The direct functionalization of CH bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon–carbon and carbon–heteroatom bonds. This Review provides ...an overview of CH bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.
The ideal case: The direct functionalization of CH bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon–carbon and carbon–heteroatom bonds. This Review provides an overview of CH functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
•Tractography indicated the major streamlines arise from the posterior precuneus projecting to the MTL.•The posterior precuneus represented a higher SC-rsFC correlation with the posterior MTL.•The ...posterior precuneus is highly connected to MTL structurally, possibly having an effect on the functional connectivity.
The precuneus, involved in various cognitive processes, is considered to form the midline core of the default mode network (DMN), while the medial temporal lobe (MTL) is a subsystem of the DMN. Until now, the anatomical study of the precuneus-MTL connection is limited in humans. One possible reason is the precuneus’ territory of the posteromedial cortex (PMC) is inconsistent across studies. The primary purpose of this study is to investigate the structural connectivity (SC) of precuneus-MTL, focusing on its anatomical organization using the Human Connectome Project Multi-modal Parcellation (HCP MMP) atlas. We first conducted the quantitative tractography analyses using the HCP dataset. The major streamlines originated from the posterior precuneus and were projected to the MTL extensively. Next, to complement the tractography data, we conducted the white matter dissection in the post-mortem human brain. We observed the major fiber bundles arise from the posterior precuneus extending to the anterior parahippocampal gyrus, which could support our tractography results. Then we analyzed the relationship between SC and resting-state functional connectivity (rsFC) of the precuneus-MTL. Although the SC-rsFC correlation was scarce on the whole, the posterior precuneus (POS2, 7Pm, 7m) showed a relatively high correlation (r = 0.38349, p < 0.05) with the posterior MTL (PreS, H, ProS, PHA1, PHA2). Our findings suggest the posterior precuneus is highly connected to MTL structurally, which could have an effect on the resting-state functional connectivity. In addition, the precuneus might consist of the heterogeneous connectivity-based subdivisions.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
It is generally hypothesized that functional connectivity (FC) reflects the underlying structural connectivity (SC). The precuneus is associated with highly integrated cognitive functions. However, ...our understanding of the structural connections that could underlie them is limited. This study aimed to characterize the cortico-cortical connections by probabilistic tractography. The precuneus corresponds to the five cortical areas (7Am, PCV, 7Pm, 7m, POS2) on the HCP MMP atlas. We first conducted the atlas-based probabilistic tractography. The anterior part (7Am) was strongly connected to the sensorimotor region. The dorsal part (7Am, 7Pm) was highly connected with the adjacent parietal and temporal cortex, while the ventral part (PCV, 7m) showed strong connections with the adjacent posterior cingulate and medial prefrontal cortex. The most posterior part (POS2) was explicitly connected to the visual cortex. In addition, there was a correlation between SC and resting-state fMRI connectivity (Spearman's rank correlation coefficient = 0.322 ± 0.019, p < 0.05 corrected at subject level). Collectively, the current study revealed the characteristic connectional profile of precuneus, which could shed light on the structural heterogeneity for the future functional analyses.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Fused in sarcoma/translocated in liposarcoma (FUS/TLS) is one of causative genes for familial amyotrophic lateral sclerosis (ALS). In order to identify binding partners for FUS/TLS, we performed a ...yeast two-hybrid screening and found that protein arginine methyltransferase 1 (PRMT1) is one of binding partners primarily in the nucleus. In vitro and in vivo methylation assays showed that FUS/TLS could be methylated by PRMT1. The modulation of arginine methylation levels by a general methyltransferase inhibitor or conditional over-expression of PRMT1 altered slightly the nucleus-cytoplasmic ratio of FUS/TLS in cell fractionation assays. Although co-localized primarily in the nucleus in normal condition, FUS/TLS and PRMT1 were partially recruited to the cytoplasmic granules under oxidative stress, which were merged with stress granules (SGs) markers in SH-SY5Y cell. C-terminal truncated form of FUS/TLS (FUS-dC), which lacks C-terminal nuclear localization signal (NLS), formed cytoplasmic inclusions like ALS-linked FUS mutants and was partially co-localized with PRMT1. Furthermore, conditional over-expression of PRMT1 reduced the FUS-dC-mediated SGs formation and the detergent-insoluble aggregates in HEK293 cells. These findings indicate that PRMT1-mediated arginine methylation could be implicated in the nucleus-cytoplasmic shuttling of FUS/TLS and in the SGs formation and the detergent-insoluble inclusions of ALS-linked FUS/TLS mutants.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alternatively activated (also known as M2) macrophages are involved in the repair of various types of organs. However, the contribution of M2 macrophages to cardiac repair after myocardial infarction ...(MI) remains to be fully characterized. Here, we identified CD206+F4/80+CD11b+ M2-like macrophages in the murine heart and demonstrated that this cell population predominantly increases in the infarct area and exhibits strengthened reparative abilities after MI. We evaluated mice lacking the kinase TRIB1 (Trib1-/-), which exhibit a selective depletion of M2 macrophages after MI. Compared with control animals, Trib1-/- mice had a catastrophic prognosis, with frequent cardiac rupture, as the result of markedly reduced collagen fibril formation in the infarct area due to impaired fibroblast activation. The decreased tissue repair observed in Trib1-/- mice was entirely rescued by an external supply of M2-like macrophages. Furthermore, IL-1α and osteopontin were suggested to be mediators of M2-like macrophage-induced fibroblast activation. In addition, IL-4 administration achieved a targeted increase in the number of M2-like macrophages and enhanced the post-MI prognosis of WT mice, corresponding with amplified fibroblast activation and formation of more supportive fibrous tissues in the infarcts. Together, these data demonstrate that M2-like macrophages critically determine the repair of infarcted adult murine heart by regulating fibroblast activation and suggest that IL-4 is a potential biological drug for treating MI.
The intraparietal sulcus (IPS) in the posterior parietal cortex (PPC) is well-known as an interface for sensorimotor integration in visually guided actions. However, our understanding of the human ...neural network between the IPS and the cortical visual areas has been devoid of anatomical specificity. We here identified a distinctive association fiber tract "IPS-FG" to connect the IPS areas and the fusiform gyrus (FG), a high-level visual region, by white matter dissection and tractography. The major fiber bundles of this tract appeared to arise from the medial bank of IPS, in the superior parietal lobule (SPL), and project to the FG on the ventral temporal cortex (VTC) in post-mortem brains. This tract courses vertically at the temporo-parieto-occipital (TPO) junction where several fiber tracts intersect to connect the dorsal-to-ventral cortical regions, including the vertical occipital fasciculus (VOF). We then analyzed the structural connectivity of this tract with diffusion-MRI (magnetic resonance imaging) tractography. The quantitative tractography analysis revealed the major streamlines of IPS-FG interconnect the posterior IPS areas (e.g., IP1, IPS1) with FG (e.g., TF, FFC, VVC, PHA2, PIT) on the Human Connectome Project multimodal parcellation atlas (HCP MMP 1.0). Since the fronto-parietal network, including the posterior IPS areas, is recruited by multiple cognitive demands, the IPS-FG could play a role in the visuomotor integration as well as the top-down modulation of various cognitive functions reciprocally.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Synthesis of Dragmacidin D via Direct C–H Couplings Mandal, Debashis; Yamaguchi, Atsushi D; Yamaguchi, Junichiro ...
Journal of the American Chemical Society,
12/2011, Volume:
133, Issue:
49
Journal Article
Peer reviewed
Dragmacidin D, an emerging biologically active marine natural product, has attracted attention as a lead compound for treating Parkinson’s and Alzheimer’s diseases. Prominent structural features of ...this compound are the two indole–pyrazinone bonds and the presence of a polar aminoimidazole unit. We have established a concise total synthesis of dragmacidin D using direct C–H coupling reactions. Methodological developments include (i) Pd-catalyzed thiophene–indole C–H/C–I coupling, (ii) Pd-catalyzed indole–pyrazine N-oxide C–H/C–H coupling, and (iii) acid-catalyzed indole–pyrazinone C–H/C–H coupling. These regioselective catalytic C–H couplings enabled us to rapidly assemble simple building blocks to construct the core structure of dragmacidin D in a step-economical fashion.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
Syntheses of dictyodendrins A and F have been achieved using a sequential C–H functionalization strategy. The N-alkylpyrrole core is fully functionalized by means of a rhodium(I)-catalyzed C–H ...arylation at the C3-position, a rhodium(II)-catalyzed double C–H insertion at the C2- and C5-positions, and a Suzuki–Miyaura cross-coupling reaction at the C4-position. The syntheses of dictyodendrins A and F were completed by formal 6π-electrocyclization to generate the pyrrolo2,3-ccarbazole core of the natural products.
Full text
Available for:
IJS, KILJ, NUK, PNG, UL, UM
•Aggregation of ALS-linked FUS mutant sequesters ALS-associated RNA-binding proteins (FUS wt, hnRNP A1, and hnRNP A2).•Aggregation of ALS-linked FUS mutant sequesters SMN1 in the detergent-insoluble ...fraction.•Aggregation of ALS-linked FUS mutant reduced the number of speckles in the nucleus.•Overproduced ALS-linked FUS mutant reduced the number of processing-bodies (PBs).
Protein aggregate/inclusion is one of hallmarks for neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). FUS/TLS, one of causative genes for familial ALS, encodes a multifunctional DNA/RNA binding protein predominantly localized in the nucleus. C-terminal mutations in FUS/TLS cause the retention and the inclusion of FUS/TLS mutants in the cytoplasm. In the present study, we examined the effects of ALS-linked FUS mutants on ALS-associated RNA binding proteins and RNA granules. FUS C-terminal mutants were diffusely mislocalized in the cytoplasm as small granules in transiently transfected SH-SY5Y cells, whereas large aggregates were spontaneously formed in ∼10% of those cells. hnRNP A1, hnRNP A2, and SMN1 as well as FUS wild type were assembled into stress granules under stress conditions, and these were also recruited to FUS mutant-derived spontaneous aggregates in the cytoplasm. These aggregates stalled poly(A) mRNAs and sequestered SMN1 in the detergent insoluble fraction, which also reduced the number of nuclear oligo(dT)-positive foci (speckles) in FISH (fluorescence in situ hybridization) assay. In addition, the number of P-bodies was decreased in cells harboring cytoplasmic granules of FUS P525L. These findings raise the possibility that ALS-linked C-terminal FUS mutants could sequester a variety of RNA binding proteins and mRNAs in the cytoplasmic aggregates, which could disrupt various aspects of RNA equilibrium and biogenesis.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
