scholarly journals Epistatic genetic interactions govern morphogenesis during sexual reproduction and infection in a global human fungal pathogen

2021 ◽  
Author(s):  
Sheng Sun ◽  
Cullen Roth ◽  
Anna F. Averette ◽  
Paul M. Magwene ◽  
Joseph Heitman
Keyword(s):  
Sexual Reproduction ◽  
Signaling Pathways ◽  
Quantitative Trait ◽  
Fungal Pathogens ◽  
Rho Gtpase ◽  
Large Cell ◽  
Cell Phenotype ◽  
Type Locus ◽  
Complex Genetics ◽  
Cellular Development

Cellular development is orchestrated by evolutionarily conserved signaling pathways, which are often pleiotropic and involve intra- and inter-pathway epistatic interactions that form intricate, complex regulatory networks. Cryptococcus species are a group of closely-related human fungal pathogens that grow as yeasts yet transition to hyphae during sexual reproduction. Additionally, during infection they can form large, polyploid titan cells that evade immunity and develop drug resistance. Multiple known signaling pathways regulate cellular development, yet how these are coordinated and interact with genetic variation is less well understood. Here, we conducted quantitative trait locus (QTL) analyses of a mapping population generated by sexual reproduction of two parents, only one of which is unisexually fertile. We observed transgressive segregation of the unisexual phenotype among progeny, as well as a novel large-cell phenotype under mating-inducing conditions. These large-cell progeny were found to produce titan cells both in vitro and in infected animals. Two major QTLs and corresponding quantitative trait genes (QTGs) were identified: RIC8 (encoding a guanine-exchange factor) and CNC06490 (encoding a putative Rho-GTPase activator), both involved in G-protein signaling. The two QTGs interact epistatically with each other and with the mating-type locus in phenotypic determination. These findings provide insights into the complex genetics of morphogenesis during unisexual reproduction and pathogenic titan cell formation and illustrate how QTL analysis can be applied to identify epistasis between genes. This study shows that phenotypic outcomes are influenced by the genetic background upon which mutations arise, implicating dynamic, complex genotype-to-phenotype landscapes in fungal pathogens and beyond.

Primary Cutaneous CD30-Positive Anaplastic Large Cell Lymphoma in Childhood: Report of 4 Cases and Review of the Literature

2005 ◽  
Vol 8 (1) ◽  
pp. 52-60 ◽  
Author(s):  
Shimareet Kumar ◽  
Stefania Pittaluga ◽  
Mark Raffeld ◽  
Michael Guerrera ◽  
Nita L. Seibel ◽  
...  
Keyword(s):  
T Cell ◽  
Anaplastic Large Cell Lymphoma ◽  
Cell Lymphoma ◽  
Subcutaneous Tissue ◽  
Pediatric Population ◽  
Large Cell ◽  
Lymphoid Cells ◽  
Cell Phenotype ◽  
Anaplastic Lymphoma ◽  
Large Cell Lymphoma

We present the clinicopathologic findings in 4 children with primary cutaneous anaplastic large cell lymphoma (C-ALCL). The patients ranged in age from 13 months to 8 years, with 3 females and 1 male. All presented with a rapidly enlarging mass involving the skin and subcutaneous tissue. Histologic evaluation showed sheets of large pleomorphic lymphoid cells that were diffusely and strongly CD30+. Tumor cells were CD45+ in 1 of 4 cases. Cells were of T-cell phenotype, with variable positivity for CD3 (3 of 4 cases) and CD5 (2 of 4 cases). All 4 cases were positive for CD4 and clusterin. Staining for anaplastic lymphoma kinase was negative in all cases. No evidence of systemic involvement was noted at initial presentation or over a follow-up of 5 to 78 months, although 3 patients had cutaneous recurrences. Primary C-ALCL has only rarely been described in the pediatric population. The high-grade histologic appearance of this lymphoma belies its generally favorable clinical course and prognosis. Recognition of this entity and its differentiation from other T-cell lymphomas that secondarily involve the skin is important to avoid unnecessarily aggressive therapy in these children.

Angiotropic (Intravascular) Large Cell Lymphoma of T-Cell Phenotype Presenting as Acute Appendicitis in a Patient With Acquired Immunodeficiency Syndrome

1999 ◽  
Vol 123 (4) ◽  
pp. 335-337 ◽  
Author(s):  
Denise M. Malicki ◽  
Yae K. Suh ◽  
Gregory N. Fuller ◽  
Sung S. Shin
Keyword(s):  
T Cell ◽  
Acute Appendicitis ◽  
Acquired Immunodeficiency Syndrome ◽  
Cell Lymphoma ◽  
Immunohistochemical Analysis ◽  
Large Cell ◽  
Cell Phenotype ◽  
Acquired Immunodeficiency ◽  
Large Cell Lymphoma ◽  
Immunodeficiency Syndrome

Abstract We describe a patient with acquired immunodeficiency syndrome who presented with acute appendicitis but was found to have angiotropic large cell lymphoma (ALCL) by pathologic examination of the appendectomy specimen, without acute inflammation. Very rare cases of angiotropic large cell lymphoma have been reported in patients with human immunodeficiency virus infection, and most cases of this rare lymphoma are of B-cell origin, but in this instance immunohistochemical analysis showed a T-cell phenotype.

scholarly journals Characterization of the Roles of Vimentin in Regulating the Proliferation and Migration of HSCs during Hepatic Fibrogenesis

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1184 ◽  
Author(s):  
Pei-Wen Wang ◽  
Tung-Ho Wu ◽  
Tung-Yi Lin ◽  
Mu-Hong Chen ◽  
Chau-Ting Yeh ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Messenger Rna ◽  
Rho Gtpase ◽  
Focal Adhesions ◽  
Cytoskeletal Proteins ◽  
Nuclear Antigen ◽  
Dependent Manner ◽  
Hepatic Fibrogenesis ◽  
And Migration ◽  
Proliferation And Migration

The activation of hepatic stellate cells (HSCs) manifested as proliferation and migration is the pivotal event involved in liver fibrogenesis. The vimentin network, an intermediate filament (IF) system, is one of the critical cascades by which the cell morphology, growth, and motility are modulated. However, the vimentin-mediated cytoskeletal cross talk, as well as the signaling transduction, which further coordinates the cellular responses during hepatic fibrogenesis, is poorly understood. In the current study, both messenger RNA (mRNA) and the vimentin protein were significantly increased in a time-dependent manner in the dimethylnitrosamine (DMN)-exposed liver. In particular, vimentin was highly expressed in the activated HSCs. Again, the overexpressed vimentin was observed in the plasma samples derived from patients with hepatic fibrosis/cirrhosis, suggesting that vimentin may be a key factor in regulating the progression of liver fibrosis. Meanwhile, vimentin knockdown suppressed the migratory propensity, provoked morphological changes, and disturbed the focal adhesions in the HSCs due to the breakdown of associated cytoskeletal proteins. Western blotting showed that vimentin deletion inhibited proliferating cell nuclear antigen (PCNA) and arrested the Rho GTPase family, thereby impairing the HSCs’ growth as well as motility. The phosphorylated extracellular-signal regulated kinase (ERK) and AKT signals were also notably reduced in response to the silence of vimentin. Inhibitors of selected signaling pathways suppressed the migration and differentiation of activated HSCs by regulating specific serine phosphorylated sites on vimentin. Taken together, these findings revealed a novel mechanism of vimentin through which various signaling pathways controlled the proliferation, differentiation, and movement of the HSCs via the ERK/AKT and Rho cascades.

Activation of the lectin DC-SIGN induces an immature dendritic cell phenotype triggering Rho-GTPase activity required for HIV-1 replication

2007 ◽  
Vol 8 (6) ◽  
pp. 569-577 ◽  
Author(s):  
Ashleigh Hodges ◽  
Katherine Sharrocks ◽  
Mariola Edelmann ◽  
Dilair Baban ◽  
Arnaud Moris ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Rho Gtpase ◽  
Immature Dendritic Cell ◽  
Cell Phenotype ◽  
Gtpase Activity ◽  
Hiv 1

scholarly journals Update on Myopia Risk Factors and Microenvironmental Changes

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Valeria Coviltir ◽  
Miruna Burcel ◽  
Alina Popa Cherecheanu ◽  
Catalina Ionescu ◽  
Dana Dascalescu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Environmental Factors ◽  
Signaling Pathways ◽  
Candidate Genes ◽  
Therapeutic Targets ◽  
Current Evidence ◽  
Complex Genetics ◽  
Recent Advances

The focus of this update is to emphasize the recent advances in the pathogenesis and various molecular key approaches associated with myopia in order to reveal new potential therapeutic targets. We review the current evidence for its complex genetics and evaluate the known or candidate genes and loci. In addition, we discuss recent investigations regarding the role of environmental factors. This paper also covers current research aimed at elucidating the signaling pathways involved in the pathogenesis of myopia.

Cytotoxic Cell Antigen Expression in Anaplastic Large Cell Lymphomas of T- and Null-Cell Type and Hodgkin's Disease: Evidence for Distinct Cellular Origin

Blood ◽  
1997 ◽  
Vol 89 (3) ◽  
pp. 980-989 ◽  
Author(s):  
Laszlo Krenacs ◽  
Axel Wellmann ◽  
Lynn Sorbara ◽  
Andreas W. Himmelmann ◽  
Eniko Bagdi ◽  
...  
Keyword(s):  
T Cell ◽  
Antigen Expression ◽  
Large Cell ◽  
Cell Phenotype ◽  
Cytotoxic Lymphocytes ◽  
Cell Type ◽  
Null Cell ◽  
Cytotoxic Cell ◽  
Granule Protein ◽  
Cytotoxic Granule

Abstract Anaplastic large cell lymphoma (ALCL) is composed of large, frequently bizarre, cells of T- or null-cell phenotype that show a preferential sinusoidal growth pattern and consistent CD30 positivity. Whether these tumors represent a single entity or several, and what the exact cell origin, is controversial. Recently, granzyme B, a cytotoxic granule component, was reported in a small percentage of ALCL, suggesting that some cases may originate from cytotoxic lymphocytes. To further investigate this possibility, we performed an immunohistochemical study of 33 ALCLs of T- and null-cell type, using monoclonal antibodies to cytotoxic cell-associated antigens, including CD8, CD56, CD57, and the cytotoxic granular proteins perforin and TIA-1. In addition, CD4 expression was also evaluated. ALCL cases included 27 classical systemic forms and variants, 3 primary cutaneous (PC) forms, and 3 acquired immunodeficiency syndrome-associated forms. Cytotoxic antigen expression was also studied in 51 cases of Hodgkin's disease (HD) and 17 large B-cell lymphomas (LBCLs) with anaplastic cytomorphology and/or CD30 positivity. We found that 76% of ALCLs, representing all subtypes except the PC forms, expressed either TIA-1, perforin, or both proteins. Expression of TIA-1 and perforin were highly correlated (P < .001). On the basis of their immunophenotypic profiles, several subtypes of cytotoxic antigen positive and negative ALCL could be recognized. Fifty-five percent of ALCLs (18 of 33) displayed an immunophenotypic profile consistent with cytotoxic T cells. Six cases expressed cytotoxic granular proteins in the absence of lineage specific markers, and one case expressed both T-cell – and natural killer cell–like markers. These 7 cases (21%) were placed into a phenotypic category of cytotoxic lymphocytes of unspecified subtype. Twenty-four percent (8 cases) of ALCLs were cytotoxic granule protein negative. All but one of these displayed a T-cell phenotype. Cytotoxic granule protein expression did not correlate with the presence of the NPM-ALK fusion transcript. Only 10% of the 51 HD cases were found to be TIA-1+, and none expressed perforin. Cytotoxic antigen expression was absent in LBCL. The expression of cytotoxic granule proteins in the majority of ALCL implies a cytotoxic lymphocyte phenotype and suggests that most cases originate from lymphocytes with cytotoxic potential. Furthermore, the demonstration of cytotoxic cell related proteins may be a useful addition to the current panel of antibodies used to distinguish ALCL, HD, and anaplastic LBCL.

Regulation of I Cl,swell in neuroblastoma cells by G protein signaling pathways

2001 ◽  
Vol 281 (1) ◽  
pp. C89-C98 ◽  
Author(s):  
Ana Y. Estevez ◽  
Tamara Bond ◽  
Kevin Strange
Keyword(s):  
Signaling Pathways ◽  
Cholera Toxin ◽  
G Protein ◽  
Kinase Inhibitors ◽  
Rho Gtpase ◽  
Neuroblastoma Cells ◽  
Anion Channel ◽  
Protein Signaling ◽  
Induced Current ◽  
Independent Manner

Guanosine 5′- O-(3-thiotriphosphate) (GTPγS) activated the I Cl,swell anion channel in N1E115 neuroblastoma cells in a swelling-independent manner. GTPγS-induced current was unaffected by ATP removal and broadly selective tyrosine kinase inhibitors, demonstrating that phosphorylation events do not regulate G protein-dependent channel activation. Pertussis toxin had no effect on GTPγS-induced current. However, cholera toxin inhibited the current ∼70%. Exposure of cells to 8-bromoadenosine 3′,5′-cyclic monophosphate did not mimic the effect of cholera toxin, and its inhibitory action was not prevented by treatment of cells with an inhibitor of adenylyl cyclase. These results demonstrate that GTPγS does not act through Gαi/o GTPases and that Gαs/Gβγ G proteins inhibit the channel and/or channel regulatory mechanisms through cAMP-independent mechanisms. Swelling-induced activation of I Cl,swell was stimulated two- to threefold by GTPγS and inhibited by 10 mM guanosine 5′- O-(2-thiodiphosphate). The Rho GTPase inhibitor Clostridium difficile toxin B inhibited both GTPγS- and swelling-induced activation of I Cl,swell. Taken together, these findings indicate that Rho GTPase signaling pathways regulate the I Cl,swell channel via phosphorylation-independent mechanisms.

scholarly journals The immunologic and clinicopathologic heterogeneity of cutaneous lymphomas other than mycosis fungoides

Blood ◽  
1983 ◽  
Vol 62 (2) ◽  
pp. 464-472 ◽  
Author(s):  
GS Wood ◽  
JS Burke ◽  
S Horning ◽  
RS Doggett ◽  
R Levy ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycosis Fungoides ◽  
Survival Data ◽  
Large Cell ◽  
Cell Phenotype ◽  
Time Interval ◽  
Histologic Subtype ◽  
Interval Therapy ◽  
Cutaneous Lymphomas

Abstract Twenty-one cases of non-Hodgkin's lymphoma with cutaneous involvement, other than mycosis fungoides, were evaluated immunologically, histologically, and clinically. Ten patients presented with skin disease alone, seven with concurrent cutaneous and extracutaneous disease, and four with extracutaneous disease only. Twenty of the 21 cases were nonepidermotropic tumors and were equally likely to express B or T phenotypes. None of the cases expressed a true histiocytic phenotype. Almost all cases expressed la and class 1 HLA determinants. Immunophenotypes were stable regardless of time interval, therapy, or body site sampled in seven of eight patients studied serially. In contrast to mycosis fungoides, the T lymphomas exhibited noncerebriform cytology, tumor la expression, lack of mature helper T-cell phenotype, nonepidermotropic histology, a tendency for marrow involvement, and presented as nodules rather than patches or plaques. Since each T lymphoma expressed an abnormal but uniform T-cell phenotype other than mature cytotoxic/suppressor or helper, the neoplastic population could be distinguished from reactive T cells. Reactive elements averaged one- third of the cellular infiltrates and were mainly T cells and macrophages. Langerhans cells were generally normal in number and distribution. Several histopathologic subtypes were identified with diffuse large cell lymphomas, including immunoblastic lymphomas, comprising 71% of cases (15/21). Prediction of the immunophenotype based on cytologic criteria was correct in 67% of cases (14/21). All errors occurred among the 13 high-grade lymphomas. Survival data were consistent with those of prior studies that have indicated that clinical course is dependent on stage and histologic subtype. Non- Hodgkin's cutaneous lymphomas constitute an immunologically, histologically, and clinically heterogeneous group of neoplasms.

scholarly journals Expression of the c-kit receptor in human lymphomas is restricted to Hodgkin's disease and CD30+ anaplastic large cell lymphomas

Blood ◽  
1994 ◽  
Vol 83 (3) ◽  
pp. 785-792 ◽  
Author(s):  
A Pinto ◽  
A Gloghini ◽  
V Gattei ◽  
D Aldinucci ◽  
V Zagonel ◽  
...  
Keyword(s):  
Lymph Node ◽  
Tumor Cells ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Large Cell ◽  
Lymphoid Cells ◽  
Receptor Protein ◽  
Cell Phenotype ◽  
Northern Blot Hybridization ◽  
Kit Receptor

Abstract The product of the proto-oncogene c-kit is a transmembrane receptor protein that plays an important role in the regulation of normal and neoplastic hematopoiesis via the interaction with its specific ligand termed stem cell factor. To examine whether c-kit product is possibly involved in the pathogenesis of human lymphomas, we analyzed the expression of the c-kit protein in neoplastic cells from a variety of lymphoid tumors by immunostaining of lymph node frozen sections with the 17F11 antibody, detecting an extracellular epitope of the c-kit receptor, and of c-kit RNA by Northern blot hybridization. Of 24 nonHodgkin's lymphomas (NHL) of B- and T-cell phenotype, none expressed immunodetectable c-kit protein that was also not evidenced in lymphoid cells of reactive lymph nodes and normal tonsils. In contrast, c-kit protein was expressed by Reed-Sternberg cells and their mononuclear variants from 11 of 21 Hodgkin's disease (HD) cases, and in tumor cells from 11 of 16 cases of CD30+ anaplastic large cell lymphoma (ALCL). c-kit specific mRNA was also detected in lymph node tissues from HD and ALCL cases but not in neoplastic tissues from NHL other than ALCL. In addition, c-kit/CD30+ tumor cells were evidenced by flow cytometry in a patient displaying massive bone marrow involvement by ALCL. With the exclusion of lymphocyte predominance cases of HD that resulted c-kit expression and the other histologic subtypes of HD or the immunologic phenotype of tumor cells (B, T, nonB-nonT) in both HD and ALCL. The highly restricted expression of the c-kit product among human lymphomas to HD and ALCL provides a further biologic link between these two closely related lymphoma entities.

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