bluuebunny/crossref_metadata_2025 huggingface dataset:
Clusters of bioactive compounds target dynamic endomembrane networks in vivo
Authors: Drakakaki Georgia , Robert Stéphanie , Szatmari Anna-Maria , Brown Michelle Q. , Nagawa Shingo , Van Damme Daniel , Leonard Marilyn , Yang Zhenbiao , Girke Thomas , Schmid Sandra L. , Russinova Eugenia , Friml Jiří , Raikhel Natasha V. , Hicks Glenn R.
Published: October 2011

Endomembrane trafficking relies on the coordination of a highly complex, dynamic network of intracellular vesicles. Understanding the network will require a dissection of cargo and vesicle dynamics at the cellular level in vivo. This is also a key to establishing a link between vesicular networks and their functional roles in development. We used a high-content intracellular screen to discover small molecules targeting endomembrane trafficking in vivo in a complex eukaryote,
Arabidopsis thaliana
. Tens of thousands of molecules were prescreened and a selected subset was interrogated against a panel of plasma membrane (PM) and other endomembrane compartment markers to identify molecules that altered vesicle trafficking. The extensive image dataset was transformed by a flexible algorithm into a marker-by-phenotype-by-treatment time matrix and revealed groups of molecules that induced similar subcellular fingerprints (clusters). This matrix provides a platform for a systems view of trafficking. Molecules from distinct clusters presented avenues and enabled an entry point to dissect recycling at the PM, vacuolar sorting, and cell-plate maturation. Bioactivity in human cells indicated the value of the approach to identifying small molecules that are active in diverse organisms for biology and drug discovery.
Solution X-ray scattering combined with computational modeling reveals multiple conformations of covalently bound ubiquitin on PCNA
Authors: Tsutakawa Susan E. , Van Wynsberghe Adam W. , Freudenthal Bret D. , Weinacht Christopher P. , Gakhar Lokesh , Washington M. Todd , Zhuang Zhihao , Tainer John A. , Ivanov Ivaylo
Published: October 2011

PCNA ubiquitination in response to DNA damage leads to the recruitment of specialized translesion polymerases to the damage locus. This constitutes one of the initial steps in translesion synthesis (TLS)—a critical pathway for cell survival and for maintenance of genome stability. The recent crystal structure of ubiquitinated PCNA (Ub–PCNA) sheds light on the mode of association between the two proteins but also revealed that paradoxically, the ubiquitin surface engaged in PCNA interactions was the same as the surface implicated in translesion polymerase binding. This finding implied a degree of flexibility inherent in the Ub–PCNA complex that would allow it to transition into a conformation competent to bind the TLS polymerase. To address the issue of segmental flexibility, we combined multiscale computational modeling and small angle X-ray scattering. This combined strategy revealed alternative positions for ubiquitin to reside on the surface of the PCNA homotrimer, distinct from the position identified in the crystal structure. Two mutations originally identified in genetic screens and known to interfere with TLS are positioned directly beneath the bound ubiquitin in the alternative models. These computationally derived positions, in an ensemble with the crystallographic and flexible positions, provided the best fit to the solution scattering, indicating that ubiquitin dynamically associated with PCNA and is capable of transitioning between a few discrete sites on the PCNA surface. The finding of new docking sites and the positional equilibrium of PCNA–Ub occurring in solution provide unexpected insight into previously unexplained biological observations.
Oxygen modulation of neurovascular coupling in the retina
Authors: Mishra Anusha , Hamid Arif , Newman Eric A.
Published: October 2011

Neurovascular coupling is a process through which neuronal activity leads to local increases in blood flow in the central nervous system. In brain slices, 100% O
2
has been shown to alter neurovascular coupling, suppressing activity-dependent vasodilation. However, in vivo, hyperoxia reportedly has no effect on blood flow. Resolving these conflicting findings is important, given that hyperoxia is often used in the clinic in the treatment of both adults and neonates, and a reduction in neurovascular coupling could deprive active neurons of adequate nutrients. Here we address this issue by examining neurovascular coupling in both ex vivo and in vivo rat retina preparations. In the ex vivo retina, 100% O
2
reduced light-evoked arteriole vasodilations by 3.9-fold and increased vasoconstrictions by 2.6-fold. In vivo, however, hyperoxia had no effect on light-evoked arteriole dilations or blood velocity. Oxygen electrode measurements showed that 100% O
2
raised pO
2
in the ex vivo retina from 34 to 548 mm Hg, whereas hyperoxia has been reported to increase retinal pO
2
in vivo to only ∼53 mm Hg [Yu DY, Cringle SJ, Alder VA, Su EN (1994)
Am J Physiol
267:H2498-H2507]. Replicating the hyperoxic in vivo pO
2
of 53 mm Hg in the ex vivo retina did not alter vasomotor responses, indicating that although O
2
can modulate neurovascular coupling when raised sufficiently high, the hyperoxia-induced rise in retinal pO
2
in vivo is not sufficient to produce a modulatory effect. Our findings demonstrate that hyperoxia does not alter neurovascular coupling in vivo, ensuring that active neurons receive an adequate supply of nutrients.
Ischemia-induced calpain activation causes eukaryotic (translation) initiation factor 4G1 (eIF4GI) degradation, protein synthesis inhibition, and neuronal death
Authors: Vosler Peter S. , Gao Yanqin , Brennan Christopher S. , Yanagiya Akiko , Gan Yu , Cao Guodong , Zhang Feng , Morley Simon J. , Sonenberg Nahum , Bennett Michael V. L. , Chen Jun
Published: October 2011

Persistent protein synthesis inhibition (PSI) is a robust predictor of eventual neuronal death following cerebral ischemia. We thus tested the hypothesis that persistent PSI inhibition and neuronal death are causally linked. Neuronal viability strongly correlated with both protein synthesis and levels of eukaryotic (translation) initiation factor 4G1 (eIF4G1). We determined that in vitro ischemia activated calpain, which degraded eIF4G1. Overexpression of the calpain inhibitor calpastatin or eIF4G1 resulted in increased protein synthesis and increased neuronal viability compared with controls. The neuroprotective effect of eIF4G1 overexpression was due to restoration of cap-dependent protein synthesis, as well as protein synthesis-independent mechanisms, as inhibition of protein synthesis with cycloheximide did not completely prevent the protective effect of eIF4G1 overexpression. In contrast, shRNA-mediated silencing of eIF4G1 exacerbated ischemia-induced neuronal injury, suggesting eIF4G1 is necessary for maintenance of neuronal viability. Finally, calpain inhibition following global ischemia in vivo blocked decreases in eIF4G1, facilitated protein synthesis, and increased neuronal viability in ischemia-vulnerable hippocampal CA1 neurons. Collectively, these data demonstrate that calpain-mediated degradation of a translation initiation factor, eIF4G1, is a cause of both persistent PSI and neuronal death.
A soluble α-synuclein construct forms a dynamic tetramer
Authors: Wang Wei , Perovic Iva , Chittuluru Johnathan , Kaganovich Alice , Nguyen Linh T. T. , Liao Jingling , Auclair Jared R. , Johnson Derrick , Landeru Anuradha , Simorellis Alana K. , Ju Shulin , Cookson Mark R. , Asturias Francisco J. , Agar Jeffrey N. , Webb Brian N. , Kang ChulHee , Ringe Dagmar , Petsko Gregory A. , Pochapsky Thomas C. , Hoang Quyen Q.
Published: October 2011

A heterologously expressed form of the human Parkinson disease-associated protein α-synuclein with a 10-residue N-terminal extension is shown to form a stable tetramer in the absence of lipid bilayers or micelles. Sequential NMR assignments, intramonomer nuclear Overhauser effects, and circular dichroism spectra are consistent with transient formation of α-helices in the first 100 N-terminal residues of the 140-residue α-synuclein sequence. Total phosphorus analysis indicates that phospholipids are not associated with the tetramer as isolated, and chemical cross-linking experiments confirm that the tetramer is the highest-order oligomer present at NMR sample concentrations. Image reconstruction from electron micrographs indicates that a symmetric oligomer is present, with three- or fourfold symmetry. Thermal unfolding experiments indicate that a hydrophobic core is present in the tetramer. A dynamic model for the tetramer structure is proposed, based on expected close association of the amphipathic central helices observed in the previously described micelle-associated “hairpin” structure of α-synuclein.
Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma
Authors: Wang Nicholas J. , Sanborn Zachary , Arnett Kelly L. , Bayston Laura J. , Liao Wilson , Proby Charlotte M. , Leigh Irene M. , Collisson Eric A. , Gordon Patricia B. , Jakkula Lakshmi , Pennypacker Sally , Zou Yong , Sharma Mimansa , North Jeffrey P. , Vemula Swapna S. , Mauro Theodora M. , Neuhaus Isaac M. , LeBoit Philip E. , Hur Joe S. , Park Kyunghee , Huh Nam , Kwok Pui-Yan , Arron Sarah T. , Massion Pierre P. , Bale Allen E. , Haussler David , Cleaver James E. , Gray Joe W. , Spellman Paul T. , South Andrew P. , Aster Jon C. , Blacklow Stephen C. , Cho Raymond J.
Published: October 2011

Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than
TP53
mutations, few causative somatic aberrations have been identified. We identified
NOTCH1
or
NOTCH2
mutations in ∼75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression.
NOTCH
aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in
NOTCH1
commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.
How Kondo-holes create intense nanoscale heavy-fermion hybridization disorder
Authors: Hamidian Mohammad H. , Schmidt Andrew R. , Firmo Inês A. , Allan Milan P. , Bradley Phelim , Garrett Jim D. , Williams Travis J. , Luke Graeme M. , Dubi Yonatan , Balatsky Alexander V. , Davis J. C.
Published: October 2011

Replacing a magnetic atom by a spinless atom in a heavy-fermion compound generates a quantum state often referred to as a “Kondo-hole”. No experimental imaging has been achieved of the atomic-scale electronic structure of a Kondo-hole, or of their destructive impact [Lawrence JM, et al. (1996)
Phys Rev B
53:12559–12562] [Bauer ED, et al. (2011)
Proc Natl Acad Sci
. 108:6857–6861] on the hybridization process between conduction and localized electrons which generates the heavy-fermion state. Here we report visualization of the electronic structure at Kondo-holes created by substituting spinless thorium atoms for magnetic uranium atoms in the heavy-fermion system URu
2
Si
2
. At each thorium atom, an electronic bound state is observed. Moreover, surrounding each thorium atom we find the unusual modulations of hybridization strength recently predicted to occur at Kondo-holes [Figgins J, Morr DK (2011)
Phys Rev Lett
107:066401]. Then, by introducing the “hybridization gapmap” technique to heavy-fermion studies, we discover intense nanoscale heterogeneity of hybridization due to a combination of the randomness of Kondo-hole sites and the long-range nature of the hybridization oscillations. These observations provide direct insight into both the microscopic processes of heavy-fermion forming hybridization and the macroscopic effects of Kondo-hole doping.
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing
Authors: Walsh Tom , Casadei Silvia , Lee Ming K. , Pennil Christopher C. , Nord Alex S. , Thornton Anne M. , Roeb Wendy , Agnew Kathy J. , Stray Sunday M. , Wickramanayake Anneka , Norquist Barbara , Pennington Kathryn P. , Garcia Rochelle L. , King Mary-Claire , Swisher Elizabeth M.
Published: October 2011

Inherited loss-of-function mutations in
BRCA1
and
BRCA2
and other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due to inherited mutations is not known. Using targeted capture and massively parallel genomic sequencing, we screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma. Subjects were consecutively enrolled at diagnosis and not selected for age or family history. All classes of mutations, including point mutations and large genomic deletions and insertions, were detected. Of 360 subjects, 24% carried germ-line loss-of-function mutations: 18% in
BRCA1
or
BRCA2
and 6% in
BARD1
,
BRIP1
,
CHEK2
,
MRE11A
,
MSH6
,
NBN
,
PALB2
,
RAD50
,
RAD51C
, or
TP53
. Six of these genes were not previously implicated in inherited ovarian carcinoma. Primary carcinomas were generally characterized by genomic loss of normal alleles of the mutant genes. Of women with inherited mutations, >30% had no family history of breast or ovarian carcinoma, and >35% were 60 y or older at diagnosis. More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost.
The Steward Street School experiment: a critical case study of possibilities
Authors: Burke Catherine , Grosvenor Ian
Published: October 2011

This article presents a critical case study of an inner city state school that for a decade (1940s–1950s) attracted the interest of a wide contingency of educationalists, policy makers, researchers, artists and various press and film media. It has been argued that if we are to progress ‘social alternatives’ in education, researchers need to construct ‘critical case studies of possibilities’ drawing inspiration from traces of experimental and utopian practice in schools from the past as well as the present. The article demonstrates how this might be achieved through research that questions dominant narratives, goes beyond the public accounts of particular sites of experimentation and explores multiple‐narratives embedded in the records of past practice. The authors argue that such situated counter‐currents in the history of education are necessary both to inform our collective notions of past experience and enrich our regard for future possibilities.
Hysteresis of gating underlines sensitization of TRPV3 channels
Authors: Liu Beiying , Yao Jing , Zhu Michael X. , Qin Feng
Published: October 2011

Vanilloid receptors of the transient receptor potential family have functions in thermal sensation and nociception. Among them, transient receptor potential vanilloid (TRPV)3 displays a unique property by which the repeated stimulation causes successive increases in its activity. The property has been known as sensitization and is observed in both native cells and cells heterologously expressing TRPV3. Transient increases in intracellular calcium levels have been implicated to play a key role in this process by mediating interaction of calmodulin with the channel. In support of the mechanism, BAPTA, a fast calcium chelator, accelerates the sensitization, whereas the slow chelator EGTA is ineffectual. Here, we show that the sensitization of TRPV3 also occurred independently of Ca2+. It was observed in both inside-out and outside-out membrane patches. BAPTA, but not EGTA, has a direct potentiation effect on channel activation. Analogues of BAPTA lacking Ca2+-buffering capability were similarly effective. The stimulation-induced sensitization and the potentiation by BAPTA are distinguishable in reversibility. We conclude that the sensitization of TRPV3 is intrinsic to the channel itself and occurs as a result of hysteresis of channel gating. BAPTA accelerates the sensitization process by potentiating the gating of the channel.
Interaction between the basolateral amygdala and dorsal hippocampus is critical for cocaine memory reconsolidation and subsequent drug context-induced cocaine-seeking behavior in rats
Authors: Wells Audrey M. , Lasseter Heather C. , Xie Xiaohu , Cowhey Kate E. , Reittinger Andrew M. , Fuchs Rita A.
Published: October 2011

Contextual stimulus control over instrumental drug-seeking behavior relies on the reconsolidation of context-response-drug associative memories into long-term memory storage following retrieval-induced destabilization. According to previous studies, the basolateral amygdala (BLA) and dorsal hippocampus (DH) regulate cocaine-related memory reconsolidation; however, it is not known whether these brain regions interact or independently control this phenomenon. To investigate this question, rats were trained to lever press for cocaine reinforcement in a distinct environmental context followed by extinction training in a different context. Rats were then briefly re-exposed to the cocaine-paired context to destabilize cocaine-related memories, or they were exposed to an unpaired context. Immediately thereafter, the rats received unilateral microinfusions of anisomycin (ANI) into the BLA plus baclofen/muscimol (B/M) into the contralateral (BLA/DH disconnection) or ipsilateral DH, or they received contralateral or ipsilateral microinfusions of vehicle. They then remained in their home cages overnight or for 21 d, followed by additional extinction training and a test of cocaine-seeking behavior (nonreinforced active lever responding). BLA/DH disconnection following re-exposure to the cocaine-paired context, but not the unpaired context, impaired subsequent drug context-induced cocaine-seeking behavior relative to vehicle or ipsilateral ANI + B/M treatment. Prolonged home cage stay elicited a time-dependent increase, or incubation, of drug-context-induced cocaine-seeking behavior, and BLA/DH disconnection inhibited this incubation effect despite some recovery of cocaine-seeking behavior. Thus, the BLA and DH interact to regulate the reconsolidation of cocaine-related associative memories, thereby facilitating the ability of drug-paired contexts to trigger cocaine-seeking behavior and contributing to the incubation of cocaine-seeking behavior.
Emotional Health and Well‐being in Schools: Involving Young People
Authors: Coombes Lindsey , Appleton Jane V. , Allen Debby , Yerrell Paul
Published: October 2011

Prevalence studies of emotional health and well‐being (EHWB) of young people indicate that that there is cause for concern. Very few studies have examined EHWB from the perspective of young people. This study examined the views of young people about their EHWB in the context of secondary education in the UK. Eight focus groups were conducted in five secondary schools with pupils in year 10 (aged 13–14). The findings suggested that whilst pupils thought some aspects of EHWB are well provided for in the school curriculum, there were problems with coherence of EHWB policy. Mental health topics were thought to be neglected in the EHWB curriculum especially in relation to self‐harm. Three problems regarding talking about EHWB were identified. Firstly, the quality of EHWB lessons depended on the enthusiasm and creativity of the teacher taking the lesson. Secondly, pupils were concerned about confidentiality. Thirdly, many pupils preferred to talk to friends about EHWB issues. The findings of the study suggest a need for greater involvement of young people in the planning, implementation and evaluation of the EHWB curriculum.
Self‐management, preventable conditions and assessment of care among young adults with myelomeningocele
Authors: Mahmood D. , Dicianno B. , Bellin M.
Published: October 2011

Aim  In this multicentre cross‐sectional study we aimed to identify whether self‐management ability and healthcare service delivery factors were related to preventable conditions [urinary tract infections (UTIs), pressure ulcers] and healthcare utilization [emergency room (ER) visits, hospitalizations] specifically in a sample of young adults with myelomeningocele.

Background  Spina bifida is one of the most common congenital birth defects, affecting over 166 000 individuals living in the USA. Participants completed a questionnaire comprised of a self‐report measure of healthcare services (Patient Assessment of Chronic Illness Care), recent healthcare utilization and preventable medical conditions. A structured clinical interview [Adolescent Self‐Management and Independence Scale 2 (AMIS)] was administered to assess self‐management. Multiple linear regression models were run to explore individual and combined effects of the AMIS, Patient Assessment of Chronic Illness Care, condition severity variables (shunted hydrocephalus, lesion level) and demographic factors in explaining variability in ER visits, hospitalizations, UTIs and pressure ulcers.

Results  Higher number of UTIs were associated with no history of shunting, lower educational levels, higher employment levels and lower AMIS scores (adjusted R2 = 0.774, P = 0.002). Higher number of ulcers was associated with higher motor level and higher educational level (adjusted R2 = 0.378, P = 0.017). Higher number of hospitalizations was associated with higher number of wounds and lower AMIS scores (adjusted R2 = 0.544, P = 0.012). A significant model for ER visits was not identified.

Conclusions  Initiatives aimed at improving self‐management skills or providing support for skin and bladder care may be warranted for those with high levels of motor impairment or lower educational levels. Better detection of wounds may be seen in those with higher employment levels. Spina bifida is a complex condition, but one whose most prevalent concomitant secondary conditions may be preventable through simple measures that improve self‐management and through health educational initiatives targeted to specific patient groups.
T cell receptor (TCR) signal strength controls arthritis severity in proteoglycan-specific TCR transgenic mice
Authors: Olasz K , Boldizsar F , Kis-Toth K , Tarjanyi O , Hegyi A , van Eden W , Rauch T A , Mikecz K , Glant T T
Published: October 2011

T cell receptor transgenic (TCR-Tg) mice specific for the arthritogenic 5/4E8 epitope in the G1 domain of cartilage proteoglycan were generated and back-crossed into arthritis-prone BALB/c background. Although more than 90% of CD4+ T cells of all TCR-Tg lines were 5/4E8-specific, one (TCR-TgA) was highly sensitive to G1-induced or spontaneous arthritis, while another (TCR-TgB) was less susceptible. Here we studied whether fine differences in TCR signalling controlled the onset and severity of arthritis. Mice from the two TCR-Tg lines were immunized side by side with purified recombinant human G1 (rhG1) domain for G1 domain of cartilage proteoglycan (PG)-induced arthritis (GIA). TCR-TgA mice developed severe and early-onset arthritis, whereas TCR-TgB mice developed weaker arthritis with delayed onset, although TCR-TgB CD4+ T cells expressed approximately twice more TCR-Vβ4 chain protein. The more severe arthritis in TCR-TgA mice was associated with higher amounts of anti-G1 domain-specific antibodies, larger numbers of B cells and activated T helper cells. Importantly, TCR-TgB CD4+ T cells were more sensitive to in vitro activation-induced apoptosis, correlating with their higher TCR and CD3 expression and with the increased TCR signal strength. These findings indicate that TCR signal strength determines the clinical outcome of arthritis induction: ‘optimal’ TCR signal strength leads to strong T cell activation and severe arthritis in TCR-TgA mice, whereas ‘supra-optimal’ TCR signal leads to enhanced elimination of self-reactive T cells, resulting in attenuated disease.
The connective tissue changes of Crohn’s disease
Authors: Shelley‐Fraser Golda , Borley Neil R , Warren Bryan F , Shepherd Neil A
Published: October 2011

Shelley‐Fraser G, Borley N R, Warren B F & Shepherd N A  (2012) Histopathology 60, 1034–1044

The connective tissue changes of Crohn’s disease

Although the inflammatory pathology of Crohn’s disease is manifestly its most important attribute, the connective tissue changes are important in the genesis of the more chronic features of the disease, and yet these have received little attention from clinicians, pathologists, and scientists. Fat‐wrapping appears to be pathognomonic of Crohn’s disease, and is an important marker of disease for surgeons. There is evidence of a complex interplay between the effector inflammatory cells of Crohn’s disease and adipocytes, hyperplasia of which results in fat‐wrapping. Pathologically, this is exhibited in the close relationship between the transmural inflammation that is so characteristic of Crohn’s disease and fat‐wrapping. Fibrosis and muscularization are also important components of the chronic changes of intestinal Crohn’s disease. Neuronal and vascular changes make up the remaining connective tissue changes: these constitute a distinctive feature, and are even specific for Crohn’s disease. For pathologists, the combination of these connective changes will allow a diagnosis of chronic ‘burnt‐out’ Crohn’s disease, even in the absence of its highly characteristic inflammatory features. The connective tissue changes of Crohn’s disease form an important part of its long‐term pathology. They deserve more attention from clinicians, diagnostic pathologists and researchers alike.
Evaluation of reconstructed images with different voxel sizes of acquisition in the diagnosis of simulated external root resorption using cone beam computed tomography
Authors: Neves F. S. , Vasconcelos T. V. , Vaz S. L. A. , Freitas D. Q. , Haiter‐Neto F.
Published: October 2011

Neves FS, Vasconcelos TV, Vaz SLA, Freitas DQ, Haiter‐Neto F. Evaluation of reconstructed images with different voxel sizes of acquisition in the diagnosis of simulated external root resorption using cone beam computed tomography. International Endodontic Journal, 45, 234–239, 2012.

Aim  To evaluate the diagnosis of simulated external root resorption in cone beam computed tomography (CBCT) images acquired with different voxel sizes, then reconstructed with the same voxel size.

Methodology  Buccal, mesial and distal root surfaces of twenty single‐rooted premolar teeth were evaluated for the presence or absence of simulated resorption defects. Images were obtained using a Classic i‐CAT CBCT unit with two different voxel sizes (0.25 and 0.30 mm). Then all images were reconstructed to 0.25 mm voxel size. The McNemar’s test was applied to evaluate the agreement between the two protocols (different voxel sizes/reconstruction parameters) with the gold standard (defects created in the root). Accuracy, sensitivity, specificity, positive and negative predictive values were calculated for each voxel and defect sizes.

Results  Better sensitivity and accuracy were obtained with 0.25 (0.25 mm) voxel size. Specificity, positive and negative predictive values were highest with the 0.25 (0.30 mm) voxel size. McNemar’s test results revealed significant differences between the protocols with the gold standard (P < 0.0001). The results revealed that as the cavity size increased, sensitivity, accuracy, positive and negative predictive values also increased. When correlating the voxel size and root third, better sensitivity, accuracy, positive and negative predictive values were obtained in the middle third.

Conclusions  In the diagnosis of simulated external root resorption with the Classic i‐CAT CBCT unit, images acquired with 0.30 mm voxel size and reconstructed with 0.25 mm voxel size provided the best protocol with a lower radiation dose than the 0.25 mm voxel size.
Reproductive synchrony in a recovering bottlenecked sea turtle population
Authors: Plot Virginie , de Thoisy Benoît , Blanc Stéphane , Kelle Laurent , Lavergne Anne , Roger‐Bérubet Hélène , Tremblay Yann , Fossette Sabrina , Georges Jean‐Yves
Published: October 2011

1. The assessment of species extinction risk has been well established for some time now. Assessing the potential for recovery in endangered species is however much more challenging, because complementary approaches are required to detect reliable signals of positive trends.

2. This study combines genetics, demography and behavioural data at three different time‐scales to assess historical and recent population changes and evidence of reproductive synchrony in a small population of olive ridley sea turtle Lepidochelys olivacea. Lepidochelys is considered as the most extraordinary example of reproductive synchrony in reptiles, yet to date, it has only been reported in large populations.

3. Using Bayesian coalescent‐based models on microsatellite nuclear DNA variability, we demonstrate that effective population size in olive ridleys nesting in French Guiana has dramatically declined by 99% over the last 20 centuries. This low current population size is further illustrated by the absence of genetic mitochondrial DNA diversity in the present nesting population. Yet, monitoring of nesting sites in French Guiana suggests a possible recovery of the population over the last decade.

4. Satellite telemetry shows that over the first 14 days of their 28‐days inter‐nesting interval, i.e. when eggs maturation is likely to occur, gravid females disperse over the continental shelf. They then gather together with a striking spatiotemporal consistency close to the nesting site, where they later emerge for their second nesting event.

5. Our results therefore suggest that reproductive synchrony also occurs in small populations. Olive ridleys may ensure this synchrony by adjusting the duration of the second half of their inter‐nesting interval prior to landing, possibly through social mediation.

6. Such reproductive synchrony may be related to the maintenance of some species‐specific strategy despite former collapse and may contribute to the present population recovery. The gregarious behaviour of reproductive individuals close to shore where human‐induced perturbations occur is however a cause for conservation concern for this still poorly known species.
Global patterns in the shape of species geographical ranges reveal range determinants
Authors: Baselga Andrés , Lobo Jorge M. , Svenning Jens‐Christian , Araújo Miguel B.
Published: October 2011

Aim  Do species range shapes follow general patterns? If so, what mechanisms underlie those patterns? We show for 11,582 species from a variety of taxa across the world that most species have similar latitudinal and longitudinal ranges. We then seek to disentangle the roles of climate, extrinsic dispersal limitation (e.g. barriers) and intrinsic dispersal limitation (reflecting a species’ ability to disperse) as constraints of species range shape. We also assess the relationship between range size and shape.

Location  Global.

Methods  Range shape patterns were measured as the slope of the regression of latitudinal species ranges against longitudinal ranges for each taxon and continent, and as the coefficient of determination measuring the degree of scattering of species ranges from the 1:1 line (i.e. latitudinal range = longitudinal range). Two major competing hypotheses explaining species distributions (i.e. dispersal or climatic determinism) were explored. To this end, we compared the observed slopes and coefficients of determination with those predicted by a climatic null model that estimates the potential range shapes in the absence of dispersal limitation. The predictions compared were that species distribution shapes are determined purely by (1) intrinsic dispersal limitation, (2) extrinsic dispersal limitations such as topographic barriers, and (3) climate.

Results  Using this methodology, we show for a wide variety of taxa across the globe that species generally have very similar latitudinal and longitudinal ranges. However, neither neutral models assuming random but spatially constrained dispersal, nor models assuming climatic control of species distributions describe range shapes adequately. The empirical relationship between the latitudinal and longitudinal ranges of species falls between the predictions of these competing models.

Main conclusions  We propose that this pattern arises from the combined effect of macroclimate and intrinsic dispersal limitation, the latter being the major determinant among restricted‐range species. Hence, accurately projecting the impact of climate change onto species ranges will require a solid understanding of how climate and dispersal jointly control species ranges.
Effects of Oestradiol on Brain Lipid Class and Fatty Acid Composition: Comparison Between Pregnant and Ovariectomised Oestradiol‐Treated Rats
Authors: Fabelo N. , Martin V. , González C. , Alonso A. , Diaz M.
Published: October 2011

To determine the involvement of physiological doses of oestradiol on brain lipid composition, we have analysed the lipid class and fatty acid composition of phospholipids in the brain from pregnant and 17β‐oestradiol‐treated rats. Rats were randomly divided into three groups: ovariectomised control (OVX + VEH), ovariectomised oestradiol‐treated (OVX + E2) and pregnant (PREG) rats. Rats from the OVX + E2 group were injected daily with different doses of 17β‐oestradiol mimicking the plasma levels observed during pregnancy. Analyses of brain lipid class composition showed that physiological doses of oestradiol increased cholesterol levels of the OVX + E2 group compared to the OVX + VEH group. It was also found that cholesterol levels in the PREG group were significantly lower than in the OVX + VEH and OVX + E2 groups, indicating the involvement of gestational hormones other than oestradiol in the regulation of brain cholesterol during pregnancy. Brains from pregnant rats also exhibited reduced levels of plasmalogens and saturated fatty acids compared to the ovariectomised groups, especially in the second half of pregnancy. Interestingly, analyses of fatty acid composition of phospholipids revealed that physiological doses of oestradiol increased brain docosahexaenoic acid (DHA; 22:6 n‐3) levels. Moreover, DHA levels in pregnant rats were similar to those observed in the OVX + E2 group at all stages, suggesting that oestradiol is the main hormone in the regulation of brain DHA levels during pregnancy. Liver appears to be the major source for n‐3 and n‐6 long chain polyunsaturated fatty acids (LCPUFAs) DHA and arachidonic acid, which are released and transported to the maternal brain and the developing foetus under the influence of oestrogens. We also observed that the largest depots of n‐3 and n‐6 LCPUFA precursors (linolenic acid and linoleic acid, respectively) occur in adipose tissue triglycerides, which, in turn are significantly increased during pregnancy. Our observations are in accordance with an oestradiol‐induced increased bioavailability of brain DHA in pregnant rats. We hypothesise that the reduction of maternal brain DHA observed at the end of pregnancy is a result of the very high demand DHA of foetal brain, which overcomes the maximal maternal (and likely foetal) capacity for de novo DHA synthesis in the liver and brain.
An ABA‐regulated and Golgi‐localized protein phosphatase controls water loss during leaf senescence in Arabidopsis
Authors: Zhang Kewei , Xia Xiuying , Zhang Yanyan , Gan Su‐Sheng
Published: October 2011

It is known that a senescing leaf loses water faster than a non‐senescing leaf and that ABA has an important role in promoting leaf senescence. However, questions such as why water loss is faster, how water loss is regulated, and how ABA functions in leaf senescence are not well understood. Here we report on the identification and functional analysis of a leaf senescence associated gene called SAG113. The RNA blot and GUS reporter analyses all show that SAG113 is expressed in senescing leaves and is induced by ABA in Arabidopsis. The SAG113 expression levels are significantly reduced in aba2 and abi4 mutants. A GFP fusion protein analysis revealed that SAG113 protein is localized in the Golgi apparatus. SAG113 encodes a protein phosphatase that belongs to the PP2C family and is able to functionally complement a yeast PP2C‐deficient mutant TM126 (ptc1Δ). Leaf senescence is delayed in the SAG113 knockout mutant compared with that in the wild type, stomatal movement in the senescing leaves of SAG113 knockouts is more sensitive to ABA than that of the wild type, and the rate of water loss in senescing leaves of SAG113 knockouts is significantly reduced. In contrast, inducible over‐expression of SAG113 results in a lower sensitivity of stomatal movement to ABA treatment, more rapid water loss, and precocious leaf senescence. No other aspects of growth and development, including seed germination, were observed. These findings suggest that SAG113, a negative regulator of ABA signal transduction, is specifically involved in the control of water loss during leaf senescence.
Phosphoinositide‐specific phospholipase C9 is involved in the thermotolerance of Arabidopsis
Authors: Zheng Shu‐Zhi , Liu Yu‐Liang , Li Bing , Shang Zhong‐ lin , Zhou Ren‐Gang , Sun Da‐Ye
Published: October 2011

Intracellular calcium (Ca2+) increases rapidly after heat shock (HS) in the Ca2+/calmodulin (Ca2+/CaM) HS signal transduction pathway: a hypothesis proposed based on our previous findings. However, evidence for the increase in Ca2+ after HS was obtained only through physiological and pharmacological experiments; thus, direct molecular genetic evidence is needed. The role of phosphoinositide‐specific phospholipase C (PI‐PLC) is poorly understood in the plant response to HS. In this work, atplc9 mutant plants displayed a serious thermosensitive phenotype compared with wild‐type (WT) plants after HS. Complementation of atplc9 with AtPLC9 rescued both the basal and acquired thermotolerance phenotype of the WT plants. In addition, thermotolerance was even improved in overexpressed lines. The GUS staining of AtPLC9 promoter:GUS transgenic seedlings showed that AtPLC9 expression was ubiquitous. The fluorescence distribution of the fusion protein AtPLC9 promoter:AtPLC9:GFP revealed that the subcellular localization of AtPLC9 was restricted to the plasma membrane. The results of a PLC activity assay showed a reduction in the accumulation of inositol‐1,4,5‐trisphosphate (IP3) in atplc9 during HS and improved IP3 generation in the overexpressed lines. Furthermore, the heat‐induced increase in intracellular Ca2+ was decreased in atplc9. Accumulation of the small HS proteins HSP18.2 and HSP25.3 was downregulated in atplc9 and upregulated in the overexpressed lines after HS. Together, these results provide molecular genetic evidence showing that AtPLC9 plays a role in thermotolerance in Arabidopsis.
Patch test results may vary depending on where testing is performed: a comparison of patch test results from three geographically distinct sites in the USA
Authors: Davis Mark D. P. , Yiannias James A. , Weaver Amy L. , Farmer Sara A. , Scalf Leigh Ann , Prakash Amy V. , Fett Debra D. , Richardson Donna M. , Connolly Suzanne M. , Keeling James H. , el‐Azhary Rokea A.
Published: October 2011

Background  Do patch test results vary from one part of the USA to another? Few reports directly compare the results of patch testing across centers within the USA.

Objectives  Our objective was to compare results of patch testing from three geographically disparate Mayo Clinic sites in the USA to ascertain whether there are any differences in allergic patch test rates.

Methods  We retrospectively reviewed patch test results for patients tested with a standard allergen series using our enterprise‐wide protocol for patch testing. We compared data collected from January 1, 2001, through to December 31, 2007, from our practice sites in the Midwest, Southwest, and Southeast regions of the USA.

Results  In total, 5063 patients underwent patch testing. The mean (standard deviation) number of allergens tested per patient was 70.3 (3.8) (range: 10–87; interquartile range: 68–73). Analyses were conducted separately for 72 allergens with positive reactions from at least 20 patients. Risk‐adjusted positive reaction rates (RAPRRs) for 44 allergens differed significantly (P < 0.05) among the geographic sites; RAPRRs differed significantly across all three sites for 11 allergens and between two of the three sites for 33 allergens.

Conclusions  Allergic patch test rates differed among our three practice sites for many allergens. It is likely that many factors contributed to these observed differences, including variations in the population undergoing patch testing, variations in allergen exposure, and variations in climate.
How useful is the Mantoux test in the diagnosis of doubtful cases of cutaneous tuberculosis?
Authors: Ramam M. , Malhotra Amit , Tejasvi Trilokraj , Manchanda Yashpal , Sharma Sandeep , Mittal Rashmi , Ramesh V.
Published: October 2011

Background  Diagnostic tests are critical to management when the clinical picture is unclear. We analyzed the records of patients in whom the initial diagnosis of cutaneous tuberculosis was doubtful to evaluate the utility of the Mantoux test in this setting.

Materials and methods  Of 375 patients with cutaneous tuberculosis seen in our department, the initial clinical diagnosis was doubtful in 90 patients. A Mantoux test was performed with 5 TU of purified protein derivative using standard techniques and read after two days. Patients also underwent skin biopsy and other laboratory tests and received treatment with antitubercular drugs. Patients who had case notes recording satisfactory improvement following antitubercular therapy were classified as having cutaneous tuberculosis; those with evidence of another diagnosis based on the laboratory tests and response to therapy were categorized as non‐tuberculosis cases. Patients with inadequate evidence for a diagnosis of either cutaneous tuberculosis or another disorder were classified as unresolved diagnosis.

Results  Readings were available in 79 patients: 39 were categorized as tuberculosis; 16 as non‐tuberculosis; while a final diagnosis could not be reached in 24 cases. Readings ranged from 0 to 40 mm in the cases and from 0 to 30 mm in non‐cases. The area under the receiver‐operating characteristic curve was 0.66 (95% CI 0.55–0.81). Using a cut‐off of 10 mm, the sensitivity and specificity of the tests were 58.97 and 62.50%, respectively.

Conclusion  The Mantoux test is of low accuracy in the diagnosis of doubtful cases of cutaneous tuberculosis.
Modified Jaipur block for the treatment of post‐herpetic neuralgia
Authors: Puri Neerja
Published: October 2011

Post‐herpetic neuralgia means pain which occurs for longer than one to three months after the resolution of the rash of herpes zoster. We conducted a study of 30 patients having post herpetic neuralgia. All the patients were treated with modified Jaipur block consisting of local subcutaneous infiltration of 2% Xylocaine, 0.5% bupivacaine and methylprednisolone. In our study, it was seen that 20% patients had complete relief of pain after first injection, 60% patients had complete relief of pain after second injection, 10% patients had complete relief of pain after third injection, and only 10% patients did not respond to treatment. The non‐responders were either old (over 60 years) or had pain lasting for more than two years.
Enteric‐coated mycophenolate sodium in de novo and maintenance kidney–pancreas transplant recipients
Authors: Ricart María J. , Oppenheimer Frederic , Andrés Amado , Morales José M. , Alonso Ángel , Fernández Constantino ,   on behalf of the Epi‐trasplante Study, MIDATA Kidney–Pancreas Sub‐study Group
Published: October 2011

Ricart MJ, Oppenheimer F, Andrés A, Morales JM, Alonso Á, Fernández C, on behalf of the Epi‐trasplante Study, MIDATA Kidney–Pancreas Sub‐study Group. Enteric‐coated mycophenolate sodium in de novo and maintenance kidney–pancreas transplant recipients.  Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01526.x.  © 2011 John Wiley & Sons A/S.

Abstract:  Background:  Our objective was to describe efficacy and safety of enteric‐coated mycophenolate sodium (EC‐MPS) in de novo and maintenance recipients of kidney–pancreas transplant in the clinical practice.

Methods:  Observational, multicentre, prospective, 12‐month study.

Results:  We included 24 de novo and 24 maintenance patients. EC‐MPS mean (±SD) doses at initiation in de novo patients were 1440 ± 0 vs. 1268 ± 263 mg/d at month 12 (M12). Patient and renal graft survival at one yr were 100%, and pancreatic graft survival was 83.3% (two losses owing to technical failure and two owing to rejection). In the maintenance cohort, EC‐MPS was introduced at a median (P25–P75) of 30 (6–71) months after transplant. Baseline doses were 585 ± 310 vs. 704 ± 243 mg/d at M12. In this group, a significant increase in creatinine clearance was observed (65 ± 22 at baseline vs. 74 ± 20 mL/min at M12, p = 0.011). Patient, renal, and pancreatic graft survival were 100%, 95.8%, and 100%, respectively (one kidney graft loss owing to rejection). During follow‐up, one patient from each group discontinued EC‐MPS.

Conclusions:  The efficacy of EC‐MPS in the clinical practice of kidney–pancreas transplantation is good, with high patient and grafts survival at 12 months, and good safety profile. The maintenance group displayed an improvement in renal function.
Post‐reperfusion syndrome during isolated intestinal transplantation: outcome and predictors
Authors: Siniscalchi Antonio , Cucchetti Alessandro , Miklosova Zuzana , Lauro Augusto , Zanoni Andrea , Spedicato Salvatore , Bernardi Enrico , Aurini Lucia , Pinna Antonio D. , Faenza Stefano
Published: October 2011

Siniscalchi A, Cucchetti A, Miklosova Z, Lauro A, Zanoni A, Spedicato S, Bernardi E, Aurini L, Pinna AD, Faenza S. Post‐reperfusion syndrome during isolated intestinal transplantation: outcome and predictors.  Clin Transplant 2011 DOI: 10.1111/j.1399‐0012.2011.01530.x  © 2011 John Wiley & Sons A/S.

Abstract:  Background:  Post‐reperfusion syndrome (PRS) during isolated intestinal transplantation (ITx) is characterized by decreased systemic blood pressure, systemic vascular resistance, and cardiac output and by a moderate increased pulmonary arterial pressure. We hypothesize that the more severe PRS causes a poorer long‐term outcome. The primary aim of this study was to determine the independent clinical predictors of intra‐operative PRS, as well as to investigate the link between the severity of PRS and the intra‐operative profiles and to examine the post‐operative complications and their relationship with transplant outcome.

Methods:  This observational study was conducted on 27 patients undergoing isolated ITx in a single adult liver and multivisceral transplantation center. PRS was considered when the mean arterial blood pressure was 30% lower than the pre‐unclamping value and lasted for at least one min within 10 min after unclamping.

Results and conclusions:  The main results of this study can be summarized in two findings: in patients undergoing ITx, the duration of cold ischemia and the pre‐operative glomerular filtration rate were independent predictors of PRS and the occurrence of intra‐operative PRS was associated with significantly more frequent post‐operative renal failure and early post‐operative death.