bluuebunny/crossref_metadata_2025 huggingface dataset:
Mobile website characteristics of leading tobacco product brands: cigarettes, smokeless tobacco, e-cigarettes, hookah and cigars
Authors: O’Brien Erin Keely , Navarro Mario Antonio , Hoffman Leah
Published: August 2018

Significance

Most US adults use smartphones for internet access. Understanding what they see when they view smartphone-optimised (mobile) tobacco websites is important, as it can inform tobacco education and cessation strategies. This study describes mobile tobacco websites for leading brands of cigarettes, cigars, smokeless tobacco (smokeless), e-cigarettes and hookah.

Methods

We identified 130 leading tobacco brands based on sales, advertising spending and self-report data. Of these, 62 brands had mobile websites. We conducted an inductive content analysis (ie, where we derived the coding scheme from what we observed) of website characteristics by dual-coding: age requirements, warning display, brand engagement methods (eg, social features) and sales strategies (eg, coupons).

Results

All cigarette and most smokeless websites required age-verified accounts for entry, while 76% of e-cigarette websites required accounts only for making purchases. All cigarette and smokeless websites showed warnings, but a minority of e-cigarette and cigar websites did, and no hookah websites did. Many websites required users to scroll up to view warnings. Most e-cigarette websites, most hookah websites, and half of cigar websites linked to multiple social media platforms; however, most cigarette and smokeless websites facilitated socialisation internally. All cigarette, most smokeless and no hookah websites offered coupons. Many cigarette and smokeless coupons were time-sensitive and location-based.

Conclusions

We highlight issues in how tobacco brand websites address youth access, display warnings, engage consumers and facilitate purchase. Results can help public health educators and practitioners better understand tobacco marketing as a context for designing tobacco interventions.
Projected effects of US tariffs on Canadian softwood lumber and newsprint imports: a cobweb model
Authors: Buongiorno Joseph
Published: August 2018

Starting from the cobweb theorem, a model of demand, supply, multilateral trade, and prices was formulated for the softwood lumber and newsprint markets in Canada, the United States (US), and the rest of the world. Parameters were estimated with panel data from multiple years and countries. The model was used to project the effects of US tariffs on softwood lumber and newsprint imports from Canada. To assess the uncertainty of the projections, multiple replications were performed by repeated sampling from the parameters’ statistical distributions. The results suggested that the initial shock of the tariffs dampened out and took 3 to 4 years to stabilize. In the long run, other things being equal, a 20.83% US tariff on softwood lumber imports from Canada decreased US imports from Canada by 4.7% to 8.0% and raised the US price by 0.3% to 2.3% and the US production by 0.9% to 1.7%, with 95% probability, while it lowered the Canadian price by 0.7% to 3.0% and Canadian production by 1.1% to 2.4%. A 28.69% US tariff on newsprint imports from Canada decreased US imports from Canada by 3.2% to 7.0% and raised the US price by 1.4% to 3.3% and the US production by 2.9 to 6.3%, while it lowered the Canadian price by 0.8% to 1.9% and the Canadian production by 1.6% to 3.5%.
Neuromechanical Modelling of Articulatory Movements from Surface Electromyography and Speech Formants
Authors: Gómez-Vilda Pedro , Gómez-Rodellar Andrés , Vicente José M. Ferrández , Mekyska Jiri , Palacios-Alonso Daniel , Rodellar-Biarge Victoria , Álvarez-Marquina Agustín , Eliasova Ilona , Kostalova Milena , Rektorova Irena
Published: August 2018

Speech articulation is produced by the movements of muscles in the larynx, pharynx, mouth and face. Therefore speech shows acoustic features as formants which are directly related with neuromotor actions of these muscles. The first two formants are strongly related with jaw and tongue muscular activity. Speech can be used as a simple and ubiquitous signal, easy to record and process, either locally or on e-Health platforms. This fact may open a wide set of applications in the study of functional grading and monitoring neurodegenerative diseases. A relevant question, in this sense, is how far speech correlates and neuromotor actions are related. This preliminary study is intended to find answers to this question by using surface electromyographic recordings on the masseter and the acoustic kinematics related with the first formant. It is shown in the study that relevant correlations can be found among the surface electromyographic activity (dynamic muscle behavior) and the positions and first derivatives of the first formant (kinematic variables related to vertical velocity and acceleration of the joint jaw and tongue biomechanical system). As an application example, it is shown that the probability density function associated to these kinematic variables is more sensitive than classical features as Vowel Space Area (VSA) or Formant Centralization Ratio (FCR) in characterizing neuromotor degeneration in Parkinson’s Disease.
Optimum Backup Policies with Update Failure at Random Times
Authors: Nakamura Syouji , Zhao Xufeng , Qian Cunhua
Published: August 2018

In order to ensure the data security, plans of incremental and differential backups are usually set up to save the costs which suffer from full backups. In this paper, we suppose that failures occur at data updating times and backups are implemented only at the end of data updates, and full backups are done at time [Formula: see text], over time [Formula: see text] and update [Formula: see text] to balance the costs of data backup and failure recovery. Using the theory of renewal process, we obtain the expected costs of backup and recovery and the expected cost rates for full backups. Optimum solutions of [Formula: see text] and [Formula: see text] to minimize the expected cost rates are obtained, and their comparisons are discussed from the optimizations of the integrated models in analytical ways.
An Attribute np Control Chart for Monitoring Mean Life Using Multiple Deferred State Sampling Based on Truncated Life Tests
Authors: Balamurali S. , Jeyadurga P.
Published: August 2018

In this paper, we design an attribute [Formula: see text] control chart for monitoring the mean life of the product where the lifetime follows the Pareto distribution of the second kind. The lifetime of the product is determined by time truncated life test and the multiple deferred state sampling is used to declare the status of the manufacturing process. Control limit coefficients and multiple deferred state sampling parameters such as sample size and number of successive subgroups required to declare the state of the process are determined such that the in-control average run length is as near as possible to the target average run length. Out-of-control average run lengths are calculated for the determined parameters using various shift constants. The performance of the chart is compared with other existing chart in terms of average run length.
Estimation of Stress–Strength Reliability from Exponentiated Inverse Rayleigh Distribution
Authors: Rao G. Srinivasa , Mbwambo Sauda , Josephat P. K.
Published: August 2018

This paper considers the estimation of stress–strength reliability when two independent exponential inverse Rayleigh distributions with different shape parameters and common scale parameter. The maximum likelihood estimator (MLE) of the reliability, its asymptotic distribution and asymptotic confidence intervals are constructed. Comparisons of the performance of the estimators are carried out using Monte Carlo simulations, the mean squared error (MSE), bias, average length and coverage probabilities. Finally, a demonstration is delivered on how the proposed reliability model may be applied in data analysis of the strength data for single carbon fibers test data.
Scaling limit for escapes from unstable equilibria in the vanishing noise limit: Nontrivial Jordan block case
Authors: Bakhtin Yuri , Pajor-Gyulai Zsolt
Published: August 2018

We consider white noise perturbations of a nonlinear dynamical system in the neighborhood of an unstable critical point with linearization given by a Jordan block of full dimension. For the associated exit problem, we study the joint limiting behavior of the exit location and exit time, in the vanishing noise limit. The exit typically happens near one of two special deterministic points associated with the eigendirection, and we obtain several more terms in the expansion for the exit point. The leading correction term is deterministic and logarithmic in the noise magnitude, while the random remainder satisfies a scaling limit.
On Reliability Analysis of Smart Grids under Topology Attacks
Authors: Li Beibei , Lu Rongxing , Choo Kim-Kwang Raymond , Wang Wei , Luo Sheng
Published: August 2018

Building an efficient, smart, and multifunctional power grid while maintaining high reliability and security is an extremely challenging task, particularly in the ever-evolving cyber threat landscape. The challenge is also compounded by the increasing complexity of power grids in both cyber and physical domains. In this article, we develop a stochastic Petri net based analytical model to assess and analyze the system reliability of smart grids, specifically against topology attacks under system countermeasures (i.e., intrusion detection systems and malfunction recovery techniques). Topology attacks, evolving from false data injection attacks, are growing security threats to smart grids. In our analytical model, we define and consider both conservative and aggressive topology attacks, and two types of unreliable consequences (i.e., system disturbances and failures). The IEEE 14-bus power system is employed as a case study to clearly explain the model construction and parameterization process. The benefit of having this analytical model is the capability to measure the system reliability from both transient and steady-state analysis. Finally, intensive simulation experiments are conducted to demonstrate the feasibility and effectiveness of our proposed model.
Reachability Is in DynFO
Authors: Datta Samir , Kulkarni Raghav , Mukherjee Anish , Schwentick Thomas , Zeume Thomas
Published: August 2018

Patnaik and Immerman introduced the dynamic complexity class DynFO of database queries that can be maintained by first-order dynamic programs with the help of auxiliary relations under insertions and deletions of edges. This article confirms their conjecture that the reachability query is in DynFO.

As a byproduct, it is shown that the rank of a matrix with small values can be maintained in DynFO. It is further shown that the (size of the) maximum matching of a graph can be maintained in non-uniform DynFO, an extension of DynFO, with non-uniform initialisation of the auxiliary relations.
Deterministic Parallel Algorithms for Fooling Polylogarithmic Juntas and the Lovász Local Lemma
Authors: Harris David G.
Published: August 2018

Many randomized algorithms can be derandomized efficiently using either the method of conditional expectations or probability spaces with low (almost-) independence. A series of papers, beginning with Luby (1993) and continuing with Berger and Rompel (1991) and Chari et al. (2000), showed that these techniques can be combined to give deterministic parallel algorithms for combinatorial optimization problems involving sums of
w
-juntas. We improve these algorithms through derandomized variable partitioning, reducing the processor complexity to essentially independent of
w
and time complexity to linear in
w
.

As a key subroutine, we give a new algorithm to generate a probability space which can fool a given set of neighborhoods. Schulman (1992) gave an NC algorithm to do so for neighborhoods of size
w
≤
O
(log
n
). Our new algorithm is in NC
1
, with essentially optimal time and processor complexity, when
w
=
O
(log
n
); it remains in NC up to
w
= polylog(
n
). This answers an open problem of Schulman.

One major application of these algorithms is an NC algorithm for the Lovász Local Lemma. Previous NC algorithms, including the seminal algorithm of Moser and Tardos (2010) and the work of Chandrasekaran et. al (2013), required that (essentially) the bad-events could span only
O
(log
n
) variables; we relax this to polylog(
n
) variables. We use this for an NC
2
algorithm for defective vertex coloring, which works for arbitrary degree graphs.
Block Cooperation
Authors: Tavana Mohammad Khavari , Ziabari Amir Kavyan , Kaeli David
Published: August 2018

Block-level cooperation is an endurance management technique that operates on top of error correction mechanisms to extend memory lifetimes. Once an error recovery scheme fails to recover from faults in a data block, the entire physical page associated with that block is disabled and becomes unavailable to the physical address space. To reduce the page waste caused by early block failures, other blocks can be used to support the failed block, working cooperatively to keep it alive and extend the faulty page’s lifetime.

We combine the proposed technique with existing error recovery schemes, such as Error Correction Pointers (ECP) and Aegis, to increase memory lifetimes. Block cooperation is realized through metadata sharing in ECP, where one data block shares its unused metadata with another data block. When combined with Aegis, block cooperation is realized through reorganizing data layout, where blocks possessing few faults come to the aid of failed blocks, bringing them back from the dead.

Our evaluation using Monte Carlo simulation shows that block cooperation at a single level (or multiple levels) on top of ECP and Aegis, boosts memory lifetimes by 28% (37%) and 8% (14%) on average, respectively. Furthermore, using trace-driven benchmark evaluation shows that lifetime boost can reach to 68% (30%) exploiting metadata sharing (or data layout reorganization).
Mosaic
Authors: Ausavarungnirun Rachata , Landgraf Joshua , Miller Vance , Ghose Saugata , Gandhi Jayneel , Rossbach Christopher J. , Mutlu Onur
Published: August 2018

Contemporary discrete GPUs support rich memory management features such as virtual memory and demand paging. These features simplify GPU programming by providing a virtual address space abstraction similar to CPUs and eliminating manual memory management, but they introduce high performance overheads during (1) address translation and (2) page faults. A GPU relies on high degrees of thread-level parallelism (TLP) to hide memory latency. Address translation can undermine TLP, as a single miss in the translation lookaside buffer (TLB) invokes an expensive serialized page table walk that often stalls multiple threads. Demand paging can also undermine TLP, as multiple threads often stall while they wait for an expensive data transfer over the system I/O (e.g., PCIe) bus when the GPU demands a page.

In modern GPUs, we face a trade-off on how the page size used for memory management affects address translation and demand paging. The address translation overhead is lower when we employ a larger page size (e.g., 2MB large pages, compared with conventional 4KB base pages), which increases TLB coverage and thus reduces TLB misses. Conversely, the demand paging overhead is lower when we employ a smaller page size, which decreases the system I/O bus transfer latency. Support for multiple page sizes can help relax the page size trade-off so that address translation and demand paging optimizations work together synergistically. However, existing page coalescing (i.e., merging base pages into a large page) and splintering (i.e., splitting a large page into base pages) policies require costly base page migrations that undermine the benefits multiple page sizes provide. In this paper, we observe that GPGPU applications present an opportunity to support multiple page sizes without costly data migration, as the applications perform most of their memory allocation en masse (i.e., they allocate a large number of base pages at once).We show that this en masse allocation allows us to create intelligent memory allocation policies which ensure that base pages that are contiguous in virtual memory are allocated to contiguous physical memory pages. As a result, coalescing and splintering operations no longer need to migrate base pages.
Extreme Datacenter Specialization for Planet-Scale Computing
Authors: Xie Shaolin , Davidson Scott , Magaki Ikuo , Khazraee Moein , Vega Luis , Zhang Lu , Taylor Michael B.
Published: August 2018

Planet-scale applications are driving the exponential growth of the cloud, and datacenter specialization is the key enabler of this trend, providing order of magnitudes improvements in cost-effectiveness and energy-efficiency. While exascale computing remains a goal for supercomputing, specialized datacenters have emerged and have demonstrated beyond-exascale performance and efficiency in specific domains. This paper generalizes the applications, design methodology, and deployment challenges of the most extreme form of specialized datacenter: ASIC Clouds. It analyzes two game-changing, real-world ASIC Clouds-Bitcoin Cryptocurrency Clouds and Tensor Processing Clouds-discuss their incentives, the empowering technologies and how they benefit from the specialized ASICs. Their business models, architectures and deployment methods are useful for envisioning future potential ASIC Clouds and forecasting how they will transform computing, the economy and society.
On the equivalence between multiclass processor sharing and random order scheduling policies
Authors: Avrachenkov Konstantin , Bodas Tejas
Published: August 2018

Consider a single server system serving a multiclass population. Some popular scheduling policies for such system are the discriminatory processor sharing (DPS), discriminatory random order service (DROS), generalized processor sharing (GPS) and weighted fair queueing (WFQ). In this paper, we propose two classes of policies, namely MPS (multiclass processor sharing) and MROS (multiclass random order service), that generalize the four policies mentioned above. For the special case when the multiclass population arrive according to Poisson processes and have independent and exponential service requirement with parameter ?, we show that the tail of the sojourn time distribution for a class i customer in a system with the MPS policy is a constant multiple of the tail of the waiting time distribution of a class i customer in a system with the MROS policy. This result implies that for a class i customer, the tail of the sojourn time distribution in a system with the DPS (GPS) scheduling policy is a constant multiple of the tail of the waiting time distribution in a system with the DROS (respectively WFQ) policy.
Transgenerational Epigenetic Inheritance
Authors: Bošković Ana , Rando Oliver J.
Published: August 2018

Inheritance of genomic DNA underlies the vast majority of biological inheritance, yet it has been clear for decades that additional epigenetic information can be passed on to future generations. Here, we review major model systems for transgenerational epigenetic inheritance via the germline in multicellular organisms. In addition to surveying examples of epivariation that may arise stochastically or in response to unknown stimuli, we also discuss the induction of heritable epigenetic changes by genetic or environmental perturbations. Mechanistically, we discuss the increasingly well-understood molecular pathways responsible for epigenetic inheritance, with a focus on the unusual features of the germline epigenome.
Obesity increases airway smooth muscle responses to contractile agonists
Authors: Orfanos Sarah , Jude Joseph , Deeney Brian T. , Cao Gaoyuan , Rastogi Deepa , van Zee Mark , Pushkarsky Ivan , Munoz Hector E. , Damoiseaux Robert , Di Carlo Dino , Panettieri Reynold A.
Published: August 2018

The asthma-obesity syndrome represents a major public health concern that disproportionately contributes to asthma severity and induces insensitivity to therapy. To date, no study has shown an intrinsic difference between human airway smooth muscle (HASM) cells derived from nonobese subjects and those derived from obese subjects. The objective of this study was to address whether there is a greater response to agonist-induced calcium mobilization, phosphorylation of myosin light chain (MLC), and greater shortening in HASM cells derived from obese subjects. HASM cells derived from nonobese and obese subjects were age and sex matched. Phosphorylation of MLC was measured after having been stimulated by carbachol. Carbachol- or histamine-induced mobilization of calcium and cell shortening were assessed in HASM cells derived from nonobese and obese donors. Agonist-induced MLC phosphorylation, mobilization of calcium, and cell shortening were greater in obese compared with non-obese-derived HASM cells. The MLC response was comparable in HASM cells derived from obese nonasthma and nonobese fatal asthma subjects. HASM cells derived from obese female subjects were more responsive to carbachol than HASM cells derived from obese male subjects. Insulin pretreatment had little effect on these responses. Our results show an increase in agonist-induced calcium mobilization associated with an increase in MLC phosphorylation and an increase in ASM cell shortening in favor of agonist-induced hyperresponsiveness in HASM cells derived from obese subjects. Our studies suggest that obesity induces a retained phenotype of hyperresponsiveness in cultured human airway smooth muscle cells.
Cardiovascular and skeletal muscle health with lifelong exercise
Authors: Gries Kevin J. , Raue Ulrika , Perkins Ryan K. , Lavin Kaleen M. , Overstreet Brittany S. , D’Acquisto Leonardo J. , Graham Bruce , Finch W. Holmes , Kaminsky Leonard A. , Trappe Todd A. , Trappe Scott
Published: August 2018

The purpose of this study was to examine the effects of aerobic lifelong exercise (LLE) on maximum oxygen consumption (V̇o2max) and skeletal muscle metabolic fitness in trained women ( n = 7, 72 ± 2 yr) and men ( n = 21, 74 ± 1 yr) and compare them to old, healthy nonexercisers (OH; women: n = 10, 75 ± 1 yr; men: n = 10, 75 ± 1 yr) and young exercisers (YE; women: n = 10, 25 ± 1 yr; men: n = 10, 25 ± 1 yr). LLE men were further subdivided based on intensity of lifelong exercise and competitive status into performance (LLE-P, n = 14) and fitness (LLE-F, n = 7). On average, LLE exercised 5 day/wk for 7 h/wk over the past 52 ± 1 yr. Each subject performed a maximal cycle test to assess V̇o2maxand had a vastus lateralis muscle biopsy to examine capillarization and metabolic enzymes [citrate synthase, β-hydroxyacyl-CoA dehydrogenase (β-HAD), and glycogen phosphorylase]. V̇o2maxhad a hierarchical pattern (YE > LLE > OH, P < 0.05) for women (44 ± 2 > 26 ± 2 > 18 ± 1 ml·kg−1·min−1) and men (53 ± 3 > 34 ± 1 > 22 ± 1 ml·kg−1·min−1) and was greater ( P < 0.05) in LLE-P (38 ± 1 ml·kg−1·min−1) than LLE-F (27 ± 2 ml·kg−1·min−1). LLE men regardless of intensity and women had similar capillarization and aerobic enzyme activity (citrate synthase and β-HAD) as YE, which were 20%–90% greater ( P < 0.05) than OH. In summary, these data show a substantial V̇o2maxbenefit with LLE that tracked similarly between the sexes, with further enhancement in performance-trained men. For skeletal muscle, 50+ years of aerobic exercise fully preserved capillarization and aerobic enzymes, regardless of intensity. These data suggest that skeletal muscle metabolic fitness may be easier to maintain with lifelong aerobic exercise than more central aspects of the cardiovascular system.

NEW & NOTEWORTHY Lifelong exercise (LLE) is a relatively new and evolving area of study with information especially limited in women and individuals with varying exercise intensity habits. These data show a substantial maximal oxygen consumption benefit with LLE that tracked similarly between the sexes. Our findings contribute to the very limited skeletal muscle biopsy data from LLE women (>70 yr), and similar to men, revealed a preserved metabolic phenotype comparable to young exercisers.
Cerebral blood flow regulation and cognitive function in women with posttraumatic stress disorder
Authors: Ogoh Shigehiko , Yoo Jeung-Ki , Badrov Mark B. , Parker Rosemary S. , Anderson Elizabeth H. , Wiblin Jessica L. , North Carol S. , Suris Alina , Fu Qi
Published: August 2018

Posttraumatic stress disorder (PTSD) is associated with structural and functional alterations in a number of interacting brain regions, but the physiological mechanism for the high risk of cerebrovascular disease or impairment in brain function remains unknown. Women are more likely to develop PTSD after a trauma than men. We hypothesized that cerebral blood flow (CBF) regulation is impaired in women with PTSD, and it is associated with impairment in cognitive function. To test our hypothesis, we examined dynamic cerebral autoregulation (CA) and cognitive function by using a transfer function analysis between arterial pressure and middle cerebral artery blood velocity and the Stroop Color and Word test (SCWT), respectively. We did not observe any different responses in these hemodynamic variables between women with PTSD ( n = 15) and healthy counterparts (all women; n = 8). Cognitive function was impaired in women with PTSD; specifically, reaction time for the neutral task of SCWT was longer in women with PTSD compared with healthy counterparts ( P = 0.011), but this cognitive dysfunction was not affected by orthostatic stress. On the other hand, transfer function phase, gain, and coherence were not different between groups in either the supine or head-up tilt (60°) position, or even during the cognitive challenge, indicating that dynamic CA was well maintained in women with PTSD. In addition, there was no relationship between cognitive function and dynamic CA. These findings suggest that PTSD-related cognitive dysfunction may not be due to compromised CBF regulation.

NEW & NOTEWORTHY Cognitive function was impaired; however, dynamic cerebral autoregulation (CA) as an index of cerebral blood flow regulation was not impaired during supine and 60° head-up tilt in women with PTSD compared with healthy females. In addition, there was no relationship between cognitive function and dynamic CA. These findings suggest that the mechanism of PTSD-related cognitive dysfunction may not be due to CBF regulation.
Spinal protein phosphatase 1 constrains respiratory plasticity after sustained hypoxia
Authors: Huxtable Adrianne G. , Peterson Timothy J. , Ouellette Jonathan N. , Watters Jyoti J. , Mitchell Gordon S.
Published: August 2018

Plasticity is an important aspect of the neural control of breathing. One well-studied form of respiratory plasticity is phrenic long-term facilitation (pLTF) induced by acute intermittent but not sustained hypoxia. Okadaic acid-sensitive protein phosphatases (PPs) differentially regulate phrenic nerve activity with intermittent vs. sustained hypoxia, at least partially accounting for pLTF pattern sensitivity. However, okadaic acid inhibits multiple serine/threonine phosphatases, and the relevant phosphatase (PP1, PP2A, PP5) for pLTF pattern sensitivity has not been identified. Here, we demonstrate that sustained hypoxia (25 min, 9–10.5% O2) elicits phrenic motor facilitation in rats pretreated with bilateral intrapleural injections of small interfering RNAs (siRNAs; Accell-modified to preferentially transfect neurons, 3.33 μM, 3 days) targeting PP1 mRNA (48 ± 14% change from baseline, n = 6) but not PP2A (14 ± 9% baseline, n = 6) or nontargeting siRNAs (4 ± 10% baseline, n = 7). In time control rats (no hypoxia) treated with siRNAs ( n = 6), no facilitation was evident (−9 ± 9% baseline). siRNAs had no effect on the hypoxic phrenic response. Immunohistochemistry revealed PP1 and PP2A protein in identified phrenic motoneurons. Although PP1 and PP2A siRNAs significantly decreased PP1 and PP2A mRNA in PC12 cell cultures, we were not able to verify “knockdown” in vivo after siRNA treatment. On the other hand, PP1 and PP2A siRNAs significantly decreased PP1 and PP2A mRNA in PC12 cell cultures, verifying the intended siRNA effects. In conclusion, PP1 (not PP2A) is the relevant okadaic acid-sensitive phosphatase constraining phrenic motor facilitation after sustained hypoxia and likely contributing to pLTF pattern sensitivity.

NEW & NOTEWORTHY This study demonstrates that the relevant okadaic acid-sensitive Ser/Thr protein phosphatase (PP) constraining facilitation after sustained hypoxia is PP1 and not PP2A. It suggests that PP1 may be critical in the pattern sensitivity of hypoxia-induced phrenic motor plasticity.
Community Pharmacists’ Knowledge, Attitudes, and Practice of Herbal Medicines in Asir Region, Kingdom of Saudi Arabia
Authors: Alsayari Abdulrhman , Almghaslah Dalia , Khaled Arwa , Annadurai Sivakumar , Alkhairy Mona Ali , Alqahtani Hagar Abdulhadi , Alsayed Boshra Abduh , Alasiri Rawabi Mohammed , Assiri Abeer Mohammed
Published: August 2018

Background. A dramatic increase in the use of natural products and herbal medicines has been observed globally. Simultaneously, there has been an increase in safety concerns regarding the extensive use of these herbal remedies among health care practitioners. The urban and rural populations of Saudi Arabia still rely on traditional Arabic herbal medicines for the treatment of various diseases. Objectives. This study aimed to evaluate community pharmacists’ knowledge, attitudes, and practices of herbal medicines in the Asir region, Saudi Arabia. Methods. An online cross‐sectional study was conducted among 233 community pharmacists using a structured questionnaire. Results. Pharmacists showed considerable knowledge of the indications of herbal products, with an average score of 84% correct answers, total P value < 0.05 and < 0.001. They were also knowledgeable about contraindications, side effects, and interactions, with an average score of 75% correct answers, total P value < 0.05 and < 0.001. Community pharmacists had a positive attitude towards herbal products, as 71% of them “agreed” or “strongly agreed” that herbal products were efficacious and 77% of them “agreed” or “strongly agreed” that those products should be sold only in a pharmacy. Herbal products were “often” or "always” dispensed by 67.3% of pharmacists in a pharmacy. Conclusion. Pharmacists generally exhibited good knowledge, a positive attitude, and effective practice towards herbal products. However, continuing education programs are needed to train pharmacists in providing client counseling on herbal medicine usage and dispensing them.
A Composite Renal Tumor with Dual Differentiation, Chromophobe and Collecting Duct Carcinoma
Authors: Pearson Lauren , Taatjes Douglas J. , von Turkovich Michele , King Benjamin J. , Zenali Maryam
Published: August 2018

Chromophobe carcinoma constitutes a small subset of all renal carcinomas. Within this category, rare tumors with divergent differentiation have been recognized. Herein, we report a rare case of composite chromophobe and collecting duct carcinoma and describe its pathologic and clinical features.
Dissolution and Solubility Product of Cd-Fluorapatite [Cd5(PO4)3F] at pH of 2–9 and 25–45°C
Authors: Lin Ju , Zhu Zongqiang , Zhu Yinian , Liu Huili , Zhang Lihao , Jiang Zhangnan
Published: August 2018

Dissolution of the synthetic cadmium fluorapatite [Cd5(PO4)3F] at 25°C, 35°C, and 45°C was experimentally examined in HNO3 solution, pure water, and NaOH solution. The characterization results confirmed that the cadmium fluorapatite nanorods used in the experiments showed no obvious variation after dissolution. During the dissolution of Cd5(PO4)3F in HNO3 solution (pH = 2) at 25°C, the fluoride, phosphate, and cadmium ions were rapidly released from solid to solution, and their aqueous concentrations had reached the highest values after dissolution for <1 h, 1440 h, and 2880 h, respectively. After that, the total dissolution rates declined slowly though the solution Cd/P molar ratios increased incessantly from 1.55∼1.67 to 3.18∼3.22. The solubility product for Cd5(PO4)3F (Ksp) was determined to be 10−60.03 (10−59.74∼10−60.46) at 25°C, 10−60.38 (10−60.32∼10−60.48) at 35°C, and 10−60.45 (10−60.33∼10−60.63) at 45°C. Based on the log Ksp values obtained at an initial pH of 2 and 25°C, the Gibbs free energy of formation for Cd5(PO4)3F (ΔGf0) was calculated to be −4065.76 kJ/mol (−4064.11∼−4068.23 kJ/mol). The thermodynamic parameters for the dissolution process were computed to be 342515.78 J/K·mol, −85088.80 J/mol, −1434.91 J/K·mol, and 2339.50 J/K·mol for ΔG0, ΔH0, ΔS0, and ΔCp0, correspondingly.
Mn Inhibits GSH Synthesis via Downregulation of Neuronal EAAC1 and Astrocytic xCT to Cause Oxidative Damage in the Striatum of Mice
Authors: Yang Xinxin , Yang Haibo , Wu Fengdi , Qi Zhipeng , Li Jiashuo , Xu Bin , Liu Wei , Xu Zhaofa , Deng Yu
Published: August 2018

Excessive manganese (Mn) can accumulate in the striatum of the brain following overexposure. Oxidative stress is a well‐recognized mechanism in Mn‐induced neurotoxicity. It has been proven that glutathione (GSH) depletion is a key factor in oxidative damage during Mn exposure. However, no study has focused on the dysfunction of GSH synthesis‐induced oxidative stress in the brain during Mn exposure. The objective of the present study was to explore the mechanism of Mn disruption of GSH synthesis via EAAC1 and xCT in vitro and in vivo. Primary neurons and astrocytes were cultured and treated with different doses of Mn to observe the state of cells and levels of GSH and reactive oxygen species (ROS) and measure mRNA and protein expression of EAAC1 and xCT. Mice were randomly divided into seven groups, which received saline, 12.5, 25, and 50 mg/kg MnCl2, 500 mg/kg AAH (EAAC1 inhibitor) + 50 mg/kg MnCl2, 75 mg/kg SSZ (xCT inhibitor) + 50 mg/kg MnCl2, and 100 mg/kg NAC (GSH rescuer) + 50 mg/kg MnCl2 once daily for two weeks. Then, levels of EAAC1, xCT, ROS, GSH, malondialdehyde (MDA), protein sulfhydryl, carbonyl, 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG), and morphological and ultrastructural features in the striatum of mice were measured. Mn reduced protein levels, mRNA expression, and immunofluorescence intensity of EAAC1 and xCT. Mn also decreased the level of GSH, sulfhydryl, and increased ROS, MDA, 8‐OHdG, and carbonyl in a dose‐dependent manner. Injury‐related pathological and ultrastructure changes in the striatum of mice were significantly present. In conclusion, excessive exposure to Mn disrupts GSH synthesis through inhibition of EAAC1 and xCT to trigger oxidative damage in the striatum.
UPLC‐QTOF/MS‐Based Lipidomic Profiling of Liver Qi‐Stagnation and Spleen‐Deficiency Syndrome in Patients with Hyperlipidemia
Authors: Shenghua Piao , Shuyu Tan , Kunping Li , Huixia Zhan , Xue Xiao , Jiao Guo
Published: August 2018

Hyperlipidemia is a common disease caused by abnormal plasma lipid metabolism. Lipidomics is a powerful and efficient technology to study the integration of disease and syndrome of Chinese medicine. This study investigated specific changes in lipid metabolites from hyperlipidemia patients with syndrome of liver qi‐stagnation and spleen‐deficiency (SLQSD). Lipid profiles in plasma samples from 29 hyperlipidemia patients including 10 SLQSD and 19 non‐SLQSD and 26 healthy volunteers (NC) were tested by UPLC‐QTOF/MS. PLS‐DA analysis and database searching were performed to discover differentiating metabolites. Differences in lipid metabolites between hyperlipidemia and healthy people mainly include phosphatidylcholines, phosphatidylethanolamines, phosphatidylglycerols, and ceramides. Hyperlipidemia patients with SLQSD and non‐SLQSD could be differentiated by using identified lipid metabolites including phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, triglycerides, diacylglycerols, lysophosphatidylethanolamines, sphingomyelins, lysophosphatidylcholines, and lactosylceramides. There were significant differences of lipid metabolism between between different syndromes of the same disease such as hyperlipidemia which showed significant differences between SLQSD and non‐SLQSD.
Association Rule Analysis for Validating Interrelationships of Combined Medication of Compound Kushen Injection in Treating Colon Carcinoma: A Hospital Information System‐Based Real‐World Study
Authors: Yang Huisheng , Xie Yanming , Ni Jisheng , Liu Yue , Song Rui , Chen Cen , Zhuang Yan , Zhang Yin
Published: August 2018

Background. Real world evidence is important for informing healthcare practice and developing medical products and has gained broad interest in healthcare. Compound Kushen Injection (CKI) has been widely applied into treatment of colon carcinoma (CC) in China. Postapproval drug assessment related retrospective studies using electrical medical record (EMR) collected from hospital information system (HIS) is one of the most important categories of real‐world study (RWS). Based on HIS EMR, interrelationships of combined medication of CKI in treating CC can be validated in real world settings. Methods. This study was conducted based on a large‐scale integrated database of EMR derived from HIS. EMR of 3328 patients initially diagnosed with CC among 49,597 patients treated with CKI were included in the study. Descriptive statistical analyses and apriori algorithm based association rule analyses were performed, respectively, to validate frequency distribution and interrelationships of combined medication of CKI in treating CC. Results. The pharmacological mechanisms of TCMs that have been commonly used in conjunction with CKI include heat‐clearing and detoxifying, qi‐reinforcing, blood circulation‐promoting and stasis‐removing, blood‐stanching, and qi‐regulating. For modern medicines, antibiotics, antineoplastic chemotherapeutic drugs, immunomodulator, 5‐HT receptor antagonist drugs, and corticosteroids are most often combined with CKI. The association rules of medication combinations of CKI in treating CC in real world manifest certain laws for both TCMs and modern medicines. They are generally in line with CC treatment guidelines. Conclusions. It is a common practice for CKI to be integrated with both modern medicines and TCMs when treating CC in China. The associations of medication combinations of CKI in treating CC manifest certain laws for both TCMs and modern medicines. The RWS for validating interrelationships of combined medication may provide evidence for rational use of CKI. Further explorations are needed to verify and expand the conclusions.
Temporal Evolution of Immunity Distributions in a Population with Waning and Boosting
Authors: Barbarossa M. V. , Polner M. , Röst G.
Published: August 2018

We investigate the temporal evolution of the distribution of immunities in a population, which is determined by various epidemiological, immunological, and demographical phenomena: after a disease outbreak, recovered individuals constitute a large immune population; however, their immunity is waning in the long term and they may become susceptible again. Meanwhile, their immunity can be boosted by repeated exposure to the pathogen, which is linked to the density of infected individuals present in the population. This prolongs the length of their immunity. We consider a mathematical model formulated as a coupled system of ordinary and partial differential equations that connects all these processes and systematically compare a number of boosting assumptions proposed in the literature, showing that different boosting mechanisms lead to very different stationary distributions of the immunity at the endemic steady state. In the situation of periodic disease outbreaks, the waveforms of immunity distributions are studied and visualized. Our results show that there is a possibility to infer the boosting mechanism from the population level immune dynamics.
Systematic Analysis of Compounds Specifically Targeting Telomeres and Telomerase for Clinical Implications in Cancer Therapy
Authors: Lee Hee-Sheung , Carmena Mar , Liskovykh Mikhail , Peat Emma , Kim Jung-Hyun , Oshimura Mitsuo , Masumoto Hiroshi , Teulade-Fichou Marie-Paule , Pommier Yves , Earnshaw William C. , Larionov Vladimir , Kouprina Natalay
Published: August 2018

The targeting of telomerase and telomere maintenance mechanisms represents a promising therapeutic approach for various types of cancer. In this work, we designed a new protocol to screen for and rank the efficacy of compounds specifically targeting telomeres and telomerase. This approach used two isogenic cell lines containing a circular human artificial chromosome (HAC, lacking telomeres) and a linear HAC (containing telomeres) marked with the EGFP transgene; compounds that target telomerase or telomeres should preferentially induce loss of the linear HAC but not the circular HAC. Our assay allowed quantification of chromosome loss by routine flow cytometry. We applied this dual-HAC assay to rank a set of known and newly developed compounds, including G-quadruplex (G4) ligands. Among the latter group, two compounds, Cu-ttpy and Pt-ttpy, induced a high rate of linear HAC loss with no significant effect on the mitotic stability of a circular HAC. Analysis of the mitotic phenotypes induced by these drugs revealed an elevated rate of chromatin bridges in late mitosis and cytokinesis as well as UFB (ultrafine bridges). Chromosome loss after Pt-ttpy or Cu-ttpy treatment correlated with the induction of telomere-associated DNA damage. Overall, this platform enables identification and ranking of compounds that greatly increase chromosome mis-segregation rates as a result of telomere dysfunction and may expedite the development of new therapeutic strategies for cancer treatment.

Significance: An assay provides a unique opportunity to screen thousands of chemical compounds for their ability to inactivate replication of telomeric ends in cancer cells and holds potential to lay the foundation for the discovery of new treatments for cancer. Cancer Res; 78(21); 6282–96. ©2018 AACR.
Development, Function, and Clinical Significance of Plasmacytoid Dendritic Cells in Chronic Myeloid Leukemia
Authors: Inselmann Sabrina , Wang Ying , Saussele Susanne , Fritz Lea , Schütz Christin , Huber Magdalena , Liebler Simone , Ernst Thomas , Cai Dali , Botschek Sarah , Brendel Cornelia , Calogero Raffaele A. , Pavlinic Dinko , Benes Vladimir , Liu Edison T. , Neubauer Andreas , Hochhaus Andreas , Burchert Andreas
Published: August 2018

Plasmacytoid dendritic cells (pDC) are the main producers of a key T-cell–stimulatory cytokine, IFNα, and critical regulators of antiviral immunity. Chronic myeloid leukemia (CML) is caused by BCR-ABL, which is an oncogenic tyrosine kinase that can be effectively inhibited with ABL-selective tyrosine kinase inhibitors (TKI). BCR-ABL–induced suppression of the transcription factor interferon regulatory factor 8 was previously proposed to block pDC development and compromise immune surveillance in CML. Here, we demonstrate that pDCs in newly diagnosed CML (CML-pDC) develop quantitatively normal and are frequently positive for the costimulatory antigen CD86. They originate from low-level BCR-ABL–expressing precursors. CML-pDCs also retain their competence to maturate and to secrete IFN. RNA sequencing reveals a strong inflammatory gene expression signature in CML-pDCs. Patients with high CML-pDC counts at diagnosis achieve inferior rates of deep molecular remission (MR) under nilotinib, unless nilotinib therapy is combined with IFN, which strongly suppresses circulating pDC counts. Although most pDCs are BCR-ABL–negative in MR, a substantial proportion of BCR-ABL+ CML-pDCs persists under TKI treatment. This could be of relevance, because CML-pDCs elicit CD8+ T cells, which protect wild-type mice from CML. Together, pDCs are identified as novel functional DC population in CML, regulating antileukemic immunity and treatment outcome in CML.

Significance: CML-pDC originates from low-level BCR-ABL expressing stem cells into a functional immunogenic DC-population regulating antileukemic immunity and treatment outcome in CML. Cancer Res; 78(21); 6223–34. ©2018 AACR.
Augmentation of Nab-Paclitaxel Chemotherapy Response by Mechanistically Diverse Antiangiogenic Agents in Preclinical Gastric Cancer Models
Authors: Awasthi Niranjan , Schwarz Margaret A. , Zhang Changhua , Schwarz Roderich E.
Published: August 2018

Gastric adenocarcinoma (GAC) remains the third most common cause of cancer-related deaths worldwide. Systemic chemotherapy is commonly recommended as a fundamental treatment for metastatic GAC; however, standard treatment has not been established yet. Angiogenesis plays a crucial role in the progression and metastasis of GAC. We evaluated therapeutic benefits of mechanistically diverse antiangiogenic agents in combination with nab-paclitaxel, a next-generation taxane, in preclinical models of GAC. Murine survival studies were performed in peritoneal dissemination models, whereas tumor growth studies were performed in subcutaneous GAC cell-derived or patient-derived xenografts. The mechanistic evaluation involved IHC and Immunoblot analysis in tumor samples. Nab-paclitaxel increased animal survival that was further improved by the addition of antiangiogenic agents ramucirumab (or its murine version DC101), cabozantinib and nintedanib. Nab-paclitaxel combination with nintedanib was most effective in improving animal survival, always greater than 300% over control. In cell-derived subcutaneous xenografts, nab-paclitaxel reduced tumor growth while all three antiangiogenic agents enhanced this effect, with nintedanib demonstrating the greatest inhibition. Furthermore, in GAC patient-derived xenografts the combination of nab-paclitaxel and nintedanib reduced tumor growth over single agents alone. Tumor tissue analysis revealed that ramucirumab and cabozantinib only reduced tumor vasculature, whereas nintedanib in addition significantly reduced tumor cell proliferation and increased apoptosis. Effects of nab-paclitaxel, a promising chemotherapeutic agent for GAC, can be enhanced by new-generation antiangiogenic agents, especially nintedanib. The data suggest that nab-paclitaxel combinations with multitargeted antiangiogenic agents carry promising potential for improving clinical GAC therapy. Mol Cancer Ther; 17(11); 2353–64. ©2018 AACR.
Mutational Landscape of Ovarian Adult Granulosa Cell Tumors from Whole Exome and Targeted TERT Promoter Sequencing
Authors: Alexiadis Maria , Rowley Simone M. , Chu Simon , Leung Dilys T.H. , Stewart Colin J.R. , Amarasinghe Kaushalya C. , Campbell Ian G. , Fuller Peter J.
Published: August 2018

Adult granulosa cell tumor (aGCT), the most common malignant ovarian sex cord-stromal tumor, is characterized by the forkhead transcription factor FOXL2 p.C134W somatic mutation. Late recurrences are relatively common but the molecular mechanisms of relapse or aggressive behavior are not known. The mutational landscape of FOXL2 p.C134W mutation–positive tumors (n = 22) was determined using whole-exome sequencing (WES). An average of 64 coding and essential splice-site variants were identified per tumor. As the TERT promoter region is poorly covered by the WES, targeted sequencing identified the TERT -124C>T promoter mutation as the only recurrent mutation (∼40% of cases). Pathway analysis suggested an association with DNA replication/repair and the EGFR family canonical pathways. Copy number analysis confirmed that gains of chromosomes 12 and 14 occur in approximately 30% of aGCT and loss of chromosome 22 occurs in approximately 40% of cases. In summary, exome-wide analysis of the mutational landscape of aGCT revealed that, except for the TERT promoter mutation, recurrence and/or aggressive behavior is not defined by activation or loss of specific genes.

Implications:

This study found that although aGCTs are defined by the presence of a common FOXL2 gene mutation, recurrence and/or aggressive behavior cannot be attributed to subsequent mutation of specific gene(s) or pathways; however, there is a high frequency of the TERT -124C>T promoter mutation, which is associated with more aggressive disease.