine than asthmatics to achieve the same changes. However, parallel heterogeneity (median (IQR) 33% (27–53%) vs 11% (9–18%), p<0.001) and airway closure (24.1% and 7.7%, p=0.001, χ2) were greater in asthmatics versus non-asthmatics.ConclusionWe found clear evidence of differences in airway behaviour in the asthmatic group. Asthmatic airways were narrower at baseline and responded to inhaled methacholine by more heterogeneous narrowing of parallel sister airways and greater airway closure.

The acceptability of lifelong antiretroviral therapy (ART) among HIV-positive women in high-burden Nigeria, is not well-known. We explored readiness of users and providers of prevention of mother-to-child transmission of HIV (PMTCT) services to accept lifelong ART -before Option B plus was implemented in Nigeria. We conducted 142 key informant interviews among 100 PMTCT users (25 pregnant-newly-diagnosed, 26 pregnant-in-care, 28 lost-to-follow-up (LTFU) and 21 postpartum women living with HIV) and 42 PMTCT providers in rural North-Central Nigeria. Qualitative data were manually analyzed via Grounded Theory. PMTCT users had mixed views about lifelong ART, strongly influenced by motivation to prevent infant HIV and by presence or absence of maternal illness. Newly-diagnosed women were most enthusiastic about lifelong ART, however postpartum and LTFU women expressed conditionalities for acceptance and adherence, including minimal ART side effects and potentially serious maternal illness. Providers corroborated user findings, identifying the postpartum period as problematic for lifelong ART acceptability/adherence. Option B plus scale-up in Nigeria will require proactively addressing PMTCT user fears about ART side effects, and continuous education on long-term maternal and infant benefits. Structural barriers such as the availability of trained providers, long clinic wait times and patient access to ART should also be addressed.

In Trypanosoma cruzi DNA is packaged into chromatin by octamers of histone proteins that form nucleosomes. Transcription of protein coding genes in trypanosomes is constitutive producing polycistronic units and gene expression is primarily regulated post-transcriptionally. However, chromatin organization influences DNA dependent processes. Hence, determining nucleosome position is of uppermost importance to understand the peculiarities found in trypanosomes. To map nucleosomes genome-wide in several organisms, digestion of chromatin with micrococcal nuclease followed by deep sequencing has been applied. Nonetheless, the special requirements for cell manipulation and the uniqueness of the chromatin organization in trypanosomes entails a customized analytical approach. In this work, we adjusted this broadly used method to the hybrid reference strain, CL Brener. Particularly, we implemented an exhaustive and thorough computational workflow to overcome the difficulties imposed by this complex genome. We tested the performance of two aligners, Bowtie2 and HISAT2, and discuss their advantages and caveats. Specifically, we highlight the relevance of using the whole genome as a reference instead of the commonly used Esmeraldo-like haplotype to avoid spurious alignments. Additionally, we show that using the whole genome refines the average nucleosome representation, but also the quality of mapping for every region represented. Moreover, we show that the average nucleosome organization around trans-splicing acceptor site described before, is not just an average since the same chromatin pattern is detected for most of the represented regions. In addition, we extended the study to a non-hybrid strain applying the experimental and analytical approach to Sylvio-X10 strain. Furthermore, we provide a source code for the construction of 2D plots and heatmaps which are easy to adapt to any T . cruzi strain.