Genotype-phenotype mapping of a patient-derived lung cancer organoid biobank identifies NKX2-1-defined Wnt dependency in lung adenocarcinoma.

Human lung cancer is a constellation of tumors with various histological and molecular properties. To build a preclinical platform that covers this broad disease spectrum, we obtained lung cancer specimens from multiple sources, including sputum and circulating tumor cells, and generated a living biobank consisting of 43 lines of patient-derived lung cancer organoids. The organoids recapitulated the histological and molecular hallmarks of the original tumors.

Effective treatment with mitotane for a canine case of presumed ectopic Cushing's syndrome-related pheochromocytoma.

Background: In humans, ectopic Cushing's syndrome (ECS) is characterized by hypercortisolemia, which is caused by small lung carcinoma, bronchial carcinoids, and pheochromocytoma. In dogs, only a few cases of ECS associated with pheochromocytoma have been reported to date.

Case Description: Herein, we describe a canine case of malignant pheochromocytoma that is presumed to be the cause of ECS.

Intestinal epithelial organoids: regeneration and maintenance of the intestinal epithelium.

Vital functions of the intestines: digestion, absorption, and surface barrier are performed by the intestinal epithelium, which consists of various differentiated cells and intestinal stem cells. Recent technological advances in sequencing technology, including single-cell transcriptomics and epigenetic analysis, have facilitated the genetic characterization of diverse intestinal epithelial cell types and surrounding mesenchymal niche environments. Organoids have allowed biological analysis of the human intestinal epithelium in coordination with genome engineering, genetic lineage tracing, and transplantation into orthotopic tissue.

Identification of Quiescent LGR5 Stem Cells in the Human Colon.

Background & Aims: In the mouse intestinal epithelium, Lgr5 stem cells are vulnerable to injury, owing to their predominantly cycling nature, and their progenies de-differentiate to replenish the stem cell pool. However, how human colonic stem cells behave in homeostasis and during regeneration remains unknown.

Methods: Transcriptional heterogeneity among colonic epithelial cells was analyzed by means of single-cell RNA sequencing analysis of human and mouse colonic epithelial cells.

OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy.

O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs.

Consultation on the Functional Assessment of Students with Severe Challenging Behavior in a Japanese Special School for Intellectual Disabilities.

Background: It is important to intervene early and treat children and individuals with behavioral disorders. We conducted a functional assessment-based consultation for teachers of several students with severe behavioral disorders and examined the effects of the consultation.

Methods: Eight students with severe behavioral disorders were selected from two special schools for intellectual disabilities in western Japan.

Generation and Profiling of 2,135 Human ESC Lines for the Systematic Analyses of Cell States Perturbed by Inducing Single Transcription Factors.

Transcription factors (TFs) play a pivotal role in determining cell states, yet our understanding of the causative relationship between TFs and cell states is limited. Here, we systematically examine the state changes of human pluripotent embryonic stem cells (hESCs) by the large-scale manipulation of single TFs. We establish 2,135 hESC lines, representing three clones each of 714 doxycycline (Dox)-inducible genes including 481 TFs, and obtain 26,998 microscopic cell images and 2,174 transcriptome datasets-RNA sequencing (RNA-seq) or microarrays-48 h after the presence or absence of Dox.

Transcriptomic features of trophoblast lineage cells derived from human induced pluripotent stem cells treated with BMP 4.

Introduction: Early development of the human placenta remains poorly understood due to the lack of proper model systems. Previous reports have demonstrated that human induced pluripotent stem cells (hiPSCs) treated with bone morphogenetic protein 4 (BMP4) can differentiate into extraembryonic tissues as useful models of the early stage of trophoblast (TB) differentiation. In our previous study, we optimized the culture conditions of hiPSC-derived TB lineages, but the differentiated cells were heterogeneous.

Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients.

Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. Gene mutations causing HCM have been found in about half of HCM patients, while the genetic etiology and pathogenesis remain unknown for many cases of HCM. To identify novel mechanisms underlying HCM pathogenesis, we generated a cardiovascular-mutant medaka fish, (), which showed diastolic dysfunction and hypertrophic myocardium.

Loss of TET proteins in regulatory T cells promotes abnormal proliferation, Foxp3 destabilization and IL-17 expression.

Ten-eleven translocation (TET) proteins regulate DNA methylation and gene expression by converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Although Tet2/Tet3 deficiency has been reported to lead to myeloid cell, B-cell and invariant natural killer T (iNKT) cell malignancy, the effect of TET on regulatory T cells (Tregs) has not been elucidated. We found that Tet2/Tet3 deficiency in Tregs led to lethal hyperproliferation of CD4+Foxp3+ T cells in the spleen and mesenteric lymph nodes after 5 months of age.

Induction of human pluripotent stem cells into kidney tissues by synthetic mRNAs encoding transcription factors.

The derivation of kidney tissues from human pluripotent stem cells (hPSCs) and its application for replacement therapy in end-stage renal disease have been widely discussed. Here we report that consecutive transfections of two sets of synthetic mRNAs encoding transcription factors can induce rapid and efficient differentiation of hPSCs into kidney tissues, termed induced nephron-like organoids (iNephLOs). The first set - FIGLA, PITX2, ASCL1 and TFAP2C, differentiated hPSCs into SIX2SALL1 nephron progenitor cells with 92% efficiency within 2 days.

Tbx6 Induces Nascent Mesoderm from Pluripotent Stem Cells and Temporally Controls Cardiac versus Somite Lineage Diversification.

The mesoderm arises from pluripotent epiblasts and differentiates into multiple lineages; however, the underlying molecular mechanisms are unclear. Tbx6 is enriched in the paraxial mesoderm and is implicated in somite formation, but its function in other mesoderms remains elusive. Here, using direct reprogramming-based screening, single-cell RNA-seq in mouse embryos, and directed cardiac differentiation in pluripotent stem cells (PSCs), we demonstrated that Tbx6 induces nascent mesoderm from PSCs and determines cardiovascular and somite lineage specification via its temporal expression.

Selective modulation of local linkages between active transcription and oxidative demethylation activity shapes cardiomyocyte-specific gene-body epigenetic status in mice.

Background: Cell-type-specific genes exhibit heterogeneity in genomic contexts and may be subject to different epigenetic regulations through different gene transcriptional processes depending on the cell type involved. The gene-body regions (GBRs) of some cardiomyocyte (CM)-specific genes are long and highly hypomethylated in CMs. To explore the cell-type specificities of epigenetic patterns and functions, multiple epigenetic modifications of GBRs were compared among CMs, liver cells and embryonic stem cells (ESCs).

Epigenetic barrier against the propagation of fluctuating gene expression in embryonic stem cells.

The expression of pluripotency genes fluctuates in a population of embryonic stem (ES) cells and the fluctuations in the expression of some pluripotency genes correlate. However, no correlation in the fluctuation of Pou5f1, Zfp42, and Nanog expression was observed in ES cells. Correlation between Pou5f1 and Zfp42 fluctuations was demonstrated in ES cells containing a knockout in the NuRD component Mbd3.

Epigenetic Manipulation Facilitates the Generation of Skeletal Muscle Cells from Pluripotent Stem Cells.

Human pluripotent stem cells (hPSCs) have the capacity to differentiate into essentially all cell types in the body. Such differentiation can be directed to specific cell types by appropriate cell culture conditions or overexpressing lineage-defining transcription factors (TFs). Especially, for the activation of myogenic program, early studies have shown the effectiveness of enforced expression of TFs associated with myogenic differentiation, such as PAX7 and MYOD1.

Salt suppresses IFNγ inducible chemokines through the IFNγ-JAK1-STAT1 signaling pathway in proximal tubular cells.

The mechanisms of immunoactivation by salt are now becoming clearer. However, those of immunosuppression remain unknown. Since clinical evidence indicates that salt protects proximal tubules from injury, we investigated mechanisms responsible for salt causing immunosuppression in proximal tubules.

Violet Light Exposure Can Be a Preventive Strategy Against Myopia Progression.

Prevalence of myopia is increasing worldwide. Outdoor activity is one of the most important environmental factors for myopia control. Here we show that violet light (VL, 360-400nm wavelength) suppresses myopia progression.

[Survey on Information Sharing and Approaches to Cooperation between Hospitals and Community Pharmacies in the Care of Outpatients Receiving Chemotherapy].

Outpatients undergoing chemotherapy receive oral anticancer drugs, supportive care medicine, and drugs for complications from health insurance pharmacies(ie, drugstores). Therefore, drugstore personnel and patients were surveyed using a questionnaire to ascertain the current conditions of information sharing between drugstores and hospitals. Only 31% of the patients surveyed responded that they received cancer chemotherapy via the drugstores, while a few of them understood the need for information sharing with the drugstore.

Expression analysis of the endogenous Zscan4 locus and its coding proteins in mouse ES cells and preimplantation embryos.

Mouse Zinc finger and SCAN domain containing 4 (Zscan4) is encoded in multiple copies of Zscan4 genes, which are expressed in late two-cell stage preimplantation embryos and in 1-5% of the embryonic stem (ES) cell population at a given time. Due to the highly identical nucleotide sequences of multiple copies of Zscan4 paralogs and pseudogenes in the mouse Zscan4 genomic cluster, previous analyses have been done using exogenous transgenes under the regulation of Zscan4c promoter. In this manuscript, we generated knock-in mouse ES cell lines and mouse lines, in which the expression of endogenous Zscan4c, one of the Zscan4 genes, can be specifically monitored with a green fluorescent protein variant, Emerald.

H1foo Has a Pivotal Role in Qualifying Induced Pluripotent Stem Cells.

Embryonic stem cells (ESCs) are a hallmark of ideal pluripotent stem cells. Epigenetic reprogramming of induced pluripotent stem cells (iPSCs) has not been fully accomplished. iPSC generation is similar to somatic cell nuclear transfer (SCNT) in oocytes, and this procedure can be used to generate ESCs (SCNT-ESCs), which suggests the contribution of oocyte-specific constituents.

Subjective and objective assessment of oxaliplatin-induced peripheral neuropathy.

Numbness and pain are currently evaluated using subjective methods such as the visual analog scale (VAS). However, because assessment of pain can vary greatly depending on the mood and physical state of the patient at the time of assessment, it is best to evaluate pain objectively. pain vision PS-2100 (PV) is an analytical instrument that was designed to quantitatively and objectively assess sense perception and nociception in patients.

Transient bursts of Zscan4 expression are accompanied by the rapid derepression of heterochromatin in mouse embryonic stem cells.

Mouse embryonic stem cells (mESCs) have a remarkable capacity to maintain normal genome stability and karyotype in culture. We previously showed that infrequent bursts of Zscan4 expression (Z4 events) are important for the maintenance of telomere length and genome stability in mESCs. However, the molecular details of Z4 events remain unclear.

Biomineralization-inspired synthesis of functional organic/inorganic hybrid materials: organic molecular control of self-organization of hybrids.

Organisms produce various organic/inorganic hybrid materials, which are called biominerals. They form through the self-organization of organic molecules and inorganic elements under ambient conditions. Biominerals often have highly organized and hierarchical structures from nanometer to macroscopic length scales, resulting in their remarkable physical and chemical properties that cannot be obtained by simple accumulation of their organic and inorganic constituents.

CK2 phosphorylates Sec31 and regulates ER-To-Golgi trafficking.

Protein export from the endoplasmic reticulum (ER) is an initial and rate-limiting step of molecular trafficking and secretion. This is mediated by coat protein II (COPII)-coated vesicles, whose formation requires small GTPase Sar1 and 6 Sec proteins including Sec23 and Sec31. Sec31 is a component of the outer layer of COPII coat and has been identified as a phosphoprotein.