bluuebunny/crossref_metadata_2025 huggingface dataset:
Widespread and Long-Lasting Alterations in GABAA-Receptor Subtypes after Focal Cortical Infarcts in Rats: Mediation by NMDA-Dependent Processes
Authors: Redecker Christoph , Wang Wei , Fritschy Jean-Marc , Witte Otto W.
Published: December 2015

Impairment of inhibitory neurotransmission has been reported to occur in widespread, structurally intact brain regions after focal ischemic stroke. These long-lasting alterations contribute to the functional deficit and influence long-term recovery. Inhibitory neurotransmission is primarily mediated by γ-aminobutyric acid (GABA)A receptors assembled of five subunits that allow a variety of adaptive changes. In this study, the regional distribution of five major GABAA-receptor subunits (α1, α2, α3, α5, and γ2) was analyzed immunohistochemically 1, 7, and 30 days after photochemically induced cortical infarcts. When compared with sham-operated controls, a general and regionally differential reduction in immunostaining was found within the cortex, hippocampus, and thalamus of both hemispheres for almost all subunits. Within ipsilateral and contralateral neocortical areas, a specific pattern of changes with a differential decrease of subunits α1, α2, α5, and γ2 and a significant upregulation of subunit α3 was observed in the contralateral cortex homotopic to the infarct. This dysregulation was most prominent at day 7 and still present at day 30. Interestingly, a single application of the noncompetitive N-methyl-D-aspartate–receptor antagonist MK-801 during lesion induction completely blocked these bihemispheric alterations. Cortical spreading depressions induced by topical application of KCl do not change GABAA-receptor subunit expression. As alterations in subtype distribution crucially influence inhibitory function, ischemia-induced modifications in GABAA-receptor subtype expression may be of relevance for functional recovery after stroke.
Traumatic Axonal Injury Results in Biphasic Calpain Activation and Retrograde Transport Impairment in Mice
Authors: Saatman Kathryn E. , Abai Babak , Grosvenor Ashley , Vorwerk Christian K. , Smith Douglas H. , Meaney David F.
Published: December 2015

Traumatic axonal injury (TAI) is one of the most important pathologies associated with closed head injury, and contributes to ensuing morbidity. The authors evaluated the potential role of calpains in TAI using a new model of optic nerve stretch injury in mice. Male C57BL/6 mice were anesthetized, surgically prepared, and subjected to a 2.0-mm optic nerve stretch injury (n = 34) or sham injury (n = 18). At various intervals up to 2 weeks after injury, optic nerves were examined for neurofilament proteins and calpain-mediated spectrin breakdown products using immunohistochemistry. In addition, fluorescent tracer was injected into the superior colliculi of mice 1 day before they were killed, to investigate the integrity of retrograde axonal transport to the retina. Optic nerve stretch injury resulted in persistent disruption of retrograde axonal transport by day 1, progressive accumulation and dephosphorylation of neurofilament protein in swollen and disconnected axons, and subsequent loss of neurofilament protein in degenerating axons at day 14. Calpains were transiently activated in intact axons in the first minutes to hours after stretch injury. A second stage of calpain-mediated proteolysis was observed at 4 days in axonal swellings, bulbs, and fragments. These data suggest that early calpain activation may contribute to progressive intra-axonal structural damage, whereas delayed calpain activation may be associated with axonal degeneration.
Mild Hypothermia Reduces Zinc Translocation, Neuronal Cell Death, and Mortality after Transient Global Ischemia in Mice
Authors: Tsuchiya Daisuke , Hong Shwuhuey , Suh Sang Won , Kayama Takamasa , Panter S. Scott , Weinstein Philip R.
Published: December 2015

The authors sought to determine whether Zn2+ translocation associated with neuronal cell death occurs after transient global ischemia (TGI) in mice, as has been previously shown in rats, and to determine the effect of mild hypothermia on this reaction. To validate the TGI model, carbon-black injection and laser-Doppler flowmetry were compared in three strains of mice (C57BL/6, SV129, and HSP70 transgenic mice) to assess posterior communicating artery (PcomA) development and cortical perfusion. In C57BL/6 mice, optimal results were obtained when subjected to 20-minute TGI. Brain and rectal temperature measurements were compared to monitor hypothermia. Results of TGI were compared in normothermia (NT; 37°C) and mild hypothermia groups (HT; 33°C) by staining with Zn2+-specific fluorescent dye, N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) and hematoxylin– eosin 72 hours after reperfusion. The Zn2+ translocation observed in hippocampus CA1, CA2, and Hilus 72 hours after 20 minutes of TGI was significantly reduced by mild hypothermia. The number of degenerating neurons in the HT group was significantly less than in the NT group. Mild hypothermia reduced mortality significantly (7.1% in HT, 42.9% in NT). Results suggest that mild hypothermia may reduce presynaptic Zn2+ release in mice, which protects vulnerable hippocampal neurons from ischemic necrosis. Future studies may further elucidate mechanisms of Zn2+-induced ischemic injury.
Role of Cytoplasmic Phospholipase A2 in Endothelium-Derived Hyperpolarizing Factor Dilations of Rat Middle Cerebral Arteries
Authors: You Junping , Marrelli Sean P. , Bryan Robert M.
Published: December 2015

Very little is known regarding the mechanism of action for the endothelium-derived hyperpolarizing factor (EDHF) response in cerebral vessels. The authors tested two hypotheses: (1) activation of the cytoplasmic form of phospholipase A2 (cPLA2) is involved with EDHF-mediated dilations in rat middle cerebral arteries; and (2) activation of the cPLA2 involves an increase in endothelial Ca2+ through activation of phospholipase C. Middle cerebral arteries were isolated from the rat, pressurized to 85 mm Hg, and luminally perfused. The EDHF response was elicited by luminal application of uridine triphosphate (UTP) after NO synthase and cyclooxygenase inhibition (10−5 mol/L N-nitro-l-arginine methyl ester and 10−5 mol/L indomethacin, respectively). AACOCF3 and PACOCF3, inhibitors of cPLA2 (Ca2+-sensitive) and Ca2+-insensitive PLA2 (iPLA2), dose dependently attenuated the EDHF response. A selective inhibitor for iPLA2, haloenol lactone suicide substrate, had no effect on the EDHF response. The EDHF response elicited by UTP was accompanied by an increase in endothelial Ca2+ (144 to 468 nmol/L), and the EDHF dilation was attenuated with U73122, a phospholipase C inhibitor. The authors conclude that the EDHF response elicited by luminal UTP in rat middle cerebral arteries involved activation of phospholipase C, an increase in endothelial Ca2+, and activation of cPLA2.
Cerebral Blood Flow and Oxidative Metabolism during Human Endotoxemia
Authors: Møller Kirsten , Strauss Gitte Irene , Qvist Jesper , Fonsmark Lise , Knudsen Gitte Moos , Larsen Fin Stolze , Krabbe Karen Suarez , Skinhøj Peter , Pedersen Bente Klarlund
Published: December 2015

The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α), has been suggested to mediate septic encephalopathy through an effect on cerebral blood flow (CBF) and metabolism. The effect of an intravenous bolus of endotoxin on global CBF, metabolism, and net flux of cytokines and catecholamines was investigated in eight healthy young volunteers. Cerebral blood flow was measured by the Kety-Schmidt technique at baseline (during normocapnia and voluntary hyperventilation for calculation of subject-specific cerebrovascular CO2 reactivity), and 90 minutes after an intravenous bolus of a reference Escherichia coli endotoxin. Arterial TNF-α peaked at 90 minutes, coinciding with a peak in subjective symptoms. At this time, CBF and Paco2 were significantly reduced compared to baseline; the CBF decrease was readily explained by hypocapnia. The cerebral metabolic rate of oxygen remained unchanged, and the net cerebral flux of TNF-α, interleukin (IL)-1β, and IL-6 did not differ significantly from zero. Thus, high circulating levels of TNF-α during human endotoxemia do not induce a direct reduction in cerebral oxidative metabolism.
Positron Emission Tomography Compartmental Models: A Basis Pursuit Strategy for Kinetic Modeling
Authors: Gunn Roger N. , Gunn Steve R. , Turkheimer Federico E. , Aston John A. D. , Cunningham Vincent J.
Published: December 2015

A kinetic modeling approach for the quantification of in vivo tracer studies with dynamic positron emission tomography (PET) is presented. The approach is based on a general compartmental description of the tracer's fate in vivo and determines a parsimonious model consistent with the measured data. The technique involves the determination of a sparse selection of kinetic basis functions from an overcomplete dictionary using the method of basis pursuit denoising. This enables the characterization of the systems impulse response function from which values of the systems macro parameters can be estimated. These parameter estimates can be obtained from a region of interest analysis or as parametric images from a voxel-based analysis. In addition, model order estimates are returned that correspond to the number of compartments in the estimated compartmental model. Validation studies evaluate the methods performance against two preexisting data led techniques, namely, graphical analysis and spectral analysis. Application of this technique to measured PET data is demonstrated using [11C]diprenorphine (opiate receptor) and [11C]WAY-100635 (5-HT1A receptor). Although the method is presented in the context of PET neuroreceptor binding studies, it has general applicability to the quantification of PET/SPECT radiotracer studies in neurology, oncology, and cardiology.
Effect of Dopamine Loss and the Metabolite 3-O-Methyl-[18F]Fluoro-dopa on the Relation between the 18F-Fluorodopa Tissue Input Uptake Rate Constant Kocc and the [18F]Fluorodopa Plasma Input Uptake Rate Constant Ki
Authors: Sossi V. , Holden J. E. , de la Fuente-Fernandez R. , Ruth T. J. , Stoessl A. J.
Published: December 2015

Parkinson disease is characterized by the loss of dopaminergic neurons, thus decreasing the system's ability to produce and store dopamine (DA). Such ability is often investigated using 18F-fluorodopa (FD) positron emission tomography. A commonly used model to investigate the DA synthesis and storage rate is the modified Patlak graphical approach. This approach allows for both plasma and tissue input functions, yielding the respective uptake rate constants Ki and Kocc. This method requires the presence of an irreversible compartment and the absence of any nontrapped tracer metabolite. In the case of Kocc, this last assumption is violated by the presence of the FD metabolite 3- O-methyl-[18F]fluoro-dopa (3OMFD), which makes the Kocc evaluation susceptible to a downward bias. It was found that both Ki and Kocc are influenced by DA loss and thus are not pure measures of DA synthesis and storage. In the case of Kocc, the presence of 3OMFD exacerbates the effect of DA egress, thus introducing a disease-dependent bias in the Kocc determination. These findings imply that Ki and Kocc provide different assessments of disease severity and that, as disease progresses, Ki and especially Kocc become more related to DA storage capacity and less to the DA synthesis rate.
On the Undecidability among Kinetic Models: From Model Selection to Model Averaging
Authors: Turkheimer Federico E. , Hinz Rainer , Cunningham Vincent J.
Published: December 2015

This article deals with the problem of model selection for the mathematical description of tracer kinetics in nuclear medicine. It stems from the consideration of some specific data sets where different models have similar performances. In these situations, it is shown that considerate averaging of a parameter's estimates over the entire model set is better than obtaining the estimates from one model only. Furthermore, it is also shown that the procedure of averaging over a small number of “good” models reduces the “generalization error,” the error introduced when the model selected over a particular data set is applied to different conditions, such as subject populations with altered physiologic parameters, modified acquisition protocols, and different signal-to-noise ratios. The method of averaging over the entire model set uses Akaike coefficients as measures of an individual model's likelihood. To facilitate the understanding of these statistical tools, the authors provide an introduction to model selection criteria and a short technical treatment of Akaike's information–theoretic approach. The new method is illustrated and epitomized by a case example on the modeling of [11C]flumazenil kinetics in the brain, containing both real and simulated data.
Heterologous Expression of Human VEGF165 in Rat Brain: Dose-Dependent, Heterogeneous Effects on CBF in Relation to Vascular Density and Cross-Sectional Area
Authors: Vogel Johannes , Hörner Christian , Haller Christlieb , Kuschinsky Wolfgang
Published: December 2015

Vascular endothelial growth factor (VEGF) induces increased vessel permeability and formation of abnormal vessels. To investigate cerebral blood flow (CBF) during local overexpression of VEGF recombinant adenoviruses carrying the human VEGF165 complementary DNA (2.3 to 23 · 108 pfu/mL) were injected stereotactically into the caudate nucleus of anesthetized rats. Saline and adenoviruses carrying the β-galactosidase gene served as controls. Eleven days later (1) size and density of vessels were assessed in hematoxylin–eosin–stained sections, (2) vascular permeability was measured by intravenous Evans blue injections, and (3) local CBF (lCBF) was quantified using the iodo-[14C]antipyrine technique. Dose-dependent increases were found in (1) vessel density and size (only vessels >43 μm could be quantified morphologically), (2) Evans blue extravasation and brain edema formation, and (3) lCBF (up to eightfold). At medium doses, hyperemic areas and smaller areas of decreased lCBF were found. In low flow areas, vascular cross-sectional areas were increased 223-fold and vessel density up to 10-fold. In high flow areas, these parameters were increased 32-fold and up to 15-fold, respectively. Adenovirus mediated VEGF overexpression results in (1) increased vessel size and density, (2) areas of increased and of decreased flow, and (3) more and smaller vessels in high flow than in low flow areas. These results indicate a diverging flow pattern of newly formed vessels.
Regulation of Body Temperature and Neuroprotection by Endogenous Interleukin-6 in Cerebral Ischemia
Authors: Herrmann Oliver , Tarabin Victoria , Suzuki Shigeaki , Attigah Nicolas , Coserea Irinel , Schneider Armin , Vogel Johannes , Prinz Simone , Schwab Stefan , Monyer Hannah , Brombacher Frank , Schwaninger Markus
Published: December 2015

Although the function of fever is still unclear, it is now beyond doubt that body temperature influences the outcome of brain damage. An elevated body temperature is often found in stroke patients and denotes a bad prognosis. However, the pathophysiologic basis and treatment options of elevated body temperature after stroke are still unknown. Cerebral ischemia rapidly induced neuronal interleukin-6 (IL-6) expression in mice. In IL-6–deficient mice, body temperature was markedly decreased after middle cerebral artery occlusion (MCAO), but infarct size was comparable to that in control mice. If body temperature was controlled by external warming after MCAO, IL-6–deficient mice had a reduced survival, worse neurologic status, and larger infarcts than control animals. In cell culture, IL-6 exerted an antiapoptotic and neuroprotective effect. These data suggest that IL-6 is a key regulator of body temperature and an endogenous neuroprotectant in cerebral ischemia. Neuroprotective properties apparently compensate for its pyretic action after MCAO and enhance the safety of this endogenous pyrogen.
Cyclooxygenase-2 Expression Associated with Spreading Depression in a Primate Model
Authors: Yokota Chiaki , Inoue Hiroyasu , Kuge Yuji , Abumiya Takeo , Tagaya Masafumi , Hasegawa Yasuhiro , Ejima Norimasa , Tamaki Nagara , Minematsu Kazuo
Published: December 2015

The authors previously provided evidence that spreading depression (SD) can be evoked in primates. Cyclooxygenase-2 (COX-2) expression has been found to increase in the rodent cortex undergoing SD, and the authors sought to determine whether this association exists in primate brain. In the present study, neuronal COX-2 expression was induced during SD in the primate cortex. The mean expression ratio of COX-2 messenger RNA in animals with SD was significantly higher than that measured in controls (1.69 vs. 0.5; P = 0.02). Induction of COX-2 in these animals was also detected by human microarray analysis. Results show that, as in rodents, neuronal COX-2 is induced in the primate cortex in response to SD.
Dysfunction of the Unfolded Protein Response during Global Brain Ischemia and Reperfusion
Authors: Kumar Rita , Krause Gary S. , Yoshida Hiderou , Mori Kazutoshi , DeGracia Donald J.
Published: December 2015

A variety of endoplasmic reticulum (ER) stresses trigger the unfolded protein response (UPR), a compensatory response whose most proximal sensors are the ER membrane–bound proteins ATF6, IRE1α, and PERK. The authors simultaneously examined the activation of ATF6, IRE1α, and PERK, as well as components of downstream UPR pathways, in the rat brain after reperfusion after a 10-minute cardiac arrest. Although ATF6 was not activated, PERK was maximally activated at 10-minute reperfusion, which correlated with maximal eIF2α phosphorylation and protein synthesis inhibition. By 4-h reperfusion, there was 80% loss of PERK immunostaining in cortex and 50% loss in brain stem and hippocampus. PERK was degraded in vitro by μ-calpain. Although inactive IRE1α was maximally decreased by 90-minute reperfusion, there was no evidence that its substrate xbp-1 messenger RNA had been processed by removal of a 26-nt sequence. Similarly, there was no expression of the UPR effector proteins 55-kd XBP-1, CHOP, or ATF4. These data indicate that there is dysfunction in several key components of the UPR that abrogate the effects of ER stress. In other systems, failure to mount the UPR results in increased cell death. As other studies have shown evidence for ER stress after brain ischemia and reperfusion, the failure of the UPR may play a significant role in reperfusion neuronal death.
Microbiology of the subglacial Lake Vostok: first results of borehole-frozen lake water analysis and prospects for searching for lake inhabitants
Authors: Bulat Sergey A.
Published: December 2015

This article examines the question of the possible existence of microbial life inhabiting the subglacial Lake Vostok buried beneath a 4 km thick Antarctic ice sheet. It represents the results of analysis of the only available frozen lake water samples obtained upon the first lake entry and subsequent re-coring the water frozen within the borehole. For comparison, results obtained by earlier molecular microbiological studies of accretion ice are included in this study, with the focus on thermophiles and an unknown bacterial phylotype. A description of two Lake Vostok penetrations is presented for the first time from the point of view of possible clean water sampling. Finally, the results of current studies of Lake Vostok frozen water samples are presented, with the focus on the discovery of another unknown bacterial phylotype w123-10 distantly related to the above-mentioned unknown phylotype AF532061 detected in Vostok accretion ice, both successfully passing all possible controls for contamination. The use of clean-room facilities and the establishment of a contaminant library are considered to be prerequisites for research on microorganisms from Lake Vostok. It seems that not yet recorded microbial life could exist within the Lake Vostok water body. In conclusion, the prospects for searching for lake inhabitants are expressed with the intention to sample the lake water as cleanly as possible in order to make sure that further results will be robust.
An Invariants-based Method for Efficient Identification of Hybrid Species From Large-scale Genomic Data
Authors: Kubatko Laura S. , Chifman Julia
Published: December 2015

Coalescent-based species tree inference has become widely used in the analysis of genome-scale multilocus and SNP datasets when the goal is inference of a species-level phylogeny. However, numerous evolutionary processes are known to violate the assumptions of a coalescence-only model and complicate inference of the species tree. One such process is hybrid speciation, in which a species shares its ancestry with two distinct species. Although many methods have been proposed to detect hybrid speciation, only a few have considered both hybridization and coalescence in a unified framework, and these are generally limited to the setting in which putative hybrid species must be identified in advance. Here we propose a method that can examine genome-scale data for a large number of taxa and detect those taxa that may have arisen via hybridization, as well as their potential “parental” taxa. The method is based on a model that considers both coalescence and hybridization together, and uses phylogenetic invariants to construct a test that scales well in terms of computational time for both the number of taxa and the amount of sequence data. We test the method using simulated data for up 20 taxa and 100,000bp, and find that the method accurately identifies both recent and ancient hybrid species in less than 30 seconds. We apply the method to two empirical datasets, one composed ofSistrurusrattlesnakes for which hybrid speciation is not supported by previous work, and one consisting of several species ofHeliconiusbutterflies for which some evidence of hybrid speciation has been previously found.
Effects of the Dutch Skills for Life program on the health behavior, bullying, and suicidal ideation of secondary school students
Authors: Fekkes M. , van de Sande M.C. E. , Gravesteijn J. C. , Pannebakker F.D. , Buijs G. J. , Diekstra R.F.W. , Kocken P. L.
Published: December 2015

Purpose

– The purpose of this paper is to evaluate the effects of the Dutch “Skills for Life” programme on students’ health behaviours, bullying behaviour and suicidal ideation.

Design/methodology/approach

– The effectiveness of the “Skills for Life” programme on health behaviour outcomes was evaluated at three points in time in using a cluster randomized controlled study design with a follow-up of 20 months. In total, 27 schools and 1,394 students were included.

Findings

– The programme was judged to be well implemented in just under half of cases. The outcome results for the experimental group (EG) compared with controls present a complex picture at the three different time points used for evaluation. There was a clearly positive effect on levels of alcohol consumption and a clearly negative effect on smoking across time. There was a mixed picture over time for suicide ideation and for bullying including sexual bullying (although the prevalence rates for bullying were low and thus results should be treated with caution). There were generally more positive impacts on students with lower educational levels including less suicidal ideation and less bullying.

Research limitations/implications

– Limitations were the dropping out of several schools during the study and the low level of fidelity of the curriculum. Social emotional learning (SEL) programs can be part of a health promoting school framework but should be more tailored to disadvantaged school populations.

Originality/value

– The findings indicate that students with a less optimal starting position, when it comes to health related behaviours, benefit most from a SEL programme. This indicates that schools with disadvantaged school populations could benefit most from a Health Promoting School approach.
Collaborate to build effective teams to achieve organizational excellence and effectiveness
Authors: Rao M.S.
Published: December 2015

Purpose

– The purpose of this paper is to collaborate to build effective teams to achieve organizational excellence and effectiveness.

Design/methodology/approach

– The paper outlines a blueprint to build an effective team based on various personality types leveraging their competencies and capabilities.

Findings

– It implores to identify various personality types of your team members, leverage their strengths, understand their expectations and apply different leadership tools and techniques as per the situation to build an effective team.

Practical implications

– The tools and techniques adopted by leaders to build teams can be applied in any industry and in any size of organization.

Social implications

– The social implications of this research suggests that leaders can do much better by collaborating to bring synergy in team members.

Originality/value

– It outlines to lead three types of employees – actors, spectators and speed breakers in the workplace. It underscores to replace competitive mindset with a collaborative mindset to build successful teams.
Affective and developmental transitions: qualitative themes in multicultural counseling journals
Authors: Mayes Renae D. , Dollarhide Colette T. , Marshall Bowen , Rae Alexis
Published: December 2015

Purpose

– The purpose of this paper is to examine how multicultural counseling students expressed their understandings about themselves and others in relation to diversity. The authors wanted to know how cognitive development, affective development, and sense of self-evolved during a multicultural counseling class to examine all aspects of growth.

Design/methodology/approach

– Themes from a phenomenological qualitative analysis of journals from a multicultural counseling class suggest that students struggle with cognitive challenges (dealing with ambiguity, internalizing multicultural concepts, and self- and other-acceptance) and affective challenges (anger, guilt, and fear) in attaining multicultural growth.

Findings

– This expanded view of multicultural growth that includes affective challenges can fill a prior gap in understanding how multicultural learning occurs.

Research limitations/implications

– Implications are explored for counselor educators and supervisors.

Originality/value

– Recent use of journals to provide empirical insights into student growth include a study by Cohenet al.(2015), who used qualitative analyses of journal contents to examine growth in student attitudes toward geriatric clients, death, and dying. Knowing that student journals can provide insights into changing multicultural attitudes, and that qualitative methodology can provide tools for analysis, the authors decided that it might be possible to better understand multicultural growth by studying the journals written in a multicultural counseling class.
On docility: a research note on Herbert Simon’s social learning theory
Authors: McMillan Charles J.
Published: December 2015

Purpose

– The purpose of this paper is to address the core concept of docility in Simon’s learning theories and elaborate docility as a missing link in organizational performance structures. In his book,Administrative Behavior, first published in 1947 with three subsequent editions, Herbert A. Simon introduced a new concept to the emerging field of organizational theory, docility.

Design/methodology/approach

– InAdministrative Behavior, Herbert A. Simon introduced to management and organization theorists the concept of docility. Simon adopted the concept and meaning from E.C. Tolman’s (1932) classic work,Purposive Behavior in Animals and Men, and his novel views on learning processes and key concepts like purpose (goals), thought processes (cognitive psychology) and cognitive maps. This paper elaborates on docility mechanisms and the implications for social learning in organizations.

Findings

– This paper addresses this lacuna in the organizational literature, and the implications for current theories of organizations and organizational learning.

Practical implications

– Docility is a tool to link individual learning with organizational learning in complex environments and changing technologies.

Originality/value

– The paper traces origins of Simon’s docility and learning theories.
Detection of asymptomatic enthesitis in psoriasis patients: An onset of psoriatic arthritis?
Authors: Takata Tomoya , Takahashi Aya , Taniguchi Yoshinori , Terada Yoshio , Sano Shigetoshi
Published: December 2015

Presence of asymptomatic joint involvement is recognized in patients with psoriasis. However, it remains elusive whether such patients develop psoriatic arthritis (PsA). The aim of the present study was to examine the incidence of asymptomatic joint lesions, in particular, enthesitis in patients with psoriasis vulgaris (PsV) and to further assess the clinical features. Eighteen PsV and 28 PsA patients were enrolled for examination by positron emission tomography/computed tomography (PET/CT) using 18F‐fluorodeoxyglucose (FDG). Any nail, scalp and intergluteal involvements were reported. Levels of serum C‐reactive protein (CRP), white blood cell (WBC) counts and erythrocyte sedimentation rate (ESR) were examined. All of the PsA patients showed FDG accumulation in the affected joints. Notably, asymptomatic enthesitis was detected in six out of 18 PsV patients (33%), and they were diagnosed as having subclinical PsA. Incidences of scalp, intergluteal and nail psoriasis in subclinical PsA patients were 100%, 83% and 64%, respectively, which were higher than those in PsV patients (67%, 25% and 40%, respectively). CRP, WBC counts and ESR were invariable between PsV and subclinical PsA groups. PET/CT imaging could discover asymptomatic enthesitis. Our data suggested that the subpopulation of subclinical PsA was much higher than expected. Higher prevalence of nail, scalp and intergluteal psoriasis confirmed the risk of PsA as previously described.
Organoids derived from digestive tract, liver, and pancreas
Authors: Xu An Tao , Tong Jin Lu , Ran Zhi Hua
Published: December 2015

Lgr5 marks stem cells in digestive epithelial tissues by lineage tracing, and in vitro ever‐expansion of Lgr5 stem cells form organoids, which can be directed to differentiate into functional somatic cells. Organoids derived from gastrointestinal epithelium even recapitulate the morphologic features of their in vivo counterpart. Culture conditions are also modified to establish cancer organoids from individual patients. With great genetic stability during derivation and expansion, organoids retain either single mutation in patients with inherited disease or multiple mutations of cancer tissues. Together with efficient gene‐editing protocol, organoids are emerging as powerful in vitro disease models.
Does optimal access to dental care counteract the oral health‐related quality of life social gradient?
Authors: Crocombe LA , Mahoney GD
Published: December 2015

Background

The aim of this study was to determine if an oral health‐related quality of life (OHRQoL) social gradient existed when Australian Defence Force (ADF) members have universal and optimal access to dental care.

Methods

A nominal roll included 4089 individuals who were deployed to the Solomon Islands as part of Operation ANODE and a comparison group of 4092 ADF personnel frequency matched to the deployed group on gender, age group and service type, from which 500 deployed and 500 comparison individuals were randomly selected. The dependent variables were the OHIP‐14 summary measures. Rank was used to determine socioeconomic status. The demographic variables selected were: gender and age.

Results

The response rate was 44%. Of the individual OHIP‐14 items, being self‐conscious, painful aching and having discomfort when eating were the most common problems. Mean OHIP‐14 severity was 2.8. In bivariate analysis, there was not a significant difference in mean OHIP‐14 severity (p = 0.52) or frequency of OHIP‐14 impacts (p = 0.57) by military rank. There was a significant increasing OHIP‐14 extent score from commissioned officer to non‐commissioned officer to other ranks (0.07, 0.19, 0.40, p = 0.03).

Conclusions

Even with optimal access to dental care, there was an OHRQoL social gradient between military ranks in the ADF.
Discovery of 1,3‐Diaryl‐pyridones as Potent VEGFR‐2 Inhibitors: Design, Synthesis, and Biological Evaluation
Authors: Yan Wei , Huang Zhaoru , Wang Zhengyu , Cao Sufen , Tong Linjiang , Zhang Tao , Wang Chen , Zhou Lin , Ding Jian , Luo Cheng , Zhou Jinpei , Xie Hua , Duan Wenhu
Published: December 2015

In this study, we described the design, synthesis, and biological evaluation of 1,3‐diaryl‐pyridones as vascular endothelial growth factor receptor‐2 (VEGFR‐2) inhibitors. The 1,3‐diaryl‐pyridones were synthesized via Chan‐Lam and Suzuki coupling reactions. Two representative compounds, 17 and 35h, displayed excellent enzymatic inhibitory activities, with IC50 values of 3.5 and 3.0 nm, respectively. Furthermore, compounds 17 and 35h blocked the tube formation and suppressed the VEGF‐induced phosphorylation of VEGFR‐2 and downstream extracellular signal‐regulated kinases (Erk) in human umbilical vein endothelial cells (HUVECs) at 10 nm concentration. The docking simulation showed that compound 17 bound well into the active site of VEGFR‐2 via two hydrogen bonds and hydrophobic interactions.
The use of statistical methodology to determine the accuracy of grading within a diabetic retinopathy screening programme
Authors: Oke J. L. , Stratton I. M. , Aldington S. J. , Stevens R. J. , Scanlon P. H.
Published: December 2015

Aims

We aimed to use longitudinal data from an established screening programme with good quality assurance and quality control procedures and a stable well‐trained workforce to determine the accuracy of grading in diabetic retinopathy screening.

Methods

We used a continuous time‐hidden Markov model with five states to estimate the probability of true progression or regression of retinopathy and the conditional probability of an observed grade given the true grade (misclassification). The true stage of retinopathy was modelled as a function of the duration of diabetes and HbA1c.

Results

The modelling dataset consisted of 65 839 grades from 14 187 people. The median number [interquartile range (IQR)] of examinations was 5 (3, 6) and the median (IQR) interval between examinations was 1.04 (0.99, 1.17) years. In total, 14 227 grades (21.6%) were estimated as being misclassified, 10 592 (16.1%) represented over‐grading and 3635 (5.5%) represented under‐grading. There were 1935 (2.9%) misclassified referrals, 1305 were false‐positive results (2.2%) and 630 were false‐negative results (11.0%). Misclassification of background diabetic retinopathy as no detectable retinopathy was common (3.4% of all grades) but rarely preceded referable maculopathy or retinopathy.

Conclusion

Misclassification between lower grades of retinopathy is not uncommon but is unlikely to lead to significant delays in referring people for sight‐threatening retinopathy.
Life‐history differences of juvenile Chinook salmon Oncorhynchus tshawytscha across rearing locations in the Shasta River, California
Authors: Roddam Meiling , Ward Darren M.
Published: December 2015

Salmon from different locations in a watershed can have different life histories. It is often unclear to what extent this variation is a response to the current environmental conditions an individual experiences as opposed to local‐scale genetic adaptation or the environment experienced early in development. We used a mark–recapture transplant experiment in the Shasta River, CA, to test whether life‐history traits of juvenile Chinook salmon Oncorhynchus tshawytscha varied among locations, and whether individuals could adopt a new life history upon encountering new habitat type. The Shasta River, a Klamath River tributary, has two Chinook salmon spawning and juvenile rearing areas, a lower basin canyon (river km 0–12) and upper basin spring complex (river km 40–56), characterised by dramatically different in‐stream habitats. In 2012 and 2013, we created three experimental groups: (i) fish caught, tagged and released in the upper basin; (ii) fish caught at the river mouth (confluence with the Klamath River, river km 0), tagged and released in the upper basin; and (iii) fish caught at the river mouth, tagged and released in the lower basin. Fish released in the upper basin outmigrated later and at a larger size than those released in the lower basin. The traits of fish transplanted to the upper basin were similar to fish originating in the upper basin. Chinook salmon juvenile life‐history traits reflected habitat conditions fish experienced rather than those where they originated, indicating that habitat modification or transportation to new habitats can rapidly alter the life‐history composition of populations.
The extremely broad odorant response profile of mouse olfactory sensory neurons expressing the odorant receptor MOR256‐17 includes trace amine‐associated receptor ligands
Authors: Tazir Bassim , Khan Mona , Mombaerts Peter , Grosmaitre Xavier
Published: December 2015

The mouse olfactory system employs ~1100 G‐protein‐coupled odorant receptors (ORs). Each mature olfactory sensory neuron (OSN) is thought to express just one OR gene, and the expressed OR determines the odorant response properties of the OSN. The broadest odorant response profile thus far demonstrated in native mouse OSNs is for OSNs that express the OR gene SR1 (also known as Olfr124 and MOR256‐3). Here we showed that the odorant responsiveness of native mouse OSNs expressing the OR gene MOR256‐17 (also known as Olfr15 and OR3) is even broader than that of OSNs expressing SR1. We investigated the electrophysiological properties of green fluorescent protein (GFP)+ OSNs in a MOR256‐17‐IRES‐tauGFP gene‐targeted mouse strain, in parallel with GFP+ OSNs in the SR1‐IRES‐tauGFP gene‐targeted mouse strain that we previously reported. Of 35 single chemical compounds belonging to distinct structural classes, MOR256‐17+ OSNs responded to 31 chemicals, compared with 10 for SR1+ OSNs. The 10 compounds that activated SR1+ OSNs also activated MOR256‐17+ OSNs. Interestingly, MOR256‐17+ OSNs were activated by three amines (cyclohexylamine, isopenthylamine, and phenylethylamine) that are typically viewed as ligands for chemosensory neurons in the main olfactory epithelium that express trace amine‐associated receptor genes, a family of 15 genes encoding G‐protein‐coupled receptors unrelated in sequence to ORs. We did not observe differences in membrane properties, indicating that the differences in odorant response profiles between the two OSN populations were due to the expressed OR. MOR256‐17+ OSNs appear to be at one extreme of odorant responsiveness among populations of OSNs expressing distinct OR genes in the mouse.
Directional selection for flowering time leads to adaptive evolution in Raphanus raphanistrum (Wild radish)
Authors: Ashworth Michael B. , Walsh Michael J. , Flower Ken C. , Vila‐Aiub Martin M. , Powles Stephen B.
Published: December 2015

Herbicides have been the primary tool for controlling large populations of yield depleting weeds from agro‐ecosystems, resulting in the evolution of widespread herbicide resistance. In response, nonherbicidal techniques have been developed which intercept weed seeds at harvest before they enter the soil seed bank. However, the efficiency of these techniques allows an intense selection for any trait that enables weeds to evade collection, with early‐flowering ecotypes considered likely to result in early seed shedding. Using a field‐collected wild radish population, five recurrent generations were selected for early maturity and three generations for late maturity. Phenology associated with flowering time and growth traits were measured. Our results demonstrate the adaptive capacity of wild radish to halve its time to flowering following five generations of early‐flowering selection. Early‐maturing phenotypes had reduced height and biomass at maturity, leading to less competitive, more prostrate growth forms. Following three generations of late‐flowering selection, wild radish doubled its time to flowering time leading to increased biomass and flowering height at maturity. This study demonstrates the potential for the rapid evolution in growth traits in response to highly effective seed collection techniques that imposed a selection on weed populations within agro‐ecosystems at harvest.
Modeling neurodevelopmental cognitive deficits in tasks with cross‐species translational validity
Authors: Cope Z. A. , Powell S. B. , Young J. W.
Published: December 2015

Numerous psychiatric disorders whose cognitive dysfunction links to functional outcome have neurodevelopmental origins including schizophrenia, autism and bipolar disorder. Treatments are needed for these cognitive deficits, which require development using animal models. Models of neurodevelopmental disorders are as varied and diverse as the disorders themselves, recreating some but not all aspects of the disorder. This variety may in part underlie why purported procognitive treatments translated from these models have failed to restore functioning in the targeted patient populations. Further complications arise from environmental factors used in these models that can contribute to numerous disorders, perhaps only impacting specific domains, while diagnostic boundaries define individual disorders, limiting translational efficacy. The Research Domain Criteria project seeks to ‘develop new ways to classify mental disorders based on behavioral dimensions and neurobiological measures’ in hopes of facilitating translational research by remaining agnostic toward diagnostic borders derived from clinical presentation in humans. Models could therefore recreate biosignatures of cognitive dysfunction irrespective of disease state. This review highlights work within the field of neurodevelopmental models of psychiatric disorders tested in cross‐species translational cognitive paradigms that directly inform this newly developing research strategy. By expounding on this approach, the hopes are that a fuller understanding of each model may be attainable in terms of the cognitive profile elicited by each manipulation. Hence, conclusions may begin to be drawn on the nature of cognitive neuropathology on neurodevelopmental and other disorders, increasing the chances of procognitive treatment development for individuals affected in specific cognitive domains.
Capillary seal capacity of faults under hydrodynamic conditions
Authors: Underschultz J. , Strand J.
Published: December 2015

Many fault bound traps are underfilled despite the top seal capacity being secure. The hydrocarbon sealing performance of faults themselves can be compromised either by mechanical or capillary process. Capillary process can be important either due to juxtaposition or to fine‐grained clay or cataclastic material within the fault zone itself. There is debate about how important each of these mechanisms is over geological timescales of hydrocarbon trapping. Recent work has provided insights into fine‐tuning capillary‐related fault seal calibration methodologies. Over the last 15 years, vigorous scientific debate with multiple published laboratory experiments and modelling studies has led some researchers and industry technologists to theorise that for water‐wet conventional hydrocarbon reservoirs, the relative water permeability in the reservoir (towards the top of the hydrocarbon column) may become very small, but in practice never reach zero. While not advocating for either side in this debate, the importance of accounting for hydrodynamic conditions regardless of the capillary sealing mechanism is demonstrated. Additionally, it is noted that nonzero relative water permeability has implications on how a seal's capillary threshold pressure for the nonwetting hydrocarbon phase is estimated from field data. In the particular case where there are pressure differences between unproduced hydrocarbon reservoirs on either side of a fault, then the hydrocarbon saturation must be discontinuous across the fault. For hydrocarbon leakage to occur across the entire thickness of the fault zone, the hydrocarbon pressure must exceed the threshold pressure on the side of the fault zone with the highest formation water hydraulic head. This approach to estimating across‐fault pressure difference will result in an improved calibration data set used for predrill estimation of capillary fault seal capacity.
Germination responses of the halophyte Chloris virgata to temperature and reduced water potential caused by salinity, alkalinity and drought stress
Authors: Lin J. , Shao S. , Wang Y. , Qi M. , Lin L. , Wang Y. , Yan X.
Published: December 2015

Chloris virgata is considered a useful grass species for grassland restoration in northern China. However, little information exists concerning the germination responses of this species to temperature and water potential caused by stress conditions. Experiments were conducted in growth chambers to assess the effect of temperature, salinity, alkalinity, drought and the interactions of temperature and stress on seed germination. Seeds were germinated at three diurnal temperature regimes, with four water potentials in NaCl, NaHCO3 and PEG solutions. Results showed that optimal germination under stress occurred at 15–25 °C, and germination percentages and rates were inhibited by either an increase or decrease in temperature from the optimal temperature. The inhibitory effects of the low water potential caused by salinity and drought on germination were greater at 25–35 °C, but seeds were subjected to more stress despite the relatively higher water potential because of the alkalinity at this temperature. The recovery percentage under salinity was highest at −1·2 MPa at 15–25 °C, and more than 80% of seeds also germinated at this water potential after they were transferred from drought stress. However, seeds lost their viability in higher alkalinities under all temperatures, and at 25–35 °C, there was lower recovery percentage under stress. Results suggest that salinity, alkalinity and drought stress have different impacts on seed germination, and the tolerance to stress of C. virgata seeds is affected by the interactions of temperature and water potential caused by salinity, alkalinity and drought. Chloris virgata shows potential utility as a promising grass species in salinity–alkalinity and drought‐stressed environments.