bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNA‐138 promotes tau phosphorylation by targeting retinoic acid receptor alpha
Authors: Wang Xiong , Tan Lu , Lu Yanjun , Peng Jing , Zhu Yaowu , Zhang Yadong , Sun Ziyong
Published: February 2015

Alzheimer's disease (AD) is a progressive neurodegenerative dementia characterized by Aβ deposition and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Emerging evidence shows that microRNAs (miRNAs) contribute to the pathogenesis of AD. Herein, we investigated the role of miR‐138, a brain enriched miRNA, which is increased in AD patients. We found that miR‐138 is increased in AD models, including N2a/APP and HEK293/tau cell lines. Overexpression of miR‐138 activates glycogen synthase kinase‐3β (GSK‐3β), and increases tau phosphorylation in HEK293/tau cells. Furthermore, we confirm that retinoic acid receptor alpha (RARA) is a direct target of miR‐138, and supplement of RARA substantially suppresses GSK‐3β activity, and reduces tau phosphorylation induced by miR‐138. In conclusion, our data suggest that miR‐138 promotes tau phosphorylation by targeting the RARA/GSK‐3β pathway.
The activity of cAMP‐phosphodiesterase 4D7 (PDE4D7) is regulated by protein kinase A‐dependent phosphorylation within its unique N‐terminus
Authors: Byrne Ashleigh M. , Elliott Christina , Hoffmann Ralf , Baillie George S.
Published: February 2015

The cyclic AMP phosphodiesterases type 4 (PDE4s) are expressed in a cell specific manner, with intracellular targeting directed by unique N‐terminal anchor domains. All long form PDE4s are phosphorylated and activated by PKA phosphorylation within their upstream conserved region 1 (UCR1). Here, we identify and characterise a novel PKA site (serine 42) within the N‐terminal region of PDE4D7, an isoform whose activity is known to be important in prostate cancer progression and ischemic stroke. In contrast to the UCR1 site, PKA phosphorylation of the PDE4D7 N‐terminus appears to occur constitutively and inhibits PDE4 activity to allow cAMP signalling under basal conditions.
Factors associated with poor attendance at the postpartum clinic six weeks after delivery in Cameroon
Authors: Nkwabong Elie , Ilue Elisabeth E. , Bisong Calvin E.
Published: February 2015

Objective

To identify reasons why women do not attend the 6‐week postpartum clinic in Cameroon.

Methods

A retrospective cross‐sectional cohort survey was undertaken among women who had delivered at the University Teaching Hospital in Yaoundé between November 15 and December 31, 2013. Their medical files were retrieved and reviewed. Women who had not attended the 6‐week postpartum clinic were contacted by telephone 2 months after delivery to establish reasons for non‐attendance.

Results

Among 120 included women, 85 (70.8%) did not attend the 6‐week postpartum clinic. Compared with women who had attended the 6‐week visit, more women who had not attended the visit had delivered vaginally, had no postpartum complications, and had not been counseled to attend the visit (P < 0.001 for all). The main reason given for not attending this clinic was the feeling of well‐being (n = 36 [42.4%]).

Conclusion

The benefits of attending the 6‐week postpartum clinic should be emphasized in Cameroon, especially to women who have experienced uncomplicated vaginal delivery.
Targeting High Value Customers While under Resource Constraint: Partial Order Constrained Optimization with Genetic Algorithm
Authors: Cui Geng , Wong Man Leung , Wan Xiang
Published: February 2015

To maximize sales or profit given a fixed budget, direct marketing targets a preset top percentage of consumers who are the most likely to respond and purchase a greater amount. Existing forecasting models, however, largely ignore the resource constraint and render sup-optimal performance in maximizing profit given the budget constraint. This study proposes a model of partial order constrained optimization (POCO) using a penalty weight that represents the marginal penalty for selecting one more customer. Genetic algorithms as a tool of stochastic optimization help to select models that maximize the total sales at the top deciles of a customer list. The results of cross-validation with a direct marketing dataset indicate that the POCO model outperforms the competing methods in maximizing sales under the resource constraint and has distinctive advantages in augmenting the profitability of direct marketing.
Coexistence of persistent left superior vena cava with common inferior pulmonary vein in a patient with atrial fibrillation
Authors: Kiuchi Kunihiko , Okajima Katsunori , Takahashi Yu , Yokoi Kiminobu , Shimane Akira
Published: February 2015

Coexistence of a persistent left superior vena cava (PLSVC) with a common inferior pulmonary vein (CIPV) is very rare. The electrical assessment of those thoracic veins was performed during the atrial fibrillation ablation.
Stable Isotopes in Yellow-Bellied Marmot (Marmota Flaviventris) Fossils Reveal Environmental Stability in the Late Quaternary of the Colorado Rocky Mountains
Authors: Reynard Linda M. , Meltzer David J. , Emslie Steven D. , Tuross Noreen
Published: February 2015

High elevation plant and animal communities are considered extremely sensitive to environmental change. We investigated an exceptional fossil record of yellow-bellied marmot (Marmota flaviventris) specimens that was recovered from Cement Creek Cave (elev. 2860 m) and ranged in age from radiocarbon background circa 49.8 cal ka BP to ~ 1 cal ka BP. We coupled isotopic and radiocarbon measurements (δ18O, δD, δ15N, δ13C, and14C) of bone collagen from individually-AMS dated specimens of marmots to assess ecological responses by this species to environmental change over time in a high elevation basin in the Rocky Mountains of southwestern Colorado, USA. We find little change in all four isotope ratios over time, demonstrating considerable environmental stability during periods when the marmots were present. The stable ecology and the apparent persistence of the small mammal community in the cave fauna throughout the late Quaternary are in marked contrast to the changes that occurred in the large mammal community, including local extirpation and extinction, at the end of the Pleistocene.
Partially hyperbolic diffeomorphisms with a uniformly compact center foliation: the quotient dynamics
Authors: BOHNET DORIS , BONATTI CHRISTIAN
Published: February 2015

We show that a partially hyperbolic$C^{1}$-diffeomorphism$f:M\rightarrow M$with a uniformly compact$f$-invariant center foliation${\mathcal{F}}^{c}$is dynamically coherent. Further, the induced homeomorphism$F:M/{\mathcal{F}}^{c}\rightarrow M/{\mathcal{F}}^{c}$on the quotient space of the center foliation has the shadowing property, i.e. for every${\it\epsilon}>0$there exists${\it\delta}>0$such that every${\it\delta}$-pseudo-orbit of center leaves is${\it\epsilon}$-shadowed by an orbit of center leaves. Although the shadowing orbit is not necessarily unique, we prove the density of periodic center leaves inside the chain recurrent set of the quotient dynamics. Other interesting properties of the quotient dynamics are also discussed.
Extension of Hölder’s theorem in
Authors: AKHMEDOV AZER
Published: February 2015

We prove that if ${\rm\Gamma}$ is a subgroup of $\text{Diff}_{+}^{\,1+{\it\epsilon}}(I)$ and $N$ is a natural number such that every non-identity element of ${\rm\Gamma}$ has at most $N$ fixed points, then ${\rm\Gamma}$ is solvable. If in addition ${\rm\Gamma}$ is a subgroup of $\text{Diff}_{+}^{\,2}(I)$, then we can claim that ${\rm\Gamma}$ is meta-abelian.
Toeplitz flows and their ordered K-theory
Authors: HØYNES SIRI-MALÉN
Published: February 2015

To a Toeplitz flow$(X,T)$we associate an ordered$K^{0}$-group, denoted$K^{0}(X,T)$, which is order isomorphic to the$K^{0}$-group of the associated (non-commutative)$C^{\ast }$-crossed product$C(X)\rtimes _{T}\mathbb{Z}$. However,$K^{0}(X,T)$can be defined in purely dynamical terms, and it turns out to be a complete invariant for (strong) orbit equivalence. We characterize the$K^{0}$-groups that arise from Toeplitz flows$(X,T)$as exactly those simple dimension groups$(G,G^{+})$that contain a non-cyclic subgroup$H$of rank one that intersects$G^{+}$non-trivially. Furthermore, the Bratteli diagram realization of$(G,G^{+})$can be chosen to have the ERS property, i.e. the incidence matrices of the Bratteli diagram have equal row sums. We also prove that for any Choquet simplex$K$there exists an uncountable family of pairwise non-orbit equivalent Toeplitz flows$(X,T)$such that the set of$T$-invariant probability measures$M(X,T)$is affinely homeomorphic to$K$, where the entropy$h(T)$may be prescribed beforehand. Furthermore, the analogous result is true if we substitute strong orbit equivalence for orbit equivalence, but in that case we can actually prescribe both the entropy and the maximal equicontinuous factor of$(X,T)$. Finally, we present some interesting concrete examples of dimension groups associated to Toeplitz flows.
Extreme probing of particle motions in turbulence
Authors: Borgas M. S.
Published: February 2015

Extreme behaviour of fluid and material motions needs to be understood for engineering processes and the behaviour of clouds or plumes of pollution. Applications in the natural environment require scaling of turbulence behaviour and models beyond current computational or laboratory understanding. New computational studies of Biferale et al. (J. Fluid Mech., 2014, vol. 757, pp. 550–572) are probing new regimes of scaling of extreme random events in nature produced by turbulent fluctuations trending towards applications in environmental prediction.
Formation of Prestellar Cores via Non-Isothermal Gas Fragmentation
Authors: Anathpindika S.
Published: February 2015

Sheet-like clouds are common in turbulent gas and perhaps form via collisions between turbulent gas flows. Having examined the evolution of an isothermal shocked slab in an earlier contribution, in this work we follow the evolution of a sheet-like cloud confined by (thermal) pressure and gas in it is allowed to cool. The extant purpose of this endeavour is to study the early phases of core-formation. The observed evolution of this cloud supports the conjecture that molecular clouds themselves are three-phase media (comprising viz. a stable cold and warm medium, and a third thermally unstable medium), though it appears, clouds may evolve in this manner irrespective of whether they are gravitationally bound. We report, this sheet fragments initially due to the growth of the thermal instability (TI) and some fragments are elongated, filament-like. Subsequently, relatively large fragments become gravitationally unstable and sub-fragment into smaller cores. The formation of cores appears to be a three stage process: first, growth of the TI leads to rapid fragmentation of the slab; second, relatively small fragments acquire mass via gas-accretion and/or merger and third, sufficiently massive fragments become susceptible to the gravitational instability and sub-fragment to form smaller cores. We investigate typical properties of clumps (and smaller cores) resulting from this fragmentation process. Findings of this work support the suggestion that the weak velocity field usually observed in dense clumps and smaller cores is likely seeded by the growth of dynamic instabilities. Simulations were performed using the smooth particle hydrodynamics algorithm.
DOMINATION CONDITIONS UNDER WHICH A COMPACT SPACE IS METRISABLE
Authors: DOW ALAN , GUERRERO SÁNCHEZ DAVID
Published: February 2015

In this note we partially answer a question of Cascales, Orihuela and Tkachuk [‘Domination by second countable spaces and Lindelöf ${\rm\Sigma}$-property’, Topology Appl.158(2) (2011), 204–214] by proving that under $CH$ a compact space $X$ is metrisable provided $X^{2}\setminus {\rm\Delta}$ can be covered by a family of compact sets $\{K_{f}:f\in {\it\omega}^{{\it\omega}}\}$ such that $K_{f}\subset K_{h}$ whenever $f\leq h$ coordinatewise.
Methanolic extract ofOriganum vulgareameliorates type 1 diabetes through antioxidant, anti-inflammatory and anti-apoptotic activity
Authors: Vujicic Milica , Nikolic Ivana , Kontogianni Vassiliki G. , Saksida Tamara , Charisiadis Pantelis , Orescanin-Dusic Zorana , Blagojevic Dusko , Stosic-Grujicic Stanislava , Tzakos Andreas G. , Stojanovic Ivana
Published: February 2015

Type 1 diabetes (T1D), an autoimmune inflammatory disorder, develops as a consequence of pancreatic β-cell destruction and results in hyperglycaemia. Since current T1D therapy mainly involves insulin replacement, the aim of the present study was to evaluate the therapeutic potential ofOriganum vulgareL. ssp.hirtum(Greek oregano) leaf extract rich in biophenols for the treatment of T1D. The phytochemical profile of methanolic oregano extract (MOE) and aqueous oregano extract (AOE) was determined by liquid chromatography/electrospray ion-trap tandem MS (LC/DAD/ESI-MSn), while their main compounds were quantified by HPLC with diode array detection. After establishing their potentin vitroantioxidant activity, the extracts were administered to C57BL/6 mice treated with multiple low doses of streptozotocin for diabetes induction. While prophylactic AOE therapy had no impact on diabetes induction, MOE reduced diabetes incidence and preserved normal insulin secretion. In addition, MOE scavenged reactive oxygen and nitrogen species and, therefore, alleviated the need for the up-regulation of antioxidant enzymes. MOE treatment specifically attenuated the pro-inflammatory response mediated by T helper 17 cells and enhanced anti-inflammatory T helper 2 and T regulatory cells through the impact on specific signalling pathways and transcription factors. Importantly, MOE preserved β-cells fromin vitroapoptosis via blockade of caspase 3. Finally, rosmarinic acid, a predominant compound in MOE, exhibited only partial protection from diabetes induction. In conclusion, acting as an antioxidant, immunomodulator and in an anti-apoptotic manner, MOE protected mice from diabetes development. Seemingly, there is more than one compound responsible for the beneficial effect of MOE.
Compete or Coordinate? Aid Fragmentation and Lead Donorship
Authors: Steinwand Martin C.
Published: February 2015

Donor proliferation and the fragmentation of aid delivery is an important problem besetting foreign aid policy. Increased donor coordination is widely seen as a fix to this problem. This article explores theoretically and empirically the collective action problems and incentives that donors face when coordinating their actions, based on the distinction between private and public goods properties of aid. I introduce the concept of lead donorship, develop a measure that accounts for the exclusive and long-lasting ties between a lead donor and a recipient country, and show that lead donorship is in long-term decline. I test my theory combining spatial autoregressive (SAR) models, nonparametric model discrimination techniques, and data on aid delivery channels. I recover evidence of collusion in the provision of private goods aid in the presence of a lead donor, and lack of coordination and competition in the absence of a lead donor.
Edge effects without habitat fragmentation? Small mammals and a railway in the Atlantic Forest of southern Brazil
Authors: Cerboncini Ricardo A. S. , Roper James J. , Passos Fernando C.
Published: February 2015

Edge effects have been studied extensively in fragmented landscapes, often with conflicting findings. Edge effects may also be important in other situations, such as linear clearings (e.g. along roads, power lines or train tracks). We tested for responses of small mammals to a narrow (c. 10 m) linear clearing created by a railway in the largest area of Atlantic Forest in southern Brazil. Only two environmental variables, light intensity and train noise, were greatest at the edge and decreased with distance from the edge. Temperature differed (greater extremes and more variable) only at the edge itself. The few small mammal species that were only rarely captured at the edge resulted in an apparent edge-effect with respect to species richness. The abundance of small mammals, however, was independent of distance from the railway. There was no correlation between resource availability at the tracks and abundance of small mammals. Edge effects were minimal, which suggests that narrow railways (in contrast with roads) in unfragmented landscapes probably do not have a significant impact (if any) on wildlife, as found elsewhere and especially in tropical forests. The use of railways instead of roads is a potential strategy to minimize the effects of traversing important habitats for commercial reasons.
Occurrence ofGiardiaandCryptosporidiumin wild birds in Galicia (Northwest Spain)
Authors: REBOREDO-FERNÁNDEZ AURORA , ARES-MAZÁS ELVIRA , CACCIÒ SIMONE M. , GÓMEZ-COUSO HIPÓLITO
Published: February 2015

Faecal samples were obtained from 433 wild birds being treated in wildlife recovery centres in Galicia (Northwest Spain), between February 2007 and September 2009. The birds belonged to 64 species representing 17 different orders.Giardiacysts andCryptosporidiumoocysts were detected by an immunofluorescence antibody test and identified at the molecular level by established PCR-sequencing methods. The overall prevalence ofGiardiawas 2·1% and that ofCryptosporidium, 8·3%. To our knowledge, this is the first description ofGiardiasp. inTyto albaandCaprimulgus europaeus; and ofCryptosporidiumsp. inApus apus, Athene noctua, C. europaeus, Falco tinnunculus, Morus bassanus, Parabuteo unicinctusandStrix aluco. Furthermore, the first PCR-sequence confirmed detection ofGiardia duodenalisassemblage B in,Buteo buteo, Coturnix coturnixandPica pica; G. duodenalisassemblage D inGarrulus glandarius; andG. duodenalisassemblage F inAnas platyrhynchos; Cryptosporidium parvuminAccipiter nisus, B. buteo, Milvus migrans, Pernis apivorusandP. pica; andCryptosporidium meleagridisinStreptopelia turtur. The study findings demonstrate the wide spread ofGiardiaandCryptosporidiumbetween wild birds.
Ban Gu: copyist, creator and critic
Authors: Loewe Michael
Published: February 2015

Ban Gu's compilation of theHan shumay be seen in the context of a number of intellectual and religious developments. By his time the idea of theTian mingand the theory of theWu xingwere being applied to imperial times. Officials were quoting the sayings of Kongzi to support their arguments, and the writings of distinguished scholars such as Jing Fang, Liu Xiang, Liu Xin and Yang Xiong were well known. The religious controversies that had begun in the reign of Chengdi had died down. The pursuit of scholarship had received a new impetus thanks partly to the discussions held in 79ce. Ban Gu drew somewhat freely on existing literature, being prudent to select material that would not arouse enmity; his sister called on official documents to complete her part of the history. As an innovator Ban Gu introduced chapters on subjects that had not been treated in theShi ji, such as bibliography and the laws. Ready to criticize the actions of officials or the character of an emperor openly, he also contrived to do so implicitly.
Identification and causes of lexical variation in Chinese Business English
Authors: Carrió-Pastor María Luisa , Muñiz-Calderón Rut
Published: February 2015

English is a global language used by millions of people in very different contexts, such as academia, science, technology, business, mass media, entertainment, etc. The number of non-native speakers of English outnumbers native speakers, as a high number of multinational companies use English as a lingua franca. Electronic communication has also led to an increase in the use of English as an international language. People from different social backgrounds communicate using this lingua franca, and the language may be evolving faster than before.
TWELFTH INTERNATIONAL SYMPOSIUM ON SPANISH KEYBOARD MUSIC ‘DIEGO FERNÁNDEZ’ MOJÁCAR, 7–9 AUGUST 2014
Authors: RAMÍREZ CARLOS ROBERTO
Published: February 2015

This conference took as its theme ‘Early Music Revivals and the Performance of Spanish Keyboard Music’. It was organized and directed by Luisa Morales, and was held concurrently with the fifteenth iteration of the Festival Internacional de Música de Tecla Española (FIMTE). The symposium and festival (usually held in October) took full advantage of Mojácar's vibrant August atmosphere, which attracts many visitors from around the world for the picturesque beauty of the fifteenth-century town and its proximity to the Mediterranean. This year the symposium, dedicated to the memory of harpsichordist Rafael Puyana, hosted speakers and performers from Australia, Colombia, Mexico, Puerto Rico, Spain, Sweden, the United States, the United Kingdom and Venezuela.
Confirmatory factor analysis of the Frommelt Attitude Toward Care of the Dying Scale (FATCOD–B) among Italian medical students
Authors: Leombruni Paolo , Loera Barbara , Miniotti Marco , Zizzi Francesca , Castelli Lorys , Torta Riccardo
Published: February 2015

Objective:

A steady increase in the number of patients requiring end-of-life care has been observed during the last decades. The assessment of healthcare students' attitudes toward end-of-life care is an important step in their curriculum, as it provides information about their disposition to practice palliative medicine. The Frommelt Attitude Toward Care of the Dying Scale (FATCOD–B) was developed to detect such a disposition, but its psychometric properties are yet to be clearly defined.

Method:

A convenience sample of 608 second-year medical students participated in our study in the 2012/2013 and 2013/2014 academic years. All participants completed the FATCOD–B. The sample was randomly divided in two subsamples. In the item analysis, reliability (Cronbach's α), internal consistency (item–total correlations), and an exploratory factor analysis (EFA) were conducted using the first subsample (n= 300). Using the second subsample (n= 308), confirmatory factor analysis (CFA) was performed using the robust ML method in the Lisrel program.

Results:

Reliability for all items was 0.699. Item–total correlations, ranging from 0.03 to 0.39, were weak. EFA identified a two-dimensional orthogonal solution, explaining 20% of total variance. CFA upheld the two-dimensional model, but the loadings on the dimensions and their respective indicators were weak and equal to zero for certain items.

Significance of Results:

The findings of the present study suggest that the FATCOD–B measures a two-dimensional construct and that several items seem in need of revision. Future research oriented toward building a revised version of the scale should pay attention to item ambiguity and take particular care to distinguish among items that concern emotions and beliefs related to end-of-life care, as well as their subjects (e.g., the healthcare provider, the patient, his family).
Toward a model of continuous care: A necessity for caregiving partners
Authors: Masterson Melissa P. , Hurley Karen E. , Zaider Talia , Kissane David W.
Published: February 2015

Objective:

Caregiving partners constitute a unique group, who provide both physical and emotional care for patients. There has been extensive research conducted on caregivers during either the caregiving or bereavement phase; however, these phases are often treated as separate entities rather than as part of a continuum.

Method:

In this paper, utilizing relevant literature and clinical observations, we map the emotional journey and lived experience of caregivers moving from disease progression, to the end of life, to the dying process itself, and then through life after the death of a partner. Along this journey, we identify the links between pre-death caregiving and bereavement.

Results:

Our illustration raises awareness regarding the unmet needs experienced by caregiving partners across the continuum and provides an alternative framework through which clinicians can view this course.

Significance:

of Results We bolster arguments for improved palliative care services and early interventions with distressed caregiving partners by emphasizing continuity of care both before and after a patient's death.
CONSISTENCY AND THE THEORY OF TRUTH
Authors: HECK RICHARD G.
Published: February 2015

What is the logical strength of theories of truth? That is: If you take a theory${\cal T}$and add a theory of truth to it, how strong is the resulting theory, as compared to${\cal T}$? Once the question has been properly formulated, the answer turns out to be about as elegant as one could want: At least when${\cal T}$is finitely axiomatized theory, theories of truth act more or less as a kind of abstract consistency statement. To prove this result, however, we have to formulate truth-theories somewhat differently from how they have been and instead follow Tarski in ‘disentangling’ syntactic theories from object theories.
Neurologische Manifestation einer einfach therapierbaren Erkrankung
Authors: Gautschi Mirja , Pless Misha , von Matt Dominik , Gaudenz Roman , Knoblauch Christoph
Published: February 2015

Ein 34-jähriger Eritreer mit seit drei Wochen bestehenden beidseitigen Bein- sowie Flankenschmerzen zeigt eine abdominale beidseitige Unterbauchdruckdolenz und eine Ataxie sowie Fallneigung nach hinten. Die Bildgebung und Lumbalpunktion liefern weitere Hinweise. Unsere differenzialdiagnostischen Überlegungen zu diesem Zeitpunkt: Tuberkulose, lymphatische Erkrankung oder eine granulomatöse Pathologie. Wegen beginnender Paraplegie Verlegung ins Zentrumspital unter hochdosiertem intravenösem Methylprednisolon, worauf sich eine vollständige Regredienz der Cauda-equina-Symptomatik entwickelt. Der ELISA-Test bringt die Diagnose einer Schistosomiasis Erkrankung. Somit Start von Praziquantel unter Fortsetzung der Steroidtherapie.
Glucose and Oxygen Metabolism after Penetrating Ballistic-Like Brain Injury
Authors: Gajavelli Shyam , Kentaro Shimoda , Diaz Julio , Yokobori Shoji , Spurlock Markus , Diaz Daniel , Jackson Clayton , Wick Alexandra , Zhao Weizhao , Leung Lai Y , Shear Deborah , Tortella Frank , Bullock M Ross
Published: February 2015

Traumatic brain injury (TBI) is a major cause of death and disability in all age groups. Among TBI, penetrating traumatic brain injuries (PTBI) have the worst prognosis and represent the leading cause of TBI-related morbidity and death. However, there are no specific drugs/interventions due to unclear pathophysiology. To gain insights we looked at cerebral metabolism in a PTBI rat model: penetrating ballistic-like brain injury (PBBI). Early after injury, regional cerebral oxygen tension and consumption significantly decreased in the ipsilateral cortex in the PBBI group compared with the control group. At the same time point, glucose uptake was significantly reduced globally in the PBBI group compared with the control group. Examination of Fluorojade B-stained brain sections at 24 hours after PBBI revealed an incomplete overlap of metabolic impairment and neurodegeneration. As expected, the injury core had the most severe metabolic impairment and highest neurodegeneration. However, in the peri-lesional area, despite similar metabolic impairment, there was lesser neurodegeneration. Given our findings, the data suggest the presence of two distinct zones of primary injury, of which only one recovers. We anticipate the peri-lesional area encompassing the PBBI ischemic penumbra, could be salvaged by acute therapies.
The Effects of Capillary Transit Time Heterogeneity (CTH) on Brain Oxygenation
Authors: Angleys Hugo , Østergaard Leif , Jespersen Sune N
Published: February 2015

We recently extended the classic flow–diffusion equation, which relates blood flow to tissue oxygenation, to take capillary transit time heterogeneity ( CTH) into account. Realizing that cerebral oxygen availability depends on both cerebral blood flow ( CBF) and capillary flow patterns, we have speculated that CTH may be actively regulated and that changes in the capillary morphology and function, as well as in blood rheology, may be involved in the pathogenesis of conditions such as dementia and ischemia-reperfusion injury. The first extended flow–diffusion equation involved simplifying assumptions which may not hold in tissue. Here, we explicitly incorporate the effects of oxygen metabolism on tissue oxygen tension and extraction efficacy, and assess the extent to which the type of capillary transit time distribution affects the overall effects of CTH on flow–metabolism coupling reported earlier. After incorporating tissue oxygen metabolism, our model predicts changes in oxygen consumption and tissue oxygen tension during functional activation in accordance with literature reports. We find that, for large CTH values, a blood flow increase fails to cause significant improvements in oxygen delivery, and can even decrease it; a condition of malignant CTH. These results are found to be largely insensitive to the choice of the transit time distribution.
Poly-Arginine and Arginine-Rich Peptides are Neuroprotective in Stroke Models
Authors: Meloni Bruno P , Brookes Laura M , Clark Vince W , Cross Jane L , Edwards Adam B , Anderton Ryan S , Hopkins Richard M , Hoffmann Katrin , Knuckey Neville W
Published: February 2015

Using cortical neuronal cultures and glutamic acid excitotoxicity and oxygen-glucose deprivation (OGD) stroke models, we demonstrated that poly-arginine and arginine-rich cell-penetrating peptides (CPPs), are highly neuroprotective, with efficacy increasing with increasing arginine content, have the capacity to reduce glutamic acid-induced neuronal calcium influx and require heparan sulfate preotoglycan-mediated endocytosis to induce a neuroprotective effect. Furthermore, neuroprotection could be induced with immediate peptide treatment or treatment up to 2 to 4 hours before glutamic acid excitotoxicity or OGD, and with poly-arginine-9 (R9) when administered intravenously after stroke onset in a rat model. In contrast, the JNKI-1 peptide when fused to the (non-arginine) kFGF CPP, which does not rely on endocytosis for uptake, was not neuroprotective in the glutamic acid model; the kFGF peptide was also ineffective. Similarly, positively charged poly-lysine-10 (K10) and R9 fused to the negatively charged poly-glutamic acid-9 (E9) peptide (R9/E9) displayed minimal neuroprotection after excitotoxicity. These results indicate that peptide positive charge and arginine residues are critical for neuroprotection, and have led us to hypothesize that peptide-induced endocytic internalization of ion channels is a potential mechanism of action. The findings also question the mode of action of different neuroprotective peptides fused to arginine-rich CPPs.
Gliovascular Disruption and Cognitive Deficits in a Mouse Model with Features of Small Vessel Disease
Authors: Holland Philip R , Searcy James L , Salvadores Natalia , Scullion Gillian , Chen Guiquan , Lawson Greig , Scott Fiona , Bastin Mark E , Ihara Masafumi , Kalaria Rajesh , Wood Emma R , Smith Colin , Wardlaw Joanna M , Horsburgh Karen
Published: February 2015

Cerebral small vessel disease (SVD) is a major cause of age-related cognitive impairment and dementia. The pathophysiology of SVD is not well understood and is hampered by a limited range of relevant animal models. Here, we describe gliovascular alterations and cognitive deficits in a mouse model of sustained cerebral hypoperfusion with features of SVD (microinfarcts, hemorrhage, white matter disruption) induced by bilateral common carotid stenosis. Multiple features of SVD were determined on T2-weighted and diffusion-tensor magnetic resonance imaging scans and confirmed by pathologic assessment. These features, which were absent in sham controls, included multiple T2-hyperintense infarcts and T2-hypointense hemosiderin-like regions in subcortical nuclei plus increased cerebral atrophy compared with controls. Fractional anisotropy was also significantly reduced in several white matter structures including the corpus callosum. Investigation of gliovascular changes revealed a marked increase in microvessel diameter, vascular wall disruption, fibrinoid necrosis, hemorrhage, and blood–brain barrier alterations. Widespread reactive gliosis, including displacement of the astrocytic water channel, aquaporin 4, was observed. Hypoperfused mice also demonstrated deficits in spatial working and reference memory tasks. Overall, gliovascular disruption is a prominent feature of this mouse, which could provide a useful model for early-phase testing of potential SVD treatment strategies.
Intracranial Pressure Elevation Reduces Flow through Collateral Vessels and the Penetrating Arterioles they Supply. a Possible Explanation for ‘Collateral Failure’ and Infarct Expansion after Ischemic Stroke
Authors: Beard Daniel J , McLeod Damian D , Logan Caitlin L , Murtha Lucy A , Imtiaz Mohammad S , van Helden Dirk F , Spratt Neil J
Published: February 2015

Recent human imaging studies indicate that reduced blood flow through pial collateral vessels (‘collateral failure’) is associated with late infarct expansion despite stable arterial occlusion. The cause for ‘collateral failure’ is unknown. We recently showed that intracranial pressure (ICP) rises dramatically but transiently 24 hours after even minor experimental stroke. We hypothesized that ICP elevation would reduce collateral blood flow. First, we investigated the regulation of flow through collateral vessels and the penetrating arterioles arising from them during stroke reperfusion. Wistar rats were subjected to intraluminal middle cerebral artery (MCA) occlusion (MCAo). Individual pial collateral and associated penetrating arteriole blood flow was quantified using fluorescent microspheres. Baseline bidirectional flow changed to MCA-directed flow and increased by 4450% immediately after MCAo. Collateral diameter changed minimally. Second, we determined the effect of ICP elevation on collateral and watershed penetrating arteriole flow. Intracranial pressure was artificially raised in stepwise increments during MCAo. The ICP increase was strongly correlated with collateral and penetrating arteriole flow reductions. Changes in collateral flow post-stroke appear to be primarily driven by the pressure drop across the collateral vessel, not vessel diameter. The ICP elevation reduces cerebral perfusion pressure and collateral flow, and is the possible explanation for ‘collateral failure’ in stroke-in-progression.
Ischemic Tolerance in Pre-Myelinated White Matter: The Role of Astrocyte Glycogen in Brain Pathology
Authors: Fern Robert
Published: February 2015

In isolated white matter, ischemic tolerance changes dramatically in the period immediately before the onset of myelination. In the absence of an extrinsic energy source, postnatal day 0 to 2 (P0 to P2) white matter axons are here shown to maintain excitability for over twice as long as axons > P2, a differential that was dependent on glycogen metabolism. Prolonged withdrawal of extrinsic energy supply tended to spare axons in zones around astrocytes, which are shown to be the sole repository for glycogen particles in developing white matter. Analysis of mitochondrial volume fraction revealed that neither axons nor astrocytes had a low metabolic rate in neonatal white matter, while oligodendroglia at older ages had an elevated metabolism. The astrocyte population is established early in neural development, and exhibits reduced cell density as maturation progresses and white matter expands. The findings show that this event establishes the necessary conditions for ischemia sensitivity in white matter and indicates that astrocyte proximity may be significant for the survival of neuronal elements in conditions associated with compromised energy supply.
Cerebral Autoregulation in the Microvasculature Measured with Near-Infrared Spectroscopy
Authors: Kainerstorfer Jana M , Sassaroli Angelo , Tgavalekos Kristen T , Fantini Sergio
Published: February 2015

Cerebral autoregulation (CA) is the mechanism that allows the brain to maintain a stable blood flow despite changes in blood pressure. Dynamic CA can be quantified based on continuous measurements of systemic mean arterial pressure (MAP) and global cerebral blood flow. Here, we show that dynamic CA can be quantified also from local measurements that are sensitive to the microvasculature. We used near-infrared spectroscopy (NIRS) to measure temporal changes in oxy- and deoxy-hemoglobin concentrations in the prefrontal cortex of 11 human subjects. A novel hemodynamic model translates those changes into changes of cerebral blood volume and blood flow. The interplay between them is described by transfer function analysis, specifically by a high-pass filter whose cutoff frequency describes the autoregulation efficiency. We have used pneumatic thigh cuffs to induce MAP perturbation by a fast release during rest and during hyperventilation, which is known to enhance autoregulation. Based on our model, we found that the autoregulation cutoff frequency increased during hyperventilation in comparison to normal breathing in 10 out of 11 subjects, indicating a greater autoregulation efficiency. We have shown that autoregulation can reliably be measured noninvasively in the microvasculature, opening up the possibility of localized CA monitoring with NIRS.
Combined Local Blood–Brain Barrier Opening and Systemic Methotrexate for the Treatment of Brain Tumors
Authors: Cooper Itzik , Last David , Guez David , Sharabi Shirley , Goldman Shirin Elhaik , Lubitz Irit , Daniels Dianne , Salomon Sharona , Tamar Gregory , Tamir Tzur , Mardor Ronni , Fridkin Mati , Shechter Yoram , Mardor Yael
Published: February 2015

Despite aggressive therapy, existing treatments offer poor prognosis for glioblastoma multiforme patients, in part due to poor penetration of most drugs across the blood–brain barrier (BBB). We propose a minimal-invasive combined treatment approach consisting of local BBB disruption in the tumor in parallel to systemic drug administration. Local BBB disruption is obtained by convection-enhanced delivery of a novel BBB disruption agent, enabling efficient/targeted delivery of the systemically administered drug by the tumors own vasculature. Various human serum albumin (HSA) analogs were synthesized and screened for BBB disruption efficacy in custom in vitro systems. The candidate analogs were then delivered into naïve rat brains by convection-enhanced delivery and screened for maximal BBB disruption and minimal brain toxicity. These studies found a noncationized/neutralized analog, ethylamine (EA)–HSA, to be the optimal BBB-opening agent. Immunocytochemical studies suggested that BBB disruption by EA–HSA may be explained by alterations in occludin expression. Finally, an efficacy study in rats bearing intracranial gliomas was performed. The rats were treated by convection-enhanced delivery of EA–HSA in parallel to systemic administration of Methotrexate, showing significant antineoplastic effects of the combined approached reflected in suppressed tumor growth and significantly (~x3) prolonged survival.
Dabigatran Abrogates Brain Endothelial Cell Permeability in Response to Thrombin
Authors: Hawkins Brian Thomas , Gu Yu-Huan , Izawa Yoshikane , del Zoppo Gregory John
Published: February 2015

Atrial fibrillation (AF) increases the risk and severity of thromboembolic stroke. Generally, antithrombotic agents increase the hemorrhagic risk of thromboembolic stroke. However, significant reductions in thromboembolism and intracerebral hemorrhage have been shown with the antithrombin dabigatran compared with warfarin. As thrombin has been implicated in microvessel injury during cerebral ischemia, we hypothesized that dabigatran decreases the risk of intracerebral hemorrhage by direct inhibition of the thrombin-mediated increase in cerebral endothelial cell permeability. Primary murine brain endothelial cells (mBECs) were exposed to murine thrombin before measuring permeability to 4-kDa fluorescein isothiocyanate-dextran. Thrombin increased mBEC permeability in a concentration-dependent manner, without significant endothelial cell death. Pretreatment of mBECs with dabigatran completely abrogated the effect of thrombin on permeability. Neither the expressions of the endothelial cell β1-integrins nor the tight junction protein claudin-5 were affected by thrombin exposure. Oxygen-glucose deprivation (OGD) also increased permeability; this effect was abrogated by treatment with dabigatran, as was the additive effect of thrombin and OGD on permeability. Taken together, these results indicate that dabigatran could contribute to a lower risk of intracerebral hemorrhage during embolism-associated ischemia from AF by protection of the microvessel permeability barrier from local thrombin challenge.
Mechanism of erosion of nanostructured porous silicon drug carriers in neoplastic tissues
Authors: Tzur-Balter Adi , Shatsberg Zohar , Beckerman Margarita , Segal Ester , Artzi Natalie
Published: February 2015

Nanostructured porous silicon (PSi) is emerging as a promising platform for drug delivery owing to its biocompatibility, degradability and high surface area available for drug loading. The ability to control PSi structure, size and porosity enables programming itsin vivoretention, providing tight control over embedded drug release kinetics. In this work, the relationship between thein vitroandin vivodegradation of PSi under (pre)clinically relevant conditions, using breast cancer mouse model, is defined. We show that PSi undergoes enhanced degradation in diseased environment compared with healthy state, owing to the upregulation of reactive oxygen species (ROS) in the tumour vicinity that oxidize the silicon scaffold and catalyse its degradation. We further show that PSi degradationin vitroandin vivocorrelates in healthy and diseased states when ROS-free or ROS-containing media are used, respectively. Our work demonstrates that understanding the governing mechanisms associated with specific tissue microenvironment permits predictive material performance.
Neuropilin 1 is an entry factor that promotes EBV infection of nasopharyngeal epithelial cells
Authors: Wang Hong-Bo , Zhang Hua , Zhang Jing-Ping , Li Yan , Zhao Bo , Feng Guo-Kai , Du Yong , Xiong Dan , Zhong Qian , Liu Wan-Li , Du Huamao , Li Man-Zhi , Huang Wen-Lin , Tsao Sai Wah , Hutt-Fletcher Lindsey , Zeng Yi-Xin , Kieff Elliott , Zeng Mu-Sheng
Published: February 2015

Epstein–Barr virus (EBV) is implicated as an aetiological factor in B lymphomas and nasopharyngeal carcinoma. The mechanisms of cell-free EBV infection of nasopharyngeal epithelial cells remain elusive. EBV glycoprotein B (gB) is the critical fusion protein for infection of both B and epithelial cells, and determines EBV susceptibility of non-B cells. Here we show that neuropilin 1 (NRP1) directly interacts with EBV gB23–431. Either knockdown of NRP1 or pretreatment of EBV with soluble NRP1 suppresses EBV infection. Upregulation of NRP1 by overexpression or EGF treatment enhances EBV infection. However, NRP2, the homologue of NRP1, impairs EBV infection. EBV enters nasopharyngeal epithelial cells through NRP1-facilitated internalization and fusion, and through macropinocytosis and lipid raft-dependent endocytosis. NRP1 partially mediates EBV-activated EGFR/RAS/ERK signalling, and NRP1-dependent receptor tyrosine kinase (RTK) signalling promotes EBV infection. Taken together, NRP1 is identified as an EBV entry factor that cooperatively activates RTK signalling, which subsequently promotes EBV infection in nasopharyngeal epithelial cells.
Hiding scattering layers for noninvasive imaging of hidden objects
Authors: Wu Kedi , Cheng Qiluan , Shi Yile , Wang Hui , Wang Guo Ping
Published: February 2015

The ability to noninvasive image through turbid media has long been a major scientific and technological goal in many disciplines. A breakthrough has been made to observe objects that were completely hidden behind an opaque scattering layer. However, such approach needs not only to scan both illumination light and detector but further off-line procedures to numerically retrieve the image of the objects. Here, we report a distant invisibility-based noninvasive method that can hide scattering layers and allows to directly image objects behind. By recording holograms of the objects through a ground glass and then using the holograms produced time-reversal lights to re-illuminate the objects, we implemented to observe objects with feature size ranging from 39 μm to 80 μm that were hidden behind a 3 mm thick ground glass. Of importance, our approach opens a door towards real-time, high speed biomedical imaging and in-site inspection of integrated devices.
Circadian rhythm phase shifts and endogenous free-running circadian period differ between African-Americans and European-Americans
Authors: Eastman Charmane I. , Suh Christina , Tomaka Victoria A. , Crowley Stephanie J.
Published: February 2015

Successful adaptation to modern civilization requires the internal circadian clock to make large phase shifts in response to circumstances (e.g., jet travel and shift work) that were not encountered during most of our evolution. We found that the magnitude and direction of the circadian clock's phase shift after the light/dark and sleep/wake/meal schedule was phase-advanced (made earlier) by 9 hours differed in European-Americans compared to African-Americans. European-Americans had larger phase shifts, but were more likely to phase-delay after the 9-hour advance (to phase shift in the wrong direction). The magnitude and direction of the phase shift was related to the free-running circadian period and European-Americans had a longer circadian period than African-Americans. Circadian period was related to the percent Sub-Saharan African and European ancestry from DNA samples. We speculate that a short circadian period was advantageous during our evolution in Africa and lengthened with northern migrations out of Africa. The differences in circadian rhythms remaining today are relevant for understanding and treating the modern circadian-rhythm-based disorders which are due to a misalignment between the internal circadian rhythms and the times for sleep, work, school and meals.
Dimensional crossover and cold-atom realization of topological Mott insulators
Authors: Scheurer Mathias S. , Rachel Stephan , Orth Peter P.
Published: February 2015

Interacting cold-atomic gases in optical lattices offer an experimental approach to outstanding problems of many body physics. One important example is the interplay of interaction and topology which promises to generate a variety of exotic phases such as the fractionalized Chern insulator or the topological Mott insulator. Both theoretically understanding these states of matter and finding suitable systems that host them have proven to be challenging problems. Here we propose a cold-atom setup where Hubbard on-site interactions give rise to spin liquid-like phases: weak and strong topological Mott insulators. They represent the celebrated paradigm of an interacting and topological quantum state with fractionalized spinon excitations that inherit the topology of the non-interacting system. Our proposal shall help to pave the way for a controlled experimental investigation of this exotic state of matter in optical lattices. Furthermore, it allows for the investigation of a dimensional crossover from a two-dimensional quantum spin Hall insulating phase to a three-dimensional strong topological insulator by tuning the hopping between the layers.