bluuebunny/crossref_metadata_2025 huggingface dataset:
cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection
Authors: Lio Chan-Wang J. , McDonald Bryan , Takahashi Mariko , Dhanwani Rekha , Sharma Nikita , Huang Jenny , Pham Elise , Benedict Chris A. , Sharma Sonia
Published: June 2016

Several innate sensing pathways contribute to the control of early cytomegalovirus (CMV) infection, leading to a multiphasic type I interferon (IFN-I) response that limits viral replication and promotes host defenses. Toll-like receptor (TLR)-dependent pathways induce IFN-I production in CMV-infected plasmacytoid dendritic cells; however, the initial burst of IFN-I that occurs within the first few hours
in vivo
is TLR independent and emanates from stromal cells. Here we show that primary human endothelial cells mount robust IFN-I responses to human CMV that are dependent upon cyclic GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3) signaling. Disruption of STING expression in endothelial cells by clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 revealed that it is essential for the induction of IFN-I and restriction of CMV replication. Consistently, STING was necessary to mount the first phase of IFN-I production and curb CMV replication in infected mice. Thus, DNA sensing through STING is critical for primary detection of both human and mouse CMV in nonhematopoietic cells and drives the initial wave of IFN-I that is key for controlling early viral replication
in vivo
.

IMPORTANCE
Cytomegalovirus (CMV) is one of the most common viral pathogens, with the majority of people contracting the virus in their lifetime. Although acute infection is mostly asymptomatic in healthy persons, significant pathology is observed in immunocompromised individuals, and chronic CMV infection may exacerbate a myriad of inflammatory conditions. Here we show that primary human endothelial cells mount robust IFN-I responses against CMV via a cGAS/STING/IRF3 pathway. Disruption of STING expression by CRISPRs revealed an essential role in eliciting IFN-I responses and restricting CMV replication. Consistently, in mice, STING is necessary for the first phase of IFN-I production that limits early CMV replication. Our results demonstrate a pivotal role for the cGAS-STING pathway in the initial detection of CMV infection.
A pilot study to demonstrate diagnostic potential of galectin-3 levels in saliva
Authors: Zhang Xi , Wan Yunxia , Chata Roberto , Brazzale Anthony , Atherton John J , Kostner Karam , Dimeski Goce , Punyadeera Chamindie
Published: June 2016

Aim

Heart failure (HF) affects millions of older individuals in both developed and low/middle-income countries. Serum galectin-3 levels have been shown to have prognostic value. However, its use as a diagnostic biomarker has not been explored. The aim was to establish a saliva galectin-3 reference range and to demonstrate the potential diagnostic utility of salivary and serum galectin-3 levels in assessing HF.

Methods

Blood and saliva samples were collected from age-matched healthy controls (n=51) and patients with HF (n=63). Customised immunoassays were developed to quantify salivary galectin-3 levels. The diagnostic performances of these assays were evaluated by receiver operator characteristic (ROC) curves analysis.

Results

The galectin-3 concentrations were significantly elevated in saliva and serum samples of patients with HF compared with controls (p<0.001 and p<0.0001, respectively). Using ROC curve analysis, both serum and salivary galectin-3 gave area under the curve (AUC)=0.86 and AUC=0.73, respectively. There was also a significant correlation (r=0.4, p<0.01) between serum and salivary galectin-3 levels.

Conclusions

For the first time, we have quantified galectin-3 levels in human saliva and have demonstrated potential clinical utility in diagnosing HF. Further, larger multicentre clinical trials are needed before salivary galectin-3 levels can be implemented in a clinical setting.
Physico-chemical and in-silico analysis of a phytocystatin purified fromBrassica junceacultivar RoAgro 5444
Authors: Khan Shumaila , Ahmad Sabahuddin , Siddiqi Mohammad Imran , Bano Bilqees
Published: June 2016

This study describes the isolation and purification of a phytocystatin from seeds of Brassica juncea (Indian mustard; cultivar RoAgro 5444), which is an important oilseed crop both agriculturally and economically. The protein was purified by gel filtration chromatography with 24.3% yield and 204-fold purification, and visualised by 2D gel electrophoresis. The 18.1 kDa mustard cystatin was highly specific for cysteine proteinases. The plant cystatin inhibited cathepsin B, confirming its role in conferring pest resistance. The inhibitor was highly stable over a pH range of 3–10 and retained significant inhibitory potential up to 70 °C. The stoichiometry of its interaction with papain, determined by isothermal calorimetry, suggests a 1:1 complex. Secondary structural elements calculated by far-UV circular dichroism (CD) spectroscopy show an 18.8% α-helical and 21% β-sheet structure. The protein was a non-competitive inhibitor of thiol proteinases. The Stokes radius and frictional co-efficient were used to describe the shape and size of the protein. Homology modelling and docking studies proposed a prototype illustrating the Brassica phytocystatin mediated papain inhibition. Molecular dynamics (MD) study revealed the excellent stability of the papain–phytocystatin complex during a simulation for 100 ns. Detailed results identify the mustard cystatin as an important member of the phytocystatin family.
The effects of drivers’ aggressive characteristics on traffic stability from a new car-following model
Authors: Peng Guanghan , Qing Li
Published: June 2016

In this paper, a new car-following model is proposed by considering the drivers’ aggressive characteristics. The stable condition and the modified Korteweg-de Vries (mKdV) equation are obtained by the linear stability analysis and nonlinear analysis, which show that the drivers’ aggressive characteristics can improve the stability of traffic flow. Furthermore, the numerical results show that the drivers’ aggressive characteristics increase the stable region of traffic flow and can reproduce the evolution and propagation of small perturbation.
Decoupled sectors and Wolf–Rayet galaxies
Authors: Fischler Willy , Jimmy  , Lorshbough Dustin
Published: June 2016

It has recently been proposed that gamma-ray burst (GRB) events may be modified by the presence of a dark matter sector subcomponent that is charged under an unbroken U(1). This proposal depends upon there being a nontrivial density of charged dark matter in star forming regions of galaxies which host GRBs. We discuss four Wolf–Rayet galaxies (NGC 1614, NGC 3367, NGC 4216 and NGC 5430) which should contain comparable amounts of dark matter gas and visible matter gas in the star forming regions. We show that the ratio of dark jet power to visible jet power depends only on the ratio of particle mass and charge when the densities are equal, allowing for these input parameters to be probed directly by future observations of GRBs.
Energy level and half-life determinations from photonuclear reaction on Ga target
Authors: Akkoyun Serkan , Bayram Tuncay , Dulger Fatih , Đapo Haris , Boztosun Ismail
Published: June 2016

Photonuclear reactions are important tools in the understanding of the nucleus. These reactions are also interesting for realizing the element creation processes in stellar environment. The use of bremsstrahlung photons generated from clinic linear accelerator is practical for performing these type of reactions. In this study, the bremsstrahlung photons with endpoint energy of 18[Formula: see text]MeV have been used for activating gallium target material. After irradiation, the transition energies and half-lives associated with the decay of [Formula: see text], [Formula: see text] and [Formula: see text] isotopes have been determined The values obtained for half-life of [Formula: see text], [Formula: see text] and [Formula: see text] isotopes are [Formula: see text][Formula: see text]min, [Formula: see text][Formula: see text]min and [Formula: see text][Formula: see text]h, respectively. It has been seen that the values are consistent with the present literature values. In addition, the new measurements of gamma-ray energies for transition energies have been obtained comparable to the literature values with good uncertainties.
Size-Dependent Dynamic Behavior of Electrostatically Actuated Microaccelerometers Under Mechanical Shock
Authors: Rahaeifard M. , Mojahedi M.
Published: June 2016

This paper studies the size-dependent dynamic behavior of electrostatically actuated microaccelerometers using the modified couple stress theory. The device is modeled as a cantilevered microbeam with an electrostatically actuated proof mass attached to its free end. The equation of motion is derived based on the Hamilton’s principle and solved both numerically (using the finite element and finite difference methods) and analytically (using the perturbation technique) and the dynamic response and pull-in instability of the device is studied. The results of these methods are compared and the source of error in the analytical results at high values of external acceleration is discussed. Furthermore, the results are compared with those evaluated based on the classical theory. It is found that for cantilevered accelerometers with a beam thickness of the order of the material length scale parameter, the classical theory gives a rough estimation of the dynamic response of the system. In this situation, the error of using the classical theory may change the prediction of the system behavior from unstable to stable.
Semi-Analytical Modeling and Vibration Control of a Geometrically Nonlinear Plate
Authors: Oveisi Atta , Nestorović Tamara , Nguyen Ngoc Linh
Published: June 2016

This paper presents the dynamic modeling of a piezolaminated plate considering geometrical nonlinearities. The piezo-actuator and piezo-sensor are connected via proportional derivative feedback control law. The Hamilton’s principle is used to extract the strong form of the equation of motion with the reflection of the higher order strain terms by means of the strain–displacement relationship of the von Karman type. Then the nonlinear partial differential equation (PDE) obtained is converted to a nonlinear algebraic equation by employing the combination of harmonic balance method and single-mode Galerkin’s technique. Finally, the vibration suppression performance and sensitivity of the dynamic response is evaluated for various control parameters and magnitudes of external disturbance.
Duality results for iterated function systems with a general family of branches
Authors: Mengue Jairo K. , Oliveira Elismar R.
Published: June 2016

Given [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] compact metric spaces, we consider two iterated function systems [Formula: see text] and [Formula: see text], where [Formula: see text] and [Formula: see text] are contractions. Let [Formula: see text] be the set of probabilities [Formula: see text] with [Formula: see text]-marginal being holonomic with respect to [Formula: see text] and [Formula: see text]-marginal being holonomic with respect to [Formula: see text]. Given [Formula: see text] and [Formula: see text], let [Formula: see text] be the set of probabilities in [Formula: see text] having [Formula: see text]-marginal [Formula: see text] and [Formula: see text]-marginal [Formula: see text]. Let [Formula: see text] be the relative entropy of [Formula: see text] with respect to [Formula: see text] and [Formula: see text] be the relative entropy of [Formula: see text] with respect to [Formula: see text]. Given a cost function [Formula: see text], let [Formula: see text]. We will prove the duality equation: [Formula: see text] In particular, if [Formula: see text] and [Formula: see text] are single points and we drop the entropy, the equation above can be rewritten as the Kantorovich duality for the compact spaces [Formula: see text] and a continuous cost function [Formula: see text].
The Analysis of Transaction Costs in Water Policy Implementation in South Africa: Trends, Determinants and Economic Implications
Authors: Njiraini Georgina W. , Thiam Djiby Racine , Coggan Anthea
Published: June 2016

Water is a complex economic good. It requires optimal management to control rising scarcity and competition for use. South Africa like many other parts of the world is in the process of implementing market-based water policy reforms to attain equity, efficiency, and sustainability in water use. However, these reforms have not been entirely successful and water allocation problems persist. This could be due to many contributing factors, certainly, but this paper narrows down to identify possible transaction costs that would arise from the policy process. Transaction costs can be great hindrances to policy formation and implementation especially if they constitute a large component of total policy costs. However, transaction costs remain generally unmeasured and this study fills in this gap for the Olifants basin of South Africa. Specifically, the study identifies and quantifies transaction costs incurred by various stakeholders in the water policy process in the Olifants basin in South Africa. Further, determinants of irrigation farmers’ transaction costs are assessed using regression approaches. Results from this study allow evaluating existing policies ex-post for improvement purposes.
Lifelong strength training mitigates the age-related decline in efferent drive
Authors: Unhjem Runar , Nygård Mona , van den Hoven Lene T. , Sidhu Simranjit K. , Hoff Jan , Wang Eivind
Published: June 2016

Recently, we documented age-related attenuation of efferent drive to contracting skeletal muscle. It remains elusive if this indication of reduced muscle strength is present with lifelong strength training. For this purpose, we examined evoked potentials in the calf muscles of 11 [71 ± 4 (SD) yr] strength-trained master athletes (MA) contrasted with 10 (71 ± 4 yr) sedentary (SO) and 11 (73 ± 6 yr) recreationally active (AO) old subjects, as well as 9 (22 ± 2 yr) young controls. As expected, MA had higher leg press maximal strength (MA, 185 ± 32 kg; AO, 128 ± 15 kg; SO, 106 ± 11 kg; young, 147 ± 22 kg, P < 0.01) and rate of force development (MA, 5,588 ± 2,488 N/s; AO, 2,156 ± 1,100 N/s; SO, 2,011 ± 825 N/s; young, 3,663 ± 1,140 N/s, P < 0.05) than the other groups. MA also exhibited higher musculus soleus normalized V waves during maximal voluntary contractions (MVC) [maximal V wave amplitude/maximal M wave during MVC (Vsup/Msup); 0.28 ± 0.15] than AO (0.13 ± 0.06, P < 0.01) and SO (0.11 ± 0.05, P < 0.01), yet lower than young (0.45 ± 0.12, P < 0.01). No differences were apparent between the old groups in H reflex recorded at rest or during MVC [maximal H reflex amplitude/maximal M wave during rest (Hmax/Mmax); maximal H reflex amplitude during MVC/maximal M wave during MVC (Hsup/Msup)], and all were lower ( P < 0.01) than young. MA (34.4 ± 2.1 ms) had shorter ( P < 0.05) H reflex latency compared with AO (36.4 ± 3.7 ms) and SO (37.3 ± 3.2 ms), but longer ( P < 0.01) than young (30.7 ± 2.0 ms). Using interpolated twitch analysis, MA (89 ± 7%) had plantar flexion voluntary activation similar to young (90 ± 6%), and this was higher ( P < 0.05), or tended to be higher ( P = 0.06–0.09), than SO (83 ± 10%) and AO (84 ± 5%). These observations suggest that lifelong strength training has a protective effect against age-related attenuation of efferent drive. In contrast, no beneficial effect seems to derive from habitual recreational activity, indicating that strength training may be particularly beneficial for counteracting age-related loss of neuromuscular function.
A simple approach to ignoring irrelevant variables by population decoding based on multisensory neurons
Authors: Kim HyungGoo R. , Pitkow Xaq , Angelaki Dora E. , DeAngelis Gregory C.
Published: June 2016

Sensory input reflects events that occur in the environment, but multiple events may be confounded in sensory signals. For example, under many natural viewing conditions, retinal image motion reflects some combination of self-motion and movement of objects in the world. To estimate one stimulus event and ignore others, the brain can perform marginalization operations, but the neural bases of these operations are poorly understood. Using computational modeling, we examine how multisensory signals may be processed to estimate the direction of self-motion (i.e., heading) and to marginalize out effects of object motion. Multisensory neurons represent heading based on both visual and vestibular inputs and come in two basic types: “congruent” and “opposite” cells. Congruent cells have matched heading tuning for visual and vestibular cues and have been linked to perceptual benefits of cue integration during heading discrimination. Opposite cells have mismatched visual and vestibular heading preferences and are ill-suited for cue integration. We show that decoding a mixed population of congruent and opposite cells substantially reduces errors in heading estimation caused by object motion. In addition, we present a general formulation of an optimal linear decoding scheme that approximates marginalization and can be implemented biologically by simple reinforcement learning mechanisms. We also show that neural response correlations induced by task-irrelevant variables may greatly exceed intrinsic noise correlations. Overall, our findings suggest a general computational strategy by which neurons with mismatched tuning for two different sensory cues may be decoded to perform marginalization operations that dissociate possible causes of sensory inputs.
Optogenetic manipulation of neural circuits in awake marmosets
Authors: MacDougall Matthew , Nummela Samuel U. , Coop Shanna , Disney Anita , Mitchell Jude F. , Miller Cory T.
Published: June 2016

Optogenetics has revolutionized the study of functional neuronal circuitry (Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. Nat Neurosci 8: 1263–1268, 2005; Deisseroth K. Nat Methods 8: 26–29, 2011). Although these techniques have been most successfully implemented in rodent models, they have the potential to be similarly impactful in studies of nonhuman primate brains. Common marmosets ( Callithrix jacchus) have recently emerged as a candidate primate model for gene editing, providing a potentially powerful model for studies of neural circuitry and disease in primates. The application of viral transduction methods in marmosets for identifying and manipulating neuronal circuitry is a crucial step in developing this species for neuroscience research. In the present study we developed a novel, chronic method to successfully induce rapid photostimulation in individual cortical neurons transduced by adeno-associated virus to express channelrhodopsin (ChR2) in awake marmosets. We found that large proportions of neurons could be effectively photoactivated following viral transduction and that this procedure could be repeated for several months. These data suggest that techniques for viral transduction and optical manipulation of neuronal populations are suitable for marmosets and can be combined with existing behavioral preparations in the species to elucidate the functional neural circuitry underlying perceptual and cognitive processes.
A two-stage model of concurrent interval timing in monkeys
Authors: Kleinman Matthew R. , Sohn Hansem , Lee Daeyeol
Published: June 2016

Accurate timing is critical for a wide range of cognitive processes and behaviors. In addition, complex environments frequently necessitate the simultaneous timing of multiple intervals, and behavioral performance in concurrent timing can constrain formal models of timing behavior and provide important insights into the corresponding neural mechanisms. However, the accuracy of such concurrent timing has not been rigorously examined. We developed a novel behavioral paradigm in which rhesus monkeys were incentivized to time two independent intervals. The onset asynchrony of two overlapping intervals varied randomly, thereby discouraging the animals from adopting any habitual responses. We found that only the first response for each interval was strongly indicative of the internal timing of that interval, consistent with previous findings and a two-stage model. In addition, the temporal precision of the first response was comparable in the single-interval and concurrent-interval conditions, although the first saccade to the second interval tended to occur sooner than in the single-interval condition. Finally, behavioral responses during concurrent timing could be well accounted for by a race between two independent stochastic processes resembling those in the single-interval condition. The fact that monkeys can simultaneously monitor and respond to multiple temporal intervals indicates that the neural mechanisms for interval timing must be sufficiently flexible for concurrent timing.
Neural mechanisms of selective attention in the somatosensory system
Authors: Gomez-Ramirez Manuel , Hysaj Kristjana , Niebur Ernst
Published: June 2016

Selective attention allows organisms to extract behaviorally relevant information while ignoring distracting stimuli that compete for the limited resources of their central nervous systems. Attention is highly flexible, and it can be harnessed to select information based on sensory modality, within-modality feature(s), spatial location, object identity, and/or temporal properties. In this review, we discuss the body of work devoted to understanding mechanisms of selective attention in the somatosensory system. In particular, we describe the effects of attention on tactile behavior and corresponding neural activity in somatosensory cortex. Our focus is on neural mechanisms that select tactile stimuli based on their location on the body (somatotopic-based attention) or their sensory feature (feature-based attention). We highlight parallels between selection mechanisms in touch and other sensory systems and discuss several putative neural coding schemes employed by cortical populations to signal the behavioral relevance of sensory inputs. Specifically, we contrast the advantages and disadvantages of using a gain vs. spike-spike correlation code for representing attended sensory stimuli. We favor a neural network model of tactile attention that is composed of frontal, parietal, and subcortical areas that controls somatosensory cells encoding the relevant stimulus features to enable preferential processing throughout the somatosensory hierarchy. Our review is based on data from noninvasive electrophysiological and imaging data in humans as well as single-unit recordings in nonhuman primates.
Target-specific M1 inputs to infragranular S1 pyramidal neurons
Authors: Kinnischtzke Amanda K. , Fanselow Erika E. , Simons Daniel J.
Published: June 2016

The functional role of input from the primary motor cortex (M1) to primary somatosensory cortex (S1) is unclear; one key to understanding this pathway may lie in elucidating the cell-type specific microcircuits that connect S1 and M1. Recently, we discovered that a subset of pyramidal neurons in the infragranular layers of S1 receive especially strong input from M1 (Kinnischtzke AK, Simons DJ, Fanselow EE. Cereb Cortex 24: 2237–2248, 2014), suggesting that M1 may affect specific classes of pyramidal neurons differently. Here, using combined optogenetic and retrograde labeling approaches in the mouse, we examined the strengths of M1 inputs to five classes of infragranular S1 neurons categorized by their projections to particular cortical and subcortical targets. We found that the magnitude of M1 synaptic input to S1 pyramidal neurons varies greatly depending on the projection target of the postsynaptic neuron. Of the populations examined, M1-projecting corticocortical neurons in L6 received the strongest M1 inputs, whereas ventral posterior medial nucleus-projecting corticothalamic neurons, also located in L6, received the weakest. Each population also possessed distinct intrinsic properties. The results suggest that M1 differentially engages specific classes of S1 projection neurons, thereby regulating the motor-related influence S1 exerts over subcortical structures.
Adherence to Diet and Physical Activity Cancer Prevention Guidelines and Cancer Outcomes: A Systematic Review
Authors: Kohler Lindsay N. , Garcia David O. , Harris Robin B. , Oren Eyal , Roe Denise J. , Jacobs Elizabeth T.
Published: June 2016

Many studies have reported that adherence to health promotion guidelines for diet, physical activity, and maintenance of healthy body weight may decrease cancer incidence and mortality. A systematic review was performed to examine associations between adherence to established cancer prevention guidelines for diet and physical activity and overall cancer incidence and mortality. PubMed, Google Scholar, and Cochrane Reviews databases were searched following the current recommendations of Preferred Reporting Items for Systematic Reviews and Meta-analysis Approach (PRISMA). Twelve studies met inclusion criteria for this review. High versus low adherence to established nutrition and physical activity cancer prevention guidelines was consistently and significantly associated with decreases of 10% to 61% in overall cancer incidence and mortality. Consistent significant reductions were also shown for breast cancer incidence (19%–60%), endometrial cancer incidence (23%–60%), and colorectal cancer incidence in both men and women (27%–52%). Findings for lung cancer incidence were equivocal, and no significant relationships were found between adherence and ovarian or prostate cancers. Adhering to cancer prevention guidelines for diet and physical activity is consistently associated with lower risks of overall cancer incidence and mortality, including for some site-specific cancers. Cancer Epidemiol Biomarkers Prev; 25(7); 1018–28. ©2016 AACR.
Selective Detection of the D-enantiomer of 2-Hydroxyglutarate in the CSF of Glioma Patients with Mutated Isocitrate Dehydrogenase
Authors: Kalinina Juliya , Ahn Jun , Devi Narra S. , Wang Liya , Li Yuancheng , Olson Jeffrey J. , Glantz Michael , Smith Thomas , Kim Ella L. , Giese Alf , Jensen Randy L. , Chen Clark C. , Carter Bob S. , Mao Hui , He Miao , Van Meir Erwin G.
Published: June 2016

Purpose: Elevation in D-2-Hydroxyglutarate (D-2HG) has recently emerged as a mandatory byproduct of mutated Isocitrate Dehydrogenase (IDH) genes 1 and 2 in glioma patients. The goal of the present study was to demonstrate the feasibility of detection of elevated levels of D-2HG in the cerebrospinal fluid (CSF) of glioma patients that carry point substitutions in the IDH gene.

Experimental Design: We developed a mass spectrometry (MS)–based platform to detect and quantify the D- and L-forms of 2HG in the CSF of glioma patients. Three independent cohorts of patients were analyzed, comprising a total of 176 samples derived from 84 patients. The levels of D- and L-2HG were used to stratify patients into IDH wild-type or IDH-mutated groups using an empirically obtained threshold of 0.69 μmol/L.

Results: Using this platform, a greater than 17-fold mean increase in D-2HG was observed in the CSF of patients with IDH mutant versus wild-type gliomas. The means for the D-2HG levels in CSF were 0.427 μmol/L in wild-type and 7.439 μmol/L in mutant groups. The C statistic for the receiver operator curve was 0.938, with 84% sensitivity, 90% specificity, and 89% accuracy to detect D-2HG. The levels of D- and L-2HG in CSF from wild-type patients varied by location of CSF draw (cisternal > ventricular > lumbar).

Conclusions: Our findings demonstrate that the CSF of patients harboring IDH mutant gliomas contain increased levels of D-2HG, which can be reliably detected with a MS-based platform. Clin Cancer Res; 22(24); 6256–65. ©2016 AACR.
A New Model to Study the Role of Arachidonic Acid in Colon Cancer Pathophysiology
Authors: Fan Yang-Yi , Callaway Evelyn , M. Monk Jennifer , S. Goldsby Jennifer , Yang Peiying , Vincent Logan , S. Chapkin Robert
Published: June 2016

A significant increase in cyclooxygenase 2 (COX2) gene expression has been shown to promote cylcooxygenase-dependent colon cancer development. Controversy associated with the role of COX2 inhibitors indicates that additional work is needed to elucidate the effects of arachidonic acid (AA)-derived (cyclooxygenase and lipoxygenase) eicosanoids in cancer initiation, progression, and metastasis. We have recently developed a novel Fads1 knockout mouse model that allows for the investigation of AA-dependent eicosanoid deficiency without the complication of essential fatty acid deficiency. Interestingly, the survival rate of Fads1-null mice is severely compromised after 2 months on a semi-purified AA-free diet, which precludes long-term chemoprevention studies. Therefore, in this study, dietary AA levels were titrated to determine the minimal level required for survival, while maintaining a distinct AA-deficient phenotype. Null mice supplemented with AA (0.1%, 0.4%, 0.6%, 2.0%, w/w) in the diet exhibited a dose-dependent increase (P < 0.05) in AA, PGE2, 6-keto PGF1α, TXB2, and EdU-positive proliferative cells in the colon. In subsequent experiments, null mice supplemented with 0.6% AA diet were injected with a colon-specific carcinogen (azoxymethane) in order to assess cancer susceptibility. Null mice exhibited significantly (P < 0.05) reduced levels/multiplicity of aberrant crypt foci (ACF) as compared with wild-type sibling littermate control mice. These data indicate that (i) basal/minimal dietary AA supplementation (0.6%) expands the utility of the Fads1-null mouse model for long-term cancer prevention studies and (ii) that AA content in the colonic epithelium modulates colon cancer risk. Cancer Prev Res; 9(9); 750–7. ©2016 AACR.
Remote Controlled CARs: Towards a Safer Therapy for Leukemia
Authors: June Carl H.
Published: June 2016

Genetic engineering of patient T cells with chimeric antigen receptors (CAR T cells) provides a powerful tool for inducing remissions in patients with various cancers derived from B cells. Challenges stemming from the inability to control the CAR T cells once given pose significant safety concerns. An article in Cancer Immunology Research presents an approach to circumvent this issue. Cancer Immunol Res; 4(8); 643. ©2016 AACR.

See article by Sakemura et al., p. 658.
Home- or Institutional Hemodialysis? - a Matched Pair-Cohort Study Comparing Survival and Some Modifiable Factors Related to Survival
Authors: Rydell Helena , Clyne Naomi , Segelmark Mårten
Published: June 2016

Background/Aims: Survival for dialysis patients is poor. Earlier studies have shown better survival in home-hemodialysis (HHD). The aims of this study are to compare survival for matched patients with HHD and institutional hemodialysis (IHD) and to elucidate the effect on factors related to survival such as hyperphosphatemia, fluid overload and anemia. Methods: In this retrospective, observational study, incident patients starting HHD and IHD were matched according to sex, age, comorbidity and date of start. Survival analysis was performed both as ”intention to treat” including renal transplantation and ”on treatment” with censoring at the date of transplantation. Dialysis doses, laboratory parameters and prescriptions of medications were compared. Results: After matching, 41 pairs of patients, with HHD and IHD, were included. Survival among HHD patients was longer compared with IHD, median survival being 17.3 and 13.0 years (p=0.016), respectively. The “on treatment” analysis, also favoured HHD (p=0.015). HHD patients had lower phosphate, 1.5 mmol/L compared with 2.1 mmol/L (p<0.001) and no antihypertensives and diuretics compared with 2 for IHD patients at 6 (p=0.001) and 18 months (p=0.014). There were no differences in hemoglobin or albumin. Conclusion: HHD shows better survival compared with IHD, also after controlling for patient selection. This could be caused by better phosphate and/or fluid balance associated with higher dialysis doses.
Power Comparisons of Methods for Joint Association Analysis of Multiple Phenotypes
Authors: Zhu Huanhuan , Zhang Shuanglin , Sha Qiuying
Published: June 2016

Background/Aims: Genome-wide association studies (GWAS) have identified many variants that each affect multiple phenotypes, which suggests that pleiotropic effects on human complex phenotypes may be widespread. Therefore, statistical methods that can jointly analyze multiple phenotypes in GWAS may have advantages over analyzing each phenotype individually. Several statistical methods have been developed to utilize such multivariate phenotypes in genetic association studies; however, the performance of these methods under different scenarios is largely unknown. Our goal was to provide researchers with useful guidelines on selecting statistical methods for the application of real data to multiple phenotypes. Methods: In this study, we evaluated the performance of some of the existing methods for association studies using multiple phenotypes. These methods included the O'Brien method (OB), cross-validation method (CV), optimal weight method (OW), Trait-based Association Test that uses Extended Simes procedure (TATES), principal components of heritability (PCH), canonical correlation analysis (CCA), multivariate analysis of variance (MANOVA), and a joint model of multiple phenotypes (MultiPhen). We used simulation studies to compare the powers of these methods under a variety of scenarios, including different numbers of phenotypes, different values of between-phenotype correlation, different minor allele frequencies, and different mean and variance models. Results and Conclusion: Our simulation results show that there is no single method with consistently good performance among all the scenarios. Each method has its own advantages and disadvantages.
Advanced Mucinous Adenocarcinoma Arising from a Mature Cystic Teratoma: A Case Report and Literature Review
Authors: Miyasaka Aki , Nishikawa Tadaaki , Kozawa Eito , Yasuda Masanori , Fujiwara Keiichi , Hasegawa Kosei
Published: June 2016

Purpose: To describe the postoperative progressive course of advanced-stage adenocarcinoma arising from a mature cystic teratoma (MCT) and review the literature regarding this disease. Methods: A 59-year-old woman visited our hospital with an abdominal mass. Laparotomy showed enlargement of the left ovary and dissemination throughout the abdominal and pelvic cavities. The diagnosis was FIGO stage IIIB adenocarcinoma arising from a MCT. We report this case in detail with a review of the literature. Results: A literature search yielded 9 cases of stage III adenocarcinoma with malignant transformation. Six of these 9 patients died within 12 months after diagnosis. Of the 8 patients who underwent postoperative chemotherapy, 3 survived for over 39 months. The review indicates that prognosis of adenocarcinoma is as poor as that for squamous cell carcinoma arising from a MCT. Conclusions: In general, as with this case, prognosis of advanced adenocarcinoma associated with a MCT is poor. However, we should be aware that not all patients are resistant to chemotherapy.
Left Prefrontal Repetitive Transcranial Magnetic Stimulation in a Logopenic Variant of Primary Progressive Aphasia: A Case Report
Authors: Bereau Matthieu , Magnin Eloi , Nicolier Magali , Berthet Louis , Dariel Elfried , Ferreira Sabrina , Sylvestre Géraldine , Monnin Julie , Chopard Gilles , Bouladour Hatem , Vandel Pierre , Haffen Emmanuel
Published: June 2016

Background/Aims: High frequency repetitive transcranial magnetic stimulation (hf-rTMS) improves language skills in Alzheimer's disease (AD). We report the use of hf-rTMS in a patient with logopenic primary progressive aphasia (LPPA) due to AD. Method: hf-rTMS was applied to the left dorsolateral prefrontal cortex of a LPPA patient. Cerebral perfusion, neuropsychological and linguistic performances were evaluated before and 1 month after hf-rTMS. Results: The tolerance was good. Improvements on linguistic (fluency, naming, lesser paraphasia) and cognitive skills (Mini Mental State Examination, verbal memory free recall, speed processing) and cerebral perfusion were observed. Conclusion: hf-rTMS can be used in LPPA patients. A procognitive effect persisting several weeks after stimulation in LPPA patients was suggested and should therefore be evaluated in a clinical trial as an adjunctive therapeutic tool.
РОЗПОВСЮДЖЕННЯ ШТАМІВ-ПРОДУЦЕНТІВ МЕТАЛО-β-ЛАКТАМАЗ СЕРЕД МНОЖИННОСТІЙКИХ НЕФЕРМЕНТАЦІЙНИХ ГРАМ-НЕГАТИВНИХ БАКТЕРІЙ У СУЧАСНИЙ ПЕРІОД В УКРАЇНІ
Authors: Pokas O. V. , Melezhyk I. O. , Mariyevsky V. F. , Bartsytska I. F.
Published: June 2016

Серед множиннорезистентних до антибіотиків неферментаційних грам-негативних бактерій, виділених у хворих хірургічного профілю з різних стаціонарів України, у 54,0-56,0 % штамів виявлено продукцію метало-β-лактамаз, що зумовлюють стійкість до карбапенемів. Всі штами були резистентними до цефалоспоринових антибіотиків, мали низьку чутливість до не-β-лактамних антибіотиків. Найбільш активним препаратом до A. baumannii залишається нетилміцин. 
ТРУДНОЩІ І ПОМИЛКИ ДИФЕРЕНЦІЙНОЇ ДІАГНОСТИКИ ПРИ ТУБЕРКУЛЬОЗНОМУ МЕНІНГОЕНЦЕФАЛІТІ У ДИТИНИ 6,5 МІСЯЦІВ
Authors: Dasho M. B. , Lyshenyuk C. A. , Chulovska U. B. , Lytvyn H. O.
Published: June 2016

У контексті диференційної діагностики гострих інфекційних уражень центральної нервової системи (ЦНС) проаналізовано випадок туберкульозного менінгоенцефаліту у дитини першого року життя на всіх етапах його розвитку – від туберкульозу легень до генералізованої форми з ураженням ЦНС та причини, що призвели до пізньої (постмортальної) діагностики даного захворювання. 
ВІЙСЬКОВА ЕПІДЕМІОЛОГІЯ З ЕПІДЕМІОЛОГІЄЮ НАДЗВИЧАЙНИХ СИТУАЦІЙ : ПІДРУЧНИК / М. А. АНДРЕЙЧИН, О. Д. КРУШЕЛЬНИЦЬКИЙ, В. С. КОПЧА, І. В. ОГОРОДНІЙЧУК ; за ред. М. А. Андрейчина. – Тернопіль : ТДМУ, 2015. – 320 с.
Authors: Badiuk M. I.
Published: June 2016

У разі виникнення природних і техногенних катастроф
будуть потрібні значні людські сили й засоби. Тому в лік-
відації природних і соціальних катаклізмів провідна роль
належить війську, що діє у тісній співпраці з цивільними
формуваннями.
Extracellular ATP Induces Vascular Inflammation and Atherosclerosis via Purinergic Receptor Y
2
in Mice
Authors: Stachon Peter , Geis Serjosha , Peikert Alexander , Heidenreich Adrian , Michel Nathaly Anto , Ünal Fatih , Hoppe Natalie , Dufner Bianca , Schulte Lisa , Marchini Timoteo , Cicko Sanja , Ayata Korcan , Zech Andreas , Wolf Dennis , Hilgendorf Ingo , Willecke Florian , Reinöhl Jochen , von zur Mühlen Constantin , Bode Christoph , Idzko Marco , Zirlik Andreas
Published: June 2016

Objective—

A solid body of evidence supports a role of extracellular ATP and its P2 receptors in innate and adaptive immunity. It promotes inflammation as a danger signal in various chronic inflammatory diseases. Thus, we hypothesize contribution of extracellular ATP and its receptor P2Y
2
in vascular inflammation and atherosclerosis.

Approach and Results—

Extracellular ATP induced leukocyte rolling, adhesion, and migration in vivo as assessed by intravital microscopy and in sterile peritonitis. To test the role of extracellular ATP in atherosclerosis, ATP or saline as control was injected intraperitoneally 3× a week in low-density lipoprotein receptor
−/−
mice consuming high cholesterol diet. Atherosclerosis significantly increased after 16 weeks in ATP-treated mice (n=13; control group, 0.26 mm2; ATP group, 0.33 mm2;
P
=0.01). To gain into the role of ATP-receptor P2Y
2
in ATP-induced leukocyte recruitment, ATP was administered systemically in P2Y
2
-deficient or P2Y
2
-competent mice. In P2Y
2
-deficient mice, the ATP-induced leukocyte adhesion was significantly reduced as assessed by intravital microscopy. P2Y
2
expression in atherosclerosis was measured by real-time polymerase chain reaction and immunohistochemistry and demonstrates an increased expression mainly caused by influx of P2Y
2
-expressing macrophages. To investigate the functional role of P2Y
2
in atherogenesis, P2Y
2
-deficient low-density lipoprotein receptor
−/−
mice consumed high cholesterol diet. After 16 weeks, P2Y
2
-deficient mice showed significantly reduced atherosclerotic lesions with decreased macrophages compared with P2Y
2
-competent mice (n=11; aortic arch: control group, 0.25 mm
2
; P2Y
2
-deficient, 0.14 mm2;
P
=0.04). Mechanistically, atherosclerotic lesions from P2Y
2
-deficient mice expressed less vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 RNA.

Conclusions—

We show that extracellular ATP induces vascular inflammation and atherosclerosis via activation of P2Y
2
.
α7 Nicotinic Acetylcholine Receptor Relieves Angiotensin II–Induced Senescence in Vascular Smooth Muscle Cells by Raising Nicotinamide Adenine Dinucleotide–Dependent SIRT1 Activity
Authors: Li Dong-Jie , Huang Fang , Ni Min , Fu Hui , Zhang Liang-Sheng , Shen Fu-Ming
Published: June 2016

Objective—

α7 nicotinic acetylcholine receptor (α7nAChR) is a subtype of nAChR and has been reported to be involved in hypertension end-organ damage. In this study, we tested the role of α7nAChR in angiotensin II (Ang II)–induced senescence of vascular smooth muscle cells (VSMCs).

Approach and Results—

Expression of α7nAChR was not influenced by Ang II. Ang II induced remarkable senescent phenotypes in rodent and human VSMCs, including increased senescence-associated β-galactosidase activity, phosphorylation of H2A.X
Ser139
, phosphorylation of Chk1
Ser317
, reduced replication, and downregulation of proliferating cell nuclear antigen. Activation of α7nAChR with a selective agonist PNU-282987 blocked Ang II–induced senescence in cultured VSMCs. Moreover, PNU-282987 treatment attenuated the Ang II infusion–induced VSMC senescence in wild-type but not in α7nAChR
−/−
mice. PNU-282987 reduced the Ang II–enhanced reactive oxygen species, lipid peroxidation, and the expression of NADPH oxidase 1, NADPH oxidase 4, and p22
phox
in cultured VSMCs isolated from wild-type but not in α7nAChR
−/−
mice. Furthermore, PNU-282987 diminished Ang II–induced prosenescence signaling pathways, including p53, acetyl-p53, p21, and p16
INK4a
. Finally, although α7nAChR activation by PNU-282987 did not affect the Ang II–induced downregulation of sirtuin 1 (SIRT1), it significantly increased intracellular NAD
+
levels, and thereby enhanced SIRT1 activity in an AMP-dependent protein kinase–independent manner. Depletion of SIRT1 by knockdown or SIRT1 inhibitor EX527 abrogated the antisenescence effect of α7nAChR against Ang II.

Conclusions—

Our results demonstrate that activation of α7nAChR alleviates Ang II–induced VSMC senescence through promoting NAD
+
–SIRT1 pathway, suggesting that α7nAChR may be a potential therapeutic target for the treatment of Ang II–associated vascular aging disorders.
N-Terminal Pro-B–Type Natriuretic Peptide Is Related to Retinal Microvascular Damage
Authors: Mutlu Unal , Ikram M. Arfan , Hofman Albert , de Jong Paulus T.V.M. , Klaver Caroline C.W. , Ikram M. Kamran
Published: June 2016

Objective—

N-terminal pro-B–type natriuretic peptide (NT-proBNP) is a marker of cardiac dysfunction and has been linked to various indices of large vessel disease. However, it remains unclear whether NT-proBNP also relates to microvascular damage. In a community-dwelling population, we studied the association between NT-proBNP and retinal microvascular damage.

Approach and Results—

From the population-based Rotterdam Study, we included 8437 participants (mean age 64.1 years and 59% women) without a history of cardiovascular disease, with NT-proBNP data and gradable retinal images. NT-proBNP serum levels were measured using an immunoassay. Retinopathy signs, that is, exudates, microaneurysms, cotton wool spots, and dot/blot hemorrhages, present on fundus photographs were graded in the total study population; retinal vascular calibers, that is, arteriolar and venular calibers, were semiautomatically measured in a subsample (n=2763) of the study population. We conducted cross-sectional analyses on the association between NT-proBNP and retinal microvascular damage using logistic and linear regression models, adjusting for age, sex, and cardiovascular risk factors. We found that NT-proBNP was associated with the presence of retinopathy (adjusted odds ratio [95% confidence interval] per SD increase in natural log-transformed NT-proBNP: 1.14 [1.03–1.27]). We also found that higher NT-proBNP was associated with narrower arteriolar calibers (adjusted mean difference in arteriolar caliber per SD increase in natural log-transformed NT-proBNP: −0.89 µm [−1.54 to −0.24]). This association remained unchanged after excluding participants with retinopathy signs.

Conclusions—

In participants free of clinical cardiovascular disease, higher levels of NT-proBNP are associated with retinal microvascular damage, suggesting a potential role for NT-proBNP as marker for small vessel disease.
Exercise Prevents Upregulation of RyRs–BK
Ca
Coupling in Cerebral Arterial Smooth Muscle Cells From Spontaneously Hypertensive Rats
Authors: Shi Lijun , Zhang Yanyan , Liu Yujia , Gu Boya , Cao Run , Chen Yu , Zhao Tengteng
Published: June 2016

Objective—

Regular exercise is an effective nonpharmacological means of preventing and controlling hypertension. However, the molecular mechanisms underlying its effects remain undetermined. The hypothesis that hypertension increases the functional coupling of large-conductance Ca
2+
-activated K
+
(BK
Ca
) channels with ryanodine receptors in spontaneously hypertensive rats (SHR) as a compensatory response to an increase in intracellular Ca
2+
concentration in cerebral artery smooth muscle cells was assessed here. It was further hypothesized that exercise training would prevent this increase in functional coupling.

Approach and Results—

SHR and Wistar–Kyoto (WKY) rats were randomly assigned to sedentary groups (SHR-SED and WKY-SED) and exercise training groups (SHR-EX and WKY-EX). Cerebral artery smooth muscle cells displayed spontaneous transient outward currents at membrane potentials more positive than −40 mV. The amplitude of spontaneous transient outward currents together with the spontaneous Ca
2+
sparks in isolated cerebral artery smooth muscle cells was significantly higher in SHR-SED than in WKY-SED. Moreover, hypertension displayed increased whole-cell BK
Ca
, voltage-gated Ca
2+
channel, but decreased K
V
currents in cerebral artery smooth muscle cells. In SHRs, the activity of the single BK
Ca
channel increased markedly, and the protein expression of BK
Ca
(β1, but not α-subunit) also increased, but K
V
1.2 decreased significantly. Exercise training ameliorated all of these functional and molecular alterations in hypertensive rats.

Conclusions—

These data indicate that hypertension leads to enhanced functional coupling of ryanodine receptors–BK
Ca
to buffer pressure–induced constriction of cerebral arteries, which attributes not only to an upregulation of BK
Ca
β1-subunit function but also to an increase of Ca
2+
release from ryanodine receptors. However, regular aerobic exercise efficiently prevents augmented coupling and so alleviates the pathological compensation and restores cerebral arterial function.