ABSTRACT
Multicellular eukaryotes have evolved a range of mechanisms for immune recognition. A widespread family involved in innate immunity are the NACHT-domain and leucine-rich-repeat-containing (NLR) proteins. Mammals have small numbers of NLR proteins, whereas in some species, mostly those without adaptive immune systems, NLRs have expanded into very large families. We describe a family of nearly 400 NLR proteins encoded in the zebrafish genome. The proteins share a defining overall structure, which arose in fishes after a fusion of the core NLR domains with a B30.2 domain, but can be subdivided into four groups based on their NACHT domains. Gene conversion acting differentially on the NACHT and B30.2 domains has shaped the family and created the groups. Evidence of positive selection in the B30.2 domain indicates that this domain rather than the leucine-rich repeats acts as the pathogen recognition module. In an unusual chromosomal organization, the majority of the genes are located on one chromosome arm, interspersed with other large multigene families, including a new family encoding zinc-finger proteins. The NLR-B30.2 proteins represent a new family with diversity in the specific recognition module that is present in fishes in spite of the parallel existence of an adaptive immune system.
Subject(s)
Evolution, Molecular , NLR Proteins/chemistry , NLR Proteins/genetics , Zebrafish Proteins/chemistry , Zebrafish Proteins/genetics , Zebrafish/metabolism , Amino Acid Sequence , Animals , Conserved Sequence , Genome , Multigene Family , Protein Domains , Time Factors , Zebrafish/geneticsABSTRACT
The atypical protein kinase C (aPKC) is a key regulator of polarity and cell fate in lower organisms. However, whether mammalian aPKCs control stem cells and fate in vivo is not known. Here we show that loss of aPKCλ in a self-renewing epithelium, the epidermis, disturbed tissue homeostasis, differentiation, and stem cell dynamics, causing progressive changes in this tissue. This was accompanied by a gradual loss of quiescent hair follicle bulge stem cells and a temporary increase in proliferating progenitors. Lineage tracing analysis showed that loss of aPKCλ altered the fate of lower bulge/hair germ stem cells. This ultimately led to loss of proliferative potential, stem cell exhaustion, alopecia, and premature aging. Inactivation of aPKCλ produced more asymmetric divisions in different compartments, including the bulge. Thus, aPKCλ is crucial for homeostasis of self-renewing stratifying epithelia, and for the regulation of cell fate, differentiation, and maintenance of epidermal bulge stem cells likely through its role in balancing symmetric and asymmetric division.
Subject(s)
Cell Differentiation , Cell Proliferation , Epidermal Cells , Homeostasis/physiology , Isoenzymes/physiology , Protein Kinase C/physiology , Stem Cells/cytology , Animals , Animals, Newborn , Apoptosis , Blotting, Western , Cells, Cultured , Epidermis/metabolism , Female , Immunoenzyme Techniques , Keratinocytes/cytology , Keratinocytes/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction , Stem Cells/metabolismABSTRACT
BACKGROUND: Hepatorenal syndrome (HRS) is a frequent complication of end-stage liver cirrhosis. HRS type I has a very poor prognosis. From which of the more or less established therapies, such as use of vasoconstrictors together with albumin or placement of a Transjugular Intrahepatic Portosystemic Shunt patients might profit remains elusive. Therefore, it is important to define parameters that predict an improved outcome in respect to kidney function and survival. METHODS: The clinical charts of 91 patients with cirrhosis and HRS type I were studied. The parameters associated with response to therapy, defined as a decrease in serum creatinine of more than 1.5 mg/dl on day 14 after diagnosis of HRS, and those associated with survival were assessed by multivariate analysis. RESULTS: The median survival was 2.7 (1.5-3.8) months. Three independent predictive factors for survival were identified: Child-Pugh score (P = 0.05), Model of End-Stage Liver Disease (MELD) score less than 20 (P = 0.01), and response to therapy (P = 0.02). The Child-Pugh score (P = 0.00) and MELD score less than 20 (P = 0.02) were the parameters independently associated with the response to therapy, which occurred in 26% of the patients. CONCLUSION: Our data of this large monocentric series with HRS type I confirm the poor prognosis in these patients, especially in those with high Child-Pugh and MELD scores, and in those in whom kidney function does not improve within 2 weeks.
Subject(s)
Hepatorenal Syndrome/diagnosis , Adult , Biomarkers/blood , Creatinine/blood , Epidemiologic Methods , Female , Hepatorenal Syndrome/etiology , Hepatorenal Syndrome/physiopathology , Hepatorenal Syndrome/therapy , Humans , Kidney/physiopathology , Liver Cirrhosis/complications , Male , Middle Aged , Portasystemic Shunt, Transjugular Intrahepatic , Prognosis , Treatment OutcomeABSTRACT
By screening genome databases, 12 genes encoding membrane proteins homologous to nucleobase-ascorbate transporters (NATs) were identified in Arabidopsis thaliana. A similar number of genes was found in the rice genome. The plant NAT proteins split into five clades (I-V) based on protein multisequence alignments. This classification nicely correlates with the patterns of organ- and tissue-specific expression during the whole life cycle of A. thaliana. Interestingly, expression of two members of clade III, AtNAT7 and AtNAT8, was found to be up-regulated in undifferentiated tissues such as callus or tumors produced by Agrobacterium tumefaciens. Clade V comprises AtNAT12 possessing a hydrophilic N-terminal extension. Transient expression of green fluorescent protein (GFP) fusions in different systems showed that AtNAT12 along with AtNAT7 and -8 are located in the plasma membrane. Mutations in any of the AtNAT genes do not induce phenotypic alterations. The absence of obvious mutant phenotypes in single but also in double and triple mutants suggests a high degree of functional redundancy between AtNAT genes, but might also point to redundant functions provided by genes or pathways unrelated to the AtNATs.
Subject(s)
Arabidopsis Proteins/genetics , Arabidopsis/genetics , Ascorbic Acid/genetics , Genome, Plant , Nucleobase Transport Proteins/genetics , Ascorbic Acid/metabolism , Base Sequence , Evolution, Molecular , Gene Expression Regulation, Plant , Molecular Sequence Data , Multigene Family , Nucleobase Transport Proteins/metabolism , Phylogeny , Up-RegulationABSTRACT
BACKGROUND/AIM: Hepatorenal syndrome (HRS) is associated with a poor prognosis. The incidence and prognostic impact of kidney dysfunction due to other causes in cirrhotic patients are less well known. The current study prospectively evaluated the incidence and the prognostic relevance of different etiologies of kidney failure in cirrhotic patients. METHODS: Eighty-eight consecutive patients with cirrhosis and serum creatinine > or =1.5 mg/dl were enrolled. The etiologies of kidney dysfunction were analyzed, and prognostic factors including Model for End-Stage Liver Disease (MELD) score were evaluated in a multivariate Cox model. RESULTS: HRS was present in 35 (40%) patients (15 HRS 1, 20 HRS 2), followed by renal parenchymal disease (23%), drug-induced kidney dysfunction (19%) and prerenal failure due to bleeding or infections (15%). HRS patients had a significantly higher MELD score and shorter survival. In addition to the MELD score, only HRS 1 was independently predictive for survival. HRS 2 patients had a similar outcome as patients with non-HRS kidney dysfunction. CONCLUSIONS: In patients with cirrhosis and renal failure, hepatorenal syndrome is associated with a worse prognosis than kidney dysfunction due to other conditions but only HRS type 1 has independent prognostic relevance in addition to the MELD score in these patients.
