bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual Heterogeneous Catalysis for a Regioselective Three‐ Component Synthesis of Bi‐ and Tri(hetero)arylpyridines
Authors: Allais Christophe , Liéby‐Muller Frédéric , Constantieux Thierry , Rodriguez Jean
Published: August 2012

We have designed a new, user‐friendly oxidative dual heterogeneous catalytic system capable of promoting polysubstituted pyridines as unique products from simple activated Michael acceptors, 1,3‐dicarbonyls and ammonium acetate. This metal‐free environmentally‐respectful and totally regioselective domino reaction proved to be a great strategy to access bi‐ and triaryl‐type pyridines as well as challenging bi‐ and triheteroaryl‐type pyridines in a single operation.
Palladium(II)‐Catalyzed Hydration of Alkynylphosphonates to β‐Ketophosphonates
Authors: Li Xiubin , Hu Gaobo , Luo Ping , Tang Guo , Gao Yuxing , Xu Pengxiang , Zhao Yufen
Published: August 2012

A highly efficient palladium(II)‐catalyzed hydration of a wide range of alkynylphosphonates to the corresponding β‐ketophosphonates has been developed to give high yields at 80 °C in 1, 4‐dioxane, with no acidic or alkaline cocatalysts required. The described catalytic system should provide an efficient alternative to highly toxic mercury‐catalyzed methodologies and be useful in synthetic programs.
Aluminum Triflate as a Powerful Catalyst for Direct Amination of Alcohols, Including Electron‐Withdrawing Group‐Substituted Benzhydrols
Authors: Ohshima Takashi , Ipposhi Junji , Nakahara Yasuhito , Shibuya Ryozo , Mashima Kazushi
Published: August 2012

Direct aminations of allylic alcohols, benzylic alcohols, and benzhydrols with electron‐withdrawing (F, Br, I, NO2, or CN) substituents were efficiently catalyzed by aluminum triflate [Al(OTf)3] to afford the corresponding biarylamines in high yield, and the dibromo‐substituted product was further transformed into letrozole.
Quantifying patterns of endocranial heat distribution: Brain geometry and thermoregulation
Authors: Bruner Emiliano , De La Cuétara José Manuel , Musso Fabio
Published: August 2012

Objectives:

The mechanisms involved in brain thermoregulation are still poorly known, and many disagreements still exist concerning the selective cooling capacity of the brain volume. This issue has also been discussed in human evolution and paleoneurology, speculating on possible changes associated with hominid encephalization. Although the vascular system is supposed to be the main component responsible for thermoregulation, brain geometry also plays an important role in the pattern of heat distribution.

Methods:

In fossils, the only neuroanatomical evidence available for quantitative analyses is the endocranial form, molded by the brain morphology. Here, we present a quantitative method based on numerical simulations to quantify and localize variation in heat dissipation patterns associated with endocranial morphological changes, presenting a case‐study on modern humans and chimpanzees.

Results:

Thermic maps provide a graphic tool to visualize heat loading on the endocranial surface. The distribution of the values (thermic spectrum) supplies a quantification which can help describe and compare the patterns of heat distribution within and between groups. Absolute values are largely influenced by size differences. Normalized values suggest further differences associated with brain shape.

Conclusions:

Simulation and numerical modeling are useful to provide a descriptive and quantitative approach to endocranial thermoregulation, supplying a quantitative tool to investigate ontogenic and phylogenetic changes. This is particularly relevant in paleoneurology, considering the large shape and size differences described for fossil hominid brains. Am. J. Hum. Biol., 2012. © 2012 Wiley Periodicals, Inc.
Autistic disorder phenotype associated to a complex 15q intrachromosomal rearrangement
Authors: Christofolini Denise Maria , Meloni Vera Ayres , de Paula Ramos Marco Antonio , Oliveira Mariana Moysés , de Mello Claudia Berlim , Pellegrino Renata , Takeno Sylvia Satomi , Melaragno Maria Isabel
Published: August 2012

The proximal regions of acrocentric chromosomes, particularly 15q11.2, are frequently involved in structural rearrangement. However, interstitial duplications involving one of the chromosome 15 homologues are less frequent, with few patients described with molecular techniques. These patients present distinctive clinical findings including developmental delay and intellectual disability, minor dysmorphic facial features, epilepsy, and autistic behavior. Here we describe an interstitial rearrangement of chromosome 15 composed of a triplication ∼6.9 Mb from 15q11.2 to 15q13.2 followed by a duplication of ∼2.4 Mb from 15q13.2 to 15q13.3, defined using different approaches as MLPA, qPCR, array and FISH. FISH revealed that the middle part of the triplicated segment was in inverted position. The parental origin of the rearrangement was assessed using methylation assay and SNP array that revealed the maternal origin of the additional material. The patient presents most of the clinical features associated to 15q11.2 triplication: minor dysmorphic facial features, generalized epilepsy, absence seizures, intellectual disability, and autistic behavior. In conclusion, the use of more accurate molecular tools enabled a detailed investigation, providing the identification of intrachromosome duplication/triplication and bringing new light to the study of genetic causes of autistic disorders. © 2012 Wiley Periodicals, Inc.
Rare variants in TMEM132D in a case–control sample for panic disorder
Authors: Quast Carina , Altmann Andre , Weber Peter , Arloth Janine , Bader Daniel , Heck Angela , Pfister Hildegard , Müller‐Myhsok Bertram , Erhardt Angelika , Binder Elisabeth B.
Published: August 2012

Genome‐wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we use next‐generation sequencing to test whether such variants contribute to the risk for anxiety disorders by re‐sequencing 40 kb including all exons of the TMEM132D locus which we have previously shown to be associated with panic disorder and anxiety severity measures. DNA from 300 patients suffering from anxiety disorders, mostly panic disorder (84.7%), and 300 healthy controls was screened for the presence of genetic variants using next‐generation re‐sequencing in a pooled approach. Results were verified by individual re‐genotyping. We identified 371 variants of which 247 had not been reported before, including 15 novel non‐synonymous variants. The majority, 76% of these variants had a minor allele frequency less than 5%. While we did not identify additional common variants in TMEM132D associated with panic disorders, we observed an overrepresentation of presumably functional coding variants in healthy controls as compared to cases as well as a higher rate of private coding variants in cases, with one non‐synonymous coding variant present in four patients but not in any of the matched controls nor in over 5,500 individuals of different ethnic origins from publicly available re‐sequencing datasets. Our data suggest that not only common but also putatively functional and/or rare variants within TMEM132D might contribute to the risk to develop anxiety disorders. © 2012 Wiley Periodicals, Inc.
The STREAM X Multichannel GPR System: First Test at Vieil‐Evreux (France) and Comparison with Other Geophysical Data
Authors: Novo Alexandre , Dabas Michel , Morelli Gianfranco
Published: August 2012

A new multichannel ground‐penetrating radar (GPR) system was tested at the Gallo‐Roman site of Vieil‐Evreux (Evreux, France). The resultant maps are compared with previous ones obtained with the ARP© system and other standard geophysical techniques at the same site. Results show how full‐resolution GPR data acquisition methodologies, together with a robust integration of navigation and positioning mounted on a vehicle for fast prospection, provide the best results. The objective of this work was to present the results of the first test of the system STREAM X as a new option for non‐destructive prospection of large archaeological sites. Copyright © 2012 John Wiley & Sons, Ltd.
Crystal Structure of Quinine: The Effects of Vinyl and Methoxy Groups on Molecular Assemblies of Cinchona Alkaloids Cannot Be Ignored
Authors: Hisaki Ichiro , Hiraishi Eri , Sasaki Toshiyuki , Orita Hideo , Tsuzuki Seiji , Tohnai Norimitsu , Miyata Mikiji
Published: August 2012

Quinine, one of Cinchona alkaloids, has been of great interest from medical, synthetic, and supramolecular viewpoints. However, unaccountably, the guest‐free (GF) crystal of quinine containing no solvent or other molecules has not been reported for nearly three decades, although GF crystals of other Cinchona alkaloids, such as quinidine, cinchonidine, and cinchonine, are already known. In this study, we successfully revealed the crystal structure of quinine, which belongs to the P21 space group with the cell parameters of a=6.0587(1), b=19.2492(5), c=22.2824(7) Å, β=92.1646(11)°, and V=2596.83(12) Å3. Interestingly, the crystal has three crystallographically independent molecules in the cell (Z′=3) that are connected through a N(quinoline)⋅⋅⋅HO hydrogen bond to form a pseudo three‐two‐fold (32) double‐helical motif. The helical motif is completely different from those observed in GF crystals of other Cinchona alkaloids. Hierarchical comparison on the crystal structures of a series of Cinchona alkaloids including quinine clearly demonstrated that only small structural differences of a molecule, particularly the position of the vinyl group, cause a significant variety of assembly manner in the crystalline state. There have been no reports systematically demonstrating such steric effect in crystals of Cinchona alkaloids, and, therefore, the present system contributes to the design of desired functional crystal structures.
Changes in Negative Reciprocity as a Function of Age
Authors: Bereby‐Meyer Yoella , Fiks Shelly
Published: August 2012

Standard economic models assume people exclusively pursue material self‐interests in social interactions. However, people exhibit social preferences; that is, they base their choices partly on the outcomes others obtained in a social interaction. People care about fairness, and reciprocity affects behavior. This study examines the differences in negative reciprocity (costly punishment for unfair divisions) as a function of age. Sixty‐one kindergarteners (5‐year‐olds), 53 second graders (8‐year‐olds), and 57 sixth graders (12‐year‐olds) played a dictator game or a mini–ultimatum game either with a human proposer or with a random machine that determined the division between the two players. By keeping the divisions between the players constant and varying the source of the unfair proposal, we were able to differentiate between reciprocity‐based and inequality‐aversion preferences. We found that kindergarteners proposed and accepted unfair divisions regardless of the source of the offer, behaving according to the standard economic model. Children in the sixth grade tended to reject unfair offers from a human proposer but accept unfair divisions from a random device, indicating the emergence of negative reciprocity preferences by age eight (and contrary to inequality aversion). Children at this age also tended to give more fair offers in the ultimatum game than in the dictator game, indicating the emergence of strategic thinking. Copyright © 2012 John Wiley & Sons, Ltd.
Epigenetics meets mathematics: Towards a quantitative understanding of chromatin biology
Authors: Steffen Philipp A. , Fonseca João P. , Ringrose Leonie
Published: August 2012

How fast? How strong? How many? So what? Why do numbers matter in biology? Chromatin binding proteins are forever in motion, exchanging rapidly between bound and free pools. How do regulatory systems whose components are in constant flux ensure stability and flexibility? This review explores the application of quantitative and mathematical approaches to mechanisms of epigenetic regulation. We discuss methods for measuring kinetic parameters and protein quantities in living cells, and explore the insights that have been gained by quantifying and modelling dynamics of chromatin binding proteins.
Integration of bioinformatics into an undergraduate biology curriculum and the impact on development of mathematical skills
Authors: Wightman Bruce , Hark Amy T.
Published: August 2012

The development of fields such as bioinformatics and genomics has created new challenges and opportunities for undergraduate biology curricula. Students preparing for careers in science, technology, and medicine need more intensive study of bioinformatics and more sophisticated training in the mathematics on which this field is based. In this study, we deliberately integrated bioinformatics instruction at multiple course levels into an existing biology curriculum. Students in an introductory biology course, intermediate lab courses, and advanced project‐oriented courses all participated in new course components designed to sequentially introduce bioinformatics skills and knowledge, as well as computational approaches that are common to many bioinformatics applications. In each course, bioinformatics learning was embedded in an existing disciplinary instructional sequence, as opposed to having a single course where all bioinformatics learning occurs. We designed direct and indirect assessment tools to follow student progress through the course sequence. Our data show significant gains in both student confidence and ability in bioinformatics during individual courses and as course level increases. Despite evidence of substantial student learning in both bioinformatics and mathematics, students were skeptical about the link between learning bioinformatics and learning mathematics. While our approach resulted in substantial learning gains, student “buy‐in” and engagement might be better in longer project‐based activities that demand application of skills to research problems. Nevertheless, in situations where a concentrated focus on project‐oriented bioinformatics is not possible or desirable, our approach of integrating multiple smaller components into an existing curriculum provides an alternative.
Mild cognitive impairment: effect of education on the verbal and nonverbal tasks performance decline
Authors: Vadikolias Konstantinos , Tsiakiri‐Vatamidis Anna , Tripsianis Grigorios , Tsivgoulis Georgios , Ioannidis Panagiotis , Serdari Aspasia , Heliopoulos John , Livaditis Miltos , Piperidou Charitomeni
Published: August 2012

We sought to longitudinally evaluate the potential association of educational level with performance on verbal and nonverbal tasks in individuals with mild cognitive impairment (MCI). We evaluated patients with MCI, age >50 years, no medication intake, absent vascular risk factors, and no lesions on brain magnetic resonance imaging (MRI). Each patient underwent a clinical assessment packet and a series of neuropsychological tests of the language and constructional praxis subtests of Cambridge Cognitive Examination (CAMGOG) and the Boston naming test (BNT), at baseline, 6 months, and 12 months. Educational levels were defined taking into account the total years of education, the school level, and diplomas. MCI patients with low education level showed a stepwise reduction in scores of naming objects (NO; P = 0.009), definition (DF; P = 0.012), language (LT; P = 0.021), constructional praxis (CD; P = 0.022), confrontation naming skills (BXB; P = 0.033), phonemic help (BFB; P = 0.041), and BNT (P = 0.002). Analysis of covariance, controlling for baseline scores, showed that education was associated with NO score (P = 0.002), DF score (P = 0.005), LT (P = 0.008), CD score (P = 0.008), BXB score (44.36 ± 1.84, P = 0.0001), BFB (P = 0.022), and BNT (P = 0.004). Our findings indicate that education appeared to affect verbal and nonverbal task performance in MCI patients. Despite the fact that higher educated patients are more acquainted with the tasks, slower deterioration in consecutive follow‐up examinations could be explained by the cognitive reserve theory. The potential association of this protective effect with delayed onset of symptoms deserves further investigation.
Considering water availability and the effect of solute concentration on high solids saccharification of lignocellulosic biomass
Authors: Selig Michael J. , Hsieh Chia‐Wen Carmen , Thygesen Lisbeth G. , Himmel Michael E. , Felby Claus , Decker Stephen R.
Published: August 2012

Milliliter scale (ligno)cellulose saccharifications suggest general solute concentration and its impact on water availability plays a significant role in detrimental effects associated with high solids lignocellulose conversions. A microtumbler developed to enable free‐fall mixing at dry solids loadings up to 35% (w/w) repeatedly produced known detrimental conversion trends on cellulose, xylan and pretreated lignocellulose with commercial enzymes. Despite this, high concentrations of insoluble nonhydrolysable dextrans did not depress saccharification extents in 5% (w/w) cellulose slurries suggesting mass transfer limitations may not significantly limit hydrolysis extents at high solids loadings. Interestingly, cellulose saccharification by purified cellulases showed increased conversions with increasing dry solids loadings. This prompted investigations into impacts the concentration of soluble species, such as sugar alcohols, low molecular weight enzyme preparation components, and monomer hydrolysis products, have on the hydrolysis environment. Such substances significantly depress conversion rates and were shown to correlatively lower water activity (Aw) in the hydrolysis environment while high insoluble solids concentrations did not. Furthermore, low‐field NMR on concentrated slurries of insoluble complex carbohydrates, including the nonhydrolysable dextrans, showed all solids constrained water significantly more than high concentrations of soluble species (inhibitory) suggesting water constraint may not be as problematic an issue at high solids loadings compared to the availability of water in the system. Additionally, the introduction of soluble species lessened overall water constraint in high solids systems and appears to shift the distribution of water away from insoluble surfaces. This is potentially a critical issue for industrial processes operating at high dry solids levels. © 2012 American Institute of Chemical Engineers Biotechnol. Prog., 2012
Solvent selection and optimization of α‐chymotrypsin‐catalyzed synthesis of N‐Ac‐Phe‐Tyr‐NH2 using mixture design and response surface methodology
Authors: Hu Shih‐Hao , Kuo Chia‐Hung , Chang Chieh‐Ming J. , Liu Yung‐Chuan , Chiang Wen‐Dee , Shieh Chwen‐Jen
Published: August 2012

A peptide, N‐Ac‐Phe‐Tyr‐NH2, with angiotensin I‐converting enzyme (ACE) inhibitor activity was synthesized by an α‐chymotrypsin‐catalyzed condensation reaction of N‐acetyl phenylalanine ethyl ester (N‐Ac‐Phe‐OEt) and tyrosinamide (Tyr‐NH2). Three kinds of solvents: a Tris–HCl buffer (80 mM, pH 9.0), dimethylsulfoxide (DMSO), and acetonitrile were employed in this study. The optimum reaction solvent component was determined by simplex centroid mixture design. The synthesis efficiency was enhanced in an organic‐aqueous solvent (Tris‐HCl buffer: DMSO: acetonitrile = 2:1:1) in which 73.55% of the yield of N‐Ac‐Phe‐Tyr‐NH2 could be achieved. Furthermore, the effect of reaction parameters on the yield was evaluated by response surface methodology (RSM) using a central composite rotatable design (CCRD). Based on a ridge max analysis, the optimum condition for this peptide synthesis included a reaction time of 7.4 min, a reaction temperature of 28.1°C, an enzyme activity of 98.9 U, and a substrate molar ratio (Phe:Tyr) of 1:2.8. The predicted and the actual (experimental) yields were 87.6 and 85.5%, respectively. The experimental design and RSM performed well in the optimization of synthesis of N‐Ac‐Phe‐Tyr‐NH2, so it is expected to be an effective method for obtaining a good yield of enzymatic peptide. © 2012 American Institute of Chemical Engineers Biotechnol. Prog., 2012
Using growth factor conditioning to modify the properties of human cell derived extracellular matrix
Authors: Wolchok Jeffrey C. , Tresco Patrick A.
Published: August 2012

We have recently reported on a bench‐top approach for isolating extracellular matrix (ECM) from pure populations of cells grown in culture using sacrificial, open‐celled foams to concentrate and capture the ECM. To increase both the accumulation and the strength of the ECM harvested, cell‐seeded polyurethane (PU) foams were cultured in media supplemented with either transforming growth factor β‐1 (TGFβ1) or hepatocyte growth factor (HGF). At the end of a 3‐week culture period, ECM yield was significantly increased for samples conditioned in supplemented media. Control foams yielded 48 ± 12 mg of material for every gram of PU foam seeded. Yield values increased to 102 ± 21 and 243 ± 25 mg for HGF and TGFβ1‐treated samples, respectively. HGF supplementation increased the modulus by 59%, while TGFβ1 treatment increased the elastic modulus by 204%. TGFβ1‐stimulated material was organized into a network that was markedly denser than control material, with HGF‐stimulated network density intermediate to TGFβ1 and controls. Our study showed that TGFβ1‐treated samples were collagen enriched while HGF samples had an increased gylcosaminoglycan concentration. The results demonstrate that growth factor supplementation, particularly with TGFβ1, can significantly alter the biomechanical properties of cell‐derived ECM that may be used for therapeutic applications. © 2012 American Institute of Chemical Engineers Biotechnol. Prog., 2012
Hemilabile BINAP(O) as a Chiral Ligand in Desymmetrizing Mizoroki–Heck Cyclizations
Authors: Wöste Thorsten H. , Oestreich Martin
Published: August 2012

BINAP(O), rarely used as a chiral ligand, was found to induce significantly higher levels of enantioselection in representative desymmetrizing Mizoroki–Heck cyclizations where conventional BINAP produces essentially racemic material. BINAP(O) is a ligand with a stronger and weaker donor atom, and that hemilabile nature lends itself the ability to act as either a bi‐ or monodentate ligand. On that basis, we introduce mechanistic models where the weak donor, in one case, mediates the equilibration of diastereomeric alkene–palladium(II) complexes and, in another case, dissociates from the palladium(II) atom, thereby rendering BINAP(O) as a monodentate ligand. These new findings, along with the recently reported effects in intermolecular Mizoroki–Heck reactions, suggest that BINAP(O) ought to be included into ligand screenings.
Polymeric Adsorption of Methylene Blue in TiO2 Colloids—Highly Sensitive Thermochromism and Selective Photocatalysis
Authors: Liu Baoshun , Wen Liping , Nakata Kazuya , Zhao Xiujian , Liu Shanhu , Ochiai Tsuyoshi , Murakami Taketoshi , Fujishima Akira
Published: August 2012

The polymeric adsorption of methylene blue (MB) on a TiO2 surface is reported. The MB molecule on the TiO2 surface mainly exists as the H‐trimeric adsorption state, which results in the MB@TiO2 polymeric sol. The trimeric adsorption leads to a remarkable “blueshift” of visible‐light adsorption of MB. Electrostatic attraction is important for trimeric adsorption of MB on TiO2 surfaces. The trimer–monomer equilibrium is highly sensitive on temperature changes, showing an interesting reversible thermochromism. The MB@TiO2 polymeric sol can be photodegraded under UV illumination without destroying the equilibrium of trimer–monomer. Compared with anionic methyl orange, the TiO2 colloid hydrosol shows highly selective photocatalysis of MB and other cationic dyes, including crystal violet, methylene green, and victoria blue B. The MB@TiO2 polymeric sol is stable under visible‐light illumination because interfacial transfer of electrons does not exist between MB and TiO2.
Molecular Propellers that Consist of Dehydrobenzo[14]annulene Blades
Authors: Nobusue Shunpei , Mukai Yuichi , Fukumoto Yo , Umeda Rui , Tahara Kazukuni , Sonoda Motohiro , Tobe Yoshito
Published: August 2012

A new class of propel‐ ler‐shaped compound (4), which consisted of dehydrobenzo[14]annulene ([14]DBA) blades, as well as its naphtho homologues (5 and 6), have been prepared. Although NMR studies of compound 4 did not provide useful information regarding its conformation in solution, DFT calculations with different functionals and the 6‐31G* basis set all indicated that the D3‐symmetric structure was energetically more favorable than the C2 conformer. From X‐ray crystallographic analysis, it appeared that compound 4 adopted a propeller‐shaped‐, approximately D3‐symmetric structure in the solid state, in which the [14]DBA blades were twisted substantially owing to steric repulsion between the neighboring benzene rings. On the contrary, in the case of compound 6, although the DFT calculations with the B3LYP functional predicted that the D3‐symmetric conformation was more stable, calculations with the M05 and M05‐2X functionals indicated that the C2 conformer was more favorable because of π–π interactions between the naphthalene units of a pair of neighboring blades. Indeed, X‐ray analysis of compound 6 showed that it adopted an approximately C2‐symmetric conformation. Moreover, on the basis of variable‐temperature 1H NMR measurements, we found that compound 6 adopted a C2 conformation and the barrier for interconversion between the C2–C2 conformers was estimated to be 16.2 kcal mol−1; however, no indication of the presence of the D3 isomer was obtained. The relatively small energy barriers to interconversion, despite the large overlapping of neighboring blades, was ascribed to the flexibility of the acetylene linkages, which could be deformed substantially in the transition state of the ring‐flip.
Water Oxidation with Molecularly Defined Iridium Complexes: Insights into Homogeneous versus Heterogeneous Catalysis
Authors: Junge Henrik , Marquet Nicolas , Kammer Anja , Denurra Stefania , Bauer Matthias , Wohlrab Sebastian , Gärtner Felix , Pohl Marga‐Martina , Spannenberg Anke , Gladiali Serafino , Beller Matthias
Published: August 2012

Molecularly defined Ir complexes and different samples of supported IrO2 nanoparticles have been tested and compared in the catalytic water oxidation with cerium ammonium nitrate (CAN) as the oxidant. By comparing the activity of nano‐scaled supported IrO2 particles to the one of organometallic complexes it is shown that the overall activity of the homogeneous Ir precursors is defined by both the formation of the homogeneous active species and its conversion to IrIV‐oxo nanoparticles. In the first phase of the reaction the activity is dominated by the homogeneous active species. With increasing reaction time, the influence of nano‐sized Ir‐oxo particles becomes more evident. Notably, the different conversion rates of the homogeneous precursor into the active species as well as the conversion into Ir‐oxo nanoparticles and the different particle sizes have a significant influence on the overall activity. In addition to the homogeneous systems, IrO2@MCM‐41 has also been synthesized, which contains stabilized nanoparticles of between 1 and 3 nm in size. This latter system shows a similar activity to IrCl3⋅xH2O and complexes 4 and 5. Mechanistic insights were obtained by in situ X‐ray absorption spectroscopy and scanning transmission electron microscopy.
Psychological Woundedness and its Evaluation in Applications for Clinical Psychology Training
Authors: Ivey Gavin , Partington Theresa
Published: August 2012

This paper reports on a qualitative study investigating clinical psychology programme selectors' perceptions of psychological ‘woundedness’ in the autobiographical narratives of applicants for clinical psychology training. Woundedness was here defined in terms of the ongoing or residual psychological impact of adverse experiences and psychic conflicts. Ten selectors were presented with a sample of applicants' written autobiographical narratives, differentiated by the conspicuous presence or absence of psychological woundedness. The selectors, who were not informed of the specific aims of the study, ranked applicant protocols and were interviewed individually about their impressions of the protocols and the criteria that they used to rank them. Most selectors were positively biased toward ‘wounded’ narratives and suspicious of those in which woundedness was manifestly absent. Although generally disposed to favour wounded applicants, how woundedness was presented, rather than the mere presence of it, was a discriminating feature in selectors' appraisal of wounded narratives. Selectors were concerned that unresolved woundedness may compromise applicants' professional boundaries, impair self‐reflective capacity and lead to damaging countertransference enactments. The relative extent to which applicant woundedness appeared to be resolved was significant in selectors' assessment of applicants' clinical training potential. A distinction is thus proposed between obstructive and facilitative woundedness in clinical psychology applicants. Copyright © 2012 John Wiley & Sons, Ltd.

Key Practitioner Message

A sample of clinical psychology programme selectors identified psychological woundedness as a significant feature in applicant autobiographies.

Selectors favoured applicant autobiographies showing evidence of woundedness.

The distinction between obstructive and facilitative woundedness is important in how the selector sample evaluated woundedness.
Less bluster ahead? Ecohydrological implications of global trends of terrestrial near‐surface wind speeds
Authors: McVicar Tim R. , Roderick Michael L. , Donohue Randall J. , Van Niel Thomas G.
Published: August 2012

Why, in a globally warming climate, have observed rates of atmospheric evaporative demand (AED) declined at many sites over recent decades? The answer is that the evaporative process is primarily driven by radiative and aerodynamic components (the latter mainly influenced by wind speed and atmospheric humidity). So, although increases in air temperatures in isolation would result in increases of both pan evaporation (Epan) observations, and fully physically based model estimates of potential evapotranspiration (ETp), results show that changes in the other meteorological variables governing AED are currently exerting a greater opposing influence. Widespread declines in wind speed (denoted ‘stilling’) of ~−0.014 m s−1 a−1 have recently been reported. In studies assessing the relative contribution of the four primary meteorological variables on AED dynamics, wind speed trends are often indentified as being important. Stilling reduces AED, but its impact on actual evapotranspiration and streamflow is situation dependant. For wet catchments under steady state conditions, stilling‐induced declines in actual evapotranspiration will result in an approximate complementary increase in streamflow. In contrast, for dry catchments, actual evapotranspiration dynamics more closely follow precipitation dynamics so stilling has negligible impact on streamflow. In ‘equitant’ catchments (i.e. those that straddle the energy–water limitation divide), the likely impact of stilling on the catchment water balance depends on sub‐annual processes and requires that new approaches (either top–down or bottom–up) be developed to allow better predictions to be made. Copyright © 2012 Commonwealth of Australia
Online photolytic optical gating of caged fluorophores in capillary zone electrophoresis utilizing an ultraviolet light‐emitting diode
Authors: Gallagher Elyssia S. , Comi Troy J. , Braun Kevin L. , Aspinwall Craig A.
Published: August 2012

Photolytic optical gating (POG) facilitates rapid, on‐line and highly sensitive analyses, though POG utilizes UV lasers for sample injection. We present a low‐cost, more portable alternative, employing an ultraviolet light‐emitting diode (UV‐LED) array to inject caged fluorescent dyes via photolysis. Utilizing the UV‐LED array, labeled amino acids were injected with nanomolar limits of detection (270 ± 30 nM and 250 ± 30 nM for arginine and citrulline, respectively). When normalized for the difference in light intensity, the UV‐LED array provides comparable sensitivity to POG utilizing UV lasers. Additionally, the UV‐LED array yielded sufficient beam quality and stability to facilitate coupling with a Hadamard transform, resulting in increased sensitivity. This work shows, for the first time, the use of an UV‐LED for online POG with comparable sensitivity to conventional laser sources but at a lower cost.
Correlations of CSF tau and amyloid levels with Alzheimer pathology in neuropathologically verified dementia with Lewy bodies
Authors: Brunnström Hans , Hansson Oskar , Zetterberg Henrik , Londos Elisabet , Englund Elisabet
Published: August 2012

Objective

The presence of concomitant Alzheimer pathology has been linked to earlier death in cases with dementia with Lewy bodies (DLB). Recently, elevated cerebrospinal fluid (CSF) tau protein levels have been reported to be associated with shorter survival in clinically diagnosed DLB. Correlations between CSF biomarkers and neuropathological findings in DLB are missing. The aim of this study was to investigate correlations between CSF biomarker levels and histopathological findings, with a focus on concomitant Alzheimer pathology, in neuropathologically verified DLB cases.

Methods

The extent of neurofibrillary pathology (Braak stage), neuritic plaques (CERAD stage), Alzheimer pathology (PPAD9 stage) and cerebral amyloid angiopathy was assessed in 16 cases with DLB in whom total tau (T‐tau), hyperphosphorylated tau and amyloid beta 1–42 (Aβ42) protein levels in CSF had been analyzed in vivo. Demographic and clinical data were collected.

Results

Both Braak and PPAD9 stages were inversely correlated with Aβ42 levels, whereas CERAD stage showed no significant correlations. Cerebral amyloid angiopathy correlated positively with T‐tau and T‐tau/Aβ42 ratio, and inversely with Aβ42 levels, but the group showed a very heterogeneous extent of cerebral amyloid angiopathy.

Conclusions

The burden of concomitant Alzheimer pathology correlates with CSF Aβ42 but not with T‐tau levels in cases with neuropathologically defined DLB. Copyright © 2012 John Wiley & Sons, Ltd.
Activated tumor-infiltrating CD4+ regulatory T cells restrain antitumor immunity in patients with primary or metastatic liver cancer
Authors: Pedroza-Gonzalez Alexander , Verhoef Cornelis , Ijzermans Jan N. M. , Peppelenbosch Maikel P. , Kwekkeboom Jaap , Verheij Joanne , Janssen Harry L. A. , Sprengers Dave
Published: August 2012

The mechanisms that enable liver cancer to escape elimination by the immune system remain unclear, but their elucidation may provide novel therapeutic interventions. We investigated the influence of tumor-infiltrating regulatory T cells on tumor-specific T cell responses in patients with liver cancer, using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC). Here we report that in both HCC and LM-CRC, CD4+CD25+Foxp3+ regulatory T cells (Tregs) accumulate in the tumor milieu and are potent suppressors of autologous tumor-specific T cell responses. Especially in LM-CRC, where Treg accumulation is more prominent, there is good evidence for local proliferation of Tregs at the cancer site. We show that tumor Tregs up-regulate the expression of glucocorticoid-induced tumor necrosis factor receptor (GITR) compared with Tregs in tumor-free liver tissue and blood. Importantly, treatment with soluble GITR ligand (GITRL) induces a decrease in the suppression mediated by the activated tumor-infiltrating Tregs and restores the proliferative capacity and cytokine production of CD4+CD25− T cells. Conclusion: Our results show that tumor-associated Tregs are critical for immune evasion in liver cancer, and we propose that GITRL constitutes a rational treatment for this disease. (Hepatology 2013)
Ablation of Very Long Acyl Chain Sphingolipids Causes Hepatic Insulin Resistance in Mice Due to Altered Detergent-Resistant Membranes
Authors: Park Joo-Won , Park Woo-Jae , Kuperman Yael , Boura-Halfon Sigalit , Pewzner-Jung Yael , Futerman Anthony H.
Published: August 2012

Sphingolipids are important structural components of cell membranes and act as critical regulators of cell function by modulating intracellular signaling pathways. Specific sphingolipids, such as ceramide, glucosylceramide, and ganglioside GM3, have been implicated in various aspects of insulin resistance, because they have been shown to modify several steps in the insulin signaling pathway, such as phosphorylation of either protein kinase B (Akt) or of the insulin receptor. We now explore the role of the ceramide acyl chain length in insulin signaling by using a ceramide synthase 2 (CerS2) null mouse, which is unable to synthesize very long acyl chain (C22-C24) ceramides. CerS2 null mice exhibited glucose intolerance despite normal insulin secretion from the pancreas. Both insulin receptor and Akt phosphorylation were abrogated in liver, but not in adipose tissue or in skeletal muscle. The lack of insulin receptor phosphorylation in liver correlated with its inability to translocate into detergent-resistant membranes (DRMs). Moreover, DRMs in CerS2 null mice displayed properties significantly different from those in wild-type mice, suggesting that the altered sphingolipid acyl chain length directly affects insulin receptor translocation and subsequent signaling.

Conclusion:

We conclude that the sphingolipid acyl chain composition of liver regulates insulin signaling by modifying insulin receptor translocation into membrane microdomains.
Monocyte subsets in human liver disease show distinct phenotypic and functional characteristics
Authors: Liaskou Evaggelia , Zimmermann Henning W. , Li Ka-Kit , Oo Ye H. , Suresh Shankar , Stamataki Zania , Qureshi Omar , Lalor Patricia F. , Shaw Jean , Syn Wing-kin , Curbishley Stuart M. , Adams David H.
Published: August 2012

Liver fibrosis is a wound healing response to chronic liver injury and inflammation in which macrophages and infiltrating monocytes participate in both the development and resolution phase. In humans, three monocyte subsets have been identified: the classical CD14++CD16−, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes. We studied the phenotype and function of these monocyte subsets in peripheral blood and liver tissue from patients with chronic inflammatory and fibrotic liver diseases. The frequency of intrahepatic monocytes increased in disease compared with control liver tissue, and in both nondiseased and diseased livers there was a higher frequency of CD14++CD16+ cells with blood. Our data suggest two nonexclusive mechanisms of CD14++CD16+ accumulation in the inflamed liver: (1) recruitment from blood, because more than twice as many CD14++CD16+ monocytes underwent transendothelial migration through hepatic endothelial cells compared with CD14++CD16− cells; and (2) local differentiation from CD14++CD16− classical monocytes in response to transforming growth factor β and interleukin (IL)-10. Intrahepatic CD14++CD16+ cells expressed both macrophage and dendritic cell markers but showed high levels of phagocytic activity, antigen presentation, and T cell proliferation and secreted proinflammatory (tumor necrosis factor α, IL-6, IL-8, IL-1β) and profibrogenic cytokines (IL-13), chemokines (CCL1, CCL2, CCL3, CCL5), and growth factors (granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor), consistent with a role in the wound healing response. Conclusion: Intermediate CD14++CD16+ monocytes preferentially accumulate in chronically inflamed human liver as a consequence of enhanced recruitment from blood and local differentiation from classical CD14++CD16− monocytes. Their phagocytic potential and ability to secrete inflammatory and profibrogenic cytokines suggests they play an important role in hepatic fibrogenesis. (Hepatology 2013)
Hepatitis C virus NS4B protein targets STING and abrogates RIG-I–mediated type I interferon-dependent innate immunity
Authors: Nitta Sayuri , Sakamoto Naoya , Nakagawa Mina , Kakinuma Sei , Mishima Kako , Kusano-Kitazume Akiko , Kiyohashi Kei , Murakawa Miyako , Nishimura-Sakurai Yuki , Azuma Seishin , Tasaka-Fujita Megumi , Asahina Yasuhiro , Yoneyama Mitsutoshi , Fujita Takashi , Watanabe Mamoru
Published: August 2012

Hepatitis C virus (HCV) infection blocks cellular interferon (IFN)-mediated antiviral signaling through cleavage of Cardif by HCV-NS3/4A serine protease. Like NS3/4A, NS4B protein strongly blocks IFN-β production signaling mediated by retinoic acid–inducible gene I (RIG-I); however, the underlying molecular mechanisms are not well understood. Recently, the stimulator of interferon genes (STING) was identified as an activator of RIG-I signaling. STING possesses a structural homology domain with flaviviral NS4B, which suggests a direct protein-protein interaction. In the present study, we investigated the molecular mechanisms by which NS4B targets RIG-I–induced and STING-mediated IFN-β production signaling. IFN-β promoter reporter assay showed that IFN-β promoter activation induced by RIG-I or Cardif was significantly suppressed by both NS4B and NS3/4A, whereas STING-induced IFN-β activation was suppressed by NS4B but not by NS3/4A, suggesting that NS4B had a distinct point of interaction. Immunostaining showed that STING colocalized with NS4B in the endoplasmic reticulum. Immunoprecipitation and bimolecular fluorescence complementation (BiFC) assays demonstrated that NS4B specifically bound STING. Intriguingly, NS4B expression blocked the protein interaction between STING and Cardif, which is required for robust IFN-β activation. NS4B truncation assays showed that its N terminus, containing the STING homology domain, was necessary for the suppression of IFN-β promoter activation. NS4B suppressed residual IFN-β activation by an NS3/4A-cleaved Cardif (Cardif1-508), suggesting that NS3/4A and NS4B may cooperate in the blockade of IFN-β production. Conclusion: NS4B suppresses RIG-I–mediated IFN-β production signaling through a direct protein interaction with STING. Disruption of that interaction may restore cellular antiviral responses and may constitute a novel therapeutic strategy for the eradication of HCV. (Hepatology 2013)
Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid
Authors: Honda Akira , Ikegami Tadashi , Nakamuta Makoto , Miyazaki Teruo , Iwamoto Junichi , Hirayama Takeshi , Saito Yoshifumi , Takikawa Hajime , Imawari Michio , Matsuzaki Yasushi
Published: August 2012

Bezafibrate is a widely used hypolipidemic agent and is known as a ligand of the peroxisome proliferator-activated receptors (PPARs). Recently this agent has come to be recognized as a potential anticholestatic medicine for the treatment of primary biliary cirrhosis (PBC) that does not respond sufficiently to ursodeoxycholic acid (UDCA) monotherapy. The aim of this study was to explore the anticholestatic mechanisms of bezafibrate by analyzing serum lipid biomarkers in PBC patients and by cell-based enzymatic and gene expression assays. Nineteen patients with early-stage PBC and an incomplete biochemical response to UDCA (600 mg/day) monotherapy were treated with the same dose of UDCA plus bezafibrate (400 mg/day) for 3 months. In addition to the significant improvement of serum biliary enzymes, immunoglobulin M (IgM), cholesterol, and triglyceride concentrations in patients treated with bezafibrate, reduction of 7α-hydroxy-4-cholesten-3-one (C4), a marker of bile acid synthesis, and increase of 4β-hydroxycholesterol, a marker of CYP3A4/5 activity, were observed.

In vitro

experiments using human hepatoma cell lines demonstrated that bezafibrate controlled the target genes of PPARα, as well as those of the pregnane X receptor (PXR); down-regulating CYP7A1, CYP27A1, and sinusoidal Na+/taurocholate cotransporting polypeptide (NTCP), and up-regulating CYP3A4, canalicular multidrug resistance protein 3 (MDR3), MDR1, and multidrug resistance-associated protein 2 (MRP2).

Conclusion :

Bezafibrate is a dual PPARs/PXR agonist with potent anticholestatic efficacy in early-stage PBC patients with an incomplete biochemical response to UDCA monotherapy.
Keratin 19 Demonstration of Canal of Hering Loss in Primary Biliary Cirrhosis: “Minimal Change PBC”?
Authors: Khan Fahad M. , Komarla Arathi Rajendra , Mendoza Paulo G. , Bodenheimer Henry C. , Theise Neil D.
Published: August 2012

Liver biopsy is important for diagnosing primary biliary cirrhosis (PBC). Prior investigations suggest that immunostaining for biliary keratin 19 (K19) may show the earliest changes suspicious for PBC, namely, loss of the canals of Hering (CoH). We aimed to study the clinical outcomes of patients whose biopsy specimens appeared histologically near normal or with minimal inflammatory changes, but in which K19 staining revealed widespread periportal CoH loss, a finding we termed “minimal change PBC.” Ten patients were identified prospectively as having nearly normal or mildly inflamed biopsy specimens without diagnostic or suggestive histologic features of PBC, but with near complete CoH loss; six had available follow-up clinical data, one had follow-up biopsy. Controls for clinical and/or K19 analysis included six normal livers and biopsy specimens from 10 patients with confirmed early PBC, 10 with early stage chronic hepatitis C (CHC), and nine with resolving, self-limited hepatitis (RSLH). Staining for K19 in normal controls, livers with “minimal change” PBC, CHC, and RSLH showed 9.2 ± 6.0, 0.44 ± 0.37 (

P

< 0.0001), 5.7 ± 4.6 (n.s.), 4.1 ± 2.1 (

P

< 0.02) CoH per portal tract, respectively. Patients with available clinical follow up, compared to patients with diagnostic early-stage PBC biopsies, showed identical treatment responses to ursodeoxycholic acid, similar rates and types of nonhepatic autoimmune diseases, and/or subsequent development of autoimmune hepatitis overlap syndrome.

Conclusion:

We suggest that CoH loss demonstrated by K19 immunostaining is an early feature in PBC. Clinical findings in the years following biopsy, including response to ursodeoxycholic acid, show identical changes to patients with biopsy confirmed PBC. We suggest that this “minimal change” feature may support a clinical diagnosis of PBC even in the absence of characteristic, granulomatous, duct destructive lesions.