Mutations in the
BRCA1
and
BRCA2
genes predispose afflicted individuals to breast, ovarian, and other cancers. The BRCA-encoded products form complexes with other tumor suppressor proteins and with ...the recombinase enzyme RAD51 to mediate chromosome damage repair by homologous recombination and also to protect stressed DNA replication forks against spurious nucleolytic attrition. Understanding how the BRCA tumor suppressor network executes its biological functions would provide the foundation for developing targeted cancer therapeutics, but progress in this area has been greatly hampered by the challenge of obtaining purified BRCA complexes for mechanistic studies. In this article, we review how recent effort begins to overcome this technical challenge, leading to functional and structural insights into the biochemical attributes of these complexes and the multifaceted roles that they fulfill in genome maintenance. We also highlight the major mechanistic questions that remain.
The evolutionarily conserved Hop2-Mnd1 complex is a key cofactor for the meiosis-specific recombinase Dmc1. However, emerging evidence has revealed that Hop2-Mnd1 is expressed in somatic tissues, ...primary human fibroblasts and cell lines, and that it functions in conjunction with the Rad51 recombinase to repair damaged telomeres via the alternate lengthening of telomeres mechanism. Here, we reveal how distinct DNA-binding activities of Hop2-Mnd1 mediate the stabilization of the RAD51-ssDNA presynaptic filament or stimulate the homologous DNA pairing reaction. We have also endeavored to define the interface that governs the assembly of the higher order complex of Hop2-Mnd1 with RAD51. Unexpectedly, we find that ATP enhances the interaction between Hop2-Mnd1 and RAD51, and that both Hop2 and Mnd1 are involved in RAD51 interaction via their C-terminal regions. Importantly, mutations introduced into these Hop2 and Mnd1 domains, including the HOP2 p.del201Glu mutation present in a patient of XX ovarian dysgenesis, diminish the association and functional synergy of Hop2-Mnd1 with both RAD51 and DMC1. Our findings help delineate the intricate manner in which Hop2-Mnd1 engages and functions with RAD51 and DMC1 in mammalian cells and speak to the possible cause of XX ovarian dysgenesis.
The central step in eukaryotic homologous recombination (HR) is ATP-dependent DNA-strand exchange mediated by the Rad51 recombinase. In this process, Rad51 assembles on single-stranded DNA (ssDNA) ...and generates a helical filament that is able to search for and invade homologous double-stranded DNA (dsDNA), thus leading to strand separation and formation of new base pairs between the initiating ssDNA and the complementary strand within the duplex. Here, we used cryo-EM to solve the structures of human RAD51 in complex with DNA molecules, in presynaptic and postsynaptic states, at near-atomic resolution. Our structures reveal both conserved and distinct structural features of the human RAD51-DNA complexes compared with their prokaryotic counterpart. Notably, we also captured the structure of an arrested synaptic complex. Our results provide new insight into the molecular mechanisms of the DNA homology search and strand-exchange processes.
This paper aims to study the measurement and modeling methods for delays in wide-area closed-loop control systems (WACS). The delays are classified into communication delays and operational delays ...based on the information flow of WACS. For communication delays, an affine evaluation model is proposed based on previous studies, and this model is verified by the measured communication delays of the Guizhou Power Grid in Southwest China. For operational delays, a real-time digital simulator (RTDS) hardware-in-the-loop measurement method is developed, and the measured operational delays are obtained and analyzed. Finally, an estimation method for the closed-loop delay in actual WACS is proposed, in which the uplink and downlink communication delays are modeled as constants and the operational delay is modeled as a normal distribution. Consequently, the closed-loop delay follows a normal distribution with the calculated parameters by combining the communication delays and operational delay. The measurement results and analysis presented in this paper are important for the development and applications of WACS.
It is widely accepted that mitochondria have a direct impact on neuronal function and survival. Oxidative stress caused by mitochondrial abnormalities play an important role in the pathophysiology of ...lipopolysaccharide (LPS)-induced memory impairment. Elamipretide (SS-31) is a novel mitochondrion-targeted antioxidant. However, the impact of elamipretide on the cognitive sequelae of inflammatory and oxidative stress is unknown.
We utilized MWM and contextual fear conditioning test to assess hippocampus-related learning and memory performance. Molecular biology techniques and ELISA were used to examine mitochondrial function, oxidative stress, and the inflammatory response. TUNEL and Golgi-staining was used to detect neural cell apoptosis and the density of dendritic spines in the mouse hippocampus.
Mice treated with LPS exhibited mitochondrial dysfunction, oxidative stress, an inflammatory response, neural cell apoptosis, and loss of dendritic spines in the hippocampus, leading to impaired hippocampus-related learning and memory performance in the MWM and contextual fear conditioning test. Treatment with elamipretide significantly ameliorated LPS-induced learning and memory impairment during behavioral tests. Notably, elamipretide not only provided protective effects against mitochondrial dysfunction and oxidative stress but also facilitated the regulation of brain-derived neurotrophic factor (BDNF) signaling, including the reversal of important synaptic-signaling proteins and increased synaptic structural complexity.
These findings indicate that LPS-induced memory impairment can be attenuated by the mitochondrion-targeted antioxidant elamipretide. Consequently, elamipretide may have a therapeutic potential in preventing damage from the oxidative stress and neuroinflammation that contribute to perioperative neurocognitive disorders (PND), which makes mitochondria a potential target for treatment strategies for PND.
Highlights
Pair electrosynthesis of formate was achieved by combining CO
2
reduction reaction (CO
2
RR) and formaldehyde oxidation reaction (FOR) in the membrane electrode assembly.
Replacing oxygen ...evolution reaction with thermodynamically more favorable FOR reduces energy consumption.
CO
2
RR//FOR exhibits excellent electrochemical performance (100 mA cm
−2
@ 0.86 V), electricity consumption normalized by the mass of formate was 0.413 Wh g
−1
.
Formate can be synthesized electrochemically by CO
2
reduction reaction (CO
2
RR) or formaldehyde oxidation reaction (FOR). The CO
2
RR approach suffers from kinetic-sluggish oxygen evolution reaction at the anode. To this end, an electrochemical system combining cathodic CO
2
RR with anodic FOR was developed, which enables the formate electrosynthesis at ultra-low voltage. Cathodic CO
2
RR employing the BiOCl electrode in H-cell exhibited formate Faradaic efficiency (FE) higher than 90% within a wide potential range from − 0.48 to − 1.32
V
RHE
. In flow cell, the current density of 100 mA cm
−2
was achieved at − 0.67
V
RHE
. The anodic FOR using the Cu
2
O electrode displayed a low onset potential of − 0.13
V
RHE
and nearly 100% formate and H
2
selectivity from 0.05 to 0.35
V
RHE
. The CO
2
RR and FOR were constructed in a flow cell through membrane electrode assembly for the electrosynthesis of formate, where the CO
2
RR//FOR delivered an enhanced current density of 100 mA cm
−2
at 0.86 V. This work provides a promising pair-electrosynthesis of value-added chemicals with high FE and low energy consumption.
This paper proposes a real-time data compression and adapted protocol technique for wide-area measurement systems (WAMS). The compression algorithm combines exception compression (EC) with swing door ...trending (SDT) compression. The compression logic is designed to perform this algorithm in real time. Selection of compression parameters and data reconstruction are presented. An adapted protocol is introduced by improving the format of data frames defined by IEEE standard C37.118 for compressed data packets. The proposed compression technique and protocol were applied to the phasor measurement units (PMUs) of a hydropower plant in Guizhou Power Grid in Southwest China. A low-frequency oscillation incident was recorded by this technique. The raw, compressed and reconstructed data were analyzed to verify the compression and determine the accuracy of the proposed technique. Also, the wavelet-based data compression, the standalone EC and SDT are compared with the proposed compression technique. Our results demonstrated that this compression can reach the compression ratios in the range of 6 to 11. Also, this compression and adapted protocol technique can reduce the size of data packets by approximately 75% with high accuracy in both dynamic and steady states.
DNA strand exchange plays a central role in genetic recombination across all kingdoms of life, but the physical basis for these reactions remains poorly defined. Using single-molecule imaging, we ...found that bacterial RecA and eukaryotic Rad51 and Dmc1 all stabilize strand exchange intermediates in precise three-nucleotide steps. Each step coincides with an energetic signature (0.3 kBT) that is conserved from bacteria to humans. Triplet recognition is strictly dependent on correct Watson-Crick pairing. Rad51, RecA, and Dmc1 can all step over mismatches, but only Dmc1 can stabilize mismatched triplets. This finding provides insight into why eukaryotes have evolved a meiosis-specific recombinase. We propose that canonical Watson-Crick base triplets serve as the fundamental unit of pairing interactions during DNA recombination.
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