ALBERT

Description: 〈p〉Replication stress (RS) is a cancer hallmark; chemotherapeutic drugs targeting RS are widely used as treatments for various cancers. To develop next-generation RS-inducing anticancer drugs, cell division cycle 7 (CDC7) has recently attracted attention as a target. We have developed an oral CDC7-selective inhibitor, TAK-931, as a candidate clinical anticancer drug. TAK-931 induced S phase delay and RS. TAK-931–induced RS caused mitotic aberrations through centrosome dysregulation and chromosome missegregation, resulting in irreversible antiproliferative effects in cancer cells. TAK-931 exhibited significant antiproliferative activity in preclinical animal models. Furthermore, in indication-seeking studies using large-scale cell panel data, TAK-931 exhibited higher antiproliferative activities in 〈i〉RAS〈/i〉-mutant versus 〈i〉RAS〈/i〉–wild-type cells; this finding was confirmed in pancreatic patient-derived xenografts. Comparison analysis of cell panel data also demonstrated a unique efficacy spectrum for TAK-931 compared with currently used chemotherapeutic drugs. Our findings help to elucidate the molecular mechanisms for TAK-931 and identify potential target indications.〈/p〉

Description: 〈p〉Soluble immunoglobulin M (IgM) forms a pentamer containing a joining (J) chain polypeptide. While IgM pentamer has various immune functions, it also behaves as a carrier of circulating apoptosis inhibitor of macrophage (AIM; also called CD5L) protein that facilitates repair during different diseases. AIM binds to the IgM pentamer solely in the presence of the J chain. Here, using a single-particle negative-stain electron microscopy, we found that the IgM pentamer exhibits an asymmetric pentagon containing one large gap, which is markedly different from the textbook symmetric pentagon model. A single AIM molecule specifically fits into the gap, cross-bridging two IgM-Fc that form the edges of the gap through a disulfide bond at one side and a charge-based interaction at the other side. The discovery of the bona fide shape of the IgM pentamer advances our structural understanding of the pentameric IgM and its binding mode with AIM.〈/p〉

Description: We conducted compressional, tensile, and torsional creep experiments on fine-grained forsterite plus Ca-bearing pyroxene aggregates. A distinct microstructure with aggregation of the same phase in the direction of compression was formed in our samples after all the experiments. The stress–strain rate relationship, grain-size dependent flow strength, and the achievement of large tensile strain all indicate that samples underwent creep due to grain boundary sliding (GBS). As a result of GBS, grain-switching events allow dispersed phases to contact grains of the same phase and orient in the direction of compression. We identify similar aggregated microstructures in previously reported micrographs of polymineralic granite-origin ultramylonites. Mineral phase mixing through GBS, which helps to retain fine grain size in rocks due to grain boundary pinning, has been speculated to occur during formation of mylonites. However, our results contradict this hypothesis because mineral aggregation through GBS promotes demixing rather than mixing of the mineral phases. GBS processes alone will not promote a transformation of well-developed monomineralic bands to polymineralic bands during mylonitization.

Description: 〈p〉The neural mechanisms underlying memory regulation during sleep are not yet fully understood. We found that melanin concentrating hormone–producing neurons (MCH neurons) in the hypothalamus actively contribute to forgetting in rapid eye movement (REM) sleep. Hypothalamic MCH neurons densely innervated the dorsal hippocampus. Activation or inhibition of MCH neurons impaired or improved hippocampus-dependent memory, respectively. Activation of MCH nerve terminals in vitro reduced firing of hippocampal pyramidal neurons by increasing inhibitory inputs. Wake- and REM sleep–active MCH neurons were distinct populations that were randomly distributed in the hypothalamus. REM sleep state–dependent inhibition of MCH neurons impaired hippocampus-dependent memory without affecting sleep architecture or quality. REM sleep–active MCH neurons in the hypothalamus are thus involved in active forgetting in the hippocampus.〈/p〉

Description: 〈p〉Mechanical loading plays an important role in bone homeostasis. However, molecular mechanisms behind the mechanical regulation of bone homeostasis are poorly understood. We previously reported p130Cas (Cas) as a key molecule in cellular mechanosensing at focal adhesions. Here, we demonstrate that Cas is distributed in the nucleus and supports mechanical loading–mediated bone homeostasis by alleviating NF-B activity, which would otherwise prompt inflammatory processes. Mechanical unloading modulates Cas distribution and NF-B activity in osteocytes, the mechanosensory cells in bones. Cas deficiency in osteocytes increases osteoclastic bone resorption associated with NF-B–mediated RANKL expression, leading to osteopenia. Upon shear stress application on cultured osteocytes, Cas translocates into the nucleus and down-regulates NF-B activity. Collectively, fluid shear stress–dependent Cas-mediated alleviation of NF-B activity supports bone homeostasis. Given the ubiquitous expression of Cas and NF-B together with systemic distribution of interstitial fluid, the Cas–NF-B interplay may also underpin regulatory mechanisms in other tissues and organs.〈/p〉

Description: Soluble immunoglobulin M (IgM) forms a pentamer containing a joining (J) chain polypeptide. While IgM pentamer has various immune functions, it also behaves as a carrier of circulating apoptosis inhibitor of macrophage (AIM; also called CD5L) protein that facilitates repair during different diseases. AIM binds to the IgM pentamer solely in the presence of the J chain. Here, using a single-particle negative-stain electron microscopy, we found that the IgM pentamer exhibits an asymmetric pentagon containing one large gap, which is markedly different from the textbook symmetric pentagon model. A single AIM molecule specifically fits into the gap, cross-bridging two IgM-Fc that form the edges of the gap through a disulfide bond at one side and a charge-based interaction at the other side. The discovery of the bona fide shape of the IgM pentamer advances our structural understanding of the pentameric IgM and its binding mode with AIM.

Description: Serotonin is a critical modulator of cortical function, and its metabolism is defective in autism spectrum disorder (ASD) brain. How serotonin metabolism regulates cortical physiology and contributes to the pathological and behavioral symptoms of ASD remains unknown. We show that normal serotonin levels are essential for the maintenance of neocortical excitation/inhibition balance, correct sensory stimulus tuning, and social behavior. Conversely, low serotonin levels in 15q dup mice (a model for ASD with the human 15q11-13 duplication) result in impairment of the same phenotypes. Restoration of normal serotonin levels in 15q dup mice revealed the reversibility of a subset of ASD-related symptoms in the adult. These findings suggest that serotonin may have therapeutic potential for discrete ASD symptoms.

Description: Introduction This chapter of the International Ocean Discovery Program (IODP) Expedition 350 Proceedings volume documents the procedures and tools employed in the various shipboard laboratories of the R/V JOIDES Resolution during Expedition 350. This information applies only to shipboard work described in the Expedition Reports section of this volume. Methods for shore-based analyses of Expedition 350 samples and data will be described in the individual scientific contributions to be published in the open literature or in the Expedition Research Results section of this volume. This section describes procedures and equipment used for drilling, coring, and hole completion; core handling; computation of depth for samples and measurements; and sequence of shipboard analyses. Subsequent sections describe specific laboratory procedures and instruments in more details.

Description: International Ocean Discovery Program (IODP) Hole U1436A (proposed Site IBM-4GT) lies in the western part of the Izu fore-arc basin, ~60 km east of the arc-front volcano Aogashima, ~170 km west of the axis of the Izu-Bonin Trench, and 1.5 km west of Ocean Drilling Program (ODP) Site 792, at 1776 meters below sea level (mbsl). It was drilled as a 150 m deep geotechnical test hole for potential future deep drilling (5500 meters below seafloor [mbsf]) at proposed Site IBM-4 using the D/V Chikyu. Core from Site U1436 yielded a rich record of Late Pleistocene explosive volcanism, including a distinctive black glassy mafic ash layer that may record a large-volume subaqueous eruption on the Izu arc front. Because of the importance of this discovery, Site U1436 was drilled in three additional holes (U1436B, U1436C, and U1436D), as part of a contingency operation, in an attempt to get better recovery on the black glassy mafic ash layer and its enclosing sediments and to better constrain its thickness. IODP Site U1437 is located in the Izu rear arc, ~330 km west of the axis of the Izu-Bonin Trench and ~90 km west of the arc-front volcanoes Myojinsho and Myojin Knoll, at 2117 mbsl. The primary scientific objective for Site U1437 was to characterize “the missing half of the subduction factory” because numerous ODP/Integrated Ocean Drilling Program sites had been drilled in the arc-front to fore-arc region (i.e., ODP Site 782A Leg 126), but this was the first site to be drilled in the rear-arc region of the Izu arc. A complete view of the arc system is needed to understand the formation of oceanic arc crust and its evolution into continental crust. Site U1437 on the rear arc had excellent core recovery in Holes U1437B and U1437D, and we succeeded in hanging the longest casing ever in the history of R/V JOIDES Resolution scientific drilling (1085.6 m) in Hole U1437E and cored to 1806.5 mbsf. The stratigraphy at Site U1437 was divided into seven lithostratigraphic units (I–VII) that were distinguished from each other based on the proportions and characteristics of tuffaceous mud/mudstone and interbedded tuff, lapilli-tuff, and tuff-breccia. The section is much more mud rich than expected, with ~60% tuffaceous mud for the section as a whole (89% in the uppermost 433 m) and high sedimentation rates of 100–260 m/My for the upper 1320 m (Units I–V). The proportion (40%) and grain size of volcaniclastics are much smaller than expected for an intra-arc basin, composed half of ash/tuff and half of lapilli-tuff of fine grain size (clasts 〈3 cm). These volcaniclastics were deposited by suspension settling through water and from density currents, in relatively distal settings. Volcanic blocks are only sparsely scattered through the lowermost 25% of the section (Units VI and VII, 1320–1806.5 mbsf), which includes hyaloclastite, in situ quench-fragmented blocks, and a rhyolite peperite intrusion (i.e., proximal deposits). The transition from unconsolidated to lithified rocks occurred progressively; however, sediments were considered lithified from 427 mbsf (top of Hole U1437D) downward. Alteration resulted in destruction of fresh glass from ~750 mbsf downward, but minerals are less altered. Because of the alteration, the deepest biostratigraphic datum was at ~850 mbsf and the deepest paleomagnetic datum was at ~1300 mbsf. Additional age control deeper than ~1300 mbsf is provided by an age range of 10.97–11.85 Ma inferred from a nannofossil assemblage at ~1403 mbsf and a preliminary U-Pb zircon concordia intercept age of 13.6 +1.6/−1.7 Ma, measured postcruise on a rhyolite peperite in Unit VI at ~1390 mbsf. Based on the seismic profiles, the Miocene–Oligocene hiatus (~17–23 Ma) was predicted to lie at ~1250 mbsf, but strata at that depth (Unit V, 1120–1312 mbsf) are much younger (~9 Ma), indicating that we recovered a thicker Neogene section of volcaniclastics and associated igneous rocks than anticipated. Our preliminary interpretation of shipboard geochemistry of solids is that arc-front versus rear-arc sources can be distinguished for individual intervals in the upper, relatively distal 1320 m of the section (Units I–V), whereas data for the lower, proximal 25% of the section (Units VI–VII) overlap and exceed the compositional fields for Neogene rear-arc seamounts and Quaternary arc-front volcanoes. This suggests that the compositional divergence between arc-front and rear-arc magmas only fully developed after ~13 Ma.