First-time-in-human study and prediction of early bactericidal activity for GSK3036656, a potent leucyl-tRNA synthetase inhibitor for tuberculosis treatment

This first-time-in-human (FTIH) study evaluated the safety, tolerability, pharmacokinetics, and food effect of single and repeat oral doses of GSK3036656, a leucyl-tRNA synthetase inhibitor. In part A, GSK3036656 single doses of 5 mg (fed and fasted), 15 mg, and 25 mg and placebo were administered. In part B, repeat doses of 5 and 15 mg and placebo were administered for 14 days once daily. GSK3036656 showed dose-proportional increase following single-dose administration and after dosing for 14 days. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to the end of the dosing period (AUC0–τ) showed accumulation with repeated administration of approximately 2- to 3-fold. Pharmacokinetic parameters were not altered in the presence of food. Unchanged GSK3036656 was the only drug-related component detected in plasma and accounted for approximately 90% of drug-related material in urine. Based on total drug-related material detected in urine, the minimum absorbed doses after single (25 mg) and repeat (15 mg) dosing were 50 and 78%, respectively. Unchanged GSK3036656 represented at least 44% and 71% of the 25- and 15-mg doses, respectively. Clinical trial simulations were performed to guide dose escalation during the FTIH study and to predict the GSK3036656 dose range that produces the highest possible early bactericidal activity (EBA0–14) in the prospective phase II trial, with consideration of the predefined exposure limit. GSK3036656 was well tolerated after single and multiple doses, with no reports of serious adverse events. (This study has been registered at ClinicalTrials.gov under identifier NCT03075410.

Efficient Mutual Exclusion in Peer-to-Peer Systems

Due to the recent surge in the area of Grid computing, there is an urgency to find efficient ways of protecting consistent and concurrent access to shared resources. Traditional peer-to-peer (p2p) applications such as Kazaa and Gnutella have been primarily used for sharing read-only files (such as mpegs and mp3s). This paper introduces two novel protocols, the End-to-End and Non End-to-End, for achieving mutual exclusion efficiently in dynamic p2p systems. The protocols are layered atop a distributed hash table (DHT), making them scalable and fault-tolerant. The burden of controlling access to the critical section is also evenly distributed among all the nodes in the network, making the protocols more distributed and easily adaptable to growing networks. Since the protocols are designed independent of any specific DHT implementation, they can be incorporated with any generic p2p DHT, depending on the application requirements. We present experiments comparing our implementations with existing mutual exclusion algorithms. The significant reduction in overall message overhead and better load-balancing mechanisms makes the proposed protocols very attractive in being used for current and future p2p and Grid applications

The Effect of Climate Change on Mental Health in Teenagers

The effect of climate change on mental health has been observable in cultures and populations deeply rooted in their environments, but is now becoming increasingly visible in the general population as well (Pikhala 2020). The effect of climate change on the mental health of teenagers has not been well observed, previous research has indicated that the media and narratives surrounding climate change can be damaging to both mental health and detrimental to environmental advocacy groups (McKinley 2008). The purpose of the study was to observe negative effects of climate change on the mental health of teenagers, and compare effects to positive climate action taken by participants. It was hypothesized that students who take positive climate action are more negatively affected by climate change, as mental health effects such as anxiety prompt evasive action (Stanley 2021). This study used a likert scale survey asking respondents to rate the degree to which they experience various negative emotions as a result of climate change and evaluate the positive climate action they take. The respondents were sorted into groups of those who believe they help the environment, and those who do not, and the effect of climate change on mental health was compared between the two groups. The 11 participants who take positive climate action (M=-0.5, SD=6.27) compared to the 20 who do not take positive climate action (M=5.636, SD,=5.278) were more negatively affected by climate change t(29)=5.6398, p=2.898

Determination of the Pre-Qualification Rules for the Acceptance Testing of MVDC Cable System

In the transmission and distribution network of the future, there is expected to be a mix of both Alternating Current (AC) and Direct Current (DC). In the high voltage division owing to technical and economic aspects, there is a wider use of High Voltage Direct Current (HVDC) instead of High Voltage Alternating Current (HVAC). However, when observing the medium voltage network, it is noticed that it is completely AC in nature. One major reason for this preference of AC in the medium voltage network is the better know-how of an AC network and the presence of well established and reliable MVAC components and the ability to transform (step up and down) voltage in AC. A switch to Medium Voltage Direct Current (MVDC) is expected as the cost of power electronic components is decreasing with time, and there is an improvement in their performance. Therefore, switching to MVDC would provide advantages in the form of improved transfer capacity and better power control. MVDC grids are debated to be a vital member of the future distribution network. In the present scenario, there is an absence of such an MVDC grid. Thereby, there are also no MVDC accessories available which can be used in such a grid. Therefore, there is also the absence of a testing procedure for the same. CIGRE TB 496 provides the testing strategies for DC cable systems up to 500 kV, but it does not take into consideration the difference between an MVDC system and an HVDC system. The systems may have a striking difference in construction, such as concerning materials. Additionally, there is also a difference concerning max field stresses and thickness of the insulation. The possibility of using the AC accessories for DC application needs to be analysed, and it needs to be verified how such an AC accessory would behave under the influence of prolonged DC stresses. The use of existing MVAC accessories for DC would be beneficial given the high production standards and the voluminous supply chain of MVAC systems. Additionally, this also opens possibilities of reusing existing AC cable system for DC stress. It needs to be noticed that in DC, the field distribution would depend on the conductivity of the material which is different from AC where the field distribution depends on the permittivity of the material. The permittivity of insulation is virtually independent of the temperature. However, conductivity has a strong relation to temperature and electric field, which makes DC field distribution more complex when compared to AC field distribution for any geometry. The test criteria of MVAC and pre-qualification test for HVDC are well known and need to be utilised in proposing and motivating the test sequence and test voltages for the accessories to be used in the future MVDC network. These accessories to be used in this future MVDC cable system needs to be analysed using Finite Element Method (FEM). The field simulations would give identification of locations in the joint which are undergoing maximum stresses during DC application. These maximum values of stresses are used to calculate the voltage life of the system based on electro-thermal life laws. The test results based on the representative testing procedure would help in understanding the performance and lifetime of the cable systems under DC stress. Therefore, to understand all items previously mentioned, a representative testing procedure needs to be proposed and motivated to test the use of existing MVAC accessories in the future MVDC network

Comparison of proverbs in Iraq Turkmen Turkic with proverbs in Turkey, Azerbaijan and Turkmen Turkic

Tez, yazarı tarafından 16.09.2020 tarihine kadar erişime kısıtlanmıştır.Bu çalışma, Irak Türkmen Türkçesi söz varlığında kullanılan atasözlerinin tespiti ve tespit edilen bu atasözlerinin Güney batı-Oğuz grubu Türk lehçelerinin temsilcilerinden olan Türkiye Türkçesi, Azerbaycan Türkçesi ve Türkmen Türkçesinde var olan atasözleriyle karşılaştırılması amacıyla hazırlanmıştır. Bu karşılaştırmayla Irak Türkmen Türkçesinin Oğuz grubu Türk lehçeleri içindeki yerinin tespiti ve bu lehçenin söz varlığına dair malzemenin ortaya konması hedeflenmektedir. Çalışmada malzeme olarak eş zamanlı yöntemle derlenen Irak Türkmenlerinin kullandığı 2446 atasözü ele alınmıştır. Bu atasözleri, hem söz varlığı ile ilgili hem de bu lehçenin gramer yapısı ile ilgili sonuçlara ulaşmak için kullanılmıştır.This study has been prepared with the aim of determining proverbs used in vocabulary of Iraqi Turkmen Turkic Language and comparing with the proverbs used in Turkish Language (spoken in Turkey), Azerbaijani Turkish and Turkmen Turkic Language which are representatives of South Western-Oghuz group Turkish dialects. With this comparison, it is aimed to determine the place of Iraqi Turkmen Turkic Language in Turkish dialects of Oghuz group and to reveal the materials belonging to the vocabulary of this dialect. In the study, 2446 proverbs which are used by Iraqi Turkmens and have been compiled with simultaneous method were analyzed as the material. These proverbs have been used in order to attain results both related to vocabulary and grammar structure of this dialect

Lead and Mercury Exposure and Related Health Problems in Metal Artisan Workplaces and High-Risk Household Contacts in Thimphu, Bhutan

Background. Metal artisans have been using lead and mercury in their settings for centuries. Exposure to these toxic heavy metals causes adverse health effects. We assessed the occupational exposure of metal artisans and their high-risk household contacts at Thimphu, Bhutan. Methods. A cross-sectional study in which 134 metal artisan center employees and 48 high-risk household contacts were tested for blood lead and mercury levels. Sociodemographic data, occupational exposure risk factors, and clinical syndrome related to lead and mercury exposure were further obtained and analyzed using EpiInfo 7.0. Results. The mean age of the metal artisan center employees was 36.02 ± 10.3. The prevalence of elevated blood lead and mercury level was 38.4% and 51.9%, respectively. Significantly higher prevalence of mercury level was observed among the artisans compared to nonartisans (66.97 vs, 16.0). Among three centers, the goldsmith section of the Department of National Properties had the highest (94.1%). Profession as an artisan, mold designing, performing gold amalgamation, working for >8 hours a day, working for >5 years, and working at home were significant risk factors associated with elevated blood mercury level. Significant association was observed between elevated mercury level and complaints of burning or watery eyes (p=0.001), anxiety, nervousness, irritability, severe shyness (p=0.029), muscle aches (p=0.019), and stomach cramps or pain (p=0.009). Conclusion. The prevalence of elevated blood mercury level is concerning among the artisans. Advocacy, proper usage of personal protective equipment, awareness on chemical safety, and hazard associated with lead and mercury usage are needed to minimize the exposure

Using Google classroom platform in learning comprehension materials among second stage students of the English language department

The study attempts to investigate the issue of using Google classroom platform in learning comprehension materials among students in the second stage of the English language department. The study aims to determine the impact of using Google classroom on learning comprehension materials. The study sample consists of (60) students in the second grade in the department of English at the college of Basic Education at the University of Diyala. The sample is divided into two groups, the control group consists of 30 students, and the experimental group consists of 30 students. The study findings reveal that the use of Google classroom promoted the mastery of comprehension materials among students. The findings also stress the necessity of face-to-face instruction

Precursor-Directed Generation of Indolocarbazoles with Topoisomerase IIα Inhibitory Activity

One new indolocarbazole, 3-hydroxy-K252d (3), together with the recently reported 3-hydroxyholyrine A (1) and 3′-N-acetyl-3-hydroxyholyrine A (2), were obtained by feeding a culture of the marine-derived Streptomyces strain OUCMDZ-3118 with 5-hydroxy-l-tryptophan. Their structures were elucidated on the basis of spectroscopic analysis. Compound 1 potently induced apoptosis of gastric cancer cells by inhibiting topoisomerase IIα enzyme activity and reducing the expression of antiapoptosis protein level. Compound 3 displayed moderate cytotoxicity against the A549 and MCF-7 cell lines with IC50 values of 1.2 ± 0.05 μM, 1.6 ± 0.09 μM, respectively