bluuebunny/crossref_metadata_2025 huggingface dataset:
A robust and efficient statistical method for genetic association studies using case and control samples from multiple cohorts
Authors: Wang Minghui , Wang Lin , Jiang Ning , Jia Tianye , Luo Zewei
Published: February 2013

Background

The theoretical basis of genome-wide association studies (GWAS) is statistical inference of linkage disequilibrium (LD) between any polymorphic marker and a putative disease locus. Most methods widely implemented for such analyses are vulnerable to several key demographic factors and deliver a poor statistical power for detecting genuine associations and also a high false positive rate. Here, we present a likelihood-based statistical approach that accounts properly for non-random nature of case–control samples in regard of genotypic distribution at the loci in populations under study and confers flexibility to test for genetic association in presence of different confounding factors such as population structure, non-randomness of samples etc.

Results

We implemented this novel method together with several popular methods in the literature of GWAS, to re-analyze recently published Parkinson’s disease (PD) case–control samples. The real data analysis and computer simulation show that the new method confers not only significantly improved statistical power for detecting the associations but also robustness to the difficulties stemmed from non-randomly sampling and genetic structures when compared to its rivals. In particular, the new method detected 44 significant SNPs within 25 chromosomal regions of size < 1 Mb but only 6 SNPs in two of these regions were previously detected by the trend test based methods. It discovered two SNPs located 1.18 Mb and 0.18 Mb from the PD candidates, FGF20 and PARK8, without invoking false positive risk.

Conclusions

We developed a novel likelihood-based method which provides adequate estimation of LD and other population model parameters by using case and control samples, the ease in integration of these samples from multiple genetically divergent populations and thus confers statistically robust and powerful analyses of GWAS. On basis of simulation studies and analysis of real datasets, we demonstrated significant improvement of the new method over the non-parametric trend test, which is the most popularly implemented in the literature of GWAS.
Changes in the gut microbiota of cloned and non-cloned control pigs during development of obesity: gut microbiota during development of obesity in cloned pigs
Authors: Pedersen Rebecca , Andersen Anders Daniel , Mølbak Lars , Stagsted Jan , Boye Mette
Published: February 2013

Background

Obesity induced by a high-caloric diet has previously been associated with changes in the gut microbiota in mice and in humans. In this study, pigs were cloned to minimize genetic and biological variation among the animals with the aim of developing a controlled metabolomic model suitable for a diet-intervention study. Cloning of pigs may be an attractive way to reduce genetic influences when investigating the effect of diet and obesity on different physiological sites. The aim of this study was to assess and compare the changes in the composition of the gut microbiota of cloned vs. non-cloned pigs during development of obesity by a high-fat/high-caloric diet. Furthermore, we investigated the association between diet-induced obesity and the relative abundance of the phyla Firmicutes and Bacteroidetes in the fecal-microbiota. The fecal microbiota from obese cloned (n = 5) and non-cloned control pigs (n= 6) was investigated biweekly over a period of 136 days, by terminal restriction fragment length polymorphism (T-RFLP) and quantitative real time PCR (qPCR).

Results

A positive correlation was observed between body-weight at endpoint and percent body-fat in cloned (r=0.9, P<0.0001) and in non-cloned control pigs (r=0.9, P<0.0001). Shannon Weaver and principal component analysis (PCA) of the terminal restriction fragments (T-RFs) revealed no differences in the bacterial composition or variability of the fecal microbiota between the cloned pigs or between cloned and non-cloned control pigs. Body-weight correlated positively with the relative abundance of Firmicutes in both cloned (r=0.37; P<0.02) and non cloned-control pigs (r=0.45; P<0.006), and negatively with the abundance of Bacteroidetes in cloned pigs (r=−0.33, P<0.04), but not in the non-cloned control pigs.

Conclusion

The cloned pigs did not have reduced inter-individual variation as compared to non-cloned pigs in regard to their gut microbiota in neither the obese nor the lean state. Diet-induced obesity was associated with an increase in the relative abundance of Firmicutes over time. Our results suggest that cloned pigs are not a more suitable animal model for gut microbiota-obesity related studies than non-cloned pigs. This study is the first to evaluate if cloned pigs provide a better animal model than conventional pigs in diet-intervention, obesity and gut microbiota research.
Synergistic effect of paclitaxel and epigenetic agent phenethyl isothiocyanate on growth inhibition, cell cycle arrest and apoptosis in breast cancer cells
Authors: Liu Katherine , Cang Shundong , Ma Yuehua , Chiao Jen Wei
Published: February 2013

This study examined whether combining paclitaxel (taxol) with a novel epigenetic agent phenethyl isothiocyanate (PEITC) will yield a synergistic effect on inhibiting breast cancer cells. Two drug-resistant breast cancer cell lines, MCF7 and MDA-MB-231, were treated with PEITC and taxol. Cell growth, cell cycle, and apoptosis were examined. The combination of PEITC and taxol significantly decreased the IC50 of PEITC and taxol over each agent alone. The combination also increased apoptosis by more than two fold over each single agent in both cell lines. A significant increase of cells in the G2/M phases was detected. In conclusion, the combination of PEITC and taxol exhibits a synergistic effect on growth inhibition in breast cancer cells. This combination deserves further study in vivo.
Applying a gender lens on human papillomavirus infection: cervical cancer screening, HPV DNA testing, and HPV vaccination
Authors: Branković Ivan , Verdonk Petra , Klinge Ineke
Published: February 2013

Background

Our aim is to provide a state-of-the-art overview of knowledge on sex (biological) and gender (sociocultural) aspects of Human papillomavirus (HPV) and cervical cancer for educational purposes. Considerable disparities exist in cervical cancer incidences between different subgroups of women. We provide an outline on the crucial issues and debates based on the recent literature published in leading gender medicine journals. Intersectionality was applied in order to help categorise the knowledge.

Methods

Key terms (HPV, cervical cancer) were screened in Gender Medicine, Journal of Women’s Health and Women & Health from January 2005-June 2012. Additional searches were conducted for topics insufficiently mentioned, such as HPV vaccination of boys. In total, 71 publications were included (56 original papers, four reviews, six reports, three commentaries, one editorial and one policy statement).

Results

Research reveals complexity in the way various subgroups of women adhere to cervical screening. Less educated women, older women, uninsured women, homeless women, migrant women facing language barriers, women who have sex with women and obese women participate in Pap smears less frequently. A series of barriers can act to impede decisions to vaccinate against HPV.

Conclusions

Both male and female controlled preventive methods and treatment measures should be developed in order to tackle HPV infection and different strategies are needed for different subgroups. A substantial discussion and research on alternative methods of prevention was and is lacking. In future research, sex and gender aspects of HPV-related diseases of boys and men as well as subgroup differences in HPV risk need to be addressed.
Important steps to improve translation from medical research to health policy
Authors: Jiang Fan , Zhang Jun , Wang Xiangdong , Shen Xiaoming
Published: February 2013

Translational medicine entails not only “from-bench-to-bedside” but also preventive medicine. The present article proposes a conceptual framework of translational research from scientific research to health care policy and public health policy. We highlight the importance of translational medicine to bridge between research and policy and share our experience of translating medical research to public health policy in China as well as obstacles and challenges we are facing in the translation process.
Complement activation fragment C5a receptors, CD88 and C5L2, are associated with neurofibrillary pathology
Authors: Fonseca Maria I , McGuire Susan O , Counts Scott E , Tenner Andrea J
Published: February 2013

Background

Alzheimer’s disease (AD) is a neurodegenerative dementia characterized by the decline of cognition and the presence of neuropathological changes including neuronal loss, neurofibrillary pathology and extracellular senile plaques. A neuroinflammatory process is also triggered and complement activation has been hypothesized to have a relevant role in this local inflammatory response. C5a, a proinflammatory anaphylatoxin generated after complement activation, exerts its chemotactic and inflammatory functions through the CD88 receptor while the more recently discovered C5L2 receptor has been postulated to have an anti-inflammatory role. Previously, we reported that a CD88 specific antagonist (PMX205) decreased the pathology and improved cognition in transgenic models of AD suggesting that C5a/C5aR interaction has an important role in the progression of the disease.

Methods

The present study characterizes the expression of the two receptors for C5a in human brain with confirmed post mortem diagnosis of vascular dementia (VD) or AD as well as age matched controls by immunohistochemistry and Western blot analysis using several antibodies against different epitopes of the human receptors.

Results

The CD88 and C5L2 antibodies revealed increased expression of both receptors in AD samples as compared to age-matched controls or VD brain tissue by Western blot and immunohistochemistry, using multiple antibodies and distinct cohorts of brain tissue. Immunostaining showed that both the C5L2 and CD88 antibodies similarly labeled abundant neurofibrillary tangles, neuropil threads and dystrophic neurites associated with plaques in the hippocampus and frontal cortex of AD cases. In contrast, little or no neuronal staining, tangles or dystrophic neurites associated with plaques were observed in control or VD brains. CD88 and C5L2 receptors are associated with both early (AT8) and mature (PHF1) neurofibrillary tangles and can be found either independently or colocalized with each other.

Conclusions

The observed association of CD88 and C5L2 with neurofibrillary pathology suggests a common altered pathway of degradation.
First introduction of pandemic influenza A/H1N1 and detection of respiratory viruses in pediatric patients in Central African Republic
Authors: Nakouné Emmanuel , Tricou Vianney , Manirakiza Alexandre , Komoyo Francis , Selekon Benjamin , Gody Jean Chrysostome , Victoir Kathleen , Buchy Philippe , Kazanji Mirdad
Published: February 2013

Background

Acute viral respiratory illnesses in children in sub-Saharan Africa have received relatively little attention, although they are much more frequent causes of morbidity and mortality than in developed countries. Active surveillance is essential to identify the causative agents and to improve clinical management, especially in the context of possible circulation of pandemic viruses.

Findings

A prospective study was conducted in the Central African Republic (CAR) between January and December 2010 among infants and children aged 0–15 years attending sentinel sites for influenza-like illness or acute respiratory illness. Nasopharyngeal swabs were collected, and one-step real-time and multiplex reverse transcription-polymerase chain reaction were used to detect respiratory viruses. Respiratory viruses were detected in 49 of the 329 (14.9%) nasopharyngeal samples: 29 (8.8%) contained influenza viruses (5 (1.5%) had pandemic influenza A/H1N1 virus and 24 (7.3%) had influenza B viruses), 11 (3.3%) contained parainfluenza viruses types 1 and 3 and 9 (2.7%) contained human respiratory syncytial virus. Most cases were detected during the rainy season in the CAR. Analysis of the amplicon sequences confirmed the identity of each detected virus.

Conclusions

The influenza surveillance system in the CAR has provided valuable data on the seasonality of influenza and the circulation of other respiratory viruses. Our network could therefore play a valuable role in the prevention and control of influenza epidemics in the CAR.
Bacteriophage-encoded lytic enzymes control growth of contaminating Lactobacillus found in fuel ethanol fermentations
Authors: Roach Dwayne R , Khatibi Piyum A , Bischoff Kenneth M , Hughes Stephen R , Donovan David M
Published: February 2013

Background

Reduced yields of ethanol due to bacterial contamination in fermentation cultures weaken the economics of biofuel production. Lactic acid bacteria are considered the most problematic, and surveys of commercial fuel ethanol facilities have found that species ofLactobacillusare predominant.Bacteriophage lytic enzymes are peptidoglycan hydrolases that can degrade the Gram positive cell wall when exposed externally and provide a novel source of antimicrobials that are highly refractory to resistance development.

Results

The streptococcal phage LambdaSa2 (λSa2) endolysin demonstrated strong lytic activity towards 17 of 22 strains of lactobacilli, staphylococci or streptococci and maintained an optimal specific activity at pH 5.5 and in the presence of ≤ 5% ethanol (fermentation conditions) towardL. fermentum.Lactobacillusbacteriophage endolysins LysA, LysA2 and LysgaY showed exolytic activity towards 60% of the lactobacilli tested including fourL. fermentumisolates from fuel ethanol fermentations. In turbidity reduction assays LysA was able to reduce optical density >75% for 50% of the sensitive strains and >50% for the remaining strains. LysA2 and LysgaY were only able to decrease cellular turbidity by <50%. Optimal specific activities were achieved for LysA, LysA2, and LysgaY at pH 5.5. The presence of ethanol (≤5%) did not reduce the lytic activity. Lysins were able to reduce bothL. fermentum(BR0315-1) (λSa2 endolysin) andL. reuteri(B-14171) (LysA) contaminants in mock fermentations of corn fiber hydrolysates.

Conclusion

Bacteriophage lytic enzymes are strong candidates for application as antimicrobials to control lactic acid bacterial contamination in fuel ethanol fermentations.
Purification of native HBHA from Mycobacterium avium subsp. paratuberculosis
Authors: Lefrancois Louise H , Bodier Christelle C , Lecher Sophie , Gilbert Florence B , Cochard Thierry , Harichaux Grégoire , Labas Valérie , Teixeira-Gomes Ana Paula , Raze Dominique , Locht Camille , Biet Franck
Published: February 2013

Background

Paratuberculosis remains today a major global problem in animal health, especially for dairy cattle. However, the diagnosis of its etiologic agent, Mycobacterium avium subsp. paratuberculosis (Map), still lacks sensitivity because of the lack of available antigens. Little is known about the virulence factors for this pathogen. In this study we have developed a method to produce and purify the heparin-binding hemagglutinin (HBHA), a major adhesin of Mycobacteria, from a culture of Map.

Findings

For this extremely slow-growing Mycobacterium, a culture was established in a 3-liter bioreactor. Using the bioreactor the amount of the Map biomass was increased 5-fold compared to a classical culture in flasks. The map-HBHA was purified from a Map lysate by heparin-Sepharose chromatography on HiTrap columns. Binding of map-HBHA onto heparin-Sepharose can be reduced in the presence of salt. Consequently, all steps of sample preparation and column equilibration were carried out in 20 mM Tris–HCl (pH 7.2). The map-HBHA was eluted by a linear NaCl gradient. High resolution mass spectrometry analyses revealed that the native form of map-HBHA has posttranslational modifications, including the removal of the initiation methionine, acetylation of the alanine residue at the N-terminal extremity and the presence of methylated lysines in the C-terminal domain of the protein.

Conclusions

An optimized culture of Map in a bioreactor was established to purify the native map-HBHA from a Map lysate by heparin-Sepharose chromatography. The availability of this antigen offers the possibility to study the structure of the protein and to examine its role in pathogenicity, in particular to better understand the specific interactions of Map with the intestinal tissue. The map-HBHA obtained in its native immunogenic form may also be useful to improve the diagnostic test, especially for the development of a new T-cell-based interferon gamma release assays.
Fat spouses and hours of work: are body and Pareto weights correlated?
Authors: Oreffice Sonia , Quintana-Domeque Climent
Published: February 2013

We explore the relationship between relative physical attractiveness in the household and the hours worked by married men and women. Using PSID data, we find that husbands who are thinner relative to their wives work fewer hours, while wives who are heavier relative to their husbands work more hours. These results are robust to controlling for individual, spousal characteristics, and conventional distribution factors, suggesting that high body weight leads to low Pareto weight in the household: fatter spouses may compensate with more hours of work. Our household bargaining interpretation is supported by the fact that we cannot statistically reject the collective proportionality restriction when including measures of the distribution of relative physical attractiveness in the population.

JEL codes

D1, J1, J22
How people bereaved by suicide perceive newspaper reporting: qualitative study
Authors: Chapple Alison , Ziebland Sue , Simkin Sue , Hawton Keith
Published: February 2013

Background

People bereaved by suicide are often reported to be distressed by media reporting. Current media guidelines for reporting suicide focus especially on prevention of copycat behaviour.

Aims

To explore bereaved individuals' experiences of media reporting after suicide and to examine their priorities in relation to media guidelines.

Method

In-depth interviews with 40 people bereaved by suicide, with qualitative analysis. Review of four guidelines.

Results

There is a difference of emphasis between guidance for the press that aims to prevent copycat suicides (especially avoidance of details such as method used) and the perspectives of bereaved people (who prioritise sympathetic and accurate reporting, sometimes including details of the death and images of the person who died). We found that bereaved relatives were sometimes keen to talk to the press. Those who were upset by the press focused on careless reporting, misquoting and speculation that gave an inaccurate impression of the death.

Conclusions

The Leveson Inquiry has drawn attention to the damage that can be caused by irresponsible journalism. Guidelines written to prevent ‘copycat’ suicides are important, but so are the needs of bereaved relatives. Because accuracy matters greatly to the bereaved, families should be able to work with an intermediary such as a police press officer to prepare a statement for the press to minimise the risk of misrepresentation.
The role of light in mediating the effects of ocean acidification on coral calcification
Authors: Dufault Aaron M. , Ninokawa Aaron , Bramanti Lorenzo , Cumbo Vivian R. , Fan Tung-Yung , Edmunds Peter J.
Published: February 2013

We tested the effect of light and pCO2 on the calcification and survival of Pocillopora damicornis recruits settled from larvae released in southern Taiwan. In March 2011, recruits were incubated at 31, 41, 70, 122, and 226 μmol photons m-2s-1 under ambient (493 μatm) and high pCO2 (878 μatm). After 5 days calcification was measured gravimetrically and survivorship estimated as the number of living recruits. Calcification was affected by the interaction of pCO2 with light, and at 493 μatm pCO2 the response to light intensity resembled a positive parabola. At 878 μatm pCO2, the effect of light on calcification differed from that observed at 493 μatm pCO2, with the result that there were large differences in calcification between 493 μatm and 878 μatm pCO2 at intermediate light intensities (ca. 70 μmol photons m-2s-1), but similar rates of calcification at the highest and lowest light intensities. Survivorship was affected by light and pCO2, and was highest at 122 μmol photons m-2s-1 in both pCO2 treatments, but was unrelated to calcification. In June 2012 the experiment was repeated, and again the results suggested that exposure to high pCO2 decreased calcification of P. damicornis recruits at intermediate light intensities, but not at lower or higher intensities. Together, our findings demonstrate that the effect of pCO2 on coral recruits can be light-dependent, with inhibitory effects of high pCO2 on calcification at intermediate light intensities that disappear at both higher and lower light intensities.
Unique arylalkylamine N-acetyltransferase-2 polymorphism in Salmonids and profound variations in thermal stability and catalytic efficiency conferred by two residues
Authors: Cazaméa-Catalan Damien , Magnanou Elodie , Helland Ronny , Besseau Laurence , Boeuf Gilles , Falcón Jack , Jørgensen Even H.
Published: February 2013

Melatonin contributes to synchronizing major biological and behavioral functions to the cyclic changes in the environment. The arylalkylamine N-acetyltransferase (AANAT) is responsible for a daily rhythm in melatonin secretion. Teleost possess two enzyme forms, AANAT1 and AANAT2, preferentially expressed in the retina and pineal organ, respectively. The concomitant action of light and temperature shapes the daily and seasonal changes in melatonin secretion: the former controls duration while the latter modulates amplitude. Investigating the respective roles of light and temperature is particularly relevant in the context of a global warming likely to affect the way fish decode and anticipate seasonal changes with dramatic consequences on their physiology and behavior. Here we investigated the impact of temperature on pineal melatonin secretion of a migratory species, the Arctic charr (Salvelinus alpinus), the northernmost living and cold adapted salmonid. We show that temperature impacts directly melatonin production in cultured pineal organs. We also show that one organ expresses two AANAT2 transcripts displaying high similarity between them and with trout Oncorhynchus mykiss AANAT2, differing by only two amino acid sites. We compared the kinetics and 3D models of these enzymes as well as of a chimeric construct, particularly with regard to their response to temperature. Our study brings interesting and totally new information on the evolutionary diversity of AANAT enzymes in Teleost and on the role played by specific residues in the catalytic properties of the enzymes.
Opsin1-2, Gqα and arrestin levels at Limulus rhabdoms are controlled by diurnal light and a circadian clock
Authors: Battelle Barbara-Anne , Kempler Karen E. , Parker Alexander K. , Gaddie Christina D.
Published: February 2013

Dark and light adaptation in photoreceptors involve multiple processes including those which change protein concentrations at photosensitive membranes. Light and dark-adaptive changes in protein levels at rhabdoms have been described in detail in white eyed Drosophila maintained under artificial light. Here we tested whether protein levels at rhabdoms change significantly in the highly pigmented lateral eyes of wild caught Limulus maintained in natural diurnal illumination and whether these changes are under circadian control. We found that rhabdomeral levels of opsins (Ops 1-2), the G protein activated by rhodopsin (Gqα) and arrestin change significantly day to night and that nighttime levels of each protein at rhabdoms are significantly influenced by signals from the animal's central circadian clock. Clock input at night increases Ops1-2 and Gqα and decreases arrestin levels at rhabdoms. Clock input is also required for a rapid decrease in rhabdomeral Ops1-2 beginning at sunrise. We found further that dark-adaptation during the day and night are not equivalent. During daytime dark-adaptation, when clock input is silent, the increase of Ops1-2 at rhabdoms is small and Gqα levels do not increase. However, increases in Ops1-2 and Gqα at rhabdoms are enhanced during daytime dark-adaption by treatments which elevate cAMP in photoreceptors suggesting the clock influences dark-adaptive increases in Ops1-2 and Gqα at Limulus rhabdoms by activating cAMP-dependent processes. The circadian regulation of Ops1-2 and Gqα levels at rhabdoms probably has a dual role: to increase retinal sensitivity at night and to protect photoreceptors from light damage during the day.
ONIOM Study of the Mechanism of Olefin Hydrogenation by the Wilkinson’s Catalyst: Reaction Paths and Energy Surfaces of trans- and cis-Forms
Authors: Matsubara Toshiaki , Takahashi Ryohei , Asai Saori
Published: February 2013

The mechanism of the olefin hydrogenation by Wilkinson’s catalyst is examined by the ONIOM method taking account of the substituents of the phosphine ligands. We optimized the equilibrium and transition state structures involved in the catalytic cycles by both active species, trans-[RhCl(PPh3)2] (1Rt) and cis-[RhCl(PPh3)2] (1Rc), and determined the energy profiles of these catalytic cycles. The steric repulsion between the two phosphine ligands in the cis-form was very small throughout the reaction, and in fact 1Rc was more stable by 3.3 kcal mol−1 than 1Rt by the stacking interactions between Ph groups, indicating that not only 1Rt but also 1Rc is a possible catalytically active species. The entire energy profiles showed that the olefin insertion is a rate-determining step in the case of the trans active species 1Rt. Although the activation energy of the olefin insertion is reduced so much in the case of the cis active species 1Rc, the transition states TS2 and TS3 of olefin insertion and isomerization also lie at the highest point of the energy surface. However, the cis-form is more favorable than the trans-form, since the top of the energy surface is lower for the cis-form than for the trans-form. The calculations suggested that if we think a large-size substituent of olefin, the cis-form that provides a larger space for the reaction will have an energy advantage. The steric or electronic effect of the Ph substituents of the phosphine ligands did not affect the entire energy profile substantially in both cases of trans- and cis-forms, although the inclusion of the Ph groups is important to evaluate the stability of isomers and to determine the most favorable path.
Assessment of the robustness of volumetric-modulated arc therapy for lung radiotherapy
Authors: Edmunds K , Bedford J
Published: February 2013

Volumetric-modulated arc therapy (VMAT) is increasingly popular as a treatment method in radiotherapy owing to the speed with which treatments can be delivered. However, there has been little investigation into the effect of increased modulation in lung plans with regard to interfraction organ motion. This is most likely to occur where the planning target volume (PTV) lies within areas of low density. This paper aims to investigate the effect of modulation on the dose distribution using simulated patient movement and to propose a method that is less susceptible to such movement. Simulated interfraction motion is achieved by moving the plan isocentre in steps of 0.5 cm and 1.0 cm in six directions for five clinical VMAT patients. The proposed planning method involves optimisation using a density override of 1 g cm−3, within the PTV in lung, to reduce segment boosting in the periphery of the PTV. This investigation shows that modulation can result in an increase in the maximum dose of >25%, an increase in PTV near-maximum dose of 17% and a reduction in near-minimum dose by 46%. Unacceptable organ at risk (OAR) doses are also seen. The proposed method reduces modulation, resulting in a maximum dose increase of 10%. Although safeguards are in place to prevent the increased dose to OARs from patient movement, there is nothing to prevent the increased dose as a result of modulation in lung. A simple planning method is proposed to safeguard against this effect. Investigation suggests that, where modulation exists in a plan, this method reduces it and is clinically viable.
Oligodendrocyte Precursor Cells Are Accurate Sensors of Local K+in Mature Gray Matter
Authors: Maldonado Paloma P. , Vélez-Fort Mateo , Levavasseur Françoise , Angulo María Cecilia
Published: February 2013

Oligodendrocyte precursor cells (OPCs) are the major source of myelinating oligodendrocytes during development. These progenitors are highly abundant at birth and persist in the adult where they are distributed throughout the brain. The large abundance of OPCs after completion of myelination challenges their unique role as progenitors in the healthy adult brain. Here we show that adult OPCs of the barrel cortex sense fine extracellular K+increases generated by neuronal activity, a property commonly assigned to differentiated astrocytes rather than to progenitors. Biophysical, pharmacological, and single-cell RT-PCR analyses demonstrate that this ability of OPCs establishes itself progressively through the postnatal upregulation of Kir4.1 K+channels. In animals with advanced cortical myelination, extracellular stimulation of layer V axons induces slow K+currents in OPCs, which amplitude correlates with presynaptic action potential rate. Moreover, using paired recordings, we demonstrate that the discharge of a single neuron can be detected by nearby adult OPCs, indicating that these cells are strategically located to detect local changes in extracellular K+concentration during physiological neuronal activity. These results identify a novel unitary neuron–OPC connection, which transmission does not rely on neurotransmitter release and appears late in development. Beyond their abundance in the mature brain, the postnatal emergence of a physiological response of OPCs to neuronal network activity supports the view that in the adult these cells are not progenitors only.
The Neuronal Serum- and Glucocorticoid-Regulated Kinase 1.1 Reduces Neuronal Excitability and Protects against Seizures through Upregulation of the M-Current
Authors: Miranda Pablo , Cadaveira-Mosquera Alba , González-Montelongo Rafaela , Villarroel Alvaro , González-Hernández Tomás , Lamas J. Antonio , Alvarez de la Rosa Diego , Giraldez Teresa
Published: February 2013

The M-current formed by tetramerization of Kv7.2 and Kv7.3 subunits is a neuronal voltage-gated K+conductance that controls resting membrane potential and cell excitability. InXenopus laevisoocytes, an increase in Kv7.2/3 function by the serum- and glucocorticoid-regulated kinase 1 (SGK1) has been reported previously (Schuetz et al., 2008). We now show that the neuronal isoform of this kinase (SGK1.1), with distinct subcellular localization and modulation, upregulates the Kv7.2/3 current inXenopusoocytes and mammalian human embryonic kidney HEK293 cells. In contrast to the ubiquitously expressed SGK1, the neuronal isoform SGK1.1 interacts with phosphoinositide-phosphatidylinositol 4,5-bisphosphate (PIP2) and is distinctly localized to the plasma membrane (Arteaga et al., 2008). An SGK1.1 mutant with disrupted PIP2binding sites produced no effect on Kv7.2/3 current amplitude. SGK1.1 failed to modify the voltage dependence of activation and did not change activation or deactivation kinetics of Kv7.2/3 channels. These results suggest that the kinase increases channel membrane abundance, which was confirmed with flow cytometry assays. To evaluate the effect of the kinase in neuronal excitability, we generated a transgenic mouse (Tg.sgk) expressing a constitutively active form of SGK1.1 (S515D). Superior cervical ganglion (SCG) neurons isolated from Tg.sgk mice showed a significant increase in M-current levels, paralleled by reduced excitability and more negative resting potentials. SGK1.1 effect on M-current in Tg.sgk–SCG neurons was counteracted by muscarinic receptor activation. Transgenic mice with increased SGK1.1 activity also showed diminished sensitivity to kainic acid-induced seizures. Altogether, our results unveil a novel role of SGK1.1 as a physiological regulator of the M-current and neuronal excitability.
Operant Conditioning of a Spinal Reflex Can Improve Locomotion after Spinal Cord Injury in Humans
Authors: Thompson Aiko K. , Pomerantz Ferne R. , Wolpaw Jonathan R.
Published: February 2013

Operant conditioning protocols can modify the activity of specific spinal cord pathways and can thereby affect behaviors that use these pathways. To explore the therapeutic application of these protocols, we studied the impact of down-conditioning the soleus H-reflex in people with impaired locomotion caused by chronic incomplete spinal cord injury. After a baseline period in which soleus H-reflex size was measured and locomotion was assessed, subjects completed either 30 H-reflex down-conditioning sessions (DC subjects) or 30 sessions in which the H-reflex was simply measured [unconditioned (UC) subjects], and locomotion was reassessed. Over the 30 sessions, the soleus H-reflex decreased in two-thirds of the DC subjects (a success rate similar to that in normal subjects) and remained smaller several months later. In these subjects, locomotion became faster and more symmetrical, and the modulation of EMG activity across the step cycle increased bilaterally. Furthermore, beginning about halfway through the conditioning sessions, all of these subjects commented spontaneously that they were walking faster and farther in their daily lives, and several noted less clonus, easier stepping, and/or other improvements. The H-reflex did not decrease in the other DC subjects or in any of the UC subjects; and their locomotion did not improve. These results suggest that reflex-conditioning protocols can enhance recovery of function after incomplete spinal cord injuries and possibly in other disorders as well. Because they are able to target specific spinal pathways, these protocols could be designed to address each individual's particular deficits, and might thereby complement other rehabilitation methods.
Parallel Evolution of Serotonergic Neuromodulation Underlies Independent Evolution of Rhythmic Motor Behavior
Authors: Lillvis Joshua L. , Katz Paul S.
Published: February 2013

Neuromodulation can dynamically alter neuronal and synaptic properties, thereby changing the behavioral output of a neural circuit. It is therefore conceivable that natural selection might act upon neuromodulation as a mechanism for sculpting the behavioral repertoire of a species. Here we report that the presence of neuromodulation is correlated with the production of a behavior that most likely evolved independently in two species:Tritonia diomedeaandPleurobranchaea californica(Mollusca, Gastropoda, Opisthobranchia, Nudipleura). Individuals of both species exhibit escape swimming behaviors consisting of repeated dorsal-ventral whole-body flexions. The central pattern generator (CPG) circuits underlying these behaviors contain homologous identified neurons: DSI and C2 inTritoniaand As and A1 inPleurobranchaea. Homologs of these neurons also can be found inHermissenda crassicorniswhere they are named CPT and C2, respectively. However, members of this species do not exhibit an analogous swimming behavior. InTritoniaandPleurobranchaea, but not inHermissenda, the serotonergic DSI homologs modulated the strength of synapses made by C2 homologs. Furthermore, the serotonin receptor antagonist methysergide blocked this neuromodulation and the swimming behavior. Additionally, inPleurobranchaea, the robustness of swimming correlated with the extent of the synaptic modulation. Finally, injection of serotonin induced the swimming behavior inTritoniaandPleurobranchaea, but not inHermissenda. This suggests that the analogous swimming behaviors ofTritoniaandPleurobranchaeashare a common dependence on serotonergic neuromodulation. Thus, neuromodulation may provide a mechanism that enables species to acquire analogous behaviors independently using homologous neural circuit components.
Crystal structure of 4,4'-bipyridine dihydrate, C10H8N2·2H2O, C10H12N2O2
Authors: Huang Xu , Qiu Qi-Ming , Zhou Li-Li , Jin Qiong-Hua , Zhang Cun-Lin
Published: February 2013

C10H12N2O2, monoclinic, C2 (no. 5), a = 15.811(2) Å, b = 3.7660(5) Å, c = 9.176(1) Å, β = 114.053(2)°, V = 498.9 Å3, Z = 2, Rgt(F) = 0.0555, wRref(F2) = 0.1535, T = 298 K.
Crystal structure of 4,5-dichloro-N-ethyl-2-nitrobenzenamine, C8H8Cl2N2O2
Authors: Zhu Guang Zhou , Lu Zai-Sheng , Shi Huan-Le
Published: February 2013

C8H8Cl2N2O2, orthorhombic, P212121 (no. 19), a = 3.9327(8) Å, b = 13.537(3) Å, c = 18.301(4) Å, V = 974.3 Å3, Z = 4, Rgt(F) = 0.0214, wRref(F2) = 0.0545, T = 296 K.
Quality of life is decreased in patients with paragangliomas
Authors: van Hulsteijn L T , Louisse A , Havekes B , Kaptein A A , Jansen J C , Hes F J , Smit J W A , Corssmit E P M
Published: February 2013

Context

Germline mutations in succinate dehydrogenase (SDH) genes predispose carriers for developing paragangliomas, and studies on their quality of life (QoL) are scarce.

Objectives

The objectives of this study were to assess QoL in patients with paragangliomas (PGL), to evaluate long-term QoL, and to explore potential differences in QoL between SDH mutation carriers and paraganglioma patients without an SDH mutation.

Design

Cross-sectional, case–control study.

Setting

Tertiary referral center.

Subjects

One hundred and seventy four paraganglioma patients were included: 25 SDHB, two SDHC, and 122 SDHD mutation carriers and 25 patients without an SDH mutation. They provided 100 peers as control persons. Furthermore, patients were compared with age-adjusted reference populations.

Main outcome measures

QoL was assessed using three validated health-related QoL questionnaires: the Hospital Anxiety and Depression Scale, the Multidimensional Fatigue Index 20, and the Short Form 36.

Results

Patients reported a significantly impaired QoL compared with their own controls, mainly on fatigue and physical condition subscales. Compared with age-adjusted literature values, patients had significantly impaired scores on physical, psychological, and social subscales. A decreased QoL was mainly related to paraganglioma-associated complaints.

There was no difference in QoL between the various SDH mutation carriers or paraganglioma patients without an SDH mutation. QoL in asymptomatic mutation carriers, i.e. without manifest disease, did not differ from QoL of the general population. Long-term results in 41 patients showed no alteration in QoL besides a reduced level of activity.

Conclusion

QoL is decreased in paraganglioma patients but stable when measured over time.
Inflammatory and steroid receptor gene methylation in the human amnion and decidua
Authors: Mitchell Carolyn M , Sykes Shane D , Pan Xin , Pringle Kirsty G , Lumbers Eugenie R , Hirst Jonathan J , Zakar Tamas
Published: February 2013

Correct timing of parturition requires inflammatory gene activation in the gestational tissues at term and repression during pregnancy. Promoter methylation at CpG dinucleotides represses gene activity; therefore, we examined the possibility that DNA methylation is involved in the regulation of labour-associated genes in human pregnancy. Amnion and decidua were collected at 11–17 weeks of gestation and at term following elective Caesarean delivery or spontaneous labour. Methylation of the inflammatory genesPTGS2,BMP2,NAMPTandCXCL2was analysed using the Methyl-Profiler PCR System and bisulphite sequencing. Methylation of the glucocorticoid, progesterone and oestrogen receptor genes, involved in the hormonal regulation of gestational tissue function, and the expression of the DNA methyltransferasesDNMT1,-3Aand-3Bwere also determined. Variable proportions of inflammatory and steroid receptor gene copies, to a maximum of 50.9%, were densely methylated in both tissues consistent with repression. Densely methylated copy proportions were significantly different between genes showing no relationship with varying expression during pregnancy, between tissues and in individuals. Methylated copy proportions of all genes in amnion and most genes in decidua were highly correlated in individuals.DNMT1and-3Awere expressed in both tissues with significantly higher levels in the amnion at 11–17 weeks than at term. We conclude that the unmethylated portion of gene copies is responsible for the full range of regulated expression in the amnion and decidua during normal pregnancy. Dense methylation of individually variable gene copy proportions happens in the first trimester amnion influenced by sequence context and affected strongly by individual circumstances.
Combining X-Ray Diffraction and Substrate Deflection Analysis to Understand Internal Stress in Electroless Copper Films
Authors: Sharma Tanu , Brüning Ralf , Brown Delilah A. , Bamberg Simon , Merschky Michael , Brüning Frank
Published: February 2013

Electroless copper films are usually the first conducting layer on the insulating substrates of printed circuit boards. For this and other emerging applications, the internal stress of the copper layer is an important consideration both for film adhesion and film-substrate interaction. We have combined stress/strain analysis based on X-ray diffraction, which is sensitive to the strain of the copper crystallites, with a conventionally used technique that analyses the bending of the substrate (Deposit Stress Analyzer). Both techniques were implemented in such a way that the stress could be monitored continuously during the deposition of the films from the electroless plating bath as well as afterwards. These tests were carried out for three chemical formulations and the results from both techniques agree qualitatively. For one bath, the substrate bending method detects a 60 nm region of local stress at the film-surface interface.
Electromigration in Short Al Lines Studied by High-Resolution Resistance Measurement
Authors: Verbruggen A. H. , Van Den Homberg M. J. C. , Jacobs L. C. , Kalkman A. J. , Kraayeveld J. R. , Radelaar S.
Published: February 2013

Electromigration induced resistance changes in short Al lines have been studied by high-resolution AC bridge measurements. The samples were pure, unpassivated Al lines having a length of 3, 5, 8, 12, 17 or 100 μm, a width of 2 μm, and a film thickness of ∼100 nm. Depending on current density and sample length the induced resistance changes fully recover or do not recover after removal of the DC stressing current. The transition from recoverable to non-recoverable behavior is clear-cut and is characterized by a constant critical current density - sample length product. The value of this product is close to the value of the constant critical current density - sample length product characterizing the occurrence of drift in a drift velocity experiment. Inspection of the lines after current stressing by atomic force microscopy revealed that non-recoverable resistance changes are caused by the growth of a single void, hillock or hillock/void pair. Negative resistance changes correspond to the growth of a hillock and positive resistance changes to the growth of a void. The magnitude of the non-recoverable resistance changes can be very well estimated from the dimensions of the void or hillock. The rate of change of the non-recoverable resistance changes (or the growth rate of a void or hillock) scales linearly with the current density.

The characteristic time of the relaxation process of the recoverable resistance scales with the sample length squared. The temperature dependence of the relaxation time shows a good Arrhenius behaviour with an activation energy typical for grain boundary diffusion in Al. The maximum magnitude of the recoverable resistance changes is ΔR/R∼5×10∼-4. The time and temperature dependence of the recoverable resistance changes can be very well explained by the mechanical stress evolution model of Korhonen et al. The evolution of the stress is reflected in changes of the electrical resistance by the piezoresistance effect. A good agreement is found between maximum observed recoverable resistance change and the maximum stress in the line. The good understanding of the resistance changes induced by electromigration in short lines makes this geometry very attractive for studies of fundamental aspects of electromigration in thin film conductors.
Mechanistic study on the effect of sulfate ions on polycarboxylate superplasticisers in cement
Authors: Han Song , Plank Johann
Published: February 2013

Sulfate ions are known to potentially impede the performance of polycarboxylate superplasticisers (PCEs) in cement. In this study, the effect of up to 2% potassium sulfate on two types of PCE composed of different molar ratios of methacrylic acid (MA) and methoxy-polyethylene glycol methacrylate ester (MPEG-MA) was studied, and the mechanism behind the effect of sulfate was investigated. Mini slump tests revealed that the dispersing ability of both PCEs was negatively impacted by sulfate, with the less anionic PCE being more affected than the more anionic one. This result coincided with adsorption and zeta potential measurements. These indicate that in the presence of high sulfate concentrations, the less anionic PCE adsorbs in lower amounts. A mechanistic study revealed that, contrary to previous findings by other authors, the PCE molecules do not significantly shrink and coil in the presence of elevated sulfate concentrations. Instead, it was observed that the delayed addition of potassium sulfate leads to desorption of already adsorbed PCE. Accordingly, competitive adsorption between PCE molecules and sulfate ions takes place. PCEs exhibiting higher grafting density are more negatively affected in their dispersing ability than PCEs showing higher anionic character. Thus, the latter are less sensitive to variations in cement composition.
Mitigation of liquefaction of saturated sand using biogas
Authors: HE J. , CHU J. , IVANOV V.
Published: February 2013

Some recent studies have indicated that the liquefaction potential of saturated sand can be greatly reduced if the sand can be made slightly unsaturated. One way to reduce the degree of saturation of sand is to inject gas into sand. This approach offers a cost-effective solution for mitigating liquefaction hazard over a large area. However, it is not easy to inject gas into sand in a uniform manner. A biogas method was developed in this study to overcome this difficulty. In this method, denitrifying bacteria are used to generate tiny, inert nitrogen gas bubbles in sand. Shaking table tests using a fully instrumented laminar box are conducted on both saturated sand and sand containing microbially generated nitrogen gas bubbles. Comparisons of the results of these tests indicate that the pore water pressure generated in the partially saturated sand was much smaller than that in saturated sand. Thus the proposed method is effective in reducing the liquefaction potential of sand.