Congestion game scheduling for virtual drug screening optimization.

In virtual drug screening, the chemical diversity of hits is an important factor, along with their predicted activity. Moreover, interim results are of interest for directing the further research, and their diversity is also desirable. In this paper, we consider a problem of obtaining a diverse set of virtual screening hits in a short time. To this end, we propose a mathematical model of task scheduling for virtual drug screening in high-performance computational systems as a congestion game between computational nodes to find the equilibrium solutions for best balancing the number of interim hits with their chemical diversity. The model considers the heterogeneous environment with workload uncertainty, processing time uncertainty, and limited knowledge about the input dataset structure. We perform computational experiments and evaluate the performance of the developed approach considering organic molecules database GDB-9. The used set of molecules is rich enough to demonstrate the feasibility and practicability of proposed solutions. We compare the algorithm with two known heuristics used in practice and observe that game-based scheduling outperforms them by the hit discovery rate and chemical diversity at earlier steps. Based on these results, we use a social utility metric for assessing the efficiency of our equilibrium solutions and show that they reach greatest values.

Genetic spectrum of sarcoglycanopathies in a cohort of Russian patients.

Sarcoglycanopathies encompass four distinct forms of limb-girdle muscular dystrophies (LGMD), denoted as LGMD R3-R6, arising from mutations within the SGCA, SGCB, SGCG, and SGCD genes. The global prevalence of sarcoglycanopathies is low, making it challenging to study these diseases. The principal objective of this study was to explore the spectrum of mutations in a cohort of Russian patients with sarcoglycanopathies and to ascertain the frequency of these conditions in the Russian Federation. We conducted a retrospective analysis of clinical and molecular genetic data from 49 Russian patients with sarcoglycan genes variants. The results indicated that variants in the SGCA gene were found in 71.4% of cases, with SGCB and SGCG genes each exhibiting variants in 12.2 % of patients. SGCD gene variants were detected in 4.1% of cases. Bi-allelic pathogenic and likely pathogenic variants were identified in 46 of the 49 cases of sarcoglycanopathies: LGMD R3 (n = 34), LGMD R4 (n = 4), LGMD R5 (n = 6), and LGMD R6 (n = 2). A total of 31 distinct variants were identified, comprising 25 previously reported and 6 novel variants. Two major variants, c.229C>T and c.271G>A, were detected within the SGCA, constituting 61.4% of all mutant alleles in Russian patients with LGMD R3. Both LGMD R6 cases were caused by the homozygous nonsense variant c.493C>T p.(Arg165Ter) in the SGCD gene. The incidence of sarcoglycanopathies in the Russian Federation was estimated to be at least 1 in 4,115,039, which is lower than the reported incidence in other populations.

Laser-Formed Sensors with Electrically Conductive MWCNT Networks for Gesture Recognition Applications.

Currently, an urgent need in the field of wearable electronics is the development of flexible sensors that can be attached to the human body to monitor various physiological indicators and movements. In this work, we propose a method for forming an electrically conductive network of multi-walled carbon nanotubes (MWCNT) in a matrix of silicone elastomer to make stretchable sensors sensitive to mechanical strain. The electrical conductivity and sensitivity characteristics of the sensor were improved by using laser exposure, through the effect of forming strong carbon nanotube (CNT) networks. The initial electrical resistance of the sensors obtained using laser technology was ~3 kOhm (in the absence of deformation) at a low concentration of nanotubes of 3 wt% in composition. For comparison, in a similar manufacturing process, but without laser exposure, the active material had significantly higher values of electrical resistance, which was ~19 kOhm in this case. The laser-fabricated sensors have a high tensile sensitivity (gauge factor ~10), linearity of >0.97, a low hysteresis of 2.4%, tensile strength of 963 kPa, and a fast strain response of 1 ms. The low Young's modulus values of ~47 kPa and the high electrical and sensitivity characteristics of the sensors made it possible to fabricate a smart gesture recognition sensor system based on them, with a recognition accuracy of ~94%. Data reading and visualization were performed using the developed electronic unit based on the ATXMEGA8E5-AU microcontroller and software. The obtained results open great prospects for the application of flexible CNT sensors in intelligent wearable devices (IWDs) for medical and industrial applications.

Emerging transmitted drug resistance in treatment-naïve human immunodeficiency virus-1 CRF06_cpx-infected patients in Estonia.

Human immunodeficiency virus (HIV)-1 transmitted drug resistance in the drug-naïve population is of growing relevance in Estonia, where the number of antiretroviral (ARV) treatment-experienced subjects has been exponentially increasing during the last 10 y. The aim of this study was to estimate the rate of transmitted drug resistance among newly diagnosed subjects in Estonia in 2008. Genotypic resistance testing for viral genomic RNA was conducted for 201 subjects tested HIV-positive between 1 April and 30 November 2008. Of 145 genotyped viral strains in newly diagnosed patients, 123 were CRF06_cpx, 2 were subtype A1 and 3 were subtype B; in 17 cases viral sequences revealed recombinant structures similar to CRF06_cpx, subtype A1 and CRF02_AG. Resistance mutations were found in 8 (5.5%) virus strains, and 3 strains were resistant to at least 2 ARV classes. A total of 2.8% of sequences harboured mutations indicating nucleoside/nucleotide reverse transcriptase inhibitor resistance (M41L, M184V, M184I, T215C and T215D), 2.1% non-nucleoside reverse transcriptase inhibitor resistance (K103N, P225H) and 2.8% protease inhibitor resistance (M46I, L90M). These data suggest the need to extend genotypic HIV-1 drug resistance testing to newly diagnosed HIV-positive subjects to prevent potential ARV treatment failure.

Endocrine-disrupting activity of mancozeb.

The objective of the present study was to review the existing data on the mechanisms involved in the endocrine disrupting activity of mancozeb (MCZ) in its main targets, including thyroid and gonads, as well as other endocrine tissues that may be potentially affected by MCZ. MCZ exposure was shown to interfere with thyroid functioning through impairment of thyroid hormone synthesis due to inhibition of sodium-iodine symporter (NIS) and thyroid peroxidase (TPO) activity, as well as thyroglobulin expression. Direct thyrotoxic effect may also contribute to thyroid pathology upon MCZ exposure. Gonadal effects of MCZ involve inhibition of sex steroid synthesis due to inhibition of P450scc (CYP11A1), as well as 3ß-HSD and 17ß-HSD. In parallel with altered hormone synthesis, MCZ was shown to down-regulate androgen and estrogen receptor signaling. Taken together, these gonad-specific effects result in development of both male and female reproductive dysfunction. In parallel with clearly estimated targets for MCZ endocrine disturbing activity, namely thyroid and gonads, other endocrine tissues may be also involved. Specifically, the fungicide was shown to affect cortisol synthesis that may be mediated by modulation of CYP11B1 activity. Moreover, MCZ exposure was shown to interfere with PPARγ signaling, being a key regulator of adipogenesis. The existing data also propose that endocrine-disrupting effects of MCZ exposure may be mediated by modulation of hypothalamus-pituitary-target axis. It is proposed that MCZ neurotoxicity may at least partially affect central mechanisms of endocrine system functioning. However, further studies are required to unravel the mechanisms of MCZ endocrine disrupting activity and overall toxicity.

Hepatic glycogen synthase (GYS2) deficiency: seven novel patients and seven novel variants.

Glycogen storage disease type 0 (GSD 0) is an autosomal recessive disorder of glycogen metabolism caused by mutations in the GYS2 gene manifesting in infancy or early childhood and characterized by ketotic hypoglycemia after prolonged fasting, and postprandial hyperglycemia and hyperlactatemia. GSD 0 is a rare form of hepatic glycogen storage disease with less than 30 reported patients in the literature so far.DNA samples of 93 Russian patients with clinical diagnoses of hepatic GSDs were collected and analyzed by next-generation sequencing custom target panel and by direct sequencing. Seven new GSD 0 patients with variable phenotypes were found showing 10 variants. Seven variants are novel.We present seven new GSD 0 patients with variable phenotypes. Overall, 10 different mutant alleles of the GYS2 gene were found. Seven of them are novel: c.214delC, c.845delT, c.1644C>A, c.205T>A, c.929G>T, c.1169G>C and c.1703C>A. Three of the novel variants were annotated as pathogenic and likely pathogenic; four other variants have an uncertain significance.The current results expand the spectrum of known mutations in GYS2 and suggest that phenotypes of GSD 0 are more variable and less specific than the reported ones. SYNOPSIS: Seven new patients with glycogen storage disease type 0 were found using next-generation sequencing and seven novel variants of GYS2 gene were annotated.

Absence of genotypic drug resistance and presence of several naturally occurring polymorphisms of human immunodeficiency virus-1 CRF06_cpx in treatment-naive patients in Estonia.

All non-B HIV-1 subtypes and circulating recombinant forms (CRFs) are characterized by several polymorphisms in protease (PR) region. In addition, in recent years the increasing use of antiretroviral treatment (ART) has rapidly raised the spread of transmitted drug resistance. We aimed to determine the presence of naturally occurring polymorphisms and transmitted drug resistance mutations (DRMs) in ART naïve HIV-1-positive subjects in Estonia. A total of 115 drug-naive HIV-1-infected subjects (mean age 27 years; 70% male; 65% infected via intravenous drug use and 34% by heterosexual contact) were enrolled. Viral genomic RNA from plasma was directly sequenced in PR, revertase (RT), and envelope (env) regions. Phylogenetic analysis of RT and env regions revealed that 89% and 3% of sequenced viruses belonged to CRF06_cpx and subtype A1, respectively, and 6% were described as unique recombinants (signed A1-06) between CRF06_cpx and subtype A1 viruses. No primary DRMs were found in PR or RT regions indicating the absence of transmitted drug resistance. The most common polymorphisms in the PR region were K14R, M36I, H69K, and L89M seen in 96%, 100%, 99%, and 100%, respectively. The clinical relevance of these polymorphisms in terms of success of ART has to be monitored in future clinical studies.

Decreased heart rate variability in patients with psoriatic arthritis.

The purpose of this study was to investigate autonomous regulation of the cardiac activity by means of the heart rate variability (HRV) assessment and possible influence of conventional cardiovascular risk factors and disease activity parameters on it in patients with psoriatic arthritis (PsA). In total, 38 patients with the reliable diagnosis of PsA without clinically manifest cardiovascular pathology, known rhythm or conduction disturbances, diabetes mellitus, and hypercholesterolemia were included. In the control group, 25 age- and sex-matched healthy persons comparable with PsA patients in cardiovascular risk profile were included. For the HRV analysis, we used 5-min-long ECG records obtained at rest. Time and frequency domain parameters of HRV were calculated. Patients with PsA had decreased HRV in comparison to healthy controls as reflected by decrease of the standard deviation of normal R-R intervals (65.1 ± 66.8 vs. 83.2 ± 43.3 ms, respectively, p = 0.011), of the percentage of normal R-R intervals that differ by more than 50 ms (12.9 ± 15.4 vs. 20.6 ± 17.1 %, respectively, p = 0.035), and of the total power (2,069.4 ± 1,537.8 vs. 2,942.5 ± 1,734.2 ms(2), respectively, p = 0.006). A significant correlation of HRV parameters with disease duration and parameters of disease activity in PsA was found. Patients with PsA had impaired autonomous regulation of the cardiac activity, which is likely to be related to the presence of systemic inflammation and which could contribute to the increase of cardiovascular risk in this disease.

Characterization of integrase region polymorphisms in HIV type 1 CRF06_cpx viruses in treatment-naive patients in Estonia.

Natural polymorphisms of HIV-1, often associated with drug resistance, are widely described in protease and reverse transcriptase regions but data on their presence in the integrase region, especially in non-B subtypes, are still very limited. We aimed to characterize naturally occurring polymorphisms in the integrase region in 104 treatment-naive and 10 treatment-experienced patients infected predominantly with HIV-1 CRF06_cpx and its recombinant with subtype A1 and/or CRF03_AB viruses. No primary drug resistance mutations against integrase inhibitors were found, but resistance-associated polymorphisms such as V72I, L74I, V201I, and T206S were seen in more than 90% of viruses. Substitutions E157Q and E157K, associated with raltegravir resistance, were found in only two CRF06_cpx strains. We conclude that similar to other HIV-1 non-B subtypes, the CRF06_cpx and its recombinants with subtype A1 and CRF03_AB are rich in integrase region natural polymorphisms, which may impact the development of resistance against integrase inhibitors.