bluuebunny/crossref_metadata_2025 huggingface dataset:
Rudist bivalves and the Pacific in the Late Jurassic and Early Cretaceous
Authors: Skelton Peter W. , Sano Shin-Ichi , Masse Jean-Pierre
Published: April 2013

Although rudists of Late Jurassic to earliest Cretaceous age are known from Nova Scotia to Japan, the oldest specimens recovered from Pacific seamounts are Barremian (or possibly Hauterivian). The lack of evidence for disjunct endemism limited to either side of the ocean, then, precludes the inference that earlier rudists might have been present within it. Yet trans-Pacific range expansion of Caribbean-derived taxa, by means of larval ‘island-hopping’, was accomplished by the Early Aptian. Following a mid-Aptian mass extinction, the Pacific then became an important nursery of rudist re-diversification. Late Aptian rudists in Japan and derivative Late Aptian–Albian polyconitids in the Japanese Seamounts and Cebu show affinities with those from the eastern (Himalayan) sector of the northern Tethyan margin. By contrast, the caprinid
Caprina mulleri
in the Mid-Pacific Mountains is most closely allied with the
C. choffati–C. adversa
lineage known from the Atlantic–Mediterranean Tethyan region. However, the Pacific species could have been derived from an Early Aptian Caribbean
Caprina
that survived in some Pacific refuge, later reintroducing the genus to the Tethyan region in the Late Albian. Colonization of Pacific volcanic prominences ceased in the latest Albian, with the demise of carbonate platforms there, and was not resumed until the Campanian–Maastrichtian.
Stratigraphy of the Gorges moraine system, Mount Kenya: palaeosol and palaeoclimate record
Authors: Mahaney W. C. , Barendregt René W. , Hamilton T. S. , Hancock R. G. V. , Tessler Dez , Costa Pedro J. M.
Published: April 2013

Moraines marking an Early Pleistocene glaciation on Mt. Kenya are known from several valleys along the eastern and southeastern flanks of the mountain. The most prominent group of end moraines delimiting the lowermost extent of the Early Pleistocene Gorges Glaciation (2900 m above sea level) overlie either older till or weathered bedrock, the latter composed of thin pedostratigraphic remnants covered with locally derived aeolian sediments truncated by the ingress of ice. The loess, tills and interbedded palaeosols of the Gorges Glaciation crop out adjacent to the Nithi River, which drains the Gorges Valley, and abut the upper timberline of montane forest. The lowermost palaeosols at these sites were formed either in till predating the Gorges Glaciation or in weathered bedrock of trachytic textured lavas, similar to the lithology forming the base of the Mt. Kenya volcanic series of Miocene or Pliocene age. Palaeomagnetism and weathering characteristics are here used to refine the age of sediments assigned to the Gorges Glaciation. These normally magnetized deposits carry a persistent reversed overprint, suggesting that they were deposited during one of the normal subchrons within the Matuyama Reversed Chron. They are underlain either by a reversely magnetized till, or by weathered bedrock and lower palaeosol, the latter exhibiting normal magnetization (Gauss?) with reversed overprint (Matuyama?). The sediments of the Gorges Glaciation are overlain at all three sites by normally magnetized loesses and palaeosols, presumably of Brunhes age but carrying a high percentage of well-weathered recycled grains. The normal magnetization and reversed overprint recorded in sediments of the Gorges Glaciation most probably span a considerable portion of the Olduvai subchron (1.78–1.950 Ma), which persisted for sufficient time to accommodate an extensive montane glaciation followed by a prolonged period of weathering and soil formation. The importance of these sediments in global palaeoclimate reconstruction and insolation changes is discussed. The stratigraphic evidence contradicts the cosmogenic exposure ages presented by previous workers attempting to obtain true ages of deposits using exhumed coarse clastic sediment without analysis of complex pedostratigraphic complexes.

Supplementary materials:

Tables 1S–5S are available at
www.geolsoc.org.uk/SUP18592
.
Regional metamorphism in the Ballachulish area, SW Highlands, Scotland: new perspectives on a famous old debate, with regional implications
Authors: Pattison David R. M.
Published: April 2013

The Ballachulish region of the SW Highlands of Scotland was the focal point of a famous debate in the 1920s between Sir Edward Battersby Bailey and Professor Cecil Edgar Tilley concerning the identity, geometry and timing of development of metamorphic zones in the SW Highlands. New mineral assemblage data, microstructural observations, and rock and mineral compositional data are combined with phase equilibrium modelling to reassess the metamorphism in this area. The newly revised chlorite, biotite and garnet zones are similar to those of Bailey. Compositional difference between lithologies is the primary cause of the irregular distribution of mineral assemblages in the region. Microstructural observations suggest that metamorphism occurred in the latter stages of the deformation history, in agreement with previous studies. Pressure–temperature conditions of the garnet isograd are estimated to be
c
. 7 kbar,
c
. 500 °C. These are compared with
P–T
estimates of the garnet zone elsewhere in Scotland.

Supplementary materials:

Appendix 1 lists mineral assemblages, Appendix 2 lists whole-rock compositions, and Appendices 3–7 list representative mineral compositions (garnet, biotite, muscovite, chlorite and plagioclase–epidote, respectively). Appendices 8 and 9 are the compositional input and thermodynamic input files for Theriak-Domino used to calculate the phase diagrams in this paper. The appendices are available at
www.geolsoc.org.uk/SUP18586
.
Seismic data conditioning and neural network-based attribute selection for enhanced fault detection
Authors: Chehrazi A. , Rahimpour-Bonab H. , Rezaee M. R.
Published: April 2013

In this study of the Dorood oil field, offshore Iran, 3D seismic data were utilized to identify a complex fault pattern in the highly faulted and fractured Fahliyan Formation. To enhance data quality and improve attribute accuracy and detection power, a steering cube was first computed based on a sliding 3D Fourier analysis technique, using the concept of directivity. The steering cube, which contains dip and azimuth information for each trace, was utilized for calculation of dip-steered filters and attributes. We applied the dip-steered median filter to remove random noise and to enhance laterally continuous seismic events by filtering along the structural dip. Several fault identification attributes, such as dip, curvature, coherency and similarity, and a meta-attribute of a ridge enhancement filter, were extracted from dip-steered, noise-attenuated data. A supervised, fully connected multi-layer perceptron neural network was constructed to select and combine the most sensitive fault attributes. The neural network, trained at identified fault and non-fault locations, was applied to the whole seismic volume to generate a cube of fault probability.

Interpretations of major faults and fractures were integrated with geological, reservoir engineering and production data to highlight the role of these heterogeneities on dynamic reservoir properties. Faults and fractures in the Fahliyan reservoir were identified in general to have the effect of decreasing reservoir permeability. While most of the faults recognized have locally a sealing capacity effect, when the fault throws are large enough to bring into contact the Manifa and Yamama reservoirs, they act as a conduit for fluid communication and, wherever a well crosses a major fault, early water breakthrough is observable.
Quantification of hydrodynamic effects on capillary seal capacity
Authors: Manzocchi T. , Childs C.
Published: April 2013

Whether a reduction in overpressure across a hydrocarbon column and its seal will reduce the column height that the seal is capable of supporting has been much debated. Recent studies have focused on measuring water relative permeability at high capillary pressure, and have concluded that hydrocarbon columns may be sufficiently permeable to water for the seal capacity to be unaffected by hydrodynamic flow in most situations. A new method for estimating the capillary seal capacity is developed which properly takes into account viscous as well as gravity and capillary forces. A reassessment of existing analyses indicates that hydrodynamic flow has a greater influence on the seal capacity than previously thought. Sets of sensitivity models, including a range of reservoir and seal geometrical and petrophysical characteristics, indicate that – as a general rule – hydrodynamic flow should not be neglected when assessing capillary seal capacity. The sealing capacity of thick top seals above reservoirs with a basal aquifer are least likely to be affected by hydrodynamic flow. The sealing capacity of membrane fault seals, irrespective of whether they have a basal or edge aquifer, may be influenced by realistic overpressure differences. Simple end-member equations define the possible influence of hydrodynamic flow in a particular situation, and only if this is significant should a more comprehensive evaluation be considered.
Numerical modelling of fractures induced by coal mining beneath reservoirs and aquifers in China
Authors: Wu Xiong , Jiang Xiao-Wei , Chen Yu-Fu , Wang Xiao-Lei , Tan Shu-Hong
Published: April 2013

The increasing demand in recent years for energy in China has resulted in coal being mined in complex geological conditions. This has included the mining of coal seams located beneath reservoirs, aquifers and flooded abandoned mine workings. Throughout China the extraction of coal in these circumstances has resulted in groundwater inrushes into working mines. This has caused loss of lives, disruption or abandonment of coal mining, and the sterilization of coal resources. This paper demonstrates that numerical modelling using ANSYS-2D, FLAC-2D and FLAC-3D combined with field observations may provide a method for the modelling of fractures that develop in the rock mass above a roof of coal mines. These fractures may increase significantly the permeability of the strata and groundwater flows into mine workings.
Deoxygenated gas occurrences in the Lambeth Group of central London, UK
Authors: Newman T. G. , Ghail R. C. , Skipper J. A.
Published: April 2013

Deoxygenated air poses a serious, life-threatening hazard (confined space hypoxia) for engineering projects in London, particularly within the Upnor Formation of the Lambeth Group. This paper reviews its causes and postulates that it was induced by regional-scale dewatering and drawdown of the Lower Aquifer during the industrial growth of London, bringing air into contact with these sediments, which became oxidized. Ensuing post-industrial recharge and resaturation resulted in accumulations of often compressed deoxygenated air, trapped beneath overlying impermeable clay strata. Historically, glauconite has been considered to be the mineral most likely to remove oxygen from the trapped air, but it lacks potency as a reducing agent and remains unaltered in many oxidized sediments. Pyrite and organic carbon are both plausible, but rare. Green rust, a mixed Fe(II) and Fe(III) layered double hydroxide, is more likely, as it rapidly oxidizes on contact with air and is only briefly observed in fresh core samples. Two key ground engineering hazards are, therefore, identified: the misidentification of risk by reliance on observations of glauconite; and the likelihood of encountering pressurized deoxygenated air within Lambeth Group sediments in underground projects following short- or long-term changes in the groundwater level.
Resolution of the direct interaction with and inhibition of the human GLUT1 hexose transporter by resveratrol from its effect on glucose accumulation
Authors: Salas Mónica , Obando Patricia , Ojeda Lorena , Ojeda Paola , Pérez Alejandra , Vargas-Uribe Mauricio , Rivas Coralia I. , Vera Juan C. , Reyes Alejandro M.
Published: April 2013

Resveratrol acts as a chemopreventive agent for cancer and as a potential antiobesity and antidiabetic compound, by leading to reduced body fat and improved glucose homeostasis. The exact mechanisms involved in improving hyperglycemic state are not known, but most of the glucose uptake into mammalian cells is facilitated by the GLUT hexose transporters. Resveratrol is structurally similar to isoflavones such as genistein, which inhibit the glucose uptake facilitated by the GLUT1 hexose transporter. Here we examined the direct effects of resveratrol on glucose uptake and accumulation in HL-60 and U-937 leukemic cell lines, which express mainly GLUT1, under conditions that discriminate transport from the intracellular substrate phosphorylation/accumulation. Resveratrol blocks GLUT1-mediated hexose uptake and thereby affects substrate accumulation on these cells. Consequently, we characterized the mechanism involved in inhibition of glucose uptake in human red cells. Resveratrol inhibits glucose exit in human red cells, and the displacement of previously bound cytochalasin B revealed the direct interaction of resveratrol with GLUT1. Resveratrol behaves as a competitive blocker of glucose uptake under zero- trans exit and exchange kinetic assays, but it becomes a mixed noncompetitive blocker when zero- trans entry transport was assayed, suggesting that the binding site for resveratrol lies on the endofacial face of the transporter. We propose that resveratrol interacts directly with the human GLUT1 hexose transporter by binding to an endofacial site and that this interaction inhibits the transport of hexoses across the plasma membrane. This inhibition is distinct from the effect of resveratrol on the intracellular phosphorylation/accumulation of glucose.
Glucose-stimulated insulin secretion causes an insulin-dependent nitric oxide–mediated vasodilation in the blood supply of the rat sciatic nerve
Authors: Olver T. Dylan , Mattar Louis , Grisé Kenneth N. , Twynstra Jasna , Noble Earl G. , Lacefield James C. , Shoemaker J. Kevin
Published: April 2013

This study tested the hypothesis that acute hyperglycemia reduces sciatic nerve blood flow in Sprague-Dawley rats. Anesthetized rats underwent cannulation of their right jugular vein (for anesthetic/nutrient/drug infusion) and right carotid artery (for continuous blood pressure measurement via pressure transducer). The left sciatic nerve was exposed and nerve blood velocity (NBV) was assessed from an arterial segment lying superficially along the sciatic nerve (Doppler ultrasound, 40 MHz). NBV and mean arterial pressure (MAP) values were collected, and an index of nerve vascular conductance (NVC) was established (NBV/MAP) at baseline and at 5, 10, 20, and 30 min (and 80 min for insulin) following 1) low glucose infusion, 1 g/kg (50% solution); 2) high glucose infusion, 3 g/kg; 3) high glucose infusion in the absence of a functioning pancreas; 4) euglycemic hyperinsulinemic clamp–insulin infusion (10 mU·kg−1·min−1; 0.4 IU/ml); 5) high glucose infusion + NG-nitro-l-arginine methyl ester (l-NAME) infusion (30 mg/kg); and 6) l-NAME alone followed 20 min later by high glucose infusion. High glucose infusion increased NVC by ∼120% relative to baseline ( P < 0.001), and this dilation was attenuated in rats without a functioning pancreas (i.e., without insulin secretion) ( P = 0.004) and following l-NAME infusion ( P = 0.011). Therefore, the vasodilation in rat sciatic nerve during glucose infusion was dependent upon the insulin response and acted through a nitric oxide synthase pathway.
The physiological basis of rehabilitation in chronic heart and lung disease
Authors: Vogiatzis Ioannis , Zakynthinos Spyros
Published: April 2013

Cardiopulmonary rehabilitation is recognized as a core component of management of individuals with congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) that is designed to improve their physical and psychosocial condition without impacting on the primary organ impairment. This has lead the scientific community increasingly to believe that the main effects of cardiopulmonary rehabilitative exercise training are focused on skeletal muscles that are regarded as dysfunctional in both CHF and COPD. Accordingly, following completion of a cardiopulmonary rehabilitative exercise training program there are important peripheral muscular adaptations in both disease entities, namely increased capillary density, blood flow, mitochondrial volume density, fiber size, distribution of slow twitch fibers, and decreased lactic acidosis and vascular resistance. Decreased lactic acidosis at a given level of submaximal exercise not only offsets the occurrence of peripheral muscle fatigue, leading to muscle task failure and muscle discomfort, but also concurrently mitigates the additional burden on the respiratory muscles caused by the increased respiratory drive, thereby reducing dyspnea sensations. Furthermore in patients with COPD, exercise training reduces the degree of dynamic lung hyperinflation leading to improved arterial oxygen content and central hemodynamic responses, thus increasing systemic muscle oxygen availability. In patients with CHF, exercise training has beneficial direct and reflex sympathoinhibitory effects and favorable effects on normalization of neurohumoral excitation. These physiological benefits apply to all COPD and CHF patients independently of the degree of disease severity and are associated with improved exercise tolerance, functional capacity, and quality of life.
Five types of nonspiking interneurons in local pattern-generating circuits of the crayfish swimmeret system
Authors: Smarandache-Wellmann Carmen , Weller Cynthia , Wright Terrence M. , Mulloney Brian
Published: April 2013

We conducted a quantitative analysis of the different nonspiking interneurons in the local pattern-generating circuits of the crayfish swimmeret system. Within each local circuit, these interneurons control the firing of the power-stroke and return-stroke motor neurons that drive swimmeret movements. Fifty-four of these interneurons were identified during physiological experiments with sharp microelectrodes and filled with dextran Texas red, Neurobiotin, or both. Five types of neurons were identified on the basis of combinations of physiological and anatomical characteristics. Anatomical categories were based on 16 anatomical parameters measured from stacks of confocal images obtained from each neuron. The results support the recognition of two functional classes: inhibitors of power stroke (IPS) and inhibitors of return stroke (IRS). The IPS class of interneuron has three morphological types with similar physiological properties. The IRS class has two morphological types with physiological properties and anatomical features different from the IPS neurons but similar within the class. Three of these five types have not been previously identified. Reviewing the evidence for dye coupling within each type, we conclude that each type of IPS neuron and one type of IRS neuron occur as a single copy in each local pattern-generating circuit. The last IRS type includes neurons that might occur as a dye-coupled pair in each local circuit. Recognition of these different interneurons in the swimmeret pattern-generating circuits leads to a refined model of the local pattern-generating circuit that includes synaptic connections that encode and decode information required for intersegmental coordination of swimmeret movements.
Hip proprioceptors preferentially modulate reflexes of the leg in human spinal cord injury
Authors: Onushko Tanya , Hyngstrom Allison , Schmit Brian D.
Published: April 2013

Stretch-sensitive afferent feedback from hip muscles has been shown to trigger long-lasting, multijoint reflex responses in people with chronic spinal cord injury (SCI). These reflexes could have important implications for control of leg movements during functional activities, such as walking. Because the control of leg movement relies on reflex regulation at all joints of the limb, we sought to determine whether stretch of hip muscles modulates reflex activity at the knee and ankle and, conversely, whether knee and ankle stretch afferents affect hip-triggered reflexes. A custom-built servomotor apparatus was used to stretch the hip muscles in nine chronic SCI subjects by oscillating the legs about the hip joint bilaterally from 10° of extension to 40° flexion. To test whether stretch-related feedback from the knee or ankle would be affected by hip movement, patellar tendon percussions and Achilles tendon vibration were delivered when the hip was either extending or flexing. Surface electromyograms (EMGs) and joint torques were recorded from both legs. Patellar tendon percussions and Achilles tendon vibration both elicited reflex responses local to the knee or ankle, respectively, and did not influence reflex responses observed at the hip. Rather, the movement direction of the hip modulated the reflex responses local to the joint. The patellar tendon reflex amplitude was larger when the perturbation was delivered during hip extension compared with hip flexion. The response to Achilles vibration was modulated by hip movement, with an increased tonic component during hip flexion compared with extension. These results demonstrate that hip-mediated sensory signals modulate activity in distal muscles of the leg and appear to play a unique role in modulation of spastic muscle activity throughout the leg in SCI.
Thalamic microcircuits: presynaptic dendrites form two feedforward inhibitory pathways in thalamus
Authors: Crandall Shane R. , Cox Charles L.
Published: April 2013

In the visual thalamus, retinal afferents activate both local interneurons and excitatory thalamocortical relay neurons, leading to robust feedforward inhibition that regulates the transmission of sensory information from retina to neocortex. Peculiarly, this feedforward inhibitory pathway is dominated by presynaptic dendrites. Previous work has shown that the output of dendritic terminals of interneurons, also known as F2 terminals, are regulated by both ionotropic and metabotropic glutamate receptors. However, it is unclear whether both classes of glutamate receptors regulate output from the same or distinct dendritic terminals. Here, we used focal glutamate uncaging and whole cell recordings to reveal two types of F2 responses in rat visual thalamus. The first response, which we are calling a Type-A response, was mediated exclusively by ionotropic glutamate receptors (i.e., AMPA and NMDA). In contrast, the second response, which we are calling a Type-B response, was mediated by a combination of ionotropic and type 5 metabotropic glutamate receptors (i.e., mGluR5). In addition, we demonstrate that both F2 responses are evoked in the same postsynaptic neurons, which are morphologically distinct from neurons in which no F2 responses are observed. Since photostimulation was relatively focal and small in magnitude, these results suggest distinct F2 terminals, or small clusters of terminals, could be responsible for generating the two inhibitory responses observed. Because of the nature of ionotropic and metabotropic glutamate receptors, we predict the efficacy by which the retina communicates with the thalamus would be strongly regulated by 1) the activity level of a given retinogeniculate axon, and 2) the specific type of F2 terminals activated.
GABAergic transmission facilitates ictogenesis and synchrony between CA3, hilus, and dentate gyrus in slices from epileptic rats
Authors: Gafurov Boris , Bausch Suzanne B.
Published: April 2013

The impact of regional hippocampal interactions and GABAergic transmission on ictogenesis remain unclear. Cortico-hippocampal slices from pilocarpine-treated epileptic rats were compared with controls to investigate associations between seizurelike events (SLE), GABAergic transmission, and neuronal synchrony within and between cortico-hippocampal regions. Multielectrode array recordings revealed more prevalent hippocampal SLE in epileptic tissue when excitatory transmission was enhanced and GABAergic transmission was intact [removal of Mg2+ (0Mg)] than when GABAergic transmission was blocked [removal of Mg2+ + bicuculline methiodide (0Mg+BMI)]. When activity within individual regions was analyzed, spectral and temporal slow oscillation/SLE correlations and cross-correlations were highest within the hilus of epileptic tissue during SLE but were similar in 0Mg and 0Mg+BMI. GABAergic facilitation of spectral “slow” oscillation and ripple correlations was most prominent within CA3 of epileptic tissue during SLE. When activity between regions was analyzed, slow oscillation and ripple coherence was highest between the hilus and dentate gyrus as well as between the hilus and CA3 of epileptic tissue during SLE and was significantly higher in 0Mg than 0Mg+BMI. High 0Mg-induced SLE cross-correlations between the hilus and dentate gyrus as well as between the hilus and CA3 were reduced or abolished in 0Mg+BMI. SLE cross-correlation lag measurements provided evidence for a monosynaptic connection from the hilus to the dentate gyrus during SLE. Findings implicate the hilus as an oscillation generator, whose impact on other cortico-hippocampal regions is mediated by GABAergic transmission. Data also suggest that GABAA receptor-mediated transmission facilitates back-propagation from CA3/hilus to the dentate gyrus and that this back-propagation augments SLE in epileptic hippocampus.
Prenatal stress alters noradrenergic modulation of LTP in hippocampal slices
Authors: Grigoryan Gayane , Segal Menahem
Published: April 2013

Long-term effects of stress during pregnancy on brain and behavior have been analyzed extensively in recent years. These effects include changes in emotional behavior, a reduction in learning capacity, and ability to generate long-term potentiation (LTP) in the offspring. In earlier studies, we and others have described a difference in ability to express LTP in dorsal and ventral sectors of the hippocampus (DH and VH, respectively) and its modification by prior stress. We now found that norepinephrine (NE) facilitated conversion of short-term potentiation to LTP in the normal DH but not in VH. Prenatal stress (PS) switched the locus of the facilitating action of NE from the DH to the VH. The effects of NE are likely to be mediated by activation of calcium stores. PS also facilitated ( S)-3,5-dihydroxyphenylglycine hydrate (DHPG)-induced LTD in the VH, assumed to be mediated by release of calcium from stores. These observations have important implications for the role of the hippocampus in cognitive and emotional memories.
Modulation of calcium currents and membrane properties by substance P in the lamprey spinal cord
Authors: Pérez Carolina Thörn , Hill Russell H. , Grillner Sten
Published: April 2013

Substance P is endogenously released within the locomotor network of the adult lamprey, accelerates the burst frequency of fictive locomotion, and reduces the reciprocal inhibition. Previous studies have shown that dopamine, serotonin, and GABA regulate calcium channels, which control neurotransmitter release, action potential duration, and slow afterhyperpolarization (sAHP). Here we examine the effect of substance P on calcium channels in motoneurons and commissural interneurons using whole cell patch clamp in the lamprey spinal cord. This study analyzed the effects of substance P on calcium currents activated in voltage clamp. We examined the calcium-dependent sAHP in current clamp, to determine the involvement of three calcium channel subtypes modulated by substance P. The effects of substance P on membrane potential and during N-methyl-d-aspartic acid (NMDA) induced oscillations were also analyzed. Depolarizing voltage steps induced inward calcium currents. Substance P reduced the currents carried by calcium by 61% in commissural interneurons and by 31% in motoneurons. Using specific calcium channel antagonists, we show that substance P reduces the sAHP primarily by inhibiting N-type (CaV2.2) channels. Substance P depolarized both motoneurons and commissural interneurons, and we present evidence that this occurs due to an increased input resistance. We also explored the effects of substance P on NMDA-induced oscillations in tetrodotoxin and found it caused a frequency increase. Thus the reduction of calcium entry by substance P and the accompanying decrease of the sAHP amplitude, combined with substance P potentiation of currents activated by NMDA, may both contribute to the increase in fictive locomotion frequency.
On the Regulation and Activation of JAK2: A Novel Hypothetical Model
Authors: Lee Tai-Sung
Published: April 2013

Janus kinase 2 (JAK2) is a protein tyrosine kinase central to a multitude of cellular processes. Here, a novel model of JAK2 regulation and activation is proposed. In the JAK2 dimer, instead of being auto-inhibited by its own JH2 domain, inhibition comes from the JH2 domain of the partnering JAK2 monomer. Upon ligand binding, the receptor undergoes a conformational rotation that is passed to its dimeric partner. The activation is achieved by the rotation of two JAK2 molecules, which relieves the JH1/JH2 inhibitory interface and brings two JH1 domains in proximity for the subsequent trans-phosphorylation event. This hypothetical model is consistent with most of the currently available experimental evidence and warrants further tests. Based on the proposed model, it is possible to rationalize the differential responses of JAK2 signaling involving various receptors and ligands.

Implications: The proposed model of JAK2 regulation and activation is poised to suggest potential alternative drug-discovery strategies that could impact a number of relevant diseases. Mol Cancer Res; 11(8); 811–4. ©2013 AACR.
The Acoustic Parameters of Polish Voiceless Fricatives: An Analysis of Variance
Authors: Jassem Wiktor
Published: April 2013

Averaged spectra of the Polish voiceless fricatives are described in terms of three central moments, and the variables are analysed using both univariate and multivariate analysis of variance. The vowel context effect is strong, but that of the (male) speaker is not. /∫/ is not distinct from /ҩ/ in this experiment, but this failure should not be a handicap in automatic speech recognition.
Prediction of BRCA1 Germ-Line Mutation Status in Patients with Breast Cancer Using Histoprognosis Grade, MS110, Lys27H3, Vimentin, and KI67
Authors: Hassanein Mohamed , Huiart Laetitia , Bourdon Violaine , Rabayrol Laetitia , Geneix Jeanine , Nogues Catherine , Peyrat Jean Philippe , Gesta Paul , Meynard Paule , Dreyfus Helene , Petrot Dominique , Lidereau Rosette , Noguchi Tetsuro , Eisinger François , Extra Jean Marc , Viens Patrice , Jacquemier Jocelyne , Sobol Hagay
Published: April 2013

Family structure, lack of reliable information, cost, and delay are usual concerns when deciding to perform BRCA analyses. Testing breast cancer tissues with four antibodies (MS110, lys27H3, vimentin, and KI67) in addition to grade evaluation enabled us to rapidly select patients for genetic testing identification. We constituted an initial breast cancer tissue microarray, considered as a learning set, comprising 27 BRCA1 and 81 sporadic tumors. A second independent validation set of 28 BRCA1 tumors was matched to 28 sporadic tumors using the same original conditions. We investigated morphological parameters and 21 markers by immunohistochemistry. A logistic regression model was used to select the minimal number of markers providing the best model to predict BRCA1 status. The model was applied to the validation set to estimate specificity and sensibility. In the initial set, univariate analyses identified 11 markers significantly associated with BRCA1 status. Then, the best multivariate model comprised only grade 3, MS110, Lys27H3, vimentin, and KI67. When applied to the validation set, BRCA1 tumors were correctly classified with a sensitivity of 83% and a specificity of 81%. The performance of this model was superior when compared to other profiles. This study offers a new rapid and cost-effective method for the prescreening of patients at high risk of being BRCA1 mutation carriers, to guide genetic testing, and finally to provide appropriate preventive measures, advice, and treatments including targeted therapy to patients and their families.
Cytomorphological Factors and BRAF Mutation Predicting Risk of Lymph Node Metastasis in Preoperative Liquid-Based Fine Needle Aspirations of Papillary Thyroid Carcinoma
Authors: Chung Soo Young , Lee Jae Seok , Lee Hyebin , Park Sung Hee , Kim Soo Jin , Ryu Han Suk
Published: April 2013

Objective: Preoperative fine needle aspiration biopsy (FNAB) has become the initial diagnostic method for papillary thyroid carcinoma (PTC). Identification of cytomorphologic factors predicting lymph node metastasis (LNM) is clinically important for determining the appropriate treatment regimen due to the high rate of lymph node involvement in PTC at the time of diagnosis. Hobnail features (HF) have previously been described as potential histomorphologic features in the histological examination of PTC. This study evaluated the value of HF as a predictor of LNM. Study Design: Histologically confirmed FNABs (n = 111) of papillary thyroid microcarcinoma prepared by the liquid-based method were enrolled. Along with other cytomorphologic parameters, HF were evaluated for their value in predicting LNM. Results: Although HF were closely correlated with cytoplasmic vacuoles of tumor cells and background macrophages (p < 0.05), which were considered diagnostic indicators of PTC with cystic changes, HF were only found to be significantly correlated with LNM (p = 0.008). The BRAFV660E mutation was not associated with LNM. All combinations including HF were revealed as stronger predictors of LNM (odds ratios: 2.254-2.524, p < 0.05). Conclusions: HF, a distinctive cytomorphologic feature, may be used as a factor predicting LNM in preoperative FNAB of PTC.
Differences in the Receptor Status between Primary and Recurrent Breast Cancer - The Frequency of and the Reasons for Discordance
Authors: Heitz Florian , Barinoff Jana , du Bois Ondra , Hils Rita , Fisseler-Eckhoff Annette , Harter Philipp , Heitz Julia , Willenbrock Klaus , Traut Alexander , du Bois Andreas
Published: April 2013

Objective: Receptor discordances between primary and recurrent breast cancer have been described for years, but only a few analyses have elucidated the factors that influence receptor changes. Methods: Explorative analyses of prospective data from a breast cancer database of a tertiary breast cancer unit. Results: Recurrent tumours that had expressed oestrogen (ER) and progesterone receptors (PR) and human epidermal growth factor receptor 2 (HER2) as primary tumours were negative for the respective receptor in 22.8, 41.4 and 40.8% of cases. ER, PR and HER2 expression was found in 19.8, 16.7 and 11.5% of recurrent tumours, although no expression had been observed in primary tumours. Receptor discordances in recurrent disease leading to different therapeutic approaches were noted in 126 of 411 patients (30.7%). In patients with tumours expressing primary ER and HER2, independent factors associated with discordance were endocrine therapy and treatment with trastuzumab. Conclusion: High rates of receptor discordance were found. The impact of factors that influence receptor changes is small so that no subgroup of patients with recurrent breast cancer should be excluded from biopsy. Whenever possible, a biopsy should be taken to confirm the diagnosis of a possible relapse as well as the receptor status of patients with breast cancer.
Utility of the Quantitative Ki-67 Proliferation Index and CD56 Together in the Cytologic Diagnosis of Small Cell Lung Carcinoma and Other Lung Neuroendocrine Tumors
Authors: Zheng Gang , Ettinger David S. , Maleki Zahra
Published: April 2013

Background: Distinction of small cell lung carcinoma (SCLC) from non-small cell lung carcinoma (NSCLC) is critical because of the differences in prognosis and management. Patients with SCLC usually present with distant metastasis, and clinicians demand an accurate diagnosis in order to initiate appropriate therapy. Limited cytology material, occasionally with crush artifact, is not uncommon. Therefore, robust cytomorphologic features and a small immunostaining panel would be ideal to differentiate SCLC from NSCLC and other neuroendocrine neoplasms. We evaluated CD56 and the quantitative Ki-67 immunohistochemical panel in comparison to synaptophysin and chromogranin, along with cytomorphology to diagnose SCLC. Design: Eighty-eight cases of SCLC were retrieved from the cytology archives of The Johns Hopkins Hospital. Forty neuroendocrine neoplasms were used as control cases. Results: SCLCs included 33 lung cases and 55 metastatic lesions. The specimens were obtained by fine needle aspiration, thoracocentesis, bronchoalveolar lavage and abdominal paracentesis. CD56 was expressed in 98.9% of SCLCs, which is significantly more sensitive than synaptophysin and chromogranin. The Ki-67 labeling index was high (>70%) in all cases, which is a reliable marker to differentiate SCLC from other neuroendocrine neoplasms and NSCLC. Conclusion: CD56 and quantitative Ki-67 along with cytomorphology is a robust immunohistochemical panel to differentiate SCLC from other neuroendocrine neoplasms and NSCLC.
WNT5A is a Key Regulator of the Epithelial-Mesenchymal Transition and Cancer Stem Cell Properties in Human Gastric Carcinoma Cells
Authors: Kanzawa Maki , Semba Shuho , Hara Shigeo , Itoh Tomoo , Yokozaki Hiroshi
Published: April 2013

Objective: Direct interaction with cancer-associated fibroblasts triggers WNT5A expression in human gastric carcinoma (GC) cells. In this study, we performed gene transduction experiments to investigate the significance of WNT5A in the GC tumor microenvironment. Methods: Gene transduction (pWNT5A and shWNT5A) was performed in human GC-derived MKN-7 cells. Altered gene expression was examined by RT-PCR and cDNA microarray analysis. Immunohistochemical examination was carried out in human GC tissues. Results: Transduction of exogenous WNT5A expression into MKN-7 cells upregulated genes related to the epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs), and the pWNT5A transfectant showed high tumorigenicity in vivo. These results were confirmed by knockdown experiments using a lentivirus expressing shWNT5A. A cDNA microarray analysis suggested that depletion of endogenous WNT5A downregulated genes involved in intracellular signaling, chemokine-cytokine interaction and focal adhesion. High levels of WNT5A expression were observed in 66% of GC cases, with significant correlation with histological type. Interestingly, in intestinal-type GCs, WNT5A expression was detected in the periphery of tumor nests. Conclusions: WNT5A regulates the induction of EMT and the maintenance of CSC properties in MKN-7 cells. WNT5A may play an important role in constructing an advantageous tumor microenvironment for the progression and development of human GC.
Modeling of the Impact on Health Outcomes of the Use of Dabigatran in Patients with Atrial Fibrillation
Authors: Chevalier Julie , Giroud Maurice , de Pouvourville Gérard
Published: April 2013

Background: Atrial fibrillation (AF) is the main direct cause of stroke. Prevention by anticoagulation or antithrombotic treatment is required, vitamin K antagonists (VKAs) and aspirin being the main agents. Dabigatran etexilate is a novel oral direct thrombin inhibitor. The RE-LY study demonstrated that in patients with AF, the rates of stroke and systemic embolism were similar (at a dose of 110 mg) or lower (at a dose of 150 mg) than those observed in patients treated with warfarin, a VKA. The aim of the present study was to estimate, through modeling, the number of severe events avoided with dabigatran at dosages of 110 mg (D110) or 150 mg (D150) twice daily compared to warfarin, when prescribed in the French population for patients with AF who meet the inclusion criteria of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study. Methods: We used a decision tree type model to simulate the outcome at 5 years in a cohort of patients eligible for treatment with dabigatran. We compared 3 hypothetical cohorts: all AF patients are treated with D110, D150 and warfarin. Based on the probabilities of occurrence of the different outcomes observed in the RE-LY study and in the Dijon Stroke Registry, we simulated for each year during 5 years the evolution of the 3 cohorts. The model allows to simulate a prevalent cohort of 461,392 patients at year zero, with a follow-up of 5 years (‘constant prevalence model'), and it can also take into account incident patients during 5 years (‘dynamic prevalence model'). The different events taken into account were: major hemorrhages (excluding hemorrhagic strokes), myocardial infarctions, hemorrhagic strokes, ischemic strokes, recurrence of strokes (without differentiating the mechanism) or deaths. Results: Considering the constant prevalence model, the use of D110 instead of warfarin for the whole target population in France would permit to avoid 10,012 events and to save 18,879 years of life in a period of 5 years. These figures are 13,484 and 27,736 for D150 instead of warfarin. Considering the dynamic prevalence model, the use of D110 for the whole target population in France would permit to avoid 13,620 events and to save 22,674 years of life in a period of 5 years. These figures are 18,186 and 33,091 for D150. Conclusion: The use of dabigatran would lead to a significant reduction of strokes and deaths attributable to AF in France.
Adherence to Cholinesterase Inhibitors in Alzheimer's Disease: A Review
Authors: Brady Roseanna , Weinman John
Published: April 2013

Background/Aims: Treatment adherence is a major problem in numerous medical conditions, and is a particular challenge in patients with Alzheimer's disease (AD). Methods: This non-systematic review summarises the current literature on factors that affect adherence to cholinesterase inhibitors, the mainstay of AD treatment. Articles listed on PubMed and published during the last 10 years were included. Results: Intentional factors affecting adherence include patient, caregiver and prescriber beliefs about therapies and the disease itself. Unintentional factors include tolerability, physical limitations of the patient and caregiver burden. Interventions aiming to improve adherence include educational programmes and new drug delivery methods. Conclusion: Due to the high level of caregiver involvement in the care of patients with AD, strategies that address caregiver concerns may improve adherence.
Time-Dependent Effects of Systemic Lipopolysaccharide Injection on Regulators of Antioxidant Defence Nrf2 and PGC-1α in the Neonatal Rat Brain
Authors: Correa Fernando , Ljunggren Elin , Patil Jaspal , Wang Xiaoyang , Hagberg Henrik , Mallard Carina , Sandberg Mats
Published: April 2013

Background/Aims: Both excitotoxicity and neuroinflammation are associated with oxidative stress. One transcription factor, nuclear factor E2-related factor 2 (Nrf2), and one transcription cofactor, peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), increase the endogenous antioxidant defence and can thus modulate neuronal cell death. Here, we investigated the temporal effects (after 24 and 72 h) of systemic (i.p.) administration of lipopolysaccharide (LPS) on the cerebral Nrf2 and PGC-1α systems. Methods and Results: Seven-day-old rat pups were injected with LPS (0.3 mg/kg). After 24 h, the protein levels of γ-glutamylcysteine ligase modulatory subunit, γ-glutamylcysteine ligase catalytic subunit, Nrf2, PGC-1α and manganese superoxide dismutase (MnSOD) were increased in parallel with decreased levels of Keap1. These effects were correlated with an increased level of phosphorylated Akt and elevated acetylation of histone 4. In contrast, 72 h following LPS, a decrease in the components of the Nrf2 system in parallel with an increase in Keap1 was observed. The down-regulation after 72 h correlated with phosphorylation of p38 mitogen-activated protein kinase, while there were no changes in PGC-1α and MnSOD protein levels or the acetylation/methylation pattern of histones. Conclusion: Systemic LPS in neonatal rats induced time-dependent changes in brain Nrf2 and PGC-1α that correlated well with the protective effect observed after 24 h (pre-conditioning) and the deleterious effects observed after 72 h (sensitizing) of systemic LPS reported earlier. Collectively, the results point towards Nrf2 and PGC-1α as a possible mechanism behind these effects.
NOX2 Protects against Prolonged Inflammation, Lung Injury, and Mortality following Systemic Insults
Authors: Whitmore Laura C. , Hilkin Brieanna M. , Goss Kelli L. , Wahle Erin M. , Colaizy Tarah T. , Boggiatto Paola M. , Varga Steven M. , Miller Francis J. , Moreland Jessica G.
Published: April 2013

The systemic inflammatory response syndrome (SIRS) is a clinical condition occurring in intensive care unit patients as a consequence of both infectious and noninfectious insults. The mechanisms underlying resolution of SIRS are not well characterized. NOX2 (NADPH oxidase 2)-derived reactive oxygen species are critical for killing of certain pathogens by polymorphonuclear leukocytes (PMN). Patients with chronic granulomatous disease who lack functional NOX2 are not only prone to serious infections, they also exhibit chronic inflammatory conditions, suggesting a local anti-inflammatory role for NOX2. We hypothesized that NOX2 is required for the resolution of sterile systemic inflammation. Using a murine model of sterile generalized inflammation, we observed dramatically increased mortality of gp91phox-/y (NOX2-deficient) as compared to wild-type (WT) mice. Both genotypes developed robust SIRS with hypothermia, hypotension, and leukopenia; however, WT mice recovered within 48 h whereas NOX2-deficient mice did not. Although both groups displayed rapid peritoneal PMN recruitment, the recruited NOX2-deficient PMN demonstrated an enhanced inflammatory phenotype. Moreover, NOX2-deficient mice exhibited a hemorrhagic inflammatory response in the lungs with rapid and persistent recruitment of neutrophils to the alveolar space, whereas WT mice had minimal lung pathology. Several proinflammatory cytokines remained elevated in NOX2-deficient mice. The persistent inflammatory environment observed in NOX2-deficient mice resulted from continued peritoneal chemokine secretion and not delayed apoptosis of PMN. These data suggest a requirement for NOX2 in the resolution of systemic inflammation.
Lexical Priming in Alzheimer's Disease and Aphasia
Authors: Arroyo-Anlló Eva Maria , Beauchamps Mireille , Ingrand Pierre , Neau Jean Philippe , Gil Roger
Published: April 2013

Lexical priming was examined in patients with Alzheimer's disease and in aphasic patients. Control participants were divided into young and elderly [cf. Arroyo-Anlló et al.: Eur J Cogn Psychol 2004;16:535-553]. For lexical priming, a word-stem completion task was used. Normal elderly participants had lexical priming scores that were significantly lower than those of young individuals. Analysis of covariance with age and educational level as covariates showed that the control participants, aphasic and Alzheimer patients did not differ significantly on the lexical priming task. Our results suggest that performance in the lexical priming task diminishes with physiological aging, but is not significantly affected by mild or moderate Alzheimer's disease or by fluent or non-fluent aphasia.