Regional and global changes in TCR [alpha][beta] T cell repertoires in the gut are dependent upon the complexity of the enteric microflora

The repertoire of gut associated T cells is shaped by exposure to microbes, including the natural enteric microflora. Previous studies compared the repertoire of gut associated T cell populations in germ free (GF) and conventional mammals often focussing on intra-epithelial lymphocyte compartments. Using GF, conventional and monocolonised (gnotobiotic) chickens and chicken TCRbeta-repertoire analysis techniques, we determined the influence of microbial status on global and regional enteric TCRbeta repertoires. The gut of conventionally reared chickens exhibited non-Gaussian distributions of CDR3-lengths with some shared over-represented peaks in neighbouring gut segments. Sequence analysis revealed local clonal over-representation. Germ-free chickens exhibited a polyclonal, non-selected population of T cells in the spleen and in the gut. In contrast, gnotobiotic chickens exhibited a biased repertoire with shared clones evident throughout the gut. These data indicate the dramatic influence of enteric microflora complexity on the profile of TCRbeta repertoire in the gut at local and global levels

Patched1 Haploinsufficiency Increases Adult Bone Mass and Modulates Gli3 Repressor Activity

SummaryHedgehog (Hh)-Patched1 (Ptch1) signaling plays essential roles in various developmental processes, but little is known about its role in postnatal homeostasis. Here, we demonstrate regulation of postnatal bone homeostasis by Hh-Ptch1 signaling. Ptch1-deficient (Ptch1+/−) mice and patients with nevoid basal cell carcinoma syndrome showed high bone mass in adults. In culture, Ptch1+/− cells showed accelerated osteoblast differentiation, enhanced responsiveness to the runt-related transcription factor 2 (Runx2), and reduced generation of the repressor form of Gli3 (Gli3rep). Gli3rep inhibited DNA binding by Runx2 in vitro, suggesting a mechanism that could contribute to the bone phenotypes seen in the Ptch1 heterozygotes. Moreover, systemic administration of the Hh signaling inhibitor cyclopamine decreased bone mass in adult mice. These data provide evidence that Hh-Ptch1 signaling plays a crucial role in postnatal bone homeostasis and point to Hh-Ptch1 signaling as a potential molecular target for the treatment of osteoporosis

Quantum Phase Transitions in the One-Dimensional S=1 Spin-Orbital Model: Implications for Cubic Vanadates

We investigate ground-state properties and quantum phase transitions in the one-dimensional S=1 spin-orbital model relevant to cubic vanadates. Using the density matrix renormalization group, we compute the ground-state energy, the magnetization and the correlation functions for different values of the Hund's coupling $J_H$ and the external magnetic field. It is found that the magnetization jumps at a certain critical field, which is a hallmark of the field-induced first-order phase transition. The phase transition driven by $J_H$ is also of first order. We also consider how the lattice-induced ferro-type interaction between orbitals modifies the phase diagram, and discuss the results in a context of the first-order phase transition observed in YVO$_3$ at 77K.Comment: 7 pages, 7 figur

Histopathologic Characteristics of Intestinal Biopsy Samples from Dogs With Chronic Inflammatory Enteropathy With and Without Hypoalbuminemia

BACKGROUND: Previous studies have identified hypoalbuminemia as a risk factor for negative outcome in dogs with chronic enteropathy (CE), but it has not been determined whether histopathology differs between CE dogs with and without hypoalbuminemia. OBJECTIVE: To compare histopathologic findings in dogs with biopsy‐diagnosed inflammatory CE with and without hypoalbuminemia. ANIMALS: 83 dogs that had intestinal biopsy performed between January 2010–July 2015. Dogs had signs compatible with CE of at least 3‐weeks' duration and no evidence of clinically relevant extra‐gastrointestinal (GI) disease or potential non‐GI causes of hypoalbuminemia. Dogs had primary diagnosis of inflammatory enteritis based on histopathology. METHODS: Dogs were grouped into CE with normoalbuminemia (CEN; serum albumin concentration ≥3.0 g/dL, N = 46) or chronic enteropathy with hypoalbuminemia (CEH; serum albumin concentration <3.0 g/dL, N = 37). A pathologist (SLP) blinded to the groups reviewed biopsy samples and applied the World Small Animal Veterinary Association scoring system to all samples. RESULTS: Intestinal biopsy samples from dogs in the CEH group were significantly more likely to display villous stunting, epithelial injury, crypt distension, and lacteal dilatation, and were more likely to have intraepithelial lymphocytes and lamina propria neutrophils than biopsy samples from dogs in the CEN group. Additionally, higher scores for each of the above listed histopathologic criteria were associated with a lower serum albumin concentration. CONCLUSIONS AND CLINICAL IMPORTANCE: Histopathologic features of chronic inflammatory enteropathy differ between dogs that are hypo‐ versus normoalbuminemic. Additional work is needed to elucidate the clinical relevance of these differences

Forebrain Ptf1a Is Required for Sexual Differentiation of the Brain

The mammalian brain undergoes sexual differentiation by gonadal hormones during the perinatal critical period. However, the machinery at earlier stages has not been well studied. We found that Ptf1a is expressed in certain neuroepithelial cells and immature neurons around the third ventricle that give rise to various neurons in several hypothalamic nuclei. We show that conditional Ptf1a-deficient mice (Ptf1a cKO) exhibit abnormalities in sex-biased behaviors and reproductive organs in both sexes. Gonadal hormone administration to gonadectomized animals revealed that the abnormal behavior is caused by disorganized sexual development of the knockout brain. Accordingly, expression of sex-biased genes was severely altered in the cKO hypothalamus. In particular, Kiss1, important for sexual differentiation of the brain, was drastically reduced in the cKO hypothalamus, which may contribute to the observed phenotypes in the Ptf1a cKO. These findings suggest that forebrain Ptf1a is one of the earliest regulators for sexual differentiation of the brain

Stepwise Development of MAIT Cells in Mouse and Human

Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)α (iTCRα) chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC) molecule, MHC-related molecule 1 (MR1). MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanVα7.2 antibody and MAIT cell-specific iTCRα and TCRβ transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRα and TCRβ transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT) cells, MAIT cells display a naïve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%–4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naïve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the periphery in a process dependent both upon B cells and the bacterial flora. Thus, their development follows a unique pattern at the crossroad of NKT and γδ T cells

Spontaneous Rupture of Hepatocellular Carcinoma

Of 105 patients of hepatocellular carcinoma (HCC) treated during 1970-1988, twelve patients had spontaneous rupture of carcinomatous nodules. 1) Of previous 6 cases, five were treated by conventional surgical procedures such as packing and suture, and all died. One case underwent right lobectomy following guaze pack and lived for 15 months. 2) The recent 6 cases underwent emergency transcatheter arterial embolization (TAE ) and two died of hepatic failure due to severe cirrhosis. The other 4 cases had successful control , of bleeding which allowed further treatment of HCC ; hepatectomy in 3 and repeated TAE in one. 3) All cases had precirrhosis or cirrhosis. Pathologically, ruptured tumors expansively growing with capsule invasion of cancer cells, and portal tumor thrombus were recognized in resected or autopsy specimens. DNA aneuploid HCC on flow cytometric DNA analysis were found in 4 out of 5 cases. In conclusion, hepatic resection following embolization, when possible, would seem to be rational treatment for spontaneous rupture of HCC, although the prognosis is still extremely poor despite successful control of bleeding

Congenital Web-like Tracheal Stenosis Cured Surgically in Adult

A 60-year-old, Japanese woman, with congenital web-like tracheal stenosis surgically treated. Successful relief from tracheal stenosis was obstained. Detection in adulthood and chance of the treatment for congenital tracheal stenosis is very rare. As far as this case is concerned, delay in detection and treatment is discussed of congenital tracheal stenosis

Intestinal barrier interactions with specialized CD8 T Cells

Copyright: © 2017 Konjar, Ferreira, Blankenhaus and Veldhoen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.The trillions of microorganisms that reside in the gastrointestinal tract, essential for nutrient absorption, are kept under control by a single cell barrier and large amounts of immune cells. Intestinal epithelial cells (IECs) are critical in establishing an environment supporting microbial colonization and immunological tolerance. A large population of CD8+ T cells is in direct and constant contact with the IECs and the intraepithelial lymphocytes (IELs). Due to their location, at the interphase of the intestinal lumen and external environment and the host tissues, they seem ideally positioned to balance immune tolerance and protection to preserve the fragile intestinal barrier from invasion as well as immunopathology. IELs are a heterogeneous population, with a large innate-like contribution of unknown specificity, intercalated with antigen-specific tissue-resident memory T cells. In this review, we provide a comprehensive overview of IEL physiology and how they interact with the IECs and contribute to immune surveillance to preserve intestinal homeostasis and host-microbial relationships.Members of the Veldhoen laboratory are supported by European Union H2020 ERA project (N°667824—EXCELLtoINNOV), publication costs were provided by LISBOA-01-0145-FEDER-007391, projeto cofinanciado pelo FEDER através POR Lisboa 2020—Programa Operacional Regional de Lisboa, do PORTUGAL 2020, e pela Fundação para a Ciência e a Tecnologia.info:eu-repo/semantics/publishedVersio

Malignant mixed Mullerian tumors of the uterus: histopathological evaluation of cell cycle and apoptotic regulatory proteins

<p>Abstract</p> <p>Aim</p> <p>The aim of our study was to evaluate survival outcomes in malignant mixed Mullerian tumors (MMMT) of the uterus with respect to the role of cell cycle and apoptotic regulatory proteins in the carcinomatous and sarcomatous components.</p> <p>Methods</p> <p>23 cases of uterine MMMT identified from the Saskatchewan Cancer Agency (1970-1999) were evaluated. Immunohistochemical expression of Bad, Mcl-1, bcl-x, bak, mdm2, bax, p16, p21, p53, p27, EMA, Bcl-2, Ki67 and PCNA was correlated with clinico-pathological data including survival outcomes.</p> <p>Results</p> <p>Histopathological examination confirmed malignant epithelial component with homologous (12 cases) and heterologous (11 cases) sarcomatous elements. P53 was strongly expressed (70-95%) in 15 cases and negative in 5 cases. The average survival in the p53+ve cases was 3.56 years as opposed to 8.94 years in p53-ve cases. Overexpression of p16 and Mcl-1 were observed in patients with longer survival outcomes (> 2 years). P16 and p21 were overexpressed in the carcinomatous and sarcomatous elements respectively. Cyclin-D1 was focally expressed only in the carcinomatous elements.</p> <p>Conclusions</p> <p>Our study supports that a) cell cycle and apoptotic regulatory protein dysregulation is an important pathway for tumorigenesis and b) p53 is an important immunoprognostic marker in MMMT of the uterus.</p