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The successful generation of induced pluripotent stem cells (iPSCs) has significantly impacted many scientific fields. In the field of regenerative medicine, iPSC-derived somatic cells are expected to recover impaired organ functions through cell transplantation therapy. Subsequent studies using genetically engineered mouse models showed that somatic cells are also reprogrammable in vivo. Notably, cyclic expression of reprogramming factors, so-called partial reprogramming in vivo ameliorates cellular and physiological hallmarks of aging without inducing teratoma formation or premature death of animals. Subsequent studies provided evidence supporting the beneficial effects of partial reprogramming in various organs. Although in vivo reprogramming appears to be a promising strategy for tissue regeneration and rejuvenation, there remain unsolved issues that hinder its clinical application, including concerns regarding its safety, controllability, and unexpected detrimental effects. Here, we review the pathway that research of in vivo reprogramming has followed and discuss the future perspective as we look toward its clinical application in regenerative medicine.

Abstract Dupuytren’s contracture, a superficial dermal fibrosis, causes flexion contracture of the affected finger, impairing hand function. Specific single-nucleotide polymorphisms within genes in the Wnt signalling pathway are associated with the disease. However, the precise role of Wnt signalling dysregulation in the onset and progression of Dupuytren’s contracture remains unclear. Here, using a fibrosis mouse model and clinical samples of human Dupuytren’s contractures, we demonstrate that the activation of Wnt/β-catenin signalling in Tppp3-positive cells in the dermis of the paw is associated with the development of fibrosis. Fibrosis development and progression via Wnt/β-catenin signalling are closely related to stromal cell–macrophage interactions, and Wnt/β-catenin signalling activation in Tppp3-positive stromal cells causes M2 macrophage infiltration via chemokine Cxcl14, resulting in the formation of a TGF-β-expressing fibrotic niche. Inhibition of Cxcl14 mitigates fibrosis by decreasing macrophage infiltration. These findings suggest that Cxcl14-mediated stromal cell–macrophage interaction is a promising therapeutic target for Wnt/β-catenin-induced fibrosis.

Objectives: Superficial temporal artery (STA) to middle cerebral artery (MCA) bypass surgery is a common treatment for preventing cerebral ischemia in patients with intracranial artery stenosis. The aim of this study was to analyze the surgical outcomes of the STA-MCA bypass procedure, particularly with regard to the invasiveness of targeted bypass (TB) with preoperative planning using Amira® software. Methods: Consecutive patients with single STA-MCA bypass performed by a single neurosurgeon from January 2019 to May 2022 were included. The clinical parameters of seven TB patients were compared with those of 11 patients treated with the conventional method (CM). Results: Compared with CM patients, TB using Amira® software patients had a shorter scalp incision (median [interquartile range]=11.2 [9.7–12.7] cm vs. 16.9 [16.0–17.7] cm, respectively; p=0.004], smaller craniotomy size (11.8 [11.5–14.4] cm2 vs. 20.9 [17.1–22.2] cm2, respectively; p=0.01], shorter surgery duration (201 [195–218] min vs. 277 [229–310] min, respectively; p=0.003], and less intraoperative bleeding (10 [10–20] g vs. 23 [20–50] g, respectively; p=0.033]. However, there were no differences in surgical complications between the two groups. Conclusions: Detailed preoperative evaluation using Amira® software can reduce the invasiveness of the STA-MCA bypass procedure.

Abstract The phenomenon of partial synchronization has attracted significant interest in the field of nonlinear dynamics, largely due to observations of related phenomena in real-world situations. In particular, the coexistence of synchronized and desynchronized phases, known as a chimera state, has been the subject of intense study. In this work, we experimentally demonstrate that networks of identical photonic spiking neurons based on coupled degenerate optical parametric oscillators can exhibit various chimera states in which, depending on their local synchronization and desynchronization, different kinds of spiking dynamics can develop in a self-organized manner. Even when only a static interaction is implemented, the spiking mode of photonic neurons can be spontaneously and adaptively changed between the Class-I and Class-II modes classified by A. L. Hodgkin. This spontaneous spiking-mode shift induces a significant change in the spiking frequency despite all neurons having the same natural spiking frequency, which encourages the generation of chimera states.

In the published article “Vapor-Phase Oxidant-Free Dehydrogenation of 2,3- and 1,4-Butanediol over Cu/SiO2 Catalyst Prepared by Crown-Ether-Assisted Impregnation“ [...]

A silica-supported copper (Cu/SiO2) catalyst containing highly dispersed Cu nanoparticles was prepared via a crown-ether-assisted impregnation method. A 12-crown-4-ether-assisted Cu/SiO2 catalyst outperformed several Cu/SiO2 catalysts prepared with various organic additives in the dehydrogenation of 2,3- and 1,4-butanediol. It was found that the catalytic activity, i.e., the formation rate of acetoin from 2,3-butanediol and that of γ-butyrolactone from 1,4-butanediol, was proportional to the copper surface area.

Abstract Gene targeting of embryonic stem (ES) cells followed by chimera production has been conventionally used for developing gene-manipulated mice. Although direct knock-in (KI) using murine zygote via CRISPR/Cas9-mediated genome editing has been reported, ES cell targeting still has merits, e.g., high throughput work can be performed in vitro. In this study, we first compared the KI efficiency of mouse ES cells with CRISPR/Cas9 expression vector and ribonucleoprotein (RNP), and confirmed that KI efficiency was significantly increased by using RNP. Using CRISPR/Cas9 RNP and circular plasmid with homologous arms as a targeting vector, knock-in within ES cell clones could be obtained efficiently without drug selection, thus potentially shortening the vector construction or cell culture period. Moreover, by incorporating a drug-resistant cassette into the targeting vectors, double DNA KI can be simultaneously achieved at high efficiency by a single electroporation. This technique will help to facilitate the production of genetically modified mouse models that are fundamental for exploring topics related to human and mammalian biology.

The calcium carbonate (CaCO3) scale generated in water pipes and heat exchangers causes serious problems such as pipe blockage and corrosion. This study investigates the effect of the 4-to-10 μm-long and 350-to-700 nm centering-nucleus-wide ZnO tetrapod-like nanomaterials and polydimethylsiloxane composite (t-ZnO/PDMS) on deposition and polymorphism of CaCO3 crystals on the stainless-steel substrate. The results showed that the t-ZnO/PDMS coating inhibited CaCO3 depositions and represented an excellent antifouling coating. The weight-based inhibition efficiencies of CaCO3 deposition were up to 81.3% and 63.2% at 20 °C and 60 °C, respectively. The t-ZnO/PDMS coating also exhibited good inhibition in the presence of liquid flow. The inhibition is primarily because the very fine concave-convex microstructure of the t-ZnO/PDMS coated surface lowered the surface energy of the substrates, making it difficult for CaCO3 crystals to adhere to the surface. Also, metastable vaterite and aragonite precipitations were dominant in the t-ZnO/PDMS coated coupons at 20 °C and 60 °C, respectively, whereas the uncoated coupon exhibited calcite as the predominant polymorph in all the studied conditions. The t-ZnO/PDMS composite subject to the liquid flow made calcites distorted and framboidal vaterite aggregates, likely due to their mechanical effects. The inhibition of CaCO3 depositions is due to achieving hydrophobicity on substrate surfaces, changing preferential polymorph formation, and tailoring the morphology of the given polymorph by the t-ZnO/PDMS composite.

Naked mole rats are found to be resistant to cancer development through dampened inflammatory response due to genetically determined impaired necroptosis, with essential necroptosis genes RIPK3 and MLKL containing mutations causing premature stop codons.

Abstract To compare gastrointestinal (GI) and genitourinary (GU) toxicities in patients with localized prostate cancer treated with ultrahypofractionated radiotherapy (UHF) or brachytherapy [BT; low dose rate, LDR or high dose rate (HDR) with or without external beam radiotherapy (EBRT)]. We compared 253 UHF and 1664 BT ± EBRT groups. The main outcomes were the incidence and severity of acute and late GU and GI toxicities. The secondary endpoint was biochemical control rate. Cumulative late actuarial GU toxicity did not differ for grade ≥ 2 (8.6% at 5-years in UHF and 13.3% in BT ± EBRT, hazard ratio [HR], 0.7066; 95% CI, 0.4093–1.22, p = 0.2127). Actuarial grade ≥ 2 late GI toxicity was higher in UHF (5.8% at 5-years, HR: 3.619; 95% CI, 1.774–7.383, p

Abstract Recent studies have documented the occurrence of shallow very low frequency earthquakes (VLFE) in subduction zones. The heterogeneity of the materials or stresses that act on the plate interface results in the variable slip rate. Stress on the décollement can be controlled by the décollement geometry and the regional stress, which is also able to control the material properties. We determined the distribution of stress along the shallow portion of the décollement in the Nankai Trough using a three-dimensional (3D) seismic survey and regional stress analysis to construct maps of normalized slip tendency (T s ′) and dilation tendency (T d ). Alignments of VLFEs trend parallel to the trends of $${T}_{s}^{^{\prime}}$$ T s ′ and $${T}_{d}$$ T d . On the other hand, very low $${T}_{s}^{^{\prime}}$$ T s ′ and $${T}_{d}$$ T d areas probably act as barriers that limit the number of VLFEs that can migrate towards the trench. Because the $${T}_{s}^{^{\prime}}$$ T s ′ and $${T}_{d}$$ T d distributions are derived only from the décollement geometry and the regional stress without incorporating any data on sediment properties, the consistency between the trends suggests that the décollement geometry is the primary control on VLFE activity.

The mechanisms by which in vivo expression of the Yamanaka transcription factors (OSKM) renders somatic cells permissive for differentiation remain unclear. Here, the authors show that in vivo reprogramming using OSKM generates germ cell tumors and drives acquisition of totipotency-like features in somatic cells through DMRT1.

Prostate squamous cell carcinoma (pSCC) rarely develops as a secondary cancer after treatment with low-dose-rate brachytherapy (LDR-BT). There is no established effective treatment for the disease condition. Herein, we present a 78-year-old man who developed pSCC 8 years after LDR-BT. He was subsequently selected to receive a combined multimodal treatment with high-dose-rate interstitial brachytherapy (HDR-ISBT), external beam radiation therapy, and chemotherapy for his pSCC. Eleven months later, he displayed no biochemical failure nor clinical radiographic recurrence. However, MRI detected a newly developed prostatic-rectal fistula (grade 4), and a colostomy was performed to relieve pain and inflammation. To our knowledge, this is the first report to perform a combined multimodal treatment with HDR-ISBT for pSCC suspected as a secondary cancer due to LDR-BT.

Through metabolome and transcriptome analyses, Nakasuka et al find that TGF-β-induced epithelial–mesenchymal transition (EMT) in non-small cell lung cancer cells is associated with reprogramming of amino acid metabolism. They also identify P4HA3 as a key enzyme involved in these changes altogether providing insights into potential mechanisms of metastasis.

Abstract The objective of this study was to compare the efficacy of abiraterone acetate with that of bicalutamide in combination with gonadotropin-releasing hormone (GnRH) antagonist treatment for patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). A total of 149 patients with mHSPC who underwent treatment at our hospital and affiliated hospitals between December 2013 and July 2020 were retrospectively identified. Fifty patients were administered abiraterone acetate (1000 mg/day) plus prednisolone (5 mg/day) with a GnRH antagonist (degarelix) (group A), and 99 patients were administered bicalutamide (80 mg/day) with a GnRH antagonist (group B). The prostate-specific antigen (PSA) progression-free survival (PSA-PFS) was significantly longer in group A than in group B. Abiraterone acetate therapy and Gleason score were significant independent factors of PSA-PFS. Using propensity score matching, 56 matched patients were obtained. The PSA-PFS (p

Abstract Seafloor massive sulphide (SMS) deposits, modern analogues of volcanogenic massive sulphide (VMS) deposits on land, represent future resources of base and precious metals. Studies of VMS deposits have proposed two emplacement mechanisms for SMS deposits: exhalative deposition on the seafloor and mineral and void space replacement beneath the seafloor. The details of the latter mechanism are poorly characterised in detail, despite its potentially significant role in global metal cycling throughout Earth’s history, because in-situ studies require costly drilling campaigns to sample SMS deposits. Here, we interpret petrographic, geochemical and geophysical data from drill holes in a modern SMS deposit and demonstrate that it formed via subseafloor replacement of pumice. Samples from the sulphide body and overlying sediment at the Hakurei Site, Izena Hole, middle Okinawa Trough indicate that sulphides initially formed as aggregates of framboidal pyrite and matured into colloform and euhedral pyrite, which were replaced by chalcopyrite, sphalerite and galena. The initial framboidal pyrite is closely associated with altered material derived from pumice, and alternating layers of pumiceous and hemipelagic sediments functioned as a factory of sulphide mineralisation. We infer that anhydrite-rich layers within the hemipelagic sediment forced hydrothermal fluids to flow laterally, controlling precipitation of a sulphide body extending hundreds of meters.

Abstract To compare the outcomes of localized prostate cancer treatment with high-dose-rate brachytherapy (HDR-BT) and low-dose-rate brachytherapy (LDR-BT), we examined 924 patients treated with HDR-BT + external beam radiotherapy (EBRT) and 500 patients treated with LDR-BT ± EBRT using multi-institutional retrospective data. The HDR-BT treated advanced disease with more hormonal therapy than LDR-BT. To reduce background selection bias, we performed inverse probability of treatment weighting (IPTW) analysis using propensity scores and excluded patients with T3b-4 disease/ initial prostate-specific antigen (PSA) levels > 50 ng/ml. The actuarial 5-year biochemical control rates (5y-bNED) were 96.3% and 95.7% in the HDR-BT and LDR-BT groups, respectively. The corresponding values were 100% and 96.5% in the low-risk group; 97.4% and 97.1% in the intermediate-risk group (97.2% and 97% in the higher titer group and 97.5% and 94.6% in the lower titer group, respectively); and 95.7% and 94.9% in the selected high-risk group, respectively. IPTW correction indicated no significant difference among the groups. The 5y-bNED in the HDR-BT + EBRT, LDR-BT + EBRT, and LDR-BT alone groups were 96.3%, 95.5%, and 97%, respectively (P = 0.3011). The corresponding values were 97.4%, 94.7%, and 96.6% (P = 0.1004) in the intermediate-risk group (97.5%, 100%, and 94.5% in the lower titer group [P = 0.122] and 97.2%, 96.2%, and 100% [P = 0.664] in the higher titer group, respectively) and 95.7%, 95.5%, and 100% (P = 0.859) in the high-risk group, respectively. The HDR-BT group showed a lower incidence of acute grade ≥ 2 genitourinary toxicities; the incidence of other early and late grade ≥ 2 toxicities were similar between the HDR-BT and LDR-BT groups. Acute genitourinary toxicity predicted the occurrence of late genitourinary toxicity. EBRT increased the risk of grade ≥ 2 gastrointestinal toxicity. HDR-BT + EBRT is a good alternative to LDR-BT ± EBRT for low-, intermediate-, and selected high-risk patients.

How boundary regions form in the epithelia of tissues, for example, the squamous–columnar junction is unclear. Here, the authors identify the transcription factors Sox2 and Gata4 as specifying the transitional epithelium in the murine squamous–columnar junction region in the stomach epithelia.

PTBP1, a well-conserved RNA-binding protein, regulates cellular development by tuning posttranscriptional mRNA modification such as alternative splicing (AS) or mRNA stabilization. We previously revealed that the loss of Ptbp1 in spermatogonia causes the dysregulation of spermatogenesis, but the molecular mechanisms by which PTBP1 regulates spermatogonium homeostasis are unclear. In this study, changes of AS or transcriptome in Ptbp1-knockout (KO) germline stem cells (GSC), an in vitro model of proliferating spermatogonia, was determined by next generation sequencing. We identified more than 200 differentially expressed genes, as well as 85 genes with altered AS due to the loss of PTBP1. Surprisingly, no differentially expressed genes overlapped with different AS genes in Ptbp1-KO GSC. In addition, we observed that the mRNA expression of Nanos3, an essential gene for normal spermatogenesis, was significantly decreased in Ptbp1-KO spermatogonia. We also revealed that PTBP1 protein binds to Nanos3 mRNA in spermatogonia. Furthermore, Nanos3+/−;Ptbp1+/− mice exhibited abnormal spermatogenesis, which resembled the effects of germ cell-specific Ptbp1 KO, whereas no significant abnormality was observed in mice heterozygous for either gene alone. These data implied that PTBP1 regulates alternative splicing and transcriptome in spermatogonia under different molecular pathways, and contributes spermatogenesis, at least in part, in concert with NANOS3.

De novo DNA methylation is carried out by DNMT3A and DNMT3B, but the distinct functions of these two enzymes is poorly understood. Here the authors present a comprehensive, genome-wide identification of target sites for de novo DNA methylation by the DNMT3A and DNMT3B in mouse ES cells and embryos, identifying unique de novo DNA methylation target sites for both DNMT3 enzymes.

Abstract To explore a local relationship between geological structures and the occurrence of very-low-frequency earthquakes (VLFEs), a particular class of slow earthquakes with characteristic periods of 10–100 s, we investigated three-dimensional (3D) structural features using reprocessed 3D seismic data from the Nankai Trough off Kumano, southwestern Japan. In this region, VLFEs have been observed along the subducting Philippine Sea Plate. Although the detailed source distribution of VLFEs was estimated by means of recent land-based and offshore seismic networks, the relation with geological features is not well understood. First, we reprocessed the 3D seismic data with advanced techniques and reinterpreted the fault distribution in the sediment layer of the accretionary prism and tracked two key horizons: a décollement and the oceanic crust surface. In the accretionary prism sediments, multiple continuous reflectors of basal detachments in the underthrust sequence and conjugate faults cutting the shallow imbricated thrust sequence were identified. In contrast to the gentle variation in the décollement surface, the topographic relief of the oceanic crust was prominent, with ridges and surface displacement due to faults in the oceanic crust. Then, we compared the structural features with the VLFE source locations. Most VLFEs were located deep in the underthrust sediments where the sediments may consist of underconsolidated muds. Furthermore, a high spatial correlation was observed between the VLFE distribution and the oceanic crust topographic relief. The maximum stress direction, which was inferred from the conjugate faults in the imbricated thrust zone, was consistent with the spatial relation between the VLFE localization and the oceanic crust central ridge. Oceanic crust ridges may cause strain accumulation in the underthrust sediments on the landward sides of the ridges, and low-angle slow thrust movements might be caused using weak slip planes in the underthrust muddy sediments. That is, the topographic relief of the oceanic crust may control the occurrence of shallow VLFEs in the Nankai Trough.

High-dose-rate interstitial brachytherapy (HDR-ISBT) is widely used for the treatment of pelvic tumors. However, there are a few reports on complications of applicator implantation in HDR-ISBT. We describe a case of small bowel perforation caused by applicator implantation in an 82-year-old male patient with recurrence tumor in the pelvis treated with HDR-ISBT. Eventually, the patient underwent laparotomy and partial intestinal resection. We recognized the site where the applicator was inserted into a part of the tumor on the mucosal surface. Pathological examination confirmed that the tumor had infiltrated the small intestine directly and that the infiltrated part had reached the submucosa. This is the first published report about small bowel perforation caused by applicator implantation. In cases where intestinal infiltration of the tumor is suspected, HDR-ISBT should be performed with maximum caution.

Objective: Endoscopic microvascular decompression (eMVD) for hemifacial spasm (HFS) clearly demonstrates the root entry zone (REZ) of the facial nerve with minimal invasiveness. The aim of this study was to identify the trajectory of the angled view under eMVD for HFS and to better understand the relevant anatomical landmarks using a virtual straight microscopic view on three-dimensional (3D) fusion images. Methods: Each 3D fusion image including arteries, veins, brainstem, cranial nerves, and skull was created using an image processing workstation. A trajectory of view under a 30° angled endoscope was defined as the angled view trajectory (AVT). To investigate the anatomy along the AVT, 3D fusion images were manually made consistent with the 30° endoscopic view, and a straight microscopic approach to obtain the same view as the endoscopic surgery was analyzed on 3D fusion images. Results: The 30° endoscopic view during eMVD visualized the lateral side of the pons, pontomedullary junction, REZ of the facial nerve, and offending arteries. The 30° endoscopic view correlated with 3D fusion images from the straight microscopic view obtained by the posterior petrosal approach after mastoidectomy with incision of the transition between the sigmoid sinus and jugular bulb. Conclusions: This 3D fusion image analysis revealed the AVT of eMVD for HFS. The present results explain how the angled endoscope can effectively visualize the REZ of the facial nerve without needing extensive skull base resection.

In Japan, a 51-year-old man had minimally symptomatic severe acute respiratory syndrome coronavirus 2 infection. Multisystem inflammatory syndrome was diagnosed ≈5 weeks later; characteristics included severe inflammation, cardiac dysfunction, and IgG positivity. Clinicians should obtain detailed history and examine IgG levels for cases of inflammatory disease with unexplained cardiac decompensation.

Spiral ganglion neurons (SGNs) are primary auditory neurons in the spiral ganglion that transmit sound information from the inner ear to the brain and play an important role in hearing. Impairment of SGNs causes sensorineural hearing loss (SNHL), and it has been thought until now that SGNs cannot be regenerated once lost. Furthermore, no fundamental therapeutic strategy for SNHL has been established other than inserting devices such as hearing aids and cochlear implants. Here we show that the mouse spiral ganglion contains cells that are able to proliferate and indeed differentiate into neurons in response to injury. We suggest that SRY-box transcription factor 2/SRY-box transcription factor 10–double-positive (Sox2/Sox10–double-positive) Schwann cells sequentially started to proliferate, lost Sox10 expression, and became neurons, although the number of new neurons generated spontaneously was very small. To increase the abundance of new neurons, we treated mice with 2 growth factors in combination with valproic acid, which is known to promote neuronal differentiation and survival. This treatment resulted in a dramatic increase in the number of SGNs, accompanied by a partial recovery of the hearing loss induced by injury. Taken together, our findings offer a step toward developing strategies for treatment of SNHL.

Introduction Horseshoe kidney has unique anatomical features, such as a complex blood supply. We report a patient with renal cell carcinoma in a horseshoe kidney, who underwent tumor resection by robot‐assisted laparoscopic partial nephrectomy based on preoperative three‐dimensional computed tomography. Case presentation A 66‐year‐old man was referred to our hospital with a 2‐cm enhancing mid‐pole mass in the left moiety of a horseshoe kidney. The clinical diagnosis was renal cell carcinoma cT1aN0M0 (R.E.N.A.L. nephrometry score: 1 + 2 + 3 + 3 = 9p). Robot‐assisted laparoscopic partial nephrectomy was performed with selective clamping based on reconstructed three‐dimensional images. The warm ischemia time was 13 min. Pathologic examination confirmed a diagnosis of pT1a clear cell renal cell carcinoma with negative surgical margins. At 6 months postoperatively, computed tomography showed no local recurrence or metastasis and renal function was intact. Conclusion Robot‐assisted laparoscopic partial nephrectomy with preoperative three‐dimensional computed tomography may have advantages for resection of tumors in patients with horseshoe kidney.

The EWS-ATF1 fusion gene causes clear cell sarcoma (CCS). Here, the authors show that the downstream effects of EWS-ATF1 expression are strictly context dependent, and reveal the cell of origin for CCS to be Tppp3-expressing cells in peripheral nerves.

Background: Once the decision is made to treat the intracranial aneurysm, we should consider between two competing treatment options; open surgery or endovascular therapy. The rationale underlying the choice of treatment modality is usually unclear, as there is little good quality evidence available. Methods: We discuss here the patient, risk factors and the aneurysm related factors for decision making in management of intracranial aneurysm between endovascular and microsurgical modalities of management. Results: The relevance of age of patient, modifiable and nonmodifiable risk actors, family history, rupture status of aneurysm, aneurysm related factors like morphology of aneurysm and multiplicity are discussed here. Perceived differences in efficacy and safety of the two different treatment approaches are commonly used in an attempt to justify treatment choices. Difficulties with treatment selection and case to case management plan should be considered. Conclusion: Properly designed and randomized controlled trials need to be done to address these issues for choosing best management to the patient and definitive guidelines must be made to solve this confusion. Keywords: Intracranial aneurysm, Endovascular coiling, Neurosurgical clipping, Unruptured intracranial aneurysms, Ruptured intracranial aneurysm, Subarachnoid hemorrhage, ISAT

Summary: CpG islands (CGIs) including those at imprinting control regions (ICRs) are protected from de novo methylation in somatic cells. However, many cancers often exhibit CGI hypermethylation, implying that the machinery is impaired in cancer cells. Here, we conducted a comprehensive analysis of CGI methylation during somatic cell reprogramming. Although most CGIs remain hypomethylated, a small subset of CGIs, particularly at several ICRs, was often de novo methylated in reprogrammed pluripotent stem cells (PSCs). Such de novo ICR methylation was linked with the silencing of reprogramming factors, which occurs at a late stage of reprogramming. The ICR-preferred CGI hypermethylation was similarly observed in human PSCs. Mechanistically, ablation of Dnmt3a prevented PSCs from de novo ICR methylation. Notably, the ICR-preferred CGI hypermethylation was observed in pediatric cancers, while adult cancers exhibit genome-wide CGI hypermethylation. These results may have important implications in the pathogenesis of pediatric cancers and the application of PSCs. : In this article, Yamada, Yamamoto and colleagues show that Dnmt3a-mediated DNA methylation occurs at imprinting loci during reprogramming into naive and primed PSCs. Similar de novo ICR methylation is detected in pediatric cancers, which raises the possibility that reprogramming is involved in development of childhood cancers. Keywords: pluripotent stem cells, naive and primed pluripotency, reprogramming, pediatric cancers, DNA methylation, genomic imprinting, CpG islands, Dnmt3a

To identify prognostic factors, array CGH (aCGH) patterns and mutations in WT1 and 9 other genes were analyzed in 128 unilateral Wilms tumors (WTs). Twenty patients had no aCGH aberrations, and 31 had WT1 alterations [silent and WT1 types: relapse-free survival (RFS), 95% and 83%, respectively]. Seventy-seven patients had aCGH changes without WT1 alterations (nonsilent/non-WT1 type) and were subtyped into those with or without +12, 11q−, 16q−, or HACE1 loss. RFS was better for those with than those without +12 (P = .010) and worse for those with than those without 11q−, 16q−, or HACE1 loss (P = .001, .025, or 1.2E-04, respectively). Silent and WT1 type and 8 subtype tumors were integrated and classified into 3 risk groups: low risk for the silent type and +12 subgroup; high risk for the no +12 plus 11q−, 16q−, or HACE1 loss subgroup; intermediate risk for the WT1 type and no +12 plus no 11q−, 16q−, or HACE1 loss subgroup. Among the 27 WTs examined, the expression of 146 genes on chromosome 12 was stronger in +12 tumors than in no +12 tumors, while that of 10 genes on 16q was weaker in 16q− tumors than in no 16q− tumors. Overexpression in 75 out of 146 upregulated genes and underexpression in 7 out of 10 downregulated genes correlated with better and worse overall survival, respectively, based on the public database. +12 was identified as a potential new marker predicting a favorable outcome, and chromosome abnormalities may be related to altered gene expression associated with these abnormalities.

Abstract The study investigates the in-situ strength of sediments across a plate boundary décollement using drilling parameters recorded when a 1180-m-deep borehole was established during International Ocean Discovery Program (IODP) Expedition 370, Temperature-Limit of the Deep Biosphere off Muroto (T-Limit). Information of the in-situ strength of the shallow portion in/around a plate boundary fault zone is critical for understanding the development of accretionary prisms and of the décollement itself. Studies using seismic reflection surveys and scientific ocean drillings have recently revealed the existence of high pore pressure zones around frontal accretionary prisms, which may reduce the effective strength of the sediments. A direct measurement of in-situ strength by experiments, however, has not been executed due to the difficulty in estimating in-situ stress conditions. In this study, we derived a depth profile for the in-situ strength of a frontal accretionary prism across a décollement from drilling parameters using the recently established equivalent strength (EST) method. At site C0023, the toe of the accretionary prism area off Cape Muroto, Japan, the EST gradually increases with depth but undergoes a sudden change at ~ 800 mbsf, corresponding to the top of the subducting sediment. At this depth, directly below the décollement zone, the EST decreases from ~ 10 to 2 MPa, with a change in the baseline. This mechanically weak zone in the subducting sediments extends over 250 m (~ 800–1050 mbsf), corresponding to the zone where the fluid influx was discovered, and high-fluid pressure was suggested by previous seismic imaging observations. Although the origin of the fluids or absolute values of the strength remain unclear, our investigations support previous studies suggesting that elevated pore pressure beneath the décollement weakens the subducting sediments.

Summary: Fibrodysplasia ossificans progressiva (FOP) is a rare and intractable disorder characterized by extraskeletal bone formation through endochondral ossification. FOP patients harbor gain-of-function mutations in ACVR1 (FOP-ACVR1), a type I receptor for bone morphogenetic proteins. Despite numerous studies, no drugs have been approved for FOP. Here, we developed a high-throughput screening (HTS) system focused on the constitutive activation of FOP-ACVR1 by utilizing a chondrogenic ATDC5 cell line that stably expresses FOP-ACVR1. After HTS of 5,000 small-molecule compounds, we identified two hit compounds that are effective at suppressing the enhanced chondrogenesis of FOP patient-derived induced pluripotent stem cells (FOP-iPSCs) and suppressed the heterotopic ossification (HO) of multiple model mice, including FOP-ACVR1 transgenic mice and HO model mice utilizing FOP-iPSCs. Furthermore, we revealed that one of the hit compounds is an mTOR signaling modulator that indirectly inhibits mTOR signaling. Our results demonstrate that these hit compounds could contribute to future drug repositioning and the mechanistic analysis of mTOR signaling. : Focusing on the ligand-independent constitutive activation of mutated ACVR1 in fibrodysplasia ossificans progressiva (FOP) patients, Ikeya and colleagues have identified two hit compounds that were effective in multiple FOP model mice. One of the hit compounds, TAK 165, was an mTOR signaling modulator that indirectly regulated enhanced mTOR signaling. These findings shed light on a therapeutic strategy for FOP. Keywords: mammalian target of rapamycin (mTOR), induced pluripotent stem cell (iPSC), fibrodysplasia ossificans progressiva (FOP), endochondral ossification, heterotopic ossification, bone morphogenetic protein (BMP), transforming growth factor β (TGF-β), activin A, high-throughput screening (HTS), ACVR1

Abstract The 2011 Tohoku-oki earthquake unexpectedly ruptured to the shallowest portion of the plate boundary fault and triggered a large tsunami. The shallow portion had generally been regarded as a seismically stable zone until this event, but its significance has now been dramatically revealed for future disaster mitigation. This research approaches the shallow portion, especially the formation process of its structure and plate boundary faults. Scientific drilling conducted near the Japan Trench after the earthquake reported a thin plate boundary fault (~ 7 m) and thick deformation zone (~ 100 m). This thin fault would be expected given the relatively small displacement near the trench (~ 3.2 km), but the deformation zone thickness is anomalously wide given this small magnitude of slip. To understand the dynamic deformation processes that lead to the development of a thick deformation zone surrounding a thin fault core, we conducted forward modeling of an analog experiment with the technique to visualize fault activity. Sandbox experiments are effective for the approximation of the geological phenomenon and structure. The seismic profile of the largest slip region in the 2011 earthquake shows that a half-graben structure has been subducted underneath the frontal wedge, thus we focused on this structural architecture. As a result, we found a new fault formation pattern, i.e., the frontal thrust (the most frontal part of décollement) periodically partitioned into pieces, which connect again to form a large-continuous fault. The fault also oscillates up and down during this process, which we call “dancing,” and a thick shear zone is formed in a relatively short time where this occurs, even though the fault only has a small displacement. By analogy, the thick deformation zone observed at the Japan Trench could be formed by such fault dancing. The energy of the fault activity is commonly estimated from the fault displacement derived from the thickness of the shear zones. Applying the thickness-displacement law without considering the effect of the dancing may cause overestimation. The architecture of the shear zone formed is similar to that of a mélange, and the origin of tectonic mélanges may be explained by this mechanism.

Cellular reprogramming and cancer development share properties. Here, the authors examine the impact of in vivo reprogramming on Kras-induced cancer and show reprogramming-mediated repression of somatic cell enhancers in conjunction with Kras mutation results in rapid PDAC development.

The transcription factor Srf is a central regulator of immediate-early and actin cytoskeletal genes. Here the authors show that Srf is activated by repression of β-actin, promoting iPSC reprogramming of neural progenitor cells and hepatoblasts by repressing cell-type specific genes.

Carbon-based materials are promising alternatives to noble metal catalysts, but their structures are typically disordered and difficult to control. Here, the authors obtain ordered carbonaceous frameworks with advantageous electrocatalytic properties via the carbonization of nickel-containing porphyrin dimer networks.

It remains unclear what cells are proper for the generation of induced pluripotent stem cells (iPSCs). Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) is well known as a tissue stem cell and progenitor marker, both of which are reported to be sensitive to reprogramming. In the present study, we examined the reprogramming behavior of Lgr5-expressing cells (Lgr5+ cells). First, we compared reprogramming behavior using mouse Lgr5+ and Lgr5 negative (Lgr5−) hair follicles (HFs). The number of alkaline phosphatase staining-positive cells was lesser in a well of Lgr5+ HFs than in Lgr5− HFs; however, the ratio of Nanog+ SSEA1+ cells in the cell mixture derived from Lgr5+ HFs was much higher than that from Lgr5− HFs. Lgr5+ cells could be induced from mouse embryonic fibroblasts (MEFs) after transduction with Yamanaka factors. As shown in HFs, the progeny of Lgr5+ cells arising from MEFs highly converted into Nanog+ cells and did not form Nanog− colonies. The progeny represented the status of the late reprogramming phase to a higher degree than the nonprogeny. We also confirmed this using human Lg5+ cells. Our findings suggest that the use of Lgr5+ cells will minimize sorting efforts for obtaining superior iPSCs.

Introduction: Mirror Aneurysms [MA] are a subset of multiple aneurysms which account for nearly 5% of all intracranial aneurysms and approximately 40% of all multiple aneurysms. The purpose of our study was to evaluate the etiopathogenesis, preferential location, clinical characteristics and outcome of mirror aneurysms in comparison with non-mirror multiple aneurysms. Methods: We retrospectively reviewed the clinical and radiological data of 358 patients with intracranial aneurysms who were treated at our institute between January 2014 and June 2018. The patients were further divided into non-mirror multiple and mirror aneurysm groups. There were 13 patients who had MA and 45 patients with non-mirror aneurysms [NMA]. Results: Multiple aneurysms were found in 16.2% of all patients [58 out of 358]. MA were observed in 3.6% [13 out of 358 patients]. There was a slight female predominance in the MA group [84.6% vs 73.3%]. The commonest location of MA in our series was MCA. There was no statistically significant difference in age, smoking, hypertension or postoperative outcome between the two groups. Conclusion: Management of mirror aneurysms should be determined individually based on the location, size, and morphology of the aneurysms, as well as the clinical manifestations of the patient. Therefore, emergent treatment of the ruptured aneurysm and staged management of the contra lateral unruptured twin can be considered as a rational treatment strategy to manage mirror aneurysms. The decision of single or multistage approach/surgical or endovascular coiling should be based on the aneurysm location, morphology, rupture status and available expertise

Background: Whole-gland therapy for prostate cancer, which might cause more harm than no therapy (observation or active surveillance), might be a overtreatment. In order to avoid overtreatment as well as undertreatment of localize prostate cancer, novel strategy of organ-preserving therapies have been developed to achieve both cancer control and functional preservation. For the therapeutic techniques, microwave ablation would be an option for lesion-targeted focal therapy to eradicate biopsy-proven cancer lesion with its safety margin. Following our recent pilot clinical study of lesion-targeted focal cryotherapy, prospective clinical trial was designed to investigate the safety and therapeutic effects of lesion-targeted microwave therapy for localized prostate cancer. Methods: This is a single-center, phase I, clinical study to evaluate primarily the safety of lesion-targeted focal microwave treatment for prostate cancer. Patients with a magnetic resonance imaging (MRI)-visible, MR-ultrasound image-fusion targeted biopsy-proven clinically significant cancer will be enrolled. The target sample size is 5. Transrectal ultrasound-guided focal microwave ablation will be performed under general anesthesia. The primary endpoint is adverse events after microwave focal therapy. Secondary endpoint includes to assess both cancer control and quality of life (functional preservation). Discussion: This single-center, phase I, clinical study aims to evaluate the safety and efficacy of lesion-targeted focal microwave treatment for prostate cancer. The importance of this clinical trial is that it may establish new treatment for prostate cancer. Trial registration: This study was registered with Japan Registry of Clinical Trials (jRCTs052190026). Keywords: Focal therapy, Microwave, Prostate cancer, Index lesion

Introduction: Multiple intracranial aneurysms [MIA] occur in 7% to 34% of patients with intracranial aneurysms. They can be treated with both surgical and endovascular techniques. Here we report 2 cases of multiple intracranial aneurysms with 6 and 7 aneurysms respectively who were treated at our institute by surgery followed by a discussion on incidence, conditions associated with multiple aneurysms, ethnicity and management strategies. Methods: A retrospective analysis of 2 patients with incidentally detected aneurysms with 6 and 7 aneurysms respectively, who were treated with microsurgical clipping was conducted. A systematic search was performed using the PUBMED database and relevant articles were reviewed with particular attention to incidence, associated conditions, risk factors and management strategies. Results: Both the patients were females with incidental detection of the aneurysms. One had 6 and the other had 8 aneurysms respectively. Both patients underwent bilateral pterional craniotomy and clipping of all the aneurysms except for one aneurysm in the cavernous ICA, for which the patient is planned for an endovascular procedure. Both had an uneventful postoperative course with the CT angiogram showing obliteration of all the aneurysms except one. Conclusions: There is a lack of prospective randomized controlled trials to analyse management options, particularly in comparing intervention with conservative management. Most of the available data is retrospective in nature and lacks objective short and long-term outcome analysis. Furthermore, we need randomized trials to directly compare clipping and coiling of multiple unruptured aneurysms to decide the best intervention strategy of this pathology. Keywords: management strategies, multiple intracranial aneurysms, risk factors

Hepatocytes are regarded as the only effective cell source for cell transplantation to treat liver diseases; however, their availability is limited due to a donor shortage. Thus, a novel cell source must be developed. We recently reported that mature rodent hepatocytes can be reprogrammed into progenitor-like cells with a repopulative capacity using small molecule inhibitors. Here, we demonstrate that hepatic progenitor cells can be obtained from human infant hepatocytes using the same strategy. These cells, named human chemically induced liver progenitors (hCLiPs), had a significant repopulative capacity in injured mouse livers following transplantation. hCLiPs redifferentiated into mature hepatocytes in vitro upon treatment with hepatic maturation-inducing factors. These redifferentiated cells exhibited cytochrome P450 (CYP) enzymatic activities in response to CYP-inducing molecules and these activities were comparable with those in primary human hepatocytes. These findings will facilitate liver cell transplantation therapy and drug discovery studies.

X-ray computed tomography (XCT) can be used to identify lithologies and deformation structures within geological core, with the potential for the identification processes to be applied automatically. However, because of drilling disturbance and other artifacts, the use of large XCT-datasets in automated processes requires methods of quality control that can be applied systematically. We propose a new systematic method for quality control of XCT data that applies numerical measures to CT slices, and from this obtains data reflective of core quality. Because the measures are numerical they can be applied quickly and consistently between different sections and cores. This quality control processing protocol produces downhole radiodensity profiles from mean CT-values that can be used for geological interpretation. The application of this quality control protocols was applied to XCT data from International Ocean Discovery Program (IODP) Expedition 370 Site C0023 located at the toe of the Nankai accretionary complex. The evaluation of core quality based on this protocol was found to be a good fit to standard-evaluations based on the visual description of core, and could be used to select samples free from drilling disturbance or contamination. The quality-controlled downhole mean CT-value profile has features that can be used to identify lithologies within a formation, the presence and type of deformation structures and to distinguish formations.

Objective: Intracranial aneurysms are considered large if >10 mm and giant if >25 mm. The risk of aneurysmal rupture compounds with increase in size of the aneurysm, thus, warranting appropriate intervention. In this study, we have analyzed the outcome and effectiveness of microsurgical procedures in large and giant aneurysms. Methods: A retrospective analysis of all the patients who underwent microsurgical procedures for large and giant cerebral aneurysms from 2014–2018 in our institute was conducted. There were a total of 52 patients, in which direct clipping was performed in 42 (80.7%) patients, proximal trapping in 3 (5.7%) patients, trapping with bypass in 3 (5.7%) patients, suction decompression in 3 (5.7%) patients, and 1 (1.9%) patient underwent surgical reconstruction. Results: Among the 52 patients, in the postoperative period, 1 (1.9%) patient became comatose, 1 (1.9%) patient developed hemiplegia, 1 (1.9%) patient had a transient hemiparesis, and 1 (1.9%) patient had transient lower cranial nerve palsy. Two (3.8%) patients had chronic subdural hematoma during the 3-month follow-up. There was no mortality in our series. Conclusions: There are several treatment strategies available to manage large and giant cerebral aneurysms. In this study, we had minimal morbidity (3.8%), favorable outcome (96.1%), and no mortality. Therefore, we would like to conclude that appropriate microsurgical procedures, in experienced hands, can be considered as first line in the management for large and giant intracranial aneurysms, especially those with complex anatomy, wide neck, mass effect, partial thrombosis, and the presence of critical perforating vessels from the aneurysm wall. Key words: Bypass, Clipping, DIVA, Giant, Intracranial aneurysm, Outcome, Trapping

Summary: Atypical teratoid/rhabdoid tumor (AT/RT), which harbors SMARCB1 mutation and exhibits a characteristic histology of rhabdoid cells, has a poor prognosis because of the lack of effective treatments. Here, we establish human SMARCB1-deficient pluripotent stem cells (hPSCs). SMARCB1-deficient hPSC-derived neural progenitor-like cells (NPLCs) efficiently give rise to brain tumors when transplanted into the mouse brain. Notably, activation of an embryonic stem cell (ESC)-like signature confers a rhabdoid histology in SMARCB1-deficient NPLC-derived tumors and causes a poor prognosis. Consistently, we find the activation of the ESC-like gene expression signature and an ESC-like DNA methylation landscape in clinical specimens of AT/RT. Finally, we identify candidate genes that maintain the activation of the ESC-like signature and the growth of AT/RT cells. Collectively, SMARCB1-deficient hPSCs offer the human models for AT/RT, which uncover the role of the activated ESC-like signature in the poor prognosis and unique histology of AT/RT. : Terada et al. present SMARCB1-deficient human pluripotent stem cell-derived atypical teratoid/rhabdoid tumor (AT/RT) models and show that ESC-like signature is a critical driver of malignant phenotypes of AT/RT. Genetic ablation targeting the maintenance of pluripotency inhibits AT/RT cell growth, suggesting that the ESC-like signature could be a promising therapeutic target for AT/RT. Keywords: atypical teratoid/rhabdoid tumor, pediatric tumor, embryonic stem cell, induced pluripotent stem cell, ESC-like signature, pluripotency, dedifferentiation, SMARCB1

EWS-FLI1, a multi-functional fusion oncogene, is exclusively detected in Ewing sarcomas. However, previous studies reported that rare varieties of osteosarcomas also harbor EWS-ETS family fusion. Here, using the doxycycline-inducible EWS-FLI1 system, we established an EWS-FLI1-dependent osteosarcoma model from murine bone marrow stromal cells. We revealed that the withdrawal of EWS-FLI1 expression enhances the osteogenic differentiation of sarcoma cells, leading to mature bone formation. Taking advantage of induced pluripotent stem cell (iPSC) technology, we also show that sarcoma-derived iPSCs with cancer-related genetic abnormalities exhibited an impaired differentiation program of osteogenic lineage irrespective of the EWS-FLI1 expression. Finally, we demonstrate that EWS-FLI1 contributed to secondary sarcoma development from the sarcoma iPSCs after osteogenic differentiation. These findings demonstrate that modulating cellular differentiation is a fundamental principle of EWS-FLI1-induced osteosarcoma development. This in vitro cancer model using sarcoma iPSCs should provide a unique platform for dissecting relationships between the cancer genome and cellular differentiation.

Acute vertigo is a common problem in emergency departments. However, clinical strategies of acute vertigo care vary among care providers. The aim of the study was to investigate differences in diagnosis [Dix-Hallpike test, the head impulse, nystagmus, and the test of skew (HINTS) procedure, and imaging modalities] and treatment (pharmacological treatments and the Epley maneuver) by otolaryngologists and non-otolaryngologists in emergency medicine settings. We used a multicenter case-based survey for the study. Four clinical vignettes of acute vertigo (posterior canal benign paroxysmal positional vertigo, vestibular neuritis, Meniere disease, and nonspecific vertigo) were used. Total 151 physicians from all study sites participated in the study. There were 84 non-otolaryngologists (48 emergency physicians and 36 internists) and 67 otolaryngologists. The multivariate analysis indicated that otolaryngologists ordered fewer CT scans (odds ratio (OR), 0.20; 95% confidence interval (CI), 0.07-0.53) and performed fewer HINTS procedures (OR, 0.17; 95% CI, 0.06-0.46), but used the Dix-Hallpike method more often (OR, 2.36; 95% CI, 1.01-5.52) for diagnosis compared to non-otolaryngologists. For treatment, otolaryngologists were less likely to use the Epley method (OR, 0.19; 95% CI, 0.07-0.53) and metoclopramide (OR, 0.09; 95% CI, 0.01-0.97) and more likely to use sodium bicarbonate (OR, 20.50; 95% CI, 6.85-61.40) compared to non-otolaryngologists. We found significant differences in the acute vertigo care provided by non-otolaryngologists and otolaryngologists from a vignette-based research. To improve acute vertigo care, educational systems focusing on acute vertigo are needed.

Context: Newer Imaging tool for diagnosing offending vessel in trigeminal neuralgia (TN) and Hemifacial spasms (HFS). Aim: To find out if Computational FluidDynamics (CFD) can correctly predict the offending vessel in HFS and TN & thus improving the outcome of Microvascular Decompression) MVD. Settings and Design: CFD is a relatively new mode of imaging. Its application to indicate offending vessel in TN & HFS was tested. Materials & Methods: Retrospectively we studied 13 consecutive patients operated in 2017 for either HFS or TN. Preoperatively MRI & Computed Tomography Angiogram (CTA) were done and the offending vessel identified along with its point of contact with the concerned nerve. CFD was done using Hemoscope 2015 software and wall pressure, wall shear stress, vector & streamline flow were obtained in the offending vessel (test) & contralateral vessel (control). Results of these were charted on an excel sheet & results analyzed. The postoperativeoutcome were assessed and compared with CFD results. Statistical analysis used: Small study group hence statistical analysis couldn’t be applied. Results: Of the 13 patients, offending artery had high wall pressure in 12 and increased wall shear stress innine. Among the controls six had high wall pressure and only two had high wall shear stress. Conclusion: CFD can be used to determine offending vessel and can predict good outcome following microvascular decompression.