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At least 271 records · Page 15Linked to original sources
PubMed2004

Simvastatin preserves cardiac function in genetically determined cardiomyopathy.

Endothelial dysfunction characterizes heart failure (HF). Simvastatin (Sim) increases endothelial nitric oxide (NO) independent of lipid-lowering. We evaluated the effect of Sim on cardiac function, apoptosis, and NO availability in HF. Five-month-old cardiomyopathic (CM) hamsters were divided into 2 groups: Sim (20 mg/kg, 6 weeks, n = 6) and Untreated (n = 6). Age-matched normal hamsters served as controls (n = 6). Serial echocardiograms were performed to measure LV function. Myocardial apoptosis, eNOS, and capillary density were measured at 6 weeks. Cardiomyopathic hamsters had lower LV shortening fraction (SF) compared with controls (17 +/- 3% vs 59 +/- 2%), higher LV end-diastolic volume (30 +/- 3 vs 6 +/- 2 mL/m2), and lower LV mass/volume ratio (0.5 +/- 0.04 vs 0.72 +/- 0.02 mg/ml, P < 0.001). During follow-up, SF decreased (9 +/- 2%) and LV volume increased (38 +/- 1 mL/m2) in untreated hamsters (P < 0.05 from baseline) but did not change significantly in the Sim group (P < 0.05 vs untreated). Myocardial caspase-3 activity was higher and apoptotic nuclear density was lower in Sim compared with untreated CM hamsters (0.072 +/- 0.02% vs 0.107 +/- 0.03%, P < 0.01). Myocardial capillary density was highest in the Sim group (P < 0.05). eNOS expression was not different between groups. Sim retards the progression of HF in CM hamsters. This may be related to an increase in coronary microvasculature, increase in NO availability, and decreased apoptosis.

Angiogenesis Inducing Agents↗
PubMed2002

Molecular genetics and function of NAT1 and NAT2: role in aromatic amine metabolism and carcinogenesis.

Aromatic and heterocyclic amines require metabolic activation to electrophilic intermediates that initiate carcinogenesis. N-Acetyltransferase 1 (NAT1) and 2 (NAT2) are important enzymes in the biotransformation of these carcinogens and exhibit genetic polymorphism. Human NAT1 and NAT2 alleles are listed at: http://www.louisville.edu/medschool/pharmacology/NAT.html by an international gene nomenclature committee. The high frequency of the NAT1 and NAT2 acetylation polymorphisms in human populations together with ubiquitous exposure to aromatic and heterocyclic amines suggest that NAT1 and NAT2 acetylator genotypes are important modifiers of human cancer susceptibility. For cancers in which N-acetylation is a detoxification step such as aromatic amine-related urinary bladder cancer, NAT2 slow acetylator phenotype is at higher risk. Multiple studies have shown that the urinary bladder cancer risk is particularly high in the slowest NAT2 acetylator phenotype or genotype (NAT2(*)5). In contrast, for cancers in which N-acetylation is negligible and O-acetylation is an activation step such as for heterocyclic amine-related colon cancer, NAT2 rapid acetylator phenotype is at higher risk. Although studies have found associations between NAT1 genotype and various cancers, the findings are less consistent and are not well understood. Since cancer risk requires exposure to aromatic and/or heterocyclic amine carcinogens modified by NAT1 and/or NAT2 acetylator genotype, the results from human epidemiology studies are dependent upon the quality and accuracy of the exposure assessment and genotype determination. Conclusions require understanding the relationship between genotype and phenotype, as well as the role of genetic variation in carcinogen metabolism, DNA repair, and host susceptibility. Investigations have been carried out in rapid and slow acetylator rodent models in which both exposure and genetic variability are tightly controlled. Human NAT1 and NAT2 alleles have been characterized by recombinant expression to further understand the effects of nucleotide polymorphisms on function and phenotype.

Acetylation↗
PubMed2003

A second and unusual pucBA operon of Rhodobacter sphaeroides 2.4.1: genetics and function of the encoded polypeptides.

A new operon (designated the puc2BA operon) displaying a high degree of similarity to the original pucBA genes of Rhodobacter sphaeroides 2.4.1 (designated puc1) was identified and studied genetically and biochemically. The puc2B-encoded polypeptide is predicted to exhibit 94% identity with the original beta-apoprotein. The puc2A-encoded polypeptide is predicted to be much larger (263 amino acids) than the 54-amino-acid puc1A-encoded polypeptide. In the first 48 amino acids of the puc2A-encoded polypeptide there is 58% amino acid sequence identity to the original puc1A-encoded polypeptide. We found that puc2BA is expressed, and DNA sequence data suggested that puc2BA is regulated by the PpsR/AppA repressor-antirepressor and FnrL. Employing genetic and biochemical approaches, we obtained evidence that the puc2B-encoded polypeptide is able to enter into LH2 complex formation, but neither the full-length puc2A-encoded polypeptide nor its N-terminal 48-amino-acid derivative is able to enter into LH2 complex formation. Thus, the sole source of alpha-polypeptides for the LH2 complex is puc1A. The role of the puc1C-encoded polypeptide was also determined. We found that the presence of this polypeptide is essential for normal levels of transcription and translation of the puc1 operon but not for transcription and translation of the puc2 operon. Thus, the puc1C gene product appears to have both transcriptional and posttranscriptional roles in LH2 formation. Finally, the absence of any LH2 complex when puc1B was deleted in frame was surprising since we know that in the presence of functional puc2BA, approximately 30% of the LH2 complexes normally observed contain a puc2B-encoded beta-polypeptide.

Amino Acid Sequence↗
PubMed1998

Genetic and functional relationship between Rvsp, myosin and actin in Saccharomyces cerevisiae.

The rvs mutants display phenotypes close to those described for the actin mutants: disorganization of the actin cytoskeleton, random budding of the diploids, loss of polarity and sensitivity to salt. Mutations in the RVS genes lead to synthetic lethality with a set of mutations in the actin gene, ACT1. This synthetic lethality is allele-specific regarding the act1 mutations, pointing to a region on the actin molecule where contacts with the myosin head have been described. The possible involvement of a myosin in a vital function fulfilled both by the Rvsp proteins and actin is strengthened further by the fact that the double mutants rvs167, myo1 and rvs167, myo2 are lethal and severely affected in growth respectively. These data support the idea that actin, myosin and Rvsp proteins are linked in a common functional pathway in yeast.

Actins↗
PubMed2004

Investigating the morphology, function and genetics of cytotoxic cells in bony fish.

Bony fish (teleosts) possess multiple cytotoxic cell lineages that recognize and destroy virally infected and transformed cells. In general, these lineages parallel their functional equivalents in mammals and include neutrophilic granulocytes, macrophages, cytotoxic T lymphocytes (CTL) and natural killer (NK) cells. These four cell types have been morphologically identified in multiple fish species but only limited information is available about their function. In contrast, much work has gone into examining the function of a fifth cytotoxic cell lineage, termed nonspecific cytotoxic cells (NCC), that has been referred to as the bony fish equivalent of NK cells. However, evidence suggesting that NCC do not represent the NK lineage has come through the development of multiple cytotoxic catfish cell lines that are morphologically and functionally similar to human NK cells and are distinct from NCC. In addition to characterizing cytotoxic cells from fish, recent work has identified the novel immune-type receptors (NITR) and cichlid killer leukocyte receptors (cKLR) that are structurally related to mammalian NK receptors and likely play a role in cytotoxic function in fish. This review summarizes the morphological and functional evidence for cytotoxic cells within bony fish and discusses future directions for examining cytotoxicity through genomics and transgenics.

Animals↗
PubMed1998

Structural, functional, and genetic characterization of Gastrophilus hemoglobin.

Hemoglobin of Gastrophilus intestinalis (Insecta, Diptera), was purified and characterized. At least two isoforms have been identified by isoelectrofocusing, mass spectrometry, and genomic Southern blotting. Functional studies show a high oxygen affinity due to a low ligand dissociation rate (koff = 2.4 s-1) and a relatively high autoxidation rate (t1/2 = 1.6/h). The globins were separated under denaturing conditions, and the sequence of Hb1 (Mr = 17,965 +/- 2) was determined at the protein and DNA level. The open reading frame codes for a polypeptide of 150 amino acids. Although the globin is distantly related to globins from other species, it has a low penalty score against globin templates. Freshly isolated hemoglobin was crystallized from polyethylene glycol. Crystals contain two hemoglobin molecules per asymmetric unit. Solution of the three-dimensional structure by molecular replacement could not be achieved, possibly due to the presence of three protein isoforms in the crystals. In order to determine its three-dimensional structure, G. intestinalis Hb1 was overexpressed in Escherichia coli, resulting in a fully functional molecule as confirmed by ligand binding affinity. The globin gene contains two introns at positions D7.0 and G7.0. The D7.0 intron is unprecedented, suggesting that globin gene evolution is much more complex than originally thought.

Amino Acid Sequence↗
PubMed2004

Functional and genetic diversity in the concentrative nucleoside transporter, CNT1, in human populations.

The concentrative nucleoside transporter, CNT1 (SLC28A1), mediates the cellular uptake of naturally occurring pyrimidine nucleosides and many structurally diverse anticancer and antiviral nucleoside analogs. As a first step toward understanding whether genetic variation in CNT1 contributes to variation in the uptake and disposition of clinically used nucleoside analogs, we determined the haplotype structure and functionally analyzed all coding region variants of CNT1 identified in ethnically diverse populations (100 African Americans, 100 European Americans, 30 Asians, 10 Mexican Americans, and 7 Pacific Islanders) (Leabman et al., 2003). A total of 58 coding region haplotypes were identified using PHASE analysis, 44 of which contained at least one amino acid variant. More than half of the coding region haplotypes were population-specific. Using site-directed mutagenesis, 15 protein-altering CNT1 variants, including one amino acid insertion and one base pair (bp) deletion, were constructed and expressed in Xenopus laevis oocytes. All variant transporters took up [3H]thymidine with the exception of CNT1-Ser546Pro, a rare variant, and CNT1-1153del, a single bp deletion found at a frequency of 3% in the African American population. The bp deletion results in a frame-shift followed by a stop-codon. The anticancer nucleoside analog gemcitabine had a reduced affinity for CNT1-Val189Ile (a common CNT1 variant found at a frequency of 26%) compared with reference CNT1 (IC50=13.8 +/- 0.60 microM for CNT1-reference and 23.3 +/- 1.5 microM for CNT1-Val189Ile, p<0.05). These data suggest that common genetic variants of CNT1 may contribute to variation in systemic and intracellular levels of anti-cancer nucleoside analogs.

Amino Acid Sequence↗
PubMed1996

Impairment of immunological functions in genetically epilepsy-prone rats.

1. In genetically epilepsy-prone rats (GEPR-9s), which represent a natural genetic model of epilepsy, we observed that the number of peritoneal macrophages was significantly lower with respect to normal rats, and that some functional parameters (i.e. phagocytosis and intracellular killing) of these macrophages were impaired. 2. The count of lymphocyte populations showed a predominance of T-helper over T-cytotoxic/suppressor both in the spleen and lymph nodes. Moreover, an increased T-cell/B-cell ratio was observed in GEPR-9s. Flow cytometry revealed that GEPR-9s spleens possessed a large percentage of T-helper cells in comparison to normal rats. 3. By using concanavalin A-induced proliferation of GEPR-9s cultured lymphocytes, we have shown increased functional activation. 4. We suggest that the alterations in T-cell functions in GEPR-9s could be due to the involvement of the neuroendocrine system in the modulation of immunity, in the shift between Th1 and Th2, and in the activation of stress response.

Animals↗
PubMed1997

Molecular, genetic, and functional analysis of homozygous C8 beta-chain deficiency in two siblings.

UNLABELLED: C8 deficiency is associated with an increased susceptibility to neisserial infections. We present a case of an 11 year old boy who suffered from infection with Neisseria meningitidis. Medical history of the patient and his family (n = 5) did not indicate any previous immunodeficiency symptoms. Results from the analysis of phagocyte and lymphocyte functions were within the normal range. No hemolytic activities of the classical (CH50) and the alternative (APH50) pathways of complement were measurable, and SC5b-9 protein complexes could not be detected in the patient's plasma. Further analysis by highly sensitive ELISA and functional assays revealed a complete deficiency of C8. Upon the reconstitution with purified C8 total hemolytic activity could be restored. SDS-PAGE and Western blot analysis established a deficiency of the C8 beta chain. Genetic analysis at the genomic DNA level demonstrated the common C-T mutation in exon 9 of the C8B gene. Family analysis presented the older sister with non-detectable function of C8 in serum, both parents with about half-normal C8 titres, and the younger sister with normal C8 function. The parents and both sisters were asymptomatic, although the older of the sisters presented with the same complete C8 beta-chain deficiency as the patient described. IN CONCLUSION: the common C-T mutation in the C8B genes is the genetic basis of C8 beta-chain deficiency in two members of this Bosnian family.

Alleles↗
PubMed2003

Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.

Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.

Amino Acid Metabolism, Inborn Errors↗
PubMedDate not supplied

An attempt to add biological functions by genetic engineering in order to produce high-performance bioreactor cells for hybrid artificial liver: transfection of glutamine synthetase into Chinese hamster ovary (CHO) cell.

In the course of immortalization, hepatocyte cell lines lose their original differentiated functions, such as ammonia removal and urea formation, drug metabolism, serum protein synthesis, etc. (Enosawa et al., Cell Transplant. 5:S39-S40; 1996). With the aim of adding lost or deficient functions and producing cell lines for the bioreactor of a hybrid artificial liver, rat glutamine synthetase (GS) gene was transfected into Chinese hamster ovary (CHO) cells, because it is able to lower the ammonia level. The GS gene-inserted pSV2 plasmid was transfected into the CHO-K1 line by electroporation. Transfected CHO (GS-CHO) cells were cultured in a glutamine-free medium containing ammonia, glutamic acid, and the GS inhibitor methionine sulfoximine (MSX). The MSX concentration was increased stepwise from 25 mumol/L to 1600 mumol/L to amplify the GS gene. In several GS-CHO sublines resistant to 300-1600 mumol/L of MSX, the specific activities of GS were increased from 0.2 x 10(4) to 1.7-2.9 x 10(4) unit/10(6) cells. When the amplified GS-CHO cells were cultured in the ammonia-containing medium, a slow but steady decrease of the ammonia level was observed when the level was high. Finally, the prospect of genetically modulated cells for bioreactors in the hybrid artificial liver is discussed.

Ammonia↗
PubMed2003

Morphological, genetic and functional variability of a T-cell hybridoma line.

The variability in the morphology, modal number of chromosomes, TCR expression and functional reactivity of a CII-specific T-cell hybridoma at continuous subcultivation have been investigated. As the number of passages increased, besides the oval semiadherent cells (normal phenotype), fibroblast-like cells (transformed phenotype) were also observed. The two cell subpopulations differed in their karyotype characteristic, as well as in their functional reactivity. The cell population with a normal phenotype was characterized by a tetramodal number of chromosomes (30, 40, 48 and 70) and trisomies of chromosomes 6 and 14, while the cell population with a transformed phenotype was characterized by a trimodal number of chromosomes (11, 68 and 74) and trisomy of chromosome 12. A nullisomy of sex chromosomes was established in both types of cells. In the initial passages of subcultivation, 73.04% of the cells with a normal morphological phenotype expressed TCR-CD3 complexes on their surface and possessed high functional reactivity. After a two-week subcultivation, the values of these indices went down considerably: 46.11% of the cells expressed functional TCR-CD3 complexes, as a result of which their functional reactivity decreased. Only 2.71% of the cells with a transformed morphological phenotype expressed functional TCR-CD3 complexes on their surface. In these cells, a total loss of reactivity towards the specific antigens was established. The achieved results show that at continuous subcultivation the T-cell hybridomas are unstable, and with the increase in the number of passages there appear chromosome rearrangements, leading to loss of their functional reactivity.

Animals↗
PubMed2003

The use of transgenic and knock-out mice in the investigation of ocular surface cell biology.

The transgenic and knock-out mice created by transgenesis and gene targeting techniques are very useful for elucidating the pathophysiology of human diseases caused by altered genetic functions. Many of the experimental mouse lines exhibit ocular surface disorders. However, embryonic lethality and congenital defects found in many of the transgenic and knock-out mice preclude their use for studying the consequences of altered genetic functions in adult animals. To circumvent these difficulties, we have established binary inducible mouse models, using the corneal keratocyte-specific keratocan promoter, and the tetracycline-inducible gene expression system (reverse tetracycline transcription activator--rtTA). In these models, the animals function normally until they are fed doxycycline, thus inducing the overexpression of inserted transgenes by keratocytes. We have also developed inserted rtTA and Cre reporter gene constructs to create genetically modified mouse lines that have tissue-specific gene alterations to study acquired conditions, e.g., wound healing and irregular hormone and cytokine signaling that offsets homeostasis in adults. Furthermore, the genes that are ubiquitously expressed in many tissues can be specifically ablated solely in ocular surface tissues to examine their function, since the loss of such a gene in ocular surface tissues will not be life-threatening. It is noteworthy that these altered mouse lines can also be used as models for the development of therapeutic treatment regimens of diseases using gene therapy and stem cell strategies.

Journal Article↗
PubMed2001

Density-dependent competition and selection on immune function in genetic lizard morphs.

Density-dependent territorial interactions have been suggested to cause immunosuppression and thereby decrease fitness, but empirical support from natural populations is lacking. Data from a natural lizard population (Uta stansburiana) showed that breeding females surrounded by many territorial neighbors had suppressed immune function. Furthermore, variation in immunological condition had different effects on the fitness of the two heritable female throat-color morphs in this population. These interactive fitness effects caused correlational selection between female throat color and immune responsiveness. Population genetic theory predicts that this should have lead to the buildup and preservation of a genetic correlation between female morphotype and immunological condition. Accordingly, the throat color of a female was genetically correlated (r(A) = -1.36; SE = 0.55) with her daughter's immune responsiveness.

Journal Article↗
PubMed2024

Obesity: exploring its connection to brain function through genetic and genomic perspectives.

Obesity represents an escalating global health burden with profound medical and economic impacts. The conventional perspective on obesity revolves around its classification as a "pure" metabolic disorder, marked by an imbalance between calorie consumption and energy expenditure. Present knowledge, however, recognizes the intricate interaction of rare or frequent genetic factors that favor the development of obesity, together with the emergence of neurodevelopmental and mental abnormalities, phenotypes that are modulated by environmental factors such as lifestyle. Thirty years of human genetic research has unveiled >20 genes, causing severe early-onset monogenic obesity and ~1000 loci associated with common polygenic obesity, most of those expressed in the brain, depicting obesity as a neurological and mental condition. Therefore, obesity's association with brain function should be better recognized. In this context, this review seeks to broaden the current perspective by elucidating the genetic determinants that contribute to both obesity and neurodevelopmental and mental dysfunctions. We conduct a detailed examination of recent genetic findings, correlating them with clinical and behavioral phenotypes associated with obesity. This includes how polygenic obesity, influenced by a myriad of genetic variants, impacts brain regions associated with addiction and reward, differentiating it from monogenic forms. The continuum between non-syndromic and syndromic monogenic obesity, with evidence from neurodevelopmental and cognitive assessments, is also addressed. Current therapeutic approaches that target these genetic mechanisms, yielding improved clinical outcomes and cognitive advantages, are discussed. To sum up, this review corroborates the genetic underpinnings of obesity, affirming its classification as a neurological disorder that may have broader implications for neurodevelopmental and mental conditions. It highlights the promising intersection of genetics, genomics, and neurobiology as a foundation for developing tailored medical approaches to treat obesity and its related neurological aspects.

Humans↗
PubMed1997

Genetic and functional complementation of the HSV1 UL27 gene and gB glycoprotein by simian alpha-herpesvirus homologs.

Utilizing co-transfection of DNA from glycoprotein gB- strain of HSV1 and cloned fragments of several simian alpha-herpesviruses containing the UL26, UL27 (gB glycoprotein), and UL28 gene homologs, replication-competent recombinant viruses were produced. Genetic analysis of one HSV1/SA8 recombinant (HSV1/SgB) demonstrated the presence of SA8 DNA comprising the entire UL27 (gB) gene and parts of the UL28 and UL26 ORFs in an otherwise HSV1 genome. The recombinant was shown to express the SA8 gB and p40 proteins (UL27 & UL26.5 gene products, respectively); all other proteins were indistinguishable from those of HSV1. The recombinant behaved like SA8 in gB-specific virus neutralization and cell surface antibody binding assays, while plaque morphology and replication kinetics were very similar to HSV1. Despite its overwhelming HSV1 genetic constitution, the recombinant displayed a pathogenic phenotype in mice very different from the parental HSV1. While HSV1 produced corneal disease in ocularly infected mice and readily spread to the nervous system. HSV1/SgB was markedly impaired in both respects. These results demonstrate the functional equivalency of the cercopithecine monkey virus gB glycoproteins and genes (including transcriptional regulatory elements) in HSV1, the functional nature of HSV1/SA8 chimeric UL28 and UL26 genes/proteins, and that UL28, gB and/or p40 proteins may effect the pathogenicity of HSV1.

3T3 Cells↗
PubMed2004

Function of genetically encoded pyrrolysine in corrinoid-dependent methylamine methyltransferases.

Methanogenesis from trimethylamine, dimethylamine or monomethylamine is initiated by a series of corrinoid-dependent methyltransferases. The non-homologous genes encoding the full-length methyltransferases each possess an in-frame UAG (amber) codon that does not terminate translation. The amber codon is decoded by a dedicated tRNA, and corresponds to the novel amino acid pyrrolysine in one of the methyltransferases, indicating pyrrolysine to be the 22nd genetically encoded amino acid. Pyrrolysine has the structure of lysine with the (epsilon)N in amide linkage with a pyrroline ring. The reactivity of the electrophilic imine bond is the basis for the proposed function of pyrrolysine in activating and optimally orienting methylamine for methyl transfer to the cobalt ion of a cognate corrinoid protein. This reaction is essential for methane formation from methylamines, and may underlie the retention of pyrrolysine in the genetic code of methanogens.

Amides↗