bluuebunny/crossref_metadata_2025 huggingface dataset:
Potential Clinical Targets of Repetitive Transcranial Magnetic Stimulation Treatment in Schizophrenia
Authors: Cordes J. , Arends M. , Mobascher A. , Brinkmeyer J. , Kornischka J. , Eichhammer P. , Klimke A. , Winterer G. , Agelink M.W.
Published: November 2006

Despite the introduction of atypical antipsychotic drugs, treatment-resistant symptoms still represent a serious problem in schizophrenia. Currently, there is evidence from clinical studies suggesting that treatment with repetitive transcranial magnetic stimulation (rTMS) may improve schizophrenia symptoms. Our review provides an overview of clinical rTMS studies in schizophrenic patients. A systematic search of the literature (Cochrane and Medline databases up to December 2005) was conducted. Most studies showed methodological problems due to their explorative character and small sample sizes. In some studies, a treatment effect of high-frequency rTMS applied over the prefrontal cortex was seen with respect to negative symptoms. On the other hand, low-frequency rTMS in the temporal lobe area might lead to a suppression of auditory hallucinations. It is concluded that larger sham-controlled studies are required to allow an adequate assessment of the clinical and neurobiological effects of rTMS in schizophrenic patients. The currently available data provide insufficient evidence to support the use of rTMS as an adjuvant treatment for schizophrenic psychopathology, but encourage further investigation of rTMS as a novel treatment approach.
Association of β-Defensin 1 Single Nucleotide Polymorphisms with Atopic Dermatitis
Authors: Prado-Montes de Oca Ernesto , García-Vargas Alejandro , Lozano-Inocencio Reymundo , Gallegos-Arreola Martha Patricia , Sandoval-Ramírez Lucila , Dávalos-Rodríguez Nory Omara , Figuera Luis Eduardo
Published: November 2006

Background: Atopic dermatitis (AD) is a chronic multifactorial allergic disease with unclear etiology. The antimicrobial human β-defensin 1 is chemotactic for dendritic cells, which are important regulators of allergic immune responses. In an attempt to identify useful markers that could predict susceptibility to AD, we investigated single nucleotide polymorphisms (SNPs) of the β-defensin 1 gene (DEFB1) with potential functional consequences. Methods: Four SNPs of the DEFB1 gene were genotyped either by real-time polymerase chain reaction or polymerase chain reaction-restriction fragment length polymorphisms in 59 patients with AD and 151 controls from the Mexican population. Correlation analyses were carried out between genetic, environmental and clinical variables in AD patients. Results: The genotypes associated with susceptibility to AD and no other allergy were 692 GG (OR = 3.21, 95% CI 1.37–7.34) and 1654 AA (OR = 17.37, 95% CI 1.62–860.83). The allele 668 C is a risk factor for AD (OR = 2.23, 95% CI 1.22–4.01) and the allele A in site 1836 correlates with earlier age at onset (Spearman’s ρ = 0.232; p = 0.03). The prolonged duration of breastfeeding correlates with earlier age at onset as well as with the severity of AD. Conclusions: The DEFB1 gene is probably involved in the incidence and development of AD, but additional functional studies will be necessary to understand the biological role of these SNPs.
Interlayer adsorption of macrocyclic compounds (crown-ethers and cryptands) in 2:1 phyllosilicates: I. Isotherms and kinetics
Authors: Casal B. , Ruiz-Hitzky E.
Published: November 2006

The intercalation process of crown-ethers and cryptands into Ba2+- and Na+-montmorillonites leads to H-type adsorption isotherms according to the Giles et al. classification. The experimental monolayer capacity shows that 1:1 or 2:1 macrocyclic ligand/interlayer cation complexes can be produced. Kinetic experiments at different temperatures indicate that the intercalation is diffusion-controlled. The activation energies deduced from Arrhenius plots are 25–38 kJ mol−1.
A petrographic study of the Rotliegendes Sandstone reservoir (Lower Permian) in the Rough Gas Field
Authors: Goodchild M. W. , Whitaker J. H. McD.
Published: November 2006

The diagenetic history of the Rotliegendes Sandstone reservoir in the Rough Gas Field was studied using thin-sections, XRD analyses and SEM. The Rotliegendes comprises a sequence of fine-grained fluvial sheet-flood sandstones and coarse, gravelly, low-sinuosity channel sandstones, with thin aeolian interbeds, overlain by a sequence of aeolian dune and interdune sandstones. Early, environmentally-related diagnesis (eogenesis) shows a marked variability with sedimentary facies. Within aeolian sandstones, poikilotopic anhydrite and fine, rhombic dolomite are preserved. Fluvially-derived sandstones typically contain infiltrated detrital clays and early authigenic mixed-layer clays, together with coarse, framework-displacive dolomite. Feldspars show varying degrees of alteration within all facies. These eogenetic features reflect patterns of groundwater movement during the Rotliegendes and early Zechstein. Mineral dissolution and precipitation were controlled by the chemistry of the groundwaters. Burial diagenetic (mesogenetic) features are superimposed on eogenetic cements. Authigenic clays have been converted to illitic clays. In addition, mesogenetic chlorite has formed and quartz and strongly ferroan dolomite cements are recognized. These minerals may be related to clay diagenesis within the underlying Carboniferous Coal Measures. Early, framework-supporting anyhdrite, and both phases of dolomite, have been partially dissolved, creating secondary porosity. This is attributed to the action of acidic porewaters, generated by the maturation of organic material within the Carboniferous. Post-dissolution kaolinite, gypsum and minor pyrite infill secondary pores. Gas emplacement from the Late Cretaceous onwards effectively halted further diagenetic reactions.
Diagenesis of a deeply buried sandstone reservoir: Hild Field, Northern North Sea
Authors: Lønøy A. , Akselsen J. , Rønning K.
Published: November 2006

Calcite cementation and extensive dissolution of feldspar with formation of authigenic kaolinite, quartz cement and secondary porosity are the main diagenetic processes in the deeply buried Hild Field. Mineralogical and isotopic analyses, reservoir pressure and depositional environment suggest that these diagenetic processes occurred prior to burial at a depth of 1·5–2 km. The timing of the diagenetic sequence suggests that feldspar dissolution is related to meteoric water flow. Calcite occurs as an early diagenetic iron-poor cement, and as two types of later diagenetic (<120°C) ferroan calcite cements. The ferroan calcites are mainly an in situ dissolution-reprecipitation product of the early diagenetic phase. Extensive local dissolution of calcite was important for forming secondary porosity which is closely associated with a prominent ‘gas chimney’ in the area studied. A high CO2 content in the natural gases of the reservoir suggests that the solvent was carbonic acid formed from CO2 generated during thermal maturation of organic matter. Calcite dissolution probably occurred between 70° and 100°C.
The effect of fluid/rock ratio on feldspar dissolution and illite formation under reservoir conditions
Authors: Huang W. L. , Bishop A. M. , Brown R. W.
Published: November 2006

Experiments on the conversion of feldspar to illite reveal that variation of the fluid/rock ratio (flow rate) has a significant effect on the kinetics of feldspar dissolution and illite formation. Dissolution of albite in near-neutral KCl solution at 200°C and 500 bar shows that the Si and Na release rate per unit surface area of albite is faster with higher fluid/rock ratio. These results have application to the interpretation of secondary porosity formation. The experiments also reveal a special set of conditions under which rapid illite formation can occur. In contrast to the slow process of illite formation in neutral solution, there can be mass nucleation and growth of illite platelets on albite surfaces in an initially acidic solution with low fluid/rock ratio. In similar experiments with higher fluid/rock ratio, kaolinite forms instead of illite because there is insufficient solid to titrate the large volume of solution. This study suggests that illitization of feldspar or kaolinite may be triggered by a decreased rate of acidic fluid-influx during burial diagenesis.
The development and destruction of porosity within Upper Jurassic reservoir sandstones of the Piper and Tartan Fields, Outer Moray Firth, North Sea
Authors: Burley S. D.
Published: November 2006

Upper Jurassic Piper Formation sandstones of the Outer Moray Firth Basin, UK North Sea, form the main reservoir for the Piper and Tartan Fields, and are sealed by either the Kimmeridge Clay or Cretaceous marls. The main reservoir sandstones can be broadly considered as stacked coarsening-upward units that accumulated in a predominantly high-energy, shallow marine complex with depositional waters of inferred normal marine salinity, Eh and ionic composition. The amount of porosity and its distribution throughout these sandstones differs between the individual structural entities of the Piper and Tartan Fields. On the Piper structure all the sandstones are highly porous. Oil-zone porosities average 25% and are only slightly reduced in the water zone. Sandstones in the upthrown block of the Tartan structure are also generally porous but porosities are typically reduced to below 20%. Porosities are the most variable in the Tartan downthrown block and in the 15/17-9 well, off-structure Piper, where porous sandstones with between 14 and 18% porosity are associated with highly compacted and cemented sandstones with <5% porosity. Thin-section and SEM textural evidence indicate that much of the porosity in these sandstones is secondary, produced through the dissolution of an intergranular cement that provided support for the detrital framework, was peripherally replacive with respect to most detrital grains, and extensively replaced feldspars. Nodular concretions and sporadic, irregular crystals of ferroan calcite are inferred to be the remnants of this intergranular cement. The distribution of porosity zones in the Tartan downthrown block is related to the present structure and oil-water contact, supporting the interpretation of a secondary origin for much of the present porosity. Highly compacted sandstones interbedded with the porous sandstones result from a combination of early compaction, brittle framework collapse following the generation of secondary porosity and late grain-to-grain contact dissolution. Aggressive fluids responsible for the generation of the cement dissolution porosity are inferred to have been expelled from the Kimmeridge Clay in the adjacent Witch Ground Graben. The preservation of secondary porosity in Piper Formation sandstones is due to the relative timing of secondary porosity generation and subsequent hydrocarbon migration.
Interleukin-1R antagonist gene and pre-natal smoke exposure are associated with childhood asthma
Authors: Ramadas R. A. , Sadeghnejad A. , Karmaus W. , Arshad S. H. , Matthews S. , Huebner M. , Kim D-Y. , Ewart S. L.
Published: November 2006

The interleukin-1 receptor antagonist (IL1RN) is a potent anti-inflammatory cytokine. In the present study, association of the humanIL1RNgene polymorphisms with asthma, bronchial hyperresponsiveness and forced expiratory volume in one second/forced vital capacity ratio was tested and the data was stratified by environmental tobacco smoke exposure in order to investigate a gene-smoking interaction.

In an unselected subset (n = 921) of the Isle of Wight birth (UK) cohort, which has previously been evaluated for asthma and related manifestations at ages 1, 2, 4 and 10 yrs, threeIL1RNsingle nucleotide polymorphisms (SNP) were genotyped. Logistic regression and repeated measurement models for tests of association using a representative SNP rs2234678 were used, as all SNPs tested were in strong linkage disequilibrium.

In the overall analysis, the SNP rs2234678 was not associated with asthma. However, in the stratum with maternal smoking during pregnancy the rs2234678 GG genotype significantly increased the relative risk of asthma in children, both in analyses of repeated asthma occurrences and persistent asthma.

In conclusion, the present results show that in the first decade of life, the gene–environment interaction of the interleukin-1 receptor antagonist gene polymorphism rs2234678 and maternal smoking during pregnancy increased the risk for childhood asthma.
ACEI/D but notAGT(-6)A/G polymorphism is a risk factor for mortality in ARDS
Authors: Adamzik M. , Frey U. , Sixt S. , Knemeyer L. , Beiderlinden M. , Peters J. , Siffert W.
Published: November 2006

The intrapulmonary renin–angiotensin systemviatissue concentration of angiotensin II or bradykinin may have multiple effects on pulmonary pathophysiology. Therefore, it was investigated whether the presence of the D allele of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism or the A allele of angiotensinogen (AGT) promoter polymorphism (-6)A/G are independent risk factors for 30-day survival in acute respiratory distress syndrome (ARDS) patients.

In a prospective study, adults (Germans of Caucasian ethnicity)with ARDS (n = 84) were recruited from the current authors’ intensive care unit and genotyped for theACEI/D and theAGT(-6)A/G polymorphisms, as were 200 healthy Caucasian controls.

Mortality was increased in theACEDD genotype compared with the I allele, and theACEI/D polymorphism was an independent prognostic factor for 30-day survival. Patients with a homozygous DD genotype were at highest risk for death (hazard ratio 5.7; 95% confidence interval 1.7–19.2) compared with the II genotype. In contrast, theAGT(-6)A/G polymorphism was neither associated with an increased risk for development of ARDS nor with outcome.

In patients with acute respiratory distress syndrome, the angiotensin-converting enzyme insertion/deletion polymorphism but not the angiotensinogen (-6)A/G promoter polymorphism is an independent risk factor with a pronounced effect on 30-day survival.
Beclomethasone/formoterolversusbudesonide/formoterol combination therapy in asthma
Authors: Papi A. , Paggiaro P. L. , Nicolini G. , Vignola A. M. , Fabbri L. M.
Published: November 2006

The present study was designed to compare the fixed combination of beclomethasone and formoterol in a hydrofluoroalkane Modulite® (Chiesi Farmaceutici, Parma, Italy) pressurised metered-dose inhaler (pMDI), with a combination of budesonide and formoterol administeredviaa Turbuhaler® (AstraZeneca, Lund, Sweden) dry powder inhaler (DPI).

This was a phase III, multinational, multicentre, double-blind, double-dummy, randomised, two-arm parallel groups, controlled study design. After a 2-week run-in period, 219 patients with moderate-to-severe asthma were randomised to a 12-week treatment with beclomethasone 200 μg plus formoterol 12 μgb.i.d.deliveredviaa pMDI or budesonide 400 μg plus formoterol 12 μgb.i.d.deliveredviaa DPI.

The analysis of noninferiority on primary outcome, morning peak expiratory flow in the last 2 weeks of treatment, showed no difference between groups. A statistically significant improvement from baseline in lung function, symptoms and rescue medication use was observed in both groups at all time-points. No differences were observed between treatments in either rate of asthma exacerbations or frequency of adverse events.

The new fixed combination of beclomethasone and formoterol in hydrofluoroalkane Modulite® pressurised metered-dose inhaler is equivalent to the marketed combination of budesonide and formoterol in terms of efficacy and tolerability profile.
BALF-derived fibroblasts differ from biopsy-derived fibroblasts in systemic sclerosis
Authors: Scheja A. , Larsen K. , Todorova L. , Tufvesson E. , Wildt M. , Åkesson A. , Hansson L. , Ellis S. , Westergren Thorsson G.
Published: November 2006

Growth of fibroblasts from bronchoalveolar lavage fluid (BALF) in patients with systemic sclerosis (SSc) has previously been described. The purpose of the present study was to characterise fibroblasts from BALF and bronchial biopsies from SSc patients with alveolitis and from controls, to analyse fibroblast proliferation, migration, stress fibres and proteoglycan production.

BALF and bronchial biopsies were collected from 10 patients with SSc and alveolitis and from 15 controls.

Outgrowth of fibroblasts was observed from the BALF of four patients, particularly in those with a markedly increased percentage of eosinophils in BALF, but not in any member of the control group. Increased levels of granulocyte-macrophage colony-stimulating factor, correlating with the percentage of eosinophils in BALF, were found in patients when compared with controls. Fibroblasts from BALF showed an elongated, mobile phenotype and increased proteoglycan production compared to the corresponding biopsy fibroblasts.

In conclusion, outgrowth of fibroblasts with an altered phenotype is reported from bronchoalveolar lavage fluid in systemic sclerosis patients with alveolitis and an increased percentage of eosinophils in the bronchoalveolar lavage fluid. These findings indicate a possible role for eosinophil–fibroblast interaction in pulmonary fibrosis in systemic sclerosis.
Serendipitous identification of natural Intergenotypic recombinants of hepatitis C in Ireland
Authors: Moreau Isabelle , Hegarty Susan , Levis John , Sheehy Patrick , Crosbie Orla , Kenny-Walsh Elizabeth , Fanning Liam J
Published: November 2006

Background

Recombination between hepatitis C single stranded RNA viruses is a rare event. Natural viable intragenotypic and intergenotypic recombinants between 1b-1a, 1a-1c and 2k-1b, 2i-6p, respectively, have been reported. Diagnostically recombinants represent an intriguing challenge. Hepatitis C genotype is defined by interrogation of the sequence composition of the 5' untranslated region [5'UTR]. Occasionally, ambiguous specimens require further investigation of the genome, usually by interrogation of the NS5B region. The original purpose of this study was to confirm the existence of a suspected mixed genotype infection of genotypes 2 and 4 by clonal analysis at the NS5B region of the genome in two specimens from two separate individuals. This initial identification of genotype was based on analysis of the 5'UTR of the genome by reverse line probe hybridisation [RLPH].

Results

The original diagnosis of a mixed genotype infection was not confirmed by clonal analysis of the NS5B region of the genome. The phylogenetic analysis indicated that both specimens were natural intergenotypic recombinant forms of HCV. The recombination was between genotypes 2k and 1b for both specimens. The recombination break point was identified as occurring within the NS2 region of the genome.

Conclusion

The viral recombinants identified here resemble the recombinant form originally identified in Russia. The RLPH pattern observed in this study may be a signature indicative of this particular type of intergenotype recombinant of hepatitis C meriting clonal analysis of NS2.
The homeobox transcription factor Even-skipped regulates acquisition of electrical properties in Drosophila neurons
Authors: Pym Edward CG , Southall Tony D , Mee Christopher J , Brand Andrea H , Baines Richard A
Published: November 2006

Background

While developmental processes such as axon pathfinding and synapse formation have been characterized in detail, comparatively less is known of the intrinsic developmental mechanisms that regulate transcription of ion channel genes in embryonic neurons. Early decisions, including motoneuron axon targeting, are orchestrated by a cohort of transcription factors that act together in a combinatorial manner. These transcription factors include Even-skipped (Eve), islet and Lim3. The perdurance of these factors in late embryonic neurons is, however, indicative that they might also regulate additional aspects of neuron development, including the acquisition of electrical properties.

Results

To test the hypothesis that a combinatorial code transcription factor is also able to influence the acquisition of electrical properties in embryonic neurons we utilized the molecular genetics of Drosophila to manipulate the expression of Eve in identified motoneurons. We show that increasing expression of this transcription factor, in two Eve-positive motoneurons (aCC and RP2), is indeed sufficient to affect the electrical properties of these neurons in early first instar larvae. Specifically, we observed a decrease in both the fast K+ conductance (IKfast) and amplitude of quantal cholinergic synaptic input. We used charybdotoxin to pharmacologically separate the individual components of IKfast to show that increased Eve specifically down regulates the Slowpoke (a BK Ca2+-gated potassium channel), but not Shal, component of this current. Identification of target genes for Eve, using DNA adenine methyltransferase identification, revealed strong binding sites in slowpoke and nAcRα-96Aa (a nicotinic acetylcholine receptor subunit). Verification using real-time PCR shows that pan-neuronal expression of eve is sufficient to repress transcripts for both slo and nAcRα-96Aa.

Conclusion

Taken together, our findings demonstrate, for the first time, that Eve is sufficient to regulate both voltage- and ligand-gated currents in motoneurons, extending its known repertoire of action beyond its already characterized role in axon guidance. Our data are also consistent with a common developmental program that utilizes a defined set of transcription factors to determine both morphological and functional neuronal properties.
Recorded Earthquake Responses from the Integrated Seismic Monitoring Network of the Atwood Building, Anchorage, Alaska
Authors: Çelebi Mehmet
Published: November 2006

An integrated seismic monitoring system with a total of 53 channels of accelerometers is now operating in and at the nearby free-field site of the 20-story steel-framed Atwood Building in highly seismic Anchorage, Alaska. The building has a single-story basement and a reinforced concrete foundation without piles. The monitoring system comprises a 32-channel structural array and a 21-channel site array. Accelerometers are deployed on 10 levels of the building to assess translational, torsional, and rocking motions, interstory drift (displacement) between selected pairs of adjacent floors, and average drift between floors. The site array, located approximately a city block from the building, comprises seven triaxial accelerometers, one at the surface and six in boreholes ranging in depths from 15 to 200 feet (∼5–60 meters). The arrays have already recorded low-amplitude shaking responses of the building and the site caused by numerous earthquakes at distances ranging from tens to a couple of hundred kilometers. Data from an earthquake that occurred 186 km away traces the propagation of waves from the deepest borehole to the roof of the building in approximately 0.5 seconds. Fundamental structural frequencies [0.58 Hz (NS) and 0.47 Hz (EW)], low damping percentages (2–4%), mode coupling, and beating effects are identified. The fundamental site frequency at approximately 1.5 Hz is close to the second modal frequencies (1.83 Hz NS and 1.43 EW) of the building, which may cause resonance of the building. Additional earthquakes prove repeatability of these characteristics; however, stronger shaking may alter these conclusions.
Circulating DNA
Authors: GAHAN P.B.
Published: November 2006

Abstract:  The circulation of both foreign and endogenous DNA within plants and its ability to be expressed in the host plants and FI generation is described. These data, together with those from animal systems are used to support the concept that a DNA fraction can act as a messenger between cells and tissues.
Epigenetic Analysis of Body Fluids and Tumor Tissues
Authors: TABACK BRET , GIULIANO ARMANDO E. , LAI RON , HANSEN NORA , SINGER FREDERICK R. , PANTEL KLAUS , HOON DAVE S.B.
Published: November 2006

Abstract:  Breast cancer recurrence is a result of undetected metastasis present at the time of primary patient treatment. More sensitive methods are needed to identify subclinical disease progression to better accompany those increasing advances in early breast cancer screening. Aberrant hypermethylation of tumor‐suppressor genes is found frequently in primary breast tumors and has been implicated in disease initiation and progression. Epigenetic characterization of tumor cells may provide highly specific and sensitive molecular surrogates for surveillance. We evaluated whether tumor‐associated methylated DNA markers could be identified circulating in bone marrow (BM) aspirates and paired serum samples from 33 early‐stage patients undergoing surgery for breast cancer. Quantitative methylation‐specific PCR (qMSP) was performed using a selected tumor‐related gene panel for RAR‐ß2, MGMT, RASSF1A, and APC. Tumor‐associated hypermethylated DNA was identified in 7 (21%) of 33 BM aspirates and 9 (27%) serum samples. In three patients both BM and serum were positive for hypermethylation. The most frequently detected hypermethylation marker was RASSF1A occurring in 7 (21%) patients. Concordance was present between gene hypermethylation detected in BM or serum samples, and matched‐pair primary tumors. Advanced AJCC stage was associated with an increased incidence of circulating gene hypermethylation. In addition, methylation patterns in the sentinel lymph node (SLN) metastasis corresponded with that of the primary tumor, confirming epigenetic clonality is associated with early tumor dissemination. This study demonstrates the novel finding of tumor‐associated epigenetic markers in BM aspirates/blood and their potential role as targets for molecular detection.
Higher Amount of Free Circulating DNA in Serum than in Plasma Is Not Mainly Caused by Contaminated Extraneous DNA during Separation
Authors: UMETANI NAOYUKI , HIRAMATSU SUZANNE , HOON DAVE S.B.
Published: November 2006

Abstract:  Circulating DNA isolated from serum and plasma has been shown to be a useful biomarker in various diseases including cancer. Serum reportedly contains a higher amount of free circulating DNA than it does in plasma. The underlying reason for this is unclear, but important because it may have clinical implications in interpreting results and using the appropriate resource. Twenty‐four pairs of serum and plasma samples were collected from patients with tumors, and free circulating DNA was quantified by real‐time quantitative PCR (qPCR) for the ALU repeats, which had a sensitivity of 0.1 pg/μL of DNA in serum/plasma. The possibility of DNA loss was eliminated because ALU‐qPCR does not require DNA purification from serum/plasma. The DNA concentrations of serum and plasma samples were 970 ± 730 pg/μL and 180 ± 150 pg/μL (mean ± SD), respectively. The amount of DNA in paired serum and plasma specimens was positively correlated (R= 0.72 and P= 0.0002). An estimated 8.2% of total DNA in serum was extraneous; the concentration of DNA was 6.1 ± 3.5 (mean ± SD)‐fold higher in serum than in paired plasma after subtraction of it. Contribution of extraneous DNA from cells in blood ruptured during the separation step was minor for explaining the difference between serum and plasma. A possible explanation was unequal distribution of DNA during separation from whole blood. We advocate that serum is a better specimen source for circulating cancer‐related DNA as a biomarker.
Steel factor controls midline cell death of primordial germ cells and is essential for their normal proliferation and migration
Authors: Runyan Christopher , Schaible Kyle , Molyneaux Kathleen , Wang Zhuoqiao , Levin Linda , Wylie Christopher
Published: November 2006

During germ-cell migration in the mouse, the dynamics of embryo growth cause many germ cells to be left outside the range of chemoattractive signals from the gonad. At E10.5, movie analysis has shown that germ cells remaining in the midline no longer migrate directionally towards the genital ridges, but instead rapidly fragment and disappear. Extragonadal germ cell tumors of infancy, one of the most common neonatal tumors, are thought to arise from midline germ cells that failed to die. This paper addresses the mechanism of midline germ cell death in the mouse. We show that at E10.5, the rate of apoptosis is nearly four-times higher in midline germ cells than those more laterally. Gene expression profiling of purified germ cells suggests this is caused by activation of the intrinsic apoptotic pathway. We then show that germ cell apoptosis in the midline is activated by down-regulation of Steel factor (kit ligand) expression in the midline between E9.5 and E10.5. This is confirmed by the fact that removal of the intrinsic pro-apoptotic protein Bax rescues the germ-cell apoptosis seen in Steel null embryos. Two interesting things are revealed by this: first, germ-cell proliferation does not take place in these embryos after E9.0; second, migration of germ cells is highly abnormal. These data show first that changing expression of Steel factor is required for normal midline germ cell death, and second, that Steel factor is required for normal proliferation and migration of germ cells.
The CRM domain: An RNA binding module derived from an ancient ribosome-associated protein
Authors: Barkan Alice , Klipcan Larik , Ostersetzer Oren , Kawamura Tetsuya , Asakura Yukari , Watkins Kenneth P.
Published: November 2006

The CRS1–YhbY domain (also called the CRM domain) is represented as a stand-alone protein in Archaea and Bacteria, and in a family of single- and multidomain proteins in plants. The function of this domain is unknown, but structural data and the presence of the domain in several proteins known to interact with RNA have led to the proposal that it binds RNA. Here we describe a phylogenetic analysis of the domain, its incorporation into diverse proteins in plants, and biochemical properties of a prokaryotic and eukaryotic representative of the domain family. We show that a bacterial member of the family, Escherichia coli YhbY, is associated with pre-50S ribosomal subunits, suggesting that YhbY functions in ribosome assembly. GFP fused to a single-domain CRM protein from maize localizes to the nucleolus, suggesting that an analogous activity may have been retained in plants. We show further that an isolated maize CRM domain has RNA binding activity in vitro, and that a small motif shared with KH RNA binding domains, a conserved “GxxG” loop, contributes to its RNA binding activity. These and other results suggest that the CRM domain evolved in the context of ribosome function prior to the divergence of Archaea and Bacteria, that this function has been maintained in extant prokaryotes, and that the domain was recruited to serve as an RNA binding module during the evolution of plant genomes.
Modular evolution and increase of functional complexity in replicating RNA molecules
Authors: Manrubia Susanna C. , Briones Carlos
Published: November 2006

At early stages of biochemical evolution, the complexity of replicating molecules was limited by unavoidably high mutation rates. In an RNA world, prior to the appearance of cellular life, an increase in molecular length, and thus in functional complexity, could have been mediated by modular evolution. We describe here a scenario in which short, replicating RNA sequences are selected to perform a simple function. Molecular function is represented through the secondary structure corresponding to each sequence, and a given target secondary structure yields the optimal function in the environment where the population evolves. The combination of independently evolved populations may have facilitated the emergence of larger molecules able to perform more complex functions (including RNA replication) that could arise as a combination of simpler ones. We quantitatively show that modular evolution has relevant advantages with respect to the direct evolution of large functional molecules, among them the allowance of higher mutation rates, the shortening of evolutionary times, and the very possibility of finding complex structures that could not be otherwise directly selected.
High-Volume Extraction of Nucleic Acids by Magnetic Bead Technology for Ultrasensitive Detection of Bacteria in Blood Components
Authors: Störmer Melanie , Kleesiek Knut , Dreier Jens
Published: November 2006

Background: Nucleic acid isolation, the most technically demanding and laborious procedure performed in molecular diagnostics, harbors the potential for improvements in automation. A recent development is the use of magnetic beads covered with nucleic acid–binding matrices. We adapted this technology with a broad-range 23S rRNA real-time reverse transcription (RT)-PCR assay for fast and sensitive detection of bacterial contamination of blood products.

Methods: We investigated different protocols for an automated high-volume extraction method based on magnetic-separation technology for the extraction of bacterial nucleic acids from platelet concentrates (PCs). We added 2 model bacteria, Staphylococcus epidermidis and Escherichia coli, to a single pool of apheresis-derived, single-donor platelets and assayed the PCs by real-time RT-PCR analysis with an improved primer–probe system and locked nucleic acid technology. Coamplification of human β2-microglobulin mRNA served as an internal control (IC). We used probit analysis to calculate the minimum concentration of bacteria that would be detected with 95% confidence.

Results: For automated magnetic bead–based extraction technology with the real-time RT-PCR, the 95% detection limit was 29 × 103 colony-forming units (CFU)/L for S. epidermidis and 22 × 103 CFU/L for E. coli. No false-positive results occurred, either due to nucleic acid contamination of reagents or externally during testing of 1030 PCs.

Conclusions: High-volume nucleic acid extraction improved the detection limit of the assay. The improvement of the primer–probe system and the integration of an IC make the RT-PCR assay appropriate for bacteria screening of platelets.
Intermittent Practice Facilitates Stable Motor Memories
Authors: Overduin Simon A. , Richardson Andrew G. , Lane Courtney E. , Bizzi Emilio , Press Daniel Z.
Published: November 2006

Humans adaptively control reaching movements to maintain good performance in the presence of novel forces acting on the arm. A recent study suggested that motor memories of different force conditions are not transformed from fragile to stable states, but rather are always vulnerable to interference from newly learned conditions (Caithness et al., 2004). This is contrary to the results of previous studies (Brashers-Krug et al., 1996; Shadmehr and Brashers-Krug, 1997), although all of these studies followed similar methods. Here, we show that a seemingly insignificant and inconsistently applied methodological detail may reconcile this discrepancy. Catch trials, in which the novel forces are removed, may be randomly interspersed among the more frequent force trials to assess how a subject is learning to predict the pattern of forces. In the absence of an interfering condition, subjects retained their learning until retest a day later regardless of whether they experienced catch trials. But in the presence of an interfering condition, only the subjects who had experienced forces intermittently retained their learning and thereby showed resistance to the interference. Thus, intermittent rather than constant practice conditions appear to be critical for dynamic motor memory stabilization.
Vesicular Glutamate Transporter VGLUT2 Expression Levels Control Quantal Size and Neuropathic Pain
Authors: Moechars Diederik , Weston Matthew C. , Leo Sandra , Callaerts-Vegh Zsuzsanna , Goris Ilse , Daneels Guy , Buist A. , Cik M. , van der Spek P. , Kass Stefan , Meert Theo , D'Hooge Rudi , Rosenmund Christian , Hampson R. Mark
Published: November 2006

Uptake ofl-glutamate into synaptic vesicles is mediated by vesicular glutamate transporters (VGLUTs). Three transporters (VGLUT1–VGLUT3) are expressed in the mammalian CNS, with partial overlapping expression patterns, and VGLUT2 is the most abundantly expressed paralog in the thalamus, midbrain, and brainstem. Previous studies have shown that VGLUT1 is necessary for glutamatergic transmission in the hippocampus, but the role of VGLUT2 in excitatory transmission is unexplored in glutamatergic neurons andin vivo. We examined the electrophysiological and behavioral consequences of loss of either one or both alleles of VGLUT2. We show that targeted deletion of VGLUT2 in mice causes perinatal lethality and a 95% reduction in evoked glutamatergic responses in thalamic neurons, although hippocampal synapses function normally. Behavioral analysis of heterozygous VGLUT2 mice showed unchanged motor function, learning and memory, acute nociception, and inflammatory pain, but acquisition of neuropathic pain, maintenance of conditioned taste aversion, and defensive marble burying were all impaired. Reduction or loss of VGLUT2 in heterozygous and homozygous VGLUT2 knock-outs led to a graded reduction in the amplitude of the postsynaptic response to single-vesicle fusion in thalamic neurons, indicating that the vesicular VGLUT content is critically important for quantal size and demonstrating that VGLUT2-mediated reduction of excitatory drive affects specific forms of sensory processing.
Precise Spatial Relationships between Mossy Fibers and Climbing Fibers in Rat Cerebellar Cortical Zones
Authors: Pijpers Angelique , Apps Richard , Pardoe Joanne , Voogd Jan , Ruigrok Tom J. H.
Published: November 2006

Classically, mossy fiber and climbing fiber terminals are regarded as having very different spatial distributions in the cerebellar cortex. However, previous anatomical studies have not studied these two major cerebellar inputs with sufficient resolution to confirm this assumption. Here, we examine the detailed pattern of collateralization of both types of cerebellar afferent using small injections of the bidirectional tracer cholera toxin b subunit into the posterior cerebellum. The cortical and zonal location of these injections was characterized by mapping climbing fiber field potentials, the distribution of retrogradely labeled olivary neurons, and the intrinsic zebrin pattern of Purkinje cells.

Labeled climbing fiber collaterals were distributed as longitudinal strips and were always accompanied by clusters of labeled mossy fiber rosettes in the subjacent granular layer. Two- and three-dimensional reconstructions and quantitative analysis showed that mossy fibers also collateralized to other stripe-like regions usually below Purkinje cells with the same zebrin-positive or zebrin-negative characteristics as that of the injection site and associated climbing fiber collaterals. The distribution of retrogradely labeled neurons in two major sources of mossy fibers, the lateral reticular and basilar pontine nuclei, revealed interlobular and some interzonal differences.

These data indicate that nonadjacent cerebellar zones, sharing the same climbing fiber input and zebrin identity, also share a common mossy fiber input. Other cerebellar cortical regions that receive collaterals from the same mossy fibers usually also have the same zebrin signature. Together with the distribution of neurons in precerebellar centers, the findings suggest a revision of the modular hypothesis for information processing in the cerebellar cortex.
Leukemia Inhibitory Factor Promotes Neural Stem Cell Self-Renewal in the Adult Brain
Authors: Bauer Sylvian , Patterson Paul H.
Published: November 2006

Although neural stem cells (NSCs) persist in various areas of the adult brain, their contribution to brain repair after injury is very limited. Treatment with exogenous growth factors can mitigate this limitation, suggesting that the brain environment is normally deficient in permissive cues and that it may be possible to stimulate the latent regenerative potential of endogenous progenitors with appropriate signals. We analyzed the effects of overexpressing the cytokine leukemia inhibitory factor (LIF) on adult neurogenesis in the normal brain. We found that LIF reduces neurogenesis in the olfactory bulb and subventricular zone by acting directly on NSCs. LIF appears to promote NSC self-renewal, preventing the emergence of more differentiated cell types. This ultimately leads to an expansion of the NSC pool. Our results have implications for the development of therapeutic strategies for brain repair and suggest that LIF may be useful, in combination with other factors, in promoting regeneration in the adult brain.
Suppression of the p75 Neurotrophin Receptor in Uninjured Sensory Neurons Reduces Neuropathic Pain after Nerve Injury
Authors: Obata Koichi , Katsura Hirokazu , Sakurai Jun , Kobayashi Kimiko , Yamanaka Hiroki , Dai Yi , Fukuoka Tetsuo , Noguchi Koichi
Published: November 2006

The p75 neurotrophin receptor (p75NTR) has been implicated in diverse neuronal responses, including survival, cell death, myelination, and inhibition of regeneration. However, the role of p75NTR in neuropathic pain, for which there is currently no effective therapy, has not been explored. Here, we report that the pharmacological blockade of p75NTR in primary sensory neurons reversed neuropathic pain after nerve injury. Nerve injury increased the expression and axonal transport of p75NTR and phosphorylation of TrkA in the uninjured primary afferents. Functional inhibition of p75NTR suppressed injury-induced neuropathic pain and decreased the phosphorylation of TrkA and p38 mitogen-activated protein kinase, and the induction of transient receptor potential channels in dorsal root ganglion (DRG) neurons. Our results show that p75NTR induced in undamaged DRG neurons facilitates TrkA signaling and contributes to heat and cold hyperalgesia.
Boundary Completion Is Automatic and Dissociable from Shape Discrimination
Authors: Murray Micah M. , Imber Michelle L. , Javitt Daniel C. , Foxe John J.
Published: November 2006

Normal visual perception readily overcomes suboptimal or degraded viewing conditions through perceptual filling-in processes, enhancing object recognition and discrimination abilities. This study used visual evoked potential (VEP) recordings in conjunction with electrical neuroimaging analyses to determine the spatiotemporal brain dynamics of boundary completion and shape discrimination processes in healthy humans performing the so-called “thin/fat” discrimination task (Ringach and Shapley, 1996) with stimuli producing illusory contours. First, results suggest that boundary completion processes occur independent of subjects' accuracy on the discrimination task. Modulation of the VEP to the presence versus absence of illusory contours [the IC effect (Murray et al., 2002)] was indistinguishable in terms of response magnitude and scalp topography over the 124–186 ms poststimulus period, regardless of whether task performance was correct. This suggests that failure on this discrimination task is not primarily a consequence of failed boundary completion. Second, the electrophysiological correlates of thin/fat shape discrimination processes are temporally dissociable from those of boundary completion, occurring during a substantially later phase of processing (∼330–406 ms). The earlier IC effect was unaffected by whether the perceived contour produced a thin or fat shape. In contrast, later time periods of the VEP modulated according to perceived shape only in the case of stimuli producing illusory contours, but not for control stimuli for which performance was at near-chance levels. Collectively, these data provide further support for a multistage model of object processing under degraded viewing conditions.
Allometric Relationships between Size of Calcified Structures and Round Goby Total Length
Authors: Dietrich J. P. , Taraborelli A. C. , Morrison B. J. , Schaner T.
Published: November 2006

Allometric relationships between calcified structures and total length of round goby Neogobius melanostomus were determined from a sample of fish ranging in total length from 53 to 152 mm. Each of the 10 allometric equations gave coefficients of determination (r2) that were greater than 0.80 and highly significant. The equations with the most predictive ability were those relating total length to cleithral, opercular, mouth, and pharyngeal bone measurements. Round goby remains were found in the stomachs of 10 predator species from the Bay of Quinte, Lake Ontario. Round goby were ingested most often by yellow perch Perca flavescens (40% of the stomachs examined) and largemouth bass Micropterus salmoides (27%) and less frequently by other predators. Round goby calcified structures most frequently found in the stomachs of predators were mouth parts (premaxilla and dentary), pharyngeal bones (dentigerous plate and pharyngobranchial plates), and otoliths. The predictive equations, diagnostic features of calcified structures, and list of predatory species in this study may serve as helpful tools for future analyses of round goby predator diets.
Lapatinib: Current Status and Future Directions in Breast Cancer
Authors: Moy Beverly , Goss Paul E.
Published: November 2006

Lapatinib is an oral receptor tyrosine kinase inhibitor, targeting both the ErbB-1 and ErbB-2 receptors. Pre-clinical in vitro and in vivo models indicate that lapatinib is active as monotherapy, synergistically in combination with trastuzumab, and in trastuzumab-resistant cell lines. Early clinical trials also provide evidence in patients that lapatinib is active against breast cancer. This paper reviews results of phase II and III clinical trials of lapatinib in metastatic breast cancer, evidence for its potential in patients with brain metastases, and current clinical trials as adjuvant treatment in early-stage disease. Our improved understanding of the biology of breast cancer and the use of biomarkers for identification of specific subtypes is allowing us to bring patient-specific novel therapies such as lapatinib to the clinic.
Comparison of Performance of Heuristic Search Methods for Phase Velocity Inversion in Shallow Surface Wave Method
Authors: Yamanaka Hiroaki
Published: November 2006

Three heuristic search methods, Genetic Algorithm, Simulated Annealing and Tabu Search are implemented to invert Rayleigh wave phase velocity for shallow S-wave velocity profiling in seismic surface wave surveying. Unlike linearized least-squares inversion, they do not require derivative calculation, or an initial model, only the forward modeling calculation. In this study, the performances of the three heuristic techniques are compared with numerical experiments. With common paramerization and search limits, the three algorithms can accurately reconstruct shallow S-wave profiles with and without a velocity reversal from the synthetic data without any specific initial models. The Genetic Algorithms and the Simulated Annealing show fast convergence. However, the Simulated Annealing can find models with the smallest misfits. It is also found that the decrease of the misfits is the most gradual in the Tabu Search.
Propagation of Data Uncertainty in Surface Wave Inversion
Authors: Lai Carlo G. , Foti Sebastiano , Rix Glenn J.
Published: November 2006

Although in recent years surface wave methods have undergone significant development that has greatly enhanced their capabilities, little effort has been spent to determine the uncertainty associated with surface wave measurements. The objective of this study is to determine how the uncertainty of the experimental data is mapped into the uncertainty of the shear wave velocity profile via the inversion algorithm. The methodology developed in this study for estimating the uncertainty of the shear wave velocity profile from surface wave measurements is based on the assumption that the experimental data are normally distributed. The validity of this hypothesis was experimentally verified using data gathered at two sites in Italy where surface wave tests were performed using linear arrays of multiple receivers. The experimental dispersion curve measured at the site was subsequently inverted to obtain the expected shear wave velocity profile together with an estimate of the associated standard deviation. The final results show that uncorrelated noise has a very little influence on multistation surface wave tests, confirming their robustness for applications in noisy environments.