Damage characteristics of weak rocks with different dip angles during creep.

To investigate the influence of the weak layer dip angle on the creep rupture of the composite rock mass, this paper conducts a graded loading creep experiment on the composite rock mass with different dip angles using the acoustic emission method to examine the fracture evolution process. With increasing load grade, the cumulative total ring count of the rock mass shows a "U"-shaped trend, and the acoustic emission spatial positioning results show that acoustic emission events in the rock mass fracture process are primarily concentrated in the vicinity of the weak layer, while events in other areas are few and dispersed. For rock masses with weak layer dip angles of 0° and 15°, cracks occur in both soft and hard rocks, where shear cracks are dominant in soft rocks, tensile cracks are dominant in hard rocks, and finally, the rock mass mainly exhibits tensile splitting failure. For rock masses with weak layer dip angles of 30° and 45°, most of the cracks exist in the interior of the soft rock, which is dominated by shear cracks. With increasing graded loads, the shear cracks continue to develop along the direction of the weak layer, the upper rock mass keeps slipping and dislocating, and the final failure mode is mainly shear-slip failure. The damage evolution varies with the inclination angle of the weak layer, which can be divided into three stages: initial damage accumulation, damage acceleration, and damage destruction. This demonstrates the ability to predict, prevent, and control the occurrence of creep disasters in rock masses with weak layers.

Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential.

Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4's core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4's substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds' cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4-expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability.

Suramin inhibits cullin-RING E3 ubiquitin ligases.

Cullin-RING E3 ubiquitin ligases (CRL) control a myriad of biological processes by directing numerous protein substrates for proteasomal degradation. Key to CRL activity is the recruitment of the E2 ubiquitin-conjugating enzyme Cdc34 through electrostatic interactions between E3's cullin conserved basic canyon and the acidic C terminus of the E2 enzyme. This report demonstrates that a small-molecule compound, suramin, can inhibit CRL activity by disrupting its ability to recruit Cdc34. Suramin, an antitrypansomal drug that also possesses antitumor activity, was identified here through a fluorescence-based high-throughput screen as an inhibitor of ubiquitination. Suramin was shown to target cullin 1's conserved basic canyon and to block its binding to Cdc34. Suramin inhibits the activity of a variety of CRL complexes containing cullin 2, 3, and 4A. When introduced into cells, suramin induced accumulation of CRL substrates. These observations help develop a strategy of regulating ubiquitination by targeting an E2-E3 interface through small-molecule modulators.