bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of adverse childhood experiences, age of menarche, and adult reproductive behavior: Does the androgen receptor gene play a role?
Authors: Jorm Anthony F. , Christensen Helen , Rodgers Bryan , Jacomb Patricia A. , Easteal Simon
Published: January 2004

Previous research has reported associations between adverse childhood experiences, early menarche, and early sexual activity. One hypothesis to account for these findings is that an X‐linked androgen receptor GGC‐repeat polymorphism predisposes fathers to behaviors which include family abandonment and their daughters to earlier menarche and sexual activity and less stable relationships. Retrospective data relevant to this theory were examined from a community survey involving 3,702 women in the age groups 20–24, 40–44, and 60–64 years, and another involving 908 women aged 18–79 years. Earlier age of menarche was found to be associated with adverse childhood experiences and earlier sexual activity. However, the androgen receptor gene polymorphism was unrelated to adverse fathering behavior or to marital breakdown. © 2003 Wiley‐Liss, Inc.
Is the WKL1 gene associated with schizophrenia?
Authors: Kaganovich M. , Peretz A. , Ritsner M. , Bening Abu‐Shach U. , Attali B. , Navon R.
Published: January 2004

A missense mutation Leu309Met in the WKL1 (MLC1, KIAA0027) gene, mapped to 22q13.3, was reported to co‐segregate with periodic catatonic schizophrenia (SCZ) in a single large German pedigree with seven affected individuals (Meyer et al. [2001: Mol Psychiatry 6:302–306]). This report raised the following questions that were dealt with in the present study: does the Leu309Met mutation have a role in SCZ, or only in catatonic SCZ? Does the mutation Leu309Met in the WKL1 gene, encoding a putative membrane protein, non‐selective cation channel, have any effect on the channel activity? Is the WKL1 gene, which is expressed exclusively in brain, expressed differently in SCZ brains compared to controls? These questions were answered by screening the Leu309Met mutation in 117 Israeli Jewish patients with SCZ (55 Ashkenazi and 62 non‐Ashkenazi Jews) and 176 matched controls. In search of differences in the level of WKL1 gene expression, postmortem dorsalateral prefrontal cortex of 16 schizophrenic patients and 15 controls was checked. We also measured the putative channel activity of normal WKL1 subcloned in pcDNA3 to determine the effect of the reported Leu309Met mutation. Our results argue against the involvement of WKL1 in SCZ susceptibility. © 2003 Wiley‐Liss, Inc.
The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia
Authors: Zarranz Juan J. , Alegre Javier , Gómez‐Esteban Juan C. , Lezcano Elena , Ros Raquel , Ampuero Israel , Vidal Lídice , Hoenicka Janet , Rodriguez Olga , Atarés Begoña , Llorens Verónica , Tortosa Estrella Gomez , del Ser Teodoro , Muñoz David G. , de Yebenes Justo G.
Published: January 2004

Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to α‐synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the α‐synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary α‐synucleinopathies, dementia with Lewy bodies is related to mutation of α‐synuclein.
Characterizing the diffusion/perfusion mismatch in experimental focal cerebral ischemia
Authors: Meng Xiangjun , Fisher Marc , Shen Qiang , Sotak Christopher H. , Duong Timothy Q.
Published: January 2004

Diffusion‐weighted imaging (DWI) and perfusion‐weighted imaging (PWI) can rapidly detect lesions in acute ischemic stroke patients. The PWI volume is typically substantially larger than the DWI volume shortly after onset, that is, a diffusion/ perfusion mismatch. The aims of this study were to follow the evolution of the diffusion/ perfusion mismatch in permanent and 60‐ minute temporary focal experimental ischemia models in Sprague‐Dawley rats using the intraluminal middle cerebral artery occlusion (MCAO) method. DWI and arterial spin‐labeled PWI were performed at 30, 60, 90, 120, and 180 minutes after occlusion and lesion volumes (mm3) calculated At 24 hours after MCAO, and infarct volume was determined using triphenyltetrazolium chloride staining. In the permanent MCAO group, the lesion volume on the ADC maps was significantly smaller than that on the cerebral blood flow maps through the first 60 minutes after MCAO; but not after 90 minutes of occlusion. With 60 minutes of transient ischemia, the diffusion/perfusion mismatch was similar, but after reperfusion, the lesion volumes on ADC and cerebral blood flow maps became much smaller. There was a significant difference in 24‐ hour infarct volumes between the permanent and temporary occlusion groups.
Clinical features of cerebral cavernous malformations patients with KRIT1 mutations
Authors: Denier Christian , Labauge Pierre , Brunereau Laurent , Cavé‐Riant Florence , Marchelli Florence , Arnoult Minh , Cecillon Michaelle , Maciazek Jacqueline , Joutel Anne , Tournier‐Lasserve Elisabeth
Published: January 2004

Cerebral Cavernous Malformations (CCM/OMIM 604214) are vascular malformations causing seizures and cerebral hemorrhages. They occur as a sporadic and autosomal dominant condition, the latter being characterized by the presence of multiple CCM lesions. Stereotyped truncating mutations of KRIT1, the sole CCM gene identified so far, have been identified in CCM1 linked families but the clinical features associated with KRIT1 mutations have not yet been assessed in a large series of patients. We conducted a detailed clinical, neuroradiological and molecular analysis of 64 consecutively recruited CCM families segregating a KRIT1 mutation. Those families included 202 KRIT1 mutation carriers. Among the 202 KRIT1 mutation carriers, 126 individuals were symptomatic and 76 symptom‐free. Mean age at clinical onset was 29.7 years (range, 2–72); initial clinical manifestations were seizures in 55% of the cases and cerebral hemorrhages in 32%. Average number of lesions on T2 weighted MRI was 4.9 (±7.2) and on gradient echo sequences 19.8 (±33.2). Twenty‐six mutation carriers harbored only one lesion on T2‐weighted MRI, including 4 mutation carriers, aged from 18 to 55 yr‐old, who presented only one CCM lesion both on T2‐weighted and on highly sensitive gradient echo MRI sequences. Five symptom free mutation carriers, aged from 27 to 48 yr‐old, did not have any detectable lesion both on T2WI and gradient echo MRI sequences. Within KRIT1/CCM1 families, both clinical and radiological penetrance are incomplete and age dependent. Importantly for genetic counseling, nearly half of the KRIT1 mutation carriers aged 50 or more are symptom‐free. The presence of only one lesion, even when using gradient echo MRI sequences, can be observed in some patients with an hereditary form of the disease. Incomplete neuroradiological penetrance precludes the use of cerebral MRI to firmly establish a non carrier status, even at an adult age and even when using highly sensitive gradient echo MRI. Altogether these data suggest that the hereditary nature of the disorder may be overlooked in some mutation carriers presenting as sporadic cases with a unique lesion. Ann Neurol 2004
Presence of dendritic cells, MCP‐1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue
Authors: Henkel Jenny S. , Engelhardt Joseph I. , Siklós László , Simpson Ericka P. , Kim Seung H. , Pan Tianhong , Goodman J. Clay , Siddique Teepu , Beers David R. , Appel Stanley H.
Published: January 2004

Dendritic cells are potent antigen‐presenting cells that initiate and amplify immune responses. To determine whether dendritic cells participate in inflammatory reactions in amyotrophic lateral sclerosis (ALS), we examined mRNA expression of dendritic cell surface markers in individual sporadic ALS (sALS), familial ALS (fALS), and nonneurological disease control (NNDC) spinal cord tissues using semiquantitative and real‐time reverse transcription polymerase chain reaction (RT‐PCR). Immature (DEC205, CD1a) and activated/mature (CD83, CD40) dendritic cell transcripts were significantly elevated in ALS tissues. The presence of immature and activated/mature dendritic cells (CD1a+ and CD83+) was confirmed immunohistochemically in ALS ventral horn and corticospinal tracts. Monocytic/macrophage/microglial transcripts (CD14, CD18, SR‐A, CD68) were increased in ALS spinal cord, and activated CD68+ cells were demonstrated in close proximity to motor neurons. mRNA expressions of the chemokine MCP‐1, which attracts monocytes and myeloid dendritic cells, and of the cytokine macrophage‐colony stimulating factor (M‐CSF) were increased in ALS tissues. The MCP‐1 protein was expressed in glia in ALS but not in control tissues and was increased in the CSF of ALS patients. Those patients who progressed most rapidly expressed significantly more dendritic transcripts than patients who progressed more slowly. These results support the involvement of immune/inflammatory responses in amplifying motor neuron degeneration in ALS.
Somatic mutations in VHL germline deletion kindred correlate with mild phenotype
Authors: Wait Scott D. , Vortmeyer Alexander O. , Lonser Russell R. , Chang David T. , Finn Michael A. , Bhowmick Deb A. , Pack Svetlana D. , Oldfield Edward H. , Zhuang Zhengping
Published: January 2004

Generally, von Hippel–Lindau (VHL) disease is caused by a germline mutation of the VHL gene (chromosome 3p), and tumorigenesis is initiated from a “second‐hit” deletion. A subset of VHL patients have a germline deletion of the VHL gene, and the molecular events leading to tumorigenesis are not fully understood. To determine the molecular pathogenesis of tumor formation in this setting, we analyzed five central nervous system hemangioblastomas from three patients of a single VHL germline deletion kindred, all displaying mild clinical phenotype. Rather than loss of heterozygosity (the “second hit” in VHL germline mutation patients), all tumors from this kindred showed “second‐hit” point mutations on the wild‐type allele. Moreover, in two patients who each had two hemangioblastomas resected each tumor contained a unique mutation. The specific germline deletion and the overall genetic makeup of the patient did not predict these random “second‐hit” point mutations. These results suggest that in patients with germline deletion of a tumor suppressor gene there is a unique genetic mechanism underlying tumorigenesis. This unique genetic mechanism correlates with and may help to understand the mild clinical phenotype seen in these patients.
Aprataxin, the causative protein for EAOH is a nuclear protein with a potential role as a DNA repair protein
Authors: Sano Yasuteru , Date Hidetoshi , Igarashi Shuichi , Onodera Osamu , Oyake Mutsuo , Takahashi Toshiaki , Hayashi Shintaro , Morimatsu Mitsunori , Takahashi Hitoshi , Makifuchi Takao , Fukuhara Nobuyoshi , Tsuji Shoji
Published: January 2004

Early‐onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is an autosomal recessive neurodegenerative disorder characterized by early‐onset ataxia, ocular motor apraxia, and hypoalbuminemia. Recently, the causative gene for EAOH, APTX, has been identified. Of the two splicing variants of APTX mRNA, the short and the long forms, long‐form APTX mRNA was found to be the major isoform. Aprataxin is mainly located in the nucleus, and, furthermore, the first nuclear localization signal located near the amino terminus of the long‐form aprataxin is essential for its nuclear localization. We found, based on the yeast two‐hybrid and coimmunoprecipitation experiments, that the long‐form but not the short‐form aprataxin interacts with XRCC1 (x‐ray repair cross‐complementing group 1). Interestingly the amino terminus of the long‐form aprataxin is homologous with polynucleotidekinase‐3′‐phosphatase, which has been demonstrated to be involved in base excision repair, a subtype of single‐strand DNA break repair, through interaction with XRCC1, DNA polymerase β, and DNA ligase III. These results strongly support the possibility that aprataxin and XRCC1 constitute a multiprotein complex and are involved in single‐strand DNA break repair, and furthermore, that accumulation of unrepaired damaged DNA underlies the pathophysiological mechanisms of EAOH.
Cerebral palsy is characterized by protein mediators in cord serum
Authors: Kaukola Tuula , Satyaraj Ebenezer , Patel Dhavalkumar D. , Tchernev Velizar T. , Grimwade Brian G. , Kingsmore Stephen F. , Koskela Pentti , Tammela Outi , Vainionpää Leena , Pihko Helena , Äärimaa Tuula , Hallman Mikko
Published: January 2004

Cerebral palsy (CP) is a major neurodevelopmental disability in childhood. An association between intrauterine infection and CP has been reported. We examined the relationship between inflammatory mediators in cord serum and CP in term and preterm children. Regional multicenter study was conducted on 19 CP children and 19 gestation‐matched paired controls. CP children (n = 27) were further compared with controls of similar gestation at birth (n = 25). Serum levels of 78 protein mediators were analyzed. Eleven analytes correlated with the length of gestation both in cases and controls. In paired analysis, B‐lymphocyte chemoattractant, ciliary neurotrophic factor, epidermal growth factor, interleukin (IL)–5, IL‐12, IL‐13, IL‐15, macrophage migration inhibitory factor, monocyte chemoattractant protein–3, monokine induced by interferon γ, and tumor necrosis factor–related apoptosis‐inducing ligand were higher in children with CP (p ≤ 0.05). Preterm infants with CP showed higher epidermal growth factor and lower levels of granulocyte‐macrophage colony‐stimulating factor, IL‐2, macrophage‐derived chemokine, and pulmonary and activation‐regulated chemokine than their paired controls. Inflammatory mediators and growth factors serve as a footprint of the fetal response to an insult manifesting after birth as a permanent brain damage. The cytokine patterns at birth differ between premature and term infants who develop CP.
Constitutive activation of MAPK cascade in acute quadriplegic myopathy
Authors: Di Giovanni Simone , Molon Annamaria , Broccolini Aldobrando , Melcon Gisela , Mirabella Massimiliano , Hoffman Eric P. , Servidei Serenella
Published: January 2004

Acute quadriplegic myopathy (AQM; also called “critical illness myopathy”) shows acute muscle wasting and weakness and is experienced by some patients with severe systemic illness, often associated with administration of corticosteroids and/or neuroblocking agents. Key aspects of AQM include muscle atrophy and myofilament loss. Although these features are shared with neurogenic atrophy, myogenic atrophy in AQM appears mechanistically distinct from neurogenic atrophy. Using muscle biopsies from AQM, neurogenic atrophy, and normal controls, we show that both myogenic and neurogenic atrophy share induction of myofiber‐specific ubiquitin/proteosome pathways (eg, atrogin‐1). However, AQM patient muscle showed a specific strong induction of transforming growth factor (TGF)–β/MAPK pathways. Atrophic AQM myofibers showed coexpression of TGF‐β receptors, p38 MAPK, c‐jun, and c‐myc, including phosphorylated active forms, and these same fibers showed apoptotic features. Our data suggest a model of AQM pathogenesis in which stress stimuli (sepsis, corticosteroids, pH imbalance, osmotic imbalance) converge on the TGF‐β pathway in myofibers. The acute stimulation of the TGF‐β/MAPK pathway, coupled with the inactivity‐induced atrogin‐1/proteosome pathway, leads to the acute muscle loss seen in AQM patients. Ann Neurol 2004
Deterioration of naming nouns versus verbs in primary progressive aphasia
Authors: Hillis Argye E. , Oh Sangjin , Ken Lynda
Published: January 2004

Disproportionate impairment of naming nouns versus verbs and the opposite pattern have been reported in cases of focal brain damage or degenerative disease, indicating that processing of nouns and verbs may rely on different brain regions. However, it has not been clear whether it is the spoken word forms or the meanings (or both) of nouns and verbs that depend on separate neural regions. We tested oral and written naming of nouns and verbs, matched in difficulty, in patients with nonfluent primary progressive aphasia (nonfluent PPA; n = 15), fluent primary progressive aphasia (fluent PPA; n = 7), and amyotrophic lateral sclerosis with frontotemporal dementia (ALS‐FTD; n = 6). Patients with nonfluent PPA and ALS‐FTD, both individually and as groups, were significantly more impaired on verb naming than on noun naming and significantly more impaired on oral naming than written naming. Patients with fluent PPA showed the opposite pattern for both word class and modality, significantly more impaired naming of nouns versus verbs and significantly more impaired written versus oral naming. Results indicate that separate regions of the brain are essential for access to oral and written word forms of verbs and nouns, and that these neural regions can be differentially damaged in separate forms of PPA.
SCA17 homozygote showing Huntington's disease‐like phenotype
Authors: Toyoshima Yasuko , Yamada Mitsunori , Onodera Osamu , Shimohata Mitsuteru , Inenaga Chikanori , Fujita Nobuya , Morita Masahiro , Tsuji Shoji , Takahashi Hitoshi
Published: January 2004

We report a homozygous case of spinocerebellar ataxia type 17 with 48 glutamines. The age of the patient at disease onset was not lower than those of heterozygotes with the same CAG‐repeat sizes, but the clinical manifestations were rapidly progressive dementia and chorea. Neuronal loss was relatively restricted and most prominent in the Purkinje cell layer and striatum; however, intranuclear neuronal polyglutamine accumulation was widespread, with a high frequency in the cerebral cortex and striatum.
Perturbation of sphingolipid metabolism and ceramide production in HIV‐dementia
Authors: Haughey Norman J. , Cutler Roy G. , Tamara Anita , McArthur Justin C. , Vargas Diana L. , Pardo Carlos A. , Turchan Jadwiga , Nath Avindra , Mattson Mark P.
Published: January 2004

Infection by the human immunodeficiency virus type 1 (HIV‐1) often results in neurological dysfunction including HIV dementia (HIVD). Alterations in cytokine and redox balance are thought to play important roles in the pathogenesis of HIVD, but the specific mechanisms underlying neuronal dysfunction and death are unknown. Activation of cytokine receptors and oxidative stress can induce the production of ceramide from membrane sphingomyelin, and recent findings suggest that ceramide is an important mediator of a form of programmed cell death called apoptosis. We now report that levels of ceramide, sphingomyelin, and hydroxynonenal (HNE) are significantly increased in brain tissues and cerebrospinal fluid of HIVD patients. Exposure of cultured neurons to the neurotoxic HIV proteins gp120 and Tat resulted in increased cellular levels of sphingomyelin, ceramide, and HNE. The ceramide precursor palmitoyl‐CoA sensitized neurons to Tat and gp120 toxicity, whereas an inhibitor of ceramide production reduced Tat and gp120‐induced increases of ceramide and HNE and protected the neurons from Tat and gp120‐induced death. These results suggest that HIV‐1 infection may promote a lipid imbalance in neural cells, resulting in an overproduction of ceramide and consequent cellular dysfunction and death.
Rhabdomyolysis and paraneoplastic stiff‐man syndrome with amphiphysin autoimmunity
Authors: Petzold Gabor C. , Marcucci Melissa , Butler Margaret H. , Van Landeghem Frank K. H. , Einhäupl Karl M. , Solimena Michele , Valdueza José M. , De Camilli Pietro
Published: January 2004

Stiff‐Man syndrome (SMS) is a rare disease of the central nervous system characterized by chronic muscle rigidity and autoimmunity directed against synaptic antigens. In a subset of patients, generally positive for antiamphiphysin autoantibodies, SMS has an autoimmune paraneoplastic origin. Amphiphysin isoforms are expressed at high levels in brain and skeletal muscle and often are overexpressed in breast cancer. We report here the occurrence of rhabdomyolysis in a patient with SMS, breast cancer, and antibodies that recognize both brain and muscle amphiphysin isoforms. Immunotherapy induced a remission of both rhabdomyolysis and SMS symptoms. Autoimmune rhabdomyolysis may represent a paraneoplastic complication of cancer patients with amphiphysin autoimmunity.
Comparison of kindreds with parkinsonism and α‐synuclein genomic multiplications
Authors: Farrer Matt , Kachergus Jennifer , Forno Lysia , Lincoln Sarah , Wang Deng‐Shun , Hulihan Mary , Maraganore Demetrius , Gwinn‐Hardy Katrina , Wszolek Zbigniew , Dickson Dennis , Langston J. William
Published: January 2004

Genomic triplication of the α‐synuclein gene recently has been associated with familial Parkinson's disease in the Spellman–Muenter kindred. Here, we present an independent family, of Swedish‐American descent, with hereditary early‐onset parkinsonism with dementia due to α‐synuclein triplication. Brain tissue available from affected individuals in both kindreds provided the opportunity to compare their clinical, pathological, and biochemical phenotypes. Of note, studies of brain mRNA and soluble protein levels demonstrate a doubling of α‐synuclein expression, consistent with molecular genetic data. Pathologically, cornu ammonis 2/3 hippocampal neuronal loss appears to be a defining feature of this form of inherited parkinsonism. The profound implications of α‐synuclein overexpression for idiopathic synucleinopathies are discussed.
Autosomal dominant acute necrotizing encephalopathy maps to 2q12.1‐2q13
Authors: Neilson Derek E. , Feiler Heidi S. , Wilhelmsen Kirk C. , Lynn Audrey , Eiben Robert M. , Kerr Douglas S. , Warman Matthew L.
Published: January 2004

In autosomal dominant acute necrotizing encephalopathy (ADANE), apparently healthy children develop necrotizing lesions in their thalami and brainstems in the course of febrile illnesses. We used DNA from affected subjects and obligate carriers to map ADANE to a 6.5Mb region on chromosome 2. Sequencing of four candidate genes in the interval (BCL2L11, ST6GalII, CHT1, and FLJ20019), involved in apoptosis, viral recognition, choline transport, and electron transport, showed no disease causing mutations.
Solution conformations of cyclosporins and magnesium‐cyclosporin complexes determined by vibrational circular dichroism
Authors: Bodack Louise A. , Freedman Teresa B. , Chowdhry Babur Z. , Nafie Laurence A.
Published: January 2004

Vibrational circular dichroism (VCD) spectroscopy was used to investigate the solution conformations of cyclosporins A, C, D, G, and H in CDCl3, in the amide I and NH/OH‐stretching regions, and their corresponding magnesium complexes in CD3CN, in the amide I region. VCD spectra are sensitive to the chiral arrangement of CO and NH bonds in this cyclic undecapeptide. Calculations of molecular geometries, as well as IR and VCD intensities of model cyclosporin fragments that include the intramolecular hydrogen bonds of the crystal conformations of cyclosporins A and H (CsA and CsH), were carried out at the density functional theory (DFT; BPW91 functional/6‐31G* basis set) level. The good agreement between IR and VCD spectra from experiment and DFT calculations provides evidence that the crystal conformation of CsA is dominant in CDCl3 solution; CsH, however, assumes both an intramolecularly hydrogen‐bonded crystal conformation and more open forms in solution. Comparisons of the experimental and calculated VCD spectra in the NH/OH‐stretching region of the noncomplexed cyclosporins indicate that conformers with both free and hydrogen‐bonded NH and OH groups are present in solution. Differences between the IR and VCD spectra for the metal‐free and magnesium‐complexed cyclosporins are indicative of strong interactions between cyclosporins and magnesium ions. © 2003 Wiley Periodicals, Inc. Biopolymers 73: 163–177, 2004
The ribbon of hydrogen bonds in globular proteins. IV. The example of the papain family
Authors: Peters David , Peters Jane
Published: January 2004

A study of the role of the hydrogen‐bonding side chains in the ribbon of hydrogen bonds in globular proteins, using the papain family as an example, suggests that these side chains may be divided into three categories depending on their position in the molecule. In the first category, they form part of the local ribbon, in the second they form part of the ribbon at a site remote along the main chain, and in the third they play no role in the formation of the ribbon. The second case is particularly interesting because it provides a natural mechanism for the formation of the tertiary structure of the globular proteins. The results suggest that the robustness of the globular proteins towards mutations arises from the fact that many mutations that involve hydrogen‐bonding side chains either leave the hydrogen bonding of the ribbon essentially unchanged or their hydrogen bonding plays no part in the formation of the ribbon in the first place. The results show that it is possible to obtain the ribbon of hydrogen bonds for a family of proteins whose data set's are of intermediate quality by studying the ribbons of several members of such a family and then taking an average over the different partial ribbons to create a standard ribbon of hydrogen bonds for the family as a whole. This method is used here to derive the standard ribbon for the papain family with papain itself, actinidin, and human liver cathepsin B as the representatives of the family. All three members of the family fit the standard ribbon with an accuracy of 85–91%. This result opens up the use of this technique for the study of a large number of globular proteins whose recorded data sets are of intermediate quality. © 2003 Wiley Periodicals, Inc. Biopolymers 73: 178–191, 2004
Molecular dynamics simulations of papilloma virus E2 DNA sequences: Dynamical models for oligonucleotide structures in solution
Authors: Byun K. Suzie , Beveridge D. L.
Published: January 2004

The specificity of papilloma virus E2 protein–DNA binding depends critically upon the sequence of a region of the DNA not in direct contact with the protein, and represents one of the simplest known examples of indirect readout. A detailed characterization of this system in solution is important to the further investigation hypothesis of a structural code for DNA recognition by regulatory proteins. In the crystalline state, the E2 DNA oligonucleotide sequence, d(ACCGAATTCGGT), exhibits three different structural forms. We report herein studies of the structure of E2 DNA in solution based on a series of molecular dynamics (MD) simulations including counterions and water, utilizing both the canonical and various crystallographic structures as initial points of departure. All MDs converged on a single dynamical structure of d(ACCGAATTCGGT) in solution. The predicted structure is in close accord with two of the three crystal structures, and indicates that a significant kink in the double helix at the central ApT step in the other crystal molecule may be a packing effect. The dynamical fine structure was analyzed on the basis of helicoidal parameters. The calculated curvature in the sequence was found to originate primarily from YPR steps in the regions flanking the central AATT tract. In order to study the role of structural adaptation of the DNA in the binding process, a subsequent simulation on the 16‐mer cognate sequence d(CAACCGAATTCGGTTG) was initiated from the crystallographic coordinates of the bound DNA in the crystal structure of the protein DNA complex. MD simulations starting with the protein‐bound form relaxed rapidly back to the dynamical structure predicted from the previous simulations on the uncomplexed DNA. The MD results show that the bound form E2 DNA is a dynamically unstable structure in the absence of protein, and arises as a consequence of both structural changes intrinsic to the sequence and induced by the interaction with protein. © 2003 Wiley Periodicals, Inc. Biopolymers 73:369–379, 2004
DNA fine structure and dynamics in crystals and in solution: The impact of BI/BII backbone conformations
Authors: Djuranovic D. , Hartmann B.
Published: January 2004

Sugar–phosphate backbone conformations are an important structural element for a complete understanding of specific recognition in nucleic acid–protein interactions. They can be involved both in early stages of target discrimination and in structural adaptation upon binding. In the first part of this study, we have analyzed high‐resolution structures of double‐stranded B‐DNA either isolated or bound to proteins, and explored the impact of both the standard BI and the unusual BII phosphate backbone conformations on neighboring sugar puckers and on selected helical parameters. Correlations are found to be similar for free and bound DNA, and in both categories, the possible facing backbone conformations (BI.BI, BI.BII, and BII.BII) define well‐characterized substates in the B‐DNA conformational space. Notably, BII.BII steps are characterized by specific, and sequence‐independent, structural effects involving reduced standard deviations for almost all conformational parameters. In the second part of this work, we analyze four 10 ns molecular dynamics simulations in explicit solvent on the DNA targets of NF‐κB and bovine papillomavirus E2 proteins, highlighting the multiplicity of backbone dynamical behavior. These results show sequence effects on the percentages of BI and BII conformers, the preferential state of facing backbones, the occurrence of coupled transitions. The backbone states can consequently be seen as a mechanism for transmitting information from the bases to the phosphate groups and thus for modulating the overall structural properties of the target DNA. © 2003 Wiley Periodicals, Inc. Biopolymers 73:356–368, 2004
Packaging double‐helical DNA into viral capsids
Authors: LaMarque Jaclyn C. , Le Thuc‐vy L. , Harvey Stephen C.
Published: January 2004

DNA packaging in bacteriophage P4 has been examined using a molecular mechanics model with a reduced representation containing one pseudoatom per turn of the double helix. The model is a discretized version of an elastic continuum model. The DNA is inserted piecewise into the model capsid, with the structure being reoptimized after each piece is inserted. Various optimization protocols were investigated, and it was found that molecular dynamics at a very low temperature (0.3 K) produces the optimal packaged structure. This structure is a concentric spool, rather than the coaxial spool that has been commonly accepted for so many years. This geometry, which was originally suggested by Hall and Schellman in 1982 (Biopolymers Vol. 21, pp. 2011–2031), produces a lower overall elastic energy than coaxial spooling. © 2003 Wiley Periodicals, Inc. Biopolymers 73: 348–355, 2004
Volumetric properties of the formation of double stranded DNA: A nearest‐neighbor analysis
Authors: Dubins David N. , Macgregor Robert B.
Published: January 2004

The kinetics of the helix‐coil transition have been studied by performing UV‐monitored melting and reannealing curves of DNA and analyzing the resultant hysteresis between these curves. The analysis assumes a single‐step bimolecular transition with duplex formation defined as the forward reaction. Volume parameters of the helix‐coil transition were obtained by measuring the pressure dependence of the rate constants from 5–200 MPa. The data were interpreted in terms of several possible nearest‐neighbor models, ranging from one to eleven parameters. Twenty‐four oligonucleotide duplexes 22 base pairs in length were used to solve for individual nearest‐neighbor activation volumes and transition volumes. Statistically, the most valid fit of the volumetric data was obtained with a six‐parameter model in which the directionality of the dinucleotide steps is not considered, for example, 5′AG/CT is the same as 5′GA/TC. The resultant transition volumes at 48°C ranged from −7.1 ± 0.8 mL/mol (GC/CG) to +2.9 ± 0.3 mL/mol (AA/TT). The success of the six‐parameter model suggests that the relative size of the nearest‐neighbor dinucleotides is the most important factor determining the magnitude of the volumetric parameters. The finding that the magnitude of the volumetric parameters correlates with the change in the solvent accessible surface area of the bases during the helix‐coil transition corroborates this hypothesis. © 2003 Wiley Periodicals, Inc. Biopolymers 73: 242–257, 2004
Temperature and pressure effects on conformational equilibria of alanine dipeptide in aqueous solution
Authors: Takekiyo Takahiro , Imai Takashi , Kato Minoru , Taniguchi Yoshihiro
Published: January 2004

We investigated the temperature and pressure effects on conformational equilibria of N‐acetyl‐L‐alanine‐N′‐methylamide (AAlaMA) in aqueous solution by Raman spectroscopy. Scattering intensities in the skeletal stretching mode of AAlaMA in aqueous solution were decomposed into some component bands by the spectra analysis. Our results indicate that each component band for AAlaMA adopts not only the PII and αR conformations but also the C7eq conformation. From temperature and pressure dependencies of the band intensities, we determined the enthalpy differences and the volume differences between the conformers. The C7eq conformer is enthalpically most stable due to the intramolecular hydrogen bond. The partial molar volume of the C7eq conformer is the smallest through the solvent‐exclusion effect rather than the solute‐solvent electrostatic interaction effect. © 2004 Wiley Periodicals, Inc. Biopolymers 73: 283–290, 2004
Conformational and structural analysis of the equilibrium between single‐ and double‐strand β‐helix of a D,L‐alternating oligonorleucine
Authors: Navarro E. , Fenude E. , Celda B.
Published: January 2004

Alternating sequences of D and L residues in peptides are directly related to the formation of several kinds of regular helical conformations usually called β‐helices. The major feature of these structures is that they can be associated with the transmembrane ion‐conducting channel activity in some natural antibacterial peptides. The study of alternating D,L synthetic peptides is critical to understand how factors such as surrounding media, main chain length, type of side chain and terminal groups, among others, can determine the adoption of a specific kind of β‐helix. Early studies pointed out that the peptides Boc(D‐NLeuL‐NLeu)6D‐MeNLeL‐NleD‐NleL‐NleOMe (Boc: tert‐butyloxycarbonyl) and BocL‐Nle(D‐NleL‐Nle)5D‐MeNleL‐NleD‐NleL‐NleOMe adopt in chloroform a unique detectable conformation single β4.4‐ and double β5.6↑↓‐helix, respectively. The influence of terminal groups on the final stable conformation of N‐formylated peptides has been studied in this work. The initial basic NMR data analysis of a synthetic alternating D,L‐oligopeptide with ten norleucines, N‐methylated on the residue 7 and having HCO and OMe as terminal groups clearly indicates the coexistence of two different conformations in equilibrium. NMR data and molecular dynamics calculations point to a dimeric antiparallel β‐helix structure β5.6↑↓ for the main conformation. On the other hand, NMR data suggest a single β‐helix structure β4.4 for the second conformation. Finally, a thermodynamic analysis of the equilibrium between both conformations has been carried out by one‐dimensional NMR measurements at ten different temperatures. The temperature at which 50% of dimer conformation is dissociated is 319 K. In addition, the dimer–monomer equilibrium curve obtained shows a ΔG>0 for the whole range of studied temperatures, and its behavior can be considered similar to the thermodynamic denaturation protein processes. © 2003 Wiley Periodicals, Inc. Biopolymers 73:229–241, 2004
Identification of possible kinetically significant anion‐binding sites in human serum transferrin using molecular modeling strategies
Authors: Amin Elizabeth Ambrose , Harris Wesley R. , Welsh William J.
Published: January 2004

Certain anions have been shown experimentally to influence the rate of iron release from human serum transferrin (HST), implying the existence of one or more allosteric kinetically significant anion‐binding (KISAB) sites on or near the surface of the protein. A rank‐ordered selection of potential HST KISAB sites has been obtained using a novel three‐stage molecular modeling strategy. The crystal structure of HST (1A8E.pdb) was first subjected to a heuristic analysis, in which positively charged and hydrogen‐bonding residues on or near the surface of the protein were identified. In this stage, a preliminary electrostatic potential map was also calculated, yielding six preliminary sites. Next, energy‐grid calculations were conducted in order to identify anion–protein interaction energy minima, which resulted in the inclusion of three additional sites. Finally, three anions already shown experimentally to demonstrate varied effects on HST iron‐release kinetics were placed at each potential site; molecular dynamics and molecular mechanics calculations were performed in order to elucidate the hydrogen‐bonding environment around each anion of the protein as well as to calculate anion–protein‐binding energies. © 2003 Wiley Periodicals, Inc. Biopolymers 73: 205–215, 2004
Exploring the interaction of the surfactant N‐terminal domain of γ‐Zein with soybean phosphatidylcholine liposomes
Authors: Kogan Marcelo J. , López Olga , Cocera Mercè , López‐Iglesias Carmen , De la Maza Alfonso , Giralt Ernest
Published: January 2004

Zeins are maize storage proteins that accumulate inside large vesicles called protein bodies. γ‐Zein lines the inner surface of the protein body membrane, and its N‐terminal, proline‐rich, repetitive domain with the sequence (VHLPPP)8 appears to be necessary for the accumulation of the protein within the organelle. Synthetic (VHLPPP)8 adopts an amphipathic polyproline II conformation and forms cylindrical micelles in aqueous solution. Here we explore the interaction of (VHLPPP)8 with soybean phosphatidylcholine unilamellar lipid vesicles and examine its effect on the stability and permeability of the liposome membrane. The amphipathic N‐terminal domain of γ‐zein interacts with the membrane and assembles to form extended domains over the phospholipid membrane. The interaction between the peptide and the membrane increases the stability and permeability of the liposome membrane. The spontaneous amphipathic aggregation of (VHLPPP)8 on the membrane suggests a mechanism of γ‐zein deposition inside maize protein bodies. © 2003 Wiley Periodicals, Inc. Biopolymers 73: 258–268, 2004
DNA melting profiles from a matrix method
Authors: Poland Douglas
Published: January 2004

In this article we give a new method for the calculation of DNA melting profiles. Based on the matrix formulation of the DNA partition function, the method relies for its efficiency on the fact that the required matrices are very sparse, essentially reducing matrix multiplication to vector multiplication and thus making the computer time required to treat a DNA molecule containing N base pairs proportional to N2. A key ingredient in the method is the result that multiplication by the inverse matrix can also be reduced to vector multiplication. The task of calculating the melting profile for the entire genome is further reduced by treating regions of the molecule between helix‐plateaus, thus breaking the molecule up into independent parts that can each be treated individually. The method is easily modified to incorporate changes in the assignment of statistical weights to the different structural features of DNA. We illustrate the method using the genome of Haemophilus influenzae. © 2003 Wiley Periodicals, Inc. Biopolymers 73: 216–228, 2004
Excluded volume effect in unzipping DNA with a force
Authors: Lam Pui‐Man , Levy J.C.S. , Huang Hanchen
Published: January 2004

A double stranded DNA molecule when pulled with a force acting on one end of the molecule can become either partially or completely unzipped depending on the magnitude of the force F. For a random DNA sequence, the number M of unzipped base pairs goes as M≈(F − Fc)−2 and diverges at the critical force Fc with an exponent χ = 2. We find that when excluded volume effect is taken into account for the unzipped part of the DNA, the exponent χ = 2 is not changed but the critical force Fc is changed. The force versus temperature phase diagram depends on only two parameters in the model, the persistence length and the denaturation temperature. Furthermore a scaling form of the phase diagram can be found. This scaling form is parameter independent and depends only on the spatial dimension. It applies to all DNA molecules and should provide a useful framework for comparison with experiments. © 2004 Wiley Periodicals, Inc. Biopolymers 73: 293–300, 2004
Molecular dynamics simulations of a guaiacyl β‐O‐4 lignin model compound: Examination of intramolecular hydrogen bonding and conformational flexibility
Authors: Besombes Stéphane , Mazeau Karim
Published: January 2004

The dynamical conformational behavior of a guaiacyl β‐O‐4 lignin model compound has been investigated by molecular simulations. The potential energy surface of the molecule in vacuum has been examined by means of an adiabatic map, showing a large accessible conformational space with multiple energy minima separated by low barriers. Molecular dynamics simulations have been performed in vacuum and with explicit solvent molecules for 10 and 2.1 ns, respectively. Molecular dynamics trajectories recorded in vacuum have shown the molecule to be flexible and to visit a large number of conformations. Many intramolecular H‐bonds have been observed, existing for more than 90% of the total simulation time. The presence of explicit solvent molecules induces a significant broadening of some regions of the accessible conformational space and also largely reduces the statistical significance of intramolecular H‐bonding. Intramolecular H‐bonds observed in vacuum do not persist significantly and are preferentially exchanged with intermolecular H‐bonds to the surrounding solvent molecules. The theoretical results are in good agreement with experimental NMR data that do not support the existence of strong and persistent intramolecular H‐bonds in solution but instead indicate that H‐bonds to solvent predominate. Finally, both molecular modeling and NMR approaches predict the guaiacyl β‐O‐4 structure to be flexible and indicate that intramolecular H‐bonds are not strong and persistent enough to confer rigidity to the molecule in solution. © 2004 Wiley Periodicals, Inc. Biopolymers 73: 301–315, 2004
Structural similarity of E. coli 5S rRNA in solution and within the ribosome
Authors: Skibinska Lidia , Banachowicz Ewa , Gapiński Jacek , Patkowski Adam , Barciszewski Jan
Published: January 2004

The article presents translational and rotational diffusion coefficients of 5S rRNA determined experimentally by the method of dynamic light scattering (DLS) and its comparison with the values predicted for different models of this molecule. The tertiary structure of free 5S rRNA was proposed on the basis of the atomic structures of the 5S rRNA from E. coli and H. marismortui extracted from the ribosome. A comparison of the values of DT, τR, and Rg predicted for different models with experimental results for the free molecule in solution suggests that free 5S rRNA is less compact than that in the complex with ribosomal proteins. In general, the molecules of 5S rRNA consist of three domains: a short one and two longer ones. As follows from a comparison of the results of our simulations with experimental values, in the molecule in solution the two closest helical fragments of the longer domains remain collinear, whereas the short domain takes a position significantly deviated from them. © 2004 Wiley Periodicals, Inc. Biopolymers 73: 316–325, 2004
Molecular dynamics simulations of DNA curvature and flexibility: Helix phasing and premelting
Authors: Beveridge D. L. , Dixit Surjit B. , Barreiro Gabriela , Thayer Kelly M.
Published: January 2004

Recent studies of DNA axis curvature and flexibility based on molecular dynamics (MD) simulations on DNA are reviewed. The MD simulations are on DNA sequences up to 25 base pairs in length, including explicit consideration of counterions and waters in the computational model. MD studies are described for ApA steps, A‐tracts, for sequences of A‐tracts with helix phasing. In MD modeling, ApA steps and A‐tracts in aqueous solution are essentially straight, relatively rigid, and exhibit the characteristic features associated with the B′‐form of DNA. The results of MD modeling of A‐tract oligonucleotides are validated by close accord with corresponding crystal structure results and nuclear magnetic resonance (NMR) nuclear Overhauser effect (NOE) and residual dipolar coupling (RDC) structures of d(CGCGAATTCGCG) and d(GGCAAAAAACGG). MD simulation successfully accounts for enhanced axis curvature in a set of three sequences with phased A‐tracts studied to date. The primary origin of the axis curvature in the MD model is found at those pyrimidine/purine YpR “flexible hinge points” in a highroll, open hinge conformational substate. In the MD model of axis curvature in a DNA sequence with both phased A‐tracts and YpR steps, the A‐tracts appear to act aspositioning elementsthat make the helix phasing more precise, and key YpR steps in the open hinge state serve ascurvature elements. Our simulations on a phased A‐tract sequence as a function of temperature show that the MD simulations exhibit a premelting transition in close accord with experiment, and predict that the mechanism involves a B′‐to‐B transition within A‐tracts coupled with the prediction of a transition in key YpR steps from the high roll, open hinge, to a low roll, closed hinge substate. Diverse experimental observations on DNA curvature phenomena are examined in light of the MD model with no serious discrepancies. The collected MD results provide independent support for the “non‐A‐tract model” of DNA curvature. The “junction model” is indicated to be a special case of the non‐A‐tract model when there is a Y base at the 5′ end of an A‐tract. In accord with crystallography, the “ApA wedge model” is not supported by MD. © 2004 Wiley Periodicals, Inc. Biopolymers 73: 380–403, 2004