Directly Suppressing MYC Function with Novel Alkynyl-Substituted Phenylpyrazole Derivatives that Induce Protein Degradation and Perturb MYC/MAX Interaction.

Despite being a highly sought-after therapeutic target for human malignancies, myelocytomatosis viral oncogene homologue (MYC) has been considered intractable due to its intrinsically disordered nature, making the discovery of in vivo effective inhibitors that directly block its function challenging. Herein, we report structurally novel alkynyl-substituted phenylpyrazole derivatives directly perturbing MYC function. Among them, compound 37 exhibited superior antiproliferative activities to those of MYCi975 against multiple malignant cell lines. It induced dose-dependent MYC degradation in cells with degradation observed at the concentration as low as 1.0 µM. Meanwhile, its direct suppression of MYC function was confirmed by the capability to inhibit the binding of MYC/MYC-associated protein X (MAX) heterodimer to DNA consensus sequence, induce MYC thermal instability, and disturb MYC/MAX interaction. Moreover, 37 demonstrated enhanced therapeutic efficacy over MYCi975 in a mouse allograft model of prostate cancer. Overall, 37 deserves further development for exploring MYC-targeting cancer therapeutics.

Exploitation of Proximity-Mediated Effects in Drug Discovery: An Update of Recent Research Highlights in Perturbing Pathogenic Proteins and Correlated Issues.

The utilization of proximity-mediated effects to perturb pathogenic proteins of interest (POIs) has emerged as a powerful strategic alternative to conventional drug design approaches based on target occupancy. Over the past three years, the burgeoning field of targeted protein degradation (TPD) has witnessed the expansion of degradable POIs to membrane-associated, extracellular, proteasome-resistant, and even microbial proteins. Beyond TPD, researchers have achieved the proximity-mediated targeted protein stabilization, the recruitment of intracellular immunophilins to disturb undruggable targets, and the nonphysiological post-translational modifications of POIs. All of these strides provide new avenues for innovative drug discovery aimed at battling human malignancies and other major diseases. This perspective presents recent research highlights and discusses correlated issues in developing therapeutic modalities that exploit proximity-mediated effects to modulate pathogenic proteins, thereby guiding future academic and industrial efforts in this field.

Hyperspectral inversion of mercury in reed leaves under different levels of soil mercury contamination.

High mercury (Hg) affects biochemical-physiological characteristics of plant leaves such as leaf chlorophyll, causing refractive discontinuity and modifications in leaf spectra. Furthermore, the hyperspectroscopy provides a potential tool for fast non-destructive estimation of leaf Hg. However, there are few studies that have investigated Hg for wetland plants via hyperspectral inversion. In this study, reeds (Phragmites australis) leaf Hg concentration and hyperspectra were measured under different soil Hg treatment. Hg-sensitive parameters were identified by basic spectral transformations and continuous wavelet transformation (CWT). Inversion models were developed using stepwise multiple linear regressions (SMLR), partial least square regression (PLSR), and random forest (RF) to estimate leaf Hg. The results indicated that CWT improved the correlation of hyperspectra and leaf Hg by 0.020-0.227, and R2 of the CWT-related model increased by 0.0557-0.2441. In addition, Hg-sensitive bands were predominant at 600-750 (visible region) and 1500-2300 nm (mid-infrared), and Hg might modify leaves spectra primarily by affecting chlorophyll and water contents. Of the studied models, SMLR using normalized transformation (NR) and CWT (NR-CWT-SMLR) model (R2 = 0.8594, RMSE = 0.0961) and RF using NR and CWT (NR-CWT-RF) model (R2 = 0.8560, RMSE = 0.1062) suited for leaf Hg inversion. For Hg content < 1.0 mg kg-1, the former model was more reliable and accurate. This study provided a method for the estimation of Hg contamination in wetland plant and indicated that model-based hyperspectral inversion was feasible for fast and non-destructive monitoring.

The effects of climate and catchment characteristic change on streamflow in a typical tributary of the Yellow River.

Hydrological cycle changes that occur due to a changing environment is a hot topic in the field of hydrological science. It is of great practical significance to study the response mechanism of hydrological process change for future water resources planning and management. In this study, the effects of climate and watershed characteristic change on the streamflow in a typical tributary of the Yellow River (the Fen River watershed) are studied based on the Budyko hypothesis. The results show that: the sensitivity coefficients of streamflow to precipitation, potential evapotranspiration, and the watershed characteristic coefficient were 0.1809, -0.0551, and -27.0882, respectively. This meant that a 1 mm decrease in the precipitation would induce a 0.1809 mm decrease in the streamflow. Additionally, a 1 mm decrease in the potential evapotranspiration would induce a 0.0551 mm increase in the streamflow, and an increase of 1 in the watershed characteristic coefficient would induce a 27.0882 mm decrease in the streamflow. The streamflow of the Fen River watershed showed a significant decreasing trend during the reference period (1951-1977). In addition, the streamflow of the change period (1978-2010) decreased 26.87 mm; and this was primarily caused by watershed characteristic change which accounted for 92.27%, while climate change only accounted for 6.50%.

[Distribution Characteristics of Mercury in Reed Leaves from the Jiapigou Gold Mine in the Songhua River Upstream].

At the Jiapigou gold mine of the Songhua River upstream, reed leaves (Phragmites australis), soil, and water samples were collected from June (summer) and September (autumn) 2016 for the determination of mercury. Moreover, the mercury concentrations in the air were determined synchronously. Furthermore, the level of mercury pollution in the reed leaves was determined by a single factor pollution index method, and the relationships among mercury concentrations in the reed leaves and environmental factors were analyzed to research the distribution characteristics, influencing factors, and correlations around the gold mining area. The results show that, in terms of spatial distribution, the mercury concentrations in reed leaves, soil, and water gradually decay with the distance from the gold mining area, and the spatial distribution of the mercury concentrations in the air was not obvious. Regarding a temporal distribution, the mercury concentrations in the reed leaves in summer were lower than those in autumn in the heavy pollution areas, while the distribution in the light pollution areas was the opposite, as the mercury concentrations of air and soil in summer were higher than those in autumn. The influence of environmental factors on the mercury concentrations in the reed leaves was soil > air > water. In addition, after stopping gold mining and processing using mercury, the mercury source in the area was the soil.

Coordinate regulation of the Escherichia coli formate dehydrogenase fdnGHI and fdhF genes in response to nitrate, nitrite, and formate: roles for NarL and NarP.

Escherichia coli possesses three distinct formate dehydrogenase enzymes encoded by the fdnGHI, fdhF, and fdoGHI operons. To examine how two of the formate dehyrogenase operons (fdnGHI and fdhF) are expressed anaerobically in the presence of low, intermediate, and high levels of nitrate, nitrite, and formate, chemostat culture techniques were employed with fdnG-lacZ and fdhF-lacZ reporter fusions. Complementary patterns of gene expression were seen. Optimal fdhF-lacZ expression occurred only at low to intermediate levels of nitrate, while high nitrate levels caused up to 10-fold inhibition of gene expression. In contrast, fdnG-lacZ expression was induced 25-fold in the presence of intermediate to high nitrate concentrations. Consistent with prior reports, NarL was able to induce fdnG-lacZ expression. However, NarP could not induce expression; rather, it functioned as an antagonist of fdnG-lacZ expression under low-nitrate conditions (i.e., it was a negative regulator). Nitrite, a reported signal for the Nar sensory system, was unable to stimulate or suppress expression of either formate dehydrogenase operon via NarL and NarP. The different gene expression profiles of the alternative formate dehydrogenase operons suggest that the two enzymes have complementary physiological roles under environmental conditions when nitrate and formate levels are changing. Revised regulatory schemes for NarL- and NarP-dependent nitrate control are presented for each operon.