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APOE4 is the strongest genetic risk factor for Alzheimer’s disease (AD)(1–3). Yet, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for APOE4 and other AD risk factors(4–8). To gain more comprehensive insight into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4-carriers compared to non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with APOE’s biological function(2–6), APOE4 significantly altered signaling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, iPSC-derived cells, and targeted-replacement mice, we further discovered that cholesterol is aberrantly deposited in oligodendrocytes, myelinating cells responsible for insulating and promoting electrical activity of neurons. We discovered altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. Our study delivers a single-cell atlas detailing the transcriptional effects of APOE4 on the aged human brain and establishes a functional link between APOE4, cholesterol, myelination, and memory; opening paths to new therapeutic opportunities for AD.

In this paper, joint probability distribution for the size and mass of deep-sea manganese nodules is investigated and reliability-based design optimization (RBDO) of a deep-sea pilot mining robot is performed. As the size and mass of the manganese nodules are strongly correlated and their data are given as bivariate type I interval multiply censored data, a new statistical modeling method should be developed to deal with these issues. However, this is significantly difficult as the conventional methods cannot resolve these issues and there is no prior knowledge of the two physical properties. The proposed method, which employs the multinomial distribution to define the likelihood function and the Akaike information criterion to select the fittest marginal distribution and copula, provides a systematic approach to find the joint probability distribution using the type I interval multiply censored data. To demonstrate the accuracy and effectiveness of the proposed method, two numerical examples are tested. Then, the RBDO of the pilot mining robot is performed using the joint probability distribution resulted from the proposed method.

In Alzheimer's disease, amyloid deposits along the brain vasculature lead to a condition known as cerebral amyloid angiopathy (CAA), which impairs blood-brain barrier (BBB) function and accelerates cognitive degeneration. Apolipoprotein (APOE4) is the strongest risk factor for CAA, yet the mechanisms underlying this genetic susceptibility are unknown. Here we developed an induced pluripotent stem cell-based three-dimensional model that recapitulates anatomical and physiological properties of the human BBB in vitro. Similarly to CAA, our in vitro BBB displayed significantly more amyloid accumulation in APOE4 compared to APOE3. Combinatorial experiments revealed that dysregulation of calcineurin-nuclear factor of activated T cells (NFAT) signaling and APOE in pericyte-like mural cells induces APOE4-associated CAA pathology. In the human brain, APOE and NFAT are selectively dysregulated in pericytes of APOE4 carriers, and inhibition of calcineurin-NFAT signaling reduces APOE4-associated CAA pathology in vitro and in vivo. Our study reveals the role of pericytes in APOE4-mediated CAA and highlights calcineurin-NFAT signaling as a therapeutic target in CAA and Alzheimer's disease.

Down syndrome (DS) is a genetic disorder driven by the triplication of chromosome 21 (T21) that is characterized by a wide-range of neurodevelopmental and physical disabilities. Transcriptomic analysis of tissue samples from individuals with DS has revealed that T21 induces a genome-wide transcriptional disruption. However, the consequences of T21 on the nuclear-architecture and its interplay with the transcriptome remain unknown. In this study, we find that unlike human induced pluripotent stem cells (iPSCs), iPSC-derived neural progenitor cells (NPCs) exhibit genome-wide “chromosomal introversion”, disruption of lamina-associated domains, and global chromatin-accessibility changes in response to T21, consistent with the transcriptional and nuclear-architecture changes characteristic of senescent cells. Treatment of T21-harboring NPCs with senolytic drugs alleviates the transcriptional, molecular and cellular dysfunctions associated with DS. Our findings provide a mechanistic link between T21 and global transcriptional disruption, and indicate that senescence-associated phenotypes may play a key role in the neurodevelopmental pathogenesis of DS.

We announce a new and integrated system for planning and executing marine geophysical surveys and for scrutinizing and visualizing incoming shipboard data. The system incorporates free software designed for use by scientists and shipboard operators and pertains to underway geophysics and multibeam sonar surveys. Regarding underway data, a crucial first step in the approach is to reduce and merge incoming center beam depth, gravity, and towed magnetic data with navigation, then reformat to the standard exchange format. We are then able to apply established quality control methods including along-track and cross-track analyses to identify error sources and to incrementally build the candidate archive file as new data are acquired. Regarding multibeam data, these are subjected to both an automated error removal scheme for quick visualization and to subsequent ping editing in detail. The candidate archive file and sonar data are automatically and periodically updated and adapted for display in Google Earth, wherein survey planning is also carried out. Data layers are also updated automatically in Google Earth, allowing scientists to focus on visual inspection and interpretation of incoming data. By visualizing underway and sonar data together with reference gravity, magnetic, and bathymetry grids in Google Earth, data familiarity is enhanced and the likelihood of noticing extreme errors increased. We hope scientists will embrace these techniques so that each data set being submitted to a data repository is vetted by the seagoing science party. U.S. National Science FoundationNational Science Foundation (NSF) [1458964, 1558403] Korea Institute of Ocean Science and Technology [PM59941, PM60321]

Design of a pick-up device using the Coanda effect in a deep-sea mining robot is vital to develop a reliable and sustainable deep-sea mining system. One of the crucial performance metrics of this device is the collection efficiency since it affects the mining efficiency of the entire system. However, the collection efficiency is significantly affected by the uncertainties of shape, size and mass of manganese nodules on the seabed. In this study, reliability-based design optimization (RBDO) was performed to improve the reliability of the collection efficiency of the pick-up device under these environmental uncertainties. First, a computational model based on the Coanda effect that predicts the collection efficiency of the pick-up device was developed. Next, RBDO based on the Akaike information criterion method was employed to design the pick-up device by using this model. The results demonstrated that the proposed design methodology significantly improved the design of the pick-up device for the pilot mining robot.

In this paper, probability distribution for the size and mass of seafloor manganese nodules is investigated to improve the reliability of a pick-up device in a deep-sea manganese nodule miner. Because the size and mass of the manganese nodules are strongly correlated, statistical models for the size and mass cannot be estimated independently. In order to consider the correlation between the size and mass in a statistical model, the joint probability density function (PDF) is estimated by using copula. This method requires the estimation of the marginal distributions and copula for the two correlated environmental variables. However, this is significantly difficult when there is no prior knowledge of the two physical properties. The proposed method, which employs the Akaike information criterion to select the fittest marginal distributions and copula, provides a systematic procedure to determine a statistical model of correlated environmental variables without any prior knowledge of their distributions. To demonstrate the effectiveness of the proposed method, the joint PDF for the size and mass of manganese nodules is modeled by using the multivariate normal distribution and the proposed method. It was found that the proposed method provides more accurate and reliable estimation results for the two correlated environmental variables.

Cobalt-rich ferromanganese crusts (Fe&ndash, Mn crusts), potential economic resources for cobalt, nickel, platinum, and other rare metals, are distributed on the surface of seamounts, ridges, and plateaus. Distribution of Fe&ndash, Mn crust deposits and their geomorphological characteristics are prerequisites to selecting possible mining sites and to predicting the environmental impact of deep-sea mining activity. Here, we map the spatial distribution of Fe&ndash, Mn crust deposits on seamount summits and flanks in the Western Pacific using shipboard multibeam echo sounder (MBES) data and seafloor images from a deep-towed camera system (DCS) and evaluate the relationship between acoustic backscatter variations and the occurrence of Fe&ndash, Mn crusts. We find a positive correlation between high backscatter intensity, steep seabed slope gradients, and the occurrence of Fe&ndash, Mn crusts. However, our analysis was not effective to distinguish the spatial boundary between several seabed types that occur over small areas in mixed seabed zones, particularly where transition zones and discontinuous seabed types are present. Thus, we conclude that MBES data can be a valuable tool for constraining spatial distribution of Fe&ndash, Mn crust deposits over a large exploration area.

A high level of confidence in resource data is a key prerequisite for conducting a reliable economic feasibility study in deep water seafloor mining. However, the acquisition of accurate resource data is difficult when employing traditional point-sampling methods to assess the resource potential of polymetallic nodules, given the vast size of the survey area and high spatial variability in nodule distribution. In this study, we analyzed high-resolution acoustic backscatter intensity images to estimate nodule abundance and increase confidence levels in nodule abundance data. We operated a 120 kHz deep-towed sidescan sonar (DSL-120) system (1×1 m resolution) across a 75 km2 representative area in the Korean Exploration Area for polymetallic nodules in the Northeastern Equatorial Pacific. A deep-towed camera system was also run along two tracks in the same area to estimate the abundance of polymetallic nodules on the seafloor. Backscatter data were classified into four facies based on intensity. The facies with the weakest and strongest backscatter intensities occurred in areas of high slope gradient and basement outcrops, respectively. The backscatter intensities of the two other facies correlated well with the nodule abundances estimated from still-camera images. A linear fit between backscatter intensity and mean nodule abundance for 10 zones in the study area yielded an excellent correlation (r2 = 0.97). This allowed us to compile a map of polymetallic nodule abundance that shows greater resolution than a map derived from the extrapolation of point-sampling data. Our preliminary analyses indicate that it is possible to greatly increase the confidence level of nodule resource data if the relationship between backscatter intensity and nodule abundance is reliably established. This approach has another key advantage over point sampling and image analyses in that detailed maps of mining obstacles along the seafloor are produced when acquiring data on the abundance of polymetallic nodules. The key limitation of this work is a poor correlation between nodule coverage, as observed from photographs, and nodule abundance. Significant additional ground truth sampling using well located box cores should be completed to determine whether or not there is a real correlation between the backscatter and abundance.

The purpose of this study was to demonstrate the effectiveness of controlled telescoping system for lateral hip pain caused by sliding of the blade following intramedullary nailing of trochanteric fractures.A retrospective cohort study was performed to compare the controlled telescoping system (Compression Hip Nail; CHN) with the conventional sliding system (Proximal Femoral Nail Antirotation; PFNA) for trochanteric fractures. 74 cases in the PFNA group and 77 cases in the CHN group were included from two university hospitals in this study. All patients had a minimum of 12-month follow up period. Lateral hip pain was evaluated and operation time and blood loss during the surgery were measured. The fracture classification was evaluated. The quality of postoperative reduction and other complications after surgery were also evaluated and tip-apex distance (TAD), telescoping and lateral protrusion of the blade and lag screw were measured.The mean age was 78.5 years in the PFNA group and 74.7 years in the CHN group (p=0.25). The mean telescoping was 19.2mm in the PFNA group and 10.7mm in the CHN group (p0.001). The mean length of lateral protrusion was 10.5mm in the PFNA group and 2.5mm in the CHN group (p0.001). Twenty-eight patients in the PFNA group complained of lateral hip pain, whereas 12 patients in the CHN group did (p=0.002). These four variables showed statistically significant differences between the PFNA and CHN groups (p0.05). The length of lateral protrusion was the only variable significantly related to lateral hip pain through multivariate logistic regression analysis (p=0.045).The degree of lateral protrusion was mainly related to lateral hip pain. Therefore, controlled telescoping would help to decrease lateral hip pain by decreasing the lateral protrusion beyond the lateral femoral cortex.

Increased p25, a proteolytic fragment of the regulatory subunit p35, is known to induce aberrant activity of cyclin-dependent kinase 5 (Cdk5), which is associated with neurodegenerative disorders, including Alzheimer's disease. Previously, we showed that replacing endogenous p35 with the noncleavable mutant p35 (Δp35) attenuated amyloidosis and improved cognitive function in a familial Alzheimer's disease mouse model. Here, to address the role of p25/Cdk5 in tauopathy, we generated double-transgenic mice by crossing mice overexpressing mutant human tau (P301S) with Δp35KImice. We observed significant reduction of phosphorylated tau and its seeding activity in the brain of double transgenic mice compared with the P301S mice. Furthermore, synaptic loss and impaired LTP at hippocampal CA3 region ofP301Smice were attenuated by blocking p25 generation. To further validate the role of p25/Cdk5 in tauopathy, we used frontotemporal dementia patient-derived induced pluripotent stem cells (iPSCs) carrying the Tau P301L mutation and generated P301L:Δp35KI isogenic iPSC lines using CRISPR/Cas9 genome editing. We created cerebral organoids from the isogenic iPSCs and found that blockade of p25 generation reduced levels of phosphorylated tau and increased expression of synaptophysin. Together, these data demonstrate a crucial role for p25/Cdk5 in mediating tau-associated pathology and suggest that inhibition of this kinase can remedy neurodegenerative processes in the presence of pathogenic tau mutation.SIGNIFICANCE STATEMENTAccumulation of p25 results in aberrant Cdk5 activation and induction of numerous pathological phenotypes, such as neuroinflammation, synaptic loss, Aβ accumulation, and tau hyperphosphorylation. However, it was not clear whether p25/Cdk5 activity is necessary for the progression of these pathological changes. We recently developed the Δp35KItransgenic mouse that is deficient in p25 generation and Cdk5 hyperactivation. In this study, we used this mouse model to elucidate the role of p25/Cdk5 in FTD mutant tau-mediated pathology. We also used a frontotemporal dementia patient-derived induced pluripotent stem cell carrying the Tau P301L mutation and generated isogenic lines in which p35 is replaced with noncleavable mutant Δp35. Our data suggest that p25/Cdk5 plays an important role in tauopathy in both mouse and human model systems.

Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT). The RTT missense MECP2R306C mutation prevents MeCP2 from interacting with the NCoR/histone deacetylase 3 (HDAC3) complex; however, the neuronal function of HDAC3 is incompletely understood. We found that neuronal deletion of Hdac3 in mice elicited abnormal locomotor coordination, sociability and cognition. Transcriptional and chromatin profiling revealed that HDAC3 positively regulated a subset of genes and was recruited to active gene promoters via MeCP2. HDAC3-associated promoters were enriched for the FOXO transcription factors, and FOXO acetylation was elevated in Hdac3 knockout (KO) and Mecp2 KO neurons. Human RTT-patient-derived MECP2R306C neural progenitor cells had deficits in HDAC3 and FOXO recruitment and gene expression. Gene editing of MECP2R306C cells to generate isogenic controls rescued HDAC3-FOXO-mediated impairments in gene expression. Our data suggest that HDAC3 interaction with MeCP2 positively regulates a subset of neuronal genes through FOXO deacetylation, and disruption of HDAC3 contributes to cognitive and social impairment.

The second Antarctic station of South Korea was constructed at Terra Nova Bay, East Antarctica, but local seafloor morphology and clay mineralogical characteristics are still not fully understood. Its small bay is connected to a modern Campbell Glacier, cliffs, and raised beaches along the coastline. Fourteen sampling sites to collect surface sediments were chosen in the small bay for grain size and clay mineral analyses to study the sediment source and sediment-transport process with multibeam bathymetry and sub-bottom profiles. Under the dominant erosional features (streamlined feature and meltwater channel), icebergs are the major geological agent for transport and deposition of coarse-sized sediments along the edge of glaciers in summer, and thus the study area can reveal the trajectory of transport by icebergs. Glacier meltwater is an important agent to deposit the clay-sized detritus and it results from the dominance of the illite content occurring along the edge of Campbell Glacier Tongue. The high smectite content compared to Antarctic sediments may be a result of the source of the surrounding volcanic rocks around within the Melbourne Volcanic Province.

The Korea Institute of Ocean Science and Technology has acquired detailed biological, chemicophysical, and geological data in the northeastern Pacific through a manganese nodule program since 1983. Plenty of manganese nodules were collected to estimate the amount of resources by free-fall grab and box corer. The collected manganese nodules have been archived systematically in the rock and mineral storage section of the Library of Marine Samples (LIMS) since 2012. The LIMS provides essencial information on the stored samples including sample name, nodule type, sampling location, depth, and equipment. Although a high quality database of the information system is under construction, the samples have tagged information for manganese nodules like chemical composition, morphology, weight, size, abundance, and photograph. In this study, we attempted to provide information on the well-organized and easily accessible archived manganese nodule samples for future studies and to introduce the usefulness of the LIMS.

Co-rich ferromanganese crusts (Fe-Mn crusts) distributed on the seamounts in the western Pacific are potential economic resources for cobalt, nickel, platinum, and other rare metals in the future. Regulations for prospecting and exploration of Fe-Mn crusts in the Area, which enables the process to obtain an exclusive exploration right for blocks of the fixed size, were enacted recently by the International Seabed Authority, which led to public attention on its potential for commercial development. Evaluation and selection of a mining site can be established based on abundance and grade of Fe-Mn crusts in the site as well as topography that should be smooth enough for mining efficiency. Therefore, acquisition of shipboard echo-sounding and acoustic backscatter data are prerequisite to select potential mine sites in addition to visual and sampling operations. Acoustic backscatter data can be used to locate crust-covered areas in a regional scale with the understanding of acoustic properties of crust through its correlation with visual and sampling data. KIOST had collected the topographic and geologic data to assess the resources potential for Fe-Mn crusts in the west Pacific region from 1994 to 2001. However, they could not obtain acoustic backscatter data that is crucial for the selection of prospective mining sites. Therefore, additional exploration surveys are required to carry out side scan sonar mapping combined with seafloor observation and sampling to decide the blocks for application of an exclusive exploration right.

The paleomagnetic records and mineral-magnetic properties of unconsolidated core sediment from the east Mariana Basin of the western Pacific have been analyzed to trace the time-dependent variations in sedimentary environments. Progressive alternating field demagnetization effectively extracts a stable remanent magnetization showing both normal and reverse polarities. Comparison of successive polarity changes, recorded in the sediment core, with reference magnetic polarity time-scale, reveals that the recovered sediment column was deposited since the late Pliocene. From the sediment age model, calculated sedimentation rate during the late Pliocene was 9.8 times higher than that during the Pleistocene. Considering the oceanic environments and geologic setting in the study area, the anomalous high sediment flux during the late Pliocene was probably caused by enhanced current flows, such as North Equatorial Current, associated with atmospheric circulation as well as by debris flows from adjacent sea mounts. In addition, the systematic variation of mineral-magnetic properties indicates periodical fluxes of coarse and magnetically stable particles, on the fine-grained dominant sedimentary environments. Such influxes, however, would not be related to syn-volcanic activities, because the summits of seamounts were totally blanketed by biogenic Pliocene-Pleistocene sediments. It is, hence, reasonable to interpret that paleomagnetic and mineral-magnetic data probably reflect drastic paleoenvironmental changes at the boundary between the Pliocene and Pleistocene, where strong current and atmospheric circulations decreased.

Research Vessel Building Unit, KIOST Ansan, P. O. Box 29, Seoul 425-600, KoreaHigh-resolution bathymetry and physico-chemical properties of manganese nodules were explored to identify therelationship between morphological features and nodule occurrences in the KR1, one of the Korean contract nodulefields located in the NE Pacific. The high-resolution seabed mapping showed that the southwestern sector of theKR1 (KR1-1) was relatively deeper than the northeastern sector (KR1-2) which is occupied by small-scale sea-mounts. In terms of nodule occurrence, manganese nodules in the KR1-1 were comparatively larger (2-4 cm) withrough surface (t-type) and discoidal shapes (D-type), while those in the KR1-2 were generally small (

Polymetallic nodule and sediment characteristics were investigated for two blocks (KR2 and KR5) in the Korea Deep Ocean Study (KODOS) area in order to better understand nodule distribution and the potential effects of sediments on nodule genesis. The northern block (KR2) is dominated by hydrogenetic nodules, whereas the southern block (KR5) is dominated by diagenetic nodules. Sediments in the study area are assigned to three major lithologic units which are distinctive in color and texture. The northern block is characterized by a thick, metalpoor Unit 1 sediment, which is thin in the southern block, where metal-rich Units 2b and 3 occur close to the surface. The distribution of different nodule genetic types in the northern and southern blocks can be attributed to topographic variations (topographic high near seamounts in KR2 and abyssal plain in KR5) and different sedimentation rates (0.1 and 0.32 mm/kyr in blocks KR2 and KR5, respectively). The southern block has a geologic setting more conducive to diagenetic nodule formation, such as flat topography and sediment composition. Nodule distribution in the studied blocks might also be explained by the distribution of the sediment units of different metal contents. The northern block, in which Unit 1 is thicker, has more abundant hydrogenetic nodules, possibly because Unit 1 prevents metals that are remobilized from the underlying sediments from reaching the seabed where the nodules are forming.

Induced pluripotent stem cells (iPSCs) have radically advanced the field of regenerative medicine by making possible the production of patient-specific pluripotent stem cells from adult individuals. While cell differentiation protocols have been successfully developed, and animal models of human disease have proved that these cells have the potential to treat human diseases and conditions produced as a consequence of aging, degeneration, injury, and birth defects, logistical issues still remain unsolved and hamper the possibility of testing these cells in human clinical trials. Among them is the widely spread use of animal products for the generation and culture of iPSCs. We report here a xeno-free iPSC generation system that addresses all the steps of iPSCs production including the isolation and culture of adult skin fibroblasts, and iPSCs generation, expansion, and maintenance. iPSCs generated with a polycistronic lentiviral vector under xeno-free conditions displayed markers of pluripotency and gave rise to embryoid bodies (EBs) displaying indicators of the 3 primary germ layers. Xeno-free iPSCs injected into nude mice produced classic teratomas, and teratoma explants cultured under conditions favoring fibroblastic cells gave rise to cells morphologically indistinguishable from input cells. Protocols here described will facilitate the implementation of new cellular therapies for preclinical and clinical studies, potentially reducing the regulatory burden without compromising the differentiation potential of the cells.

The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Aβ42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Aβ uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Aβ phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant. Video Abstract: [Figure presented] By generating and characterizing isogenic APOE3- or APOE4-carrying human brain cell types, Lin et al. show that the APOE4 variant can lead to extensive gene expression alterations, and multiple cellular phenotypes potentially related to AD pathogenesis, in neurons, astrocytes, and microglia., National Institutes of Health (NIH) (Grants RF1-AG048056, RC1-AG036106, and RF1-AG048029)

Although the value of proteomics has been demonstrated, cost and scale are typically prohibitive, and gene expression profiling remains dominant for characterizing cellular responses to perturbations. However, high-throughput sentinel assays provide an opportunity for proteomics to contribute at a meaningful scale. We present a systematic library resource (90 drugs × 6 cell lines) of proteomic signatures that measure changes in the reduced-representation phosphoproteome (P100) and changes in epigenetic marks on histones (GCP). A majority of these drugs elicited reproducible signatures, but notable cell line- and assay-specific differences were observed. Using the “connectivity” framework, we compared signatures across cell types and integrated data across assays, including a transcriptional assay (L1000). Consistent connectivity among cell types revealed cellular responses that transcended lineage, and consistent connectivity among assays revealed unexpected associations between drugs. We further leveraged the resource against public data to formulate hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. This resource is publicly available at https://clue.io/proteomics. A large compendium of cellular responses to drugs as profiled through proteomic assays of phosphosignaling and histone modifications reveals cellular responses that transcend lineage, discovers unexpected associations between drugs, and recognizes therapeutic hypotheses for treatment of multiple myeloma and acute lymphocytic leukemia. Keywords: mass spectrometry; proteomics; drug discovery; signaling; epigenetics; mechanism of action; LINCS project; GCP; P100; L1000, NIH Common Fund's Library of Integrated Network-based Cellular Signatures (LINCS) program (Grant U54HG008097), NIH Common Fund's Library of Integrated Network-based Cellular Signatures (LINCS) program (Grant U54HG008699)

The isostatic compensation and loading sequence of the Dokdo seamounts on the Ulleung Basin in the East Sea are studied by a flexure model using gravity and bathymetric data. The Dokdo seamounts comprise Dokdo (Dok Island), lying as a cluster of emerged small islets surmounting a large submerged volcanic edifice, and two voluminous tablemounts, Simheungtaek and Isabu. In spite of their similarity in topographic expression, a large difference of about 50 mGal between the observed gravity anomaly peaks over Dokdo and the Isabu Tablemount implies different amounts of compensation. A comparison between the observed and calculated gravity anomalies of the seamounts shows that the flexural compensation investigated in this study predicts well the observed data. The flexure model suggests that the Dokdo seamounts might be composed of high-density volcanic rocks. Modeling results show that the flexural rigidity or effective elastic thickness of the lithosphere under Dokdo is stronger or thicker than that under the Isabu Tablemount. It implies that the age of lithosphere at the time of loading for Isabu was younger than that for Dokdo. The effective elastic thicknesses associated with the Dokdo seamounts approximately follow 200–400 °C isotherms in the cooling plate model. The results of this study and the former age dating of Dokdo suggest that the Isabu Tablemount was formed first, followed by Dokdo after the opening of the East Sea ceased.

In the Ulleung Basin, East Sea, the Dok Do seamount group comprises Dok Do (Dok Island), consisting of very small islets/rocks and a large submerged volcanic edifice, and two voluminous tablemounts, Simheungtaek and Isabu. We attempted to reconstruct the evolution of these seamounts, using virtual geomagnetic poles (VGPs) determined by the least-squares and the seminorm magnetization methods, with 1,500 m upward continued magnetic anomalies. The VGPs of Dok Do with normal dipole anomaly, and of Simheungtaek with normal dipole anomaly are located near the present magnetic pole. The VGP of Isabu with normal dipole anomaly is located at low latitude, presumably due to overprints of reversals in the Tertiary, and the distortion of magnetization and structures associated with volcanism after its formation. In contrast to the tablemounts, magnetic anomalies over Dok Do are a combination of both normal polarity and reversed polarity dipoles in the northern hemisphere, indicating that Dok Do has had at least two major eruptions, one during normal and another during reversed polarity intervals. From these results, and information on the ages of the seamounts (either published radiometric ages of subaerial volcanic rocks, or ages reconstructed in terms of reported elastic thickness incorporated into an existing cooling plate model), we tentatively propose that (1) Isabu formed first, during a normal polarity interval after the opening of the East Sea had ceased; (2) this was followed by an initial and subsequent large eruption of Dok Do during a normal polarity and a reversed polarity interval after about 5 Ma; and (3) the formation of Simheungtaek occurred in between that of Isabu and Dok Do in a normal polarity interval. The pattern of normal/reversed magnetization is not inconsistent with the geomagnetic polarity timescale for at least the last 5 Ma. Nevertheless, precise ages of formation would need verification by additional geophysical/geochemical constraints. Evaluating various possible models explaining the successive formation of the Dok Do seamounts, we currently favor fracturing and volcanism related to compression-induced weakening of the extensional field from the late Miocene to Pliocene after the opening of the East Sea.

Fluorescent live imaging of cells and embryos at subcellular resolution poses significant challenges for biologists due to morbidity and mortality ensuing from phototoxicity. Here we report the use of a spinning-disk confocal microscope to image mouse and bovine preimplantation embryos without impairing their developmental potential. We also present data indicating that this imaging technique does not affect the functionality of subcellular components as assessed by reactive oxygen species (ROS) production, caspase activity, and DNA integrity. Spinning-disk confocal microscopy was also useful in determining cell number and allocation in transgenic bovine blastocysts. We conclude that this imaging method is suitable for monitoring preimplantation embryos.

Hydrothermal sulfides were recovered from the 16°50′S triple junction area in the North Fiji Basin, at a water depth of ca. 1900 m. The chimney samples can be divided into three groups based on their major metal contents: 1) type 1 (Fe–Cu-rich), 2) type 2 (Fe–Cu-rich with minor Zn), and 3) type 3 (Zn-rich) chimneys. Type 1 chimneys are mainly composed of chalcopyrite and pyrite, and are enriched in elements commonly precipitated under high temperature conditions (> 300 °C), such as Cu, Co, Mo, and Se. Type 3 chimneys consist dominantly of sphalerite and marcasite with traces of pyrite and chalcopyrite, and are enriched in elements commonly associated with relatively low temperatures (150 to 250 °C), such as Zn, Cd, Pb, As, and Ga. Type 2 chimneys have a mineralogy similar to that of type 1 chimneys although their trace metal contents range between those of type 1 and type 3 samples. Type 2 chimneys appear to be the products of low-temperature replacement, which might be related to formation of type 3 chimneys, of type 1 chimneys. The trace element composition of basaltic rocks indicates that magma generation in the triple junction area was influenced by two different sources: N-MORB and E-MORB. Sulfur and lead isotope patterns of the hydrothermal chimneys show distinct differences between the type 1 and type 3 chimneys. The type 1 sulfides ( δ 34 S = 2.8 ± 1.2‰; 206 Pb/ 204 Pb = 18.082 to 18.132; 207 Pb/ 204 Pb = 15.440 to 15.481; 208 Pb/ 204 Pb = 37.764 to 37.916) are depleted in 34 S and have lower Pb isotope ratios compared to types 2 and 3 chimneys ( δ 34 S = 4.1 ± 0.9‰; 206 Pb/ 204 Pb = 18.122 to 18.193; 207 Pb/ 204 Pb = 15.475 to 15.554; 208 Pb/ 204 Pb = 37.882 to 38.150). The higher δ 34 S values for types 2 and 3 sulfides than type 1 sulfides can be explained by mixing of hydrothermal fluids with ambient seawater. The more radiogenic Pb isotope composition of types 2 and 3 chimneys compared to type 1 chimneys suggest that the formation of types 2 and 3 chimneys were possibly related to E-MORB volcanism that shows higher Pb isotope composition than N-MORB rocks. However, ferromanganese crust samples have radiogenic Pb isotope compositions that are identical to those of E-MORB. Therefore, input of hydrogenous Pb is also a possible source for radiogenic Pb isotopes in the types 2 and 3 chimneys.

The aims of this study are 1) to construct a database using geostatistics and Geographic Information System (GIS), and 2) to derive the spatial relationships between manganese nodule abundance and other geological factors such as metal grade, slope, water depth, topography, and acoustic characteristics of the sub-bottom. Using GIS, it is possible to analyze a large amount of data efficiently, and to maximize the practical application, to increase specialization, and to enhance the accuracy of the analyses. The greater the copper and nickel grade, the higher the rating. The distribution pattern of nickel grade is similar to that of copper grade. The slopes are generally less than 3° except for seamounts and cliff areas. The rating shows no correlation with slope. The rating is highest for slopes between 2.5 and 3.5° in block N1 and between 4.0 and 4.5° in block N3. The topography is classified into five groups: seamount, hill crest, hill slant, hill base or plain, and seafloor basin or valley. The rating proves lowest for seamount and hill crest. Our results show that the rating increases with the water depth in the study area. Nodule abundance dose not show any significant relationship with the thickness of the upper transparent layer in the study area.

Textural and geochemical properties of ferromanganese crust (Fe−Mn crust) samples from four adjacent seamounts near the Marshall Islands were investigated to delineate the paleoceanographic condition on their growth history. The Fe−Mn crust samples of this study show four distinct layers (layers 1 to 4 from top to bottom). The uppermost layer 1 is massive and black, and is enriched in hydrogenetic elements such as Mn, Co, Ni, and Mo. The next layer 2 is porous and filled with sediment. Detrital (Al, Rb, and Ti) and biogenic (Cu, Zn, and Ba) elements are enriched in layer 2. The layers 3 and 4 are phosphatized layers which are impregnated with carbonate fluorapatite (CFA), and therefore their primary mineralogy and geochemistry were not preserved. The property of layer 2 suggested that this layer had grown under the condition of high biogenic and detrital flux. Such a condition may be met in the Inter-tropical Convergence Zone (ITCZ) where the northeast and southeast trade winds meet. Considering the present location and paleotracking of seamounts, layer 2 appears to have formed when these seamounts were beneath the ITCZ. On the other hand, layer 1 may have started to grow after the seamounts moved out of the ITCZ with the northwestward movement of the Pacific plate. Our study indicates that the Fe−Mn crusts can be used to trace the paleolocation of ITCZ when precise age determination and information on the plate movement are provided.

A detailed analysis of chirp (3–7 kHz) subbottom profiles and bathymetry was performed on data collected from seamounts near the Ogasawara Fracture Zone (OFZ) in the western Pacific. The OFZ, which is a 150 km wide rift zone showing 600 km of right-lateral movement in a NW–SE direction, is unique among the fracture zones of the Pacific in that it includes many old seamounts (e.g., Magellan Seamounts and seamounts on Dutton Ridge). Sub-seafloor acoustic echoes on the seamounts are classified into nine specific types based on the nature and continuity of the echoes, subbottom structure, and morphology of the seafloor: (1) distinct echoes (types I-1, I-2, I-3), (2) indistinct echoes (types II-1, II-2, II-3), and (3) hyperbolic echoes (types III-1, III-2, III-3). Type I-2 pelagic sediments, characterized by thin and intermittent coverage, were probably deposited in topographically sheltered areas when bottom currents were strong, whereas type I-1 pelagic sediments accumulated during continuous and widespread sedimentation. Development of seamount flank rift zones in the OFZ may have been influenced by preexisting structures in the transform fracture zone at the time of volcanism, whereas those on Ita Mai Tai seamount in the Pigafetta Basin originated solely by edifice-building processes. Flank rift zones that formed by dike intrusions and eruptions played an important role in mass wasting. Mass-wasting processes included block faulting or block slides around the summit margin, sliding/slumping, debris flows, and turbidites, which may have been triggered by faulting, volcanism, dike injection, and weathering during various stages in the evolution of the seamounts.

Deep-sea Resources Research Center (DRRC) has been using a free-fall grab (FFG) for the resource evaluation of polymetallic nodules in the KODOS (Korea Deep Ocean Study) area, NE Pacific, since 1992. A FFG model (Model 4200, Benthos) adapting one glass buoy system (diameter 17 inch, net buoyance 25.4 kg) has been used until 1993. Since then, DRRC has carried out a study to increase the recovery rate of FFG and it was found that a revised system adapting an additional buoy (diameter 10 inch, net buoyance 4.5 kg) gives improved results. The nodule sampling tests were performed using two different models for the same study area and the resulting recovery rates were compared. The result shows no distinct difference in recovery time between two models, but average recovery rate of the revised model was increased to 99.44% from 96.06% of the original model.

The aims of this study are to construct database using geostatistics and Geographic Information System (GIS), and to derive the spatial relationships between manganese nodule abundance and each factor affecting nodule abundance, such as metal grade, slope, aspect, water depth, topography, and acoustic characteristics of the subbottom using the GIS and probability methods. The greater is the copper and nickel grade, the higher is the rating. The distribution pattern of nickel grade is similar to that of copper grade. The slopes are generally less than , excluding seamounts and cliff areas. There is no increment in the rating with increasing slope. The rating is highest for slopes between 2.5 and in block B2 and between 3 and in block C1. The topography is classified into five groups: seamount, hill crest, hill slant, hill base or plain, and seafloor basin or valley. The ratings prove lowest for seamount and hill crest. The results of the study show a decrease in the rating with an increase in water depth in the study area. There was a poor relationship between manganese nodule abundance and the thickness of the upper transparent layer in block C1. Using GIS, it is possible to analyze a large amount of data efficiently, and to maximize the practical application, to increase specialization, and to enhance the accuracy of the analyses.

Sequential extraction was carried out on twenty two subsamples of three ferromanganese crustsfrom three seamounts (Lemkein, Lomilik, and Litakpooki) near the Marshall Islands in the western Pacific.The extraction was designed to fractionate Fe-Mn crust forming elements into four defined groups: (1)exchangeable and carbornate, (2) Mn-oxide, (3) Fe-oxyhydroxide, and (4) residual fraction. X-raydiffraction result shows that target material were well removed by each extraction step except for CFA inphosphatized crusts generation. According to chemical analysis of each leachate, most of elements in theFe-Mn crusts are bound with two major phases. Mn, Ba, Co, Ni, Zn, (Fe, Sr, Cu, and V) are stronglybounded with Mn-oxide (δ-MnO 2 ) phase, whereas Fe, Ti, Zr, Mo, Pb, Al, Cu, (V, P, and Zn) show chemicalaffinity with Fe-oxyhydroxide phase. This result indicates that significant amount of Al, Ti, and Zr can notbe explained by detrital origin. Ca, Mg, K, and Sr mainly occur as exchangeable elements and/or carbonatephase. Outermost layer 1 and innner layer 2 which are both young crusts generations are similar in chemicalspeciations of elements. However, some of Fe-oxyhydroxide bounded elements (Pb, Y, Mo, Ba, Al, and V)in phosphatized innermost layer 3 are released during phosphatization and incorporated into phosphate (Pb,Y, Mo, and Ba) or Mn-oxide phase (Al and V). Our sequential extraction results reveal that chemicalspeciations of elements in the hydrogenetic crusts are more or less different from interelemental relationshipcalculated by statistical method based on bulk chemistry.Key words : (sequential extraction), (Fe-Mn crusts), (phosphatization), (hydrogenetic elements)

The orbital-scale variations in biogenic CaCO_3 and opal abundance in two piston cores collected in the central equatorial Pacific (core PC5101 from a southern site at 2°N, and core PC5103 from a northern site at 6°N) were compared to assess latitudinal differences. The correlation between the oxygen isotope stratigraphy of planktonic foraminifera (＂Globigerinoides sacculifer＂) of PC5103 with the LR04 stacks provides the age of PC5103 to be approximately 950 ka. The age of PC5103 was further refined by correlating the CaCO_3 content with the well-dated core RC11-210. The age of PC5101 was also constrained by the same CaCO_3 chronostratigraphic correlation with RC11-210, resulting in an age of approximately 650 ka. Distinct orbital-scale series of CaCO_3 and opal variations appear to be parallel between the two cores during the past 600 ka, which are controlled mainly by eccentricity with an approximate periodicity of 100 ka. It is worth noting that the biogenic CaCO_3 and opal deposition patterns in the two cores differ between interglacial and glacial periods. During interglacial periods the biogenic opal content is higher in the southern core than in the northern core, which corresponds with the present-day condition. In contrast the CaCO_3 content is higher in the northern core, which is contradictory to the present-day northward decreasing CaCO_3 deposition pattern from the Equator. The collection site of PC5101 is approximately 350 m deeper than that of PC5103, which significantly promotes CaCO_3 dissolution and causes unexpectedly high CaCO_3 content at the northern site in contrast to the biogenic opal content.

The transport mechanism mediating brain uptake of tumor necrosis factor (TNF)-α has been studied. When125I-labeled rat TNF-α was used in internal carotid artery perfusions in rats, the cytokine showed transcytosis through the blood-brain barrier in intact form (permeability-surface area product 0.34 ± 0.13 μl · min−1· g−1). Uptake was inhibited by low nanomolar concentrations of unlabeled rat TNF-α. Human TNF-α, which does not interact with the p80 TNF receptor in rodents, showed no brain uptake. mRNA expression of both p60 and p80 receptors could be demonstrated in native brain microvessel preparations. These transcripts increased to 149% (p60) and 127% (p80) of control 4 h after a systemic immune stimulation (2 mg/kg bacterial endotoxin ip). Lipopolysaccharide treatment did not alter the rate of brain uptake of TNF-α measured between 4 and 24 h later. In conclusion, a receptor-mediated mechanism is responsible for the transcytosis of TNF-α. Saturable transport, requiring the p80 receptor, occurs at concentrations encountered under pathophysiological conditions and therefore constitutes a relevant mechanism of communication between the immune system and the brain.

The purpose of the present retrospective study was to describe the single oblique posterolateral approach for open reduction and internal fixation of large, displaced, posterior malleolar fractures with an associated lateral malleolar fracture. A single oblique posterolateral approach was used for osteosynthesis of the posterior and lateral malleolus in 50 consecutive patients (23 females [46%], 27 males [54%]; mean age, 47.44 ± 16.13 years; mean follow-up duration, 26.32 ± 5.15 months). The mean interval to surgery was 4.3 ± 1.9 days after the inciting trauma. During the follow-up period, the surgery was complicated by skin necrosis around the incision in 2 (4%) patients and sural nerve damage in 2 (4%) patients. We found that the single oblique posterolateral approach to large, displaced, posterior malleolar fractures with an associated lateral malleolar fracture provided easy exposure of the posterior and lateral malleoli and had the potential to decrease the incidence of sural nerve injury because of the smaller incision size.

In order to identify a potential relationship between the spatial distribution of Mn-nodule and deep-sea sediment properties in the Clarion-Clipperton fracture zone of the northeastern Pacific, physico-chemical properties of deep-sea sediments and photos of sea-floor are analyzed. In general, sediment types in the area show dramatic changes with latitude. Compared to the middle sector (8–12°N) covered with biogenic siliceous sediments, the northern (16–17°N) and southern (5–6°N) areas are dominated by pelagic red clays and calcareous sediments, respectively. Such a difference in sediment types probably produces regional-scale variations in Mn-nodule occurrence with latitude (5–17°N) along longitude (131.5°W). According to the photographic examination, manganese nodules are well exposed on the sea floor in the latitude of >8°N. In connection with the dominant oceanic environment, such observation indicates that calcareous sediments cover the diagenic nodules due to higher primary productivity and sedimentation rate in the latitude of

Previous reports have shown that antidepressants increase neuronal cell proliferation and enhance neuroplasticity both in vivo and in vitro. This study investigated the direct effects of one such antidepressant, fluoxetine , on cell proliferation and on the production of neurotrophic factors in neuronal precursors derived from human embryonic stem cells (hESCs; H9). Fluoxetine induced the differentiation of neuronal precursors, strongly enhancing neuronal characteristics. The rate of proliferation was higher in fluoxetine -treated cells than in control cells, as determined by MTT [3(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide] assay. The CPDL (cumulative population doubling level) of the fluoxetine-treated cells was significantly increased in comparison to that of control cells (p.001). Bromodeoxyuridine incorporation and staurosporine-induced apoptosis assays were elevated in fluoxetine-treated cells. Quantitative RT-PCR analysis revealed no significant differences in the expression of neurotrophic factors, brain-derived neurotrophic factor (BDNF);glial-derived neurotrophic factor (GDNF) and cAMP-responsive element-binding protein (CREB) between cells treated with fluoxetine for two weeks and their untreated counterparts. These results may help elucidate the mechanism of action of fluoxetine as a therapeutic drug for the treatment of depression. Data presented herein provide more evidence that, in addition to having a direct chemical effect on serotonin levels, fluoxetine can influence hESC-derived neuronal cells by increasing cell proliferation, while allowing them to maintain their neuronal characteristics.

무릎 반월연골판은 무릎에서 안정성과 충격 흡수능력, 그리고 축 성 압력을 받아주는 중요한 역할을 하고 있다. 각각의 반월연골 판은 환형 구조로 촘촘히 연결되어 있고, 듬성듬성 방사성 구조 로 결합되어 있으며, 무릎에 가해지는 축성 압력을 연골판 장력 (hoop tension)으로 변환시켜 준다. 실제로 체중의 약 50%-70%에 해당되는 하중이 반월연골판을 통해 전달되고 있다. 내측 반월연 골판 기시부 손상은 고리(hoop) 모양의 연속성이 끊어지게 되는 것으로 반월연골판의 이러한 생역학적 기능을 잃게 한다. 그리하 여 연골판 장력으로 변환되지 못한 축성 압력 때문에 무릎 관절 면의 퇴행성 변화를 초래한다고 알려져 있다. 이러한 반월연골판 병변의 진단 및 치료방침은 퇴행성 관절 염을 방지하는 관점에서 매우 중요하다. 내측 반월연골판 기시 부 파열은 크게 외상성 파열과 퇴행성 파열 두 가지로 나눌 수 있 다. 외상성 파열은 드물고 주로 연골판 기시부의 골부착부에서 떨어져 나오는 형태의 손상이며, 젊은 나이에서 전방십자인대 손 상과 잘 동반된다. 퇴행성 파열은 외상성 파열보다 비교적 흔하 며 기시부의 골부착부 자체가 아닌 골부착부 근처 실질에서의 파 열이 대부분이다. 50대 이상의 연령에서 여자에게 빈발하며, 큰 외상이 없이 퇴행성 변화로 생기는 파열이다. 한국에서의 통계 는 내측 반월연골판 파열의 약 25%를 차지할 정도로 수평파열 다 음으로 많다. 과거에는 동양에서 많이 발생한다고 알려졌으나 최근에는 서양에서도 많이 보고되고 있는데, 이는 관절경 검사와 자기공명영상(magnetic resonance imaging, MRI) 진단기술의 발달 pISSN : 1226-2102, eISSN : 2005-8918 372