Drug-efflux and target-site gene expression patterns in Haemonchus contortus larvae able to survive increasing concentrations of levamisole in vitro

While there is some evidence that changes in nicotinic acetylcholine receptor (nAChR) subunits confer resistance to levamisole in gastrointestinal helminth parasites, the exact nature of the resistance mechanism(s) is unclear. We utilised the presence of a resistant fraction within the Wallangra 2003 isolate of Haemonchus contortus larvae in order to subdivide the population into three subpopulations of larvae able to survive increasing concentrations of the drug. We then measured gene expression levels in the subpopulations and the larval population as a whole, focusing on genes encoding the subunit components of levamisole-sensitive receptors, genes encoding ancillary proteins involved in receptor assembly, and P-glycoprotein (P-gp) genes. The subpopulation surviving the lowest levamisole concentration showed increases of 1.5- to 3-fold in a number of P-gp genes (Hco-pgp-3, -4, -10, and -14) alongside unchanged receptor genes, compared to the whole Wallangra larval population. On the other hand, the subpopulation surviving the intermediate levamisole concentration showed an increase in only a single P-gp (Hco-pgp-14), alongside decreases in some receptor subunit (Hco-unc-63a) and ancillary protein genes (Hco-unc-50, Hco-ric-3.1 and 3.1). The subpopulation surviving the highest levamisole concentration showed further decreases in receptor subunit genes (Hco-unc-63a and Hco-unc-29 paralogs) as well as genes involved in receptor assembly (Hco-unc-74, Hco-unc-50, Hco-ric-3.1 and 3.1), alongside no increased P-gp gene levels. This suggests a biphasic pattern of drug resistance in the larvae of this worm isolate, in which a non-specific P-gp-mediated mechanism confers low levels of resistance, while higher level resistance is due to altered receptor subunit composition as a result of changes in both subunit composition and in the levels of proteins involved in receptor assembly

A generalized conformational energy function of DNA derived from molecular dynamics simulations

Proteins recognize DNA sequences by two different mechanisms. The first is direct readout, in which recognition is mediated by direct interactions between the protein and the DNA bases. The second is indirect readout, which is caused by the dependence of conformation and the deformability of the DNA structure on the sequence. Various energy functions have been proposed to evaluate the contribution of indirect readout to the free-energy changes in complex formations. We developed a new generalized energy function to estimate the dependence of the deformability of DNA on the sequence. This function was derived from molecular dynamics simulations previously conducted on B-DNA dodecamers, each of which had one possible tetramer sequence embedded at its center. By taking the logarithm of the probability distribution function (PDF) for the base-step parameters of the central base-pair step of the tetramer, its ability to distinguish the native sequence from random ones was superior to that with the previous method that approximated the energy function in harmonic form. From a comparison of the energy profiles calculated with these two methods, we found that the harmonic approximation caused significant errors in the conformational energies of the tetramers that adopted multiple stable conformations

Photometry of very bright stars with Kepler and K2 smear data

High-precision time series photometry with the Kepler satellite has been crucial to our understanding both of exoplanets, and via asteroseismology, of stellar physics. After the failure of two reaction wheels, the Kepler satellite has been repurposed as Kepler-2 (K2), observing fields close to the ecliptic plane. As these fields contain many more bright stars than the original Kepler field, K2 provides an unprecedented opportunity to study nearby objects amenable to detailed follow-up with ground-based instruments. Due to bandwidth constraints, only a small fraction of pixels can be downloaded, with the result that most bright stars which saturate the detector are not observed. We show that engineering data acquired for photometric calibration, consisting of collateral ‘smear’ measurements, can be used to reconstruct light curves for bright targets not otherwise observable with Kepler/K2. Here we present some examples from Kepler Quarter 6 and K2 Campaign 3, including the δ Scuti variables HD 178875 and 70 Aqr, and the red giant HR 8500 displaying solar-like oscillations. We compare aperture and smear photometry where possible, and also study targets not previously observed. These encouraging results suggest this new method can be applied to most Kepler and K2 fields

Crisis phenomena as an incentive to intensify ecommerce of the enterprise

The latest global crisis has negatively affected the global economy as a whole, but it has had a stimulating effect on e-commerce. Electronic commerce around the world has intensified with a breakthrough in sales and transactions. While virtually the entire world has imposed restrictions to contain the spread of the pandemic, Internet technology and e-commerce have helped many enterprises stay afloat and the impetus for a massive transition to online. Today, global digitalization allows you to make purchases without leaving your home. At the same time, customers get a complete picture of the product using modern IT technologies, such as AR & Video Consultations, Voice robots and Assistants, make payments using new payment systems, and receive the goods as soon as possible. At the same time, e-commerce faced several challenges. The article examines the trends in the development of e-commerce in the world and the correction of the share of e-commerce in total retail sales in connection with the crisis. Changes in the structure of the ecommerce market of enterprises under the influence of the crisis phenomena are noted. The article identifies the main problems that e-commerce enterprises faced during the last global crisis and the ways to solve them. Technological trends in the global e-commerce market are noted, such as chatbots, blockchain, artificial intelligence, mobile commerce, etc. The article also indicates the main trends in the development of ecommerce under the influence of the crisis. These tendencies are aimed at creating conditions that will quickly or even automatically close the questions and doubts of the user regarding the purchase of goods in the online store and at attracting the most "hot" visitors. The surge in e-commerce due to the crisis has led to increased online businesses and increased competition. Each salesperson fights for a customer, and searching for solutions to win customers generates new trends in online sales. The article highlights the following trends that are necessary to maintain positions in e-commerce: process automation; focus on m-commerce; the use of voice assistants and robots; the use of new different payment methods, including new ones; organization of fast delivery, etc

The Diamond STING Server.

Diamond STING is a new version of the STING suite of programs for a comprehensive analysis of a relationship between protein sequence, structure, function and stability. We have added a number of new functionalities by both providing more structure parameters to the STING Database and by improving/expanding the interface for enhanced data handling. The integration among the STING components has also been improved. A new key feature is the ability of the STING server to handle local files containing protein structures (either modeled or not yet deposited to the Protein Data Bank) so that they can be used by the principal STING components: JavaProtein Dossier (JPD) and STING Report. The current capabilities of the new STING version and a couple of biologically relevant applications are described here. We have provided an example where Diamond STING identifies the active site amino acids and folding essential amino acids (both previously determined by experiments) by filtering out all but those residues by selecting the numerical values/ranges for a set of corresponding parameters. This is the fundamental step toward a more interesting endeavor?the prediction of such residues. Diamond STING is freely accessible at http://sms.cbi.cnptia.embrapa.br and http://trantor.bioc.columbia.edu/SMS.Supplement

Treatment of hyperfunctioning thyroid nodules by percutaneous ethanol injection

BACKGROUND: Autonomous thyroid nodules can be treated by a variety of methods. We assessed the efficacy of percutaneous ethanol injection in treating autonomous thyroid nodules. METHODS: 35 patients diagnosed by technetium-99 scanning with hyperfunctioning nodules and suppressed sensitive TSH (sTSH) were given sterile ethanol injections under ultrasound guidance. 29 patients had clinical and biochemical hyperthyroidism. The other 6 had sub-clinical hyperthyroidism with suppressed sTSH levels (<0.24 μIU/ml) and normal thyroid hormone levels. Ethanol injections were performed once every 1–4 weeks. Ethanol injections were stopped when serum T(3), T(4 )and sTSH levels had returned to normal, or else injections could no longer be performed because significant side effects. Patients were followed up at 3, 6 and, in 15 patients, 24 months after the last injection. RESULTS: Average pre-treatment nodule volume [18.2 ± 12.7 ml] decreased to 5.7 ± 4.6 ml at 6 months follow-up [P < 0.001]. All patients had normal thyroid hormone levels at 3 and 6 months follow-up [P < 0.001 relative to baseline]. sTSH levels increased from 0.09 ± 0.02 μIU/ml to 0.65 ± 0.8 μIU/ml at the end of therapy [P < 0.05]. Only 3 patients had persistent sTSH suppression at 6 months post-therapy. T(4 )and sTSH did not change significantly between 6 months and 2 years [P > 0.05]. Ethanol injections were well tolerated by the patients, with only 2 cases of transient dysphonia. CONCLUSION: Our findings indicate that ethanol injection is an alternative to surgery or radioactive iodine in the treatment of autonomous thyroid nodules

Predicting coaxial helical stacking in RNA junctions

RNA junctions are important structural elements that form when three or more helices come together in space in the tertiary structures of RNA molecules. Determining their structural configuration is important for predicting RNA 3D structure. We introduce a computational method to predict, at the secondary structure level, the coaxial helical stacking arrangement in junctions, as well as classify the junction topology. Our approach uses a data mining approach known as random forests, which relies on a set of decision trees trained using length, sequence and other variables specified for any given junction. The resulting protocol predicts coaxial stacking within three- and four-way junctions with an accuracy of 81% and 77%, respectively; the accuracy increases to 83% and 87%, respectively, when knowledge from the junction family type is included. Coaxial stacking predictions for the five to ten-way junctions are less accurate (60%) due to sparse data available for training. Additionally, our application predicts the junction family with an accuracy of 85% for three-way junctions and 74% for four-way junctions. Comparisons with other methods, as well applications to unsolved RNAs, are also presented. The web server Junction-Explorer to predict junction topologies is freely available at: http://bioinformatics.njit.edu/junction

Risks of dengue secondary infective biting associated with aedes aegypti in home environments in Monterrey, Mexico

Abstract. Secondary dengue virus infections are a major risk for developing dengue hemorrhagic fever. Recent exposure to infectious bites of Aedes aegypti (L.) females in previously diagnosed dengue cases fulfills the epidemiological model of dengue hemorrhagic fever. A study was comprised of 357 (89.2%) dengue and 43 (10.8%) dengue hemorrhagic fever cases confirmed by laboratory tests and clinical manifestations. An entomological survey was done in homes and backyards. Concurrently, a questionnaire was used to assess the impact of healthpromotion campaigns through knowledge of the vector and its epidemiological role. Seventy-six (28.4%) of the 268 (67.0%) total wet or dry oviposition sites were positive for the presence of larvae or pupae, while adult Ae. aegypti were found in 32 (8.0%). One hundred thirty-two (33%) householders who formerly had dengue fever or dengue hemorrhagic fever had knowledge of either larval or adult dengue vector stages. According to gender distribution, 145 (36.2%) and 14 (3.5%) of the males confirmed with cases of dengue and dengue hemorrhagic fever lived in houses with 17.9 and 2% of the Ae. aegypti larval and pupal habitats. Houses with females who had dengue and dengue hemorrhagic fever were 212 (53%) and 29 (7.3%), with containers with immature Ae. aegypti in 19.4 and 7%, respectively. Lack of sustainability of government-targeted health education campaigns is the major problem for involving communities in prevention and control of dengu

Simulation of developmental changes in action potentials with ventricular cell models

During cardiomyocyte development, early embryonic ventricular cells show spontaneous activity that disappears at a later stage. Dramatic changes in action potential are mediated by developmental changes in individual ionic currents. Hence, reconstruction of the individual ionic currents into an integrated mathematical model would lead to a better understanding of cardiomyocyte development. To simulate the action potential of the rodent ventricular cell at three representative developmental stages, quantitative changes in the ionic currents, pumps, exchangers, and sarcoplasmic reticulum (SR) Ca2+ kinetics were represented as relative activities, which were multiplied by conductance or conversion factors for individual ionic systems. The simulated action potential of the early embryonic ventricular cell model exhibited spontaneous activity, which ceased in the simulated action potential of the late embryonic and neonatal ventricular cell models. The simulations with our models were able to reproduce action potentials that were consistent with the reported characteristics of the cells in vitro. The action potential of rodent ventricular cells at different developmental stages can be reproduced with common sets of mathematical equations by multiplying conductance or conversion factors for ionic currents, pumps, exchangers, and SR Ca2+ kinetics by relative activities