MRCK ensures cortex-chromatin "social distancing" to enable egg spindle rotation.

During the second meiotic cell division, egg cells discard one set of chromatids to the polar body to produce a large haploid gamete. Meiotic spindle rotation is a critical step to ensure proper polar body extrusion. In this issue, Bourdais et al.

Genetic and phenotypic determinants of morphologies in 3D cultures and xenografts of lung tumor cell lines.

We previously proposed the classification of lung adenocarcinoma into two groups: the bronchial epithelial phenotype (BE phenotype) with high-level expressions of bronchial epithelial markers and actionable genetic abnormalities of tyrosine kinase receptors and the non-BE phenotype with low-level expressions of bronchial Bronchial epithelial (BE) epithelial markers and no actionable genetic abnormalities of tyrosine kinase receptors. Here, we performed a comprehensive analysis of tumor morphologies in 3D cultures and xenografts across a panel of lung cancer cell lines. First, we demonstrated that 40 lung cancer cell lines (23 BE and 17 non-BE) can be classified into three groups based on morphologies in 3D cultures on Matrigel: round (n = 31), stellate (n = 5), and grape-like (n = 4).

Production of mouse androgenetic embryos using spindle perturbation.

To study the functional differences between maternal and paternal genomes in mammalian development, embryos with only one parental genome are often used. Androgenetic embryos are produced by the removal of maternal chromosomes before or after fertilization by techniques that require specialized skills and are associated with high risk of cellular damage. Here, we developed a novel method for producing androgenetic mouse embryos without the invasive enucleation process.

Cosmetic and Neuroprotective Placement of Custom-Made Ultra-High-Molecular-Weight Polyethylene Cranial Plate (SKULPIO) in Single-Step Surgery: Technical Note and Case Report.

Background: Cranioplasty is a common procedure in neurosurgery. However, cosmetic and neuroprotective reconstructions are necessary after cranioplasty. Treatment of patients with a meningioma with bone infiltration requires removal of the tumor-infiltrated bone and subsequent cranioplasty.

Rim15 and Sch9 kinases are involved in induction of autophagic degradation of ribosomes in budding yeast.

Autophagic degradation of ribosomes is promoted by nutrient starvation and inactivation of target of rapamycin complex 1 (TORC1). Here we show that selective autophagic degradation of ribosomes (called ribophagy) after TORC1 inactivation requires the specific autophagy receptor Atg11. Rim15 protein kinase upregulated ribophagy, while it downregulated non-selective degradation of ribosomes.

The development of colitogenic CD4(+) T cells is regulated by IL-7 in collaboration with NK cell function in a murine model of colitis.

We previously reported that IL-7(-/-)RAG(-/-) mice receiving naive T cells failed to induce colitis. Such abrogation of colitis may be associated with not only incomplete T cell maintenance due to the lack of IL-7, but also with the induction of colitogenic CD4(+) T cell apoptosis at an early stage of colitis development. Moreover, NK cells may be associated with the suppression of pathogenic T cells in vivo, and they may induce apoptosis of CD4(+) T cells.

[Visual presentation of psychiatric clinical decision-making by "graphic assessment sheet for diagnoses and treatments"].

Psychiatrists often have to treat patients even when the clinical information is insufficient to make a definite diagnosis. This is the case especially when we are treating first-visit outpatients or inpatients who have just been admitted. One of the causes of information insufficiency is a delay in obtaining clinical information on the patient, and another is a lack of characteristic manifestations of the disease because of an immature developmental stage.

Upregulated IL-7 receptor α expression on colitogenic memory CD4+ T cells may participate in the development and persistence of chronic colitis.

We have previously demonstrated that IL-7 is essential for the persistence of colitis as a survival factor of colitogenic IL-7Rα-expressing memory CD4(+) T cells. Because IL-7Rα is broadly expressed on various immune cells, it is possible that the persistence of colitogenic CD4(+) T cells is affected by other IL-7Rα-expressing non-T cells. To test this hypothesis, we conducted two adoptive transfer colitis experiments using IL-7Rα(-/-) CD4(+)CD25(-) donor cells and IL-7Rα(-/-) × RAG-2(-/-) recipient mice, respectively.

IL-2 is positively involved in the development of colitogenic CD4+ IL-7R alpha high memory T cells in chronic colitis.

IL-2 and IL-7 share a common gamma-chain receptor and are critical for T-cell homeostasis. We aimed to clarify the reciprocal roles of IL-2 and IL-7 in the development and persistence of chronic colitis. We performed a series of adoptive transfers of IL-2(-/-) CD4(+)CD45RB(high) T cells into RAG-2(-/-) mice and assessed the role of IL-2 in the induction of IL-7R alpha on colitogenic CD4(+) T cells and the development of chronic colitis.

Prevalence of metabolic syndrome is comparable between inflammatory bowel disease patients and the general population.

Background: Metabolic syndrome (MS) is associated with an increased risk of cardiovascular disease. However, its prevalence in inflammatory bowel disease (IBD) patients remains largely unknown. This study was planned to determine the prevalence of MS in Japanese IBD patients.

Long-lived colitogenic CD4+ memory T cells residing outside the intestine participate in the perpetuation of chronic colitis.

To understand the perpetuation of inflammatory bowel disease (IBD), it is important to clarify whether the colitogenic CD4(+) T cells are self-limited effector or long-lived memory T cells. We here investigate the latency of colitogenic CD4(+) T cells in the remission stage of colitis under germfree (GF) conditions. We isolated splenic (SP) CD4(+) T cells from colitic CD4(+)CD45RB(high) T cell-injected SCID mice maintained under specific pathogen-free (SPF) conditions and transferred them into SPF or GF SCID mice.

IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4(+) memory T cells in chronic colitis.

We previously demonstrated that IL-7 is essential for the persistence of T-cell-mediated colitis, by showing that adoptive transfer of CD4(+)CD45RB(high) T cells into IL-7(-/-) x RAG-1(-/-) mice did not induce colitis; and that intestinal IL-7 is not essential for this colitis model, by showing that IL-7(-/-) x RAG-1(-/-) mice parabiosed with colitic CD4(+)CD45RB(high) T-cell-transferred RAG-1(-/-) mice developed colitis. Here, we investigated the role of IL-7 in the maintenance of colitogenic CD4(+) T cells by surgically separating these parabionts. Surprisingly, the separated IL-7(-/-) x RAG-1(-/-) mice were consistently diseased after separation, although no IL-7 mRNA was detected in the tissues of separated IL-7(-/-) x RAG-1(-/-) partners.

Homeostatic (IL-7) and effector (IL-17) cytokines as distinct but complementary target for an optimal therapeutic strategy in inflammatory bowel disease.

Purpose Of Review: This review focuses on CD4+ T cells involved in the mediation of inflammatory tissue damage in murine models of inflammatory bowel diseases (IBDs). In particular, we describe the distinct roles of the homeostatic cytokine IL-7, which is essential to the maintenance of colitogenic memory CD4+ cells, and the newly discovered effector cytokine IL-17. We also discuss the close correlation between colitogenic Th17-type CD4+ T cells and inducible CD4+CD25+Foxp3+ regulatory T cells.

RANK-RANKL signaling pathway is critically involved in the function of CD4+CD25+ regulatory T cells in chronic colitis.

It is now clear that functional CD4(+)CD25(+) regulatory T (T(R)) cells exist as part of the normal immune population and prevent the development of intestinal inflammation. We have recently shown that CD4(+)CD25(+) T(R) cells reside in the intestine and control intestinal homeostasis in humans and mice. In this study, we demonstrate that the TNF family molecule RANKL and its receptor RANK are critically involved in controlling the function of CD4(+)CD25(+) T(R) cells in the intestine.

Signaling pathway via TNF-alpha/NF-kappaB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis.

Treatment with anti-TNF-alpha MAb has been accepted as a successful maintenance therapy for patients with inflammatory bowel diseases (IBD). Moreover, it has been recently reported that blockade of TNF receptor (TNFR) 1 signaling in infiltrating hematopoietic cells may prevent the development of colitis-associated cancer (CAC). However, it remains unclear whether the TNF-alpha signaling in epithelial cells is involved in the development of CAC.

Persistent retention of colitogenic CD4+ memory T cells causes inflammatory bowel diseases to become intractable.

Despite the advent of an age when "malignant" leukemia is cured by bone marrow transplantation, "benign" inflammatory bowel diseases (IBDs) are still intractable lifelong diseases. Why is it that once an IBD develops it lasts a long time? We propose that, the same as in the response to vaccination, immune memory T cells that remember the disease are formed in IBDs and, perceiving them as "benign T-cell leukemia"-like lifelong pathology that hematogenously spreads throughout the body, we here propose that the bone marrow itself, which produces large amounts of the survival factor IL-7, is the reservoir for colitogenic CD4(+) memory T cells responsible for the intractability of IBDs.

FTY720 suppresses the development of colitis in lymphoid-null mice by modulating the trafficking of colitogenic CD4+ T cells in bone marrow.

2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720) suppresses T-cell egress from LN, thereby preventing pathogenic T cells from migrating toward disease sites. However, little is known about whether FTY720 could control the trafficking of T cells without the presence of lymphoid tissues. Here we demonstrate that FTY720 treatment suppresses the recirculation of CD4(+) T cells in splenectomized (SPX) lymphotoxin-alpha(-/-) (LT-alpha(-/-)) mice that lack LN and spleen, as shown by peripheral blood (PB) lymphopenia in FTY720-treated SPX LT-alpha(-/-) mice.

Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice.

Background: Although the clinical usefulness of leukocytapheresis for patients with inflammatory bowel disease (IBD) has been reported as a selective removal therapy targeting pathogenic immune cells in blood circulation, it remains unclear whether colitogenic CD4(+) T cells continuously recirculate in peripheral blood during the chronic phase of colitis.

Methods: To resolve this question we conducted a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of CD4(+)CD45RB(high) cells into SCID mice in combination with a parabiosis system.

Results: In colitic SCID recipients, first, almost all CD4(+) CD45RB(high) donor cells were converted to CD4(+)CD44(high)CD62L(-) IL-7Ralpha(high) effector-memory T (T(EM)) cells at 8 weeks after transfer and were distributed throughout the whole body, including colonic lamina propria, mesenteric lymph nodes, thoracic duct, peripheral blood, spleen, and bone marrow.

Negative feedback regulation of colitogenic CD4+ T cells by increased granulopoiesis.

Background: Chronic inflammatory diseases are characterized by massive infiltration of innate and acquired immune cells in inflammatory sites. However, it remains unclear how these cells cooperate in the development of disease. Although bone marrow (BM) is a primary site for hematopoiesis of immune cells except T cells, BM recruits memory T cells from the periphery.

Immunosenescent colitogenic CD4(+) T cells convert to regulatory cells and suppress colitis.

Inflammatory bowel diseases progress steadily by the expansion of colitogenic CD4(+) cells. However, it remains unknown whether colitogenic CD4(+) cells are long-living like memory cells or exhausted like effector cells. To assess the longevity of colitogenic lamina propria (LP) CD4(+) cells, we performed sequential transfers of LP CD4(+) cells from colitic CD4(+)CD45RB(high) cell-transferred SCID mice into new SCID mice.

Continuous generation of colitogenic CD4(+) T cells in persistent colitis.

Inflammatory bowel diseases take chronic courses due to the expansion of colitogenic CD4(+) cells. However, it is unclear whether the persistent disease is driven by continuous reactivation of colitogenic memory CD4(+) cells to generate effector CD4(+) cells or by continuous generation of effector CD4(+) cells from naïve cells. To clarify this issue, we performed a series of sequential adoptive transfers of Ly5.

MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4+ T cells in chronic colitis.

TLRs that mediate the recognition of pathogen-associated molecular patterns are widely expressed on/in cells of the innate immune system. However, recent findings demonstrate that certain TLRs are also expressed in conventional TCRalphabeta(+) T cells that are critically involved in the acquired immune system, suggesting that TLR ligands can directly modulate T cell function in addition to various innate immune cells. In this study, we report that in a murine model of chronic colitis induced in RAG-2(-/-) mice by adoptive transfer of CD4(+)CD45RB(high) T cells, both CD4(+)CD45RB(high) donor cells and the expanding colitogenic lamina propria CD4(+)CD44(high) memory cells expresses a wide variety of TLRs along with MyD88, a key adaptor molecule required for signal transduction through TLRs.

Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis.

We previously demonstrated that IL-7 is produced by intestinal goblet cells and is essential for the persistence of colitis. It is well known, however, that goblet cells are decreased or depleted in the chronically inflamed mucosa of animal colitis models or human inflammatory bowel diseases. Thus, in this study, we assess whether intestinal IL-7 is surely required for the persistence of colitis using a RAG-1/2-/- colitis model induced by the adoptive transfer of CD4+CD45RBhigh T cells in combination with parabiosis system.

Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis.

It has been recently demonstrated that NKG2D is an activating costimulatory receptor on natural killer (NK) cells, natural killer T (NKT) cells, activated CD8(+) T cells, and gammadelta T cells, which respond to cellular stress, such as inflammation, transformation, and infection. Here we show that intestinal inflammation in colitic SCID mice induced by adoptive transfer of CD4(+)CD45RB(high) T cells is characterized by significant increase of CD4(+)NKG2D(+) T cells and constitutive expression of NKG2D ligands, such as H60, Mult-1, and Rae-1, by lamina propria CD11c(+) dendritic cells. Furthermore, treatment with nondepleting and neutralizing anti-NKG2D MAb after transfer of CD4(+)CD45RB(high) T cells into SCID mice significantly suppressed wasting disease with colitis, abrogated leukocyte infiltration, and reduced production of IFN-gamma by lamina propria CD4(+) T cells.