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Cattle-related injuries are a significant contributing factor in 84.3% of livestock-related incidents in Hokkaido Japan. The specific countermeasures to respond to its characteristics are needed because cattle move freely. This study examined the JA Kyosai mutual aid payment claim form data of the agricultural work-related incidents that occurred from 1 st January 2013 to 31 st December 2016. We extracted incidents coded ‘Cattle’ term on the ‘Causing Stuffs/Animals’ column as cattle-related injuries and analysed them. In four years, there were 227 cattle-related incidents and all were non-fatal cases. The most common age group of victims were in their 60s (37.9%). The Therapy duration was 1 to 243 days, with one day being the most common (10.1%); however, in 51.5% of the cases it required more than 30 days. The most common Activity at the moment of the incident was ‘bringing the cattle’ (22.5%), of which ‘leading the cattle by rope’ (56.9% of bringing) was most frequently mentioned. Even farmers with significant experience with cattle cannot control cattle proficiently. Neither can they predict cattle behaviour. Hence, cattle should be kept under protected contact. Since prevention of incidents has limits, harm reduction to farmers must be considered. In the short-term planning, isolated pathways and shock-absorbing lead rope are effective in preventing injuries. However, a more long-term perspective must consider, a fully automated system that reduces human contact with cattle on farms.

Magnetic insulators have wide-ranging applications, including microwave devices, permanent magnets and future spintronic devices. However, the record Curie temperature ( T C ), which determines the temperature range in which any ferri/ferromagnetic system remains stable, has stood still for over eight decades. Here we report that a highly B-site ordered cubic double-perovskite insulator, Sr 3 OsO 6 , has the highest T C (of ~ 1060 K) among all insulators and oxides; also, this is the highest magnetic ordering temperature in any compound without 3 d transition elements. The cubic B-site ordering is confirmed by atomic-resolution scanning transmission electron microscopy. The electronic structure calculations elucidate a ferromagnetic insulating state with J eff  = 3/2 driven by the large spin-orbit coupling of Os 6+ 5 d 2 orbitals. Moreover, the Sr 3 OsO 6 films are epitaxially grown on SrTiO 3 substrates, suggesting that they are compatible with device fabrication processes and thus promising for spintronic applications. Pursuing high Curie temperature magnetic insulators has been one of the extensively studied subjects due to their wide appeal for spintronic applications. Here the authors experimentally and theoretically demonstrate a record high Curie temperature over 1000 K in B-site ordered double-perovskite, Sr3OsO6.

Cytoskeleton‐associated protein 4 (CKAP4) is a cell surface receptor for Dickkopf 1 (DKK1), a secreted protein. The DKK1–CKAP4 pathway is activated in various malignant tumors, including pancreatic, lung, esophageal, and liver cancers, to promote tumor growth. Thus, CKAP4 has been expected to represent a novel molecular target of cancer therapy. Recombinant mouse anti‐CKAP4 antibodies were generated based on an original mouse antibody (3F11‐2B10) and inhibited DKK1–CKAP4 signaling and xenograft tumor formation induced by pancreatic cancer cells, which was comparable with 3F11‐2B10. From the 3F11‐2B10 nucleotide sequence, humanized anti‐CKAP4 antibody (Hv1Lt1) was subsequently developed. The binding affinity of Hv1Lt1 for CKAP4 was superior to that of 3F11‐2B10. Hv1Lt1 inhibited DKK1 binding to CKAP4, AKT activity, and sphere formation of pancreatic cancer cells, which was comparable with 3F11‐2B10. Hv1Lt1 also suppressed xenograft tumor formation induced by human pancreatic cancer cells and tumor growth in murine cancer models, in which murine pancreatic cancer organoids were orthotopically transplanted into the pancreas. In resected tumor samples from mice treated with Hv1Lt1, anti‐tumor immune reactions were modulated and cytotoxic T cells were highly infiltrated in the tumor microenvironment. Additionally, combination of Hv1Lt1 and other chemotherapy drugs exhibited stronger effects compared with monotherapy. These results suggest that Hv1Lt1 represents a promising anti‐cancer therapy. Oncogenic DKK1–CKAP4 signaling axis is activated in pancreatic cancer and associated with a poor prognosis. In this study, we have for the first time developed a humanized anti‐CKAP4 antibody based on the structure of a previously developed mouse anti‐CKAP4 monoclonal antibody 3F11‐2B10. The novel humanized anti‐CKAP4 antibody Hv1Lt1 efficiently inhibited DKK1‐CKAP4 signaling and suppressed in vivo pancreatic tumor growth either as a monotherapy or in combination with standard therapeutics.

Magnetic Weyl semimetals have novel transport phenomena related to pairs of Weyl nodes in the band structure. Although the existence of Weyl fermions is expected in various oxides, the evidence of Weyl fermions in oxide materials remains elusive. Here we show direct quantum transport evidence of Weyl fermions in an epitaxial 4 d ferromagnetic oxide SrRuO 3 . We employ machine-learning-assisted molecular beam epitaxy to synthesize SrRuO 3 films whose quality is sufficiently high to probe their intrinsic transport properties. Experimental observation of the five transport signatures of Weyl fermions—the linear positive magnetoresistance, chiral-anomaly-induced negative magnetoresistance, π phase shift in a quantum oscillation, light cyclotron mass, and high quantum mobility of about 10,000 cm 2 V −1 s −1 —combined with first-principles electronic structure calculations establishes SrRuO 3 as a magnetic Weyl semimetal. We also clarify the disorder dependence of the transport of the Weyl fermions, which gives a clear guideline for accessing the topologically nontrivial transport phenomena. Despite various predictions, the evidence of Weyl fermions in oxide materials remains elusive. Here, the authors show evidence of Weyl fermions in quantum transport measurements in an epitaxial ferromagnetic oxide SrRuO 3 .

Wnt5b is a member of the same family of proteins as Wnt5a, the overexpression of which is associated with cancer aggressiveness. Wnt5b is also suggested to be involved in cancer progression, however, details remain unclarified. We analyzed the biochemical properties of purified Wnt5b and the mode of secretion of Wnt5b by cancer cells. Wnt5b was glycosylated at three asparagine residues and lipidated at one serine residue, and these post‐translational modifications of Wnt5b were essential for secretion. Purified Wnt5b showed Dvl2 phosphorylation and Rac activation abilities to a similar extent as Wnt5a. In cultured‐cell conditioned medium, Wnt5b was detected in supernatant or precipitation fractions that were separated by centrifugation at 100 000 g. In PANC‐1 pancreatic cancer cells, 55% of secreted endogenous Wnt5b was associated with exosomes. Exosomes from wild‐type PANC‐1 cells, but not those from Wnt5b‐knockout PANC‐1 cells, activated Wnt5b signaling in CHO cells and stimulated migration and proliferation of A549 lung adenocarcinoma cells, suggesting that endogenous, Wnt5b‐associated exosomes are active. The exosomes were taken up by CHO cells and immunoelectron microscopy revealed that Wnt5b is indeed associated with exosomes. In Caco‐2 colon cancer cells, most Wnt5b was recovered in precipitation fractions when Wnt5b was ectopically expressed (Caco‐2/Wnt5b cells). Knockdown of TSG101, an exosome marker, decreased the secretion of Wnt5b‐associated exosomes from Caco‐2/Wnt5b cells and inhibited Wnt5b‐dependent cell proliferation. Exosomes secreted from Caco‐2/Wnt5b cells stimulated migration and proliferation of A549 cells. These results suggest that Wnt5b‐associated exosomes promote cancer cell migration and proliferation in a paracrine manner. The secretory modes of Wnt5b varied among cancer cells and Wnt5b‐associated exosomes promote cancer cells migration and proliferation in a paracrine manner.

Dickkopf1 (DKK1) is overexpressed in various cancers and promotes cancer cell proliferation by binding to cytoskeleton-associated protein 4 (CKAP4). However, the mechanisms underlying DKK1 expression are poorly understood. RNA sequence analysis revealed that expression of the transcription factor forkhead box M1 (FOXM1) and its target genes concordantly fluctuated with expression of DKK1 in pancreatic ductal adenocarcinoma (PDAC) cells. DKK1 knockdown decreased FOXM1 expression and vice versa in PDAC and esophageal squamous cell carcinoma (ESCC) cells. Inhibition of either the DKK1-CKAP4-AKT pathway or the ERK pathway suppressed FOXM1 expression, and simultaneous inhibition of both pathways showed synergistic effects. A FOXM1 binding site was identified in the 5ʹ-untranslated region of the DKK1 gene, and its depletion decreased DKK1 expression and cancer cell proliferation. Clinicopathological and database analysis revealed that PDAC and ESCC patients who simultaneously express DKK1 and FOXM1 have a poorer prognosis. Multivariate analysis demonstrated that expression of both DKK1 and FOXM1 is the independent prognostic factor in ESCC patients. Although it has been reported that FOXM1 enhances Wnt signaling, FOXM1 induced DKK1 expression independently of Wnt signaling in PDAC and ESCC cells. These results suggest that DKK1 and FOXM1 create a positive feedback loop to promote cancer cell proliferation.

Wnt plays important role during development and in various diseases. Because Wnts are lipidated and highly hydrophobic, they can only be purified in the presence of detergents, limiting their use in various in vitro and in vivo assays. We purified N-terminally tagged recombinant Wnt3a secreted from cells and accidentally discovered that Wnt3a co-purified with a glycoprotein afamin derived from the bovine serum included in the media. Wnt3a forms a 1:1 complex with afamin, which remains soluble in aqueous buffer after isolation, and can induce signaling in various cellular systems including the intestical stem cell growth assay. By co-expressing with afamin, biologically active afamin-Wnt complex can be easily obtained in large quantity. As afamin can also solubilize Wnt5a, Wnt3, and many more Wnt subtypes, afamin complexation will open a way to put various Wnt ligands and their signaling mechanisms under a thorough biochemical scrutiny that had been difficult for years. The Wnt signaling pathway helps animal cells to communicate with each other to coordinate the formation of tissues and organs. The pathway relies on a protein called Wnt that is released from cells and binds to a receptor protein called Frizzled on the surface of other cells to trigger changes in gene activation. Defects in the Wnt signaling pathway contribute to cancer and other diseases. Great progress has been made in understanding Wnt signaling, but certain types of experiments have been hindered because it has been difficult to isolate pure Wnt proteins. This is partly because Wnt proteins are attached to a fatty molecule that is important for their activity but also makes these proteins “hydrophobic,” or repelled by water. Hydrophobic proteins have a strong tendency to clump or aggregate when they are isolated from cells, which reduces the biological activity of proteins. Adding detergents to the aggregates can break them apart, but can also hinder the proteins’ activities and cannot be used in all experiments. Previous research has shown that mammalian cells grown in the presence of blood serum can produce Wnt proteins that do not aggregate. Blood serum is a complex mixture of different molecules obtained from blood and is commonly added to cells grown in the laboratory. However, adding serum can have also undesirable effects and it is not understood why serum stops Wnt proteins forming aggregates. Using biochemical methods, Mihara et al. have now identified the component in blood serum that prevents Wnt proteins from aggregating. The experiments showed that a protein in the blood serum called afamin binds tightly to Wnt proteins. Furthermore, the complex between afamin and Wnt was biologically active, and could bind to the Frizzled receptor and trigger an appropriate response in cells. Mihara et al. then generated cells that produced both afamin and Wnt and used them to purify large amounts of biologically active Wnt/afamin complexes. This method avoids the potentially undesirable effects of using detergents or serum, and will therefore likely be useful for future experiments and therapeutic applications. Further work is also needed to understand why afamin binds to Wnt proteins and whether this is important for Wnt signaling.

Wnt signaling is a complex pathway in which β‐catenin is typically viewed as a central mediator in regulating cell proliferation and differentiation. The significance of Wnt signaling in human cancer has been elucidated by the identification of mutations in genes coding for the β‐catenin‐dependent pathway components, adenomatous polyposis coli gene product, β‐catenin, and Axin. Within the past 15 years, evidence has been growing of a β‐catenin‐independent pathway in Wnt signaling. It is likely that this pathway activates several intracellular signaling systems to regulate cell migration, adhesion, and polarity. The β‐catenin‐independent pathway has also been shown to play an important role in tumor biology. In contrast to the β‐catenin‐dependent pathway, which is upregulated in many cancers and serves as a tumor promoter, the role of the β‐catenin‐independent pathway is still controversial. Here we review recent developments in both the functions and mechanisms of the β‐catenin‐independent pathway, with an emphasis on its functional contribution to human tumor progression. (Cancer Sci 2008; 99: 202–208)

Homologous recombination (HR) is a vital process for repairing DNA double-strand breaks. Germline variants in the HR pathway, comprising at least 10 genes, such as BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK2, NBS1(NBN), PALB2, RAD51C, and RAD51D, lead to inherited susceptibility to specific types of cancers, including those of the breast, ovaries, prostate, and pancreas. The penetrance of germline pathogenic variants of each gene varies, whereas all their associated protein products are indispensable for maintaining a high-fidelity DNA repair system by HR. The present review summarizes the basic molecular mechanisms and components that collectively play a role in maintaining genomic integrity against DNA double-strand damage and their clinical implications on each type of hereditary tumor.

A crucial problem in achieving innovative high-throughput materials growth with machine learning, such as Bayesian optimization (BO), and automation techniques has been a lack of an appropriate way to handle missing data due to experimental failures. Here, we propose a BO algorithm that complements the missing data in optimizing materials growth parameters. The proposed method provides a flexible optimization algorithm that searches a wide multi-dimensional parameter space. We demonstrate the effectiveness of the method with simulated data as well as in its implementation for actual materials growth, namely machine-learning-assisted molecular beam epitaxy (ML-MBE) of SrRuO3, which is widely used as a metallic electrode in oxide electronics. Through the exploitation and exploration in a wide three-dimensional parameter space, while complementing the missing data, we attained tensile-strained SrRuO3 film with a high residual resistivity ratio of 80.1, the highest among tensile-strained SrRuO3 films ever reported, in only 35 MBE growth runs.