Determining the Balance Between Drug Efficacy and Safety by the Network and Biological System Profile of Its Therapeutic Target

One of the most challenging puzzles in drug discovery is the identification and characterization of candidate drug of well-balanced profile between efficacy and safety. So far, extensive efforts have been made to evaluate this balance by estimating the quantitative structure–therapeutic relationship and exploring target profile of adverse drug reaction. Particularly, the therapeutic index (TI) has emerged as a key indicator illustrating this delicate balance, and a clinically successful agent requires a sufficient TI suitable for it corresponding indication. However, the TI information are largely unknown for most drugs, and the mechanism underlying the drugs with narrow TI (NTI drugs) is still elusive. In this study, the collective effects of human protein–protein interaction (PPI) network and biological system profile on the drugs' efficacy–safety balance were systematically evaluated. First, a comprehensive literature review of the FDA approved drugs confirmed their NTI status. Second, a popular feature selection algorithm based on artificial intelligence (AI) was adopted to identify key factors differencing the target mechanism between NTI and non-NTI drugs. Finally, this work revealed that the targets of NTI drugs were highly centralized and connected in human PPI network, and the number of similarity proteins and affiliated signaling pathways of the corresponding targets was much higher than those of non-NTI drugs. These findings together with the newly discovered features or feature groups clarified the key factors indicating drug's narrow TI, and could thus provide a novel direction for determining the delicate drug efficacy-safety balance

Evapotranspiration Measurement and Crop Coefficient Estimation over a Spring Wheat Farmland Ecosystem in the Loess Plateau

<div><p>Evapotranspiration (ET) is an important component of the surface energy balance and hydrological cycle. In this study, the eddy covariance technique was used to measure ET of the semi-arid farmland ecosystem in the Loess Plateau during 2010 growing season (April to September). The characteristics and environmental regulations of ET and crop coefficient (Kc) were investigated. The results showed that the diurnal variation of latent heat flux (LE) was similar to single-peak shape for each month, with the largest peak value of LE occurring in August (151.4 W m⁻²). The daily ET rate of the semi-arid farmland in the Loess Plateau also showed clear seasonal variation, with the maximum daily ET rate of 4.69 mm day⁻¹. Cumulative ET during 2010 growing season was 252.4 mm, and lower than precipitation. Radiation was the main driver of farmland ET in the Loess Plateau, which explained 88% of the variances in daily ET (p<0.001). The farmland Kc values showed the obvious seasonal fluctuation, with the average of 0.46. The correlation analysis between daily Kc and its major environmental factors indicated that wind speed (Ws), relative humidity (RH), soil water content (SWC), and atmospheric vapor pressure deficit (VPD) were the major environmental regulations of daily Kc. The regression analysis results showed that Kc exponentially decreased with Ws increase, an exponentially increased with RH, SWC increase, and a linearly decreased with VPD increase. An experiential Kc model for the semi-arid farmland in the Loess Plateau, driven by Ws, RH, SWC and VPD, was developed, showing a good consistency between the simulated and the measured Kc values.</p></div

The response of evapotranspiration (ET) to net radiation (Rn) and soil water content (SWC) over the semi-arid farmland ecosystem in the Loess Plateau.

<p>ET data were averaged with Rn bins of 1⁻² (a), and SWC bins of 1% (b), respectively, during the growing season over the semi-arid farmland ecosystem in the Loess Plateau. Error bars represent one standard error.</p

Seasonal variation of environmental factors over the semi-arid farmland ecosystem in the Loess Plateau.

<p>Seasonal variation of environmental factors over the semi-arid farmland ecosystem in the Loess Plateau.</p

Regression analysis between daily crop coefficient (Kc) and mainly environmental factors over the semi-arid farmland ecosystem in the Loess Plateau.

<p>Ws, wind speed (m s⁻¹); RH: air relative humidity (%); SWC, soil water content (%); VPD, vapor pressure deficit (kPa).</p

Seasonal variation of crop coefficient (Kc) over the semi-arid farmland ecosystem in the Loess Plateau.

<p>Seasonal variation of crop coefficient (Kc) over the semi-arid farmland ecosystem in the Loess Plateau.</p

Monthly averaged diurnal variations of energy fluxes over the semi-arid farmland ecosystem in the Loess Plateau.

<p>Error bars represent one standard error. Rn, net radiation (W m⁻²); H, sensible heat flux (W m⁻²); LE, latent heat flux (W m⁻²).</p

Effects of Temperature Increase on Pea Production in a semiarid Region of China

In this study, a field experiment was used to evaluate a pea crop ( Pisum sativum L. ) at Tongwei Experimental Station (35 ° 13'N, 105 ° 14'E), which is in a semiarid region of China. In this experiment, the mean daily temperature was designed to increase by 0.6-2.2 ° C throughout the complete growth stage of the pea crop. When the mean daily temperature increased by approximately 2.2 ° C, the water use efficiency (WUE) of the pea crop decreased by 30.4%, the duration of the growth stage was shortened by approximately 17 days, the yields were decreased by 17.5%, the number of stems with root-rot sickness were increased by 50.6%, and the input-output ratio (In/Ou) of the pea crop was 1.20. When the mean daily temperature was increased by approximately 1.4 ° C, the WUE decreased by 26.1%, the growth stage duration decreased by 10 days, the yields decreased by 11.1%, the number of stems with root-rot sickness increased by 23.3%, and the input-output ratio (In/Ou) was 1.11. In addition, supplementary irrigation was found to be beneficial to the pea yields when the temperature increased. Indeed, application of 60 mm of supplementary irrigation during the complete growth stages of crops that were subjected to an increase in mean daily temperature of 0.6-2.2 ° C resulted in crop yields improving by 8.3%-12.8%. Consequently, in this region, supplementary irrigation may play an important role in maintaining pea yields that would otherwise be affected by climate warming. However, the results also show that application of 60 mm of supplementary irrigation does not decrease the number of stems with root-rot sickness and that the In/Ou ratio of pea crops subjected to the same temperature conditions will increase

The response of crop coefficient (Kc) to wind speed (Ws), relative humidity (RH), soil water content (VPD), and vapor pressure deficit (VPD), respectively.

<p>Kc data were averaged with Ws bins of 0.5⁻¹ (a), RH bins of 10% (b), SWC bins of 2% (c) and VPD bins of 0.2 kPa, respectively, during the growing season over the semi-arid farmland ecosystem in the Loess Plateau. Error bars represent one standard error.</p