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Three structural forms of C7 have been distinguished by isoelectric focusing. They are the products of three co-dominantly expressed alleles at an autosomal locus. The C7 locus is close to that for C6, but is not close to the HLA complex.
Rats were trained to discriminate (+)-amphetamine sulfate (5.43 mumol/kg, 1 mg/kg) from saline in a food-reinforced, two-lever drug discrimination paradigm. Side chain variations of the amphetamine molecular structure were analyzed for their effects on the discriminative stimulus properties of this prototype central nervous system stimulant. Partial generalization was observed for the alpha-ethyl homologue of (+)-amphetamine, (+)-AEPEA, and for 2-aminoindan (AI), while 5,6-methylenedioxy-2-aminoindan (MDAI) elicited only saline-appropriate responding. By contrast, 2-amino-1,2-dihydronaphthalene (ADN) and 2-aminotetralin (AT) completely substituted for (+)-amphetamine. Relative to the training drug, ADN was 1/4 as potent and AT was 1/8 as potent. The S-(-)-isomer of ADN was found to be responsible for the (+)-amphetamine-like discriminative properties of the racemate. The results suggest that constraining or extending the alpha-alkyl substituent of (+)-amphetamine has a deleterious effect on the ability of the resulting analogue to adopt the active conformation of (+)-amphetamine, thereby diminishing its characteristic discriminative stimulus properties.
The structure of the Gln25 variant of ribonuclease T1 (RNase T1) crystallized at pH 7 and at high ionic strength has been solved by molecular replacement using the coordinates of the Lys25-RNase T1/2'-guanylic acid (2'GMP) complex at pH 5 [Arni et al. (1988) J. Biol. Chem. 263, 15358-15368] and refined by energy minimization and stereochemically restrained least-squares minimization to a crystallographic R-factor of 14.4% at 1.84-A resolution. The asymmetric unit contains three molecules, and the final model consists of 2302 protein atoms, 3 sulfates (at the catalytic sites), and 179 solvent water molecules. The estimated root mean square (rms) error in the coordinates is 0.15 A, and the rms deviation from ideality is 0.018 A for bond lengths and 1.8 degrees for bond angles. Significant differences are observed between the three molecules in the asymmetric unit at the base recognition and catalytic sites.
European Ash (Fraxinus excelsior) is a keystone tree species, whose populations are being decimated by ash dieback disease (ADB) - better characterisation of genetic variants associated with low susceptibility to the disease is needed. Here, we develop a F. excelsior pangenome to more fully capture sequence variability within this species compared with a linear reference genome, using a geographically diverse set of fifty F. excelsior samples. We identify 362,965 structural variants (SVs), including 174 Mb of sequence absent from the linear reference genome (22% of the linear reference size), and identify 3,412 high-confidence dispensable genes (those present only in some individuals). We use the pangenome to analyse existing genomic data from over 1,200 individuals, revealing 220 single nucleotide polymorphisms (SNPs) showing consistent allele frequency shifts between healthy individuals and those highly damaged by ADB, across UK seed sources, explicitly demonstrating the existence of a shared genetic component to low ADB susceptibility.
The ontogeny of typical (normal) nasal bone region of the European moose (Alces alces L.) and the 3 variants of the pattern, was studied. The variants, named as "extra bone type", "punctured type" and "open type" referring the morphology of the internasal suture, were originally observed in Finnish male and female moose skulls in 1971. All of the variants were later found in hunting trophy exhibitions presenting male moose trophies from Sweden, Norway, Baltic Republics of USSR and Poland. The frequencies of the variants showed regional differences. By using histological, radiological and OTC bone labelling methods, all of the nasal bone types were observed in this study in embryonal (N = 36), newborn (N = 21), juvenile (N = 38) and adult (N = 12) moose. Two twin embryos showed different nasal bone structure. The variation is considered to be of congenital origin.
The effects of three elaboration structures (compound sentences, complex sentences, and paragraphs) on the paired-associate learning and reversal of 30 8- to 10-year-old nonretarded and 30 8- to 10-year-old EMR children were investigated. Analyses of trials-to-criterion, first trial errors, and reversal errors did not reveal any differences in the effects of the three elaboration structures. Results of the present study indicate that given constant meaning and relational factors, some forms of surface structure differneces (compound sentences vs. complex sentence vs. paragraph) are not significant in determining a child's ability to understand an elaboration or to use it in a learning situation. There was no population difference found in the analysis of first-trial errors, although small significant differences between the nonretarded and EMR children were found in the analyses of trials-to-criterion and reversal performance.
The 17q21.31 locus in humans harbors several complex structural haplotypes including a ~970kb inversion. Different inversion haplotypes have been associated with susceptibility to microdeletions causing Koolen-de Vries syndrome and variation in fecundity and recombination rates. Here, using 210 haplotype-resolved human genome assemblies and pangenome graph-based approaches we characterize 11 distinct structural haplotypes, several of which have not been previously described. Extending our analyses to a set of haplotype-resolved great-ape genomes, we characterize the structure of an independent inversion in chimpanzees which extends an additional 650kb, encompasses 5 additional genes, and is ~2 million years younger than the human inversion. We further determine that gorillas exhibit an independent duplication of the KANSL1 gene which may predispose them to Koolen-de Vries syndrome causing microdeletions. Using short read sequencing data we characterize 17q21.31 haplotype diversity worldwide in ~5174 individuals from 107 populations finding increased frequencies of KANSL1 duplication-containing haplotypes in both European and South Asian populations as well as 8 double recombination events between inverted and non-inverted haplotypes ranging in size from 20-180kb. Finally, using 626 ancient Eurasian human genomes we show the frequency of haplotypes containing KANSL1 duplications has increased ~6-fold over the past 12 thousand years in Europe. Together, our results highlight the dynamics, complexity, and recurrent, independent evolution of a medically relevant locus across humans and great apes.
Hexadecylphosphocholine (HPC) and octadecylphosphocholine (OPC) show very potent antitumor activity against autochthonous methylnitrosourea-induced mammary carcinomas in rats. The longer-chain and unsaturated homologue erucylphosphocholine (EPC) forms lamellar structures rather than micelles, but nonetheless exhibits antineoplastic activity. Methylnitrosourea was used in the present study to induce autochthonous mammary carcinomas in virgin Sprague-Dawley rats. At 6 and 11 days following oral therapy, the biodistribution of HPC, OPC and EPC was analyzed in the serum, tumor, liver, kidney, lung, small intestine, brain and spleen of rats by high-performance thin-layer chromatography. In contrast to the almost identical tumor response noted, the distribution of the three homologues differed markedly. The serum levels of 50 nmol/ml obtained for OPC and EPC were much lower than the value of 120 nmol/ml measured for HPC. Nevertheless, the quite different serum levels resulted in similar tumor concentrations of about 200 nmol/g for all three of the compounds. Whereas HPC preferably accumulated in the kidney (1 mumol/g), OPC was found at increased concentrations (400 nmol/g) in the spleen, kidney and lung. In spite of the high daily dose of 120 mumol/kg EPC as compared with 51 mumol/kg HPC or OPC, EPC concentrations (100-200 nmol/g) were low in most tissues. High EPC concentrations were found in the small intestine (628 nmol/g). Values of 170 nmol/g were found for HPC and OPC in the brain, whereas the EPC concentration was 120 nmol/g. Obviously, structural modifications in the alkyl chain strongly influence the distribution pattern of alkylphosphocholines in animals. Since EPC yielded the highest tissue-to-serum concentration ratio in tumor tissue (5.1) and the lowest levels in other organs, we conclude that EPC is the most promising candidate for drug development in cancer therapy.
A number of oligonucleotide analogues containing internucleoside phosphorothioate linkages and a covalently attached cholesteryl residue was synthesized and tested for activity against HIV-1 in cultures of Molt3 cells. Structural features important for high antiviral activity are the presence of a cholesteryl moiety, a run of terminal phosphorothioate groups, and the presence of nucleoside residues. An increase in length of the tether between cholesteryl and phosphorus from six to 14 atoms has no significant effect on antiviral activity, and up to one-half of the internucleoside links in a cholesteryl-conjugated phosphorothioate oligomer and one-third of the internucleoside links in a nonconjugated phosphorothioate can be replaced with phosphodiester links without much change in antiviral activity. However, replacement of nucleoside units in the oligomers by a simple analogue (-OCH2CH2CH2O-) yields inactive or very weakly active compounds, even in the presence of a cholesteryl group. Dose-response patterns for assays in which cholesteryl-conjugated oligomers are added to test cells either simultaneously or subsequently to viral infection are similar for homooligomer derivatives and for oligomers containing "antisense" sequences, suggesting a similarity in mode of action for the two classes of oligomers in this system.
4,5-Diphenyl-2-oxazolenonanoic acid (2) and 2-[3-[2-(4,5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (3) were previously identified as nonprostanoid prostacyclin (PGI2) mimetics that inhibit ADP-induced aggregation of human platelets in vitro. The effects on biological activity of substitution and structural modification of the 4- and 5-phenyl rings of 3 was examined. Potency showed a marked sensitivity to the introduction of substituents to these aromatic rings and only the bis-4-methyl derivative 9j, IC50 = 0.34 microM, demonstrated enhanced potency compared to the parent structure 3, IC50 = 1.2 microM. Substitution at the ortho or meta positions of the phenyl rings, replacement by thiopheneyl or cyclohexyl moieties, or constraining in a planar phenanthrene system resulted in compounds that were less effective inhibitors of ADP-induced platelet aggregation. In contrast, variation of the heterocycle moiety revealed a much less stringent SAR and many 5- and 6-membered heterocycles were found to effectively substitute for the oxazole ring of 2 and 3. The diphenylmethyl moiety functioned as an effective isostere for 4,5-diphenylated heterocycles since 13aad showed similar platelet inhibitory activity to 3. With the exception of the 3,4,5-triphenylpyrazole derivative 13g, compounds presenting the (m-ethylphenoxy)acetic acid side chain discovered with 3 demonstrated enhanced potency compared to the analogously substituted alkanoic acid derivative. The structure-activity findings led to a refinement of a model of the nonprostanoid PGI2 mimetic pharmacophore.
Fluoroquinolones are potent inhibitors of bacterial topoisomerase II (DNA gyrase). They can also inhibit eukaryotic topoisomerases, which could possibly lead to clastogenicity and/or cellular toxicity. Recent studies have demonstrated a correlation between mammalian cell cytotoxicity of the fluoroquinolones and the potential of these compounds to induce micronuclei, a genetic toxicity endpoint. In an effort to identify potent nontoxic quinolone antibacterials, we have examined the structural features of the fluoroquinolones associated with mammalian cell cytotoxicity. An investigation of a wide variety of substituents at the 1, 5, 7, and 8 positions of a quinolone nucleus was conducted. The results indicate that no one position has a controlling effect on the observed cytotoxicity. Instead, a combination of the various substituents contributes to the effects seen. Certain trends were apparent, such as the fact that compounds with pyrrolidines at the R-7 position were more cytotoxic than those with piperazines, and halogens at R-8 (X-position) were associated with more cytotoxicity relative to hydrogen. A general trend also existed between the cytotoxicity of the compounds and their Gram-positive antibacterial activity. A detailed comparison between the various groups and positional variations as they controlled the cytotoxicity and antibacterial activity is presented.
Relapse during treatment of B-cell acute lymphoblastic leukemia (B-ALL) is a harbinger of poor outcomes. Identifying biomarkers for subsequent relapse risk which are detectable at B-ALL diagnosis remains a priority. Off-target recombination-activating gene (RAG)-mediated structural variants (SVs) generate genomic instability that drives leukemogenesis and may underlie treatment resistance. Leveraging sequencing data in 1,496 pediatric B-ALL patients enriched for relapse status (relapse n=532; non-relapse n=964), we characterized RAG-mediated SVs across B-ALL molecular subtypes and examined their association with patient characteristics and their impact on clinical outcomes. Off-target RAG-mediated SVs were overall frequent, particularly in ETV6::RUNX1, ETV6::RUNX1-like, and Ph-like B-ALL subtypes, while increasing age-at-diagnosis was positively associated with burden of off-target RAG-mediated SVs (P<.001). Off-target RAG-mediated SVs with a recombination signal sequence (RSS) at one breakpoint, a hallmark of off-target RAG activity, were significantly more frequent at diagnosis in patients who subsequently relapsed (P=.001). This association remained significant in multivariable regression analysis (per SV odds ratio [OR]:1.08, 95%CI:1.04-1.12), in minimal residual disease (MRD)-negative patients (OR:1.09, 95%CI:1.04-1.14) and across subtypes. Excluding deletions, MRD-negative ETV6::RUNX1 patients with ≥3 off-target RAG-mediated SVs had a >3-fold risk of relapse (hazard ratio:3.47, 95% CI:1.86-6.49). RAG-mediated SVs were also associated with relapse risk in T-cell ALL patients. Off-target RAG-mediated SV burden at diagnosis is a risk factor of relapse in pediatric ALL across molecular subtypes and independent of MRD status.
cDNA clones carrying the chicken-bek gene and a related gene were isolated. Deducing the amino acid sequence of chicken-bek allowed us to predict that it encodes for a receptor tyrosine kinase related to the fibroblast growth factor (FGF) receptor, and that the chicken-bek gene and Cek3 are closely related. However, a significant structural difference was identified between chicken-bek and Cek3 within the putative extracellular region, in such a manner that the structure of the immunoglobulin-like domain was conserved. A probe specific to the altered structure detected mRNA in the tissues as did a probe common to bek and Cek3, indicating heterogeneity in the FGF-receptor family in a novel manner. Furthermore, another bek-like gene was isolated and the expressions of its mRNA and protein product were analysed in tissues and cultured cells.
The ultrastructural appearance of different types of basement membrane was studied using histochemical methods for visualizing glycosaminoglycans. Samples of rat gingiva and mouse molar germ tissue were fixed either with glutaraldehyde, glutaraldehyde-ruthenium hexammine trichloride (RHT), glutaraldehyde-Cuprolinic Blue (CB) or cetylpyridinium chloride-glutaraldehyde (CPC). Ultrathin sections were stained with uranyl acetate and lead citrate. The results showed that the conventional trilaminar structure of the basement membrane was observed after glutaraldehyde and CB fixation. In contrast, after CPC or RHT fixation, the appearance of the basement membrane was homogeneous without any evidence of a lamina lucida. Furthermore, after single fixation with CPC, the ultrastructure of different basement membranes from oral tissues showed some differences in appearance which were related to their localizations, functions, or both.
In the inguinal region, numerous muscular and fibrous alterations are described. They are related to the unconstant position of the pubic tubercle in relation io the interspinous diameter (linea bi-spinalis). The pubic tubercle can be observed in two different locations: either high or low. The high location is characterized by the presence of the pubic tubercle at a distance of 5 to 7.5 cm below the interspinous diameter. It must be considered as normal and is found in 65% of the subjects. In the low locations, the distance between spinous tubercle and interspinous diameter reaches 7,5 to 12 cm. It is an important abnormality which interests 35% of the subjects. The lower the pubic tubercle are located, the more often morphological alterations are to be found in the following structures: obliquus externus, obliquus internus, transversus and cremaster muscles as well as fascia transversalis. Nevertheless, the pyramidalis muscle as well as the inguinal ligamentary formation, Hesselbach's interfoveolar ligament and Thompson's iliopubic tract do not follow that rule, since the important morphological variations of these deep fibrous components can never be related to the distance between pubic tubercle and interspinous diameter. The functional signification of the inguinal region and especially of the inguinal canal is modified by those ostelogical, muscular and ligamentary variations.
Two closely linked regulatory genes have been reported to control activity levels of beta-galactosidases in murine tissues. The specific effects of these genes on murine glycolipid metabolism have not been elucidated. A/HeJ kidney 4-methylumbelliferyl-beta-galactosidase exhibited lower thermostability than the corresponding C57BL/6J and SWR/J enzymes. This altered response to heat segregated with the Bgsh allele among progeny derived from backcrosses of F1 (A/HeJ; SWR/J) mice to the respective parental strains. Restriction of the heat-sensitive A/HeJ beta-galactosidase to kidney tissue suggests that it is not determined by the Bgs locus, since the latter appears to be expressed in all tissues. More likely, the Bgs region of chromosome 9 contains a gene cluster consisting of a number of regulatory and structural loci. The proposed structural genes share affinity for the artificial substrates commonly employed for their assay but may differ in their relative affinities for glycosphingolipid substrates. Presence of the Bgsh allele results in an increase of kidney GM1-ganglioside-beta-galactosidase; however, galactosylceramide-beta-galactosidase appears unaffected by this allele.
Studies of beta-monoglyceride multilayers were carried out using a variety of spin probes. Effects of variables such as chain length, unsaturation, and branching on organization of acyl chains in lipids of model membranes were assessed. In addition, effects of added cholesterol on membrane order were determined. Results indicated that pure beta-monolaurin yields highly ordered films, whereas, unsaturated glycerides such as beta-monoolein, beta-monolinolein, and analogous lecithins yield fluid films. Branched monoglycerides behaved similarly to beta-monoolein, suggesting that branching in acyl chains is an effective substitute for unsaturation in maintaining membrane integrity. Multilayers of beta-monoglycerides exhibited similar properties to those of more complex lipids such as phospholipids. beta-Monoglycerides, by virtue of the presence of a single acyl chain, provided a relatively simple and effective alternative to the use of phospholipids in studies of membrane architecture.
The amatoxins, highly toxic components of death cap Amanita mushrooms, bind strongly to RNA polymerase II (or B) in cell nuclei thus preventing the transcription of DNAs to hn-RNAs (Pre-mRNAs), the precursors of messenger RNAs. Three of the binding sites of the bicyclic octapeptides have been identified: an isoleucine side chain in position 6, a trans-4-hydroxyl group at proline in position 2 and a hydroxylated L-isoleucine side chain in position 3. No information exists about the stereochemical conditions at the beta-C-atom (C-atom 3) of this side chain. We have now synthesized the diastereomeric S-deoxo-amaninamides (Fig. 1) containing, in position 3, L-allo-isoleucine (analog 1), (2S, 3R)-2-amino-4-hydroxy-3-methyl butyric acid (analog 2), the diastereomer (2S, 3S)-2-amino-4-hydroxy-3-methylbutyric acid (analog 3) and D-isoleucine (analog 4). In the last synthesis, besides the "normal" bicyclic octapeptide 4, an isomeric Iso-4 was formed. The affinities for Drosophila RNA polymerase II were 100 times weaker as compared to gamma-amanitin for 1, 10 times weaker for 2, 200 times weaker for 3, 100 times weaker for 4, and more than 1000 times weaker for Iso-4. The results point to the importance of a methyl group in (R)-configuration at the beta-C atom of side chain 3.