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Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data (http://www.brainchart.io/). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals1–3, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood—including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)3across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.

Genetic alterations associated with prostate cancer (PCa) may be identified by sequencing metastatic tumour genomes to identify molecular markers at this lethal stage of disease. Previously, we characterized somatic alterations in metastatic tumours in the methylcytosine dioxygenase ten-eleven translocation 2(TET2), which is altered in 5–15% of myeloid, kidney, colon and PCas. Genome-wide association studies previously identified non-coding risk variants associated with PCa and melanoma. We perform fine-mapping of PCa risk across TET2using genotypes from the PEGASUS case-control cohort and identify six new risk variants in introns 1 and 2. Oligonucleotides containing two risk variants are bound by the transcription factor octamer-binding protein 1 (Oct1/POU2F1) and TET2and Oct1expression are positively correlated in prostate tumours. TET2is expressed in normal prostate tissue and reduced in a subset of tumours from the Cancer Genome Atlas (TCGA). Small interfering RNA-mediated TET2knockdown (KD) increases LNCaP cell proliferation, migration and wound healing, verifying loss drives a cancer phenotype. Endogenous TET2 bound the androgen receptor (AR) and AR-coactivator proteins in LNCaP cell extracts, and TET2KD increases prostate-specific antigen (KLK3/PSA) expression. Published data reveal TET2 binding sites and hydroxymethylcytosine proximal to KLK3. A gene co-expression network identified using TCGA prostate tumour RNA-sequencing identifies co-regulated cancer genes associated with 2-oxoglutarate (2-OG) and succinate metabolism, including TET2, lysine demethylase (KDM) KDM6A, BRCA1-associated BAP1, and citric acid cycle enzymes IDH1/2, SDHA/B, and FH. The co-expression signature is conserved across 31 TCGA cancers suggesting a putative role for TET2 as an energy sensor (of 2-OG) that modifies aspects of androgen-AR signalling. Decreased TET2mRNA expression in TCGA PCa tumours is strongly associated with reduced patient survival, indicating reduced expression in tumours may be an informative biomarker of disease progression and perhaps metastatic disease.

The utility of tumor-derived cell lines is dependent on their ability to recapitulate underlying genomic aberrations and primary tumor biology. Here, we sequenced the exomes of 25 bladder cancer (BCa) cell lines and compared mutations, copy number alterations (CNAs), gene expression and drug response to BCa patient profiles in The Cancer Genome Atlas (TCGA). We observed a mutation pattern associated with altered CpGs and APOBEC-family cytosine deaminases similar to mutation signatures derived from somatic alterations in muscle-invasive (MI) primary tumors, highlighting a major mechanism(s) contributing to cancer-associated alterations in the BCa cell line exomes. Non-silent sequence alterations were confirmed in 76 cancer-associated genes, including mutations that likely activate oncogenes TERT and PIK3CA, and alter chromatin-associated proteins (MLL3, ARID1A, CHD6 and KDM6A) and established BCa genes (TP53, RB1, CDKN2A and TSC1). We identified alterations in signaling pathways and proteins with related functions, including the PI3K/mTOR pathway, altered in 60% of lines; BRCA DNA repair, 44%; and SYNE1–SYNE2, 60%. Homozygous deletions of chromosome 9p21 are known to target the cell cycle regulators CDKN2A and CDKN2B. This loci was commonly lost in BCa cell lines and we show the deletions extended to the polyamine enzyme methylthioadenosine (MTA) phosphorylase (MTAP) in 36% of lines, transcription factor DMRTA1 (27%) and antiviral interferon epsilon (IFNE, 19%). Overall, the BCa cell line genomic aberrations were concordant with those found in BCa patient tumors. We used gene expression and copy number data to infer pathway activities for cell lines, then used the inferred pathway activities to build a predictive model of cisplatin response. When applied to platinum-treated patients gathered from TCGA, the model predicted treatment-specific response. Together, these data and analysis represent a valuable community resource to model basic tumor biology and to study the pharmacogenomics of BCa.

We investigated the phase transition behavior from the hexagonally perforated layer (HPL) to the gyroid (G) phase in supported thin film of a polystyrene-b-polyisoprene (PS-b-PI) diblock copolymer (Mn = 34.0 kg/mol, wtPI = 0.634) by grazing-incidence small-angle X-ray scattering. After annealing at 120 °C, the PS-b-PI thin film spin-coated on silicon wafer exhibited HPL morphology with its lamellae highly oriented parallel to the substrate up to a thickness as much as 1 μm. The interface-induced orientation allowed us to obtain a well-developed diffraction pattern in the absence of external mechanical strain to align the domains. The comparison with the computer-simulated diffraction pattern revealed that the HPL structure has mosaic grains oriented randomly in-plane with ABC stacking and undetectable amount of AB stacking. Upon heating, the HPL phase undergoes a phase transition to the G phase. The phase transition occurred epitaxially converting the HPL layers to the {121} planes of the G structure maintaining the G {121} plane oriented parallel to the substrate. This behavior is in contrast with the HPL to G phase transition found from the shear-oriented HPL samples, in which the G {121} plane is randomly oriented around the G [111] axis.

Three new bisindole alkaloids of the hamacanthin class (1−3) and one new bisindole alkaloid of the topsentin class (6) were isolated along with known bisindole alkaloids (4, 5, 7−11) from the MeOH extract of a marine sponge Spongosorites sp. by bioactivity-guided fractionation. The planar structures were established on the basis of NMR, MS, and IR spectroscopic analyses. Configurations of compounds 1−4 were derived from ¹H NMR data and optical rotation. Compounds 1, 4, 5, and 11 showed moderate to significant cytotoxicity against five human tumor cell lines, and compounds 1−5 showed weak antibacterial activity against clinically isolated methicillin-resistant strains.

A bioactivity-guided fractionation of a marine sponge Homaxinella sp. has led to the isolation of three new (1−3) highly degraded sterols and four new 6-O-alkylated (6−9) sterols, along with known sterol derivatives. The degraded sterols (1−5) belong to the class incisterols, previously isolated from the marine sponge Dictyonella incisa. Mainly NMR and MS spectroscopic analyses established the gross structures of the new compounds. The relationship between the stereoisomerism of the side chain and HPLC retention time has also been discussed. The compounds were tested against a panel of five human solid tumor cell lines, and especially the degraded sterols (1−4) displayed significant cytotoxicity.

Twelve new (1−7, 9−13) polyhydroxysterols and two new saponins (14 and 15) were isolated from the starfish Certonardoa semiregularis by activity-guided fractionation. Compounds 1−7 are rare examples of 15-keto steroids from starfish. The side chain of compound 11 was also unprecedented in nature. The structures were determined by combined spectroscopic methods and chemical derivatization. These compounds were evaluated for cytotoxicity against a small panel of human solid tumor cell lines, and most of them exhibited considerable activity. One of the 15-keto sterols (6) displayed the highest potency, which is comparable to that of doxorubicin.

Three new (1−3) and seven known (4−10) cytotoxic furanosesterterpenes were isolated from a marine sponge Psammocinia sp. by bioactivity-guided fractionation. The structures were established on the basis of NMR and MS analyses. The geometry and absolute configuration were determined on the basis of optical rotation, NMR, and CD data. These compounds were evaluated for cytotoxicity against a small panel of five human tumor cell lines, and most of the compounds showed toxicity to SK-MEL-2. The mixture of compounds 7 and 8 displayed significant inhibition of DNA replication and moderate antioxidant profile.

Three new butenolides (1−3), a new cyclopentenone derivative (4), and a known alcohol (5) were isolated from a marine sponge Homaxinella sp. by bioactivity-guided fractionation. The planar structures were established on the basis of NMR and MS analyses. The stereochemistry of the butenolides and cyclopentenone derivative was defined on the basis of optical rotation and CD spectroscopy. The compounds were tested for cytotoxicity against a panel of five human solid tumor cell lines and displayed marginal to significant activity.

Eleven new polyhydroxysterols (1−11) and eight new saponins (12−19) were isolated from the brine shrimp active fraction of the starfish Certonardoa semiregularis. The structures were determined on the basis of spectral analysis and chemical derivatization. The structural variations of these compounds are due to the hydroxylation pattern of the sterol nucleus, the functionalization of the side chain, or the nature and location of the saccharide moiety. These compounds displayed considerable cytotoxicity against a small panel of human solid tumor cell lines.

Three new bromotyrosine derivatives (4−6) were isolated from an association of two sponges, Jaspis wondoensis and Poecillastra wondoensis, along with the previously described (E,E)-psammaplin A (1), (E,Z)-psammaplin A (2), psammaplin D (3), bisaprasin (7), and (3-bromo-4-hydroxyphenyl)acetonitrile (8). The structures of the new compounds were established on the basis of NMR and MS spectroscopic analysis. The compounds 1, 3, and 5−7 displayed significant cytotoxicity against human lung (A549), ovarian (SK-OV-3), skin (SK-MEL-2), CNS (XF498), and colon (HCT15) cancer cell lines. Compounds 3−7 were further evaluated for antibacterial activity against methicillin- or ofloxacin-resistant Staphylococcus strains. Compound 4 exhibited more potent antibacterial activity than meropenem against several strains.

New norsesterterpenoids (3 and 4), a sesterterpenoid (6), pyrroloterpenoids (7−10), and a stereoisomer of kurospongin (5) were isolated, along with known furanosesterterpenes (11−15), from two marine sponges of the genus Sarcotragus. The gross structures were established on the basis of NMR and MS analysis. The stereochemistry was defined by combined use of NMR and CD spectroscopy. The compounds were evaluated for cytotoxicity against five human tumor cell lines and were found to exhibit marginal to moderate activity.

Three new triterpenoidal monodesmosides (1−3) and three new triterpenoidal bisdesmosides (4−6), together with two known saponins (7 and 8), were isolated from the fresh fruits of Ternstroemia japonica. The structures of 1−6 (ternstroemiasides A−F) were elucidated on the basis of spectral analysis and chemical degradation.

A miktoarm star-shaped copolymer, with one polystyrene arm (Mw = 198 kg/mol) and three polyisoprene arms (Mw = 51 kg/mol) (PSPI3), was rigorously characterized by temperature gradient interaction chromatography (TGIC). The polymer was prepared by linking active chain ends of precursor polymers to tetrachlorosilane as the linking agent, and the precursor polymers were prepared by anionic polymerization. The crude product was purified by fractional precipitation to remove the byproducts and the excess reagents. Size exclusion chromatography (SEC) analysis shows a narrow single elution peak whose molecular weight and composition are in good agreement with the predicted values in experimental precision. Therefore, it appears on the basis of conventional characterization using SEC, light scattering, and NMR that the fractionated mother represents a high-purity PSPI3 miktoarm star copolymer. However, TGIC analysis reveals the presence of significant amount of byproducts, most significantly PSPI2, which amounts to about 20% of the fractionated sample. This result clearly indicates that the analysis results utilizing conventional polymer characterization tools such as SEC, light scattering, osmometry, and viscometry are insufficient to establish the purity of polymers with complex architecture. It seems preferable to carry out a more detailed analysis such as that described in this work, in particular for polymers with complex architectures, if rigorous proof of structural purity is required.

Two new lysophosphatidylcholines (1, 2) and four new monoglycerides (5−8) were isolated from the marine sponge Stelletta sp. by bioactivity-guided fractionation. The planar structures of the new compounds were established on the basis of NMR and MS analyses. The stereochemistry was defined by comparison of the optical rotation. The compounds were evaluated for cytotoxicity against a small panel of five human tumor cell lines.

Four new acetylenic acids were isolated from the marine sponge Stelletta sp. by bioactivity-guided fractionation. The planar structures were established on the basis of NMR and MS analysis. The stereochemistry was defined by combined use of CD spectroscopy and a chiral anisotropic reagent, phenylglycine methyl ester (PGME). The compounds were evaluated for cytotoxicity against a small panel of five human tumor cell lines and exhibited marginal to moderate cytotoxicity.

Thirteen new polyhydroxysterols (1−5, 7−12, 14, 15) and two known polyhydroxysterols (6, 13) were isolated from the brine shrimp active fraction of the starfish Certonardoa semiregularis. The structures were determined on the basis of spectral analysis and chemical derivatization. These compounds displayed considerable cytotoxicity against a small panel of human solid tumor cell lines. These compounds were also evaluated for antibacterial activity against 20 clinically isolated strains. Most of the compounds showed weak antibacterial activity against Streptococcus pyogenes 308A, Pseudomonas aeruginosa 1771, and Pseudomonas aeruginosa 1771M.

Ten new saponins designated as certonardosides A−J (1−5, 7−11) and the known halityloside D (6) were isolated from the brine shrimp active fraction of the MeOH extract of the starfish Certonardoa semiregularis. The structures were determined on the basis of spectral analysis and chemical manipulation. The compounds were evaluated for antiviral activity against HIV, HSV, CoxB, EMCV, and VSV and displayed insignificant activity within the range of noncytotoxic concentrations.

Reexamination of the configuration of sarcotins A−C, first isolated from the marine sponge Sarcotragus sp., revealed that the proposed stereochemistry of the tetronic acid moiety needs to be revised as shown in 1−3. Additional new pyrrolosesterterpenes (5−11), furanosesterpene derivatives (4, 12−14, 19), and furanoterpenoids, including two trinorsesterterpenes (15, 16) and two diterpenes (17, 18), were isolated from the same sponge by bioactivity-guided fractionation. The planar structures were established on the basis of NMR and MS analysis. The stereochemistry was defined by combined use of NMR, CD spectroscopy, and chemical degradation. The compounds were evaluated for cytotoxicity against five human tumor cell lines and were found to exhibit moderate to significant activity.

The energy absorption characteristics of CFRP (Carbon-Fibre Reinforced Plastics) tubes have been investigated on static and dynamic tests. Axial static compression tests have been carried out using the static testing machine and dynamic compression tests have been utilised using a vertical crushing testing machine. When such tubes are subjected to crushing loads, the response is complex and depends on the interaction between the different mechanisms that could control the crushing process. The collapse characteristics and energy absorption have been examined for various tubes. Energy absorption of the tubes is increased as increased in the lay-up which may increase the modulus of tubes. The results have been varied significantly as a function of ply orientation and interlaminar number. In general, the stacking sequence [0/90] CFRP tubes absorbed more energy than the [15/-15] CFRP tubes.

Five new (1−3, 5, and 7) and two known (4, 6) furanosesterterpene tetronic acids were isolated from the marine sponge Sarcotragus sp. by bioactivity-guided fractionation. These compounds showed cytotoxicity against a panel of five human tumor cell lines. The gross structures were established on the basis of NMR and MS analyses. The compounds showed interesting variations of geometry and absolute configuration.

Ten new (1, 4−6, 9−14) and four known (2, 3, 7, 8) diacetylenes have been isolated from a brine shrimp active fraction of the methanolic extract of the stony coral Montipora sp. The structures were determined by combined spectroscopic methods. The compounds exhibited significant cytotoxicity against a small panel of human solid tumor cell lines. Montiporyne A (15), a previously reported congener, was also found to induce apoptosis in human colon tumor cell.

To determine whether pathogenic Acanthamoeba culbertsoni trophozoites and lysate can induce cytopathic changes in primary-culture microglial cells, morphological changes were observed by transmission electron microscopy (TEM). In addition, the secretion of two kinds of cytokines, tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta), from microglial cells was observed. Trophozoites of pathogenic A. culbertsoni made contact with microglial cells and produced digipodia. TEM revealed that microglial cells cocultured with amoebic trophozoites underwent a necrotic process, accompanied by lysis of the cell membrane. TEM of microglial cells cocultured with amoebic lysate showed that the membranes of the small cytoplasmic vacuoles as well as the cell membrane were lysed. The amounts of TNF-alpha secreted from microglial cells cocultured with A. culbertsoni trophozoites or lysate increased at 6 h of incubation. The amounts of IL-1beta secreted from microglial cells cocultured with A. culbertsoni trophozoites at 6 h of incubation was similar to those secreted from the control group, but the amounts decreased during cultivation with A. culbertsoni lysate. These results suggest that pathogenic A. culbertsoni induces the cytopathic effects in primary-culture rat microglial cells, with the effects characterized by necrosis of microglial cells and changes in levels of secretion of TNF-alpha and IL-1beta from microglial cells.

Ten new polyacetylenic alcohols (1−6, 8−11), along with a known compound, petrocortyne C (7), were isolated from the marine sponge Petrosia sp. The gross structures were established based on NMR and MS data, and the absolute configuration was determined by the modified Mosher's method. These compounds displayed considerable cytotoxicity against a small panel of human solid tumor cell lines. Compounds 1−11 were further evaluated for in vitro inhibitory activity on DNA replication.

Six new acetylenic compounds (1−6) with cytotoxic activities against human solid tumor cell lines (SK-OV-3, SK-MEL-2, XF498, and HCT15) have been isolated from the stony coral Montipora sp. Structures of the compounds 1−6 were elucidated based on analysis of the NMR and MS data.

Terminal differentiation of many vascular cells involves cell wall changes. Cells first elongate their primary wall, then lay down a lignified secondary wall, which is often followed by digestion of the primary wall. Expansins are wall proteins that regulate wall changes, but little is known about the specific functions of the many individual expansin isoforms. An in vitro cell culture of synchronously differentiating tracheary elements was used to identify three new expansins and to compare their expression kinetics with the timing of wall changes. The genes encoding these expansins from zinnia (Zinnia elegans), designated ZeExp1, ZeExp2, ZeExp3, are expressed during cell elongation. ZeExp1 and ZeExp2 mRNA decrease at the early stage of secondary wall formation, whereas ZeExp3 does not. In planta, all three ZeExp mRNAs are found predominantly in a single flank of cells adjacent to protoxylem and metaxylem vessels and in cells roughly at the radial position of the fasicular and interfasicular cambium. Furthermore, within these cells, Exp mRNA is localized exclusively either to the apical or basipetal end of cells depending on the expansin gene and organ, providing the first evidence for polar localization of mRNA in plant cells. ZeExp1 and ZeExp3 mRNA are localized at the apical tip, whereas ZeExp2 mRNA is found in the basal tip. These observations indicate that these three expansins are xylem cell specific and possibly involved in the intrusive growth of the primary walls of differentiating xylem cells.

To determine whether trophozoites and lysates of pathogenic Acanthamoeba spp. induce apoptosis in primary-culture microglial cells, transmission electron microscopic (TEM) examinations, assessment of DNA fragmentation by agarose gel electrophoresis, and the TdT-mediated dUTP nick-end labeling assay were performed. When a trophozoite of pathogenic Acanthamoeba culbertsoni came in contact with a microglial cell, the digipodium was observed by TEM. Nuclear chromatin condensation was observed in 10% of microglial cells, while it was not revealed when they were cocultured with weakly pathogenic Acanthamoeba royreba trophozoites. DNA fragmentation in microglial cells cocultured with the A. culbertsoni lysate was detected by electrophoresis, showing DNA ladder formation, whereas it was hardly observed in microglial cells cocultured with A. royreba. DNA fragmentation of microglial cells was also confirmed by flow cytometry analysis. The fluorescence of TdT-stained apoptotic bodies became intensely visible with microglial cells cocultured with the A. culbertsoni lysate. In contrast, with microglial cells cocultured with the A. royreba lysate, only a background level of fluorescence of TdT-stained apoptotic bodies was detected. These results suggest that some rat microglial cells cocultured with pathogenic A. culbertsoni undergo cytopathic changes which show the characteristics of the apoptotic process, such as nuclear condensation and DNA fragmentation.

AbstractThe planned Korea Superconducting Tokamak Advanced Research (KSTAR) divertor has been designed to provide reliable power handling and particle control with enough shaping flexibility to accommodate a wide range of plasma operation. The physics basis for the current configuration of the KSTAR divertor through analyses of the heat flux at the target, particle control, and plasma-facing component is reported. A simple zero-dimensional model based on the power balance assumptions and two-dimensional codes is utilized to estimate the heat flux to the divertor plate. The limit for the peak heat flux on the divertor plate, 3.5 MW/m2, requires advanced operating modes such as the radiative divertor and radiative mantle, which are considered to overcome the weakness of a high-recycling divertor. A simple particle balance model could estimate the pumping rate with total leakage fraction assuming particle sources. A Monte Carlo neutral transport calculation determines the dimension of a gap between the center and outer divertor targets. It also determines the number and best position of the pumps, as well as the geometry for conductance. For the initial 20-s discharges, a bolted-tile carbon-fiber-composite design is relied upon for the upper and lower divertor targets. The design of the supporting structure for the divertors will allow for future modifications to accommodate thermal steady-state 300-s operation or to optimize divertor performance based on new understanding gained during initial tokamak operation.

A series of phospholipids, including previously undescribed compounds 4−7, were isolated by a bioactivity-guided fractionation from the marine sponge Spirastrella abata as inhibitors of cholesterol biosynthesis in human liver cells. These compounds were identified as lyso-PAF analogues (1−5) and lysophosphatidylcholines (6, 7) based on NMR and MS analyses. Compounds 1−7 specifically blocked the conversion of lanosterol into cholesterol in the Chang liver cell.

A bioactive cyclitol derivative (1) was isolated from the marine sponge Petrosia sp. The chemical structure of 1 was determined as (2S)-1-O-(2‘,3‘,4‘,5‘-tetrahydroxycyclopentyl)-3-O-(10‘ ‘-methylhexadecyl)glycerol. Compound 1 inhibited DNA replication in vitro at the level of initiation.