MSH2-MSH3 promotes DNA end resection during homologous recombination and blocks polymerase theta-mediated end-joining through interaction with SMARCAD1 and EXO1.

DNA double-strand break (DSB) repair via homologous recombination is initiated by end resection. The extent of DNA end resection determines the choice of the DSB repair pathway. Nucleases for end resection have been extensively studied. However, it is still unclear how the potential DNA structures generated by the initial short resection by MRE11-RAD50-NBS1 are recognized and recruit proteins, such as EXO1, to DSB sites to facilitate long-range resection. We found that the MSH2-MSH3 mismatch repair complex is recruited to DSB sites through interaction with the chromatin remodeling protein SMARCAD1. MSH2-MSH3 facilitates the recruitment of EXO1 for long-range resection and enhances its enzymatic activity. MSH2-MSH3 also inhibits access of POLθ, which promotes polymerase theta-mediated end-joining (TMEJ). Collectively, we present a direct role of MSH2-MSH3 in the initial stages of DSB repair by promoting end resection and influencing the DSB repair pathway by favoring homologous recombination over TMEJ.

DNA polymerase θ-mediated repair of high LET radiation-induced complex DNA double-strand breaks.

DNA polymerase θ (POLQ) is a unique DNA polymerase that is able to perform microhomology-mediated end-joining as well as translesion synthesis (TLS) across an abasic (AP) site and thymine glycol (Tg). However, the biological significance of the TLS activity is currently unknown. Herein we provide evidence that the TLS activity of POLQ plays a critical role in repairing complex DNA double-strand breaks (DSBs) induced by high linear energy transfer (LET) radiation. Radiotherapy with high LET radiation such as carbon ions leads to more deleterious biological effects than corresponding doses of low LET radiation such as X-rays. High LET-induced DSBs are considered to be complex, carrying additional DNA damage such as AP site and Tg in close proximity to the DSB sites. However, it is not clearly understood how complex DSBs are processed in mammalian cells. We demonstrated that genetic disruption of POLQ results in an increase of chromatid breaks and enhanced cellular sensitivity following treatment with high LET radiation. At the biochemical level, POLQ was able to bypass an AP site and Tg during end-joining and was able to anneal two single-stranded DNA tails when DNA lesions were located outside the microhomology. This study offers evidence that POLQ is directly involved in the repair of complex DSBs.

Brainstem and early cortical auditory activities associated with language differences in acoustic cue weighting for voicing perception.

The purpose of the present study was to identify neural activities reflecting language differences in acoustic cue weighting for phonetic perception. We examined whether brainstem and early cortical auditory responses to voice-onset time (VOT) and onset frequency of fundamental frequency (onset F0) were different between two groups of listeners, native Japanese speakers and Korean second-language learners of Japanese, who use a VOT and onset F0, respectively, as the primary perceptual cue for voicing. In the experiment, we measured auditory brainstem responses (ABRs) and cortical N1 response of the Japanese and Korean participants while listening to stop-consonant stimuli varying in VOT and onset F0 (10 ms and 80 Hz, 30 ms and 80 Hz, or 30 ms and 120 Hz). We found that the N1 response was much more sensitive to VOT distinction in the Japanese than Korean participants, although the distinction of onset F0 was not reflected in early cortical responses in either language groups. There was no obvious difference in the ABRs between the Japanese and Korean participants. These results suggest that early cortical auditory activity is related to the processing of acoustic cue weighting for phonetic perception, while brainstem auditory activity is stimulus-dependent.

Does weight lifting improve visual acuity? A replication of Gonzalo-Fonrodona and Porras (2013).

OBJECTIVE: A physical effort such as lifting up a weight affects our perception and cognition. A previous study reported in two experiments that weight lifting improves visual acuity. In the previous study, participants' visual acuity was higher while lifting weights than while resting. Moreover, via a case study, that study further showed that the heavier the weight, the better the visual acuity. These experiments, although interesting, lacked methodological details and thorough statistical analyses. We thus conducted experiments similar to these two previous ones that mitigated these issues. RESULTS: Although our results of Experiment 1 echoed those of the previous study, the results of Experiment 2 did not support the latter case report. Thus, our results suggest that the bodily experience of weights improves visual acuity, but a gradual increase in weight does not seem to lead to a gradual increase in visual acuity.

A genome-wide association study of multiple longitudinal traits with related subjects.

Pleiotropy is a phenomenon that a single gene inflicts multiple correlated phenotypic effects, often characterized as traits, involving multiple biological systems. We propose a two-stage method to identify pleiotropic effects on multiple longitudinal traits from a family-based data set. The first stage analyzes each longitudinal trait via a three-level mixed-effects model. Random effects at the subject-level and at the family-level measure the subject-specific genetic effects and between-subjects intraclass correlations within families, respectively. The second stage performs a simultaneous association test between a single nucleotide polymorphism and all subject-specific effects for multiple longitudinal traits. This is performed using a quasi-likelihood scoring method in which the correlation structure among related subjects is adjusted. Two simulation studies for the proposed method are undertaken to assess both the type I error control and the power. Furthermore, we demonstrate the utility of the two-stage method in identifying pleiotropic genes or loci by analyzing the Genetic Analysis Workshop 16 Problem 2 cohort data drawn from the Framingham Heart Study and illustrate an example of the kind of complexity in data that can be handled by the proposed approach. We establish that our two-stage method can identify pleiotropic effects whilst accommodating varying data types in the model.

Possible additional antidepressant-like mechanism of sodium butyrate: targeting the hippocampus.

Chromatin remodeling mediated by histone acetylation might be involved in the pathophysiology and the treatment of depression. Recently, it has been reported that the histone deacetylase (HDAC) inhibitors, such as sodium butyrate (SB), could be a potential therapeutic agent for depression treatment. In the present study, we aimed to clarify the antidepressant mechanism of SB in the hippocampus. The mice were exposed to chronic restraint stress (CRS) for 14 consecutive days (2 h/day) to induce depression-like behaviors. To assess depression-like behaviors, sucrose preference test, light dark test (LD), tail suspension test (TST), and forced swim test (FST) were performed after CRS. We observed that CRS decreased HDAC2 and 5 mRNA and protein levels in the hippocampus. In addition, SB co-treatment decreased the depression-like behaviors that are induced by CRS. SB prevented and normalized the phosphorylation of cAMP response element binding protein (pCREB), acetylation of histone H3 (AceH3), HDAC2, and brain-derived neurotrophic factor (BDNF) expression level that were decreased by CRS in the hippocampus. These results suggest that the decreased HDAC2 and 5 expressions in the hippocampus of CRS may be a type of spontaneous coping response against CRS. However, it seems to be unsuccessful to prevent depression induction since reduction of pCREB, AceH3 and BDNF were accompanied by CRS in the hippocampus. Moreover, the reduced AceH3 level may be associated with the decreased pCREB, which appears to lead to the decreased BDNF.