bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural Stem Cell–Based Anticancer Gene Therapy: A First-in-Human Study in Recurrent High-Grade Glioma Patients
Authors: Portnow Jana , Synold Timothy W. , Badie Behnam , Tirughana Revathiswari , Lacey Simon F. , D'Apuzzo Massimo , Metz Marianne Z. , Najbauer Joseph , Bedell Victoria , Vo Tien , Gutova Margarita , Frankel Paul , Chen Mike , Aboody Karen S.
Published: December 2016

Purpose: Human neural stem cells (NSC) are inherently tumor tropic, making them attractive drug delivery vehicles. Toward this goal, we retrovirally transduced an immortalized, clonal NSC line to stably express cytosine deaminase (HB1.F3.CD.C21; CD-NSCs), which converts the prodrug 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU).

Experimental Design: Recurrent high-grade glioma patients underwent intracranial administration of CD-NSCs during tumor resection or biopsy. Four days later, patients began taking oral 5-FC every 6 hours for 7 days. Study treatment was given only once. A standard 3 + 3 dose escalation schema was used to increase doses of CD-NSCs from 1 × 107 to 5 × 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU. Serial blood samples were obtained to assess systemic drug concentrations as well as to perform immunologic correlative studies.

Results: Fifteen patients underwent study treatment. We saw no dose-limiting toxicity (DLT) due to the CD-NSCs. There was 1 DLT (grade 3 transaminitis) possibly related to 5-FC. We did not see development of anti-CD-NSC antibodies and did not detect CD-NSCs or replication-competent retrovirus in the systemic circulation. Intracerebral microdialysis revealed that CD-NSCs produced 5-FU locally in the brain in a 5-FC dose-dependent manner. Autopsy data indicate that CD-NSCs migrated to distant tumor sites and were nontumorigenic.

Conclusions: Collectively, our results from this first-in-human study demonstrate initial safety and proof of concept regarding the ability of NSCs to target brain tumors and locally produce chemotherapy. Clin Cancer Res; 23(12); 2951–60. ©2016 AACR.
Combination Epigenetic Therapy in Advanced Breast Cancer with 5-Azacitidine and Entinostat: A Phase II National Cancer Institute/Stand Up to Cancer Study
Authors: Connolly Roisin M. , Li Huili , Jankowitz Rachel C. , Zhang Zhe , Rudek Michelle A. , Jeter Stacie C. , Slater Shannon A. , Powers Penny , Wolff Antonio C. , Fetting John H. , Brufsky Adam , Piekarz Richard , Ahuja Nita , Laird Peter W. , Shen Hui , Weisenberger Daniel J. , Cope Leslie , Herman James G. , Somlo George , Garcia Agustin A. , Jones Peter A. , Baylin Stephen B. , Davidson Nancy E. , Zahnow Cynthia A. , Stearns Vered
Published: December 2016

Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC).

Experimental Design: Patients received 5-azacitidine 40 mg/m2 (days 1–5, 8–10) and entinostat 7 mg (days 3, 10) on a 28-day cycle. Continuation of epigenetic therapy was offered with the addition of endocrine therapy at the time of progression [optional continuation (OC) phase]. Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be ≥20% against null of 5% using Simon two-stage design. At least one response was required in 1 of 13 patients per cohort to continue accrual to 27 per cohort (type I error, 4%; power, 90%).

Results: There was one partial response among 27 women with hormone-resistant disease (ORR = 4%; 95% CI, 0–19), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n = 12). Mandatory tumor samples were obtained pre- and posttreatment (58% paired) with either up- or downregulation of ER observed in approximately 50% of posttreatment biopsies in the hormone-resistant, but not TNBC cohort.

Conclusions: Combination epigenetic therapy was well tolerated, but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression, but further study is needed. Clin Cancer Res; 23(11); 2691–701. ©2016 AACR.
Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers
Authors: Sun Kaiming , Atoyan Ruzanna , Borek Mylissa A. , Dellarocca Steven , Samson Maria Elena S. , Ma Anna W. , Xu Guang-Xin , Patterson Troy , Tuck David P. , Viner Jaye L. , Fattaey Ali , Wang Jing
Published: December 2016

Upregulation of MYC is a common driver event in human cancers, and some tumors depend on MYC to maintain transcriptional programs that promote cell growth and proliferation. Preclinical studies have suggested that individually targeting upstream regulators of MYC, such as histone deacetylases (HDAC) and phosphoinositide 3-kinases (PI3K), can reduce MYC protein levels and suppress the growth of MYC-driven cancers. Synergy between HDAC and PI3K inhibition in inducing cancer cell death has also been reported, but the involvement of MYC regulation is unclear. In this study, we demonstrated that HDAC and PI3K inhibition synergistically downregulates MYC protein levels and induces apoptosis in “double-hit” (DH) diffuse large B-cell lymphoma (DLBCL) cells. Furthermore, CUDC-907, a small-molecule dual-acting inhibitor of both class I and II HDACs and class I PI3Ks, effectively suppresses the growth and survival of MYC-altered or MYC-dependent cancer cells, such as DH DLBCL and BRD–NUT fusion-positive NUT midline carcinoma (NMC) cells, and MYC protein downregulation is an early event induced by CUDC-907 treatment. Consistently, the antitumor activity of CUDC-907 against multiple MYC-driven cancer types was also demonstrated in animal models, including DLBCL and NMC xenograft models, Myc transgenic tumor syngeneic models, and MYC-amplified solid tumor patient-derived xenograft (PDX) models. Our findings suggest that dual function HDAC and PI3K inhibitor CUDC-907 is an effective agent targeting MYC and thus may be developed as potential therapy for MYC-dependent cancers. Mol Cancer Ther; 16(2); 285–99. ©2016 AACR.
Imatinib Spares cKit-Expressing Prostate Neuroendocrine Tumors, whereas Kills Seminal Vesicle Epithelial–Stromal Tumors by Targeting PDGFR-β
Authors: Jachetti Elena , Rigoni Alice , Bongiovanni Lucia , Arioli Ivano , Botti Laura , Parenza Mariella , Cancila Valeria , Chiodoni Claudia , Festinese Fabrizio , Bellone Matteo , Tardanico Regina , Tripodo Claudio , Colombo Mario P.
Published: December 2016

Prostate cancer is a leading cause of cancer-related death in males worldwide. Indeed, advanced and metastatic disease characterized by androgen resistance and often associated with neuroendocrine (NE) differentiation remains incurable. Using the spontaneous prostate cancer TRAMP model, we have shown that mast cells (MCs) support in vivo the growth of prostate adenocarcinoma, whereas their genetic or pharmacologic targeting favors prostate NE cancer arousal. Aiming at simultaneously targeting prostate NE tumor cells and MCs, both expressing the cKit tyrosine kinase receptor, we have tested the therapeutic effect of imatinib in TRAMP mice. Imatinib-treated TRAMP mice experience a partial benefit against prostate adenocarcinoma, because of inhibition of supportive MCs. However, they show an unexpected outgrowth of prostate NE tumors, likely because of defective signaling pathway downstream of cKit receptor. Also unexpected but very effective was the inhibition of epithelial–stromal tumors of the seminal vesicles achieved by imatinib treatment. These tumors normally arise in the seminal vesicles of TRAMP mice, independently of the degree of prostatic glandular lesions, and resemble phyllodes tumors found in human prostate and seminal vesicles, and in breast. In both mice and in patients, these tumors are negative for cKit but express PDGFR-β, another tyrosine kinase receptor specifically inhibited by imatinib. Our results imply a possible detrimental effect of imatinib in prostate cancer patients but suggest a promising therapeutic application of imatinib in the treatment of recurrent or metastatic phyllodes tumors. Mol Cancer Ther; 16(2); 365–75. ©2016 AACR.
Cognitive Impairment and Structural Neuroimaging Abnormalities Among Patients with Chronic Kidney Disease
Authors: Pi Hai-Chen , Xu Yu-Feng , Xu Rong , Yang Zhi-Kai , Qu Zhen , Chen Yu-Qing , Liu Gui-Ling , Dong Jie
Published: December 2016

Background/Aims: Cognitive impairment and abnormal structural neuroimaging is common in chronic kidney disease patients. We aimed to explore its association with dialysis modality and the relationship between cognitive impairment and abnormal structural neuroimaging. Methods: Sixty peritoneal dialysis patients and 30 hemodialysis and 30 non-dialyzed stage 3-5 chronic kidney disease patients without history of stroke were enrolled for the study. Participants were matched for age, gender, education, diabetes status, and dialysis duration (if appropriate). Cognitive functions were measured using a battery of recognized instruments. Brain features were examined with 3-dimensional magnetic resonance imaging. Results: Cognitive impairment was significantly more severe in dialysis patients than in non-dialyzed patients. The global and specific cognitive function were not significantly different between patients on peritoneal dialysis and hemodialysis. Hemodialysis patients had more severe white matter hyperintensity, sulcal and ventricular atrophy, and SVIs than other patients. In all groups, higher white matter grade, ventricular grade, and hippocampal atrophy were significantly associated with global cognitive impairment, with hazard ratios of 1.80 (1.22-2.64), 1.67 (1.09-2.57), and 2.49 (1.07-5.77), respectively. White matter grade was also significantly associated with delayed memory (hazard ratio 1.63; 1.12-2.39). Conclusion: Dialysis modality showed no association with cognitive impairment, although hemodialysis patients had more severe neuroimaging abnormalities. For the whole group, white matter hyperintensity, and ventricular and hippocampal atrophy, were independently associated with global cognitive impairment in chronic kidney disease patients.
NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study)
Authors: Nacu Aliona , Kvistad Christopher E. , Naess Halvor , Øygarden Halvor , Logallo Nicola , Assmus Jörg , Waje-Andreassen Ulrike , Kurz Kathinka D. , Neckelmann Gesche , Thomassen Lars
Published: December 2016

Background and Purpose—

The NOR-SASS (Norwegian Sonothrombolysis in Acute Stroke Study) aimed to assess effect and safety of contrast-enhanced ultrasound treatment in an unselected acute ischemic stroke population.

Methods—

Patients treated with intravenous thrombolysis within 4.5 hours after symptom onset were randomized 1:1 to either contrast-enhanced sonothrombolysis (CEST) or sham CEST. A visible arterial occlusion on baseline computed tomography angiography was not a prerequisite for inclusion. Pulse-wave 2 MHz ultrasound was given for 1 hour and contrast (SonoVue) as an infusion for ≈30 minutes. Magnetic resonance imaging and angiography were performed after 24 to 36 hours. Primary study end points were neurological improvement at 24 hours defined as National Institutes of Health Stroke Scale score 0 or reduction of ≥4 National Institutes of Health Stroke Scale points compared with baseline National Institutes of Health Stroke Scale and favorable functional outcome at 90 days defined as modified Rankin scale score 0 to 1.

Results—

A total of 183 patients were randomly assigned to either CEST (93 patient) or sham CEST (90 patients). The rates of symptomatic intracerebral hemorrhage, asymptomatic intracerebral hemorrhage, or mortality were not increased in the CEST group. Neurological improvement at 24 hours and functional outcome at 90 days was similar in the 2 groups both in the intention-to-treat analysis and in the per-protocol analysis.

Conclusions—

CEST is safe among unselected ischemic stroke patients with or without a visible occlusion on computed tomography angiography and with varying grades of clinical severity. There was, however, statistically no significant clinical effect of sonothrombolysis in this prematurely stopped trial.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01949961.
Vernonanthura nana (Asteraceae: Vernonieae), a new species from the Paraná State (Brazil)
Authors: VEGA ALVARO JOSE , DEMATTEIS MASSIMILIANO
Published: December 2016

A new species of Vernonanthura (Asteraceae), V. nana, from the Brazilian state of Paraná is described and illustrated. The new species resembles V. squamulosa but differs in its geographical distribution, habitat, shape and pubescence of the leaves, and involucre length.
Weight-related peer-teasing moderates genetic and environmental risk and disordered eating: Twin study
Authors: Fairweather-Schmidt A. Kate , Wade Tracey D.
Published: December 2016

Background

Weight-related peer-teasing is considered a potent prospective risk factor for development of disordered eating and clinical eating disorders. Currently, the interplay between genetic and environmental influences has yet to be elucidated.

Aims

To determine whether peer-teasing moderates latent genetic and/or environmental risk for disordered eating among female adolescent twins.

Method

Full quantitative gene–environment interplay modelling of longitudinal trajectory of disordered eating in 685 female twins from the Australian Twin Registry.

Results

A model permitting moderation of disordered eating by peer-teasing involving genetic and non-shared environment effects fit these data best. As levels of peer-teasing increased, both genetic and environmental influences on disordered eating strengthened; however, genetic sources increased proportionally more than environmental sources.

Conclusions

Weight-related peer-teasing represents a particularly powerful trigger for disordered eating. Nevertheless, it is amenable to intervention/prevention activities spanning individual to universal levels of endeavour.
Effect of tranexamic acid on coagulation and fibrinolysis in women with postpartum haemorrhage (WOMAN-ETAC): protocol and statistical analysis plan for a randomized controlled trial
Authors: Shakur Haleema , Fawole Bukola , Kuti Modupe , Olayemi Oladapo O. , Bello Adenike , Ogunbode Olayinka , Kotila Taiwo , Aimakhu Chris , Huque Sumaya , Gregg Meghann , Roberts Ian
Published: December 2016

Background: Postpartum haemorrhage (PPH) is a leading cause of maternal death. Tranexamic acid has the potential to reduce bleeding and a large randomized controlled trial of its effect on maternal health outcomes in women with PPH (The WOMAN trial) is ongoing. We will examine the effect of tranexamic acid on fibrinolysis and coagulation in a subset of WOMAN trial participants. 

Methods: Adult women with clinically diagnosed primary PPH after vaginal or caesarean delivery are eligible for inclusion in the WOMAN trial. In a sub-group of trial participants, blood samples will be collected at baseline and 30 minutes after the first dose of tranexamic acid or matching placebo.  Our primary objective is to evaluate the effect of tranexamic acid on fibrinolysis. Fibrinolysis will be assessed by measuring D-dimers and by rotational thromboelastometry (ROTEM). Secondary outcomes are international normalized ratio (INR), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, haemoglobin and platelets. We aim to include about 180 women from the University College Hospital, Ibadan in Nigeria. 

Discussion: This sub-study of WOMAN trial participants should provide information on the mechanism of action of tranexamic acid in women with postpartum haemorrhage. We present the trial protocol and statistical analysis plan. The trial protocol was registered prior to the start of patient recruitment. The statistical analysis plan was completed before un-blinding. 

Trial registration:The trial was registered:ClinicalTrials.gov, Identifier NCT00872469https://clinicaltrials.gov/ct2/show/NCT00872469; ISRCTN registry, Identifier ISRCTN76912190http://www.isrctn.com/ISRCTN76912190(Registration date: 22/03/2012).
Impact Induced Damage Detecting of Aircraft CFRP Covering by Acoustic Testing
Authors: Самокрутов  , Samokrutov Andrey , Шевалдыкин  , Shevaldykin Viktor
Published: December 2016

Aircraft parts made of composite materials are susceptible to impact damage which can be negligible visually but significantly worsening their strength.

Finding such damage requires periodic monitoring of large areas of the surface of the aircraft airframe. Fundamentally, such monitoring is possible by using active thermography or acoustic methods.

Acceptable to practice, this task can be solved by scanning the surface with a rolling dry-point contact transducer array, and by analysis of Lamb wave signals propagating through the monitored material between the array adjacent transducers.

This paper presents a device based on this principle, the signal analysis algorithm, and the images recomposed by the device during composite material testing.

The developed equipment provides on-line inspection of impact-induced damage in aircraft covering made of composite materials. However, complex type of generated images requires constant monitoring of the covering state of each aircraft during its operation.
Advances in Aeronautical Nondestructive Inspection: New Methods and Configurable Robot-Based Solutions
Authors: Куэвас  , Сuevas Esmeralda , Торрес  , Torres Miguel
Published: December 2016

The application of nondestructive testing to the aerospace sector is constantly improving, as fast as technology allows, due to increasing presence of composites in structures, the use of new materials and the new geometries emerging. This makes necessary to innovate in the development of NDT methods, like ultrasonics or thermography, and in particular in ultrasounds, from using conventional piezoelectric transducers to phased-array technology, that allows the generation of the sound beam easily controlled and configurable based on the use of a multi-elements matrix of probes that can be electronically trigger. Moreover, the application of popular UT techniques (pulse-echo and through transmission) has been extended to other new innovative techniques, such as laser ultrasonic and air coupled ultrasounds.

Tecnatom participates in different innovation project in NDT and develops new equipment for inspection of composite materials. One of the studies is in the comparison of different NDT methods and techniques for the inspection of cured and non-cured materials in aeronautical components with the help of air-coupled ultrasound and thermography.

In the article are described the use of robots in automated Tecnatom system, developed in cooperation with KUKA Robotics. The use of its own developed electronics, allow working efficiently with materials with high attenuation, and specialized software, allows effectively inspecting the complex geometries aviation parts, taking into account the scanning trajectory and robot movement and control all the inspection process.
Do Underwriters Compete in IPO Pricing?
Authors: Lyandres Evgeny , Fu Fangjian , Li Erica X. N.
Published: December 2016

We propose and implement a direct test of the hypothesis of oligopolistic competition in the U.S. underwriting market against the alternative of implicit collusion among underwriters. We construct a simple model of interaction between heterogeneous underwriters and heterogeneous firms and solve it under two alternative assumptions: oligopolistic competition among underwriters and implicit collusion among them. The two solutions lead to different equilibrium relations between the compensation of underwriters of different quality on one hand and the time-varying demand for public incorporation on the other hand. Our empirical results, obtained using 39 years of initial public offering (IPO) data, are generally consistent with the implicit collusion hypothesis that banks, especially larger ones, seem to internalize the effects of their underwriting fees and IPO pricing on their rivals.

This paper was accepted by Neng Wang, finance.
Indicators of Collateral Misreporting
Authors: Demiroglu Cem , James Christopher
Published: December 2016

Automated valuation models (AVMs) are widely used in the valuation of pools of residential mortgages. In this paper, we provide evidence that high pricing errors in human and automated valuation models as well as rejection of loans with relatively low appraisals may generate the appearance of appraisal bias even when the original appraisals are unbiased. We also present evidence that the estimated frequency of appraisal overstatement is quite sensitive to assumptions about loan denial rates due to low appraisals as well as the size of and the correlation between AVM and original appraisal pricing errors.

This paper was accepted by Amit Seru, finance.
Roig-Munar, F. X. y Quintana Pou, F. J. (Coords.) (2016). Restauración y Gestión de Sistemas Dunares. Estudio de casos. Colección Recerca i Territori, 8. Cataluña: Càtedra d’Ecosistemes Litorals Mediterranis, Parc Natural de Montgrí, Illes Bledes i el Baix Ter. 220 pp.
Authors: Martín Prieto José Ángel
Published: December 2016

Los sistemas dunares costeros han sido uno de los ecosistemas más alterados a causa de la creciente presión humana sobre los espacios litorales, que en las últimas décadas se han convertido en un producto turístico. Los sistemas dunares son hábitats sensibles a la frecuentación, a las gestiones no planificadas y el pisoteo excesivos que se produce durante la temporada de baño, y que desencadena procesos erosivos a lo largo del período estival. Por sus características dinámicas de sustrato arenoso en movimiento, se encuentran además, muy afectados por las actividades relacionadas con el mantenimiento de las playas, tales como la prestación de servicios, la limpieza mecánica o la retirada de materia orgánica. Esto facilita la reactivación de procesos dinámicos que distorsionan y afectan al balance sedimentario, muchos de ellos de tipo erosivo.
Preserving a Well-Functioning 33-Year-Old Starr-Edwards Aortic Prosthesis in Repeat Aortic Root Aneurysm Repair
Authors: Alameddine Abdallah K. , Alimov Victor K. , Rousou John A. , Pluchino Fabrizio I.
Published: December 2016

We report the case of a 61-year-old obese male patient in whom we found a well-functioning 33-year-old Starr-Edwards aortic prosthesis during repeat aortic surgery. Rather than explant the prosthesis, we remodeled the aortic root, almost completely removing the aortic sinuses and leaving only a pillar of aortic tissue around the coronary ostia. The proximal end of a Hemashield tube-graft was then scalloped to accommodate the remaining aortic tissue.

The patient's heart function was excellent after his weaning from cardiopulmonary bypass. Simplifying the repeat aortic root repair, by preserving a well-functioning Starr-Edwards valve, might lead to a better outcome in similar cases.

We also discuss other instances of this valve's durability.
Accessory Mitral Valve Leaflet Causing Severe Left Ventricular Outflow Tract Obstruction in a Preterm Neonate with a Partial Atrioventricular Septal Defect
Authors: Wilkes J. Kevin , Fraser Charles D. , Seery Thomas J.
Published: December 2016

Atrioventricular septal defects represent a class of congenital cardiac malformations that vary in presentation and management strategy depending upon the severity of the particular lesions present. We present the case of a premature neonate who had a partial atrioventricular septal defect and an accessory mitral (or left atrioventricular) valve leaflet. The latter caused severe left ventricular outflow tract obstruction and severely depressed left ventricular function. We found only one other report of this atrioventricular valve abnormality in association with atrioventricular septal defect. To our knowledge, our patient (at a body weight of 1,800 g) is the smallest to survive corrective surgery of an accessory mitral valve leaflet with severe left ventricular outflow tract obstruction. In addition to our patient's case, we discuss the relevant medical literature.
Systemische Strukturaufstellungen als neue Methode zur Förderung einer nachhaltigen Entwicklung
Authors: Arnold Marlen
Published: December 2016

Um eine nachhaltige Entwicklung zu fördern und adäquat umzusetzen, bedarf es neuer Methoden und Instrumente. In inter- und transdisziplinären Zusammenhängen könnenmithilfe von Systemischen Strukturaufstellungen in Science-private-Partnerships, neue und nach haltige Impulse und Lösungsstrategien entdeckt und entwickelt werden.
Denn sie tun nicht, was sie wissen
Authors: Entzian Annett
Published: December 2016

Die Diskrepanz zwischen ökologischem Bewusstsein und Verhalten ist hinlänglich bekannt. Empirische Befunde belegen nun, dass Individuen ihr eigenes, nichtökologisches Handeln in Einklang bringen mit ihrem Anspruch, ökologisch zu denken. Insofern kann diese Kluft vielmehr als Problem der Wahrnehmung verstanden werden.
Kompass in einem magnetisierten Umfeld?
Authors: Pissarskoi Eugen
Published: December 2016

Damit die interessierte Öffentlichkeit in der Lage ist, an einem komplexen und voraussetzungsreichen Diskurs wie der Klimapolitik vernünftig teilzunehmen, bedarf es einer vereinfachenden Übersetzung des natur- und sozialwissenschaftlichen Wissens. Welche Rolle können dabei Integrierte Bewertungsmodelle spielen?
Predicting the Consequences of Marketing Policy Changes: A New Data Enrichment Method with Competitive Reactions
Authors: Kappe Eelco , Venkataraman Sriram , Stremersch Stefan
Published: December 2016

This article introduces a new data enrichment method that combines revealed data on consumer demand and competitive reactions with stated data on competitive reactions to yet-to-be-enacted, unprecedented marketing policy changes. The authors extend the data enrichment literature to include stated competitive reactions, collected from subject-matter experts through a conjoint experiment. The authors apply their method to investigate hypothetical and unprecedented sales force policy changes of pharmaceutical companies. The results from the data enrichment method have high face validity and lead to various unique insights compared with using revealed data only. The authors find that only a very large sales force decrease initiated by the market leader triggers all competitors to decrease their sales force as well, leading to substantial profit increases for each firm. With respect to sales force allocation, when competitors decrease their sales force, they mainly decrease the reach of detailing across doctors, rather than decreasing the number of details to the most-visited doctors. The proposed data enrichment method provides managers with a powerful tool to, ex ante, predict the consequences of unprecedented marketing policy changes.
Cortical Correlates of the Auditory Frequency-Following and Onset Responses: EEG and fMRI Evidence
Authors: Coffey Emily B.J. , Musacchia Gabriella , Zatorre Robert J.
Published: December 2016

The frequency-following response (FFR) is a measure of the brain's periodic sound encoding. It is of increasing importance for studying the human auditory nervous system due to numerous associations with auditory cognition and dysfunction. Although the FFR is widely interpreted as originating from brainstem nuclei, a recent study using MEG suggested that there is also a right-lateralized contribution from the auditory cortex at the fundamental frequency (Coffey et al., 2016b). Our objectives in the present work were to validate and better localize this result using a completely different neuroimaging modality and to document the relationships between the FFR, the onset response, and cortical activity. Using a combination of EEG, fMRI, and diffusion-weighted imaging, we show that activity in the right auditory cortex is related to individual differences in FFR–fundamental frequency (f0) strength, a finding that was replicated with two independent stimulus sets, with and without acoustic energy at the fundamental frequency. We demonstrate a dissociation between this FFR–f0-sensitive response in the right and an area in left auditory cortex that is sensitive to individual differences in the timing of initial response to sound onset. Relationships to timing and their lateralization are supported by parallels in the microstructure of the underlying white matter, implicating a mechanism involving neural conduction efficiency. These data confirm that the FFR has a cortical contribution and suggest ways in which auditory neuroscience may be advanced by connecting early sound representation to measures of higher-level sound processing and cognitive function.

SIGNIFICANCE STATEMENTThe frequency-following response (FFR) is an EEG signal that is used to explore how the auditory system encodes temporal regularities in sound and is related to differences in auditory function between individuals. It is known that brainstem nuclei contribute to the FFR, but recent findings of an additional cortical source are more controversial. Here, we use fMRI to validate and extend the prediction from MEG data of a right auditory cortex contribution to the FFR. We also demonstrate a dissociation between FFR–related cortical activity from that related to the latency of the response to sound onset, which is found in left auditory cortex. The findings provide a clearer picture of cortical processes for analysis of sound features.
Dynamic Reconfiguration of Visuomotor-Related Functional Connectivity Networks
Authors: Brovelli Andrea , Badier Jean-Michel , Bonini Francesca , Bartolomei Fabrice , Coulon Olivier , Auzias Guillaume
Published: December 2016

Cognitive functions arise from the coordination of large-scale brain networks. However, the principles governing interareal functional connectivity dynamics (FCD) remain elusive. Here, we tested the hypothesis that human executive functions arise from the dynamic interplay of multiple networks. To do so, we investigated FCD mediating a key executing function, known as arbitrary visuomotor mapping, using brain connectivity analyses of high-gamma activity recorded using MEG and intracranial EEG. Visuomotor mapping was found to arise from the dynamic interplay of three partly overlapping cortico-cortical and cortico-subcortical functional connectivity (FC) networks. First, visual and parietal regions coordinated with sensorimotor and premotor areas. Second, the dorsal frontoparietal circuit together with the sensorimotor and associative frontostriatal networks took the lead. Finally, cortico-cortical interhemispheric coordination among bilateral sensorimotor regions coupled with the left frontoparietal network and visual areas. We suggest that these networks reflect the processing of visual information, the emergence of visuomotor plans, and the processing of somatosensory reafference or action's outcomes, respectively. We thus demonstrated that visuomotor integration resides in the dynamic reconfiguration of multiple cortico-cortical and cortico-subcortical FC networks. More generally, we showed that visuomotor-related FC is nonstationary and displays switching dynamics and areal flexibility over timescales relevant for task performance. In addition, visuomotor-related FC is characterized by sparse connectivity with density <10%. To conclude, our results elucidate the relation between dynamic network reconfiguration and executive functions over short timescales and provide a candidate entry point toward a better understanding of cognitive architectures.

SIGNIFICANCE STATEMENTExecutive functions are supported by the dynamic coordination of neural activity over large-scale networks. The properties of large-scale brain coordination processes, however, remain unclear. Using tools combining MEG and intracranial EEG with brain connectivity analyses, we provide evidence that visuomotor behaviors, a hallmark of executive functions, are mediated by the interplay of multiple and spatially overlapping subnetworks. These subnetworks span visuomotor-related areas, the cortico-cortical and cortico-subcortical interactions of which evolve rapidly and reconfigure over timescales relevant for behavior. Visuomotor-related functional connectivity dynamics are characterized by sparse connections, nonstationarity, switching dynamics, and areal flexibility. We suggest that these properties represent key aspects of large-scale functional networks and cognitive architectures.
Sodium Pumps Mediate Activity-Dependent Changes in Mammalian Motor Networks
Authors: Picton Laurence D. , Nascimento Filipe , Broadhead Matthew J. , Sillar Keith T. , Miles Gareth B.
Published: December 2016

Ubiquitously expressed sodium pumps are best known for maintaining the ionic gradients and resting membrane potential required for generating action potentials. However, activity- and state-dependent changes in pump activity can also influence neuronal firing and regulate rhythmic network output. Here we demonstrate that changes in sodium pump activity regulate locomotor networks in the spinal cord of neonatal mice. The sodium pump inhibitor, ouabain, increased the frequency and decreased the amplitude of drug-induced locomotor bursting, effects that were dependent on the presence of the neuromodulator dopamine. Conversely, activating the pump with the sodium ionophore monensin decreased burst frequency. When more “natural” locomotor output was evoked using dorsal-root stimulation, ouabain increased burst frequency and extended locomotor episode duration, whereas monensin slowed and shortened episodes. Decreasing the time between dorsal-root stimulation, and therefore interepisode interval, also shortened and slowed activity, suggesting that pump activity encodes information about past network output and contributes to feedforward control of subsequent locomotor bouts. Using whole-cell patch-clamp recordings from spinal motoneurons and interneurons, we describe a long-duration (∼60 s), activity-dependent, TTX- and ouabain-sensitive, hyperpolarization (∼5 mV), which is mediated by spike-dependent increases in pump activity. The duration of this dynamic pump potential is enhanced by dopamine. Our results therefore reveal sodium pumps as dynamic regulators of mammalian spinal motor networks that can also be affected by neuromodulatory systems. Given the involvement of sodium pumps in movement disorders, such as amyotrophic lateral sclerosis and rapid-onset dystonia parkinsonism, knowledge of their contribution to motor network regulation also has considerable clinical importance.

SIGNIFICANCE STATEMENTThe sodium pump is ubiquitously expressed and responsible for at least half of total brain energy consumption. The pumps maintain ionic gradients and the resting membrane potential of neurons, but increasing evidence suggests that activity- and state-dependent changes in pump activity also influence neuronal firing. Here we demonstrate that changes in sodium pump activity regulate locomotor output in the spinal cord of neonatal mice. We describe a sodium pump-mediated afterhyperpolarization in spinal neurons, mediated by spike-dependent increases in pump activity, which is affected by dopamine. Understanding how sodium pumps contribute to network regulation and are targeted by neuromodulators, including dopamine, has clinical relevance due to the role of the sodium pump in diseases, including amyotrophic lateral sclerosis, parkinsonism, epilepsy, and hemiplegic migraine.
China’s Responses to Mega-Regional FTAs
Authors: Cai Penghong
Published: December 2016

This paper explores China’s responses to mega-regional negotiations, including the Trans-Pacific Partnership and the Regional Comprehensive Economic Partnership. By examining Chinese elite discourse, the policy-oriented study finds that China’s approach is related to the domestic political debate on a “second WTO accession” and China’s strategy toward the changing regional architecture.
The Ideological Campaign in Xi’s China
Authors: Zhao Suisheng
Published: December 2016

President Xi Jinping has launched the largest ideological campaign in post-Mao China, which has brought a Maoist revival. But Xi is not in a position to make a full return to the Mao era because ideologically driven repression offers no long-run solution to China’s problems. Drawing on elements of Mao’s legacy, Xi aims to rebuild the regime’s legitimacy when it is increasingly vulnerable to economic slowdown and public anger about corruption, income disparity, and pollution, an embarrassing confession of regime fragility.
Distinct cellular states determine calcium signaling response
Authors: Yao Jason , Pilko Anna , Wollman Roy
Published: December 2016

The heterogeneity in mammalian cells signaling response is largely a result of pre‐existing cell‐to‐cell variability. It is unknown whether cell‐to‐cell variability rises from biochemical stochastic fluctuations or distinct cellular states. Here, we utilize calcium response to adenosine trisphosphate as a model for investigating the structure of heterogeneity within a population of cells and analyze whether distinct cellular response states coexist. We use a functional definition of cellular state that is based on a mechanistic dynamical systems model of calcium signaling. Using Bayesian parameter inference, we obtain high confidence parameter value distributions for several hundred cells, each fitted individually. Clustering the inferred parameter distributions revealed three major distinct cellular states within the population. The existence of distinct cellular states raises the possibility that the observed variability in response is a result of structured heterogeneity between cells. The inferred parameter distribution predicts, and experiments confirm that variability in IP3R response explains the majority of calcium heterogeneity. Our work shows how mechanistic models and single‐cell parameter fitting can uncover hidden population structure and demonstrate the need for parameter inference at the single‐cell level.
SPECIFICITY OF ADHESION OF BACILLUS SUBTILIS IMV B-7023 TO ABIOTIC AND BIOTIC SURFACES
Authors: Kurdish Ivan , Roy Alla , Dyrenko Dmytro , Hetman Kateryna , Kovalenko Emma
Published: December 2016

The adhesion of Bacillus subtilis strain IMV B-7023 cells to surfaces of different nature was studied. It was demonstrated that the sorption of cells to abiotic solid materials was considerably governed by the bacterial motility which depended on the growth phase. An important role in the interaction process involving cells and biotic surfaces was attributed to bacterial lectins. It was determined that surface lectins of B. subtilis specific for D-glucosamine chloride and, in a lesser degree, to D-glucuronic and D-galacturonic acids were also active participants of specific adhesion of bacteria to plant roots. The blockage of these lectins with D-glucosamine chloride caused bacterial adhesion to the plant roots by 26%. Thus different mechanisms may be involved into the adhesion process of bacterial cells to abiotic and biotic surfaces.
IMPLICATIONS OF ANTIBIOTIC RESISTANCES PRODUCED BY PHENOTHIAZINES IN Mycobacterium tuberculosis
Authors: Debnath Sanchayita , Sinha Roy Debalina , Ghosh Bidisha , Palchoudhuri Shauroseni , Das Sukhen , G. Dastidar Sujata
Published: December 2016

Several chemotherapeutic agents applied to human beings for past few decades for different ailments, have been found to possess potent antitubercular activity. Two such agents, methdilazine (Md) and promethazine (Pz) were used to select mycobacterial mutants resistant to themselves at different levels and tested to determine if such mutants simultaneously developed cross-resistance to known antitubercular drugs. Mutants were produced by application of a heavy inoculum on Lowenstein-Jensen medium containing Md (or Pz) at concentrations higher than their respective minimum inhibitory concentrations (MICs). These were then tested to find out if such mutants have changed their resistogramme pattern with respect to the test antitubercular agents. Certain first-step Md-mutants became simultaneously resistant to ethambutol and pyrazinamide; while the step-2 Md-mutants revealed further increase in resistance to these agents along with resistance to isoniazid, rifampicin and streptomycin as well. In the study with Pz it was noted that many mutants showed distinctly higher levels of resistance to all the test drugs, particularly to isoniazid, pyrazinamide and streptomycin. The levels of MIC were distinctly high in many mutants. These observations on cross-resistances seem to be best explained on the basis of a reduction in cell-membrane permeability acting in a non-specific manner. The role of such a cross-resistance may possibly be accounting for an overall increase in the MICs of many drugs against several groups of microorganisms including Mycobacterium tuberculosis and other species of Mycobacterium during the last five decades.
STUDY OF BIOSURFACTANT PRODUCING BACTERIA AND PRELIMINARY CHARACTERIZATION OF BIOSURFACTNAT PRODUCED BY BACILLUS species ISOLATED FROM PETROLEUM CONTAMINATED SOIL
Authors: Patel Dhaval , Nataraj M.
Published: December 2016

Chemically synthesized amphiphilic molecules like surfactants are used for variety of purposes, but they are costly and less or non-degradable and may be toxic once released in the environment. Microbially produced biosurfactants are better alternatives of chemical surfactants as they are stable as well as easily biodegradable and also due to structural and functional similarities with chemical surfactants. The aim of this study was to isolate and characterize biosurfactant producing bacteria from oil contaminated sample (garage soil, Anand, Gujarat). Thirty bacterial cultures were isolated on the basis of differences in their colony characters. To confirm and compare the efficiency of biosurfactant production, hemolytic activity and reduction in surface tension was analyzed. Biochemical and morphological tests identified bacterial isolate C5C (Gram positive rods arranged in short chains) as Bacillus species. Optimum pH and temperature for biosurfactant production were 5 and 30oC, respectively. It produced 3.12 g/l of biosurfactant in MSM medium with 1% diesel as carbon source. Biosurfactant produced by C5C contains lipid. No carbohydrates or amino acid component was detected on TLC plate.
CHEMICAL AND NUTRITIONAL PROPERTIES OF SOME COMMERCIAL AVAILABLE CORN AND WHEAT PRODUCTS
Authors: Usman Khan Muhammad , Majeed Majid , Tayyab Muhammad , Ali Shariati Mohammad , Rashidzadeh Shilan
Published: December 2016

Commercial corn and wheat products were obtained and investigated for, proximate composition, mineral composition and tocopherol content. Proximate composition shows moisture content in the range of 28.75-2.75%, ash (2.70-0.32%), fats (21.52 -0.75%), protein (11.54-0.940%), crude fiber (4.06-0.250%) and carbohydrates (85.80-55.96%). The data indicate that Commercial corn and wheat products vary greatly in term of protein, fats and crude fiber. White flour and whole wheat flour were determined to contain high protein content (>10% protein) while oil popped popcorn and biscuit contain high fats content of >20%. In minerals the level of iron is 9.56-51.21mg/kg, Ca (50-560 mg/kg), Zn (1.90-32.40 mg/kg), K (820-2946) and Mg (310-1512 mg/kg). Tocopherol analysis was also done by the HPLC and found that Alpha tocopherol showed higher concentration than gamma and sigma tocopherol. In tocopherols level of alpha tocopherol is 0.3385-7.135 mg/100g, Gamma tocopherol (0.000212-9.665 mg/100g)Sigmmatocopherol (0.00212-1.685 mg/100g).
Growing Old
Authors: Bachelard Sarah , Millar Neil
Published: December 2016

This article arises out of our experience of working and reflecting theologically as chaplains in a residential aged care setting. In the first part of this article, we explore the vocation of ageing from the perspective of the Christian tradition, suggesting that this theology offers resources to engage the experience of ageing in ways that render it a journey of growth and self transcendence. In the light of this exploration, we turn to the question of the practices that support engagement with this vocation, particularly for those in the “fourth age”.
Religiously-Integrated Cognitive Behavioural Therapy for Major Depression in Chronic Medical Illness
Authors: Koenig Harold , Boucher Nathan , O’Garo Keisha-Gaye , Pearce Michelle
Published: December 2016

A randomized clinical trial was conducted over a three year period to compare the effectiveness of religiously-integrated cognitive behavioural therapy (RCBT) with conventional CBT (CCBT) for the treatment of a major depressive disorder (MDD). A total of 132 participants with chronic medical illness and MDD were enrolled in the trial (CCBT=67, RCBT=65). Ten 50-minute treatment sessions were delivered by master’s level certified counsellors over 12 weeks. All sessions were delivered remotely, largely over the telephone. In this review, we describe the findings from this trial, including the effects on depressive symptoms, positive emotions, and immune and endocrine markers in blood and urine. We also examine the effects of treatment based on genotype, in particular polymorphisms of the serotonin transporter, serotonin receptor, and monoamine oxidase genes. Lessons learned from conducting this trial are also discussed. Although not designed as a non-inferiority trial, the results suggest that RCBT is as effective as standard CBT in the treatment of major depression in this setting, especially among highly religious clients, and can be delivered by appropriately trained chaplains.
Modele doboru metod w rozwiązywaniu problemów zarządzania w ujęciu G. Nadlera
Authors: Szarucki Marek
Published: December 2016

Increasing organisational efficiency as a category of management sciences is one of the major challenges for both practitioners and theoreticians of management. Properly selecting methods to solve management problems is one factor that increases organisational efficiency. However, there is a lack of extensive methodological studies addressing method selection in the process of management problem solving. Nadler’s concept of the ideal system may serve as the basis for constructing method selection. The main objective of this study is to present the possibilities of adapting Nadler’s concept in creating the models of method selection in management problem-solving. Deduction and an analysis of the literature were the research methods employed. The article begins by exemplifying Nadler’s concept of an ideal system. This is followed by an original proposal for ideal models of method selection in management problem-solving. Finally, conclusions and suggestions for further research are discussed.
Logika kształtowania kompetencji – porównanie podejścia klasycznego i zintegrowanego
Authors: Czapla Tomasz P.
Published: December 2016

The introduction of the concept of learning outcomes to the education system has led more and more universities to adopt the idea of competencies and their development. The responsibility of universities for educating future professionals to participate in the economy has been considered through the prism of competence development. Such an approach to higher education often takes place in the context of a deeply rooted three--element (knowledge, skills, attitudes) competence model, which can be called the classic model. This model is often only partially implemented, and not integrated.The paper discusses the effects of the partial application of the model as a basis for the development of competencies. It proposes the integrated approach as an alternative and antidote to the pitfalls of a fragmented approach to competence development. The study was based on the reflective practitioner method. The paper shows how an integrated competencies model simplifies the development of those competencies. Particular emphasis is placed on the discussion of properly locating knowledge in the general competence structure. Practical implications and recommendations for the use of simplifications in a competencies model in the context of higher education are also discussed.