Crystal structures of two new high-pressure oxynitrides with composition SnGe4N4O4, from single-crystal electron diffraction.

SnGe4N4O4 was synthesized at high pressure (16 and 20 GPa) and high temperature (1200 and 1500°C) in a large-volume press. Powder X-ray diffraction experiments using synchrotron radiation indicate that the derived samples are mixtures of known and unknown phases. However, the powder X-ray diffraction patterns are not sufficient for structural characterization. Transmission electron microscopy studies reveal crystals of several hundreds of nanometres in size with different chemical composition. Among them, crystals of a previously unknown phase with stoichiometry SnGe4N4O4 were detected and investigated using automated diffraction tomography (ADT), a three-dimensional electron diffraction method. Via ADT, the crystal structure could be determined from single nanocrystals in space group P63mc, exhibiting a nolanite-type structure. This was confirmed by density functional theory calculations and atomic resolution scanning transmission electron microscopy images. In one of the syntheses runs a rhombohedral 6R polytype of SnGe4N4O4 could be found together with the nolanite-type SnGe4N4O4. The structure of this polymorph was solved as well using ADT.

OlCHR, encoding a chromatin remodeling factor, is a killer causing hybrid sterility between rice species Oryza sativa and O. longistaminata.

The genetic mechanisms of reproductive isolation have been widely investigated within Asian cultivated rice (Oryza sativa); however, relevant genes between diverged species have been in sighted rather less. Herein, a gene showing selfish behavior was discovered in hybrids between the distantly related rice species Oryza longistaminata and O. sativa. The selfish allele S13l in the S13 locus impaired male fertility, discriminately eliminating pollens containing the allele S13s from O. sativa in heterozygotes (S13s/S13l). Genetic analysis revealed that a gene encoding a chromatin-remodeling factor (CHR) is involved in this phenomenon and a variety of O. sativa owns the truncated gene OsCHR745, whereas its homologue OlCHR has a complete structure in O. longistaminata. CRISPR-Cas9-mediated loss of function mutants restored fertility in hybrids. African cultivated rice, which naturally lacks the OlCHR homologue, is compatible with both S13s and S13l carriers. These results suggest that OlCHR is a Killer gene, which leads to reproductive isolation.

Therapeutic Effect of Proteinase-Activated Receptor-1 Antagonist on Colitis-Associated Carcinogenesis.

BACKGROUND & AIMS: Inflammatory bowel disease is associated with carcinogenesis, which limits the prognosis of the patients. The local expression of proteinases and proteinase-activated receptor 1 (PAR1) increases in inflammatory bowel disease. The present study investigated the therapeutic effects of PAR1 antagonism on colitis-associated carcinogenesis. METHODS: A colitis-associated carcinogenesis model was prepared in mice by treatment with azoxymethane (AOM) and dextran sulfate sodium (DSS). PAR1 antagonist E5555 was administered in long- and short-term protocol, starting on the day of AOM injection and 1 week after completing AOM/DSS treatment, respectively. The fecal samples were collected for metagenome analysis of gut microbiota. The intestinal myofibroblasts of the Crohn's disease patients were used to elucidate underlying cellular mechanisms. Caco-2 cells were used to investigate a possible source of PAR1 agonist proteinases. RESULTS: AOM/DSS model showed weight loss, diarrhea, tumor development, inflammation, fibrosis, and increased production of inflammatory cytokines. The ß-diversity, but not α-diversity, of microbiota significantly differed between AOM/DSS and control mice. E5555 alleviated these pathological changes and altered the microbiota ß-diversity in AOM/DSS mice. The thrombin expression was up-regulated in tumor and non-tumor areas, whereas PAR1 mRNA expression was higher in tumor areas compared with non-tumor areas. E5555 inhibited thrombin-triggered elevation of cytosolic Ca2+ concentration and ERK1/2 phosphorylation, as well as IL6-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation in intestinal myofibroblasts. Caco-2 cell-conditioned medium contained immunoreactive thrombin, which cleaved the recombinant protein containing the extracellular domain of PAR1 at the thrombin cleavage site. CONCLUSIONS: PAR1 antagonism is proposed to be a novel therapeutic strategy for treatment of inflammatory bowel disease and its associated carcinogenesis.

Real-time tracking of three-dimensional atomic dynamics of Pt trimer on TiO2 (110).

Single and multi-atoms supported on oxide substrates ultimately increase the efficiency of noble metal atom use, and moreover, catalytic activity and selectivity are also improved substantially. However, single and multi-atoms are unstable under catalytic conditions, and these metal atoms spontaneously aggregate and grow into nanoparticles. Catalytic performance is strongly related to local atomic configurations, and hence, it is essential to determine the three-dimensional (3D) atomic structures of multi-atoms on the substrate and their structural dynamics. Here, we show the real-time tracking of the 3D structural evolution of a Pt trimer on TiO2 (110) substrate at a high temperature, using high-spatiotemporal-resolution scanning transmission electron microscopy, where sub-angstrom spatial resolution is maintained, while the temporal resolution reaches 40 milliseconds. With the aid of prior structural knowledge of a Pt trimer for 3D reconstruction, the present method could open the way to characterize in situ atomic-scale structural dynamics, especially meta-stable structural transition.

Ultra-stable and highly reactive colloidal gold nanoparticle catalysts protected using multi-dentate metal oxide nanoclusters.

Owing to their remarkable properties, gold nanoparticles are applied in diverse fields, including catalysis, electronics, energy conversion and sensors. However, for catalytic applications of colloidal gold nanoparticles, the trade-off between their reactivity and stability is a significant concern. Here we report a universal approach for preparing stable and reactive colloidal small (~3 nm) gold nanoparticles by using multi-dentate polyoxometalates as protecting agents in non-polar solvents. These nanoparticles exhibit exceptional stability even under conditions of high concentration, long-term storage, heating and addition of bases. Moreover, they display excellent catalytic performance in various oxidation reactions of organic substrates using molecular oxygen as the sole oxidant. Our findings highlight the ability of inorganic multi-dentate ligands with structural stability and robust steric and electronic effects to confer stability and reactivity upon gold nanoparticles. This approach can be extended to prepare metal nanoparticles other than gold, enabling the design of novel nanomaterials with promising applications.

CNN-based fully automatic mitral valve extraction using CT images and existence probability maps.

Objective. Accurate extraction of mitral valve shape from clinical tomographic images acquired in patients has proven useful for planning surgical and interventional mitral valve treatments. However, manual extraction of the mitral valve shape is laborious, and the existing automatic extraction methods have not been sufficiently accurate. In this paper, we propose a fully automated method of extracting mitral valve shape from computed tomography (CT) images for the all phases of the cardiac cycle.Approach. This method extracts the mitral valve shape based on DenseNet using both the original CT image and the existence probability maps of the mitral valve area inferred by U-Net as input. A total of 1585 CT images from 204 patients with various cardiac diseases including mitral regurgitation were collected and manually annotated for mitral valve region. The proposed method was trained and evaluated by 10-fold cross validation using the collected data and was compared with the method without the existence probability maps.Main results. The mean error of shape extraction error in the proposed method is 0.88 mm, which is an improvement of 0.32 mm compared with the method without the existence probability maps.Significance. We present a novel fully automatic mitral valve extraction method from input to output for all phases of 4D CT images. We suggest that the accuracy of mitral valve shape extraction is improved by using existence probability maps.

Wild and cultivated allele effects on rice phenotypic traits in reciprocal backcross populations between Oryza rufipogon and two cultivars, O. sativa Nipponbare and IR36.

A total of four populations of reciprocal backcross recombinant inbred lines were produced from a cross between a wild accession of Oryza rufipogon W630 and two major cultivars, O. sativa Japonica Nipponbare and Indica IR36. Using these populations, quantitative trait locus (QTL) analysis for eight morphological traits (culm length, panicle length, days to heading, panicle shape, pericarp color, hull color, seed shattering and seed awning) was carried out, and the putative QTL regions were compared among the populations. The QTLs with strong allele effects were commonly detected for culm length, panicle shape, pericarp color and hull color in all four populations, and their peak locations were close to the major genes of sd1, Spr3, Rc and Bh4, respectively. For panicle length and days to heading, some QTL regions overlapped between two or three populations. In the case of seed shattering and seed awning, strong wild allele effects at major loci were observed only in the populations with cultivated backgrounds. Since the wild and cultivated alleles have never been evaluated in the reciprocal genetic backgrounds, the present results provide new information on gene effects in breeding and domestication studies.

Functional and Structural Insights into the Human PPARα/δ/γ Targeting Preferences of Anti-NASH Investigational Drugs, Lanifibranor, Seladelpar, and Elafibranor.

No therapeutic drugs are currently available for nonalcoholic steatohepatitis (NASH) that progresses from nonalcoholic fatty liver via oxidative stress-involved pathways. Three cognate peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) are considered as attractive targets. Although lanifibranor (PPARα/δ/γ pan agonist) and saroglitazar (PPARα/γ dual agonist) are currently under investigation in clinical trials for NASH, the development of seladelpar (PPARδ-selective agonist), elafibranor (PPARα/δ dual agonist), and many other dual/pan agonists has been discontinued due to serious side effects or little/no efficacies. This study aimed to obtain functional and structural insights into the potency, efficacy, and selectivity against PPARα/δ/γ of three current and past anti-NASH investigational drugs: lanifibranor, seladelpar, and elafibranor. Ligand activities were evaluated by three assays to detect different facets of the PPAR activation: transactivation assay, coactivator recruitment assay, and thermal stability assay. Seven high-resolution cocrystal structures (namely, those of the PPARα/δ/γ-ligand-binding domain (LBD)-lanifibranor, PPARα/δ/γ-LBD-seladelpar, and PPARα-LBD-elafibranor) were obtained through X-ray diffraction analyses, six of which represent the first deposit in the Protein Data Bank. Lanifibranor and seladelpar were found to bind to different regions of the PPARα/δ/γ-ligand-binding pockets and activated all PPAR subtypes with different potencies and efficacies in the three assays. In contrast, elafibranor induced transactivation and coactivator recruitment (not thermal stability) of all PPAR subtypes, but the PPARδ/γ-LBD-elafibranor cocrystals were not obtained. These results illustrate the highly variable PPARα/δ/γ activation profiles and binding modes of these PPAR ligands that define their pharmacological actions.

Fast reconstruction of scanning transmission electron microscopy images using Markov random field model.

In this study, we proposed a fast method of reconstruction for scanning transmission electron microscopy images. The proposed method is based on the Markov random field model and Bayesian inference, and we found that the method can reconstruct such images of sizes 512 × 512 and 264 × 240 in less than 200 ms and 100 ms, respectively. Furthermore, we showed that the method of reconstruction from multiple images without averaging them has better reconstruction performance than that from the averaged image.

Detection of novel loci involved in non-seed-shattering behaviour of an indica rice cultivar, Oryza sativa IR36.

Asian rice (Oryza sativa) was domesticated from O. rufipogon, and reduced seed-shattering behaviour was selected to increase yields. Two seed-shattering loci, qSH3 and sh4, are involved in reducing seed shattering in both japonica and indica rice cultivars, while qSH1 and qCSS3 are likely specific to japonica cultivars. In indica cultivars, qSH3 and sh4 fail to explain the degree of seed shattering, as an introgression line (IL) of O. rufipogon W630 carrying domesticated alleles at qSH3 and sh4 still showed seed shattering. Here we analysed differences in seed-shattering degree between the IL and the indica cultivar IR36. The values for grain detachment in the segregating population between the IL and IR36 were continuous. Based on QTL-seq analysis using the BC1F2 population between the IL and IR36, we detected two novel loci, qCSS2 and qCSS7 (QTLs for the Control of Seed Shattering in rice on chromosomes 2 and 7), which contributed to the reduced seed shattering in IR36. We further investigated the genetic interaction of qCSS2 and qCSS7 under the presence of qSH3 and sh4 mutations in O. rufipogon W630 and found that IL carrying IR36 chromosomal segments covering all four loci are required to explain seed-shattering degree in IR36. Since qCSS2 and qCSS7 were not detected in previous studies on seed shattering in japonica, their control may be specific to indica cultivars. Therefore, they are important to understanding the history of rice domestication as well as to adjusting the seed-shattering degree of indica cultivars to maximise their yield.

MMP-7 expression is associated with a higher rate of tumor spread through air spaces in resected lung adenocarcinomas.

OBJECTIVES: The spread through air spaces (STAS) of adenocarcinoma (ADC) is a unique pattern for local invasion, which comprises the spread of tumor cells within air spaces beyond the tumor edge without a direct connection with the primary tumor. Matrix metalloproteinase-7 (MMP-7), a secreted proteolytic enzyme that degrades various extracellular matrix components and other substrates, regulates several pathophysiological processes as well as the occurrence and development of cancers in humans. Here, we retrospectively analyzed a cohort of Japanese patients with treatment-naive, surgically-resected lung ADC to assess whether MMP-7 is associated with STAS development and if it could be used as a predictor of STAS. MATERIALS AND METHODS: We performed histological evaluation using hematoxylin and eosin staining and immunohistochemical analysis using microarrays. Thereafter, we scored the examined tissues for immune markers to identify significant tumor STAS predictors. RESULTS: We identified that high MMP-7 expression is an independent predictor of a high STAS incidence. Multivariate analysis revealed that MMP-7 expression was correlated with tumor behavior and poor prognosis. Furthermore, STAS remained significantly associated with a higher risk of ADC recurrence. CONCLUSION: The development of tumor STAS could be promoted by the functioning of MMP-7. This study could be a crucial basis for future investigations on the detection of tumor STAS.

P53 immunolabeling in EUS-FNA biopsy can predict low resection rate and early recurrence in resectable or borderline resectable pancreatic cancer treated with neoadjuvant therapy.

PURPOSE: KRAS, P16, TP53, and SMAD4/DPC4 mutations are common in pancreatic ductal adenocarcinoma (PDAC). The study aimed to evaluate the association between gene mutations in pre-treatment endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) samples and clinical outcomes of patients with PDAC. METHODS: There were 43 patients with resectable (R) PDAC and 41 patients with borderline resectable (BR) PDAC. CDKN2A/p16, TP53, and SMAD4/DPC4 were evaluated through immunohistochemistry (IHC) of pretreatment EUS-FNA (n = 84) and resected specimens (n = 71). All patients received neoadjuvant therapy. RESULTS: IHC of EUS-FNA specimens revealed p16 loss in 61 (73%), abnormal p53 in 61 (73%), and Smad4 loss in 38 (45%) patients. Abnormal p53 was associated with a lower resection rate (p = .017). Abnormal p53 and Smad4 loss were associated with recurrence within 6 months post-pancreatectomy (p = .03, p = .03, respectively). Univariate Cox regression analysis was conducted to reveal that abnormal p53 (p = .07), p16 loss and abnormal p53 (p = .04), and Smad4 and p16 loss (p = .03) were associated with poor prognosis. CONCLUSIONS: Pre-treatment abnormal labeling of p53 in EUS-FNA specimen was associated with a lower resection rate and an early recurrence in R or BR PDAC cases.

Spatial and phase resolution in electron microscopy.

With the invention of the aberration corrector in electron optics, the spatial resolution in electron microscopy has progressively improved and has now reached the sub-50-pm regime, and atomic-resolution electron microscopy has become a versatile tool for investigating the atomic structures in materials and devices. Furthermore, the phase resolution in electron microscopy also exhibits outstanding progress, and it has become possible to visualize electromagnetic fields at atomic dimensions, which strongly contributes to understanding the physical and chemical properties of materials. The electron microscopy society has grown with the improvements in spatial and phase resolutions, and hence, we must continuously develop new hardware, software and methodologies to boost these resolutions. Here, we review the historical progress of spatial and phase resolutions in electron microscopy, where we clarify the definition of these resolutions. We also discuss the future targets in electron microscopy.

Grain boundary structural transformation induced by co-segregation of aliovalent dopants.

Impurity doping is a conventional but one of the most effective ways to control the functional properties of materials. In insulating materials, the dopant solubility limit is considerably low in general, and the dopants often segregate to grain boundaries (GBs) in polycrystals, which significantly alter their entire properties. However, detailed mechanisms on how dopant atoms form structures at GBs and change their properties remain a matter of conjecture. Here, we show GB structural transformation in α-Al2O3 induced by co-segregation of Ca and Si aliovalent dopants using atomic-resolution scanning transmission electron microscopy combined with density functional theory calculations. To accommodate large-sized Ca ions at the GB core, the pristine GB atomic structure is transformed into a new GB structure with larger free volumes. Moreover, the Si and Ca dopants form a chemically ordered structure, and the charge compensation is achieved within the narrow GB core region rather than forming broader space charge layers. Our findings give an insight into GB engineering by utilizing aliovalent co-segregation.

Direct Probe of the Ferromagnetic Proximity Effect at the Interface of SnTe/Fe Heterostructure by Polarized Neutron Reflectometry.

Introducing magnetic order into a topological insulator (TI) system has attracted much attention with an expectation of realizing exotic phenomena such as the quantum anomalous Hall effect (QAHE) and axion insulator states. The magnetic proximity effect (MPE) is one of the promising schemes to induce the magnetic order on the surface of a TI without introducing disorder accompanied by doping magnetic impurities in the TI. In this study, we investigate the MPE at the interface of a heterostructure consisting of the topological crystalline insulator (TCI) SnTe and Fe by employing polarized neutron reflectometry. The ferromagnetic order penetrates ∼2.2 nm deep into the SnTe layer from the interface with Fe, which persists up to room temperature. This is induced by the MPE on the surface of the TCI preserving the coherent topological states without introducing the disorder by doping magnetic impurities. This would open up a way for realizing next-generation spintronics and quantum computational devices.

A stepwise route to domesticate rice by controlling seed shattering and panicle shape.

Asian rice (Oryza sativa L.) is consumed by more than half of the world's population. Despite its global importance, the process of early rice domestication remains unclear. During domestication, wild rice (Oryza rufipogon Griff.) acquired non-seed-shattering behavior, allowing humans to increase grain yield. Previous studies argued that a reduction in seed shattering triggered by the sh4 mutation led to increased yield during rice domestication, but our experiments using wild introgression lines show that the domesticated sh4 allele alone is insufficient for shattering loss in O. rufipogon. The interruption of abscission layer formation requires both sh4 and qSH3 mutations, demonstrating that the selection of shattering loss in wild rice was not as simple as previously suggested. Here we identified a causal single-nucleotide polymorphism at qSH3 within the seed-shattering gene OsSh1, which is conserved in indica and japonica subspecies but absent in the circum-aus group of rice. Through harvest experiments, we further demonstrated that seed shattering alone did not significantly impact yield; rather, yield increases were observed with closed panicle formation controlled by SPR3 and further augmented by nonshattering, conferred by integration of sh4 and qSH3 alleles. Complementary manipulation of panicle shape and seed shattering results in a mechanically stable panicle structure. We propose a stepwise route for the earliest phase of rice domestication, wherein selection of visible SPR3-controlled closed panicle morphology was instrumental in the sequential recruitment of sh4 and qSH3, which together led to the loss of shattering.