With the continued loss of antimalarials to resistance, drug repositioning may have a role in maximising efficiency and accelerating the discovery of new antimalarial drugs. Bayesian statistics was previously used as a tool to virtually screen USFDA approved drugs for predicted β-haematin (synthetic haemozoin) inhibition and in vitro antimalarial activity. Here, we report the experimental evaluation of nine of the highest ranked drugs, confirming the accuracy of the model by showing an overall 93% hit rate. Lapatinib, nilotinib, and lomitapide showed the best activity for inhibition of β-haematin formation and parasite growth and were found to inhibit haemozoin formation in the parasite, providing mechanistic insights into their mode of antimalarial action. We then screened the USFDA approved drugs for binding to the β-haematin crystal, applying a docking method in order to evaluate its performance. The docking method correctly identified imatinib, lapatinib, nilotinib, and lomitapide. Experimental evaluation of 22 of the highest ranked purchasable drugs showed a 24% hit rate. Lapatinib and nilotinib were chosen as templates for shape and electrostatic similarity screening for lead hopping using the in-stock ChemDiv compound catalogue. The actives were novel structures worthy of future investigation. This study presents a comparison of different in silico methods to identify new haemozoin-inhibiting chemotherapeutic alternatives for malaria that proved to be useful in different ways when taking into consideration their strengths and limitations. Full article

Increasingly, funders (i.e., national, public funders, such as the National Institutes of Health and National Science Foundation in the U.S.) and scholars agree that single disciplines are ill equipped to study the pressing social, health, and environmental problems we face alone, particularly environmental exposures, increasing health disparities, and climate change. To better understand these pressing social problems, funders and scholars have advocated for transdisciplinary approaches in order to harness the analytical power of diverse and multiple disciplines to tackle these problems and improve our understanding. However, few studies look into how to conduct such research. To this end, this article provides a review of transdisciplinary science, particularly as it relates to environmental research and public health. To further the field, this article provides in-depth information on how to conduct transdisciplinary research. Using the case of a transdisciplinary, community-based, participatory action, environmental health disparities study in California’s Central Valley provides an in-depth look at how to do transdisciplinary research. Working with researchers from the fields of social sciences, public health, biological engineering, and land, air, and water resources, this study aims to answer community residents’ questions related to the health disparities they face due to environmental exposure. Through this case study, I articulate not only the logistics of how to conduct transdisciplinary research but also the logics. The implications for transdisciplinary methodologies in health disparity research are further discussed, particularly in the context of team science and convergence science. Full article

Current food traceability systems have a number of problems, such as data being easily tampered with and a lack of effective methods to intuitively analyze the causes of risks. Therefore, a novel method has been proposed that combines blockchain technology with visualization technology, which uses Hyperledger to build an information storage platform. Features such as distribution and tamper-resistance can guarantee the authenticity and validity of data. A data structure model is designed to implement the data storage of the blockchain. The food safety risks of unqualified detection data can be quantitatively analyzed, and a food safety risk assessment model is established according to failure rate and qualification deviation. Risk analysis used visual techniques, such as heat maps, to show the areas where unqualified products appeared, with a migration map and a force-directed graph used to trace these products. Moreover, the food sampling data were used as the experimental data set to test the validity of the method. Instead of difficult-to-understand and highly specialized food data sets, such as elements in food, food sampling data for the entire year of 2016 was used to analyze the risks of food incidents. A case study using aquatic products as an example was explored, where the results showed the risks intuitively. Furthermore, by analyzing the reasons and traceability processes effectively, it can be proven that the proposed method provides a basis to formulate a regulatory strategy for regions with risks. Full article

Raindrop size distributions have been characterized through the gamma family. Over the years, quite a few estimates of these gamma parameters have been proposed. The natural question for the practitioner, then, is what estimation procedure should be used. We provide guidance in answering this question when a large sample size (>2000 drops) of accurately measured drops is available. Seven estimation procedures from the literature: five method of moments procedures, maximum likelihood, and a pseudo maximum likelihood procedure, were examined. We show that the two maximum likelihood procedures provide the best precision (lowest variance) in estimating the gamma parameters. Method of moments procedures involving higher-order moments, on the other hand, give rise to poor precision (high variance) in estimating these parameters. A technique called the delta method assisted in our comparison of these various estimation procedures. Full article

Nowadays, tuberculosis, scarlet fever, measles, influenza, and mumps are five major notifiable respiratory infectious diseases (RIDs) in China. The objective of this study was to describe, visualize, and compare the spatial-temporal distributions of these five RIDs from 2006 to 2016. In addition to descriptive epidemiology analysis, seasonality and spatial autocorrelation analysis were also applied to explore the epidemiologic trends and spatial changing patterns of the five RIDs, respectively. The results indicated that the incidence of tuberculosis, measles, and mumps presented a downtrend trend, while those of scarlet fever and influenza was in a strong uptrend across the research period. The incidences of the five diseases all peaked in spring. There were significant spatial disparities in the distribution of tuberculosis, scarlet fever, and measles cases, with the hotspots mainly located in the western plateau region, northern plain region, and southern mountainous region. To conclude, notable epidemiological differences were observed across regions, indicating that some provincial units should pay more attention to prevent and control respiratory infectious diseases. Full article

Clinical research on neglected tropical diseases is a challenge in low-resource countries, and the contribution of clinical and operational research to health system strengthening is poorly documented. Developing new, simple, safe, and effective treatments may improve the effectiveness of health systems, and conducting research directly in health structures may have an additional impact. This study describes the process of conducting clinical trials in the Democratic Republic of Congo (DRC) in compliance with international standards, and the role of the trials in strengthening health system functions, including governance, human resources, health information, provision of care, and the equipping of health services with the necessary supplies and infrastructure. We conclude that conducting clinical trials in endemic areas has not only reinforced and supported the aim of conducting high-level clinical research in endemic countries, but has also brought lasting benefits to researchers, staff, and hospitals, as well as to broader health systems, which have positive knock-on effect on patients outside of the clinical trials and their communities. Sustainability, however, remains a challenge in an underfunded health system, especially with respect to specialized equipment. Clinical research in most of sub-Saharan Africa is highly dependent on international input and external technical support; there are areas of weaknesses in trial design and documentation, as well as in data management and analysis. Financing remains a critical issue, as African investigators have difficulties in directly accessing sources of international research funding. Full article

For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse. Full article

New drugs with new mechanisms of action are urgently required to tackle the global tuberculosis epidemic. Following the FDA-approval of the ATP synthase inhibitor bedaquiline (Sirturo^®), energy metabolism has become the subject of intense focus as a novel pathway to exploit for tuberculosis drug development. This enthusiasm stems from the fact that oxidative phosphorylation (OxPhos) and the maintenance of the transmembrane electrochemical gradient are essential for the viability of replicating and non-replicating Mycobacterium tuberculosis (M. tb), the etiological agent of human tuberculosis (TB). Therefore, new drugs targeting this pathway have the potential to shorten TB treatment, which is one of the major goals of TB drug discovery. This review summarises the latest and key findings regarding the OxPhos pathway in M. tb and provides an overview of the inhibitors targeting various components. We also discuss the potential of new regimens containing these inhibitors, the flexibility of this pathway and, consequently, the complexity in targeting it. Lastly, we discuss opportunities and future directions of this drug target space. Full article

A record-breaking severe heat wave was recorded in southeast Korea from 11 July to 15 August 2018, and the numerical sensitivity simulations of volatile organic compound (VOC) to secondarily generated particulate matter with diameter of less than 2.5 µm (PM2.5) concentrations were studied in the Busan and Ulsan metropolitan areas in southeast Korea. A weather research and forecasting (WRF) model coupled with chemistry (WRF-Chem) was employed, and we carried out VOC emission sensitivity simulations to investigate variations in PM_2.5 concentrations during the heat wave period that occurred from 11 July to 15 August 2018. In our study, when anthropogenic VOC emissions from the Comprehensive Regional Emissions Inventory for Atmospheric Transport Experiment-2015 (CREATE-2015) inventory were increased by approximately a factor of five in southeast Korea, a better agreement with observations of PM_2.5 mass concentrations was simulated, implying an underestimation of anthropogenic VOC emissions over southeast Korea. The simulated secondary organic aerosol (SOA) fraction, in particular, showed greater dominance during high temperature periods such as 19–21 July, 2018, with the SOA fractions of 42.3% (in Busan) and 34.3% (in Ulsan) among a sub-total of seven inorganic and organic components. This is considerably higher than observed annual mean organic carbon (OC) fraction (28.4 ± 4%) among seven components, indicating the enhancement of secondary organic aerosols induced by photochemical reactions during the heat wave period in both metropolitan areas. The PM_2.5 to PM₁₀ ratios were 0.69 and 0.74, on average, during the study period in the two cities. These were also significantly higher than the typical range in those cities, which was 0.5–0.6 in 2018. Our simulations implied that extremely high temperatures with no precipitation are significantly important to the secondary generation of PM_2.5 with higher secondary organic aerosol fraction via photochemical reactions in southeastern Korean cities. Other possible relationships between anthropogenic VOC emissions and temperature during the heat wave episode are also discussed in this study. Full article

A proposition addressed here is that, although bitted horses are viewed by many equestrians as being largely free of bit-related mouth pain, it seems likely that most behavioural signs of such pain are simply not recognised. Background information is provided on the following: the major features of pain generation and experience; cerebrocortical involvement in the conscious experience of pain by mammals; the numerous other subjective experiences mammals can have; adjunct physiological responses to pain; some general feature of behavioural responses to pain; and the neural bases of sensations generated within the mouth. Mouth pain in horses is then discussed. The areas considered exclude dental disease, but they include the stimulation of pain receptors by bits in the interdental space, the tongue, the commissures of the mouth, and the buccal mucosa. Compression, laceration, inflammation, impeded tissue blood flow, and tissue stretching are evaluated as noxious stimuli. The high pain sensitivity of the interdental space is described, as are likely increases in pain sensitivity due to repeated bit contact with bruises, cuts, tears, and/or ulcers wherever they are located in the mouth. Behavioural indices of mouth pain are then identified by contrasting the behaviours of horses when wearing bitted bridles, when changed from bitted to bit-free bridles, and when free-roaming unbitted in the wild. Observed indicative behaviours involve mouth movements, head-neck position, and facial expression (“pain face”), as well as characteristic body movements and gait. The welfare impacts of bit-related pain include the noxiousness of the pain itself as well as likely anxiety when anticipating the pain and fear whilst experiencing it, especially if the pain is severe. In addition, particular mouth behaviours impede airflow within the air passages of the upper respiratory system, effects that, in their turn, adversely affect the air passages in the lungs. Here, they increase airflow resistance and decrease alveolar gas exchange, giving rise to suffocating experiences of breathlessness. In addition, breathlessness is a likely consequence of the low jowl angles commonly maintained during dressage. If severe, as with pain, the prospect of breathlessness is likely to give rise to anxiety and the direct experience of breathlessness to fear. The related components of welfare compromise therefore likely involve pain, breathlessness, anxiety, and fear. Finally, a 12-point strategy is proposed to give greater impetus to a wider adoption of bit-free bridles in order to avoid bit-induced mouth pain. Full article

In the current call for a greater human health and well-being as a sustainable development goal, to encourage active commuting to and from school (ACS) seems to be a key factor. Research focusing on the analysis of the association between environmental factors and ACS in children and adolescents has reported limited and inconclusive evidence, so more knowledge is needed about it. The main aim of this study is to examine the association between different built environmental factors of both school neighbourhood and home-school route with ACS of children and adolescents belonging to urban areas. The ACS level was evaluated using a self-reported questionnaire. Built environment variables (i.e., density of residents, street connectivity and mixed land use) within a school catchment area and home-school route characteristics (i.e., distance and pedestrian route directness—PRD) were measured using a geographic information system (GIS) and examined together with ACS levels. Subsequently, the association between environmental factors and ACS was analysed by binary logistic regression. Several cut-off points of the route measures were explored using receiver operating characteristic (ROC) curves. In addition, the PRD was further studied regarding different thresholds. The results showed that 70.5% of the participants were active and there were significant associations between most environmental factors and ACS. Most participants walked to school when routes were short (distance variable in children: OR = 0.980; p = 0.038; and adolescents: OR = 0.866; p < 0.001) and partially direct (PRD variable in children: OR = 11.334; p < 0.001; and adolescents: OR = 3.513; p < 0.001), the latter specially for children. Mixed land uses (OR = 2.037; p < 0.001) and a high density of street intersections (OR = 1.640; p < 0.001) clearly encouraged adolescents walking and slightly discouraged children walking (OR = 0.657, p = 0.010; and OR = 0.692, p = 0.025, respectively). The assessment of ACS together with the environmental factors using GIS separately for children and adolescents can inform future friendly and sustainable communities. Full article

Activins belong to the transforming growth factor (TGF)-β family of multifunctional cytokines and signal via the activin receptors ALK4 or ALK7 to activate the SMAD2/3 pathway. In some cases, activins also signal via the bone morphogenetic protein (BMP) receptor ALK2, causing activation of the SMAD1/5/8 pathway. In this study, we aimed to dissect how activin A and activin B homodimers, and activin AB and AC heterodimers activate the two main SMAD branches. We compared the activin-induced signaling dynamics of ALK4/7-SMAD2/3 and ALK2-SMAD1/5 in a multiple myeloma cell line. Signaling via the ALK2-SMAD1/5 pathway exhibited greater differences between ligands than signaling via ALK4/ALK7-SMAD2/3. Interestingly, activin B and activin AB very potently activated SMAD1/5, resembling the activation commonly seen with BMPs. As SMAD1/5 was also activated by activins in other cell types, we propose that dual specificity is a general mechanism for activin ligands. In addition, we found that the antagonist follistatin inhibited signaling by all the tested activins, whereas the antagonist cerberus specifically inhibited activin B. Taken together, we propose that activins may be considered dual specificity TGF-β family members, critically affecting how activins may be considered and targeted clinically. Full article

An innovative automatic purge-and-trap (P&T) system coupled with fluorimetric sequential injection (SI), for the on-line separation and preconcentration of volatile compounds, is presented. The truth of concept is demonstrated for the ammonium fluorimetric determination in environmental water samples with complex matrices without any pretreatment. The P&T flow system comprises a thermostated purge-vessel where ammonium is converted into gaseous ammonia and a trap-vessel for ammonia collection. This configuration results in matrix removal as well as analyte preconcentration, avoiding membrane-associated problems. All the main parameters affecting the efficiency of a P&T system were studied and optimized. The proposed method is characterized by a working range of 2.7–150.0 μg L⁻¹ of NH₄⁺, with a detection and quantification limit of 0.80 and 2.66 μg L⁻¹, respectively, for a 10-mL sample consumption. The accuracy of the method was assessed by recovery assays in seawater, estuarine, and lake water samples as well as by the analysis of standard reference material. Full article

Alpha-1-antitrypsin deficiency (AATd) is a hereditary disease, mainly characterized by early onset and the lower lobes’ predominant emphysema. Bronchiectasis is characterized by dilatation of the bronchial wall and a clinical syndrome whose features are a cough, sputum production and frequent respiratory exacerbations. In the literature, there are many papers concerning these two clinical entities, but there is still a lot of debate about a possible association between them, in particular about the frequency of their association and causal links. The aim of this short communication is to show the literature reports about the association between AATd and bronchiectasis to establish the state of the art and possible future developments in this research field. Full article