bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical phenotype, laboratory features and genotype of 35 patients with heritable dysfibrinogenaemia
Authors: Shapiro Susan E. , Phillips Emma , Manning Richard A. , Morse Colin V. , Murden Sherina L. , Laffan Michael A. , Mumford Andrew D.
Published: October 2012

Heritable dysfibrinogenaemia (HD) is a rare qualitative disorder of fibrinogen (FGN). To better describe the clinical, laboratory and genotypic spectrum of HD, we evaluated 35 subjects identified at two UK centres using laboratory criteria. 12/35(34%) subjects with HD experienced bleeding (bleeding score >1 at any site), 3/35(9%) thrombosis and 20/35(57%) were asymptomatic. Amongst subjects with bleeding, symptoms were typically mild, at one anatomical site and seldom occurred after invasive procedures. All subject showed dry clot weight within or above laboratory reference interval (median 3·2 g/l; range 1·9–5·1), reduced Clauss fibrinogen (median 0·52 g/l; range 0·21–1·3), and prolonged thrombin (median 30·7 s; range 21·3–45·7) and reptilase (median 42·0 s; range 20·0–68·0) times. In all subjects, the prothrombin time ratio (PTR), determined by Sysmex CA‐1500 coagulometer and Innovin activator, was abnormal (median 1·42; range 1·22–1·61). The activated partial thromboplastin time ratio and PTR with other coagulometers and activators were comparatively insensitive to HD. All subjects with HD harboured heterozygous candidate nucleotide variations within known hotspots in the FGN genes. The HD variants identified in this cross‐sectional study seldom have significant clinical manifestations and show similar laboratory features irrespective of genotype. Selection of coagulometer and PT activator may markedly affect the detection of new HD cases using coagulation screening tests.
Investigation for the Interaction of Tyramine‐Based Anthraquinone Analogue with Human Serum Albumin by Optical Spectroscopic Technique
Authors: Aggarwal Swati , Tiwari Anjani K. , Srivastava Pooja , Chadha Nidhi , Kumar Vikas , Singh Gurmeet , Mishra Anil K.
Published: October 2012

A newly synthesized anthraquinone derivative ‘N‐(2‐methylanthraquinone)‐4‐(2‐aminoethyl) phenol’ (Tyan) were characterized as a fluorophore from photophysical analysis by measuring the UV‐Vis absorptive (λex = 325 nm) and fluorescence emitive (λem = 660 nm) values. Density functional theory additionally supported the spectroscopic data by modulation of highest occupied molecular orbital rather than lowest unoccupied molecular orbital due to the affect of tyramine moiety present in Tyan. The pharmacological importance of Tyan was evaluated by molecular docking with human serum albumin. The molecular docking of the Tyan was performed with the crystal structure of human serum albumin (PDB entry 1E78), which shows binding in all the three domains of human serum albumin corresponding to −7.74 as the GScore. Moreover, the interactions of human serum albumin with Tyan were assessed employing fluorescence spectroscopy under simulative physiological conditions, and the binding constant for the interaction at 25 °C was found to be 0.6 × 103/m.
Advances in the Prediction of Protein–Peptide Binding Affinities: Implications for Peptide‐Based Drug Discovery
Authors: Audie Joseph , Swanson Jon
Published: October 2012

Peptides hold great promise as novel medicinal and biologic agents, and computational methods can help unlock that promise. In particular, structure‐based peptide design can be used to identify and optimize peptide ligands. Successful structure‐based design, in turn, requires accurate and fast methods for predicting protein–peptide binding affinities. Here, we review the development of such methods, emphasizing structure‐based methods that assume rigid‐body association and the single‐structure approximation. We also briefly review recent applications of computational free energy prediction methods to enable and guide novel peptide drug and biomarker discovery. We close the review with a brief perspective on the future of computational, structure‐based protein–peptide binding affinity prediction.
Protein–Ligand Interaction Study of CpOGA in Complex with GlcNAcstatin
Authors: Sousa Paulo Robson M. , de Alencar Nelson Alberto N. , Lima Anderson H. , Lameira Jerônimo , Alves Cláudio Nahum
Published: October 2012

The GlcNAcstatin is a potent inhibitor of O‐glycoprotein 2‐acetamino‐2‐deoxy‐β‐D‐glucopyranosidase, which has been related with type II diabetes and neurodegenerative disorders. Herein, hybrid quantum mechanics/molecular mechanics, molecular dynamics simulations, and potential of mean force were employed to study the interactions established between GlcNAcstatin and a bacterial O‐GlcNAcase enzyme from Clostridium perfringens. The results reveal that the imidazole nitrogen atom of GlcNAcstatin has shown a better interaction with the active site of Clostridium perfringens in its protonated form, which is compatible with a substrate‐assisted reaction mechanism involving two conserved aspartate residues (297 and 298). Furthermore, the quantum mechanics/molecular mechanics–molecular dynamics simulations appointed a strong interaction between Asp401, Asp298, and Asp297 residues and the GlcNAcstatin inhibitor, which is in accordance with experimental data. Lastly, these results may contribute to understand the molecular mechanism of inhibition of Clostridium perfringens by GlcNAcstatin inhibitor and, consequently, this study might be useful to design new molecules with more interesting inhibitory activity.
Investigating Mammalian Tyrosine Phosphatase Inhibitors as Potential ‘Piggyback’ Leads to Target Trypanosoma brucei Transmission
Authors: Ruberto Irene , Szoor Balazs , Clark Rachel , Matthews Keith R.
Published: October 2012

African trypanosomiasis is a neglected tropical disease affecting humans and animals across 36 sub‐Saharan African countries. We have investigated the potential to exploit a ‘piggyback’ approach to inhibit Trypanosoma brucei transmission by targeting the key developmental regulator of transmission, T. brucei protein tyrosine phosphatase 1. This strategy took advantage of the extensive investment in inhibitors for human protein tyrosine phosphatase 1B, a key target for pharmaceutical companies for the treatment of obesity and diabetes. Structural predictions for human and trypanosome tyrosine phosphatases revealed the overall conservation of important functional motifs, validating the potential for exploiting cross specific compounds. Thereafter, nineteen inhibitors were evaluated; seventeen from a protein tyrosine phosphatase 1B‐targeted inhibitor library and two from literature analysis – oleanolic acid and suramin, the latter of which is a front line drug against African trypanosomiasis. The compounds tested displayed similar inhibitory activities against the human and trypanosome enzymes, mostly behaving as noncompetitive inhibitors. However, their activity against T. brucei in culture was low, necessitating further chemical modification to improve their efficacy and specificity. Nonetheless, the results validate the potential to explore a ‘piggyback’ strategy targeting T. brucei protein tyrosine phosphatase 1 through exploiting the large pharmacological investment in therapies for obesity targeting protein tyrosine phosphatase 1B.
Effects of geohelminth infection and age on the associations between allergen‐specific IgE, skin test reactivity and wheeze: a case‐control study
Authors: Moncayo A.‐L. , Vaca M. , Oviedo G. , Workman L. J. , Chico M. E. , Platts‐Mills T. A. E. , Rodrigues L. C. , Barreto M. L. , Cooper P. J.
Published: October 2012

Background

Most childhood asthma in poor populations in Latin America is not associated with aeroallergen sensitization, an observation that could be explained by the attenuation of atopy by chronic helminth infections or effects of age.

Objective

To explore the effects of geohelminth infections and age on atopy, wheeze, and the association between atopy and wheeze.

Methods

A case‐control study was done in 376 subjects (149 cases and 227 controls) aged 7–19 years living in rural communities in Ecuador. Wheeze cases, identified from a large cross‐sectional survey, had recent wheeze and controls were a random sample of those without wheeze. Atopy was measured by the presence of allergen‐specific IgE (asIgE) and skin prick test (SPT) responses to house dust mite and cockroach. Geohelminth infections were measured in stools and anti‐Ascaris IgE in plasma.

Results

The fraction of recent wheeze attributable to anti‐Ascaris IgE was 45.9%, while those for SPT and asIgE were 10.0% and 10.5% respectively. The association between atopy and wheeze was greater in adolescents than children. Although Anti‐Ascaris IgE was strongly associated with wheeze (adj. OR 2.24 (95% CI 1.33–3.78, P = 0.003) and with asIgE (adj. OR 5.34, 95% CI 2.49–11.45, P < 0.001), the association with wheeze was independent of asIgE. There was some evidence that the association between atopy and wheeze was greater in uninfected subjects compared with those with active geohelminth infections.

Conclusions and clinical relevance

Atopy to house dust mite and cockroach explained few wheeze cases in our study population, while the presence of anti‐Ascaris IgE was an important risk factor. Our data provided only limited evidence that active geohelminth infections attenuated the association between atopy and wheeze in endemic areas or that age modified this association. The role of allergic sensitization to Ascaris in the development of wheeze, independent of atopy, requires further investigation.
T cell depletion in paediatric stem cell transplantation
Authors: Booth C , Veys P
Published: October 2012

Haematopoietic stem cell transplantation (HSCT) can be a curative procedure for a growing number of paediatric diseases, but as the indications for HSCT grow, so does the need to find suitable stem cell donors. When the preferred option of a genoidentical sibling donor is not available alternative donors, including unrelated adult or umbilical cord blood donors, or haploidentical related donors may be considered. Outcome following alternative donor HSCT has improved over the past 20 years but graft-versus-host disease (GvHD) remains a significant obstacle. T cell depletion (TCD) for non-genoidentical grafts aims to reduce the morbidity and mortality associated with GvHD, but this intervention has not led directly to improved survival due to delayed immune reconstitution and increased infections, graft rejection and increased rates of disease relapse. Limited data from the paediatric population, however, suggest some encouraging results for children undergoing haploidentical HSCT: a move from positive selection of CD34+ haematopoietic stem cells towards negative depletion of specific cell subsets in order to retain useful accessory cells within the graft appears to enhance immune reconstitution and improve disease-free survival. Here we review recent paediatric outcome data for T cell-depleted HSCT, explore the role of serotherapy in conditioning regimens and look at future possibilities to improve outcome, including novel allodepletion techniques, suicide gene therapy and pathogen-specific immunotherapy.
Volume interpolated 3D‐spoiled gradient echo sequence is better than dynamic contrast spin echo sequence for MRI detection of corticotropin secreting pituitary microadenomas
Authors: Kasaliwal Rajeev , Sankhe Shilpa S. , Lila Anurag R. , Budyal Sweta R. , Jagtap Varsha S. , Sarathi Vijaya , Kakade Harshal , Bandgar Tushar , Menon Padmavathy S. , Shah Nalini S.
Published: October 2012

Background

Various techniques have been attempted to increase the yield of magnetic resonance imaging (MRI) for localization of pituitary microadenomas in corticotropin (ACTH)‐dependent Cushing's syndrome (CS).

Objective

To compare the performance of dynamic contrast spin echo (DC‐SE) and volume interpolated 3D‐spoiled gradient echo (VI‐SGE) MR sequences in the diagnostic evaluation of ACTH‐dependent CS.

Design

Data was analysed retrospectively from a series of ACTH‐dependent CS patients treated over 2‐year period at a tertiary care referral centre (2009–2011).

Patients

Thirty‐six patients (24 female and 12 male) were diagnosed to have ACTH‐dependent CS during the study period. All patients underwent MRI by both sequences during a single examination. Cases with negative and equivocal pituitary MR imaging underwent corticotropin‐releasing hormone (CRH) stimulated bilateral inferior petrosal sinus sampling (BIPSS) to confirm pituitary origin of ACTH excess state. Thirty patients were finally diagnosed to have Cushing's disease (CD) [based on histopathology proof of adenoma and/or remission (partial/complete) of hypercortisolism postsurgery]. Six patients were diagnosed to have histopathologically proven ectopic CS.

Results

Of 30 patients with CD, 24 patients had microadenomas and 6 patients had macroadenomas. DC‐SE MRI sequence was able to identify microadenomas in 16 of 24 patients, whereas postcontrast VI‐SGE sequence was able to identify microadenomas in 21 of 24 patients. All six patients of ectopic CS had negative pituitary MR imaging by both techniques (specificity: 100%).

Conclusion

VI‐SGE MR sequence was better for localization of pituitary microadenomas particularly when DC‐SE MR sequence is negative or equivocal and should be used in addition to DC‐SE MR sequence for the evaluation of ACTH‐dependent CS.
Variable magnitude of drug interaction between oral voriconazole and cyclosporine A in recipients of allogeneic hematopoietic stem cell transplantation
Authors: Kikuchi Taku , Mori Takehiko , Yamane Akiko , Kato Jun , Kohashi Sumiko , Okamoto Shinichiro
Published: October 2012

Drug interaction between voriconazole and calcineurin inhibitors is often problematic after allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. We previously demonstrated an unpredictable inter‐individual variability in the magnitude of this drug interaction; however, the route of drug administration was not taken into account. In this study, the drug interaction between voriconazole and calcineurin inhibitors was further analyzed under the condition that both agents were administered orally. Twenty adult recipients of HSCT who had already been on a steady dose of oral cyclosporine A (CsA) and were started on oral voriconazole (400 mg/d) were eligible. The changes in the concentration/dose (C/D) ratio of CsA were evaluated by comparing the trough concentrations of CsA measured before and 7–10 d after initiating voriconazole. The median C/D ratio of CsA increased significantly from 64.1 to 114.3 (ng/mL)/(mg/kg) after initiating voriconazole (p < 0.01), and the median increase was 83.0% (range, 0.3–224.7%). The plasma concentration of voriconazole did not correlate significantly with the increase of the C/D ratio (ρ = −0.18, p = 0.45). These results indicate that the magnitude of drug interaction between oral voriconazole and CsA is widely variable, and it could not be explained by the difference in the blood levels of voriconazole. Further studies are required to elucidate the mechanism for this variability.
Relevance of HLA compatibility in living donor liver transplantation: the double‐edged sword associated with the patient outcome
Authors: Uchiyama Hideaki , Kayashima Hiroto , Matono Rumi , Shirabe Ken , Yoshizumi Tomoharu , Ikegami Toru , Soejima Yuji , Matsuura Toshiharu , Taguchi Tomoaki , Maehara Yoshihiko
Published: October 2012

HLA compatibility in living donor liver transplantation (LDLT) seems relevant to the acceptability of graft livers because LDLT recipients often share most or some part of HLAs with the respective donors. This study retrospectively investigated whether HLA compatibility affected the outcome of LDLT. Three hundred ninety LDLTs were performed in this hospital, and 346 pairs of HLAs (HLA‐A, B, DR) were retrieved from the medical record between October 1996 and March 2011. The dates of the deaths were censored when a recipient apparently died of or was retransplanted by other causes than graft failure because of host‐versus‐graft (HVG) response to purely analyze the outcomes of LDLT in view of HVG response. The relationship between HLA compatibility and graft‐versus‐host disease (GVHD) was also analyzed. No recipients with recipient‐against‐donor HLA mismatch (R→D MM) 0 experienced graft failure by HVG response. On the other hand, three of five recipients with “R→D MM 0” together with “donor‐against‐recipient MM 3” died of fatal GVHD. HLA compatibility in LDLT not only affected the long‐term acceptance of graft livers but also the risk of fatal GVHD.
Delayed graft function requiring more than one‐time dialysis treatment is associated with inferior clinical outcomes
Authors: Jayaram Deepa , Kommareddi Mallika , Sung Randall S. , Luan Fu L.
Published: October 2012

Delayed graft function (DGF) is a common complication of deceased donor kidney transplantation with negative impact on clinical outcomes. In a single‐center retrospective analysis, we compared patient and kidney survival, early renal function, and the incidence of acute rejection during the first year among all adult deceased donor kidney transplant patients without DGF, with DGF requiring one‐time and/or more than one‐time dialysis treatment between January 1, 2000, and December 31, 2008. Of 831 adult kidney transplant patients, 74 (8.9%) required one‐time and 134 (16.1%) more than one‐time dialysis treatment post‐transplantation, respectively. While DGF patients with one‐time dialysis treatment had comparable clinical outcomes to that of patients without DGF, patients with DGF requiring more than one‐time dialysis treatment had a 45% increased risk for death (HR 1.45, 95% CI 1.02, 2.05, p = 0.04) after adjustment for the differences in demographic and baseline characteristics. Furthermore, DGF patients with more than one‐time dialysis requirement displayed significantly lower renal function after recovery (OR 0.32, 95% CI 0.21, 0.49, p < 0.001, for eGFR ≥ 60 mL/min) and higher incidence of acute rejection during the first year (OR 1.66, 95% CI 1.11, 2.49, p = 0.015). Additional studies of therapeutic approaches to manage patients with prolonged DGF are needed.
HIV‐associated primary cutaneous anaplastic large cell lymphoma: a clinicopathological subset with more aggressive behavior? Case report and review of the literature
Authors: Saggini Andrea , Anemona Lucia , Chimenti Sergio , Sarmati Loredana , Torti Claudia , Di Stefani Alessandro , Bianchi Luca
Published: October 2012

Human immunodeficiency virus (HIV)‐infected patients carry an increased risk of lymphomagenesis. Although the majority of HIV‐related lymphomas have a B‐cell phenotype, the incidence of peripheral T‐cell lymphomas (PTCL), including primary cutaneous subtypes, may be up to 15‐fold higher than in the general population, with anaplastic large cell lymphomas (ALCL) accounting for 18–28% of HIV‐associated PTCL. In contrast to systemic ALCL, the relation between HIV infection and primary cutaneous ALCL has been relatively neglected in the literature. We report the case of a primary cutaneous ALCL occurring in a 76‐year‐old patient with advanced HIV infection, and showing unusually aggressive course. Neither ALK1 immunohistochemical positivity nor evidence of EBV infection were detected; staging procedures at initial presentation ruled out systemic involvement. We provide a summary of the literature regarding primary cutaneous ALCL in HIV‐infected patients. We draw attention to clinicopathological features, prognostic implications and therapeutic quandaries of HIV‐related primary cutaneous ALCL. Further, we propose that a significant fraction of HIV‐associated cases might represent a more aggressive subset of primary cutaneous ALCL.
Early environment, early feeding, and later development: should milk formula be supplemented with polyunsaturated fatty acids?
Authors: VIK TORSTEIN
Published: October 2012

This commentary is on the original article by de Jong et al. on pages 1102–1108 of this issue.
Effects of rifampin and mefenamic acid on the pharmacokinetics and pharmacodynamics of dapagliflozin
Authors: Kasichayanula S. , Liu X. , Griffen S. C. , LaCreta F. P. , Boulton D. W.
Published: October 2012

Aims

Dapagliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that decreases serum glucose by reducing renal glucose reabsorption, thereby promoting urinary glucose excretion. Dapagliflozin is primarily metabolized via the uridine diphosphate‐glucuronosyltransferase (UGT)1A9 pathway to its major inactive metabolite, dapagliflozin 3‐O‐glucuronide. The aim of this study was to evaluate the potential for drug‐drug interaction between dapagliflozin and two potential UGT1A9 modulators.

Methods

The results of two open‐label, non‐randomized, single‐sequence studies are reported in which the effects of rifampin (a pleiotropic drug‐metabolizing enzyme inducer; study 1) and mefenamic acid (a strong UGT1A9 inhibitor; study 2) were evaluated on the pharmacokinetics and pharmacodynamics (assessed by urinary glucose excretion [UGE]) of dapagliflozin in healthy subjects. In study 1, 14 subjects received single doses of dapagliflozin 10 mg alone and in the presence of rifampin 600 mg QD (6 days). In study 2, 16 subjects received single doses of dapagliflozin 10 mg alone and in the presence of mefenamic acid 250 mg q6h (5 days).

Results

Rifampin reduced total exposure (area under the concentration‐time curve from time 0 to infinity [AUC0‐inf]) to dapagliflozin by 22% and mefenamic acid increased dapagliflozin AUC0‐inf by 51%. No clinically meaningful effect of rifampin or mefenamic acid on the pharmacokinetics of dapagliflozin or on dapagliflozin‐mediated urinary glucose excretion was observed.

Conclusion

Modest changes in dapagliflozin exposure were seen with rifampin and mefenamic acid with minor changes in UGE, none of which were considered clinically meaningful.
A novel mutation in the albumin gene (c.1A>C) resulting in analbuminemia
Authors: Caridi Gianluca , Dagnino Monica , Lugani Francesca , Shalev Stavit A. , Campagnoli Monica , Galliano Monica , Spiegel Ronen , Minchiotti Lorenzo
Published: October 2012

Eur J Clin Invest 2012

Background  Analbuminemia (OMIM # 103600) is a rare autosomal recessive disorder manifested by the absence or severe reduction of circulating serum albumin in homozygous or compound heterozygous subjects. The trait is caused by a variety of mutations within the albumin gene.

Design  We report here the clinical and molecular characterisation of two new cases of congenital analbuminemia diagnosed in two members of the Druze population living in a Galilean village (Northern Israel) on the basis of their low level of circulating albumin. The albumin gene was screened by single‐strand conformation polymorphism and heteroduplex analysis, and the mutated region was submitted to DNA sequencing.

Results  Both the analbuminemic subjects resulted homozygous for a previously unreported c.1 A>C transversion, for which we suggest the name Afula from the hospital where the two cases were investigated. This mutation causes the loss of the primary start codon ATG for Met1, which is replaced by a – then untranslated – triplet CTG for Leu. (p.Met1Leu). The use of an alternative downstream ATG codon would probably give rise to a completely aberrant polypeptide chain, leading to a misrouted intracellular transport and a premature degradation.

Conclusions  The discovery of this new ALB mutation, probably inherited from a common ancestor, sheds light on the molecular mechanism underlying the analbuminemic trait and may serve in the development of a rapid genetic test for the identification of a‐symptomatic heterozygous carriers in the Druze population in the Galilee.
Chondroitinase ABC promotes compensatory sprouting of the intact corticospinal tract and recovery of forelimb function following unilateral pyramidotomy in adult mice
Authors: Starkey Michelle L. , Bartus Katalin , Barritt Andrew W. , Bradbury Elizabeth J.
Published: October 2012

Chondroitin sulphate proteoglycans (CSPGs) are extracellular matrix molecules whose inhibitory activity is attenuated by the enzyme chondroitinase ABC (ChABC). Here we assess whether CSPG degradation can promote compensatory sprouting of the intact corticospinal tract (CST) following unilateral injury and restore function to the denervated forelimb. Adult C57BL/6 mice underwent unilateral pyramidotomy and treatment with either ChABC or a vehicle control. Significant impairments in forepaw symmetry were observed following pyramidotomy, with injured mice preferentially using their intact paw during spontaneous vertical exploration of a cylinder. No recovery on this task was observed in vehicle‐treated mice. However, ChABC‐treated mice showed a marked recovery of function, with forelimb symmetry fully restored by 5 weeks post‐injury. Functional recovery was associated with robust sprouting of the uninjured CST, with numerous axons observed crossing the midline in the brainstem and spinal cord and terminating in denervated grey matter. CST fibres in the denervated side of the spinal cord following ChABC treatment were closely associated with the synaptic marker vGlut1. Immunohistochemical assessment of chondroitin‐4‐sulphate revealed that CSPGs were heavily digested around lamina X, alongside midline crossing axons and in grey matter regions where sprouting axons and reduced peri‐neuronal net staining was observed. Thus, we demonstrate that CSPG degradation promotes midline crossing and reinnervation of denervated target regions by intact CST axons and leads to restored function in the denervated forepaw. Enhancing compensatory sprouting using ChABC provides a route to restore function that could be applied to disorders such as spinal cord injury and stroke.
Effects of delayed‐onset muscle soreness on masticatory function
Authors: Yoshida Eiko , Lobbezoo Frank , Fueki Kenji , Naeije Machiel
Published: October 2012

The aim was to clarify the effects of experimentally provoked delayed‐onset muscle soreness (DOMS) in the jaw‐closing muscles on subjective and objective measures of masticatory function. Twenty‐one dentate female subjects, without pain‐related signs and symptoms of temporomandibular disorders, participated. Delayed‐onset muscle soreness was provoked with eccentric and concentric contractions of the jaw‐closing muscles using a custom‐made apparatus. At baseline, and 24 h and 1 wk after the exercises, data were gathered on the subjective measures of muscle fatigue, muscle pain, and masticatory chewing ability using visual analogue scale (VAS) scores, on the maximum voluntary bite force (MVBF), and on the food Mixing Ability Index (MAI). After 24 h, muscle fatigue and muscle pain had increased and the MAI had decreased. All had returned to baseline levels after 1 wk. There were no significant changes found in the chewing ability VAS scores and in the MVBF over time. After correction for its baseline value, the MAI after 24 h was found to be significantly related to the muscle pain after 24 h. In conclusion, DOMS in the jaw‐closing muscles can cause a decrease in the objectively scored chewing ability, while the subjectively scored chewing ability remained the same.
UCHL1 regulates ubiquitination and recycling of the neural cell adhesion molecule NCAM
Authors: Wobst Hilke , Förster Sarah , Laurini Christine , Sekulla Agathe , Dreiseidler Michael , Höhfeld Jörg , Schmitz Brigitte , Diestel Simone
Published: October 2012

The neural cell adhesion molecule (NCAM) is involved in neural development and in plasticity in the adult brain. NCAM140 and NCAM180 isoforms are transmembrane proteins with cytoplasmic domains that differ only in an alternatively spliced exon in the NCAM180 isoform. Both isoforms can interact with several extracellular and cytoplasmic molecules mediating NCAM‐dependent functions. Most identified intracellular interaction partners bind to both isoforms, NCAM140 and NCAM180. To identify further intracellular interaction partners specifically binding to NCAM180 the cytosolic domain of human NCAM180 was recombinantly expressed and applied onto a protein macroarray containing the protein library from human fetal brain. We identified the ubiquitin C‐terminal hydrolase (UCHL1) which has been described as a de‐ubiquitinating enzyme as a potential interaction partner of NCAM180. Since NCAM180 and NCAM140 are ubiquitinated, NCAM140 was included in the subsequent experiments. A partial colocalization of both NCAM isoforms and UCHL1 was observed in primary neurons and the B35 neuroblastoma cell line. Overexpression of UCHL1 significantly decreased constitutive ubiquitination of NCAM180 and NCAM140 whereas inhibition of endogenous UCHL1 increased NCAM's ubiquitination. Furthermore, lysosomal localization of NCAM180 and NCAM140 was significantly reduced after overexpression of UCHL1 consistent with a partial colocalization of internalized NCAM with UCHL1. These data indicate that UCHL1 is a novel interaction partner of both NCAM isoforms that regulates their ubiquitination and intracellular trafficking.

Structured digital abstract

NCAM1 binds to UCHL1 by protein array (View interaction)

Uchl1 and NCAM180 colocalize by fluorescence microscopy (View interaction)

Uchl1 and NCAM1 colocalize by fluorescence microscopy (View interaction)

Uchl1 and NCAM140 colocalize by fluorescence microscopy (View interaction)
Electron transport during aceticlastic methanogenesis by Methanosarcina acetivorans involves a sodium‐translocating Rnf complex
Authors: Schlegel Katharina , Welte Cornelia , Deppenmeier Uwe , Müller Volker
Published: October 2012

The anaerobic methanogenic archaeon Methanosarcina acetivorans lives under extreme energy limitation. Methanogenesis from acetate as carried out by M. acetivorans involves an anaerobic electron transport chain with ferredoxin as electron donor and heterodisulfide as electron acceptor, and so far only the heterodisulfide reductase has been shown to translocate H+. Here, we describe a second Na+‐translocating coupling site in this electron transport chain. Inside‐out membrane vesicles of M. acetivorans catalyzed Na+ transport coupled to an electron transport catalyzed by the ferredoxin:heterodisulfide oxidoreductase activity. Ionophore studies revealed that Na+ transport was primary and electrogenic. A ∆rnf mutant was unable to grow on acetate and the ferredoxin:heterodisulfide oxidoreductase‐coupled Na+ transport was abolished. These data are consistent with the hypothesis that the Rnf complex of M. acetivorans is an Na+‐translocating coupling site and the entry point of electrons derived from reduced ferredoxin into the electron transport chain leading to the heterodisulfide.
Internet‐based lay person rating of facial photographs to assess effects of a cleansing product and a decent cosmetic foundation on the attractiveness of female faces
Authors: Bielfeldt S. , Henss R. , Koop U. , Degwert J. , Heinrich U. , Jassoy C. , Meyer J. , Tronnier H. , Jentzsch A. , Blume G.
Published: October 2012

Synopsis

It is well established that decorative cosmetics can enhance female facial attractiveness. In this study, we investigated the effects of a cleanser and a decent foundation on attractiveness of female faces. Comparative rating of a set of facial photographs by a group of lay persons revealed that the cleansing product was significantly reducing the attractiveness of the stimulus persons. Treatment with the foundation increased the attractiveness of the female faces clearly. The authors conclude that even unobtrusive cosmetic treatments like cleansers and light foundations may cause relevant changes of the attractiveness of female faces.
TRBV kinetics and its association with HLA disparity and aGVHD following allogeneic hematopoietic stem cell transplantation
Authors: Sun L. , Ren H. , Liu W. , Wang L. , Yin Y. , Li Y. , Ma X. , Qiu Z. , Cen X. , Shi Y.
Published: October 2012

Introduction

The relative expression of T cell receptor (TCR) beta variable (TRBV) and TCR diversity was compared between recipients receiving human leukocyte antigen (HLA)‐mismatched transplants and those receiving HLA‐matched transplants, using granulocyte colony‐stimulating factor (G‐CSF)‐mobilized peripheral blood stem cells and bone marrow as grafts.

Methods

The kinetics of the relative expression of TRBV family members were analyzed using real‐time quantitative PCR. Additionally, the association of TRBV clonotype with acute graft‐versus‐host disease (aGVHD) was determined by cloning and sequence analysis of the CDR3 region.

Results

The TCR diversity in recipients receiving HLA‐mismatched transplants was significantly lower than in those receiving HLA‐matched transplants at 1 month and 2 months after hematopoietic stem cell transplantation (HSCT) (both P < 0.05). However, these differences disappeared 3 months after transplantation. The relative expression of TRBV27 (n = 7 recipients) at the onset of aGVHD was higher than in corresponding donors (P = 0.025), but no significant differences were observed between recipients lacking aGVHD and their donors at serial time points after HSCT.

Conclusion

Our results suggest that HLA disparity may affect the relative expression of TRBV in the early phase after transplantation, and TRBV27 may be associated with the onset of aGVHD.
Evaluation of various laboratory assays in detection of heparin‐induced thrombocytopenia in an adult general ICU
Authors: Kapadia F. N. , Ketkar A. S. , Deshpande A. S. , Puri V. C. , Khodaiji S. J.
Published: October 2012

Introduction

Heparin‐induced thrombocytopenia (HIT) is an immune‐mediated complication of heparin therapy. Our objective was (i) to compare various laboratory assays for HIT against clinical probability (4‐T score) and 14C‐serotonin release assay (SRA), which was the composite gold standard and (ii) to determine the incidence of HIT in the ICU.

Methods

The study group (n = 217) consisted of consecutive ICU patients with heparin exposure followed by thrombocytopenia. The clinical probability (4‐T score) was applied to the study group. Enzyme‐linked immunosorbent assay (ELISA), particle gel immunoassay (PGIA), SRA, and platelet aggregation assay (PAA) were performed.

Results

The 4‐T score showed that 1/217 patients had high probability, 48 had intermediate probability, and 168 had low probability for HIT. One patient was positive by SRA, three by PGIA, and 33 by ELISA. The incidence based on a combination of clinical features and laboratory findings was 1.8%.

Conclusions

A greater number of false positives were observed by ELISA than by PGIA when compared to a composite gold standard of SRA and clinical probability. The incidence of SRA‐positive HIT was 0.46% (1/217).
Excessive EDTA induces morphologic changes in bone marrow smears that mimic specific features of dysplasia
Authors: Lee S.‐H. , van der Weyden C. , Mayson E. , Desai S.
Published: October 2012

Introduction

The WHO 2008 guidelines recommend that bone marrow (BM) slides for the morphological assessment of dysplasia should be made from freshly obtained BM specimens, and that specimens exposed to anticoagulants for more than two hours are unsatisfactory. However, BM aspirates may be exposed to excessive concentrations of anticoagulant, due to underfilling of the tube or inadequate mixing of the specimen. Here, we document the morphologic changes in BM smears resulting from exposure to excessive concentrations of ethylenediaminetetraacetic acid (EDTA).

Methods

Subjects with normal morphology in BM smears without anticoagulant were studied. Smears without anticoagulant and smears made from BM stored in excessive EDTA for 2 h at room temperature were stained with May–Grünwald Giemsa, and cell morphology was evaluated microscopically. Neutrophil and megakaryocyte size were measured using a calibrated microscope eyepiece graticule.

Results

Excessive EDTA concentrations induced progressive nuclear and cytoplasmic contraction with respective membrane damage, cell smudging and pyknotic nuclei. In the granulocytic and megakaryocytic series, hypolobated neutrophils, small neutrophils and micromegakaryocytes were increased in number. In erythroblasts, nuclear contour irregularities were induced, but in general, artifactual changes did not mimic dyserythropoiesis. With excessive EDTA concentrations, morphologic features of erythroblasts and megakaryocytes were obscured by nuclear and cytoplasmic contraction.

Conclusion

Excessive EDTA induces morphologic changes in BM smears that mimic the specific dysplastic features of hypolobated neutrophils, small neutrophils, and micromegakaryocytes. BM aspirates should be collected into an appropriate concentration of EDTA to minimize such artifacts.
The lunar cycle determines availability of coral‐reef fishes at fish markets
Authors: Bos A. R. , Gumanao G. S.
Published: October 2012

During 139 visits between March 2009 and May 2011, it was found that the availability of reef fishes at a local fish market in the Philippines was highly affected by the lunar cycle. The number of vendors selling reef fishes was significantly lower (13·4%) during third lunar quarters (full moon periods) than during the first, second and fourth lunar quarters (40·2, 25·0 and 30·0%, respectively). It is recommended that the influence of the lunar cycle on fish availability is considered when designing sampling strategies for catch surveys.
3D geophysical inversions of the north‐east Amer Belt and their relationship to the geologic structure
Authors: Tschirhart V. , Morris W.A. , Jefferson C.W. , Keating P. , White J.C. , Calhoun L.
Published: October 2012

The Amer Lake area is located within the Churchill Structural Province in the Kivalliq Region of Nunavut, approximately 160 km north‐west of Baker Lake. Two distinct geophysical‐geological entities are structurally intercalated: an Archean mixed granitoid gneiss – metasedimentary‐metavolcanic basement and the unconformably overlying Paleoproterozoic Amer Group metasediments. From east of Amer Lake stretching toward the south‐west, these two entities form the Amer fold and thrust belt. At the north‐east end of this belt, high‐resolution aeromagnetic data define a distinctive oval shape that has been interpreted as a south‐west trending doubly plunging synform. The outcrop within the interior of this structure is sparse resulting in limited structural data and speculative geological interpretations with multiple geometries possible. The high‐resolution aeromagnetic data compiled through an industry‐government consortium and newly acquired detailed gravity profiles were modelled to provide constraints on the geometry of this synform.

We document a geophysical‐geological feedback process whereby the available geological and geophysical data were used to derive constraints on inversion models for the synform. Starting with available limited litho‐structural data the presence of a double plunging synform was directly inferred from the aeromagnetic data. Segments of the aeromagnetic data have 2D morphology and so can be modelled using a simple parametric 2D dipping slab inversion approach. Models of profiles extracted from the aeromagnetic data were used to provide preliminary dip and magnetic susceptibility constraints for the Three Lakes mudstone with iron formation and the Five Mile Lake basalt. Landsat imagery outlined the spatial limits of the stratigraphically underlying, non‐magnetic Ayagaq quartzite. Incorporating these outputs as bounds in the input / reference model for a UBC‐GIF 3D magnetic inversion helped to accentuate the geological structure in the output mesh: an enhanced inversion that incorporates both geological and geophysical constraints. The validity of the resulting inversion model was tested by computing 2D forward models of the gravity profile data. The inversion model generated by this study emphasizes the importance of integrating information from as many knowledge sources as one can find. More trust can be placed on forward and inversion models where there is agreement among all data sets and a coherency of structural style.
Building starting models for full waveform inversion from wide‐aperture data by stereotomography
Authors: Prieux Vincent , Lambaré Gilles , Operto Stéphane , Virieux Jean
Published: October 2012

Building an accurate initial velocity model for full waveform inversion (FWI) is a key issue to guarantee convergence of full waveform inversion towards the global minimum of a misfit function. In this study, we assess joint refraction and reflection stereotomography as a tool to build a reliable starting model for frequency‐domain full waveform inversion from long‐offset (i.e., wide‐aperture) data. Stereotomography is a slope tomographic method that is based on the inversion of traveltimes and slopes of locally‐coherent events in a data cube. One advantage of stereotomography compared to conventional traveltime reflection tomography is the semi‐automatic picking procedure of locally‐coherent events, which is easier than the picking of continuous events, and can lead to a higher density of picks. While conventional applications of stereotomography only consider short‐offset reflected waves, we assess the benefits provided by the joint inversion of reflected and refracted arrivals. Introduction of the refracted waves allows the construction of a starting model that kinematically fits the first arrivals, a necessary requirement for full waveform inversion. In a similar way to frequency‐domain full waveform inversion, we design a multiscale approach of stereotomography, which proceeds hierarchically from the wide‐aperture to the short‐aperture components of the data, to reduce the non‐linearity of the stereotomographic inversion of long‐offset data. This workflow which combines stereotomography and full waveform inversion, is applied to synthetic and real data case studies for the Valhall oil‐field target. The synthetic results show that the joint refraction and reflection stereotomography for a 24‐km maximum offset data set provides a more reliable initial model for full waveform inversion than reflection stereotomography performed for a 4‐km maximum offset data set, in particular in low‐velocity gas layers and in the deep part of a structure below a reservoir. Application of joint stereotomography, full waveform inversion and reverse‐time migration to real data reveals that the FWI models and the reverse‐time migration images computed from the stereotomography model shares several features with FWI velocity models and migrated images computed from an anisotropic reflection‐traveltime tomography model, although stereotomography was performed in the isotropic approximation. Implementation of anisotropy in joint refraction and reflection stereotomography of long‐offset data is a key issue to further improve the accuracy of the method.
Moveout approximation for vertical seismic profile geometry in a 2D model with anisotropic layers
Authors: Blias Emil
Published: October 2012

I introduce a new explicit form of vertical seismic profile (VSP) traveltime approximation for a 2D model with non‐horizontal boundaries and anisotropic layers. The goal of the new approximation is to dramatically decrease the cost of time calculations by reducing the number of calculated rays in a complex multi‐layered anisotropic model for VSP walkaway data with many sources. This traveltime approximation extends the generalized moveout approximation proposed by Fomel and Stovas. The new equation is designed for borehole seismic geometry where the receivers are placed in a well while the sources are on the surface. For this, the time‐offset function is presented as a sum of odd and even functions. Coefficients in this approximation are determined by calculating the traveltime and its first‐ and second‐order derivatives at five specific rays. Once these coefficients are determined, the traveltimes at other rays are calculated by this approximation. Testing this new approximation on a 2D anisotropic model with dipping boundaries shows its very high accuracy for offsets three times the reflector depths. The new approximation can be used for 2D anisotropic models with tilted symmetry axes for practical VSP geometry calculations. The new explicit approximation eliminates the need of massive ray tracing in a complicated velocity model for multi‐source VSP surveys. This method is designed not for NMO correction but for replacing conventional ray tracing for time calculations.
Convergence improvement and noise attenuation considerations for beyond alias projection onto convex sets reconstruction
Authors: Gao Jianjun , Stanton Aaron , Naghizadeh Mostafa , Sacchi Mauricio D. , Chen Xiaohong
Published: October 2012

A reconstruction method known as Projection Onto Convex Sets (POCS) is an effective, uncomplicated and robust method for the recovery of irregularly missing seismic traces. However, slow convergence of the POCS reconstruction method could jeopardize its computational appeal. For this reason, we investigate the performance of the POCS reconstruction method in terms of different threshold schedules and present a new data driven threshold that leads to an efficient implementation of the POCS method. In particular, we show that high quality solutions can be obtained in a few iterations. In addition, we address an important issue with the classical implementations of POCS reconstruction in that they cannot interpolate regularly missing data. To solve this problem, we introduce a masking operator that is based on a dominant dip scanning method into the POCS iteration. At the end, we present a variant of the POCS method that permits de‐noising seismic volumes during the reconstruction stage. This is achieved by defining a weighted trace re‐insertion strategy that alleviates the influence of noisy traces in the final reconstruction of the seismic volume. We show the effectiveness of the proposed method using synthetic and field data.
Species‐rich dung beetle communities buffer ecosystem services in perturbed agro‐ecosystems
Authors: Beynon Sarah A. , Mann Darren J. , Slade Eleanor M. , Lewis Owen T.
Published: October 2012

Many studies document high levels of functional redundancy in ecosystems, suggesting that species extinctions will not be detrimental to ecosystem functions and services. However, apparently redundant taxa may prove critical for sustaining ecosystem functions and services in the context of environmental perturbations.

Dung beetles (Coleoptera:Scarabaeidae) provide a valuable ecosystem service in temperate agro‐ecosystems by increasing rates of dung decomposition and nutrient cycling. However, there is concern that these services may be negatively affected by changes in species richness and composition due to changes in pasture management and negative effects of anthelmintics used to control livestock parasites.

We used a mesocosm experiment to investigate the functional importance of dung beetle species richness in a system perturbed by the anthelmintic, ivermectin. We varied dung beetle species richness within three functional groups in factorial combination with ivermectin treatment.

In the short term (1–4 weeks), multi‐species dung beetle assemblages achieved higher decomposition rates than monocultures, but only in ivermectin‐treated dung. Varying species‐specific sensitivities to ivermectin meant that species‐rich assemblages sustained ecosystem functioning in the context of this anthropogenic perturbation.

Over the longer term (36 weeks), there was a significant, positive effect of species richness on dung decomposition in both ivermectin‐treated and untreated dung, underlining the functional importance of maintaining a species‐rich dung processing community even in the absence of perturbations to the system.

Synthesis and applications. The interacting effects of dung beetle species richness and ivermectin highlight the importance of maintaining diverse assemblages in the face of anthropogenic perturbations and suggest that apparent functional redundancy of species in agro‐ecosystems should be interpreted cautiously. Furthermore, different farm management practices (e.g. pesticide use and fragmentation of habitats) may have consequences for ecosystem functions and services that exceed the effects of each when considered in isolation.