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At least 757 records · Page 42Linked to original sources
PubMed2001

gmhX, a novel gene required for the incorporation of L-glycero-D-manno-heptose into lipooligosaccharide in Neisseria meningitidis.

Lipooligosaccharide (LOS) is a critical virulence factor of Neisseria meningitidis. A Tn916 insertion mutant, designated 469, was found to exhibit a markedly truncated LOS of 2.9 kDa when compared by Tricine/SDS-PAGE to the parental LOS (4.6 kDa). Electrospray mass spectrometry analysis of 469 LOS revealed that it consisted of the deep rough, heptose-deficient structure, Kdo(2)-lipid A. Sequencing of chromosomal DNA flanking the Tn916 insertion in mutant 469 revealed that the transposon had inserted into an ORF predicted to encode a 187 aa protein with sequence homology to the histidinol-phosphate phosphatase domain of Escherichia coli HisB and to a family of genes of unknown function. The gene, designated gmhX, is part of a polycistronic operon (ice-2) containing two other genes, nlaB and orfC. nlaB encodes a lysophosphatidic-acid acyltransferase and orfC is predicted to encode a N-acetyltransferase. Specific polar and non-polar gmhX mutations in the parental strain, NMB, exhibited the truncated LOS structure of mutant 469, and repair of gmhX mutants by homologous recombination with the wild-type gmhX restored the LOS parental phenotype. GmhX mutants demonstrated increased sensitivity to polymyxin B. GmhX mutants and other Kdo(2)-lipid A mutants also demonstrated increased sensitivity to killing by normal human serum but were not as sensitive as inner-core mutants containing heptose. In the genomes of Helicobacter pylori and Synechocystis, gmhX homologues are associated with heptose biosynthesis genes; however, in N. meningitidis, gmhX was found in a location distinct from that of gmhA, rfaD, rfaE, aut and rfaC. GmhX is a novel enzyme required for the incorporation of L-glycero-D-manno-heptose into meningococcal LOS, and is a candidate for the 2-D-glycero-manno-heptose phosphatase of the heptose biosynthesis pathway.

Bacterial Proteins↗
PubMed1999

Expression of cathepsin K messenger RNA in giant cells and their precursors in human osteoarthritic synovial tissues.

OBJECTIVE: To investigate the expression of cathepsin K messenger RNA (mRNA) in the giant cells found in human osteoarthritic (OA) synovium and associated reparative connective tissues, and to compare this with mRNA expression of cathepsins B, L, and S, which are cysteine proteases known to be highly expressed by cells of the monocyte/macrophage lineage. METHODS: Sections of human OA synovium were processed for in situ hybridization and probed for cathepsins K, B, L, and S. Serial sections were reacted for tartrate-resistant acid phosphatase (TRAP) and nonspecific esterase (NSE) activity, which are selective markers for the osteoclast and cells of the macrophage/monocyte lineage, respectively. RESULTS: At 3 sites of monocyte infiltration/giant cell formation (granulation tissue, the intimal and subintimal synovial layers, and deep stroma extending to the periphery of osteophytic tissue), both TRAP-positive mono- and multinucleated cells and TRAP-negative, NSE-positive mononuclear precursors were identified. Cells containing both enzyme activities were also found, potentially indicating an intermediate stage of differentiation. The TRAP-positive mononuclear/giant cells, and the occasional NSE-positive precursor, expressed an intense signal for cathepsin K mRNA, but did not express cathepsins B, L, and S. In contrast, the deep zone of phagocytic-like cells adjacent to sites of ossification expressed high levels of mRNA for cathepsins L, B, and S as well as cathepsin K mRNA. CONCLUSION: Giant cells that form within OA synovial tissue express high levels of cathepsin K mRNA. It appears that cathepsin K acts principally to digest the bone (and cartilage) fragments sheered from the joint surface during OA. The high TRAP activity and the undetectable expression of the macrophage-associated degradative proteases (cathepsins B, L, and S) by synovial giant cells strengthens the hypothesis that cathepsin K is the primary protease involved in bone degradation. At sites of synovial osteogenesis, a population of phagocytic-like cells expressed TRAP and cathepsins B, L, S, and K, and may represent blood-derived macrophages pushed toward an osteoclast phenotype.

Cathepsin B↗
PubMed2006

Neural lineages of the Drosophila brain: a three-dimensional digital atlas of the pattern of lineage location and projection at the late larval stage.

The late larval brain consists of embryonically produced primary neurons forming a deep core cortex, surrounded at the surface by approximately 100 secondary lineages. Each secondary lineage forms a tract (secondary lineage tract) with an invariant and characteristic trajectory. Within the neuropile, tracts of neighboring lineages bundle together to form secondary tract systems. In this paper, we visualized secondary lineages by the global marker BP106 (neurotactin), as well as green fluorescent protein-labeled clones and thereby establish a comprehensive digital atlas of secondary lineages. The information contained in this atlas is the location of the lineage within the cortex, the neuropile compartment contacted by the lineage tract, and the projection pattern of the lineage tract within the neuropile. We have digitally mapped the expression pattern of three genes, sine oculis, period, and engrailed into the lineage atlas. The atlas will enable us and others to analyze the phenotype of mutant clones in the larval brain. Mutant clones can only be interpreted if the corresponding wild-type clone is well characterized, and our lineage atlas, which visualizes all wild-type lineages, will provide this information. Secondly, secondary lineage tracts form a scaffold of connections in the neuropile that foreshadows adult nerve connections. Thus, starting from the larval atlas and proceeding forward through pupal development, one will be able to reconstruct adult brain connectivity at a high level of resolution. Third, the atlas can serve as a repository for genes expressed in lineage-specific patterns.

Anatomy, Artistic↗
PubMed1999

Hereditary homozygous heparin cofactor II deficiency and the risk of developing venous thrombosis.

Heparin cofactor II (HCII) is a specific inhibitor of thrombin in the presence of heparin or dermatan sulphate. Although there have been reports on families in which a heterozygous HCII deficiency is associated with thromboembolic events, several epidemiological studies revealed that heterozygous HCII deficiency is as prevalent among healthy subjects as it is among patients with deep venous thrombosis (DVT). It is therefore not yet clear whether HCII is or is not a thrombotic risk factor. We analyze and describe in an extended family the biochemical and genetic thrombophilic risk factors and evaluate the potential thrombotic risk involved in homozygous and heterozygous HCII deficiency, either alone or associated with other thrombotic or circumstantial risk factors. The propositus has had three episodes of DVT and a pulmonary embolism. During the first episode of DVT the patient was diagnosed as having AT deficiency. Later, a functional and antigenic HCII deficiency, compatible with the homozygous form, was detected. The family study shows that both the propositus and her sister have homozygous HCII deficiency and that 12 of the 27 family members have heterozygous HCII deficiency. This is possibly the first case report on a homozygous phenotype for the HCII deficiency with. in addition, partial AT deficiency. The propositus has suffered several thrombotic events, unlike the other 12 family members with heterozygous HCII deficiency and her sister, who is also homozygous for this disorder. We suggest that HCII deficiency may play a limited in vivo role as a thrombotic risk factor unless associated with AT deficiency or another congenital thrombotic risk factor.

Adolescent↗
PubMedDate not supplied

[Heredity and environment in the genesis, epigenesis and evolution of the orofacial area].

Genetic and evolutionary aspects of the dento-facial complex are described according to the concept of heredity as a force of preservation for the human species, though ruled by natural selection and by mutational changes. Ontogenesis and growth of the oral structures reflect mutual regulations between genes and environmental factors. Therefore, the authors carry out an analysis of environmental and constitutional factors affecting dental and facial development. Three levels are identified: individual morphogenesis and growth; actual heredity of parietal dento-facial traits; role and meaning of teeth, jaws and temporo-mandibular joint during evolution leading to Homo sapiens sapiens. As far as individual development is concerned, genes provide only the input for initial cell proliferation and/or differentiation. Further on, growth and morphogenesis of oro-facial structures takes place by means of cell-to-cell and cell-to-substrate interactions. The final, structural result is due to reciprocal interactions among developing structures: muscles modify bone, teeth alignment influences bony bases alignment, ecc. Each structure is genetically determined (teeth, bones, muscles) and each structure carries out epigenetic regulations on other structures: no structure is secluded from biological function of the organism. The inheritance of oro-facial "traits", then, is hardly valuable. First of all, "traits" actually do not exist: they are the product of complex, multifactorial biological mechanisms. Moreover, facial characteristics are affected by polygenic regulation, each gene often showing pleiotropic effects. It has been calculated that 85-90% of facial dimensions in due to epigenetic modifications. Evolution and phylogenesis give evidence about the deep environmental influence on oro-facial morphology. Apart from certain molecular features regarding tooth structure (several dental proteins are today the same as those of the first Vertebrates who lived 500 millions of years ago), tooth number, form, and size depend upon environmental factors. Therefore, dentistry has the important task to preserve fundamental characteristics of dentition, and to intercept environmental pathogenetic factors, as dentition represents a precious instrument for the survival of the human species.

Biological Evolution↗
PubMed1993

Expression of neuronal and glial polypeptides during histogenesis of the human cerebellar cortex including observations on the dentate nucleus.

In order to gain a more complete understanding of the sequential pattern of gene expression during neurogenesis and gliogenesis in humans, we followed the expression of well-characterized, developmentally regulated polypeptides in the cerebellar cortex and dentate nucleus by immunohistochemistry using monoclonal antibodies of highly defined specificity. At 8-10 weeks gestational age (GA), progenitor cells and their immediate progeny in the rhombencephalic ventricular zone expressed vimentin and nestin and, to a lesser extent, microtubule-associated protein 5 (MAP5) and glial fibrillary acidic protein (GFAP), but not the low affinity nerve growth factor receptor (NGFR). In contrast, postmitotic, migrating immature neurons in the intermediate zone gave strong reactions for MAP2, tau, and a nonphosphorylated form of middle molecular weight neurofilament (NF) protein (NF-M) and weak reactivity for NGFR. At 15 weeks GA, proliferating cells of the superficial part of the cerebellar external granular layer stained only for NGFR, while more deeply situated cells of the external granular layer stained positively for NGFR, MAP2, MAP5, tau, and chromogranin A, which correlates with the early outgrowth of parallel fibers. All phosphoisoforms of NF-M as well as the low (NF-L) and high (NF-H) molecular weight NF proteins and alpha-internexin were expressed in the somatodendritic domain of Purkinje cells and dentate nucleus neurons from about 20 weeks GA with a gradual compartmentalization of highly phosphorylated forms of NF-M and NF-H into axons by the end of gestation. Alpha-internexin was also expressed strongly in axons of the deep white matter from 20 weeks GA to adulthood. MAP2, synaptophysin, and NGFR showed early, transient expression in the somatodendritic domain of Purkinje cells followed by the appearance of a 220 kDa nestin-like peptide that continued to be expressed in adult Purkinje cells. Notably, developing dentate nucleus neurons expressed many of these proteins in a similar temporal sequence. Early in the developing cerebellar cortex, the expression of NF protein and synaptophysin occurred in discrete patches or columns similar to those described for other antigens (i.e., zebrins). Finally, radial glia were positive for vimentin, GFAP, and nestin from 8 weeks GA to 8 months postnatal. This study describes the distinct molecular programs of lineage commitment in cerebellar progenitor cells and in differentiating neurons and astrocytes of the human cerebellum. The acquisition of a mature molecular neuronal phenotype correlates with the establishment of structural polarity in cerebellar neurons.

Aging↗
PubMed2004

Reinekea marinisedimentorum gen. nov., sp. nov., a novel gammaproteobacterium from marine coastal sediments.

A Gram-negative, oxidase- and catalase-positive, rod-shaped bacterium, designated strain KMM 3655(T), was isolated from a coastal marine sediment sample. The novel bacterium required sodium ions for growth and grew between 0.5 and 5 % NaCl and at 4-37 degrees C, but not at 40 degrees C. It reduced nitrate, formed acids from glucose under aerobic and anaerobic conditions, utilized a limited spectrum of organic substrates and did not produce gelatinase, caseinase, amylase or chitinase. The major isoprenoid quinone was Q8. Polar lipids consisted of phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol and an unknown phospholipid. Fatty acid analysis of strain KMM 3655(T) revealed C(16 : 0), C(16 : 1)omega7c and C(18 : 1)omega7c as predominant components. The G+C content of the DNA was 51.1 mol%. Phylogenetic analysis of the 16S rDNA sequence placed the new isolate within the gamma-Proteobacteria as a separate deep branch, with about 90 % sequence similarity to representatives of the genus Oceanospirillum and other remotely related genera. Combined phylogenetic and physiological data show that the new marine sediment isolate, KMM 3655(T), represents a novel genus and species, for which the name Reinekea marinisedimentorum gen. nov., sp. nov. is proposed. The type strain is KMM 3655(T) (=DSM 15388(T)).

Base Composition↗
PubMed2004

Functional conservation and divergence of intersex, a gene required for female differentiation in Drosophila melanogaster.

In Drosophila melanogaster, somatic sexual differentiation is regulated by a well characterized genetic hierarchy, by which the ratio of X chromosomes to autosomes (X:A) ultimately directs the deployment of sex-specific transcription factors encoded by doublesex (dsx) and fruitless (fru). In other dipterans, the X:A ratio is not the primary sex-determination signal. Correspondingly, the Drosophila hierarchy is not fully conserved. In all non-drosophilid fly species examined, Sex-lethal (Sxl), the master switch at the top of the Drosophila hierarchy, does not control somatic sex. This rapid divergence contrasts with the apparently deep conservation of dsx, which in Drosophila controls virtually all aspects of somatic sex except for male courtship behavior (which is controlled by fru). Sex-specific dsx mRNAs have been reported in Diptera, Lepidoptera and Hymenoptera, and dsx homologs in nematodes and mammals are required for aspects of male differentiation. Thus, it seems that the bottom of the hierarchy is rather ancient, especially compared with the top. To test this, we cloned insect and vertebrate homologs of the Drosophila gene intersex (ix), which functions together with dsx at the bottom of the hierarchy in females. When expressed in D. melanogaster females mutant at the endogenous ix gene, dipteran and lepidopteran ix homologs restore proper sexual differentiation, substantiating the hypothesis that ix, like dsx, is broadly conserved. When the mouse homolog is expressed it produces a dominant-negative phenotype suggesting partial functional divergence. Our results raise the possibility that a functional association between ix- and dsx-related gene products existed before the origin of the bifunctional dsx gene used in insect sex determination.

Amino Acid Sequence↗
PubMed2001

Specific migratory dendritic cells rapidly transport antigen from the airways to the thoracic lymph nodes.

Antigen transport from the airway mucosa to the thoracic lymph nodes (TLNs) was studied in vivo by intratracheal instillation of fluorescein isothiocyanate (FITC)-conjugated macromolecules. After instillation, FITC(+) cells with stellate morphology were found deep in the TLN T cell area. Using flow cytometry, an FITC signal was exclusively detected in CD11c(med-hi)/major histocompatibility complex class II (MHCII)(hi) cells, representing migratory airway-derived lymph node dendritic cells (AW-LNDCs). No FITC signal accumulated in lymphocytes and in a CD11c(hi)MHCII(med) DC group containing a CD8 alpha(hi) subset (non-airway-derived [NAW]-LNDCs). Sorted AW-LNDCs showed long MHCII(bright) cytoplasmic processes and intracytoplasmatic FITC(+) granules. The fraction of FITC(+) AW-LNDCs peaked after 24 h and had reached baseline by day 7. AW-LNDCs were depleted by 7 d of ganciclovir treatment in thymidine kinase transgenic mice, resulting in a strong reduction of FITC-macromolecule transport into the TLNs. Compared with intrapulmonary DCs, AW-LNDCs had a mature phenotype and upregulated levels of MHCII, B7-2, CD40, and intracellular adhesion molecule (ICAM)-1. In addition, sorted AW-LNDCs from FITC-ovalbumin (OVA)-instilled animals strongly presented OVA to OVA-TCR transgenic T cells. These results validate the unique sentinel role of airway DCs, picking up antigen in the airways and delivering it in an immunogenic form to the T cells in the TLNs.

Animals↗
PubMed2002

Fulvimonas soli gen. nov., sp. nov., a gamma-proteobacterium isolated from soil after enrichment on acetylated starch plastic.

Six deep-yellow-pigmented strains were isolated from soil after enrichment on plasticized acetylated starch granules as a source of carbon. They showed very similar and unique fatty acid profiles, consisting almost exclusively of branched fatty acids. The strains consisted of small, motile rods, were oxidase- and catalase-positive, did not ferment sugars and were able to depolymerize starch and suspended acetylated starch in overlayer plates. The 16S rDNA sequence of a representative strain, strain LMG 19981T, showed 96.7% sequence similarity to that of Rhodanobacter lindaniclasticus, 96.0% to that of Frateuria aurantia and less than 92% to sequences of other members of the gamma-Proteobacteria. Repetitive extragenic palindromic DNA PCR fingerprinting revealed two groups, representatives of which showed 93% DNA-DNA reassociation with each other and less than 10% with Frateuria aurantia LMG 1558T. On the basis of phenotypic characteristics and the G+C content of the DNA, the strains could be differentiated from Frateuria aurantia and Rhodanobacter lindaniclasticus. The name Fulvimonas soli gen. nov., sp. nov. is proposed, with the type strain LMG 19981T (= DSM 14263T).

Acetylation↗
PubMed2003

Isolation of a methanogen from deep marine sediments that contain methane hydrates, and description of Methanoculleus submarinus sp. nov.

We isolated a methanogen from deep in the sediments of the Nankai Trough off the eastern coast of Japan. At the sampling site, the water was 950 m deep and the sediment core was collected at 247 m below the sediment surface. The isolated methanogen was named Nankai-1. Cells of Nankai-1 were nonmotile and highly irregular coccoids (average diameter, 0.8 to 2 micro m) and grew with hydrogen or formate as a catabolic substrate. Cells required acetate as a carbon source. Yeast extract and peptones were not required but increased the growth rate. The cells were mesophilic, growing most rapidly at 45 degrees C (no growth at </=10 degrees C or >/=55 degrees C). Cells grew with a maximum specific growth rate of 2.43 day(-1) at 45 degrees C. Cells grew at pH values between 5.0 and 8.7 but did not grow at pH 4.7 or 9.0. Strain Nankai-1 grew in a wide range of salinities, from 0.1 to 1.5 M Na(+). The described phenotypic characteristics of this novel isolate were consistent with the in situ environment of the Nankai Trough. This is the first report of a methanogenic isolate from methane hydrate-bearing sediments. Phylogenetic analysis of its 16S rRNA gene sequence indicated that it is most closely related to Methanoculleus marisnigri (99.1% sequence similarity), but DNA hybridization experiments indicated a DNA sequence similarity of only 49%. Strain Nankai-1 was also found to be phenotypically similar to M. marisnigri, but two major phenotypic differences were found: strain Nankai-1 does not require peptones, and it grows fastest at a much higher temperature. We propose a new species, Methanoculleus submarinus, with strain Nankai-1 as the type strain.

Culture Media↗
PubMed2001

Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes.

OBJECTIVE: To examine by immunohistochemistry the relative distributions of 6 matrix metalloproteinases (MMPs 1, 2, 3, 8, 9, and 13) and the 2 proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) in osteoarthritic (OA) cartilage compared with normal, age-matched articular cartilage. METHODS: Articular cartilage samples were obtained from the tibial plateau of OA knees removed at arthroplasty and from normal, nonarthritic, knees obtained at autopsy. Specimens were promptly fixed in Carnoy's fixative, processed, embedded in paraffin, sectioned, and examined by immunohistochemistry for MMP and cytokine production. In addition, human articular chondrocytes (HAC) were treated in vitro with either IL-1beta, TNFalpha, or phorbol myristate acetate (PMA) to assess their potential to produce each of the MMPs, as determined by Western blotting and gelatin zymography. RESULTS: Immunodetection of the collagenases (MMPs 1, 8, and 13) and stromelysin 1 (MMP-3) was demonstrated in a proportion of chondrocytes in the superficial zone of almost all of the OA specimens that had degenerative matrix changes. The gelatinases (MMPs 2 and 9) were also demonstrated by immunohistochemistry but were not so prominent. IL-1beta- and TNFalpha-positive chondrocytes were also observed in a proportion of cells in the superficial zones of OA specimens. Much less immunostaining for MMPs and cytokines was observed in the deep zone of all OA specimens, where the cartilage matrix and chondrocyte morphology appeared normal. In contrast, full-thickness normal cartilage specimens showed virtually no immunostaining for these MMPs or cytokines. Confirmation that chondrocytes can produce these 6 MMPs was obtained from HAC cultures treated with either IL-1beta, TNFalpha, or PMA; conditioned medium from activated HAC contained all the MMPs demonstrated by immunohistochemistry. Dual immunolocalization studies of OA cartilage specimens demonstrated the coexpression of IL-1 with MMP-8 by individual chondrocytes in situ. CONCLUSION: These results indicate that the superficial zone of OA cartilage specimens, which is characterized by fibrillations, chondrocyte clusters, and degenerative matrix changes, contains a variable proportion of cells that immunostain for IL-1beta, TNFalpha, and 6 different MMPs. These observations support the concept that cytokine-MMP associations reflect a modified chondrocyte phenotype and an intrinsic process of cartilage degradation in OA.

Aged↗
PubMed2000

A family with X-linked dominant Charcot-Marie-Tooth caused by a connexin32 mutation.

A family with a hereditary peripheral neuropathy is presented. Pedigree analysis suggested X-linked dominant mode of inheritance. The index patient became symptomatic at the age of 12 years. Clinical examination at 14 years revealed footdrop on the left, bilateral pes cavus, slight atrophy of thenar eminences, decreased muscle strength in both legs and brisk deep tendon reflexes. Electrophysiological studies were compatible with an axonal neuropathy. A novel point mutation located in codon 126 of the connexin32 gene, substituting a histidine for a tyrosine, was found in the index patient, in the mother, in two sisters and in a brother. The mother and the eldest sister had pes cavus bilaterally although they were asymptomatic. The younger brother and sister showed no signs of the disease.

Adolescent↗
PubMed2005

Evidence for repatterning of the gastric fundic epithelium associated with Ménétrier's disease and TGFalpha overexpression.

BACKGROUND & AIMS: Increase of intramucosal transforming growth factor alpha (TGFalpha) levels in the gastric fundus leads to oxyntic atrophy and massive foveolar hyperplasia in both metallothionein (MT)-TGFalpha mice and patients with Ménétrier's disease. We have evaluated the hypothesis that increased levels of TGFalpha in the fundus induces an antral pattern of cell differentiation in fundic glands by studying Pdx1, a transcription factor whose expression normally is confined to the gastric antrum. METHODS: Induction of Pdx1 expression was evaluated in Pdx1(lacZ/+)/MT-TGFalpha bigenic mice treated with zinc. The distribution of Pdx1 in MT-TGFalpha mice and Ménétrier's disease patients was evaluated with anti-Pdx1 antibodies. Transcript levels were evaluated by quantitative polymerase chain reaction in mouse and human tissues and AGS cells. RESULTS: In Pdx1(lacZ/+) mice, Pdx1 was expressed in antral mucosal cells including gastrin cells and TFF2-expressing deep glandular mucous cells. Zinc treatment for 2 to 8 weeks in Pdx1(lacZ/+)/MT-TGFalpha transgenic mice resulted in expression of Pdx1 throughout the fundus. No ectopic fundic Pdx1 expression was observed in either H. felis-infected or DMP777-treated mice. In MT-TGFalpha mice, 8 weeks of zinc treatment elicited nuclear Pdx1 staining throughout the fundic mucosa. TGFalpha treatment in AGS cells led to increases in Pdx1 and gastrin messenger RNA expression. Fundic sections from Ménétrier's disease patients showed nuclear Pdx1 staining throughout the fundic glands. Treatment of a Ménétrier's disease patient with an anti-epidermal growth factor receptor monoclonal antibody reduced fundic expression of both Pdx1 and gastrin. CONCLUSIONS: Overexpression of TGFalpha in MT-TGFalpha mice and Ménétrier's disease patients elicits ectopic expression in the fundus of Pdx1, consistent with the phenotype of antralization.

Animals↗
PubMed2005

Morphological divergence and origin of sympatric populations of European whitefish (Coregonus lavaretus L.) in Lake Femund, Norway.

Combining morphological and genetic analysis, we compared patterns of diversification within and between morphs among sympatric European whitefish (Coregonus lavaretus L.) populations in Lake Femund, Norway. Seven external populations, from potential colonization routes into Lake Femund were included. We found that deep-, shallow-, river- and bay spawning populations are distinct morphs in Lake Femund. Within morphs, populations range from being similar genetically (Fst=0-0.005) among deep-spawning populations to being highly differentiated (Fst=0.153) between bay-spawning populations. Between morphs, genetic differences ranged from a low (Fst=0.008-0.022) between deep- and shallow-spawning populations to high difference (Fst=0.125-0.143) between shallow- and bay-spawning populations. A higher proportion of molecular variance was seen among (3.9%) than within morphs (2.8%). The adaptive gene combinations behind the four morphs seem to have originated within the lake, although the lake could have been colonized from more than one source population.

Adaptation, Physiological↗
PubMed2000

Development and therapeutic effect of adoptively transferred T cells primed by tumor lysate-pulsed autologous dendritic cells in a patient with metastatic endometrial cancer.

We describe a 65-year-old woman with a large surgically unresectable and chemoresistant liver metastasis of endometrial carcinoma who was treated by infusion with peripheral blood T cells stimulated with tumor lysate-pulsed autologous dendritic cells (DC). Extensive in vitro characterization of the DC-activated T cells included phenotypic analysis, cytotoxicity, and intracellular cytokine secretion. High cytotoxicity was observed against autologous tumor cells, but not against NK-sensitive K562 cells, autologous Con-A lymphoblasts, or autologous Epstein-Barr virus-transformed lymphoblastoid cells. Blocking studies demonstrated that lytic activity was HLA class I restricted. Two-color flow cytometric analysis revealed that a significant proportion of CD8+ T cells was also CD56+, and analysis of intracellular IFN-gamma and IL-4 expression suggested a type 1 cytokine bias. The patient was treated by three infusions of tumor-specific T cells at 3- to 4-week intervals, and in vivo distribution of the T cells was followed by (111)In oxine labeling and serial gamma camera imaging. Tumor localization and accumulation of labeled lymphocytes was consistently detected at serial time points following each injection. However, deep infiltration of the large tumor mass by activated T cells was minimal, as evaluated in 3 dimensions by single photon emission computerized tomography (SPECT) imaging. Transient serum increases of the tumor marker lactate dehydrogenase (LDH), were detectable after each injection. Similar posttreatment elevations were seen for serum uric acid and potassium. Clinically, stabilization of the large liver metastasis was obtained during treatment. Collectively, these results indicate that tumor-specific CD8+ cytotoxic T-cell responses can be generated in patients with endometrial cancer, and suggest that T-cell immunotherapy may be of therapeutic value in patients harboring metastatic disease.

Aged↗
PubMed2026

CD109 exhibits a dynamic expression pattern in coronary endothelium and endocardial-derived valve mesenchyme during heart development with preserved morphogenesis following endothelial-specific deletion.

BACKGROUND: CD109 encodes a GPI-linked glycoprotein that acts as a signaling modulator in the TGF-&#x3b2; pathway. CD109 has emerged in several genome-wide association studies as linked to coronary artery disease, myocardial infarction, and angina pectoris. Heterozygous loss-of-function mutations in CD109 have also been reported in patients with congenital heart defects, suggesting potential developmental relevance, though CD109 has never been investigated in the context of cardiovascular development. We previously identified Cd109 upregulation in murine atrioventricular valves undergoing myxomatous degeneration following a reduction of epicardial-derived cells. Here, we characterize Cd109 expression in the murine cardiovascular system and assess its function during development using in vitro and in vivo approaches. RESULTS: We found that Cd109 is strongly expressed in the endothelium of the coronary vasculature and in endocardial-derived subpopulations in the atrioventricular valves. This expression persists through key stages in cardiovascular development. Western blotting and immunostaining confirm endothelial expression in heart and lung tissues. siRNA-mediated knockdown of CD109 in primary human endothelial cells led to dysregulation of vascular development pathways and decreased tube formation capacity. We generated endothelial-specific Cd109 knockout mice, eliminating Cd109 expression from heart and lung tissues without overt consequences for atrioventricular valve or coronary vascular morphogenesis during heart development. CONCLUSION: CD109 exhibits a highly dynamic spatiotemporal expression pattern during cardiovascular development, with enriched expression in coronary endothelial cells and endocardial-derived subpopulations in the valves. Despite this striking developmental expression pattern, previously reported human genetic associations with cardiovascular diseases, and endothelial-associated phenotypes following siRNA-mediated CD109 knockdown in a primary human endothelial cell line, endothelial/endocardial-lineage deletion of Cd109 did not produce overt abnormalities in atrioventricular valve or coronary vascular morphogenesis during embryonic development. Collectively, these findings identify CD109 as a useful marker of coronary endothelial and endocardial-derived valve cell populations and suggest that CD109 may function in a context-dependent or modulatory manner rather than as an essential regulator of cardiovascular morphogenesis under normal developmental conditions.

CD109↗
PubMed1995

[An autopsy case of corticobasal degeneration clinically misdiagnosed as Pick's disease].

We report a 69-year-old woman who was clinically diagnosed as having a frontal lobe-type of Pick's disease. The initial symptoms were personality changes and problematic behaviors. The patient showed intellectual decline, "stehende Redensarten" and abnormal attitude in interpersonal situations such as inattentiveness and indifference in the course of the disease. Brain CT revealed a marked atrophy of the frontal lobes. In the terminal stage the patient had severe dementia, mutism, parkinsonism and cervical dystonia. Neuropathologically, there was a marked atrophy of the frontal lobes. The superior frontal gyrus was most severely atrophic. Histological study revealed mild to moderate loss of neurons, hyperplasia of protoplasmic astrocytes and many balooned neurons in the deep layers of the atrophied cerebral cortex. Severe neuronal loss was even seen only in a part of the superior frontal gyrus. The cerebral white manner showed marked diffuse fibrillary gliosis. There was neuronal loss with gliosis in the thalamus, lentiform nucleus, subthalamic nucleus, substantia nigra and inferior olivary nucleus. Marked gliosis was seen in the midbrain and pontine tegmentum. Sections from several levels of the spinal cord also showed marked gliosis of the gray matter. Antibodies against human tau stained massive argyrophilic thread-like structures and oligodendroglial microtubular masses in the affected lesions. Neurofibrillary tangles were localized in the hippocampus and parahippocampal region. Neither Pick's body nor senile plaque were observed. Corticobasal degeneration (CBD) is a neurodegenerative disease initially presenting with unilateral motor disturbances. Typical initial symptoms are rigidity, akinesia and apraxia of an affected arm. The clinical phenotype might depend upon the affected areas of the cerebral cortex. Our patient initially exhibited personality changes and was clinically diagnosed as having Pick's disease. Although our case had unusual distribution pattern of the cerebral atrophy, it was pathologically diagnosed as CBD. The review of the literature suggests the presence of clinical varieties in CBD.

Aged↗