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PubMed1996

DNA sequence and structure requirements for cleavage of V(D)J recombination signal sequences.

Purified RAG1 and RAG2 proteins can cleave DNA at V(D)J recombination signals. In dissecting the DNA sequence and structural requirements for cleavage, we find that the heptamer and nonamer motifs of the recombination signal sequence can independently direct both steps of the cleavage reaction. Proper helical spacing between these two elements greatly enhances the efficiency of cleavage, whereas improper spacing can lead to interference between the two elements. The signal sequences are surprisingly tolerant of structural variation and function efficiently when nicks, gaps, and mismatched bases are introduced or even when the signal sequence is completely single stranded. Sequence alterations that facilitate unpairing of the bases at the signal/coding border activate the cleavage reaction, suggesting that DNA distortion is critical for V(D)J recombination.

Animals↗
PubMed1981

Differences among H1 histone subfractions in binding to linear and superhelical DNA. Sedimentation velocity studies.

H1 histone subfractions exhibit differential abilities in aggregating superhelical DNA, as measured by sedimentation velocity analysis. In 0.15 M NaCl, all the calf thymus H1 subfractions bound to superhelical PM2 DNA to produce nonaggregated H1-DNA complexes as well as rapidly sedimenting, aggregated complexes. Notably, the distribution of the complexes between the nonaggregated and aggregated forms was a function of ionic strength and also depended on which H1 subfraction was complexed to the superhelical DNA. All of the H1 subfractions interacted preferentially with superhelical over relaxed PM2 DNA. The cooperative binding of H1 subfractions to linear T7 DNA produced only aggregated H1-DNA complexes in 0.15 M NaCl, while leaving some DNA free. The compositional and structural variation between the subfractions of H1 histone serves as a basis for their differential effectiveness in H1-induced aggregation of superhelical DNA. The observed sensitivity of aggregation to NaCl concentration is interpreted in terms of a dependence on hydrophobic interactions, such as the proper folding of the particular H1 subfraction and intermolecular interactions between neighboring hydrophobic regions, as well as on nonspecific shielding of DNA charge. These sedimentation velocity analyses augment previous studies on the interactions of H1 subfractions with linear and superhelical DNA using circular dichroism, viscosity, and filter-binding analyses. The involvement of particular H1 and DNA conformations in producing the various types of H1-DNA interactions characterized in these studies might also apply to chromatin structure.

Animals↗
PubMed2005

Formation of a nanostructured layer on bioglass particles of different sizes immersed in tris-buffered solution. N2 adsorption and HR-TEM/EDS analysis.

Morphological and structural variations of particles of Bioglass with two different grain sizes reacted in Tris-buffered solution were analyzed by means of N(2) adsorption/desorption at 77 K and HR-TEM/EDS. A remarkable increase in specific surface area (ssa) was observed after the first hour of dissolution. A plateau value corresponding to an increase of at least 2 orders of magnitude was reached after 2 days of dissolution. The ssa increase was faster for the smaller particle size sample, and the ratio between the ssa of the starting samples was not maintained during dissolution. Both micro- and mesopores were formed at different stages of the reaction for the two samples. Increasing ssa was also connected to the formation of a microcrystalline structure rich in Ca and P, as shown by TEM images. The segregation of both a SiO(2)-rich amorphous phase and a Ca/P-rich crystalline phase was observed after the first hour of dissolution. After 2 days of reaction, Ca/P-rich particles made of fine aciculate crystals were found either in close contact with SiO(2) particles or deposited on a small SiO(2)-rich core. A preliminary analysis of TEM data showed the formation, together with hydroxy carbonate apatite, of different types of calcium phosphates not detectable by powder X-ray diffraction.

Adsorption↗
PubMed2026

A De Novo 16p13.3 Triplication Underlying Early-Onset Complex Neurodegeneration.

BACKGROUND: Neurodegenerative disorders are clinically and genetically heterogeneous, characterized by progressive neuronal loss and multidomain functional decline. Despite a presumed genetic etiology, a substantial proportion of cases remain molecularly undiagnosed. OBJECTIVE: The aim was to identify the genetic cause of an early-onset neurodegenerative disorder presenting with ataxia and cognitive impairment. METHODS: Rare copy-number variants were detected via short-read whole-genome sequencing (WGS), with candidate structural models inferred using long-read WGS. We performed transcriptomic profiling of peripheral blood leukocytes by RNA sequencing, with validation using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). RESULTS: We identified a de novo copy-number gain at 16p13.3. Combined copy-number profiling and long-read WGS suggested a candidate model comprising a triplicated segment in tandem with a proximal duplication, joined to a distal duplication via an inverted junction. Transcriptomic analysis demonstrated significant upregulation of ATP6V0C, AMDHD2, and PDPK1. CONCLUSIONS: These findings support a role for structural variation in early-onset neurodegeneration and highlight the value of combining short-read copy-number profiling with long-read WGS to detect and characterize complex genomic rearrangements. © 2026 International Parkinson and Movement Disorder Society.

16p13.3↗
PubMed1989

Surface enhanced resonance Raman scattering (SERRS) as a probe of the structural differences between the Pr and Pfr forms of phytochrome.

Surface enhanced resonance Raman scattering (SERRS) spectra have been obtained from the active, far-red light absorbing (Pfr) and biologically inactive (Pr) forms of phytochrome adsorbed on silver colloids. Substantial differences between the SERRS spectra of the two forms in the low and high wavenumber regions are observed using 406.7 nm wavelength excitation. These differences reinforce those seen with 413.1 nm wavelength excitation in the high wavenumber region. Simultaneously, extensive differences are observed in the SERRS obtained from the same form in the low wavenumber region using 406.7 nm, as compared with 413.1 nm wavelength excitation. The relative intensity differences observed for the two forms, and those obtained using two slightly different excitation wavelengths to illuminate the same form, suggest that some type of subtle, protein-controlled structural variation is responsible for the spectroscopic differences. AZ----E isomerization during the Pr----Pfr phototransformation is consistent with the SERRS data, although the overall chromophore conformations are most likely conserved for the native Pr- and Pfr-phytochrome species. Slight out-of-plane ring twisting, accompanying the Pr----Pfr photoisomerization, may be responsible for the large difference in the spectroscopic properties of the native Pr and Pfr chromophores.

Molecular Structure↗
PubMed2000

N1-(Benzenesulfonyl)tryptamines as novel 5-HT6 antagonists.

N-Benzenesulfonyl-5-methoxy-N,N-dimethyltryptamine (BS/5-OMe DMT; 5) was shown to bind at human 5-HT6 serotonin receptors with high affinity (Ki = 2.3 nM) relative to serotonin (Ki = 78 nM). Structural variation failed to result in significantly enhanced affinity. BS/5-OMe DMT acts as an antagonist of 5-HT-stimulated adenylate cyclase (pA2 = 8.88 nM) and may represent the first member of a novel class of 5-HT6 antagonists.

Adenylyl Cyclases↗
PubMed1994

VASE exon expression alters NCAM-mediated cell-cell interactions.

The neural cell adhesion molecule (NCAM) is found on cells as several related polypeptides formed by alternative splicing of the single NCAM gene. The alternatively spliced 30-bp VASE exon in the fourth immunoglobulin-like domain is the structural variation nearest those portions of the polypeptide proposed to mediate cell-cell adhesion. To test the ability of distinct forms of the NCAM molecules to mediate cell adhesion, L cells were transfected with expression vectors encoding rat 140 kD NCAM +/- the VASE exon. L cell lines which expressed these polypeptides were isolated and tested for self-aggregation in a low shear, rapid aggregation assay. Increased cellular aggregation of the transfectants was observed to be a function of the NCAM molecule expressed. These transfected cells showed segregation in a long term co-aggregation assay: cells expressing NCAM--VASE formed aggregates which tended to exclude cells expressing NCAM+VASE and vice versa. These results provide direct evidence that this small difference in NCAM structure is sufficient to allow segregation of cells.

Animals↗
PubMed2004

Solid-phase synthesis and screening of macrocyclic nucleotide-hybrid compounds targeted to hepatitis C NS5B.

A convergent strategy for the synthesis of cyclic nucleotide-hybrid molecules on controlled pore glass is reported. A major advantage of the approach is the lack of restrictions on the sequence and structural variation, allowing the incorporation of modified ribonucleosides (such as 2'-OMe-ribonucleotides), as well as threoninol derivatives. This methodology allows a fully automated assembly by means of standard phosphoramidite chemistry and is based on a recently published procedure for the preparation of cyclic oligodinucleotides in the DNA series (M. Smietana, E. T. Kool, Angew. Chem. 2002, 114, 3856-3859; Angew. Chem. Int. Ed. Engl. 2002, 41, 3704-3707). A library of potential cyclic hybrid inhibitor compounds targeting hepatitis C virus NS5B enzyme (the replicating polymerase of HCV) was generated by means of the parallel-pool strategy. Screening of the library revealed that cyclic hybrid c(C(OME)EthenodA) was a significant inhibitor of NS5B, with an IC(50) of 40 microM. Preliminary structure-activity studies of this lead compound are described.

Animals↗
PubMed2004

RNA adducts with chlorophyll and chlorophyllin: stability and structural features.

Porphyrins and their metal derivatives are strong nucleic acids binders. Some of these compounds have been used for radiation sensitization therapy of cancer and are targeted to interact with cellular DNA. Chlorophyll (Chl) binds DNA via guanine N-7 atom (major groove) and the backbone phosphate group (Neault and Tajmir-Riahi. Biophys. J. 76, 2177, 1999), whereas chlorophyllin (Chln) intercalates into A-T and G-C regions (Neault and Tajmir-Riahi. J. Phys. Chem. B. 102, 1610, 1998). This study was designed to examine the interaction of RNA with chlorophyll a and chlorophyllin in aqueous solution at physiological pH with pigment/RNA(phosphate) ratios (r) of 1/80 to 1/2. Fourier transform infrared (FTIR) and UV-visible difference spectroscopic methods were used to characterize the nature of pigment-RNA interaction and to establish correlation between spectral changes and the pigment binding mode, binding constant, RNA secondary structure and structural variations of pigment-RNA complexes in aqueous solution. Spectroscopic results showed that Chl and Chln bind RNA through G-C and A-U bases and the backbone phosphate group with overall binding constants of KChl = 1.95 x 10(5) M(-1) and KChln = 1.61 x 10(5) M(-1). The larger K value obtained for Chl-RNA complexes is attributed to the formation of more stable five or six-coordinate Mg cation in the RNA adducts, while the four-coordination Cu(II) in Chln can be more stable than that of the five or six-coordinated copper ion in the Chln-RNA complexes. Aggregation of pigment-RNA complexes occurs at high metalloporphyrin concentrations. No biopolymer secondary structural changes were observed upon pigment interaction and RNA remains in the A-family structure in these pigment complexes.

Antimutagenic Agents↗
PubMed2001

Structure-activity relationship studies of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of HCV NS3 serine protease.

A survey of isosteric replacements of the phosphonoalanine side chain coupled with a process of conformational constraint of a bisbenzimidazole-based, Zn(2+)-dependent inhibitor of hepatitis C virus (HCV) NS3 serine protease resulted in the identification of novel series of active compounds with extended side chains. However, Zn(2+)-dependent HCV NS3 inhibition was relatively insensitive to the structural variations examined but dependent on the presence of negatively charged functionality. This result was interpreted in the context of an initial electrostatic interaction between protease and inhibitor that is subsequently consolidated by Zn(2+), with binding facilitated by the featureless active site and proximal regions of the HCV NS3 protein.

Antiviral Agents↗
PubMed1991

Effect of cyclodextrins on the chemical stability of mitomycins in alkaline solution.

The effects of cyclodextrins on the chemical stability of several mitomycin antibiotics in an alkaline medium have been investigated. A stability-indicating high-performance liquid chromatographic method was used to determine the overall degradation rate constants. The influence of various parameters such as structural variations of the cyclodextrins and mitomycins, temperature and pH was studied. It appears that complexation is most favourable with gamma-cyclodextrin. All mitomycin-gamma-cyclodextrin complexes degrade at lower rates than those of the free drugs. Moreover, it was shown that gamma-cyclodextrin influences the equilibrium between mitomycin C and its zwitterion mesomer.

Alkalies↗
PubMed1995

Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB.

Echinocandin B (ECB) is a lipopeptide composed of a complex cyclic peptide acylated at the N-terminus by linoleic acid. Enzymatic deacylation of ECB provided the peptide "nucleus" as a biologically inactive substrate from which novel ECB analogs were generated by chemical reacylation at the N-terminus. Varying the acyl group revealed that the structure and physical properties of the side chain, particularly its geometry and lipophilicity, played a pivotal role in determining the antifungal potency properties of the analog. Using CLOGP values to describe and compare the lipophilicities of the side chain fragments, it was shown that values of > 3.5 were required for expression of antifungal activity. Secondly, a linearly rigid geometry of the side chain was the most effective shape in enhancing the antifungal potency. Using these parameters as a guide, a variety of novel ECB analogs were synthesized which included arylacyl groups that incorporated biphenyl, terphenyl, tetraphenyl, and arylethynyl groups. Generally the glucan synthase inhibition by these analogs correlated well with in vitro and in vivo activities and was likewise influenced by the structure of the side chain. These structural variations resulted in enhancement of antifungal activity in both in vitro and in vivo assays. Some of these analogs, including LY303366 (14a), were effective by the oral route of administration.

Acylation↗
PubMed2004

Evolutionary perspective on annexin calcium-binding domains.

Molecular systematic analysis of the annexin gene superfamily characterized the evolutionary origin, frequency and range of structural variation in calcium interaction domains that are considered intrinsic for membrane targeting and ion channel function. Approximately 36% of annexin repeat domains in an estimated 100 distinct subfamilies contained amino acid changes consistent with the functional loss of type two calcium-binding sites. At least 11% of annexin domains contained a novel K/H/RGD motif conserved in particular subfamilies and manifest in all phyla, apparently via convergent evolution. The first yeast annexin from Yarrowia lipolytica was classified in the ANXC1 subfamily with fungal and mycetozoan representatives. This clade had intact calcium-binding sites but disruption of the normally well-conserved, mid-repeat 4 region implicated in calcium channel regulation. Conversely, a tandem pair of novel annexins from the amphioxus Branchiostoma floridae resembled annexin A13 in gene structure and conserved the charged amino acids associated with the internal hydrophilic pore, but were devoid of external type 2 calcium-binding sites and incorporated K/RGD motifs instead, like annexin A9. The selective erosion of calcium-binding sites in annexin domains and the occurrence of alternate ligands in the same exposed, interhelical loops are pervasive features of the superfamily. This suggests greater complexity than previously appreciated in the mechanisms controlling annexin membrane interaction and calcium channel operation.

Amino Acid Sequence↗
PubMed2006

Ezetimibe analogs with a reorganized azetidinone ring: Design, synthesis, and evaluation of cholesterol absorption inhibitions.

The underlying principle of drug design in this paper is that the maximum retention of the functional groups that exist in the marketed drug would provide a higher probability for comparable safety while the conformational changes in the newly created analogs should not constitute a significant structural variation to adversely affect biological activity. Four individual isomers of backbone re-organized ezetimibe analogs were designed and synthesized. Their effects on the cholesterol levels in rat serum were evaluated by a high-cholesterol and high-fat diet feeding experiment. All the new analogs showed significant effect in lowering the levels of total cholesterol in serum.

Absorption↗
PubMed1997

Study of the interaction between aryloxypropanolamines and Asn386 in helix VII of the human 5-hydroxytryptamine1A receptor.

We studied the stereoselective interaction between aryloxypropanolamines and the human 5-hydroxytryptamine1A (5-HT1A) receptor. R- and S-enantiomers of propranolol, penbutolol, and alprenolol were investigated for their ability to bind to human 5-HT1A wild-type and Asn386Val mutant receptors. Asn386 seemed to act as a chiral discriminator. Although both aryloxypropanol enantiomers displayed lower affinity for the mutant receptors, the affinities for the S-enantiomers were more affected. Receptor affinities of other structurally unrelated 5-HT1A ligands were not decreased by the mutation of Asn386 to valine. In addition, a series of analogues of propranolol with structural variation in the oxypropanolamine moiety was synthesized, and affinities for wild-type and Asn386Val mutant 5-HT1A receptors were determined. Both the hydroxyl and the ether oxygen atoms of the oxypropanol moiety seem to be required for binding at wild-type 5-HT1A receptors. The hydroxyl group of propranolol probably directly interacts with Asn386. The ether oxygen atom may be important for steric reasons but can also be involved in a direct interaction with Asn386. These findings are in agreement with the interactions of aryloxypropanolamines with Asn386 in rat 5-HT1A receptors that we previously proposed. The loss of affinity for propranolol by the Asn386Val mutation could be regained by replacement of the hydroxyl group of the ligand by a methoxy group. This modification of the propranolol structure has no effect on the affinity of both enantiomers for the wild-type 5-HT1A receptor, which provides an alternative hypothesis for the interaction of Asn386 with the oxypropanol oxygen atoms. According to this novel hypothesis, the oxypropanol oxygen atoms may both act as hydrogen bond acceptors from the NH2 group of Asn386.

Alprenolol↗
PubMedDate not supplied

Structural variants of chromosome 9: a possible association with hypogonadotropic hypogonadism.

We report two cases of structural variations of chromosome 9 associated with hypogonadotropic hypogonadism and azoospermia in adolescent boys. One patient also had a partially imperforated urethral meatus. Histological examination revealed that both had hypotrophic and underdeveloped testes. There was no LH and FSH response to LH-RH stimulation nor was there any response to naloxone tests. Basal and HCG stimulated plasma testosterone values were below normal prepubertal levels. As the administration of gonadotrophins did not improve the clinical and hormonal findings, alternative androgen therapy was necessary to achieve secondary sexual characteristics. Although they reached a good level of androgenization, their testes were still very small and azoospermia remained, as confirmed by repeated semen analyses. A possible association between chromosome 9 polymorphisms and hypothalamo-pituitary axis abnormalities is suggested. It is hypothesized that structural variants of chromosome 9 are not unrelated occurrences. Furthermore, and in view of the fact that they can lead to a high risk of azoospermia and infertility, such variants call for clinical investigation.

Child↗
PubMed1979

Morphologic variations along the length of the monkey vas deferens.

Gross and microscopic morphology of the vas deferens of sexually mature macaque monkeys were studied with special reference to the changes and modifications occurring throughout its entire length. The vas deferens was subdivided into four regional segments designated proximal, middle, distal, and ampulla. Each segment showed morphologic variations and it seemed to correspond roughly to the region located in a different part of the body which it traverses. The longitudinal folds of the epithelium are simple in the proximal region but gradually become more complex towards the distal region. In the ampulla, they often branch and form crypts. Stereocilia of epithelial cells are taller and more uniform in the proximal portion in comparison with the short, irregular stereocilia found in the more distal segment of the vas deferens. The luminal epithelial cells of the proximal part apparently have no granules or cytoplasmic blebbings, while the principal cells in the distal portion contain large numbers of cytoplasmic granules and apical blebs. Cells in the middle segments possess cytological features intermediate to the proximal and distal regions. These structural variations along the length of the vas deferens sug gest that this segment of the excurrent duct of the testis performs functions other than just as a passageway for spermatozoa.

Animals↗
PubMed2006

Quantitative adsorption and local structures of gallium(III) at the water-alpha-FeOOH interface.

The adsorption of Ga(III) at the water-alpha-FeOOH (goethite) interface has been investigated by means of quantitative adsorption experiments, extended X-ray absorption fine structure (EXAFS) spectroscopy, and surface complexation modeling. Under the conditions studied, pH range 3-11 and surface coverages of 0.9-3.2 micromol/m2, Ga(III) was found to adsorb strongly to alpha-FeOOH, and the surface species were more resistant toward hydrolysis and formation of soluble Ga(OH)4- than either solid gallium hydroxides or soluble polynuclear complexes. The EXAFS measurements revealed the presence of octahedral Ga(III) complexes at the water-alpha-FeOOH interface, with practically no structural variations as a function of pH or total gallium concentration. Analysis of the first coordination shell required an anharmonic model indicating a distorted geometry of the GaO6 octahedra, with mean Ga-O distances at 1.96-1.98 angstroms. A method based on the continuous Cauchy wavelet transforms (CCWT) was used to identify backscattering atoms in the higher coordination shells. This analysis indicated predominately Fe backscattering, and the quantitative data fitting resulted in three Ga-Fe paths at 3.05, 3.2, and 3.55 angstroms, which correspond to two edge-sharing and one corner-sharing linkage, respectively. The collective results from EXAFS spectroscopy showed that Ga(III) adsorbs to Fe equivalent sites at the surface alpha-FeOOH as an extension of the rows of Fe octahedra in the bulk structure. This interpretation was further corroborated by a Ga-Fe-Fe multiple scattering path at 6.13 angstroms. The quantitative adsorption and proton data were modeled using a surface complexation formalism based on a 1 pK(a) constant capacitance model. In agreement with the EXAFS results, the model obtained included one predominating surface complex with the stoichiometry [triple bond]FeOGa(OH)2(-0.5) and the stability constant log beta(intr.) = -2.55 +/- 0.04 ([triple bond]FeOH(-0.5) + Ga3+ + 2H2O <--> [triple bond]FeOGa(OH)2(-0.5) + 3H+).

Adsorption↗