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PubMed2005

Involvement of gap junctions in placental functions and development.

Connexin (Cx) expression and gap junctional intercellular communication (GJIC) are involved in development and differentiation processes. Mediating exchanges between mother and fetus, the placenta is formed when fetal membranes are apposed or even fusing or destroying the uterine mucosa. Therefore, an extraordinary variability of placental structures is observed throughout the mammalian species. This variability affect mainly, the maternofetal blood flow interrelationships, the kind and number of tissue layers separating maternal and fetal bloods, the trophoblast invasiveness and the formation of a syncytium (syncytiotrophoblast). Here, the expression, the localisation and the possible role of Cx and GJIC in placental functions and development are discussed. In rodents, gene knock out in mice have vastly improved our understanding of the role of Cx genes in mouse placental development: Cx26 in transplacental uptake of glucose, Cx31 in the proliferative process of trophoblastic cells and Cx45 in placental vascularisation. In human, it appears that Cx43 allows a GJIC required for the fusion process of cytotrophoblastic cells leading to the formation of the syncytiotrophoblast, the site of the numerous placental functions. On other hands, Cx40 plays a critical role in the switch from a proliferative to an invasive phenotype of the trophoblastic cells invading the endometrium. Owing to the striking diversity of Cx expression in placental structures, we must be careful when extrapolating findings from one species to another.

Animals↗

PubMed2004

A retrotransposon-like element and its occurrence in British Columbia populations of Chondrostereum purpureum.

Repetitive DNA elements discovered in the basidiomycete Chondrostereum purpureum were characterized and validated for use as genetic markers. Regions of these marker sequences were similar to retrotransposon and retrotransposon-like sequences, as indicated by BLAST searches of NCBI databases. These sequences occur in multiple DNA fragments of variable length in a given C. purpureum isolate, and thus can serve as strain-specific genetic markers. The segregation of the markers within a progeny set demonstrated their stability through meiosis. The population structure of C. purpureum was assessed using the markers. There was no evidence of a barrier to gene flow between C. purpureum populations separated by 1400 km and no indication of population sub-structuring based on host or geographical source of isolate. Repetitive fragments were amplified from four other species, suggesting the occurrence of these retrotransposon-like elements in other basidiomycetes and the potential utility of these markers for other fungi.

Agaricales↗

PubMed2006

Inbreeding and reproduction in endangered ungulates: preservation of genetic variation through the Organization of Genetic Resource Banks.

There is a constant increase in the number of species suffering marked reductions in population size. This reduction in size and the lack of genetic flow may lead to a decrease in genetic variability and to matings between close relatives (i.e. inbreeding) with an ensuing reduction in fitness. It is thus important to understand the mechanism underlying the deleterious effects of inbreeding and to develop reproductive biotechnologies that will allow the reduction of inbreeding depression by facilitating gene exchange between populations. The study of three endangered species of gazelles, Cuvier's gazelle (Gazella cuvieri), Mohor gazelle (Gazella dama mhorr) and dorcas gazelle (Gazella dorcas neglecta) has revealed that inbreeding negatively affects several semen parameters (motility, sperm morphology, acrosome integrity). Semen cryopreservation has been achieved in the three species but success varies depending on the diluent employed and the level of inbreeding. Artificial insemination of Mohor gazelles have led to the birth of the first gazelle born using frozen-thawed semen but improvements are needed before this technology can be applied on a routine basis for the genetic management of the populations. Collection of oocytes after ovarian stimulation, followed by in vitro maturation, fertilization and culture has met with some initial success in the Mohor gazelle. These, together with other reproductive technologies, will offer an invaluable help in preserving the maximum of genetic diversity of these and related endangered ungulate species.

Animals↗

PubMed2004

Microsatellite DNA variation reveals high gene flow and panmictic populations in the Adriatic shared stocks of the European squid and cuttlefish (Cephalopoda).

In the semienclosed Adriatic Sea, the shared stocks of the cephalopods Loligo vulgaris and Sepia officinalis represent important marine fisheries resources exploited by all coastal countries. The improving of knowledge on the demographic features of these shared stocks is internationally relevant for adopting responsible management and conservation of these marine resources. Analyses of microsatellite variation in geographical samples collected from all parts of the Adriatic Sea were performed using arrays of species-specific di-nucleotide and tri-nucleotide loci. In L. vulgaris the level of genetic variability was consistent with that observed in other loliginid species, whereas the S. officinalis stock showed a microsatellite variation markedly lower than that estimated for the Atlantic and Mediterranean populations collected around the Iberian peninsula. The weak spatial genetic differentiation, the discordant results of the genetic divergence estimators and the lack of any geographical cline in the spatial genetic differences suggest the occurrence of single genetically homogeneous populations within the Adriatic stocks of both species, recommending a coordinated management of the squid and cuttlefish by the Adriatic fishing countries. On the contrary, significant differences detected in temporal replicates of S. officinalis might suggest that allelic frequency can change relating to reproductive behaviour.

Animals↗

PubMed1989

Characterization of a human T cell-specific chimeric antibody (CD7) with human constant and mouse variable regions.

A chimeric human-mouse anti-T lymphocyte mAb (CHT2; SDZ 214-380) has been constructed by cloning the variable region exons of both the L and H chains from the murine hybridoma RFT2 which have CD7 specificity and reactivity with a 40-kDa Ag. The variable L chain exon was joined to the human C kappa, and the variable H chain exon was joined to the human IgG1 region exon encoding the human allotype nGlm(z), nGlm(a). The gene constructs were introduced by electroporation into SP2/0, a non-Ig-producing murine myeloma. The identical tissue reactivity of the newly made CHT2 and the original murine RFT2 mAb (CD7) was confirmed by blocking experiments as well as by immunohistology and flow cytometry. Because this new mAb may have clinical use, the CD7 Ag expression of T lineage cells has also been quantitated in double and triple immunofluorescence assays in combinations with mAb to restricted forms of leukocyte common Ag that designate unprimed (CD45R+) and primed T lymphocyte populations (UCHL1+). CHT2 shows very strong reactivity with large thymic blast cells and cortical thymocytes from which T-ALL originates. Strong staining is seen on CD45R+ unprimed "virgin" T lymphocytes, whereas the expression on UCHL1+ primed "memory" cell types is weaker unless these cells are reactivated by mitogens or Ag. Thus CHT2 may spare a substantial population of resting memory T cells which is relevant to its potential therapeutic use. In addition the chimeric antibody had a greater in vitro antibody dependent cytotoxicity and a prolonged half-life (4.2 to 5.0 days) in Rhesus monkeys.

Amino Acid Sequence↗

PubMed1991

Microinjections of calcitonin gene-related peptide within the trigeminal subnucleus caudalis of the cat affects adrenal and autonomic function.

To assess the role of calcitonin gene-related peptide (CGRP) within the trigeminal subnucleus caudalis (Vc) on adrenal and autonomic function, microinjections were directed at different laminae of Vc in chloralose-anesthetized cats. Microinjections of CGRP (5 pmol, 100 nl) into laminae I-II increased significantly the adrenal secretion of epinephrine, adrenal blood flow, adrenal vascular conductance, mean arterial pressure and heart rate. Injections of CGRP into laminae V-VI decreased significantly the adrenal secretion of epinephrine, however, other measured variables were not affected. To examine if CGRP interacts with substance P within Vc to modify adrenal and autonomic function, subthreshold doses of each peptide were injected alone and simultaneously. Combined subthreshold doses of CGRP and substance P injected into laminae V-VI, but not into laminae I-II or III-IV, evoked increases in arterial pressure and in heart rate that exceeded the responses seen after injection of either peptide alone. The adrenal secretion of catecholamines was not affected by individual or combined subthreshold doses of either peptide, regardless of the laminar site of injection. These data suggest that release of CGRP within laminae I-II of Vc alters adrenal and autonomic function via mechanisms separate from those that mediate substance P-evoked responses. In contrast, CGRP and substance P may act, at least in part, through a common neural substrate within the deeper laminae of Vc to modify arterial pressure and heart rate. Thus, multiple subpopulations of peptide-responsive neurons in the medullary dorsal horn likely contribute to the reflex adrenal and autonomic responses that often accompany nociception.

Adrenal Glands↗

PubMed2005

Population genetic structure of two columnar cacti with a patchy distribution in eastern Brazil.

The genetic variability and population genetic structure of six populations of Praecereus euchlorus and Pilosocereus machrisii were investigated. The genetic variability in single populations of Pilosocereus vilaboensis, Pilosocereus aureispinus, and Facheiroa squamosa was also examined. All of these cacti species have a patchy geographic distribution in which they are restricted to small areas of xeric habitats in eastern Brazil. An analysis of genetic structure was used to gain insights into the historical mechanisms responsible for the patchy distribution of P. euchlorus and P. machrisii. High genetic variability was found at the populational level in all species (P=58.9-92.8%, A(p)=2.34-3.33, H(e)=0.266-0.401), and did not support our expectations of low variability based on the small population size. Substantial inbreeding was detected within populations (F(IS)=0.370-0.623). In agreement with their insular distribution patterns, P. euchlorus and P. machrisii had a high genetic differentiation (F(ST)=0.484 and F(ST)=0.281, respectively), with no evidence of isolation by distance. Accordingly, estimates of gene flow (N(m)) calculated from F(ST) and private alleles were below the level of N(m)=1 in P. machrisii and P. euchlorus. These results favored historical fragmentation as the mechanism responsible for the patchy distribution of these two species. The genetic distance between P. machrisii and P. vilaboensis was not compatible with their taxonomic distinction, indicating a possible local speciation event in this genus, or the occurrence of introgression events.

Alleles↗

PubMed1999

The population genetic structure of a large temperate pollinator species, Bombus pascuorum (Scopoli) (Hymenoptera: Apidae)

The genetic population structure of the bumble bee Bombus pascuorum was studied using six microsatellite loci and a partial sequence of the mitochondrial gene cytochrome b. Eighteen populations from central and northern Europe were included in the analysis. Observed levels of genetic variability and heterozygosity were high. Estimates of population differentiation based on F- and phi-statistics revealed significant genetic differentiation among B. pascuorum populations and suggest that two partially isolated gene pools, separated by the Alps, do exist. The distribution of mtDNA haplo-types supports this view and presents direct evidence for gene flow across the Alps. Estimates of the number of migrants exchanged among populations north of the Alps suggest that historical events may have left a strong imprint on population structure.

Journal Article↗

PubMed1998

Yeast meiotic mutants proficient for the induction of ectopic recombination.

A screen was designed to identify Saccharomyces cerevisiae mutants that were defective in meiosis yet proficient for meiotic ectopic recombination in the return-to-growth protocol. Seven mutants alleles were isolated; two are important for chromosome synapsis (RED1, MEK1) and five function independently of recombination (SPO14, GSG1, SPOT8/MUM2, 3, 4). Similar to the spoT8-1 mutant, mum2 deletion strains do not undergo premeiotic DNA synthesis, arrest prior to the first meiotic division and fail to sporulate. Surprisingly, although DNA replication does not occur, mum2 mutants are induced for high levels of ectopic recombination. gsg1 diploids are reduced in their ability to complete premeiotic DNA synthesis and the meiotic divisions, and a small percentage of cells produce spores. mum3 mutants sporulate poorly and the spores produced are inviable. Finally, mum4-1 mutants produce inviable spores. The meiotic/sporulation defects of gsg1, mum2, and mum3 are not relieved by spo11 or spo13 mutations, indicating that the mutant defects are not dependent on the initiation of recombination or completion of both meiotic divisions. In contrast, the spore inviability of the mum4-1 mutant is rescued by the spo13 mutation. The mum4-1 spo13 mutant undergoes a single, predominantly equational division, suggesting that MUM4 functions at or prior to the first meiotic division. Although recombination is variably affected in the gsg1 and mum mutants, we hypothesize that these mutants define genes important for aspects of meiosis not directly related to recombination.

Alleles↗

PubMed1987

Biology of the people of Sikkim, India. 2. Colour blindness, ear lobe attachment, mid-phalangeal hair and behavioural traits.

14 population groups of Sikkim (India)--Lepchas (2), Bhutias (2), Sherpas, Tamangs, Gurungs, Mangars, Rais, Limboos/Subbas, Pradhans (Newars), Brahmans, Chhetris, Scheduled Castes--have been studied in regard of the intra- and intergroup variability of colour blindness, ear lobe attachment, mid-phalangeal hair and behavioural traits (tongue folding, hand clapsing, arm folding, leg folding, handedness). Some of these variables show a considerable distribution heterogeneity, which is discussed considering history and marriage patterns of these populations. As most of them are highly endogamous one can assume that this heterogeneity is caused by locally acting factors such as drift and/or founder effects, which could be preserved due to as good as lacking gene flow among the populations under study. Beyond that the Sikkim data are compared briefly with those reported for other Indian and Asiatic populations.

Color Vision Defects↗

PubMed2006

Chemotherapeutic agents enhance AAV2-mediated gene transfer into breast cancer cells promoting CD40 ligand-based immunotherapy.

PURPOSE: Supplementing conventional treatment with gene therapy to induce an immune response might be beneficial to cancer patients. In this study, we evaluated the efficiency of transduction of breast cancer cells with recombinant adeno-associated virus (rAAV) and effects of cytotoxic agents used in chemotherapy. Furthermore, the capacity of tumor cells expressing transgenic CD40 ligand (CD40L) to stimulate dendritic cells was measured. METHODS: Breast cancer cell lines were infected with a rAAV encoding the enhanced green fluorescent protein (EGFP) or murine CD40L and transgene expression was analyzed by flow cytometry. Stimulation of isolated human dendritic cells by CD40L-expressing tumor cells was quantified by measuring secreted interleukin 12. RESULTS: Infection with an EGFP-encoding rAAV resulted in variable fractions (14-93%, mean 42%) of transgene-expressing cells. Pre-incubation of MM 157, MM 231, and MCF7 cells with epirubicin or carboplatin substantially increased AAV-mediated transgene expression. rAAV/CD40L was used to generate CD40L-transgenic tumor cells, which specifically activated immature dendritic cells, as confirmed by blocking with an antibody binding to CD40L. CONCLUSIONS: The efficiency of rAAV-mediated gene transfer into breast cancer cells is significantly higher than previously reported and can be further enhanced by co-administration of chemotherapeutic agents. We also confirmed that breast cancer cells can activate human dendritic cells after infection with a CD40L-encoding rAAV.

Antineoplastic Agents↗

PubMed1993

Detection of hepatitis B virus in plasma using flow cytometric analyses of polymerase chain reaction-amplified DNA incorporating digoxigenin-11-dUTP.

Blood donations are routinely screened by multiple serologic assays for antigens/antibodies associated with infection by blood-borne viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency viruses (HIV-1 and HIV-2), and human T-cell lymphotropic virus (HTLV-I and HTLV-II). A direct detection of these viruses would be more effective for the prevention of transfusion-transmitted infections than the indirect measurement of the variable host immune response to these agents. Because the polymerase chain reaction (PCR) for viral gene amplification offers the most sensitive and direct means of detecting viruses in blood, we have developed a nonisotopic PCR procedure for the detection of HBV, chosen as a prototype. The problems, common to previously described PCR methods, of nucleic acid extraction and inhibition of the PCR by plasma proteins were overcome by isolation of HBV from plasma by means of 450-microns polystyrene beads covalently coated with monoclonal antibody to the Pre-S1 region of the viral envelope protein. Detergent lysis and proteinase K digestion of the immunocaptured virions isolated from plasma released the HBV DNA. A modified PCR-amplification protocol, incorporating digoxigenin-labeled dUTP in the amplified gene products followed by hybridization with a specific biotinylated oligonucleotide probe bound to streptavidin-coated 2.8-microns magnetic beads, allowed flow cytometric analyses of HBV-specific PCR products by means of antibodies to digoxigenin labeled with fluorescein isothiocyanate. The endpoint serial dilutions of pedigreed human plasma samples containing chimpanzee infectious dose (CID50) of 10(7) for adw and CID50 of 10(7.5) for the ayw subtypes were compared in repeated testing of PCR products by our immunoreactive bead (PCR-IRB) assay. HBV DNA was consistently detected in a 5 x 10(-10) dilution of each sample. In testing 20 coded specimens of blood donors, with or without serologic markers of HBV infection, the PCR-IRB was specific and more sensitive than the PCR analyses by slot blot hybridization with radioactive probe. The PCR-IRB assay can be adapted for simultaneous detection of multiple blood-borne viruses by an automated flow cytometric analysis system.

Bacterial Proteins↗

PubMed1993

Transient plant gene expression: a simple and reproducible method based on flowing particle gun.

Successful transient expression of beta-glucuronidase (Gus) and luciferase (Luc) in Nicotiana tabacum leaves was obtained after gene delivery by a simple and inexpensive particle gun. Takeuchi's biolistic process system was adapted to accelerate directly in a helium stream DNA-coated microprojectiles into intact plant leaf tissues. After bombardment of p70-omega-59Gus construction (duplication of the CaMV 35S enhancer), variability inherent to the bombardment procedure was observed in Gus activity measurements between replicate samples. We therefore included an internal standard (35S-Luc) in each bombardment, allowing an accurate, sensitive and reproducible comparison of the effective strength of different Gus-reporter constructs based on Gus/Luc ratio measurements.

Gene Expression↗

PubMed1999

Examination of the Montastraea annularis Species Complex (Cnidaria: Scleractinia) Using ITS and COI Sequences.

: The Caribbean coral Montastraea annularis has recently been proposed to be a complex of at least three sibling species. To test the validity of this proposal, we sequenced the ITS region of the nuclear ribosomal RNA gene family (ITS-1, 5.8S, and ITS-2), and a portion of the mitochondrial DNA gene cytochrome c oxidase subunit I (COI) from the three proposed species (M. annularis, M. faveolata, and M. franksi) from Florida reefs. The ITS fragment was 665 nucleotides long and had 19 variable sites, of which 6 were parsimony-informative sites. None of these sites was fixed within the proposed species. The COI fragment was 658 nucleotides long with only two sites variable in one individual. Thus, under both the biological species concept and the phylogenetic species concept, the molecular evidence gathered in this study indicates the Montastraea annularis species complex to be a single evolutionary entity as opposed to three distinct species. The three proposed Montastraea species can interbreed, ruling out prezygotic barriers to gene flow (biological species concept), and the criterion of monophyly is not satisfied if hybridization is occurring among taxa (phylogenetic species concept).

Journal Article↗

PubMed2005

Molecular mechanisms involved in robustness of yeast central metabolism against null mutations.

Adaptive strategies employed by the yeast Saccharomyces cerevisiae provide robustness and adaptability of its central metabolism. Since central metabolism in yeast has been well studied at the enzymatic and genetic levels, it represents an excellent system for evaluating the relative roles of duplicate genes and alternative metabolic pathways as possible mechanisms for the stability of central metabolism against null mutations. Yeast appears to employ a variety of mechanisms to ensure functional robustness of its central metabolism. Uninterrupted flow of energy and precursor metabolites through the pathways of central metabolism via glycolysis (EMP), pentose phosphate shunt (PPS), and the tricarboxylic acid (TCA) cycle are ensured by a variety of adaptive mechanisms. One of the most significant mechanisms appears to be gene duplication events that have produced a number of isozymes functioning under variable environmental and physiological conditions. Alternative pathways represent another important mechanism for increasing the robustness of the system. The robustness of the pathways of central metabolism is apparently higher than that of the other parts of metabolism, because of its exceptional importance to the organism's vitality. The proportion of duplicated viable genes also is substantially larger in central metabolism than that in a pool of other metabolic genes.

Citric Acid Cycle↗

PubMed2022

Identification of Novel Retinal Pericyte-Targeting rAAV Vectors Through Directed Evolution.

PURPOSE: Retinal pericytes play a vital role in maintaining retinal homeostasis, and their dysfunction underlies pathogenesis in such vascular eye diseases as diabetic retinopathy and wet age-related macular degeneration. Consequently, retinal pericytes are attractive therapeutic targets for gene therapy, but effectively targeting pericytes with recombinant adeno-associated virus (rAAV) vectors remains a challenge. METHODS: We introduced genetic modifications into the surface-exposed variable regions of the rAAV2/2 capsid to generate a complex library (>1 × 107) of capsid mutants that were then screened for preferential tropism toward retinal pericytes. Using the Tg(Cspg4-DsRed.T1)1Akik/J reporter mouse model, which has red fluorescent pericytes that can be isolated via flow cytometry in order to recover vector genomes, we performed three rounds of screening and identified seven putative mutants capable of transducing retinal pericytes. RESULTS: Following intravitreal administration of mutant vectors packaging ubiquitously expressing green fluorescent protein reporters and postmortem flow cytometry of enzymatically digested retinae, two mutants in particular, Peri-E and Peri-G, demonstrated significantly greater transduction of retinal pericytes than unmodified rAAV2/2 (1.4-fold and 2.8-fold, respectively). CONCLUSIONS: Although difficult to characterize the effect of each point mutation in the context of multiple amino acid variations from the wild-type AAV2 sequence, we identified several point mutations that may play critical roles in limiting HSPG binding, evading neutralization by murine A20 monoclonal antibodies, modulating antigenicity, and evading ubiquitination to ultimately improve transduction efficiency of retinal pericytes. TRANSLATIONAL RELEVANCE: Identification of novel retinal pericyte targeting rAAV vectors enables the development of new, long-lasting gene therapies for retinal diseases such as diabetic retinopathy and wet age-related macular degeneration.

Animals↗

PubMed2001

Non-M protein(s) on the cell wall and membrane of group A streptococci induce(s) IFN-gamma production by dermal CD4+ T cells in psoriasis.

Recently we have demonstrated that a disease-specific subpopulation of CD4+ T cells isolated from skin lesions of chronic plaque psoriasis produces interferon-gamma in response to group A streptococcal (GAS) antigens. To determine if these T cells recognize M or non-M protein, extracts from cell wall of type M6 GAS (M6W) and its isogenic M gene deletion mutant (M-W), M6 membrane extract (M6M) and recombinant M6 protein (rM6) were used to stimulate GAS-reactive T-cell lines from nine patients with chronic plaque psoriasis. T-cell lines were incubated with or without streptococcal extracts for 18 h in the presence of a transport inhibitor, stained for surface CD4 and intracellular cytokine expression, and analysed by flow cytometry. Variable numbers (0.2-34%) of CD4+ T cells produced interferon-gamma, in all but one of the T-cell lines tested, in response to M6W, M-W and M6M extracts. No significant difference between the response to M6W and M-W extracts was detected. In addition, rM6 protein failed to increase CD4+/interferon-gamma+ T-cell numbers in seven of nine T-cell lines compared to medium alone. For the group, there was a highly significant correlation between the responses to the three extracts (M6W vs M-W, P = 0.0005; M6W vs M6M, P = 0.0003; M-W vs M6M, P = 0.0001). Low or minimal numbers of interleukin-4- and interleukin-10-producing CD4+ T cells were occasionally induced. These findings suggest that a subpopulation of CD4+ T cells isolated from skin lesions of chronic plaque psoriasis patients produces interferon-gamma in response to non-M protein(s) present on the cell wall and membrane of GAS.

Adult↗

PubMed2005

Genetic structure and environmental heterogeneity in the European hake (Merluccius merluccius).

This study aimed at assessing the genetic structure and the state of the stocks of the European hake (Merluccius merluccius). To this end, 15 samples were taken from the whole range of the species and analysed using allozymes. Since 11 samples were taken from the poorly studied Mediterranean Sea, the results obtained provided a complete picture of the hake's genetic structure and an initial insight into its relationships with environmental features. Atlantic and Mediterranean hake populations are separated by the Almeria-Oran front. This area has been proved to be the boundary between Atlantic and Mediterranean stocks of many marine organisms, but some doubt exists concerning the efficaciousness of the local gyres as barriers to the gene flow. Our data have evidenced a latitudinal cline at loci Gapdh and Gpi-2 within the Mediterranean Sea, with a further steep change across the Almeria-Oran front. The genetic pattern showed a strong correlation with the values of the salinity both at the surface and at -320 m and of the salinity + temperature at the surface, suggesting a role for these parameters in maintaining the genetic differentiation among the two population groups through selective processes. Finally, the levels of genetic variability were found to be slightly lower in the depleted Atlantic stock than in the Mediterranean one.

Animals↗