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Polyketide synthase 13 (Pks13), an essential enzyme for the survival of Mycobacterium tuberculosis (Mtb), is an attractive target for new anti-TB agents. In our previous work, we have identified 2-phenylindole derivatives against Mtb. The crystallography studies demonstrated that the two-position phenol was solvent-exposed in the Pks13-TE crystal structure and a crucial hydrogen bond was lost while introducing bulkier hydrophobic groups at indole N moieties. Thirty-six N-phenylindole derivatives were synthesized and evaluated for antitubercular activity using a structure-guided approach. The structure–activity relationship (SAR) studies resulted in the discovery of the potent Compounds 45 and 58 against Mtb H37Rv, with an MIC value of 0.0625 μg/mL and 0.125 μg/mL, respectively. The thermal stability analysis showed that they bind with high affinity to the Pks13-TE domain. Preliminary ADME evaluation showed that Compound 58 displayed modest human microsomal stability. This report further validates that targeting Pks13 is a valid strategy for the inhibition of Mtb and provides a novel scaffold for developing leading anti-TB compounds. [ABSTRACT FROM AUTHOR]

The energy planning process essentially requires addressing diverse planning objectives, including prioritizing resources, and the estimation of environmental emissions and associated health risks. This study investigates the impacts of atmospheric pollution for Pakistan from the energy production processes under various modalities. A national-scale bottom-up energy optimization model (Pak-TIMES) with the ANSWER-TIMES framework is developed to assess the electricity generation pathways (2015–2035) and estimate GHG emissions and major air pollutants, i.e., CH4, CO, CO2, N2O, NOX, PM1, PM10, PM2.5, PMBC, PMOC, PMTSP, SO2, and VOC under five scenarios. These scenarios are: BAU (business-as-usual), RE-30 (30% renewables), RE-40 (40% renewables), Coal-30 (30% coal), and Coal-40 (40% coal). It is revealed that to reach the electricity demand of 3091 PJ in 2035, both the Coal-30 and Coal-40 scenarios shall cause maximum emissions of GHGs, i.e., 260.13 and 338.92 Mt (million tons) alongside 40.52 and 54.03 Mt emissions of PMTSP in both of the scenarios, respectively. BAU scenario emissions are estimated to be 181.5 Mt (GHGs) and 24.30 Mt (PMTSP). Minimum emissions are estimated in the RE-40 scenario with 96.01 Mt of GHGs and 11.80 Mt of PMTSP, followed by the RE-30 scenario (143.20 GHGs and 17.73 Mt PMTSP). It is, therefore, concluded that coal-based electricity generation technologies would be a major source of emission and would contribute the highest amount of air pollution. This situation necessitates harnessing renewables in the future, which will significantly mitigate public health risks from atmospheric pollution. [ABSTRACT FROM AUTHOR]

Analyzing flooding in urban areas is a great challenge due to the lack of long-term rainfall records. This study hereby seeks to propose a modeling framework for urban flood analysis in ungauged drainage basins. A platform called "RainyDay" combined with a nine-year record of hourly, 0.1° remotely sensed rainfall data are used to generate extreme rainfall events. These events are used as inputs to a hydrological model. The comprehensive characteristics of urban flooding are reflected through the projection pursuit method. We simulate runoff for different return periods for a typical urban drainage basin. The combination of RainyDay and short-record remotely sensed rainfall can reproduce recent observed rainfall frequencies, which are relatively close to the design rainfall calculated by the intensity-duration-frequency formula. More specifically, the design rainfall is closer at high (higher than 20-yr) return period or long duration (longer than 6 h). Contrasting with the flood-simulated results under different return periods, RainyDay-based estimates may underestimate the flood characteristics under low return period or short duration scenarios, but they can reflect the characteristics with increasing duration or return period. The proposed modeling framework provides an alternative way to estimate the ensemble spread of rainfall and flood estimates rather than a single estimate value. [ABSTRACT FROM AUTHOR]