bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved Palladium and Nickel Catalysts Heterogenised on Oxidic Supports (Silica, MCM‐41, ITQ‐2, ITQ‐6)
Authors: González‐Arellano C. , Corma A. , Iglesias M. , Sánchez F.
Published: September 2004

Two series of solid catalysts in which a chiral palladium or nickel complex with Schiff bases as ligands have been immobilized on ordered mesoporous silica supports (MCM‐41), delaminated ITQ‐2, ITQ‐6 zeolites and amorphous silica have been prepared. Hydrogenation of alkenes and imines was studied with the homogeneous as well as with the counterpart heterogenized catalysts. The high accessibility introduced by the structure of the supports allows the preparation of highly efficient immobilized catalysts with TOFs of 1,000,000 h−1. A moderate acidity in the support increases the catalytic activity considerably, and the easy recoverable immobilized catalysts can duplicate the activity of the homogeneous analogues. No deactivation of the catalysts was observed after repeated recycling.
Carbene Rearrangements, 60.‡ Supramolecular Structure‐Reactivity Relationships: Photolysis of a Series of Aziadamantane@Cyclodextrin Inclusion Complexes in the Solid State
Authors: Krois Daniel , Brecker Lothar , Werner Andreas , Brinker Udo H.
Published: September 2004

Photolyses of the α‐, β‐ and γ‐cyclodextrin complexes of 2‐aziadamantane (1) in the solid state afforded markedly different product distributions, as determined by quantitative GC and HPLC analyses. The results are discussed with respect to the structures of the inclusion complexes.
Relationship between dopaminergic neurotransmission, alcoholism, and reward deficiency syndrome
Authors: Bowirrat Abdalla , Oscar‐Berman Marlene
Published: September 2004

In this review, we described the neural substrates underlying Reward Deficiency syndrome which, in turn, is posited to underlie alcohol dependency. Alcoholism is a complex, multifactorial disorder that results from the interplay between genetic and environmental factors. The D2 dopamine receptor (DRD2) has been associated with pleasure, and the DRD2 A1 allele has been referred to as a reward gene. Evidence suggests that there is a tripartite interaction involving dopamine receptor deficiency, a propensity to abuse alcohol, and reduced sensitivity to rewards. This interaction relies heavily on genetic characteristics of the individual, with certain ethnic groups having a greater tendency toward alcoholism than others. The DRD2 has been one of the most widely studied in neuropsychiatric disorders in general, and in alcoholism and other addictions in particular. The dopamine D2 (DRD2) gene, and especially its allele TaqI A1 allele and its receptor, also may be involved in comorbid antisocial personality disorder symptoms, high novelty seeking, and related traits. The mesocorticolimbic dopaminergic pathway system plays an especially important role in mediating reinforcement by abused drugs, and it may be a common denominator for addictions such as alcoholism. When the mesocorticolimbic dopamine reward system dysfunctions (perhaps caused by certain genetic variants), the end result is Reward Deficiency syndrome and subsequent drug‐seeking behaviors. Reward Deficiency syndrome refers to the breakdown of the reward cascade, and resultant aberrant conduct, due to genetic and environmental influences. Alcohol and other drugs of abuse, as well as most positive reinforcers, cause activation and neuronal release of brain dopamine, which can decrease negative feelings and satisfy abnormal cravings. A deficiency or absence of DRD2 receptors then predisposes individuals to a high risk for multiple addictive, impulsive, and compulsive behaviors. Although other neurotransmitters (e.g., glutamate, gamma‐aminobutyric acid (GABA), and serotonin) may be important in determining the rewarding and stimulating effects of ethanol, dopamine may be critical for initiating drug use and for reinstating drug use during protracted abstinence. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148‐7299:1/suppmat/index.html. © 2004 Wiley‐Liss, Inc.
Molecular genetic studies of ADHD: 1991 to 2004
Authors: Bobb Aaron J. , Castellanos F. Xavier , Addington Anjene M. , Rapoport Judith L.
Published: September 2004

Attention deficit hyperactivity disorder (ADHD) is highly heritable but is likely a complex disorder involving multiple genes of moderate effect (Smalley [1997: Am J Hum Genet 60:1276–1282]). Over 100 studies have examined the genetics of ADHD by linkage or association, though no article has presented a comprehensive overview of all published reports. We reviewed all ADHD studies, including 3 genome‐wide linkage studies, and association studies of 94 polymorphisms in 33 candidate genes. To simplify comparisons across heterogeneous articles, demographics and comorbidity were ignored; analyses of subtype and haplotypes were excluded; and only the most positive finding for each polymorphism in a study was reported. Thirty‐six percent of all findings were positive (P ≤ 0.05), 17% were trends (0.05 < P ≤ 0.15), and 47% were negative (P > 0.15). Studies utilizing dimensional measures of ADHD tended to result in higher rates of positive findings than those using categorical diagnoses (χ2 = 5.6, P = 0.018), and case‐control studies tended to result in higher rates of positive findings than family‐based studies (χ2 = 18.8, P < 0.001). However, for either dichotomy, no significant difference remained when analyzing only studies using both methods within the same population and polymorphism. Evidence for association exists for four genes in ADHD: the dopamine D4 and D5 receptors, and the dopamine and serotonin transporters; others are promising but need further replication, including the dopamine D2 and serotonin 2A receptors. All candidate gene approaches continue to face the problem of relatively low power, given modest odds ratios for even the best replicated genes. © 2004 Wiley‐Liss, Inc.
Identification of a novel 45 repeat unstable allele associated with a disease phenotype at the MJD1/SCA3 locus
Authors: Padiath Quasar Saleem , Srivastava Achal Kumar , Roy Sanghmitra , Jain Satish , Brahmachari Samir Kumar
Published: September 2004

We report a three generation Indian pedigree with the proband having 45 repeats at the Machado Joseph Disease (MJD)/spinocerebellar ataxia 3 (SCA3) disease locus. The proband exhibited clinical features of SCA and showed signs of cerebellar and brainstem atrophy on the MRI scan. The 45 repeat allele was unstable upon inter‐generational transmission and was associated with a haplotype found in the majority of MJD/SCA3 patients from around the world. This is the smallest unstable allele reported till date at the MJD/SCA3 locus and may greatly reduce the gap between normal and pathological repeat ranges. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148‐7299:1/suppmat/index.html. © 2004 Wiley‐Liss, Inc.
Relationship of MAO‐A promoter (u‐VNTR) and COMT (V158M) gene polymorphisms to CSF monoamine metabolites levels in a psychiatric sample of caucasians: A preliminary report
Authors: Zalsman Gil , Huang Yung‐yu , Harkavy‐Friedman Jill M. , Oquendo Maria A. , Ellis Steven P. , Mann J. John
Published: September 2004

Monoamine oxidase A gene promoter (MAOA‐uVNTR) and catechol‐O‐methyltransferase V158M (COMT‐V158M) gene functional polymorphisms are reported to be associated with impulsive‐aggression, but a biological intermediate effect remains to be determined. This study assessed the association of these polymorphisms with cerebrospinal fluid (CSF) monoamine metabolites as endophenotypes. Ninety‐eight Caucasian psychiatric subjects were assessed for Axis I and II diagnosis. Subjects were genotyped for the functional polymorphisms, MAOA‐uVNTR and COMT‐V158M. CSF was obtained by lumbar puncture. Relationships of the two polymorphism to monoamine metabolites: HVA, 5‐HIAA, and MHPG were examined. The higher‐expressing MAOA‐uVNTR genotype was associated with higher CSF‐HVA levels in males only (n = 46) (195.80 pmol/ml, SD = 61.64 vs. 161.13, SD = 50.23, respectively; P = 0.042). No association was found with diagnosis. COMT‐V158M had no association with CSF monoamine metabolites. The association of MAOA‐uVNTR with dopaminergic activity in males is a preliminary finding that needs to be replicated in a larger sample of Caucasian males and relationships sought with clinical phenotypes. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148‐7299:1/suppmat/index.html. © 2004 Wiley‐Liss, Inc.
Subcutaneous octreotide in cluster headache: Randomized placebo‐controlled double‐blind crossover study
Authors: Matharu Manjit S. , Levy Miles J. , Meeran Karim , Goadsby Peter J.
Published: September 2004

Current practical evidence‐based acute treatments of cluster headache are limited to subcutaneous and intranasal formulations of sumatriptan, and oxygen. Two small randomized, double‐blind trials suggested efficacy of somatostatin in cluster headache. We sought to determine whether octreotide, a somatostatin analog, is effective in the abortive treatment of acute cluster headache. Patients with episodic and chronic cluster headache, as defined by the International Headache Society, were recruited to a double‐blind placebo‐controlled crossover study. Patients were instructed to treat two attacks of at least moderate pain severity, with at least a 24‐hour break, using subcutaneous octreotide μg or matching placebo. The primary end point was the headache response defined as very severe, severe, or moderate pain becomes mild or nil, at 30 minutes. The primary end point was examined using a multilevel analysis approach. A total of 57 patients were recruited of whom 46 provided efficacy data on attacks treated with octreotide and 45 with placebo. The headache response rate with subcutaneous octreotide was 52%, whereas that with placebo was 36%. Modeling the treatment outcome as a binomial where response was determined by treatment, using the patient as the level 2 variable, and considering period effect, sex, and cluster headache type as other variables of interest, we found that the effect of subcutaneous octreotide 100μg was significantly superior to placebo (p < 0.01). Subcutaneous octreotide 100μg is effective in the acute treatment of cluster headache when compared with placebo. Nonvasconstrictor treatment of acute cluster headache is possible. Ann Neurol 2004
Pulse‐synchronous eye oscillations revealing bone superior canal dehiscence
Authors: Tilikete Caroline , Krolak‐Salmon Pierre , Truy Eric , Vighetto Alain
Published: September 2004

Superior canal dehiscence syndrome is a newly recognized syndrome characterized by vertigo and nystagmus induced by sound (Tullio phenomenon) or changes of middle ear (Hennebert sign) or intracranial pressure. We report on a patient with bilateral superior canal dehiscence syndrome who presented with unusual manifestations including pulse‐synchronous vertical pendular nystagmus and Valsalva‐induced, up and counterclockwise‐beating jerk nystagmus. These unusual symptoms may be a clue to a better understanding of the pathophysiology of superior canal dehiscence syndrome. Abnormal communication between the inner ears and the intracranial space may explain the vertical pendular and pulse‐synchronous nystagmus, modulated by increased intracranial pressure. Ann Neurol 2004;56:556–560
The acute effects of glycemic control on axonal excitability in human diabetics
Authors: Kitano Yukiko , Kuwabara Satoshi , Misawa Sonoko , Ogawara Kazue , Kanai Kazuaki , Kikkawa Yuriko , Yagui Kazuo , Hattori Takamichi
Published: September 2004

In diabetic nerves, the activation of the polyol pathway and a resulting decrease in Na+‐K+ ATPase activity lead to intra‐axonal Na+ accumulation and a smaller Na+ gradient across the axolemma than normal. To investigate whether glycemic control is associated with acutely reversible changes in axonal excitability and Na+ conductance, we measured the multiple excitability indices (strength‐duration time constant, rheobase, refractoriness, and refractory period) of the median motor axons of 21 diabetic patients before and after intensive insulin treatment. Within 4 weeks after treatment was begun, there was a significant improvement in nerve conduction velocities, associated with increased strength‐duration time constant, decreased rheobase, increased refractoriness, and prolonged refractory periods. Assuming that the strength‐duration time constant partly reflects persistent Na+ conductance, and that refractoriness/refractory periods depend on inactivation of transient Na+ channels caused by prior depolarization (the influx of Na+), the patterns of changes in these indices may reflect a reduced trans‐axonal Na+ gradient during hyperglycemia and its restoration by glycemic control in diabetic patients. Measurement of the excitability indices could provide new insights into the pathophysiology of human diabetic neuropathy. Ann Neurol 2004;56:462–467
Insulin signaling pathways in cortical dysplasia and TSC‐tubers: Tissue microarray analysis
Authors: Miyata Hajime , Chiang Alexander C. Y. , Vinters Harry V.
Published: September 2004

To evaluate the possible roles of the Akt/PKB‐mTOR‐p70S6K‐S6 and cap‐dependent translation (eIF4G) pathways in the pathogenesis of tuberous sclerosis complex (TSC)–associated cortical tubers and focal cortical dysplasia (FCD), we performed qualitative and semiquantitative immunohistochemical evaluation on surgically resected corticectomy specimens to detect phosphorylated molecules as activated downstream targets of the signaling pathways. A tissue microarray paraffin block was constructed from 63 archival specimens of surgically resected TSC tubers, FCDs with balloon cells, cortical dysplasia without balloon cells, and histologically normal–appearing neocortex obtained from cases with Rasmussen encephalitis, cystic–gliotic encephalopathy, and temporal lobe epilepsy. Abnormal neuroglial cells were positive for phospho‐S6 and phospho‐eIF4G with various staining intensities in FCDs and TSC tubers. Both proteins were much less abundantly expressed in normal‐appearing neocortex. Phospho‐mTOR expression was observed in neurons in all groups. The expression of phospho‐S6 and phospho‐eIF4G was associated with dysplastic lesions (p < 0.05), and the cytoplasmic phospho‐p70S6K expression was most specific for and abundant in TSC tubers and much less prominent in other groups (p < 0.01). These results suggest that constitutive activation of cytoplasmic p70S6K plays a pivotal role in the pathogenesis of TSC tubers and that FCDs possess a distinct mechanism for activation of S6 and eIF4G. Ann Neurol 2004;56:510–519
A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family
Authors: Rivière Jean‐Baptiste , Verlaan Dominique J. , Shekarabi Masoud , Lafrenière Ronald G. , Bénard Mélanie , Der Kaloustian Vazken M. , Shbaklo Zuhayr , Rouleau Guy A.
Published: September 2004

Hereditary sensory and autonomic neuropathy (HSAN) type II is an autosomal recessive disorder clinically characterized by distal and proximal sensory loss that is caused by the reduction or absence of peripheral sensory nerves. Recently, a novel gene called HSN2 has been found to be the cause of HSAN type II in five families from Newfoundland and Quebec. Screening of this gene in an HSAN type II Lebanese family showed a 1bp deletion mutation found in a homozygous state in all affected individuals. This novel mutation supports the hypothesis that HSN2 is the causative gene for HSAN type II. Ann Neurol 2004;56:572–575
α‐Synuclein promoter confers susceptibility to Parkinson's disease
Authors: Pals Philippe , Lincoln Sarah , Manning Jonathan , Heckman Michael , Skipper Lisa , Hulihan Mary , Van den Broeck Marleen , De Pooter Tim , Cras Patrick , Crook Julia , Van Broeckhoven Christine , Farrer Matt J.
Published: September 2004

Familial Parkinson's disease (PD) has been linked to missense and genomic multiplication mutations of the α‐synuclein gene (SNCA). Genetic variability within SNCA has been implicated in idiopathic PD in many populations. We now confirm and extend these findings, within a Belgian sample, using a high‐resolution map of genetic markers across the SNCA locus. Our study implicates the SNCA promoter in susceptibility to PD, and more specifically defines a minimum promoter haplotype, spanning approximately 15.3kb of sequence, which is overrepresented in patients. Our findings represent a biomarker for PD and may have implications for patient diagnosis, longitudinal evaluation, and treatment. Ann Neurol 2004;56:591–595
Disturbed surround inhibition in focal hand dystonia
Authors: Sohn Young H. , Hallett Mark
Published: September 2004

Disturbances in surround inhibition could account for various movement disorders. Here we test the functional operation of surround inhibition in focal hand dystonia. Transcranial magnetic stimulation was set to be triggered by self‐initiated voluntary flexion of the index finger. During this movement, motor‐evoked potential amplitudes from the little finger muscle were significantly suppressed in healthy subjects but enhanced in dystonia patients. This result supports the idea that disturbed surround inhibition is a principal pathophysiological mechanism of dystonia. Ann Neurol 2004;56:595–599
Rapid eye movement sleep behavior disorder in parkinsonism with parkin mutations
Authors: Kumru Hatice , Santamaria Joan , Tolosa Eduardo , Valldeoriola Francesc , Muñoz Esteban , Marti Maria J. , Iranzo Alex
Published: September 2004

Rapid eye movement sleep behavior disorder (RBD) in the setting of parkinsonism or dementia often reflects an underlying synucleinopathy. Lewy bodies, intraneuronal aggregates containing abnormal α‐synuclein, are absent in most cases of parkinsonism with parkin mutations (Park2). We performed clinical history and video‐polysomnography in 10 Park2 patients (seven men; age, 51.2 ± 11.6 years; parkinsonism duration, 18.3 ± 11.2 years) and found RBD in 6. In all instances, RBD followed the onset of motor symptoms by several years. Our study shows that RBD is frequent in Park2, suggesting that mechanisms other than synuclein deposition can cause RBD in neurodegenerative disorders. Ann Neurol 2004;56:599–603
A novel RAB7 mutation associated with ulcero‐mutilating neuropathy
Authors: Houlden Henry , King Rosalind H. M. , Muddle John R. , Warner Thomas T. , Reilly Mary M. , Orrell Richard W. , Ginsberg Lionel
Published: September 2004

There are two known autosomal dominant genes for the hereditary ulcero‐mutilating neuropathies: SPTLC1 (hereditary sensory neuropathy type 1) and RAB7 (Charcot–Marie–Tooth disease type 2B). We report a family with autosomal dominant ulcero‐mutilating neuropathy, developing in the teens and characterized by ulcers, amputations, sensory involvement in the feet but no motor features. Sequencing the RAB7 gene showed a novel heterozygous A to C mutation, changing asparagine to threonine at codon 161. The mutation is situated adjacent to a previously identified valine to methionine mutation at codon 162, implying a hotspot for mutations in the highly conserved C terminus of RAB7. Ann Neurol 2004;56:586–590
Im Goldenen Zeitalter der Organokatalyse
Authors: Dalko Peter I. , Moisan Lionel
Published: September 2004

Unter dem Begriff “Organokatalyse” werden chemische Reaktionen zusammengefasst, die durch Zusatz substöchiometrischer Mengen von organischen Verbindungen beschleunigt werden. Das Interesse an diesem Forschungsgebiet und den damit verbundenen neuen Konzepten hat in den vergangenen Jahren stark zugenommen. Viele der bekannten organokatalytischen Reaktionen sind bezüglich ihrer Effizienz und Selektivität mit etablierten organischen Reaktionen vergleichbar, und die Organokatalyse hat sich beim Aufbau komplexer Molekülgerüste bewährt. Die verschiedenartigen Beispiele zeigen, dass sich die Organokatalyse in den letzten Jahren zu einem selbständigen Teilgebiet der Organischen Chemie entwickelt hat, dessen “Goldenes Zeitalter” bereits angebrochen ist.
Wann und wie dimerisieren Diaminocarbene?
Authors: Alder Roger W. , Blake Michael E. , Chaker Leila , Harvey Jeremy N. , Paolini François , Schütz Jan
Published: September 2004

Bisher wurde kein eindeutiger Nachweis für eine einfache, nicht katalysierte Dimerisierung von Diaminocarbenen gefunden. Es ist somit an der Zeit zu hinterfragen, welche Faktoren die Thermodynamik dieser Reaktion steuern und welche Mechanismen für die beobachteten Dimerisierungen verantwortlich sind. In Übereinstimmung mit qualitativen experimentellen Beobachtungen ergab die Berechnung, dass die Dimerisierung von einfachen Fünf‐ und Sechsringdiaminocarbenen um 100 kJ mol−1 weniger begünstigt ist als die der acyclischen Pendants. Dieser große Unterschied kann halbquantitativ durch die Änderung von Bindungs‐ und Torsionswinkeln um die Carbenzentren herum erklärt werden. Carbene wie (Et2N)2C sind, in Einklang mit den berechneten Energiebarrieren, in THF bei 25 °C kinetisch stabil, aber sie dimerisieren schnell in Gegenwart des entsprechenden Formamidiniumions. Dieser protonenkatalysierte Prozess ist wahrscheinlich der häufigste Mechanismus der Dimerbildung. Er führt zur Bildung von C‐protonierten Dimeren, was in geeigneten Fällen beobachtet werden kann. Es wird auch die Möglichkeit der durch Alkalimetalle geförderten Dimerisierung diskutiert; hierfür werden einige Belege vorgestellt.
In the Golden Age of Organocatalysis
Authors: Dalko Peter I. , Moisan Lionel
Published: September 2004

The term “organocatalysis” describes the acceleration of chemical reactions through the addition of a substoichiometric quantity of an organic compound. The interest in this field has increased spectacularly in the last few years as result of both the novelty of the concept and, more importantly, the fact that the efficiency and selectivity of many organocatalytic reactions meet the standards of established organic reactions. Organocatalytic reactions are becoming powerful tools in the construction of complex molecular skeletons. The diverse examples show that in recent years organocatalysis has developed within organic chemistry into its own subdiscipline, whose “Golden Age” has already dawned.
When and How Do Diaminocarbenes Dimerize?
Authors: Alder Roger W. , Blake Michael E. , Chaker Leila , Harvey Jeremy N. , Paolini François , Schütz Jan
Published: September 2004

No example of a simple uncatalyzed dimerization of a diaminocarbene has been clearly established, so it is timely to ask what factors control the thermodynamics of this reaction, and what mechanisms are responsible for the observed dimerizations? In agreement with qualitative experimental observations, the dimerizations of simple five‐ and six‐membered‐ring diaminocarbenes are calculated to be 100 kJ mol−1 less favorable than those of acyclic counterparts. This large difference is semiquantitatively accounted for by bond and torsional angle changes around the carbene centers. Carbenes such as (Et2N)2C are kinetically stable in THF at 25 °C in agreement with calculated energy barriers, but they rapidly dimerize in the presence of the corresponding formamidinium ion. This proton‐catalyzed process is probably the most common mechanism for dimer formation, and involves formation of C‐protonated dimers, which can be observed in suitable cases. The possibility of alkali‐metal‐promoted dimerization is raised, and circumstantial evidence for this is presented.
Einfluß einer Mörtelschicht auf die Quertragfähigkeit von Dübelbefestigungen
Authors: Mallée Rainer
Published: September 2004

Zum Ausgleich von Unebenheiten auf der Betonoberfläche oder zur Überbrückung von Höhentoleranzen werden bei nachträglichen Befestigungen mit Dübeln zwischen Beton und Anbauteil häufig Mörtelschichten angeordnet. Auf Basis von Versuchsergebnissen wird der Einfluß der Schichtdicke auf die Quertragfähigkeit von Dübelgruppen abgeschätzt.
Quertragfähigkeit randnaher Befestigungsmittel mit Belastung senkrecht zum Bauteilrand
Authors: Hofmann Jan , Fuchs Werner , Eligehausen Rolf
Published: September 2004

Befestigungen mit Einlegeteilen sowie chemischen und mechanischen Metalldübeln werden in allen Bereichen des Bauwesens häufig eingesetzt. Bei Produkten mit Europäisch Technischen Zulassungen (ETAs) oder neueren Zulassungen des Deutschen Instituts für Bautechnik (DIBt) wird der Nachweis der Versagensart Betonbruch in der Bemessung nach der sog. CC‐Methode, die in ETAG 001, Annex C und die DIBt‐Richtlinie (1993) Eingang gefunden hat, durchgeführt. In diesem Beitrag wird erläutert, wie die sog. CC‐Methode für den Fall von randnahen querbelasteten Befestigungen mit der Versagensart Betonkantenbruch verbessert werden kann. Dieser verbesserte Ansatz wird in der künftigen europäischen Norm zur Bemessung von Befestigungsmitteln enthalten sein.
Lineares oder nichtlineares Kriechen bei Druckgliedern?
Authors: Quast Ulrich
Published: September 2004

Die neue Normengeneration beschert der Baupraxis auch lineares und nichtlineares Kriechen. Ob nichtlineares Kriechen besser mit den in der Forschung bevorzugten rheologischen Kriechmodellen erfaßt werden kann, oder ob das einfachere Vorgehen mit den für lineares Kriechen bekannten Kriechzahlen ausreicht, wird an Einzelbeispielen sehr schlanker Druckglieder miteinander verglichen. Es wird erläutert, wie die unter ständiger Gebrauchslast entstehenden Kriechauswirkungen schlanker Druckglieder in den Nachweisen im Grenzzustand der Tragfähigkeit auf vereinfachte Weise berücksichtigt werden können.
Pressure dependence of human fibrinogen correlated to the conformational α‐helix to β‐sheet transition: An Fourier transform infrared study microspectroscopic study
Authors: Lin Shan‐Yang , Wei Yen‐Shan , Hsieh Tzu‐Feng , Li Mei‐Jane
Published: September 2004

We used Fourier transform infrared (FTIR) microspectroscopy to investigate pressure‐induced conformational changes in secondary structure of fibrinogen (FBG). Solid state FBG was compressed on a KBr pellet (1KBr method) or between two KBr pellets (2KBr method). The peak positions of the original and second‐derivative ir spectra of compressed FBG samples prepared by the 1KBr method were similar to FBG sample without pressure. When FBG was prepared by the 2KBr method and pressure was increased up to 400 kg/cm2, peaks at 1625 (intermolecular β‐sheet) and 1611 (β‐sheet aggregates structure and/or the side‐chain absorption of the tyrosine residues) cm−1 were enhanced. The peaks near 1661 (β‐sheet) and 1652 (α‐helix) cm−1 also exhibited a marked change with pressure. A linear correlation was found between the peak intensity ratio of 1611/1652 cm−1 (r = 0.9879) or 1625/1652 cm−1 (r = 0.9752) and applied pressure. The curve‐fitted compositional changes in secondary structure of FBG also indicate that the composition of the α‐helix structure (1657–1659 cm−1) was gradually reduced with the increase in compression pressure, but the composition of the β‐sheet structure (1681, 1629, and 1609 cm−1) gradually increased. This indicates that pressure‐induced conformational changes in FBG include not only transformations from α‐helix to β‐sheet structure, but also unfolding and denaturation of FBG and the formation of aggregates. © 2004 Wiley Periodicals, Inc. Biopolymers, 2004
Gelation of gellan gum aqueous solutions studied by polarization modulation spectroscopy
Authors: Horinaka Jun‐ichi , Kani Kohei , Itokawa Yoshimi , Ogawa Etsuyo , Shindo Yohji
Published: September 2004

Circular birefringence (CB, or optical rotation) and linear birefringence (LB) were measured for gellan gum aqueous solutions with and without salt to examine the gelling system in the helical structure as well as in the orientation. It was found that gelling samples with salt show nonzero LB values, whereas LB is zero for the samples without salt even in the gel state. This difference can be explained by the thermal deformation of the system containing anisotropic aggregations of helices formed with the shielding effect of the added salt on the intramolecular and intermolecular electrostatic repulsions. Considering that the presence of LB in the system affects the estimation of CB, we developed an original procedure of the CB measurement to eliminate the contribution of LB. It was shown that our methods for eliminating the contribution of LB can improve the CB measurement for the gellan gum gel. The temperature dependence of [α] for the samples with salt in the gel state is quite different from that for the samples without salt, suggesting that the aggregates of helices in the samples containing a high concentration of salt form a supramolecular structure that contributes to CB. © 2004 Wiley Periodicals, Inc. Biopolymers, 2004
Removal of the side‐chain glucose groups from schizophyllan improves the thermal stability of the polycytidylic acid complexes under the physiological conditions
Authors: Koumoto Kazuya , Karinaga Ryouji , Mizu Masami , Anada Takahisa , Sakurai Kazuo , Kunitake Toyoki , Shinkai Seiji
Published: September 2004

Thermal stabilization of the complex between polycytidylic acid [poly(C)] and the modified schizophyllan (SPG) whose hydrophilic side‐chain glucose groups are selectively removed utilizing mild Smith‐degradation has been investigated. With the decrease in the side‐chain glucose groups of schizophyllan, the complex with poly(C) can be considerably stabilized compared with unmodified SPG; for example, the Tm value after the removal of the side‐chain glucose groups from 33.3 (unmodified) to 1.0 is enhanced by 14°C. In addition, the thermal stabilization effect is even operative under the physiological conditions ([NaCl] = 0.15 mol dm−3). This effect is exerted owing to the construction of the hydrophobic atmosphere around the complex. Although schizophyllan lost the side‐chain glucose groups, it still kept the protection effect of the bound poly(C) chain against RNaseA‐mediated hydrolysis as observed for unmodified schizophyllan. The assessment of the cytotoxicity for A375:human malignant melanoma, and HL60:human promyelocytic leukemia revealed that the modified schizophyllan scarcely increases the cytotoxicity. These results indicate that the present modification for schizophyllan is of great significance in a viewpoint to develop the practical gene carriers operative even under the physiological conditions. © 2004 Wiley Periodicals, Inc. Biopolymers, 2004
NMR solution structure of a highly stable de novo heterodimeric coiled‐coil
Authors: Lindhout Darrin A. , Litowski Jennifer R. , Mercier Pascal , Hodges Robert S. , Sykes Brian D.
Published: September 2004

The NMR solution structure of a highly stable coiled‐coil IAAL‐E3/K3 has been solved. The E3/K3 coiled‐coil is a 42‐residue de novo designed coiled‐coil comprising three heptad repeats per subunit, stabilized by hydrophobic contacts within the core and electrostatic interactions at the interface crossing the hydrophobic core which direct heterodimer formation. This E3/K3 domain has previously been shown to have high α‐helical content as well as possessing a low dissociation constant (70 nM). The E3/K3 structure is completely α‐helical and is an archetypical coiled‐coil in solution, as determined using a combination of 1H‐NOE and homology based structural restraints. This structure provides a structural framework for visualizing the important interactions for stability and specificity, which are key to protein engineering applications such as affinity purification and de novo design. © 2004 Wiley Periodicals, Inc. Biopolymers, 2004
Inflamatory bowel diseases as an intermediate stage between normal and cancer: A FTIR‐microspectroscopy approach
Authors: Argov Shmuel , Sahu Ranjit K. , Bernshtain Evgenia , Salman Ahmad , Shohat Guy , Zelig Udi , Mordechai Shaul
Published: September 2004

Elucidation of the evolution of inflammatory bowel disease (IBD) to cancer by clinical symptoms and histopathology of biopsies is important. Fourier transform infrared microspectroscopy (FTIR‐MSP) has shown promise as a diagnostic tool for distinction of normal and cancer cells and tissues. In the present work, FTIR‐MSP is used to evaluate IBD cases and to study the IR spectral characteristic with respect to cancer and normal tissues from formalin‐fixed colonic biopsies from patients. Specific regions of the spectra were analyzed by statistical tools to study variations in metabolites that signified changes between the two pathological conditions: IBD and cancer. IBD tissues can be grouped with cancer or normal tissue using certain parameters such as phosphate content and RNA/DNA ratio as calculated from the spectra and show intermediate levels with regard to these metabolites. Further classification of the spectra by cluster analysis indicated which cases of Crohn's disease (3 of 10 cases) or ulcerative colitis (7 of 10 cases) were more likely to progress to cancer. The study exhibits that FTIR‐MSP can detect gross biochemical changes in morphologically identical IBD and cancer tissues and suggest which cases of IBD may require further evaluation for carcinogenesis. © 2004 Wiley Periodicals, Inc. Biopolymers, 2004
Beneficial effect of helicopter emergency medical services on survival of severely injured patients
Authors: Frankema S P G , Ringburg A N , Steyerberg E W , Edwards M J R , Schipper I B , van Vugt A B
Published: September 2004

Background

In Rotterdam, the Netherlands, a helicopter-transported medical team (HMT), staffed with a trauma physician, provides additional therapeutic options at the scene of injury. This study evaluated the influence of the HMT on the chance of survival of severely injured trauma victims.

Methods

This was a 2-year prospective observational study of consecutive adults who suffered multiple trauma (Injury Severity Score (ISS) 16 or more) and presented to the Erasmus Medical Centre emergency ward. The effect of the HMT was quantified by an odds ratio (OR), adjusted for confounding variables in logistic regression models.

Results

Complete data for a total of 346 patients were available for analysis. Two hundred and thirty-nine patients were treated by ambulance personnel alone and 107 received additional HMT assistance. Patients in the HMT group had significantly lower Glasgow Coma Scale scores (mean 8·9 versus 10·6; P = 0·001) and a higher ISS (mean 30·9 versus 25·3; P < 0·001). The unadjusted OR for death was 1·7 in favour of the group treated by ambulance staff only (OR for survival 0·61 (95 per cent confidence interval (c.i.) 0·37 to 1·0, P = 0·048)). After adjustment, however, patients in the HMT group had an approximately twofold better chance of survival (all injuries: OR 2·2 (95 per cent c.i. 0·92 to 5·9), P = 0·076; blunt injuries: OR 2·8 (95 per cent c.i. 1·07 to 7·52), P = 0·036).

Conclusion

The presence of the HMT may increase chances of survival for patients suffering multiple trauma, especially for those with blunt trauma.
Systematic review of sacral nerve stimulation for faecal incontinence and constipation
Authors: Jarrett M E D , Mowatt G , Glazener C M A , Fraser C , Nicholls R J , Grant A M , Kamm M A
Published: September 2004

Background and method

This systematic review assesses the efficacy and safety of sacral nerve stimulation (SNS) for faecal incontinence and constipation. Electronic databases and selected websites were searched for studies evaluating SNS in the treatment of faecal incontinence or constipation. Primary outcome measures included episodes of faecal incontinence per week (faecal incontinence studies) and number of evacuations per week (constipation studies).

Results

From 106 potentially relevant reports, six patient series and one crossover study of SNS for faecal incontinence, and four patient series and one crossover study of SNS for constipation, were included. After implantation, 41–75 per cent of patients achieved complete faecal continence and 75–100 per cent experienced improvement in episodes of incontinence. There were 19 adverse events among 149 patients. The small crossover study reported increased episodes of faecal incontinence when the implanted pulse generator was switched off. Case series of SNS for constipation reported an increased frequency of evacuation. There were four adverse events among the 20 patients with a permanent implant. The small crossover study reported a reduced number of evacuations when the pulse generator was switched off.

Conclusion

SNS results in significant improvement in faecal incontinence in patients resistant to conservative treatment. Early data also suggest benefit in the treatment of constipation.
Evaluating the subtle impact of a ban on corporal punishment of children in Germany
Authors: Bussmann Kai‐D.
Published: September 2004

In 2000, the German Government passed a law prohibiting physical punishment in the family. A pre–post research design allows for an examination of its effects. The results of nationwide representative surveys on the experiences, perceptions, legal knowledge and attitudes of adolescents and parents are discussed. The recent surveys reveal a signiﬁcant decrease in the prevalence of corporal punishments and a high acceptance of the legal prohibition. In particular, awareness of the legal limits of parental physical sanctions has increased signiﬁcantly. For these reasons, the prohibition of corporal punishment can be said to have had an impact on the reduction of family violence against children in Germany. Copyright © 2004 John Wiley & Sons, Ltd.
Computational Design of Reduced Metabolic Networks
Authors: Holzhütter Scott , Holzhütter Hermann‐Georg
Published: September 2004

Cellular functions are based on thousands of chemical reactions and transport processes, most of them being catalysed and regulated by specific proteins. Systematic gene knockouts have provided evidence that this complex reaction network possesses considerable redundancy, that is, alternative routes exist along which signals and metabolic fluxes may be directed to accomplish an identical output behaviour. This property is of particular importance in cases where parts of the reaction network are transiently or permanently impaired, for example, due to an infection or genetic alterations. Here we present a computational concept to determine enzyme‐reduced metabolic networks that are still sufficient to accomplish a given set of cellular functions. Our approach consists of defining an objective function that expresses the compromise that has to be made between successive reduction of the network by omission of enzymes and its decreasing thermodynamic and kinetic feasibility. Optimisation of this objective function results in a linear mixed‐integer program. With increasing weight given to the reduction of the number of enzymes, the total flux in the network increases and some of the reactions have to proceed in thermodynamically unfavourable directions. The approach was applied to two metabolic schemes: the energy and redox metabolism of red blood cells and the carbon metabolism of Methylobacterium extorquens. For these two example networks, we determined various variants of reduced networks differing in the number and types of disabled enzymes and disconnected reactions. Using a comprehensive kinetic model of the erythrocyte metabolism, we assess the kinetic feasibility of enzyme‐reduced subnetworks. The number of enzymes predicted to be indispensable amounts to 14 (out of 28) for the erythrocyte scheme and 13 (out of 77) for the bacterium scheme, the largest group of enzymes predicted to be simultaneously dispensable amounts to 3 and 37 for these two systems. Our approach might contribute to identifying potential target enzymes for rational drug design, to rationalising gene‐expression profiles of metabolic enzymes and to designing synthetic networks with highly specialised metabolic functions.
NF‐κB: A Multifaceted Transcription Factor Regulated at Several Levels
Authors: Schmitz M. Lienhard , Mattioli Ivan , Buss Holger , Kracht Michael
Published: September 2004

NF‐κB is a generic name for an evolutionarily conserved transcription‐factor system that contributes to the mounting of an effective immune response but is also involved in the regulation of cell proliferation, development, and apoptosis. The implication of NF‐κB in central biological processes and its extraordinary connectivity to other signaling pathways raise a need for highly controlled regulation of NF‐κB activity at several levels. While all NF‐κB activation pathways share a central and critical proteasome‐mediated step that leads to the degradation of inhibitory proteins and the release of DNA‐binding subunits, there is evidence for a downstream level of NF‐κB regulation that employs several mechanisms. These include promoter‐specific exchange of dimers and modification of the transactivating p65 subunit by phosphorylation, acetylation, ubiquitination, or prolyl isomerization. The signaling pathways and enzymes controlling this second level of regulation and their potential use as therapeutic targets for the treatment of NF‐κB‐associated pathologies are discussed here.
Systems Biology and the Molecular Circuits of Cancer
Authors: Alberghina Lilia , Chiaradonna Ferdinando , Vanoni Marco
Published: September 2004

Proliferative disorders are a major challenge for human health. The understanding of the organization of cell‐cycle events is of the utmost importance to devise effective therapeutic strategies for cancer. The awareness that cells and organisms are complex, modular, hierarchical systems and the availability of genome‐wide gene expression and protein analyses, should make it feasible to elucidate human diseases in terms of dysfunctions of molecular systems. Here we review evidence in support of a systems model of the cell cycle, in which two sequential growth‐sensitive thresholds control entry into S‐phase. The putative molecular determinants that set the threshold for entry into S‐phase are consistently altered in cancer cells. Such a framework could be useful in guiding both experimental investigation and data analysis by allowing wiring to other relevant cell modules thereby highlighting the differential responses, or lack of response of cancer cells to intra‐ and extracellular factors. Pharmacological approaches that take advantage of transformation‐induced fragility to glucose shortage are discussed. Extension of this hierarchical, modular approach to tumors as a whole holds promise for the development of effective drug discovery approaches and more efficient therapeutic protocols.
Preliminary Studies on the In Silico Evolution of Biochemical Networks
Authors: Deckard Anastasia , Sauro Herbert M
Published: September 2004

Due to the variety and importance of roles performed by signalling networks, understanding their function and evolution is of great interest. Signalling networks allow organisms to process and react to changes in their internal and external environment. Current estimates suggest that two to three percent of all genomes code for proteins involved in signalling networks. The study of signalling networks is hindered by the complexities of the networks and difficulties in ascribing function to form. For example, a very complex dense network might comprise eighty or more densely connected proteins. In the majority of cases there is very little understanding of how these networks process signals. Unlike in electronics, where there is a broad practical and theoretical understanding of how to construct devices that can process almost any kind of signal, in biological signalling networks there is no equivalent theory. Part of the problem stems from the fact that in most cases it is unknown what particular signal processing circuits would look like in a biological form. This paper describes the evolutionary methods used to generate networks with particular signal‐ and computational‐processing capabilities. The techniques involved are described, and the approach is illustrated by evolving computational circuits such as multiplication, radicals and logarithmic functions. The experiments also illustrate the evolution of modularity within biochemical reaction networks.
mRNA Openers and Closers: Modulating AU‐Rich Element‐Controlled mRNA Stability by a Molecular Switch in mRNA Secondary Structure
Authors: Meisner Nicole‐Claudia , Hackermüller Jörg , Uhl Volker , Aszódi András , Jaritz Markus , Auer Manfred
Published: September 2004

Approximately 3 000 genes are regulated in a time‐, tissue‐, and stimulus‐dependent manner by degradation or stabilization of their mRNAs. The process is mediated by interaction of AU‐rich elements (AREs) in the mRNA's 3′‐untranslated regions with trans‐acting factors. AU‐rich element‐controlled genes of fundamentally different functional relevance depend for their activation on one positive regulator, HuR. Here we present a methodology to exploit this central regulatory process for specific manipulation of AU‐rich element‐controlled gene expression at the mRNA level. With a combination of single‐molecule spectroscopy, computational biology, and molecular and cellular biochemistry, we show that mRNA recognition by HuR is dependent on the presentation of the sequence motif NNUUNNUUU in single‐stranded conformation. The presentation of the HuR binding site in the mRNA secondary structure appears to act analogously to a regulatory on/off switch that specifically controls HuR access to mRNAs in cis. Based on this finding we present a methodology for manipulating ARE mRNA levels by actuating this conformational switch specifically in a target mRNA. Computationally designed oligonucleotides (openers) enhance the NNUUNNUUU accessibility by rearranging the mRNA conformation. Thereby they increase in vitro and endogenous HuR–mRNA complex formation which leads to specific mRNA stabilization (as demonstrated for TNFα and IL‐2, respectively). Induced HuR binding both inside and outside the AU‐rich element promotes functional IL‐2 mRNA stabilization. This opener‐induced mRNA stabilization mimics the endogenous IL‐2 response to CD28 stimulation in human primary T‐cells. We therefore propose that controlled modulation of the AU‐rich element conformation by mRNA openers or closers allows message stabilization or destabilization in cis to be specifically triggered. The described methodology might provide a means for studying distinct pathways in a complex cellular network at the node of mRNA stability control. It allows ARE gene expression to be potentially silenced or boosted. This will be of particular value for drug‐target validation, allowing the diseased phenotype to ameliorate or deteriorate. Finally, the mRNA openers provide a rational starting point for target‐specific mRNA stability assays to screen for low‐molecular‐weight compounds acting as inhibitors or activators of an mRNA structure rearrangement.
Cover Picture: Tools for Glycomics: Mapping Interactions of Carbohydrates in Biological Systems (ChemBioChem 10/2004)
Authors: Ratner Daniel M. , Adams Eddie W. , Disney Matthew D. , Seeberger Peter H.
Published: September 2004

The cover picture shows a tri(ethylene glycol) linker derivatized high‐mannose nonasaccharide and a panel of related structural determinants which were used to prepare biophysical tools for the emerging field of glycomics. The background shows carbohydrate microarray data for high‐mannose oligosaccharides bound by a panel of carbohydrate‐binding proteins, including the HIV‐inactivating proteins Cyanovirin‐N and Scytovirin (see binding profiles in middle). DC‐SIGN‐mediated endocytosis of fluorescein‐oligosaccharide conjugates (green) colocalized (yellow) with DC‐SIGN (red) in human dendritic cells (top left) and transiently transfected HeLa cells expressing DC‐SIGN (bottom right) were observed by confocal microscopy. Detailed information about the growing set of chemical and biophysical tools for use in glycomics and systems biology in general is reported in the concept article by P. Seeberger et al. on p. 1375 ff.