e Drug-resistant tuberculosis (TB), especially multidrug-resistant TB (MDR-TB), is still one of the most serious threats to TB control worldwide. Early diagnosis of MDR-TB is important for effectively blocking transmission and establishing an effective protocol for chemotherapy. Genechip is a rapid diagnostic method based on molecular biology that overcomes the poor biosafety, time consumption, and other drawbacks of traditional drug sensitivity testing (DST) that can detect MDR-TB. However, the Genechip approach has not been effectively evaluated, especially in limited-resource laboratories. In this study, we evaluated the performance of Genechip for MDR-TB in 1,814 patients in four prefectural or municipal laboratories and compared its performance with that of traditional DST. The results showed that the sensitivity and specificity of Genechip were 87.56% and 97.95% for rifampin resistance and 80.34% and 95.82% for isoniazid resistance, respectively. In addition, we found that the positive grade of the sputum smears influenced the judgment of results by Genechip. The test judged only 75% of the specimens of "scanty" positive grade. However, the positive grade of the specimens showed no influence on the accuracy of Genechip. Overall, the study suggests that, in limited-resource laboratories, Genechip showed high sensitivity and specificity for rifampin and isoniazid resistance, making it a more effective, rapid, safe, and cost-beneficial method worthy of broader use in limited-resource laboratories in China.
We have fabricated magnetic tunneling junctions by oxidizing a wedge-shaped aluminum layer to produce junctions with ideal oxidized as well as under and over oxidized junctions on a single wafer. By investigating the capacitance spectra, we are able to study the effects due to interface charge accumulation. The electron–electron interaction among accumulated interface charges leads to a voltage drop inside the magnetic electrodes, resulting in the measured capacitance differing from the geometric capacitance. We have extracted an interfacial capacitance of 16 μF/cm2 per interface and a screening length of 0.55 Å for FeNi electrodes.
A slowdown in the warming rate of the global mean surface temperature has been observed since late 1990s. However, it is still controversial whether the spatiotemporal variability of extreme temperature events will increase after global warming slowdown, and whether the regional diversity of change trends will increase. Here, we investigated the variations in extreme temperature indices over the Loess Plateau in China since 1961 and focused on the recent global warming slowdown (1998-2018). We found that, during 1961-2018, all the extreme temperature indices showed a significant warming trend and its intensity varied according to extreme temperature indices over different regions. A warming slowdown of annual mean temperature during 1998-2018 was primarily due to the slight increases of annual mean maximum temperatures (TXm) while the annual mean minimum temperature (TNm) still indicated prominently warming trends. During the recent warming slowdown period, the warm indices showed continued intensification of the warming trends, while the cold indices showed a slight cooling trend. Moreover, all extreme temperature indices showed the largest warming trend in summer and a slight cooling trend in winter. Overall, the extreme temperature events have become more diverse in spatial and temporal, indicating that regional climate are more unstable than previously reported for this region. Further analyses revealed that the extreme temperature events during the recent warming slowdown Zhiyong Ding and Jia Pu contributed equally to this study.
This article reports the rational medicinal chemistry of a natural product, agrimophol (1), as a new disruptor of intrabacterial pH (pH IB ) homeostasis in Mycobacterium tuberculosis (Mtb). Through the systematic investigation of the structure−activity relationship of 1, scaffold-hopping of the diphenylmethane scaffold, pharmacophore displacement strategies, and studies of the structure− metabolism relationship, a new derivative 5a was achieved. Compound 5a showed 100-fold increased potency in the ability to reduce pH IB to pH 6.0 and similarly improved mycobactericidal activity compared with 1 against both Mycobacterium bovis-BCG and Mtb. Compound 5a possessed improved metabolic stability in human liver microsomes and hepatocytes, lower cytotoxicity, higher selectivity index, and similar pK a value to natural 1. This study introduces a novel scaffold to an old drug, resulting in improved mycobactericidal activity through decreasing pH IB , and may contribute to the critical search for new agents to overcome drug resistance and persistence in the treatment of tuberculosis.
With the intensification of global warming, spatiotemporal variations in the climate and their mechanisms have received increasing attention. Currently, the relationship between regional precipitation regime, large-scale circulation, and topography, particularly in high-altitude areas such as the Qinghai–Tibet Plateau, are not well understood. Herein, the spatial and temporal variability in the annual and intra-annual (wet and dry periods) precipitation at 33 stations in the Three-River Headwaters (TRH) region from 1967 to 2016 are analysed. Moreover, the empirical orthogonal function and wavelet transform coherence methods are used to analyse the relationships between the different modes of precipitation change and 14 atmospheric circulation indices. The following results were obtained. (1) The mean annual precipitation and mean dry period precipitation significantly increased over the studied period. Annual and intra-annual precipitation showed a spatial southeast-to-northwest decreasing trend. (2) Two main patterns of precipitation were observed during the studied period: a dominant pattern with high- and low-value centres located in southeast and northwest TRH, respectively, and a dipole pattern with more precipitation over southwest TRH and less precipitation over northeast TRH. (3) Precipitation had a negative correlation with latitude, positive correlation with longitude, and nonlinear relationship with elevation. (4) Precipitation changes over various parts of the studied domain were determined based on changes in the weather systems affecting the area, with different indices being correlated with different components during different times of the year.
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