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PubMed2025

SVbyEye: a visual tool to characterize structural variation among whole-genome assemblies.

MOTIVATION: We are now in the era of being able to routinely generate highly contiguous (near telomere-to-telomere) genome assemblies of human and nonhuman species. Complex structural variation and regions of rapid evolutionary turnover are being discovered for the first time. Thus, efficient and informative visualization tools are needed to evaluate and directly observe structural differences between two or more genomes. RESULTS: We developed SVbyEye, an open-source R package to visualize and annotate sequence-to-sequence alignments along with various functionalities to process these alignments. The tool facilitates the characterization of complex structural variants in the context of sequence homology helping resolve the mechanisms underlying their formation. AVAILABILITY AND IMPLEMENTATION: SVbyEye is available on GitHub (https://github.com/daewoooo/SVbyEye) and via Zenodo (https://doi.org/10.5281/zenodo.15303553).

Software↗
PubMed1984

Qualitative and quantitative differences between resident peritoneal mononuclear phagocytes of beige and control mice.

A qualitative and quantitative comparison of resident peritoneal macrophages (RPM) from beige (C57BL6Jbg/bg), (bg), and control black (C57BL/6J), (BL), mice has been made. Giant anomalous lysosomes as described for other leukocytes are inconsistently demonstrable. The principal morphological expression of the bg phenotype in RPM is the presence of elongated dumbbell-shaped, horseshoe-shaped, and ring-formed cytoplasmic lysosomes demonstrable by electron microscopy. Detailed analysis indicates that these are probably variations of the same basic structure, a deformed biconcave disc with differences in form resulting from their being cut in various planes of section. Additional structural complexity results from fusion between adjacent lysosomes. Thus the distinctive lysosomes of bg mouse RPM are not totally analogous to those structures described in other cell types. A morphometric analysis of control RPM compared to those from bg animals shows a significant decrease in the lysosomal volume proportion from 5.8% to 5.0% (P less than 0.02) with a corresponding increase in the mitochondrial volume proportion in cells from bg animals (P less than 0.05). There are no differences between bg and controls in regard to cellular profile areas, nuclear profile areas, nuclear volume proportions, and the volume to surface ratios of either the average cell or nucleus. This study represents the first compilation by morphometric methods of total granule content in the bg animal and demonstrates the ability of these techniques to detect significant quantitative changes in cells as structurally complex as mononuclear phagocytes.

Animals↗
PubMed1989

Three-dimensional structure of complexes of single-stranded DNA-binding proteins with DNA. IKe and fd gene 5 proteins form left-handed helices with single-stranded DNA.

Specimen-tilting in an electron microscope was used to determine the three-dimensional architecture of the helical complexes formed with DNA by the closely related single-stranded DNA binding proteins of fd and IKe filamentous viruses. The fd gene 5 protein is the only member of the DNA-helix-destabilizing class of proteins whose structure has been determined crystallographically, and yet a parameter essential to molecular modeling of the co-operative interaction of this protein with DNA, the helix handedness, has not been available prior to this work. We find that complexes formed by titrating fd viral DNA with either the fd or IKe gene 5 protein have a left-handed helical sense. Complexes isolated from Escherichia coli infected by fd virus are also found to be left-handed helical; hence, the left-handed fd helices are not an artefact of reconstitution in vitro. Because the proteins and nucleic acid of the complexes are composed of asymmetric units which cannot be fitted equivalently to right-handed and left-handed helices, these results rule out a previous computer graphics atomic model for the helical fd complexes: a right-handed helix had been assumed for the model. Our work provides a defined three-dimensional structural framework within which to model the protein-DNA and protein-protein interactions of two structurally related proteins that bind contiguously and co-operatively on single-stranded DNAs.

DNA, Bacterial↗
PubMed1998

Implications for function and therapy of a 2.9 A structure of binary-complexed antithrombin.

The crystal structure of a binary complex of human antithrombin with a peptide of the same sequence as its reactive loop (P14-P3) has been determined at 2.9 A. The peptide binds as the middle strand s4A in the A beta-sheet, homologously to that of the reactive loop in the latent and cleaved forms of antithrombin. Peptide binding results in the complete expulsion of the hinge region of the loop from the A beta-sheet although the conformation differs from that of heparin-activated antithrombin. The 36-fold increase in the rate of reaction of the binary complex with factor Xa indicates that full loop expulsion alone is not sufficient for complete heparin activation of antithrombin but that this is also dependent on the overall conformation of the molecule. Previous studies have demonstrated that reactive loop peptides can block or reverse the polymerisation of serpins associated with cirrhosis and thrombosis. The antithrombin binary complex structure defines the precise localisation of the blocking peptide in a serpin and provides the basis for rational drug design for mimetics that will prevent polymerisation in vivo and so ameliorate the associated disease.

Amino Acid Sequence↗
PubMed1997

Role of HGF/SF and c-Met in morphogenesis and metastasis of epithelial cells.

We have analysed the role of hepatocyte growth factor/scatter factor (HGF/SF) in the process of morphogenesis and metastasis of epithelial (carcinoma) cells. HGF/SF induces various morphogenic responses in epithelial cells that derive from different tissues when these are grown in three-dimensional gels, e.g. branching tubules in kidney, breast, and prostate epithelial cells, crypt-like structures with brush border in colon epithelial cells, and alveolar-like aggregates in lung and pancreas cells. Epithelial cells are thus able to form complex structures in vitro which resemble the structures formed in the organ they originate from. We also examined the response of human breast carcinoma cells to HGF/SF in vivo. MDA MB 435 cells transfected with HGF/SF were injected into the mammary fat pad of nude mice, where they form tumours which spontaneously metastasize to the lungs. We found that expression of HGF/SF promoted metastasis whereas expression of the cell adhesion molecule E-cadherin was inhibitory. Moreover, expression of E-cadherin reconstituted the ability of the cells to form complex structures in response to HGF/SF in vitro. These data demonstrate that the different responses to HGF/SF depend on the state of the epithelial cells: morphogenesis requires epithelial differentiation and cell polarity, whereas metastasis is observed when the cells have lost their epithelial characteristics. Moreover, we have recently identified Gab-1 as a direct-binding substrate of the c-Met receptor. Gab-1 binds to c-Met phosphorylated on tyrosine residues, but not to a number of other tyrosine kinases from different subfamilies. A newly identified proline-rich domain of Gab-1 is responsible for the binding to the bidentate docking site in c-Met. Expression of Gab-1 in epithelial cells is sufficient to induce c-Met-specific cellular responses which include the formation of branching tubules. Thus, Gab-1 seem to correspond to the substrate of the c-Met receptor tyrosine kinase that mediates the epithelial morphogenesis.

Animals↗
PubMed1991

[Study of the pyruvate dehydrogenase complex by circular dichroism].

A comparative study of the pyruvate dehydrogenase complex and its pyruvate dehydrogenase component was carried out by using the circular dichroism method. It was found that the spectral properties of the pyruvate dehydrogenase complex are determined by those of its first component: i) the spectrum of the thiamine pyrophosphate-free pyruvate dehydrogenase complex displayed the main characteristics of the pyruvate dehydrogenase component; ii) the appearance of the charge transfer complex band during thiamine pyrophosphate saturation was revealed for the both proteins; iii) in both cases the charge transfer complex band disappeared after the interaction of the holoform with pyruvate and reappeared after the addition of dithiothreitol used as a deacetylating reagent. Coenzyme A in the same reaction selectively deacetylated the pyruvate dehydrogenase complex (but not its pyruvate dehydrogenase component). The spectral dynamics of pyruvate dehydrogenase reflects the functional changes in the enzyme active centers during the catalytic act. The similarity of the spectral behaviour of pyruvate dehydrogenase within the complex structure and in the isolated state provides support for the earlier proposed mechanism of the pyruvate dehydrogenase action and ensures a methodological basis for its direct investigation within the complex structure.

Acetylation↗
PubMed2000

Sensory organ generation in the chicken inner ear: contributions of bone morphogenetic protein 4, serrate1, and lunatic fringe.

The chicken inner ear is a remarkably complex structure consisting of eight morphologically distinct sensory organs. Unraveling how these sensory organs are specified during development is key to understanding how such a complex structure is generated. Previously, we have shown that each sensory organ in the chicken inner ear arises independently in the rudimentary otocyst based on Bone morphogenetic protein 4 (Bmp4) expression. Here, we compare the expression of Bmp4 with two other putative sensory organ markers, Lunatic Fringe (L-fng) and chicken Serrate1 (Ser1), both of which are components of the Notch signaling pathway. L-fng and Ser1 expression domains were asymmetrically distributed in the otic cup. At this early stage, expression of L-fng is similar to Delta1 (Dl1), in an anteroventral domain apparently corresponding to the neurogenic region, while Ser1 is expressed at both the anterior and posterior poles. By the otocyst stage, the expression of both L-fng and Ser1 largely coincided in the medial region. All presumptive sensory organs, as identified by Bmp4 expression, arose within the broad L-fng- and Ser1-positive domain, indicating the existence of a sensory-competent region in the rudimentary otocyst. In addition, there is a qualitative difference in the levels of expression between L-fng and Ser1 such that L-fng expression was stronger in the ventral anterior, whereas Ser1 was stronger in the dorsal posterior region of this broad domain. This early difference in expression may presage the differences among sensory organs as they arise from this sensory competent zone.

Age Factors↗
PubMed1991

Self-assembly in supramolecular systems.

The complex structural and functional properties of many natural molecules have spawned innumerable attempts to understand and mimic biological activity. This has often involved preparing extremely complex structures of carefully designed geometries. In natural systems the primary structure of a protein (the amino acid sequence) establishes all of the structural relationships within the molecule, although many of these are not apparent until the molecule folds, coils, or otherwise adopts the appropriate conformation. Nature has selected suitable amino acid sequences for various applications during eons of evolution. In this paper, we report our efforts to achieve similar results by providing all of the required structural elements on a flexible framework. This concept is illustrated in three ways: the design and preparation of a redox-switched vesicle and a small-molecule molecular receptor (both based on the ferrocene system) and of a functional cation channel.

Amino Acid Sequence↗
PubMed2001

Thermodynamics of Ras/effector and Cdc42/effector interactions probed by isothermal titration calorimetry.

Proliferation, differentiation, and morphology of eucaryotic cells is regulated by a large network of signaling molecules. Among the major players are members of the Ras and Rho/Rac subfamilies of small GTPases that bind to different sets of effector proteins. Recognition of multiple effectors is important for communicating signals into different pathways, leading to the question of how an individual GTPase achieves tight binding to diverse targets. To understand the observed specificity, detailed information about binding energetics is expected to complement the information gained from the three-dimensional structures of GTPase/effector protein complexes. Here, the thermodynamics of the interaction of four closely related members of the Ras subfamily with four different effectors and, additionally, the more distantly related Cdc42/WASP couple were quantified by means of isothermal titration calorimetry. The heat capacity changes upon complex formation were rationalized in light of the GTPase/effector complex structures. Changes in enthalpy, entropy, and heat capacity of association with various Ras proteins are similar for the same effector. In contrast, although the structures of the Ras-binding domains are similar, the thermodynamics of the Ras/Raf and Ras/Ral guanine nucleotide dissociation stimulator interactions are quite different. The energy profile of the Cdc42/WASP interaction is similar to Ras/Ral guanine nucleotide dissociation stimulator, despite largely different structures and interface areas of the complexes. Water molecules in the interface cannot fully account for the observed discrepancy but may explain the large range of Ras/effector binding specificity. The differences in the thermodynamic parameters, particularly the entropy changes, could help in the design of effector-specific inhibitors that selectively block a single pathway.

Animals↗
PubMed1990

Stimulus complexity and autistic children's responsivity: assessing and training a pivotal behavior.

Interdisciplinary research suggests that autistic children's limitations in responding to environmental stimuli may be directly related to the number of components contained in the stimuli; as the number of components increases, such children hypothetically would exhibit greater difficulties in responding. The central purpose of this experiment was to assess whether such children indeed exhibit greater difficulties in responding as the number of components contained in an environmental stimulus was increased from one to four. If the children's responsivity was a function of stimulus complexity, a second focus of this experiment was to assess the feasibility of teaching them to respond to a complex environmental stimulus containing up to four components and to determine whether the effects of the intervention would generalize to other situations involving complex structured and social stimuli. Data gathered using a multiple baseline design across behaviors and children indicate that all of the children exhibited fewer correct responses to a stimulus as the number of stimulus components was increased from one to four. The results further showed that the training program used in this investigation was effective in producing some generalized increases in the children's responses to complex structured and social stimuli. Conceptualizing autistic children's responses to complex multicomponent stimuli as a pivotal target behavior that can be operationally defined may have important implications for understanding and altering the children's responsivity and development.

Adolescent↗
PubMed1993

The interosseous membrane of the forearm: structure and its role in Galeazzi fractures.

A cadaveric study was performed to anatomically describe and mechanically document the interosseous membrane of the forearm using gross, histologic, scanning electron microscopic, and mechanical testing. The membrane was found to be a complex structure composed of nerves and vessels but mainly of collagen fibers that thicken to form bands coursing from radius to ulna. Strain-gauge studies demonstrated that the load transfer occurs from the radius to the ulna via the membrane and changes with supination or pronation. With specimens under a specific test load, sectioning of the membrane allowed the fractured radius to shorten by 6.25 mm and sectioning of the triangular fibrocartilage complex resulted in shortening of 7.7 mm. Total shortening after osteotomy and sectioning of the complex structure and membrane ranged from 15 to 40 mm. In Galeazzi fractures, the interosseous membrane acts as a constraint to radial shortening. Anatomic reduction with internal fixation is indicated for this fracture-dislocation.

Aged↗
PubMed2000

Resonant response of complex shell structures

Resonances of shell structures play a prominent role in determining their acoustic characteristics. Among the most important of such characteristics are radiated noise, scattering, and self-noise levels. The nature of the structural resonances, for example the number of modes within a particular frequency band or the overall spatial dependence of the response, determines the importance of these phenomena in various contexts and what steps may be taken to modify their acoustic impact. In the past, knowledge of the resonant response of highly idealized systems has been used to guide the development of quiet platforms. The results of a scale model investigation of the effects of increased complexity on the nature of the resonances of submerged shell structures are reported. Effects presented here are flexural Bloch mode resonances, localized resonances resulting from structural irregularity, and the effects of non-axisymmetry on these phenomena. The implications of these results on acoustic design and the development of systems is discussed.

Journal Article↗
PubMed1998

Two functional states of the CD11b A-domain: correlations with key features of two Mn2+-complexed crystal structures.

In the presence of bound Mn2+, the three- dimensional structure of the ligand-binding A-domain from the integrin CR3 (CD11b/CD18) is shown to exist in the "open" conformation previously described only for a crystalline Mg2+ complex. The open conformation is distinguished from the "closed" form by the solvent exposure of F302, a direct T209-Mn2+ bond, and the presence of a glutamate side chain in the MIDAS site. Approximately 10% of wild-type CD11b A-domain is present in an "active" state (binds to activation-dependent ligands, e.g., iC3b and the mAb 7E3). In the isolated domain and in the holoreceptor, the percentage of the active form can be quantitatively increased or abolished in F302W and T209A mutants, respectively. The iC3b-binding site is located on the MIDAS face and includes conformationally sensitive residues that undergo significant shifts in the open versus closed structures. We suggest that stabilization of the open structure is independent of the nature of the metal ligand and that the open conformation may represent the physiologically active form.

Amino Acid Substitution↗
PubMed1977

Structural ambiguity and limits to coping.

How well a person can cope with any situation is determined, among other factors, by his ability to resolve the ambiguity of that situation, which in turn depends on its structural complexity. We attempted to analyze a whole range of situations in terms of three dimesions: differentiations, the number of alternatives perceived; articulation, the differentiation and rankability of these alternatives; and loading, the emotional loading (positive or negative) associated with the situation. The efficiency of mapping with these dimensions was investigated by analyzing the effects of 75 situations on coping, as reported in the literature. These were divided into three groups, 25 situations in each, associated with good coping, reduced coping, and failure to come (in terms of performance relative to a baseline or to the population's norm). The interaction between the demands imposed by the complexity of the situation and the success of coping was analyzed by the Multidimensional Scalogram Analysis (MSA). Results show effectiveness of coping to be inversely related to the structural complexity of a situation, mapped in terms of articulation, loading and differentiation. The relative importance of these dimensions is as ordered above; this offers a possible way to construct an "ambiguity score" which may be the primary factor determining the coping limit set by any situation.

Adaptation, Psychological↗
PubMed2000

Structure and complex twinning of dysprosium disilicate (Dy2Si2O7), type B

Dysprosium disilicate (Dy(2)Si(2)O(7)) is triclinic with a = 6.6158 (2), b = 6.6604 (2), c = 12.0551 (4) A, alpha = 94.373 (2), beta = 90.836 (2), gamma = 91.512 (2) degrees, V = 529.4 (1) A(3), space group P1;, Z = 4 and D(x) = 6.156 g cm(-3). The structure (single-crystal X-ray, R = 0.033, wR = 0.041) is built from a linear triple tetrahedral group [Si(3)O(10)] and isolated [SiO(4)] tetrahedron cross-linked by Dy(3+) in one sixfold and three eightfold coordinated positions, and corresponds to the presently revised type B structure of Ho(2)Si(2)O(7). The formation of the unusual linear triple tetrahedral group in the type B structure allows for a more continuous transition in the mean size of REE(3+)O(n) (REE = rare earth element) polyhedra in REE disilicates through the 4f transition metal series. The crystal of Dy(2)Si(2)O(7) investigated was complexly twinned such that the diffraction pattern was also consistent with a larger dimensionally monoclinic unit cell (a = 22.5354, b = 14.2102, c = 6.6158 A, beta = 91.788 degrees ), which resulted in an apparent superstructure of the type B structure in space group C1;. Lattice coincidence with the type B unit cell appears to have been maintained during crystal synthesis and quenching by the complex sector-zoned growth twin.

Journal Article↗
PubMed1999

The bacterial flagella motor.

The bacterial flagellum is probably the most complex organelle found in bacteria. Although the ribosome may be made of slightly more subunits, the bacterial flagellum is a more organized and complex structure. The limited number of flagella must be targeted to the correct place on the cell membrane and a structure with cytoplasmic, cytoplasmic membrane, outer membrane and extracellular components must be assembled. The process of controlled transcription and assembly is still not fully understood. Once assembled, the motor complex in the cytoplasmic membrane rotates, driven by the transmembrane ion gradient, at speeds that can reach many 100 Hz, driving the bacterial cell at several body lengths a second. This coupling of an electrochemical gradient to mechanical rotational work is another fascinating feature of the bacterial motor. A significant percentage of a bacterium's energy may be used in synthesizing the complex structure of the flagellum and driving its rotation. Although patterns of swimming may be random in uniform environments, in the natural environment, where cells are confronted with gradients of metabolites and toxins, motility is used to move bacteria towards their optimum environment for growth and survival. A sensory system therefore controls the switching frequency of the rotating flagellum. This review deals primarily with the structure and operation of the bacterial flagellum. There has been a great deal of research in this area over the past 20 years and only some of this has been included. We apologize in advance if certain areas are covered rather thinly, but hope that interested readers will look at the excellent detailed reviews on those areas cited at those points.

Bacteria↗
PubMed1987

Isolation of functional alpha beta heterodimers from the purified human placental alpha 2 beta 2 heterotetrameric insulin receptor complex. A structural basis for insulin binding heterogeneity.

To investigate the role of subunit communication in the insulin binding and tyrosine-specific protein kinase activities of the purified human placental insulin receptor, we have developed the methodology to isolate a functional alpha beta heterodimeric insulin receptor complex from the native alpha 2 beta 2 heterotetrameric disulfide-linked state. The dissociation of the alpha 2 beta 2 heterotetrameric insulin receptor into an alpha beta heterodimer was found to be approximately 50% efficient by treatment with alkaline pH (8.75) and dithiothreitol (2 mM). Removal of the dithiothreitol and pH neutralization (pH 7.60) by rapid Sephadex G-50 gel filtration resulted in the preservation of tracer insulin binding activity. The nondissociated alpha 2 beta 2 heterotetrameric and alpha beta heterodimeric insulin receptor complexes could then be effectively separated by Bio-Gel A-1.5m gel filtration. Scatchard analyses of insulin binding to the alpha 2 beta 2 heterotetrameric control or dithiothreitol-treated but nondissociated alpha 2 beta 2 heterotetrameric insulin receptor complexes demonstrated a curvilinear binding isotherm with a maximum of 1 mol of insulin bound/mol of alpha 2 beta 2 heterotetrameric complex. However, binding analyses performed on the isolated alpha beta heterodimeric complex yielded a nearly linear binding curve also, with 1 mol of insulin bound/mol of alpha beta heterodimeric complex at saturation. These data demonstrate that the insulin half-site binding reactivity observed in the alpha 2 beta 2 heterotetrameric insulin receptor complex results from either an asymmetric assembly of identical alpha beta heterodimers or from absolute negative cooperativity.

Chromatography, Gel↗