Declining expression of a single epithelial cell‐autonomous gene accelerates age‐related thymic involution

Age‐related thymic involution may be triggered by gene expression changes in lymphohematopoietic and/or nonhematopoietic thymic epithelial cells (TECs). The role of epithelial cell‐autonomous gene FoxN1 may be involved in the process, but it is still a puzzle because of the shortage of evidence from gradual loss‐of‐function and exogenous gain‐of‐function studies. Using our recently generated loxP‐floxed‐FoxN1(fx) mouse carrying the ubiquitous CreER^T (uCreER^T) transgene with a low dose of spontaneous activation, which causes gradual FoxN1 deletion with age, we found that the uCreER^T‐fx/fx mice showed an accelerated age‐related thymic involution owing to progressive loss of FoxN1⁺ TECs. The thymic aging phenotypes were clearly observable as early as at 3–6 months of age, resembling the naturally aged (18–22‐month‐old) murine thymus. By intrathymically supplying aged wild‐type mice with exogenous FoxN1‐cDNA, thymic involution and defective peripheral CD4⁺ T‐cell function could be partially rescued. The results support the notion that decline of a single epithelial cell‐autonomous gene FoxN1 levels with age causes primary deterioration in TECs followed by impairment of the total postnatal thymic microenvironment, and potentially triggers age‐related thymic involution in mice.     

Enhanced angiogenic potency of monocytic endothelial progenitor cells in patients with systemic sclerosis

Introduction  

Microvasculopathy is one of the characteristic features in patients with systemic sclerosis (SSc), but underlying mechanisms still remain uncertain. In this study, we evaluated the potential involvement of monocytic endothelial progenitor cells (EPCs) in pathogenic processes of SSc vasculopathy, by determining their number and contribution to blood vessel formation through angiogenesis and vasculogenesis.     

Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis

Introduction  

MicroRNAs (miRNAs), endogenous small noncoding RNAs regulating the activities of target mRNAs and cellular processes, are present in human plasma in a stable form. In this study, we investigated whether miRNAs are also stably present in synovial fluids and whether plasma and synovial fluid miRNAs could be biomarkers of rheumatoid arthritis (RA) and osteoarthritis (OA).     

NIR fluorescent ytterbium compound for in vivo fluorescence molecular imaging

We have developed a new NIR fluorescent probe based on an ytterbium(III) (E)‐1‐(pyridin‐2‐yl‐diazenyl)naphthalen‐2‐ol (PAN) complex. This probe emits near‐infrared luminescence derived from the Yb ion through excitation of the PAN moiety with visible light (λ_ex = 530 nm, λ_em = 975 nm). The results support the possible utility of the probe for in vivo fluorescence molecular imaging. Copyright © 2009 John Wiley & Sons, Ltd.     

Simian Betaretrovirus Infection in a Colony of Cynomolgus Monkeys (Macaca fascicularis)

Of the 419 laboratory-bred cynomolgus macaques (Macaca fascicularis) in a breeding colony at our institution, 397 (95%) exhibited antibodies or viral RNA (or both) specific for simian betaretrovirus (SRV) in plasma. Pregnant monkeys (n = 95) and their offspring were tested to evaluate maternal–infant infection with SRV. At parturition, the first group of pregnant monkeys (n = 76) was antibody-positive but RNA-negative, the second group (n = 14 monkeys) was positive for both antibody and RNA, and the last group (n = 5) was antibody-negative but RNA-positive. None of the offspring delivered from the 76 antibody-positive/RNA-negative mothers exhibited viremia at birth. Eight of the offspring (including two newborns delivered by caesarian section) from the 14 dually positive mothers exhibited SRV viremia, whereas the remaining 6 newborns from this group were not viremic. All of the offspring (including 2 newborns delivered by caesarian section) of the 5 antibody-negative/RNA-positive mothers exhibited viremia at birth. One neonatal monkey delivered by CS and two naturally delivered monkeys that were viremic at birth remained viremic at 1 to 6 mo of age and lacked SRV antibodies at weaning. Family analysis of 2 viremic mothers revealed that all 7 of their offspring exhibited SRV viremia, 6 of which were also antibody-negative. The present study demonstrates the occurrence of transplacental infection of SRV in viremic dams and infection of SRV in utero to induce immune tolerance in infant monkeys.Abbreviation: SRV, simian betaretrovirusAlthough simian betaretrovirus (SRV) causes symptoms of immunodeficiency, including anemia, tumors, and persistent refractory diarrhea, in some infected macaques,^1,7,10 most infected monkeys exhibit few or no clinical signs.² Macaques free of SRV are important in many types of experiments to avoid associated immunologic and virologic effects. Establishing an SRV-free breeding colony is paramount for a steady supply of appropriate monkeys for various experiments.⁸We previously reported that SRV-T, a novel subtype of SRV, was found in the cynomolgus colony of our institution.³ Approximately 20% of the colony monkeys tested in 2005 were viremic and shed SRV-T virus in saliva, urine, and feces.^4,5 The viruses shed by these monkeys are a potential source of horizontal SRV-T infection, as occurred in a rhesus monkey colony.^6,7 In the present study, we investigated the actual prevalence and transmission of SRV in the closed cynomolgus colony through several generations, to prevent the spread of the virus and to establish an SRV-free colony.     

The Mek1 phosphorylation cascade plays a role in meiotic recombination of Schizosaccharomyces pombe

Mek1 is a Chk2/Rad53/Cds1-related protein kinase that is required for proper meiotic progression of Schizosaccharomyces pombe. However, the molecular mechanisms of Mek1 regulation and Mek1 phosphorylation targets are unclear. Here, we report that Mek1 is phosphorylated at serine-12 (S12), S14 and threonine-15 (T15) by Rad3 (ATR) and/or Tel1 (ATM) kinases that are activated by meiotic programmed double-strand breaks (DSBs). Mutations of these sites by alanine replacement caused abnormal meiotic progression and recombination rates. Phosphorylation of these sites triggers autophosphorylation of Mek1; indeed, alanine replacement mutations of Mek1-T318 and -T322 residues in the activation loop of Mek1 reduced Mek1 kinase activity and meiotic recombination rates. Substrates of Mek1 include Mus81-T275, Rdh54-T6 and Rdh54-T673. Mus81-T275 is known to regulate the Mus81 function in DNA cleavage, whereas Rdh54-T6A/T673A mutant cells showed abnormal meiotic recombination. Taken together, we conclude that the phosphorylation of Mek1 by Rad3 or Tel1, Mek1 autophosphorylation and Mus81 or Rdh54 phosphorylation by Mek1 regulate meiotic progression in S. pombe.Key words: Mek1, meiotic recombination, phosphorylation, Rdh54, Mus81     

Tissue‐dependent induction of apoptosis by matrix metalloproteinase stromelysin‐3 during amphibian metamorphosis

Matrix metalloproteinases (MMPs) are a superfamily of Zn²⁺‐dependent proteases that are capable of cleaving the proteinaceous component of the extracellular matrix (ECM). The ECM is a critical medium for cell–cell interactions and can also directly signal cells through cell surface ECM receptors, such as integrins. In addition, many growth factors and signaling molecules are stored in the ECM. Thus, ECM remodeling and/or degradation by MMPs are expected to affect cell fate and behavior during many developmental and pathological processes. Numerous studies have shown that the expression of MMP mRNAs and proteins associates tightly with diverse developmental and pathological processes, such as tumor metastasis and mammary gland involution. In vivo evidence to support the roles of MMPs in these processes has been much harder to get. Here, we will review some of our studies on MMP11, or stromelysin‐3, during the thyroid hormone‐dependent amphibian metamorphosis, a process that resembles the so‐called postembryonic development in mammals (from a few months before to several months after birth in humans when organ growth and maturation take place). Our investigations demonstrate that stromelysin‐3 controls apoptosis in different tissues via at least two distinct mechanisms. Birth Defects Research (Part C) 90:55–66, 2010. © 2010 Wiley‐Liss, Inc.