Virtual Drug Repositioning as a Tool to Identify Natural Small Molecules That Synergize with Lumacaftor in F508del-CFTR Binding and Rescuing

Cystic fibrosis is a hereditary disease mainly caused by the deletion of the Phe 508 (F508del) of the cystic fibrosis transmembrane conductance regulator (CFTR) protein that is thus withheld in the endoplasmic reticulum and rapidly degraded by the ubiquitin/proteasome system. Cystic fibrosis remains a potentially fatal disease, but it has become treatable as a chronic condition due to some CFTR-rescuing drugs that, when used in combination, increase in their therapeutic effect due to a synergic action. Also, dietary supplementation of natural compounds in combination with approved drugs could represent a promising strategy to further alleviate cystic fibrosis symptoms. On these bases, we screened by in silico drug repositioning 846 small synthetic or natural compounds from the AIFA database to evaluate their capacity to interact with the highly druggable lumacaftor binding site of F508del-CFTR. Among the identified hits, nicotinamide (NAM) was predicted to accommodate into the lumacaftor binding region of F508del-CFTR without competing against the drug but rather stabilizing its binding. The effective capacity of NAM to bind F508del-CFTR in a lumacaftor-uncompetitive manner was then validated experimentally by surface plasmon resonance analysis. Finally, the capacity of NAM to synergize with lumacaftor increasing its CFTR-rescuing activity was demonstrated in cell-based assays. This study suggests the possible identification of natural small molecules devoid of side effects and endowed with the capacity to synergize with drugs currently employed for the treatment of cystic fibrosis, which hopefully will increase the therapeutic efficacy with lower doses

Electrocardiogram Monitoring Wearable Devices and Artificial-Intelligence-Enabled Diagnostic Capabilities: A Review

Worldwide, population aging and unhealthy lifestyles have increased the incidence of high-risk health conditions such as cardiovascular diseases, sleep apnea, and other conditions. Recently, to facilitate early identification and diagnosis, efforts have been made in the research and development of new wearable devices to make them smaller, more comfortable, more accurate, and increasingly compatible with artificial intelligence technologies. These efforts can pave the way to the longer and continuous health monitoring of different biosignals, including the real-time detection of diseases, thus providing more timely and accurate predictions of health events that can drastically improve the healthcare management of patients. Most recent reviews focus on a specific category of disease, the use of artificial intelligence in 12-lead electrocardiograms, or on wearable technology. However, we present recent advances in the use of electrocardiogram signals acquired with wearable devices or from publicly available databases and the analysis of such signals with artificial intelligence methods to detect and predict diseases. As expected, most of the available research focuses on heart diseases, sleep apnea, and other emerging areas, such as mental stress. From a methodological point of view, although traditional statistical methods and machine learning are still widely used, we observe an increasing use of more advanced deep learning methods, specifically architectures that can handle the complexity of biosignal data. These deep learning methods typically include convolutional and recurrent neural networks. Moreover, when proposing new artificial intelligence methods, we observe that the prevalent choice is to use publicly available databases rather than collecting new data

SNPpy - Database Management for SNP Data from Genome Wide Association Studies

Background: We describe SNPpy, a hybrid script database system using the Python SQLAlchemy library coupled with the PostgreSQL database to manage genotype data from Genome-Wide Association Studies (GWAS). This system makes it possible to merge study data with HapMap data and merge across studies for meta-analyses, including data filtering based on the values of phenotype and Single-Nucleotide Polymorphism (SNP) data. SNPpy and its dependencies are open source software. Results: The current version of SNPpy offers utility functions to import genotype and annotation data from two commercial platforms. We use these to import data from two GWAS studies and the HapMap Project. We then export these individual datasets to standard data format files that can be imported into statistical software for downstream analyses. Conclusions: By leveraging the power of relational databases, SNPpy offers integrated management and manipulation of genotype and phenotype data from GWAS studies. The analysis of these studies requires merging across GWAS datasets as well as patient and marker selection. To this end, SNPpy enables the user to filter the data and output the results as standardized GWAS file formats. It does low level and flexible data validation, including validation of patient data. SNPpy is

Efficacy of different treatment regimes against setariosis (Setaria tundra, Nematoda: Filarioidea) and associated peritonitis in reindeer

<p>Abstract</p> <p>Background</p> <p>When a severe peritonitis outbreak in semi-domesticated reindeer was noticed in 2003 in Finland, the concerned industry urged immediate preventive actions in order to avoid detrimental effects of <it>S. tundra </it>and further economical losses. A research programme was swiftly initiated to study <it>S. tundra </it>and its impact on the health and wellbeing of reindeer.</p> <p>Methods</p> <p>The ultimate aim of this study was to test the efficacy of different treatment regimes against <it>S. tundra </it>and associated peritonitis in reindeer. The timing of the trials was planned to be compatible with the annual rhythm of the reindeer management; (1) the treatment of calves in midsummer, during routine calf ear marking, with ivermectin injection prophylaxis and deltamethrin pour-on solution as a repellent against insect vectors, (2) the treatment of infected calves in early autumn with ivermectin injection, and (3) ivermectin treatment of breeding reindeer in winter. The results were assessed using the post mortem inspection data and <it>S. tundra </it>detection. Finally, to evaluate on the population level the influence of the annual (late autumn-winter) ivermectin treatment of breeding reindeer on the transmission dynamics of <it>S. tundra</it>, a questionnaire survey was conducted.</p> <p>Results</p> <p>In autumn, ivermectin treatment was efficient against peritonitis and in midsummer had a slight negative impact on the degree of peritonitis and positive on the fat layer, but deltamethrin had none. Ivermectin was efficient against adult <it>S. tundra </it>and its smf. All the reindeer herding cooperatives answered the questionnaire and it appeared that antiparasitic treatment of reindeer population was intense during the study period, when 64–90% of the animals were treated. In the southern part of the Finnish reindeer husbandry area, oral administration of ivermectin was commonly used.</p> <p>Conclusion</p> <p>Autumn, and to a lesser degree summer, treatment of reindeer calves with injectable ivermectin resulted in decreased severity of peritonitis and perihepatitis in reindeer calves due to setariosis. In the case of necessity for animal welfare reasons, treatment during early autumn round ups should be considered. On the population level, massive and routinely applied antiparasitic treatments can improve the health of breeding reindeer and decrease the mortality and the number of carriers but during the outbreak could not prevent its movement and expansion to the North.</p

Association of herd BRSV and BHV-1 seroprevalence with respiratory disease and reproductive performance in adult dairy cattle

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to detect the associations between bovine herpesvirus 1 (BHV-1) status of a herd and respiratory disease (BRD) occurrence and reproductive performance in pregnant heifers and cows. The association between management-related factors and higher BRD occurrence was also estimated.</p> <p>Methods</p> <p>Serum samples, collected from cows and youngstock from 103 dairy cattle herds, were analyzed for antibodies against BHV-1, bovine respiratory syncytial virus (BRSV), bovine viral diarrhoea virus (BVDV), and <it>Mycoplasma bovis</it>. A questionnaire was used to collect data concerning herd management factors and reproductive performance, as well as the occurrence of clinical signs of respiratory disease in the last two years, as evaluated by the veterinarian or farm manager. Multiple correspondence analysis (MCA) and logistic regression analysis were performed to identify and quantify the risk factors.</p> <p>Results</p> <p>A low to moderate prevalence (1-49%) of BRSV antibodies among youngstock was associated with a high occurrence of respiratory disease (OR = 6.2, p = 0.010) in cows and in-calf heifers. Employees of the farm may participate in the spread of such disease. Larger herd size, loose-housing of cows, housing youngstock separately from cows until pregnancy, and purchasing new animals were factors possibly related to a high occurrence of respiratory disease symptoms in pregnant heifers and cows. The highest risk of abortions (> 1.3%) and increased insemination index (number of inseminations per pregnancy) (> 1.9) occurred in herds with a moderate prevalence of BHV-1 antibodies (1-49%) in cows.</p> <p>Conclusions</p> <p>BHV-1 was not associated with acute respiratory disease in adult dairy cattle, however was significantly related to reproductive performance. BRSV possesses the main role in respiratory disease complex in adult dairy cattle.</p