Ruffling is Essential for Staphylococcus aureus IsdG-catalyzed Degradation of Heme to Staphylobilin

Non-canonical heme oxygenases are enzymes that degrade heme to non-biliverdin products within bacterial heme iron acquisition pathways. These enzymes all contain a conserved second-sphere Trp residue that is essential for enzymatic turnover. Previous studies have revealed several important roles for the conserved second-sphere Trp in Staphylococcus aureus IsdG, S. aureus IsdI, and Mycobacterium tuberculosis MhuD. However, a general model for the geometric, electronic, and functional role of the second-sphere Trp had not been deduced prior to this work. Here, UV/Vis absorption (Abs) and circular dichroism (CD) spectroscopies were employed to show that the W67F variant of IsdG perturbs the heme substrate conformation without altering the protein secondary structure. In general, it can now be stated that a dynamic equilibrium between “planar” and “ruffled” substrate conformations exists within non-canonical heme oxygenases, and that the second-sphere Trp favors population of the “ruffled” substrate conformation. 1H nuclear magnetic resonance and magnetic CD spectroscopies were used to characterize the electronic structures of IsdG and IsdI variants with different substrate conformational distributions. These data revealed that the “ruffled” substrate conformation promotes partial porphyrin-to-iron electron transfer, which makes the meso carbons of the porphyrin ring susceptible to radical attack. Finally, UV/Vis Abs spectroscopy was utilized to quantify the enzymatic rates, and electrospray ionization mass spectrometry was used to identify the product distributions, for variants of IsdG with altered substrate conformational distributions. In general, the rate of heme oxygenation by non-canonical heme oxygenases depends upon the population of the “ruffled” substrate conformation. Also, the production of staphylobilin or mycobilin by these enzymes is correlated with the population of the “ruffled” substrate conformation, since variants that favor population of the “planar” substrate conformation yield significant amounts of biliverdin. These data can be understood within the framework of a concerted rearrangement mechanism for the monooxygenation of heme to meso-hydroxyheme by non-canonical heme oxygenases. However, the mechanisms of IsdG/IsdI and MhuD must diverge following this intermediate in order to generate distinct staphylobilin and mycobilin products, respectively.

Fusion genes in gynecologic tumors: the occurrence, molecular mechanism and prospect for therapy

Gene fusions are thought to be driver mutations in multiple cancers and are an important factor for poor patient prognosis. Most of them appear in specific cancers, thus satisfactory strategies can be developed for the precise treatment of these types of cancer. Currently, there are few targeted drugs to treat gynecologic tumors, and patients with gynecologic cancer often have a poor prognosis because of tumor progression or recurrence. With the application of massively parallel sequencing, a large number of fusion genes have been discovered in gynecologic tumors, and some fusions have been confirmed to be involved in the biological process of tumor progression. To this end, the present article reviews the current research status of all confirmed fusion genes in gynecologic tumors, including their rearrangement mechanism and frequency in ovarian cancer, endometrial cancer, endometrial stromal sarcoma, and other types of uterine tumors. We also describe the mechanisms by which fusion genes are generated and their oncogenic mechanism. Finally, we discuss the prospect of fusion genes as therapeutic targets in gynecologic tumors.

CGRA MODULO SCHEDULING FOR ACHIEVING BETTER PERFORMANCE AND INCREASED EFFICIENCY

Coarse-Grained Reconfigurable Architectures (CGRA) is an effective solution for speeding up computer-intensive activities due to its high energy efficiency and flexibility sacrifices. The timely implementation of CGRA loops was one of the hardest problems in the analysis. Modulo scheduling (MS) was productive in order to implement loops on CGRAs. The problem remains with current MS algorithms, namely to map large and irregular circuits to CGRAs over a fair period of compilation with restricted computational and high-performance routing tools. This is mainly due to an absence of awareness of major mapping limits and a time consuming approach to solving temporary and space-related mapping using CGRA buffer tools. It aims to boost the performance and robust compilation of the CGRA modulo planning algorithm. The problem with the CGRA MS is divided into time and space and the mechanisms between the two problems have to be reorganized. We have a detailed, systematic mapping fluid that addresses the algorithms of the time mapping problem with a powerful buffer algorithm and efficient connection and calculation limitations. We create a fast-stable algorithm for spatial mapping with a retransmission and rearrangement mechanism. With higher performance and quicker build-up time, our MS algorithm can map loops to CBGRA. The results show that, given the same compilation budget, our mapping algorithm results in a better rate for compilation. The performance of this method will be increased from 5% to 14%, better than the standard CGRA mapping algorithms available.

A Variation of Favorskii Rearrangement Mechanism Under Weakly Acidic Conditions: The Case of Clobetasol Propionate Degradation in Solution

This paper describes our efforts in proposing a novel mechanism for the formation of the major degradant of clobetasol propionate under weakly acidic conditions through a comprehensive investigation. In the proposed mechanism, the key Favorskii intermediate plays a critical role. This variation of the original Favorskii rearrangement, which proceeds only under alkaline conditions, has not been reported before. This mechanism enriches the understanding of the degradation chemistry of corticosteroids containing the α-haloketone moiety on their 17-position.

A Variation of Favorskii Rearrangement Mechanism Under Weakly Acidic Conditions: The Case of Clobetasol Propionate Degradation in Solution

This paper describes our efforts in proposing a novel mechanism for the formation of the major degradant of clobetasol propionate under weakly acidic conditions through a comprehensive investigation. In the proposed mechanism, the key Favorskii intermediate plays a critical role. This variation of the original Favorskii rearrangement, which proceeds only under alkaline conditions, has not been reported before. This mechanism enriches the understanding of the degradation chemistry of corticosteroids containing the α-haloketone moiety on their 17-position.