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991.
In order to investigate the molecular basis of phenylketonuria (PKU) in Spain, we analyzed the restriction fragment length polymorphism (RFLP) haplotypes and common mutations in the phenylalanine hydroxylase (PAH) gene in 32 unrelated Spanish PKU families. The distribution of RFLP haplotypes differs from that of northern Europe. Mutant haplotypes 2 and 3 were completely absent in our sample. Approximately 65% of the mutant alleles are confined to three RFLP haplotypes, namely haplotypes 1, 6 and 9, also frequently found in other Mediterranean populations. We screened for previously described PKU mutations using the polymerase chain reaction and allele-specific oligonucleotides, and found IVS10,165T, E280K and P281L as the major mutations, representing 41% of the PKU alleles. Other mutations found were Y414C, and a new one, P244L. Mutations R408W and IVS12, prevalent in northern Europe, as well as others present in southern European populations (R252W, R261Q, L249F) were not detected in our sample. Our results reveal the genetic heterogeneity present in the Spanish PKU population, which shows similarities to others of Mediterranean origin. 相似文献
992.
Abstract: In the postmortem human brain (27 specimens of frontal cortex, Brodmann area 9), the specific binding of the antagonists [3H]RX 821002 (2-methoxyidazoxan) to α2A-adrenoceptors and that of [3H]idazoxan to l2-imidazo-line sites (a nonadrenoceptor mitochondrial site) were determined in parallel to study the effect of aging (range, 4–89 years) on both brain proteins. The density of α2A-adrenoceptors and age were negatively correlated (r=-0.71; p < 0.001). In contrast, the density of l2-imidazo-line sites was positively correlated with aging (r= 0.59; p < 0.005). The ratio of receptor densities (α2A/l2) also showed a marked negative correlation with age (r=-0.76; p < 0.001). In an age-selected group (range, 10–89 years), the density of monoamine oxidase (MAO)-B sites labeled by [3H]Ro 19–6327 (lazabemide) also showed a positive correlation with age (r= 0.80; p < 0.005). In these subjects, the density of l2-imidazoline sites correlated well with the density of MAO-B sites (r= 0.70; p < 0.005). The ratio of the density of these sites (MAO-B/l2) did not correlate with the age of the subject at death (r=-0.15). In the human frontal cortex, idazoxan displayed very low affinity (Ki= 89 μM) against the binding of [3H]Ro 19–6327 to MAO-B, which discounted a direct interaction of [3H]idazoxan with the active center of the enzyme and indicated that the l2-imidazoline site cannot be identified with MAO-B. However, l2-imidazoline sites and MAO-B show a clear coexpression not only in the human frontal cortex during the process of aging, but also in various brain regions of the human and rat brains. It is suggested that the l2-imidazoline site has a specific location on glial (astrocyte) cells. 相似文献
993.
The effect of postdecapitative ischemia (5 min at 37°) and hypoxia (5% O2, 95% N2, 30 min) on the distribution of protein radioactivity in the cellular fractions of guinea pig cerebral cortex was studied. Ischemic conditions resulted in the increase of total radioactivity level and protein content in the mitochondrial fraction. In the cytosol the opposite effect was observed; the radioactivity and protein content were decreased. The amino acid analysis of microsomal proteins and the distribution of glucose-6-phosphatase activity, differing from those in control animals, suggest structural disturbances in the microsomal fraction. The results indicate a different sedimentation of proteins in the given experimental conditions. After hypoxia such effects were not observed. 相似文献
994.
Gregory Adams Jr. Magdalena Preciado Lpez Alexander X. Cartagena-Rivera Clare M. Waterman 《Molecular biology of the cell》2021,32(18):1772
Cancer cells migrating in confined microenvironments exhibit plasticity of migration modes. Confinement of contractile cells in a nonadhesive environment drives “leader bleb–based migration” (LBBM), morphologically characterized by a long bleb that points in the direction of movement separated from a cell body by a contractile neck. Although cells undergoing LBBM have been visualized within tumors, the organization of organelles and actin regulatory proteins mediating LBBM is unknown. We analyzed the localization of fluorescent organelle-specific markers and actin-associated proteins in human melanoma and osteosarcoma cells undergoing LBBM. We found that organelles from the endolysosomal, secretory, and metabolic systems as well as the vimentin and microtubule cytoskeletons localized primarily in the cell body, with some endoplasmic reticulum, microtubules, and mitochondria extending into the leader bleb. Overexpression of fluorescently tagged actin regulatory proteins showed that actin assembly factors localized toward the leader bleb tip, contractility regulators and cross-linkers in the cell body cortex and neck, and cross-linkers additionally throughout the leader bleb. Quantitative analysis showed that excess filamin-A and fascin-1 increased migration speed and persistence, while their depletion by small interfering RNA indicates a requirement in promoting cortical tension and pressure to drive LBBM. This indicates a critical role of specific actin crosslinkers in LBBM. 相似文献
995.
Fangli Chen Emilia Licarete Xue Wu Daniela Petrusca Callista Maguire Max Jacobsen Austyn Colter George E. Sandusky Magdalena Czader Maegan L. Capitano James P. Ropa H. Scott Boswell Fabrizio Carta Claudiu T. Supuran Brian Parkin Melissa L. Fishel Heiko Konig 《Journal of cellular and molecular medicine》2021,25(24):11039-11052
Acute myeloid leukaemia (AML) is an aggressive form of blood cancer that carries a dismal prognosis. Several studies suggest that the poor outcome is due to a small fraction of leukaemic cells that elude treatment and survive in specialised, oxygen (O2)-deprived niches of the bone marrow. Although several AML drug targets such as FLT3, IDH1/2 and CD33 have been established in recent years, survival rates remain unsatisfactory, which indicates that other, yet unrecognized, mechanisms influence the ability of AML cells to escape cell death and to proliferate in hypoxic environments. Our data illustrates that Carbonic Anhydrases IX and XII (CA IX/XII) are critical for leukaemic cell survival in the O2-deprived milieu. CA IX and XII function as transmembrane proteins that mediate intracellular pH under low O2 conditions. Because maintaining a neutral pH represents a key survival mechanism for tumour cells in O2-deprived settings, we sought to elucidate the role of dual CA IX/XII inhibition as a novel strategy to eliminate AML cells under hypoxic conditions. Our findings demonstrate that the dual CA IX/XII inhibitor FC531 may prove to be of value as an adjunct to chemotherapy for the treatment of AML. 相似文献
996.
Macarthur Charles Juana Magdalena Julie A. Theriot Marcia B. Goldberg 《Journal of bacteriology》1999,181(3):869-878
Shigella flexneri is a gram-negative bacterium that causes diarrhea and dysentery by invasion and spread through the colonic epithelium. Bacteria spread by assembling actin and other cytoskeletal proteins of the host into “actin tails” at the bacterial pole; actin tail assembly provides the force required to move bacteria through the cell cytoplasm and into adjacent cells. The 120-kDa S. flexneri outer membrane protein IcsA is essential for actin assembly. IcsA is anchored in the outer membrane by a carboxy-terminal domain (the β domain), such that the amino-terminal 706 amino acid residues (the α domain) are exposed on the exterior of the bacillus. The α domain is therefore likely to contain the domains that are important to interactions with host factors. We identify and characterize a domain of IcsA within the α domain that bears significant sequence similarity to two repeated domains of rickettsial OmpA, which has been implicated in rickettsial actin tail formation. Strains of S. flexneri and Escherichia coli that carry derivatives of IcsA containing deletions within this domain display loss of actin recruitment and increased accessibility to IcsA-specific antibody on the surface of intracytoplasmic bacteria. However, site-directed mutagenesis of charged residues within this domain results in actin assembly that is indistinguishable from that of the wild type, and in vitro competition of a polypeptide of this domain fused to glutathione S-transferase did not alter the motility of the wild-type construct. Taken together, our data suggest that the rickettsial homology domain of IcsA is required for the proper conformation of IcsA and that its disruption leads to loss of interactions of other IcsA domains within the amino terminus with host cytoskeletal proteins. 相似文献
997.
The effects of metabolic and protein synthesis inhibitors on NH4
+ uptake by Pisum arvense plants at low (0.05 mM) and high (1 mM) external ammonium concentration were studied. In short-time experiments cycloheximide
decreased the ammonium uptake rate at low level of NH4
+ and increased the absorption of NH4
+ from uptake medium containing high ammonium concentration. Arsenate and azide supplied into uptake solutions at low ammonium
concentration strongly decreased or completely suppressed the NH4
+ uptake rate, respectively. When the experiments were carried out at high level of ammonium only azide decreased the uptake
rate of NH4
+ and arsenate stimulated this process. Dinitrophenol very strongly repressed the uptake rate of NH4
+ at both ammonium concentrations. After removing dinitrophenol from both solutions, neither at low nor high external ammonium
level the recovery of NH4
+ uptake rate was achieved within 150 min or 3 h, respectively. The recovery of NH4
+ uptake rate after removing azide was observed within 90 min and 3 h at low and high ammonium concentrations, respectively.
The regulation of NH4
+ uptake by some inhibitors at low external ammonium level was investigated using plasma membrane vesicles isolated from roots
by two-phase partitioning. Orthovanadate completely suppressed the uptake of NH4
+ by vesicles and quinacrine decreased the NH4
+ uptake which 55 suggests that ammonium uptake depends on activities of plasma membrane-bound enzymes. On the other hand,
it was found that dinitrophenol completely reduced the NH4
+ uptake by vesicles.
The various effects of inhibitors on ammonium uptake dependent on external ammonium concentration suggest the action of different
ammonium transport systems in Pisum arvense roots. The ammonium transport into root cells at low NH4
+ level requires energy and synthesis of protein in the cytoplasm.
The research was supported by grant of KBN No. 6PO4C 068 08 相似文献
998.
Helona Havelková Marcela Kosařová Magdalena Krulová Peter Demant Marie Lipoldová 《Mammalian genome》1999,10(7):670-674
Lymphocytes of mouse strains BALB/cHeA (BALB/c) and STS/A (STS) differ in their response to CD3 antibody (anti-CD3). We analyzed
the genetic basis of this strain difference, using the Recombinant Congenic Strains (RCS) of the BALB/c-c-STS/Dem (CcS/Dem)
series. Each of the 20 CcS/Dem strains carries a different, random combination of 12.5% genes from the nonresponding strain
STS and 87.5% genes of the intermediate responder strain BALB/c. Differences in the magnitude of anti-CD3-induced response
among CcS/Dem strains indicated that in addition to Fcγ receptor 2 (Fcgr2) other genes are involved in the control of this response as well, and we have already mapped loci Tria1 (T cell receptor-induced activation 1), Tria2, and Tria3. In order to map additional Tria genes, we tested F2 hybrids between the high responder RC strain CcS-9 and the low responder strain CcS-11. Proliferation in complete RPMI medium
without anti-CD3 is controlled by locus Sprol1 (spontaneous proliferation 1) linked to the marker D4Mit23 on Chr 4. At concentration 0.375 μg/ml anti-CD3 mAb, the response was controlled by a locus Tria4, which maps to the marker D7Mit32 on Chr 7. The response to the higher concentration of mAb, 3 μg/ml, was controlled by Tria5, which mapped to the marker D9Mit15 on Chr 9. Anti-CD3 is being used for modulation of lymphocyte functions in transplantation reactions and in cancer treatment.
Study of mechanisms of action of different Tria loci could lead to better understanding of genetic regulation of these reactions.
Received: 28 October 1998 / Accepted: 17 March 1999 相似文献
999.
Ana Magdalena Hurtado Kristen Hawkes Kim Hill Hillard Kaplan 《Human ecology: an interdisciplinary journal》1985,13(1):1-28
Anthropologists have frequently proposed that sexual division of labor is produced by childcare constraints on women's subsistence work. We present data on the forest activities of Ache women that show that differences in parental investment partially account for variation in food acquisition among individual women. Data also suggest that childcare constraints are important in understanding the sexual division of labor. 相似文献