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PubMed2004

The molecular basis of the differential subcellular localization of FYVE domains.

This study systematically analyzed the structural and mechanistic basis of the regulation of subcellular membrane targeting using FYVE domains as a model. FYVE domains, which mediate the recruitment of signaling and membrane-trafficking proteins to phosphatidylinositol 3-phosphate-containing endosomes, exhibit distinct subcellular localization despite minor structural variations within the family. Biophysical measurements, cellular imaging, and computational analysis of various FYVE domains showed that the introduction of a single cationic residue and a hydrophobic loop into the membrane binding region of the FYVE domains dramatically enhanced their membrane interactions. The results indicated that there is a threshold affinity for endosomal localization and that endosomal targeting of FYVE domains is sensitive to small changes in membrane affinity about this threshold. Collectively these studies provide new insight into how subcellular localization of FYVE domains and other membrane targeting domains can be regulated by minimal structural and environmental changes.

Amino Acid Sequence↗
PubMed1996

[Analysis of the DRG rate system in cardiology. Results of a comparative study of diverse regions].

Following the introduction of the reimbursement system for services, the use of a different rate system can have a singularly negative effect on the actual clinical activity. A discipline such as cardiology can be particularly exposed to the eventual variation in rates, and we feel it is necessary to introduce appropriate systems of analysis to deal with this problem. In the present study we carried out an analysis of the rate parameters adopted in Italy, by the Ministry and by two Regions: Lombardia and the Marche. The study took into account only the DRGs of cardiological diseases. We found that regional rates differed greatly according to the evaluation given to some diagnostic groups, inevitably determining the under valuation of the clinical complexity of some cases with the risk of a financial squeeze of certain structures. Variations in the composition of rate lists can also lead to distorted behaviour when selecting cases on condition of the quality of services given. The comparison of rates between the Marche and Lombardia regions showed a great difference in the number of subjects hospitalised for critical pathologies and stable ones, putting the wards in the Marche region in potential difficulty as their activity is aimed at more intensive and emergency therapy. The present study aims at underlining these problems, identifying the most evident inconsistencies and opening a debate on the subject.

Diagnosis-Related Groups↗
PubMed1987

gem-Diphosphonate and gem-phosphonate-phosphate compounds with specific high density lipoprotein inducing activity.

New diphosphonate compounds and related derivatives were synthesized and investigated for their activity in specifically inducing plasma high density lipoproteins (HDL) and high density lipoprotein cholesterol (HDL-C) in normal rats. The screening of numerous compounds has permitted the determination of the structural variations leading to optimal plasma lipid altering activity, indicating antiatherosclerotic potential. Among the compounds observed to be the most active, dimethyl alpha-(dimethoxyphosphinyl)-p-chlorobenzyl phosphate (20, SR-202, mifobate) was selected for further pharmacological and subsequent clinical development.

Animals↗
PubMed2000

Structure activity relationship of carboxylic ester antagonists of the vitamin D(3) receptor.

A 25-carboxylic ester analog of 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)], ZK159222 (compound 1), was recently described as a novel type of antagonist of 1alpha,25(OH)(2)D(3) signaling. In this study five derivatives of compound 1 (compounds 2-6) were selected because of their sensitivity in facilitating complex formation between the 1alpha,25(OH)(2)D(3) receptor (VDR) and the retinoid X receptor on a 1alpha,25(OH)(2)D(3) response element that was comparable to that of the natural hormone (0.2-0.9 nM). Most derivatives of compound 1 reacted as typical agonists, because they were able to promote ligand-dependent interaction of the VDR with the coactivator TIF2, stabilized the VDR preferentially in its agonistic conformation c1(LPD), and stimulated VDR-dependent gene activity with a potency similar to 1alpha,25(OH)(2)D(3). In contrast, only compound 2 showed the antagonistic profile of compound 1, which includes the incompetence to induce a VDR-TIF2 contact, the stabilization of the antagonistic conformation c2(LPD), and only a very weak and insensitive functional activity. Accordingly, only compounds 1 and 2, but not compounds 3 to 6, showed prominent antagonistic effects in cellular systems. The comparison of the structures of the compounds indicates that the essential requirements for an antagonistic function are a cyclopropyl ring at carbon 25, a hydroxy group at carbon 24, and at least a butylester. Interestingly, compound 2 was an approximately 3 times more sensitive antagonist than compound 1 and even displayed a lower residual agonistic activity. In conclusion, only a very limited number of structural variations of compound 1 are possible to keep its antagonistic profile, but the tools presented here for their in vitro evaluation allow an accurate prediction of the effects and are suited to screening for even more potent 1alpha, 25(OH)(2)D(3) antagonists.

Calcitriol↗
PubMed1992

Neisseria gonorrhoeae PilC expression provides a selective mechanism for structural diversity of pili.

Pili of Neisseria gonorrhoeae undergo both phase and structural variation. Phase variation of gonococcal pili can be caused by a RecA-independent on/off switch in PilC, a protein involved in pilus biogenesis. We show here that spontaneous nonpiliated PilC- derivatives as well as PilC- insertional mutants have also acquired sequence alterations in pilE relative to the pilE gene of the piliated MS11mk(P+)-u parent, so that the pilin produced is processed to soluble S-pilin and can be released into the medium. It is proposed that pilin alterations are selected for in PilC- bacteria if the parental nonassembled pilin is toxic to the cells--i.e., is not degradable to S-pilin at rates sufficient to allow viability of the cells. Toxicity is indicated by the extreme instability of certain unassembled pilin sequences and by the low frequency of nonpiliated, pilin+, PilC- variants that emerge from piliated recA- cells. The presence of a point mutation changing leucine-39 to phenylalanine at the cleavage site for S-pilin in one nonpiliated, PilC-, recA- variant relative to its piliated parent is a further argument for a selective mechanism of structural diversity of the gonococcal pilin.

Amino Acid Sequence↗
PubMed1998

Evidence for diverse pathways of hypophysiotropic hormone transport in mammals.

Comparative studies of mammalian hypothalamic-pituitary relationships have revealed striking variations in hypophysiotropic systems and in portal vascular architecture. Immunocytochemical studies indicate that mammalian GnRH, GHRH and somatostatin systems can project to all portions of the neurohypophysis (median eminence, infundibular stem and pituitary neural lobe). In rats, primary secretion sites are located within the median eminence and upper infundibular stem, whereas in bats, most projections extend into the lower infundibular stem and pituitary neural lobe. In ferrets and monkeys, sites of secretion appear to extend throughout the neurohypophysis, from median eminence to proximal neural lobe. In this review, these interspecific differences are examined in light of observed structural variations in portal vascular systems. Correlations suggest that hypophysiotropic hormones can be delivered to target cells in the pars distalis by diverse routes, with some species relying more heavily on long and others on short portal transport. These patterns may have important functional implications with respect to regulatory mechanisms operating within the hypothalamic-pituitary complex.

Animals↗
PubMed1966

Ovarian steroid cells. II. The lutein cell.

The lutein cells of the rabbit exhibit fine structural variations during their life-span of 28 to 30 days. A systematic examination of the corpus luteum reveals that cellular distinctions may be recognized during the first, second, and third stages of pregnancy. The agranular endoplasmic reticulum reveals vesicular, tubular, and cisternal profiles after fixation with each of the following fixatives: glutaraldehyde, osmium tetroxide, and permanganate. The osmolality of the fixing solutions was varied with sucrose and recorded with an osmometer in order to determine the effect of osmotic concentration on the intracellular membranous profiles. It was determined that vesicles and short, branched tubules of similar structure are present in the agranular reticulum when the osmolalities are 300 to 800 milliosmols (iso-osmotic considered 300 milliosmols). At 900 milliosmols, the vesicular or tubular lumen is obliterated. Intracellular membrane profiles do not exhibit interconversions due to hyperosmotic fixative solutions. The agranular endoplasmic reticulum is randomly distributed as short tubular profiles during the first third of pregnancy. A continuity between these membranes and irregular, electron-opaque lipid masses is evident. When physiological and histochemical data indicate that the lutein cell may be storing sterol precursors, cytological observations show that the agranular endoplasmic reticulum exists in a more organized pattern within the cytoplasmic matrix. Vesicular and short tubular, circular aggregations as well as whorled cisternal patterns surround the larger, less electron-opaque lipid droplets. Surface views of cisternal agranular endoplasmic reticulum exhibit tubular extensions, accentuating the continuity between these two profiles. During the progress of pregnancy, the lutein cell increases in diameter, and accumulates both lipid inclusions and aggregations of intracellular membranes. The agranular endoplasmic reticulum may be peripherally packed and arranged parallel to the cell surface during later stages. In the postpartum, degenerating lutein cell, large myelin figures are present which form from the agranular endoplasmic reticulum. These cellular events are discussed in relation to lutein cell activity, including both secretion of product and storage of precursors.

Animals↗
PubMed2003

Study of electrostatic potential surface distribution of wild-type plastocyanin Synechocystis solution structure determined by homonuclear NMR.

Plastocyanin is a small (approximately 10 kDa), type I blue copper protein that works as an electron donor to photosystem I from cytochrome f in both chloroplast systems and in some strains of cyanobacteria. Comparative studies of the kinetic mechanisms of plastocyanins in different organisms show that the electron transfer from photosystem I happens by simple collision in cyanobacteria but through a intermediate transition complex in green algae and superior plants. Previous work has proved that this effect cannot be explained by structural variations across the different plastocyanins but it can be explained by differences in the electrostatic potential distribution at the protein surface. In that case, minor conformational errors at the amino acid side chain level may imply an important effect in the electrostatic potential distribution calculation. In this work we present a high resolution study of side chain conformation by homonuclear NMR for the reduced wild-type plastocyanin Synechocystis using intensity ratios for 2D-NOESY and 2D-H,H-TOCSY cross peaks at different mixing times. We also present the corresponding comparison with different plastocyanin structures and the effect in the electrostatic potential distribution at the protein surface. We discuss the importance of indirect J-coupling information from TOCSY-type experiments as complement for intraresidue distances derived from NOESY experiments in the determination of side chain orientation and stereo-specific assignments.

Cyanobacteria↗
PubMed1975

Effect of pKb on lipophilic binding of disopyramide derivatives to human plasma.

The extent of plasma binding, the partition coefficient, and the pKb of 13 disopyramide derivatives were determined. The structural variation on the diisopropylaminoethyl group of disopyramide molecules influenced these physical parameters to varying degrees. Results demonstrated that the extent of interaction between drugs and human plasma was a linear function of their lipophilicity and inversely proportional to the magnitude of the pKb value.

Blood Proteins↗
PubMed1995

The CrP operon of Chlamydia psittaci and Chlamydia pneumoniae.

One of the critical developmental events during the unique intracellular life cycle of Chlamydiae is their differentiation from a metabolically active, replicative form or reticulate body (RB) to an infectious extracellular form of the organism (elementary body or EB). This process is characterized by the expression of two extraordinarily cysteine-rich envelope proteins of molecular masses 9 kDa and 60 kDa. We describe the molecular cloning and sequence determination of the 9 kDa cysteine-rich proteins (CrPs) of C. pneumoniae and C. psittaci. Comparison of these 9 kDa CrP amino acid sequences with those of C. trachomatis showed regions of structural variation and conservation. Transcription of the 9 kDa CrP genes occurred as both a monocistronic message and as a bicistronic message which included the 60 kDa CrP gene. Transcription of the 9 kDa and 60 kDa CrP genes was tightly linked to the chlamydial growth cycle with synthesis of their mRNAs and consequent translation of the 60 kDa CrPs occurring as RBs differentiated to form EBs. The maximal rate of transcription occurred late in the growth cycle from a single but highly conserved promoter which had close similarity with the Escherichia coli consensus promoter sequences. A stem and loop structure which could be involved in regulating translation of mRNA occurred in all three species between the transcriptional start point and the ribosome binding site. Although transcription is initiated from a single promoter in all three chlamydial species, transcriptional termination points for the monocistronic and bicistronic mRNAs differ in both number and position.

Amino Acid Sequence↗
PubMed2026

De novo genome assemblies of threatened Asian hornbills (Bucerotidae) reveal declining population trajectories during the late Pleistocene.

BACKGROUND: Asian hornbills are flagship species of the wet tropics that face significant threats from hunting, habitat loss, and fragmentation. Despite being conservation flagships, whole genome information is available for only two of the 32 Asian hornbill species. In this study, we provide the first de novo genome assemblies for four hornbill species (Bucerotidae) in Asia. METHODS: We used a combination of long-read and short-read sequencing data to assemble and annotate de novo hybrid genomes of four species of hornbills. We also assembled and compared mitochondrial genomes of these species. Using a comparative genomics approach, we performed orthology assignment and gene evolution analyses to identify unique gene families in Asian hornbills, gene families that showed significant expansion, their functions and structural variation. Furthermore, using the Pairwise Sequentially Markov Coalescent (PSMC) method, we reconstructed demographic histories of hornbill species to examine changes in their population trajectories in the past. RESULTS: We present hybrid genome assemblies for Great Hornbill (B. bicornis - GH), Rufous-necked Hornbill (A. nipalensis- RNH), Malabar Pied Hornbill (A. coronatus- MPH) and Wreathed Hornbill (R. undulatus- WH). The genome sizes of these hornbills range from 1.1 Gb to 1.3 Gb, with over 95.9% completeness and gene prediction BUSCO. We reported 10,525 orthogroups shared among four Asian hornbill species and identified significant expansion in gene families associated with structural keratin development in Asian hornbills compared to their ancestors. We also provide annotated mitogenomes for each of these species. Furthermore, we found that the WH, a more abundant, widely distributed, and migratory species, showed a higher Ne than the other three hornbill species. However, an overall decline in Ne for all species was recorded during the Pleistocene climatic fluctuations. CONCLUSIONS: We present the first-ever, high-quality reference genomes for the threatened hornbill species from Asia. Hornbills have shown significant expansion in genes involved in structural keratin development. Our results indicate that Pleistocene climatic fluctuations have led to dramatic population declines in all four species. We believe that this study provides robust genomic resources to support future comparative and conservation genomics efforts for hornbills.

Animals↗
PubMed2000

Matching protein beta-sheet partners by feedforward and recurrent neural networks.

Predicting the secondary structure (alpha-helices, beta-sheets, coils) of proteins is an important step towards understanding their three dimensional conformations. Unlike alpha-helices that are built up from one contiguous region of the polypeptide chain, beta-sheets are more complex resulting from a combination of two or more disjoint regions. The exact nature of these long distance interactions remains unclear. Here we introduce two neural-network based methods for the prediction of amino acid partners in parallel as well as anti-parallel beta-sheets. The neural architectures predict whether two residues located at the center of two distant windows are paired or not in a beta-sheet structure. Variations on these architecture, including also profiles and ensembles, are trained and tested via five-fold cross validation using a large corpus of curated data. Prediction on both coupled and non-coupled residues currently approaches 84% accuracy, better than any previously reported method.

Animals↗
PubMedDate not supplied

Study of optical transmittance of AgOx nano thin film in super-resolution near-field structure.

The AgOx-type super-resolution near-field structure (super-RENS) is one of the nano thin films that can give a nonlinear optical effect similar to that of the optical probe of the scanning near-field optical microscope. Structural variations of different thicknesses of the AgOx thin film are observed and studied using a field-emission scanning electron microscope (FE-SEM). For single AgOx nano thin film, the critical temperature and threshold of the evaporation temperature are 154 degrees and 600 degrees, respectively. Results show that the sandwiched AgOx nano thin film has a higher critical temperature, that is, about 280 degrees. For the sandwiched AgOx nano thin film, the transmittance peak is dependent on the thickness of the AgOx thin film. The interesting properties of the AgOx nano thin film of the super-resolution structure indicate a great potential for photonic applications.

Journal Article↗
PubMed1999

Structural analysis of DNA-chlorophyll complexes by Fourier transform infrared difference spectroscopy.

Porphyrins and metalloporphyrins are strong DNA binders. Some of these compounds have been used for radiation sensitization therapy of cancer and are targeted to interact with cellular DNA. This study was designed to examine the interaction of calf thymus DNA with chlorophyll a (CHL) in aqueous solution at physiological pH with CHL/DNA(phosphate) ratios (r) of 1/160, 1/80, 1/40, 1/20, 1/10, and 1/5. Fourier transform infrared (FTIR) difference spectroscopy was used to characterize the nature of DNA-pigment interactions and to establish correlations between spectral changes and the CHL binding mode, binding constant, sequence selectivity, DNA secondary structure, and structural variations of DNA-CHL complexes in aqueous solution. Spectroscopic results showed that CHL is an external DNA binder with no affinity for DNA intercalation. At low pigment concentration (r = 1/160, 1/80, and 1/40), there are two major binding sites for CHL on DNA duplex: 1) Mg-PO2 and 2) Mg-N7 (guanine) with an overall binding constant of K = 1.13 x 10(4) M-1. The pigment distributions are 60% with the backbone PO2 group and 20% with the G-C base pairs. The chlorophyll interaction is associated with a major reduction of B-DNA structure in favor of A-DNA. At high chlorophyll content (r = 1/10), helix opening occurs, with major spectral alterations of the G-C and A-T bases. At high chlorophyll concentration (1/5), pigment aggregation is observed, which does not favor CHL-DNA complexation.

Animals↗
PubMed2003

The coiled-coil of the human Rad50 DNA repair protein contains specific segments of increased flexibility.

Protein structural features are usually determined by defining regularities in a large population of homogeneous molecules. However, irregular features such as structural variation and flexibility are likely to be missed, despite their vital role for their biological function. In this paper, we report the observation of striking irregularities in the flexibility of the coiled-coil region of the human Rad50 DNA repair protein. Existing methods to quantitatively analyze flexibility are applicable to homogeneous polymers only. Because protein coiled-coils cannot be assumed to be homogeneous, we develop a method to quantify the local flexibility from high-resolution atomic force microscopy images. Indeed, in Rad50 coiled-coils, two positions of increased flexibility are observed. We discuss how this dynamic structural feature is integral to Rad50 function.

Biophysical Phenomena↗
PubMed1995

Targeting pyrimidine single strands by triplex formation: structural optimization of binding.

Recent reports describe a new strategy for the binding of single-stranded pyrimidine sequences by triple helix formation. In this approach, a double-length purine-rich oligonucleotide binds a target strand, folding back to form an antiparallel pur.pur.pyr triple helix. We now describe a series of studies in which sequence and structural variations are made in such purine-rich ligands, in an effort to optimize binding properties. Comparison is made between the use of two separate strands and the use of single two-domain ligands; the latter are found to bind more tightly and to aggregate less in media containing Na+ or K+. Placement of mismatched bases in the target shows that sequence selectivity of binding is as high as that for Watson-Crick duplex formation. Variation of the lengths and sequences of loops bridging the binding domains demonstrates that dinucleotide loops composed of pyrimidines give the highest stability. Oligoethylene glycol-derived loop replacements are shown to give good binding affinity as well. The binding of an RNA target is shown to occur with the same affinity as the binding of DNA. In general, it is found that circular variants bind more tightly than do either separate strands or singly-linked ligands and unlike linear oligomers, the circular compounds do not aggregate to a large extent even in buffers containing 100 mM K+. Such structurally optimized ligands are useful in expanding the number of possible naturally-occurring sequences which can be targeted by triplex formation.

Base Sequence↗
PubMed2001

Structure-function studies of linear and cyclized peptide antagonists of the GnRH receptor.

Structurally new analogs of the peptidic GnRH receptor antagonist Cetrorelix as well as conformationally constrained cyclized deca- or pentapeptides were synthesized and selected peptides evaluated comprehensively. To understand how structural variations of the antagonistic peptide effect pharmacodynamic properties, binding affinities and antagonistic potencies toward the human and rat GnRH receptor were determined. Whereas large substituents in position 6 of linear peptides are compatible with high binding affinity (K(D) < 0.5 nM), all cyclized peptides except the cyclo[3-10] analog D-52391 depicted low binding affinity (K(D) > 10 nM). Binding affinity and antagonistic potency in vitro correlated for all peptides and surprisingly no discrimination between human and rat receptor proteins was observed. Since receptor residues W(101) and N(102) are involved in agonist and antagonist binding, equally potent but structurally different antagonists were tested for binding to the respective W(101)A and N(102)A mutants. In contrast to linear decapeptides, residues N(102) and W(101) are not involved in binding of D-23938 and W(101) is the critical residue for D-52391 binding. We conclude that although equally potent, peptidic GnRH receptor antagonists do have distinct interactions within the ligand binding pocket. Finally, selected antagonists were tested for testosterone suppression in male rats. The duration of testosterone suppression below castration levels differed largely from 1 day for Ganirelix to 27 days for D-23487. Systemic availability became evident as the most important parameter for in vivo efficacy.

Amino Acid Sequence↗
PubMed1986

Biochemical genetics of TL antigens.

TL antigens are class I glycoproteins which are expressed on thymocytes and which are coded by the Tla region of the major histocompatibility complex of the mouse. Biochemical analysis of TL molecules from different strains of mice revealed structural variation determined by the Tla region which is detectable by peptide mapping, isoelectric focusing, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, two-dimensional gels, and by differential reactivity of allelic forms of TL molecules with a panel of anti-TL reagents. The quantity of TL expressed on thymocytes is also influenced by the Tla region; three quantitative phenotypes were identified: high (Tlaa, Tlad, Tlae), intermediate (Tlac, Tlaf), and low (Tlab). (Relative amounts: 1000: 100: 1.) Some thymic leukemias arising in (Tlab, Tlac) mice with genetically determined reduced levels of thymic TL were found to express TL molecules which were structurally indistinguishable from TL isolated from thymocytes but were present in larger amounts. This suggests that TL structural genes are intrinsically capable of full expression in all mice but that the Tla region of mice expressing an intermediate or low quantity of TL is marked by some feature which causes the thymocyte to express less than the full amount of TL possible.

Age Factors↗