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PubMed1994

Nisin as a model food preservative.

Nisin is a ribosomally synthesized peptide that has broad-spectrum antibacterial activity, including activity against many bacteria that are food-spoilage pathogens. Nisin is produced as a fermentation product of a food-grade bacterium, and the safety and efficacy of nisin as a food preservative have resulted in its widespread use throughout the world, including the U.S. Nisin is a member of the class of antimicrobial substances known as lantibiotics, so called because they contain the unusual amino acid lanthionine. Lantibiotics, in general, have considerable promise as food preservatives, although only nisin has been sufficiently well characterized to be used for this purpose. As the number of known natural lantibiotics has increased and their useful characteristics have been explored, it has become desirable to synthesize structural analogs of nisin and other lantibiotics that do not occur naturally. The fact that lantibiotics are gene-encoded peptides synthesized by transcription and translation allows structural variants to be generated by mutagenesis. This review focuses on the progress that has been made in the construction and biological expression of genetically engineered nisin structural analogs. For example, a host-vector pair has been engineered that permits the construction of mutants of the structural gene for subtilin, which is a naturally occurring structural analog of nisin. The vector is designed in such a way that the mutant gene can be substituted for the natural subtilin gene in the chromosome of Bacillus subtilis, which in turn directs the transcription, translation, posttranslational modifications, and secretion of the mature form of the structural analog. Several structural analogs have been constructed, and their properties have provided insight into some of the structure-function relationships in lantibiotics, as well as their mechanism of antimicrobial action. These advances are assessed together with potential problems in the future development of nisin analogs as valuable new food preservatives.

Amino Acid Sequence↗
PubMed2001

Distribution and structural variation of the she pathogenicity island in enteric bacterial pathogens.

Shigella flexneri serotype 2a carries a chromosomal pathogenicity island (PAI), termed the she PAI, that has been implicated in the pathogenesis of diarrhoeal disease. The complete nucleotide sequence and genetic organisation of the she PAI of S. flexneri 2a strain YSH6000T was determined recently. In the current study the distribution and structure of the she PAI was investigated by PCR and Southern analysis in 65 isolates of enteric pathogens including Shigella spp., enterohaemorrhagic Escherichia coli (EHEC), enteropathogenic E. coli (EPEC), enteroinvasive E. coli (EIEC), Yersinia enterocolitica and Salmonella enterica serovar Typhimurium. The study showed that the she PAI has undergone a variety of structural changes, defined by the presence or absence of specific marker genes in the PAI. The she PAI or structural variants of this element were found in all species of Shigella as well as in EIEC, EHEC and EPEC. No evidence of the PAI was found in Y. enterocolitica or Sal. Typhimurium. The structural form of the she PAI that exists in strain YSH6000T was present in all strains of S. flexneri serotype 2a and in some strains of S. flexneri serotypes 2b and 3c. Variants of the PAI that were missing one or more marker regions were found in all species of Shigella and in pathogenic strains of E. coli. In all strains, the PAIs have inserted into either pheV or a phe tRNA gene in another location on the chromosome. It was concluded that the she PAI is one of several closely related genetic elements that have disseminated throughout Shigella and pathogenic strains of E. coli and diverged into distinct stuctural forms.

DNA-Directed RNA Polymerases↗
PubMed1998

Selective induction of apoptosis in mature T lymphocytes by variant T cell receptor ligands.

Activation, anergy, and apoptosis are all possible outcomes of T cell receptor (TCR) engagement. The first leads to proliferation and effector function, whereas the others can lead to partial or complete immunological tolerance. Structural variants of immunizing peptide-major histocompatibility complex molecule ligands that induce selective lymphokine secretion or anergy in mature T cells in association with altered intracellular signaling events have been described. Here we describe altered ligands for mature mouse CD4(+) T helper 1 cells that lead to T cell apoptosis by the selective expression of Fas ligand (FasL) and tumor necrosis factor (TNF) without concomitant IL-2, IL-3, or interferon gamma production. All ligands that stimulated cell death were found to induce FasL and TNF mRNA expression and TCR aggregation ("capping") at the cell surface, but did not elicit a common pattern of tyrosine phosphorylation of the TCR-associated signal transduction chains. Thus, TCR ligands that uniquely trigger T cell apoptosis without inducing cytokines that are normally associated with activation can be identified.

Amino Acid Sequence↗
PubMed2000

Genomic structure and novel variants of myo-inositol monophosphatase 2 (IMPA2).

Recently, we cloned the human myo-inositol monophosphatase 2 (IMPA2) cDNA and established its map location to chromosome 18p11.2, a region previously implicated in bipolar disorder. Because the myo-inositol monophosphatase enzyme has been shown to be inhibited by lithium, an effective therapeutic agent for bipolar disorder, IMPA2 is a plausible positional and functional candidate gene. To permit comprehensive screening for variants we characterized the genomic structure and isolated the potential promoter of IMPA2. The gene was found to encode eight exons spanning;27 kb. The proximal 1-kb 5' flanking region did not contain an obvious TATA box but multiple potential binding sites for Sp1 and consensus motifs for AP2 and other transcription factors were evident. Sequencing of the coding region and splice junctions in unrelated bipolar disorder patients detected novel variants. A missense mutation in exon 2, His76Tyr, was found in one patient. His76 is evolutionarily conserved and replacement with Tyr introduces a potential site for phosphorylation. The other polymorphisms included an RsaI polymorphism, IVS1-15G>A, and a T --> C silent mutation in the third nucleotide of codon 53 in exon 2. By Fisher's exact test the silent mutation showed a trend for association (P = 0.051) with bipolar disorder suggesting that further scrutiny of this gene is warranted.

Alternative Splicing↗
PubMed1999

Context and sex differences exist in the acoustic structure of phee calls by newly-paired common marmosets (Callithrix jacchus).

Captive common marmosets of all ages robustly produce a "separation" phee call during brief separations from their group. In contrast, a second structural variant, which may function as an intergroup call, is produced in the home cage primarily by the reproductive adults. A previous study found that postpubertal but nonreproductive offspring rarely produce phee calls when in the home cage with the natal group, yet these marmosets call frequently after pairing with an opposite-sex partner. The sudden increase in home cage phee calls may indicate the rapid onset of intergroup calling. Alternatively, marmosets may be producing the separation phee variant as a result of separation from the natal group. The present study investigated whether phee calls produced by recently paired individuals in the home cage were structurally distinguishable from their calls recorded in a separation paradigm. We also tested whether sex differences, known to exist in the calls of mature adults, could be found in calls recorded from younger, nonreproductive animals separated from their natal groups. We analyzed 18 acoustic parameters of phee calls produced in the home cage after pairing and of calls produced during separation both from the natal group and from a new mate. Discriminant function analyses found that home cage calls were clearly discriminable from separation calls (average 91.7% correctly classified), indicating that the rapid increase in home cage phee call production shortly after pairing is not a consequence of separation from the family group. Postpubertal marmosets appear to show a rapid behavioral adjustment to separation from their natal groups. Additionally, sex was clearly discriminable in calls recorded both before and after pairing (average 86.8% correctly classified). Like calls recorded from well-established paired marmosets, phee calls produced by recently paired, postpubertal marmosets are discriminable by context and sex.

Animals↗
PubMed1999

Absence of genetic variation in some obesity candidate genes (GLP1R, ASIP, MC4R, MC5R) among Pima indians.

OBJECTIVE: To examine the obesity candidate genes glucagon-like-peptide receptor (GLP1R), agouti signaling protein (ASIP) and the melanocortin receptors 4 and 5 (MC4R and MC5R) for DNA polymorphisms in their coding regions. SUBJECTS: Unrelated, non-diabetic Pima Indians (8 to 12 from each extreme of body fat). MEASUREMENTS: DNA sequencing within the coding regions of each gene. RESULT: Only one variant was detected, a silent substitution in exon 6 of GLP1R. CONCLUSION: The exclusion of any common amino-acid polymorphisms (allele frequency > or = 0.20). implies that structural variants of these genes do not contribute to variation in the high level of obesity observed among the Pima Indians.

Agouti Signaling Protein↗
PubMed1987

Inherited haemoglobin variants in a South African population.

We present the findings of a survey to determine the prevalence of inherited haemoglobin disorders in the Coloured (mixed ethnic origin) population of South Africa. A variety of haemoglobins was found. Of the structural variants, Hb E and Hb S were the most common, the former probably originating from South-East Asia and the latter from East Africa and possibly Madagascar. The alpha+ (-alpha) thalassaemia haplotype is particularly common with an observed frequency of 0.023. Beta thalassaemia was rather less common, while hereditary persistence of fetal haemoglobin was found for the first time in this population group, occurring in two subjects.

Epidemiologic Methods↗
PubMed2001

Specific neosaxitoxin interactions with the Na+ channel outer vestibule determined by mutant cycle analysis.

The voltage-gated Na+ channel alpha-subunit consists of four homologous domains arranged circumferentially to form the pore. Several neurotoxins, including saxitoxin (STX), block the pore by binding to the outer vestibule of this permeation pathway, which is composed of four pore-forming loops (P-loops), one from each domain. Neosaxitoxin (neoSTX) is a variant of STX that differs only by having an additional hydroxyl group at the N1 position of the 1,2,3 guanidinium (N1-OH). We used this structural variant in mutant cycle experiments to determine interactions of the N1-OH and its guanidinium with the outer vestibule. NeoSTX had a higher affinity for the adult rat skeletal muscle Na+ channel (muI or Scn4a) than for STX (DeltaG approximately = 1.3 kcal/mol). Mutant cycle analysis identified groups that potentially interacted with each other. The N1 toxin site interacted most strongly with muI Asp-400 and Tyr-401. The interaction between the N1-OH of neoSTX and Tyr-401 was attractive (DeltaDeltaG = -1.3 +/- 0.1 kcal/mol), probably with formation of a hydrogen bond. A second possible attractive interaction to Asp-1532 was identified. There was repulsion between Asp-400 and the N1-OH (DeltaDeltaG = 1.4 +/- 0.1 kcal/mol), and kinetic analysis further suggested that the N1-OH was interacting negatively with Asp-400 at the transition state. Changes in pH altered the affinity of neoSTX, as would be expected if the N1-OH site were partially deprotonated. These interactions offer an explanation for most of the difference in blocking efficacy between neoSTX and STX and for the sensitivity of neoSTX to pH. Kinetic analysis suggested significant differences in coupling energies between the transition and the equilibrium, bound states. This is the first report to identify points of interaction between a channel and a non-peptide toxin. This interaction pattern was consistent with previous proposals describing the interactions of STX with the outer vestibule (Lipkind, G. M., and H. A. Fozzard. 1994. Biophys. J. 66:1-13; Penzotti, J. L., G. Lipkind, H. A. Fozzard, and S. C. Dudley, Jr. 1998. Biophys. J. 75:2647-2657).

Animals↗
PubMed1984

Comparison of thymic and peripheral T cell Ly-2/3 antigens.

Major structural differences occur between the thymic and peripheral T cell forms of the Ly-2/3 antigen. Thymus Ly-2/3 consists of similar amounts of two types of disulfide-linked heterodimer, alpha beta and alpha' beta (Mr alpha = 38000, Mr alpha' = 35000, Mr beta = 30000). In contrast material from peripheral T cells consists almost exclusively of alpha beta dimers. The alpha chains of thymus and peripheral T cells differ also in isoelectric point with the thymic alpha chain being the more acidic. Based on peptide mapping experiments the alpha and alpha' chains of thymus are likely to be alternatively modified forms of the same polypeptide backbone. Individual T cell clones or T cell tumors propagated in vitro exhibit either a typical thymus or a typical peripheral T cell Ly-2/3 polypeptide pattern indicating that the synthesis of both alpha and alpha' chains can occur in the same cell. The heterogeneity of thymic Ly-2/3 can be considerably reduced by removal of sialic acid residues, and after desialylation the alpha chains of thymus and a cloned cytotoxic T lymphocyte (CTL) line cannot be electrophoretically distinguished. If Ly-2 structures affected the antigen specificity of CTL, a different structural variant would be expected in individual clones. The electrophoretic identity of desialylated thymus and CTL alpha chains suggests that Ly-2 does not exhibit clonal variation in polypeptide structure and, therefore, cannot contribute to antigen specificity.

Animals↗
PubMed1998

[Differential diagnosis of squamous epithelial carcinoma of the salivary glands].

Primary squamous cell carcinomas (SCC) of the salivary glands are localized predominantly in the major salivary glands and must be distinguished from metastases of extraglandular SCC of the skin, especially the head and neck area. Squamous cell metaplasia in non-tumourous diseases of the salivary gland (e.g. necrotizing sialometaplasia) as well as in benign or malignant salivary gland tumours (e.g. metaplastic Warthin tumour) can simulate SCC. Other differential diagnostic problems are the structural variants of SCC which develop predominantly in the minor salivary glands, but not in the major salivary glands. Special types include the very rare adenoid SCC with pseudoglandular structures as the result of acantholysis, the biphasic adenosquamous carcinoma with differentiation as SCC and adenocarcinoma, the biphasic basaloid squamous carcinoma with a structure as SCC and solid basaloid carcinoma (analogous to the solid type of adenoid-cystic carcinoma) and the poorly differentiated mucoepidermoid carcinoma (grade III) with biphasic structure of undifferentiated epidermoid and intermediate cells as well as inclusion of small groups of mucous-producing goblet cells. The differential diagnostic criteria are analysed concerning prognosis and treatment.

Carcinoma, Squamous Cell↗
PubMed2001

Interaction of coumarin derivatives with human serum albumin: investigation by fluorescence spectroscopic technique and modeling studies.

Interactions of several 7-aminocoumarins with human serum albumin (HSA) were studied by using fluorescence spectroscopic technique and modeling studies. There is a large change in fluorescence spectral parameters like intensity, emission maxima and anisotropy for all aminocoumarins. There were two binding sites for cou-1, 311 and a single binding site for other coumarins. The binding constant(s) are large for all coumarins reflective of a strong binding. These spectral studies show that structural variants at the third, fourth and seventh position affects binding. The probable location of these coumarins in domain II has been predicted based on modeling. The effect of structural modification on the efficiency of binding was obtained for various other coumarins, using modeling.

Binding Sites↗
PubMed2026

Mutation accumulation in a hybrid parthenogenetic vertebrate.

Asexual lineages are thought to experience elevated extinction rates compared with sexual species, yet direct evidence for the underlying genetic causes remains scarce. Muller's ratchet predicts that the absence of recombination in asexual organisms facilitates the accumulation of deleterious mutations, thereby reducing long-term fitness. Here, we test this hypothesis in the hybrid-origin, parthenogenetic whiptail lizard Aspidoscelis tesselatus by integrating short-read RNAseq and long-read IsoSeq data from both the asexual lineage and its parental sexual species. We reconstructed phased transcripts for A. tesselatus to quantify mutation accumulation relative to the parental sexual species. Comparative analyses revealed elevated ω ratios in both parental genomic complements (subgenomes) of the parthenogenetic lineage, consistent with accelerated accumulation of nonsynonymous mutations. Structural variant analyses identified multiple indels in expressed transcripts predicted to disrupt protein domains. Functional annotation indicated that genes affected by both single-nucleotide variants and indels were enriched for roles in chromatin organization, apoptosis regulation, and transcriptional control. While both parental subgenomes showed similar evolutionary patterns, the maternal complement exhibited more structural and missense mutations than the paternal complement. Together, these results provide evidence that mutations accumulate in asexual A. tesselatus in genes involved in core cellular functions, supporting theoretical predictions that Muller's ratchet contributes to mutation accumulation in asexual lineages.

Animals↗
PubMed2005

Quorum sensing in Vibrio harveyi: probing the specificity of the LuxP binding site.

Quorum sensing activity was investigated in the bacterium Vibrio harveyi using a series of both natural and nonnatural analogs of DPD, the penultimate precursor to autoinducer AI-2. The progression of molecules that were both synthesized and investigated includes enantiomeric variants, carbon-chain extension, and hydroxyl-functional group addition/deletions of DPD. The compilation of these studies reveals a binding cleft that can accommodate a number of different structural variants of DPD, albeit with invariably lower activities.

Bacterial Proteins↗
PubMed2003

Glycosphingolipids of the model fungus Aspergillus nidulans: characterization of GIPCs with oligo-alpha-mannose-type glycans.

Aspergillus nidulans is a well-established nonpathogenic laboratory model for the opportunistic mycopathogen, A. fumigatus. Some recent studies have focused on possible functional roles of glycosphingolipids (GSLs) in these fungi. It has been demonstrated that biosynthesis of glycosylinositol phosphorylceramides (GIPCs) is required for normal cell cycle progression and polarized growth in A. nidulans (Cheng, J., T.-S. Park, A. S. Fischl, and X. S. Ye. 2001. Mol. Cell Biol. 21: 6198-6209); however, the structures of A. nidulans GIPCs were not addressed in that study, nor were the functional significance of individual structural variants and the downstream steps in their biosynthesis. To initiate such studies, acidic GSL components (designated An-2, -3, and -5) were isolated from A. nidulans and subjected to structural characterization by a combination of one-dimensional (1-D) and 2-D NMR spectroscopy, electrospray ionization-mass spectrometry (ESI-MS), ESI-MS/collision-induced decomposition-MS (MS/CID-MS), ESI-pseudo-[CID-MS]2, and gas chromatography-MS methods. All three were determined to be GIPCs, with mannose as the only monosaccharide present in the headgroup glycans; An-2 and An-3 were identified as di- and trimannosyl inositol phosphorylceramides (IPCs) with the structures Man alpha 1-->3Man alpha 1-->2Ins1-P-1Cer and Man alpha 1-->3(Man alpha 1-->6)Man alpha 1-->2Ins1-P-1Cer, respectively (where Ins = myo-inositol, P = phosphodiester, and Cer = ceramide). An-5 was partially characterized, and is proposed to be a pentamannosyl IPC, based on the trimannosyl core structure of An-3.

Aspergillus nidulans↗
PubMed1999

Functional implications of structural differences between variants A and B of bovine beta-lactoglobulin.

The structure of the trigonal crystal form of bovine beta-lactoglobulin variant B at pH 7.1 has been determined by X-ray diffraction methods at a resolution of 2.22 A and refined to values for R and Rfree of 0.239 and 0.286, respectively. By comparison with the structure of the trigonal crystal form of bovine beta-lactoglobulin variant A at pH 7.1, which was determined previously [Qin BY et al., 1998, Biochemistry 37:14014-14023], the structural consequences of the sequence differences D64G and V118A of variants A and B, respectively, have been investigated. Only minor differences in the core calyx structure occur. In the vicinity of the mutation site D64G on loop CD (residues 61-67), there are small changes in main-chain conformation, whereas the substitution V118A on beta-strand H is unaccompanied by changes in the surrounding structure, thereby creating a void volume and weakened hydrophobic interactions with a consequent loss of thermal stability relative to variant A. A conformational difference is found for the loop EF, implicated in the pH-dependent conformational change known as the Tanford transition, but it is not clear whether this reflects differences intrinsic to the variants in solution or differences in crystallization.

Amino Acid Substitution↗
PubMed2026

Additional PAX3 Variants for Dominant Blue Eyes in Cats.

Since the recent publication of the first feline variant of the PAX3 (Paired Box 3) gene associated with blue eyes and minimal white spotting (DBE, Dominant Blue Eyes), three further variants of PAX3 have been reported in felines. However, these four variants do not account for all the different feline lines that exhibit DBE. Whole-genome sequencing using short-read and long-read technologies identified a large complex structural variant involving two deletions and an inversion in a purebred line of British shorthair and longhair cats. All 39 British cats with a BDE phenotype were heterozygous for the variant, that was absent in 47 non-DBE cats and 16 DBE cats from other breeding lines. The purebred British shorthair founder female named Nadeya was also heterozygous for the variant, and the segregation of the variant is consistent with dominant inheritance. We named this NC_058375.1:g.[205097674_207411974del;207411975_211290497inv;211290498_211387174del] variant the DBENAD (Nadeya Dominant Blue Eyes) allele. In addition, a candidate gene approach identified a nonsense variant, XM_019838731.3:c.784C>T, in the fifth exon of PAX3 in a second breeding line originating from a female named Marusya. The segregation of this nonsense variant is consistent with dominant inheritance, and a perfect genotype-phenotype correlation was observed in the 16 cats from this line, so we propose that this sixth variant of PAX3 represents the DBEMARU (Marusya Dominant Blue Eyes) allele in the domestic cat. Our study has identified two further variants of the PAX3 gene associated with DBE in domestic cats, which will help to improve genotyping of the breeding stock.

Animals↗
PubMed1997

Diet-gene interactions in human lipoprotein metabolism.

Genetic variation can influence the effects of hypocholesterolemic dietary interventions on lipoproteins involved in coronary artery disease (CAD). Individuals with the E4 allelic variant of the apo E gene exhibit greater low-density lipoprotein (LDL) cholesterol reductions on low-fat, low-cholesterol diets than subjects with other alleles. Another apolipoprotein structural variant, apo A-IV-2, attenuates the response of LDL cholesterol to dietary cholesterol. Other studies have associated lipoprotein response to dietary modifications with DNA polymorphisms in the genes for apo B and the LDL receptor, and in the promoter region of the apo A-I gene. Studies in our laboratory involving variation in dietary fat and carbohydrate intake have demonstrated that alleles at the apo E gene locus are associated with changes in large, buoyant but not smaller, denser LDL subclasses. On the other hand, a low-fat diet induces a reduction in small, dense LDL in individuals with a genetically influenced metabolic profile characterized by a predominance of these particles. Moreover, reductions in LDL cholesterol and apo B in these subjects are greater than in the majority of subjects with larger LDL. Since in humans a predominance of small LDL signifies a higher risk for coronary artery disease than that associated with larger LDL, metabolic and genetic factors contributing to the small LDL trait may account for a substantial portion of the coronary risk benefit attributed to reduced-fat diets. Studies in large population groups or in suitable animal models will be necessary to determine the impact of genetic influences on dietary response affecting lipoprotein metabolism and their interactions with other environmental and hormonal factors.

Apolipoproteins↗
PubMed2005

Vitamin D receptor variants in 192 patients with schizophrenia and other psychiatric diseases.

Intriguing parallels have been noted previously between the biology of Vitamin D and the epidemiology of schizophrenia. We have scanned the Vitamin D receptor (VDR) gene by DOVAM-S (Detection of Virtually All Mutations-SSCP), a robotically enhanced multiplexed scanning method. In total, 100 patients with schizophrenia (86 Caucasians and 14 African-Americans) were scanned. In addition, pilot experiments were performed in patients with bipolar disorder (BPD) (24), autism (24), attention deficit hyperactivity disorder (ADHD) (24), and alcoholism (20). A total of 762 kb of the VDR genomic sequence was scanned. R208N and V339I were each found in one African-American patient, while absent in 35 African-American controls without schizophrenia (2/14 versus 0/35, P=0.08). Within the power of the study (> or =1.6-fold relative risk), the common M1T variant is not associated with schizophrenia. In the 92 scanned patients with other psychiatric diseases, R173S was found in a single patient with bipolar disorder. In conclusion, we describe three novel structural variants of the Vitamin D receptor. Further study is required to clarify their role, if any, in psychiatric disease.

Amino Acid Sequence↗