The Differences in Structure and Function of the Cerebellum Between Cantonese-Mandarin Bilinguals and Mandarin Monolinguals: a Multi-model MRI Study.

The effects of the long-term bilingual experience on structure and function of the cerebellum remain unclear. To explore whether there are differences in cerebellar gray matter structure between Cantonese-Mandarin bilinguals and Mandarin monolinguals and whether these different cerebellar structures have different resting-state functional connectivity (RSFC) with the cerebrum between the two groups, 30 Cantonese-Mandarin bilingual and 30 Mandarin monolingual college students were scanned by the T1-weighted magnetic resonance imaging (MRI) and resting-state functional MRI. Voxel-based morphology (VBM) analysis and RSFC analysis were used to analyze the cerebellar gray matter volume (GMV) and cerebellar-cerebro functional connectivity, respectively. Correlation analysis was performed between GMV/RSFC and the rapid automatized naming (RAN) and cognitive control. Compared to Mandarin monolinguals, Cantonese-Mandarin bilinguals showed larger GMV in bilateral cerebellar inferior posterior lobe (including bilateral VIIIa, VIIIb,IX, and right X, Vermis VIIIb, and Vermis IX) and a significant increase in RSFC coupling of the right inferior cerebellar posterior lobe with orbital part of left inferior frontal gyrus (IFG). In addition, there was a positive correlation between average response time (RT) of Mandarin alphanumeric RAN and RSFC between the right inferior posterior lobe of cerebellum and left IFG of all participants. The long-term Cantonese-Mandarin bilingual experience can increase the GMV of the bilateral cerebellar inferior posterior lobe and the RSFC between the right inferior cerebellar posterior lobe with orbital part of left inferior frontal gyrus (IFG).

Helicase SUV3, polynucleotide phosphorylase, and mitochondrial polyadenylation polymerase form a transient complex to modulate mitochondrial mRNA polyadenylated tail lengths in response to energetic changes.

Mammalian mitochondrial mRNA (mt-mRNA) transcripts are polyadenylated at the 3' end with different lengths. The SUV3·PNPase complex and mtPAP have been shown to degrade and polyadenylate mt mRNA, respectively. How these two opposite actions are coordinated to modulate mt-mRNA poly(A) lengths is of interest to pursue. Here, we demonstrated that a fraction of the SUV3·PNPase complex interacts with mitochondrial polyadenylation polymerase (mtPAP) under low mitochondrial matrix inorganic phosphate (Pi) conditions. In vitro binding experiments using purified proteins suggested that SUV3 binds to mtPAP through the N-terminal region around amino acids 100-104, distinctive from the C-terminal region around amino acids 510-514 of SUV3 for PNPase binding. mtPAP does not interact with PNPase directly, and SUV3 served as a bridge capable of simultaneously binding with mtPAP and PNPase. The complex consists of a SUV3 dimer, a mtPAP dimer, and a PNPase trimer, based on the molecular sizing experiments. Mechanistically, SUV3 provides a robust single strand RNA binding domain to enhance the polyadenylation activity of mtPAP. Furthermore, purified SUV3·PNPase·mtPAP complex is capable of lengthening or shortening the RNA poly(A) tail lengths in low or high Pi/ATP ratios, respectively. Consistently, the poly(A) tail lengths of mt-mRNA transcripts can be lengthened or shortened by altering the mitochondrial matrix Pi levels via selective inhibition of the electron transport chain or ATP synthase, respectively. Taken together, these results suggested that SUV3·PNPase·mtPAP form a transient complex to modulate mt-mRNA poly(A) tail lengths in response to cellular energy changes.

Complementary interhelical interactions between three buried Glu-Lys pairs within three heptad repeats are essential for Hec1-Nuf2 heterodimerization and mitotic progression.

Hec1 and Nuf2, core components of the NDC80 complex, are essential for kinetochore-microtubule attachment and chromosome segregation. It has been shown that both Hec1 and Nuf2 utilize their coiled-coil domains to form a functional dimer; however, details of the consequential significance and structural requirements to form the dimerization interface have yet to be elucidated. Here, we showed that Hec1 required three contiguous heptad repeats from Leu-324 to Leu-352, but not the entire first coiled-coil domain, to ensure overall stability of the NDC80 complex through direct interaction with Nuf2. Substituting the hydrophobic core residues, Leu-331, Val-338, and Ile-345, of Hec1 with alanine completely eliminated Nuf2 binding and blocked mitotic progression. Moreover, unlike most coiled-coil proteins, where the buried positions are composed of hydrophobic residues, Hec1 possessed an unusual distribution of glutamic acid residues, Glu-334, Glu-341, and Glu-348, buried within the interior dimerization interface, which complement with three Nuf2 lysine residues: Lys-227, Lys-234, and Lys-241. Substituting these corresponding residues with alanine diminished the binding affinity between Hec1 and Nuf2, compromised NDC80 complex formation, and adversely affected mitotic progression. Taken together, these findings demonstrated that three buried glutamic acid-lysine pairs, in concert with hydrophobic interactions of core residues, provide the major specificity and stability requirements for Hec1-Nuf2 dimerization and NDC80 complex formation.

Restoration of vegetation in the Yellow River Basin of Inner Mongolia is limited by geographic factors.

Studying the relationships between vegetation cover and geography in the Mongolian region of the Yellow River Basin will help to optimize local vegetation recovery strategies and achieve harmonious human relations. Based on MOD13Q1 data, the spatial and temporal variations in fractional vegetation cover (FVC) in the Mongolian Yellow River Basin during 2000-2020 were investigated via trend and correlative analysis. The results are as follows: (1) From 2000 to 2020, the vegetation cover in the Mongolian section of the Yellow River Basin recovered well, the mean increase in the FVC was 0.001/a, the distribution of vegetation showed high coverage in the southeast and low coverage in the northwest, and 31.19% of the total area showed an extremely significant and significant increase in vegetation cover. (2) The explanatory power of each geographic factor significantly differed. Precipitation, soil type, air temperature, land use type and slope were the main driving factors influencing the spatial distribution of the vegetation cover, and for each factor, the explanatory power of its interaction with other factors was greater than that of the single factor. (3) The correlation coefficients between FVC and temperature and precipitation are mainly positive. The mean value of the FVC and its variation trend are characterized by differences in terrain and soil characteristics, population density and land use. Land use conversion can reflect the characteristics of human activities, and positive effects, such as returning farmland to forest and grassland and afforestation of unused land, promote the significant improvement of regional vegetation, while negative effects, such as urban expansion, inhibit the growth of vegetation.

Uncoupling the roles of the SUV3 helicase in maintenance of mitochondrial genome stability and RNA degradation.

Yeast SUV3 is a nuclear encoded mitochondrial RNA helicase that complexes with an exoribonuclease, DSS1, to function as an RNA degradosome. Inactivation of SUV3 leads to mitochondrial dysfunctions, such as respiratory deficiency; accumulation of aberrant RNA species, including excised group I introns; and loss of mitochondrial DNA (mtDNA). Although intron toxicity has long been speculated to be the major reason for the observed phenotypes, direct evidence to support or refute this theory is lacking. Moreover, it remains unknown whether SUV3 plays a direct role in mtDNA maintenance independently of its degradosome activity. In this paper, we address these questions by employing an inducible knockdown system in Saccharomyces cerevisiae with either normal or intronless mtDNA background. Expressing mutants defective in ATPase (K245A) or RNA binding activities (V272L or ΔCC, which carries an 8-amino acid deletion at the C-terminal conserved region) resulted in not only respiratory deficiencies but also loss of mtDNA under normal mtDNA background. Surprisingly, V272L, but not other mutants, can rescue the said deficiencies under intronless background. These results provide genetic evidence supporting the notion that the functional requirements of SUV3 for degradosome activity and maintenance of mtDNA stability are separable. Furthermore, V272L mutants and wild-type SUV3 associated with an active mtDNA replication origin and facilitated mtDNA replication, whereas K245A and ΔCC failed to support mtDNA replication. These results indicate a direct role of SUV3 in maintaining mitochondrial genome stability that is independent of intron turnover but requires the intact ATPase activity and the CC conserved region.

The differences of functional brain network in processing auditory phonological tasks between Cantonese-Mandarin bilinguals and Mandarin monolinguals.

OBJECTIVE: To explore the differences of functional brain networks in processing auditory phonological tasks between Cantonese-Mandarin bilinguals and Mandarin monolinguals. METHODS: 31 Cantonese-Mandarin bilinguals and 31 Mandarin monolinguals performed auditory rhyming tasks under a functional magnetic resonance imaging (fMRI) scanning. Bilinguals performed two language tasks (Cantonese, CC; Mandarin, CM), while monolinguals performed only one task (Mandarin, MM). Graph theory and network-based statistic (NBS) analyses were used to reveal the differences of functional brain networks among CC, CM and MM. RESULTS: The functional brain networks of CC, CM and MM were all small-world, and there were no differences in network properties, but widespread differences in functional connectivity among distributed brain regions. CONCLUSIONS: The Cantonese-Mandarin bilingualism and Mandarin monolingualism shared similar efficient topological structure of brain network for auditory phonological processing, but varied in widespread functional connectivity. And the two languages within bilingualism employed different functional brain networks for auditory phonological processing.

Association between dietary quality and executive functions in school-aged children with autism spectrum disorder.

Background: It is well known that children with autism spectrum disorder (ASD) had executive functions deficit. However, it is still unclear whether the poor dietary quality is related to the impairment of executive functions. The current study aimed to explore the association between dietary quality and executive functions in children with ASD. Methods: A total of 106 children with ASD (7.7 ± 1.3 years) and 207 typically developing (TD) children (7.8 ± 1.3 years) were enrolled from Guangzhou, China. The Chinese version of Behavior Rating Scale of Executive function (BRIEF), the working memory subscales of the Chinese version of Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV), and the Stroop Color-Word Test (SCWT) were used to measure the participant's executive functions. The food frequency questionnaire (FFQ) was used to collect the dietary intake information, and the Chinese Diet Balance Index (DBI_16) was used to evaluate the dietary quality. Generalized linear models were used to estimate the association between dietary quality and executive functions. Results: In children with ASD, Low Bound Score (LBS) was positively correlated with the working memory subscale score of BRIEF (ß = 0.23, 95% CI: 0.02-0.44, P < 0.05), while High Bound Score (HBS) and LBS were positively correlated with the organizable subscale score of BRIEF (ß = 0.44, 95% CI: 0.11-0.77, P < 0.01; ß = 0.19, 95% CI: 0.01-0.37, P < 0.05). Compared to TD children, children with ASD had a higher proportion of moderate and high levels of insufficient dietary intake (moderate level, 37.7% vs. 23.2%, high level, 4.7% vs. 1.4%) and moderate level of unbalanced dietary intake (36.8% vs.21.3%), higher scores on all subscales of BRIEF (P < 0.01), and lower score on the working memory (81.3 ± 32.3 vs. 104.6 ± 12.5, P < 0.01), while there was no difference on the SCWT. Conclusion: Poor dietary quality was associated with the impairment of working memory and organizational capacity in children with ASD. This study emphasized the importance of dietary quality in executive functions among children with ASD, and attention should be paid to improving their dietary quality.

Elucidation of Exosome Migration across the Blood-Brain Barrier Model In Vitro.

The delivery of therapeutics to the central nervous system (CNS) remains a major challenge in part due to the presence of the blood-brain barrier (BBB). Recently, cell-derived vesicles, particularly exosomes, have emerged as an attractive vehicle for targeting drugs to the brain, but whether or how they cross the BBB remains unclear. Here, we investigated the interactions between exosomes and brain microvascular endothelial cells (BMECs) in vitro under conditions that mimic the healthy and inflamed BBB in vivo. Transwell assays revealed that luciferase-carrying exosomes can cross a BMEC monolayer under stroke-like, inflamed conditions (TNF-α activated) but not under normal conditions. Confocal microscopy showed that exosomes are internalized by BMECs through endocytosis, co-localize with endosomes, in effect primarily utilizing the transcellular route of crossing. Together, these results indicate that cell-derived exosomes can cross the BBB model under stroke-like conditions in vitro. This study encourages further development of engineered exosomes as drug delivery vehicles or tracking tools for treating or monitoring neurological diseases.

Synthesis, molecular modeling, and biological evaluation of novel RAD51 inhibitors.

RAD51 recombinase plays a critical role for cancer cell proliferation and survival. Targeting RAD51 is therefore an attractive strategy for treating difficult-to-treat cancers, e.g. triple negative breast cancers which are often resistant to existing therapeutics. To this end, we have designed, synthesized and evaluated a panel of new RAD51 inhibitors, denoted IBR compounds. Among these compounds, we have identified a novel small molecule RAD51 inhibitor, IBR120, which exhibited a 4.8-fold improved growth inhibition activity in triple negative human breast cancer cell line MBA-MD-468. IBR120 also inhibited the proliferation of a broad spectrum of other cancer cell types. Approximately 10-fold difference between the IC50 values in normal and cancer cells were observed. Moreover, IBR120 was capable of disrupting RAD51 multimerization, impairing homologous recombination repair, and inducing apoptotic cell death. Therefore, these novel RAD51 inhibitors may serve as potential candidates for the development of pharmaceutical strategies against difficult-to-treat cancers.

Targeting tumor suppressor networks for cancer therapeutics.

Cancer is a consequence of mutations in genes that control cell proliferation, differentiation and cellular homeostasis. These genes are classified into two categories: oncogenes and tumor suppressor genes. Together, overexpression of oncogenes and loss of tumor suppressors are the dominant driving forces for tumorigenesis. Hence, targeting oncogenes and tumor suppressors hold tremendous therapeutic potential for cancer treatment. In the last decade, the predominant cancer drug discovery strategy has relied on a traditional reductionist approach of dissecting molecular signaling pathways and designing inhibitors for the selected oncogenic targets. Remarkable therapies have been developed using this approach; however, targeting oncogenes is only part of the picture. Our understanding of the importance of tumor suppressors in preventing tumorigenesis has also advanced significantly and provides a new therapeutic window of opportunity. Given that tumor suppressors are frequently mutated, deleted, or silenced with loss-of-function, restoring their normal functions to treat cancer holds tremendous therapeutic potential. With the rapid expansion in our knowledge of cancer over the last several decades, developing effective anticancer regimens against tumor suppressor pathways has never been more promising. In this article, we will review the concept of tumor suppression, and outline the major therapeutic strategies and challenges of targeting tumor suppressor networks for cancer therapeutics.

A novel role of the chromokinesin Kif4A in DNA damage response.

Chromokinesins are microtubule-motor molecules that possess chromatin binding activity and are important for mitotic and meiotic regulation. The chromokinesin-member Kif4A is unique in that it localizes to nucleus during interphase of the cell cycle. Kif4 deletion by gene targeting in mouse embryonic cells was known to associate with DNA damage response. However, its precise role in DNA damage or repair pathway is not clear. Here we report that Kif4A associates with BRCA2 in a biochemical identification and that the interaction is mediated by the Kif4A C-terminal cargo-binding domain and BRCA2 C-terminal conserved region. Upon nucleus-specific laser micro-irradiation, Kif4A was rapidly recruited to sites of DNA damage. Significantly, the depletion of Kif4A from cells by shRNA impaired the ionizing-radiation induced foci (IRIF) formation of Rad51, both quantitatively and qualitatively. In contrast, the IRIF of gamma-H2AX or NBS1 was largely intact. Moreover, Kif4A knockdown rendered cells hypersensitive to ionizing radiation in a colonogenic survival assay. We further demonstrated that Kif4A deficiency led to significantly decreased homologous recombination in an I-SceI endonuclease induced in vivo recombination assay. Together, our results suggest a novel role for a chromokinesin family member in the DNA damage response by modulating the BRCA2/Rad51 pathway.