bluuebunny/crossref_metadata_2025 huggingface dataset:
Outbreak of salmonellosis in cattle caused by the unusual Salmonella serotype Stockholm
Authors: Gobeli Brawand Stefanie , Keller Christoph , Overesch Gudrun
Published: February 2019

Salmonellosis in livestock is not only a problem for farmers due to economic losses but is also a human health concern because of its zoonotic nature. In Europe, bovine enteric salmonellosis is known to be caused by a limited number of serotypes, that is, Salmonella enterica subspecies enterica (S.) serotypes Typhimurium and Dublin. Here, we describe an outbreak of salmonellosis in a Swiss cattle herd caused by S. Stockholm. To the authors’ knowledge, in cattle, this serotype has hitherto only been described once: isolated from beef cattle in a slaughterhouse in India. On the other hand, S. Stockholm has been isolated at least once from the stool of a patient suffering from gastroenteritis (Kantele 2011). This outbreak demonstrates that all known non‐typhoidal S enterica subspecies enterica serotypes, despite their rare detection, have to be considered pathogenic and potentially zoonotic agents.
Mitigation of plastic shrinkage in fly ash concrete using basalt fibres
Authors: Hemalatha T. , Ramesh G.
Published: February 2019

Many durability related problems in concrete structures are caused due to early-age cracking. Though early-age cracking is not detrimental to the structure, this will open up the way for the long-term durability issues, hence, needs to be mitigated. Cracking of such types in concrete is commonly prevented by adding fibres. Present work aims at studying the potential use of basalt fibres in controlling the shrinkage cracks at early age, otherwise this fibre is considered not suitable for use in concrete as it would degrade under alkaline environment. Further, to sustain the long-term durability, an attempt has been made to reduce the alkalinity of the concrete by replacing the cement with fly ash up to 50%. Concrete specimens made with two water to binder ratios (w/b), six replacement levels of fly ash, and one type of fibre are used for this study. Crack width and crack area generally used for evaluating the extent of shrinkage cracks are measured and analyzed. As the shrinkage cracks are very thin to measure manually, image analysis technique has been employed to measure the crack widths. Results indicate that to a greater extent cracks developed during early age has been effectively mitigated with the incorporation of fly ash. Further, it is found that basalt fibres are effective in arresting the shrinkage cracks. Furthermore, it is concluded that manual measurement will under or overestimate the crack width, hence, image analysis technique can be successfully used for measuring the crack widths.
An Energy-Efficient Reliable Heterogeneous Uncore Architecture for Future 3D Chip-Multiprocessors
Authors: Asad Arghavan , Fazeli Mahdi , Jahed-Motlagh Mohammad Reza , Fathy Mahmood , Mohammadi Farah
Published: February 2019

Uncore components such as cache hierarchy and on-chip interconnects consume a significant portion of overall energy consumption in emerging embedded processors. In Nanoscale technologies, static power consumption due to leakage current has become a serious issue in the design of SRAM-based on-chip cache memories and interconnections. To address this issue, non-volatile memory technologies such as STT-RAMs have been proposed as a replacement for SRAM cells due to their near-zero static power and high memory density. Nonetheless, STT-RAMs suffer from some failures such as read-disturb and limited endurance as well as high switching energy. One effective way to decrease the STTRAMs’ switching energy is to reduce their retention time; however, reducing the retention time has a negative impact on the reliability of STT-RAM cells. In this paper, we propose a heterogeneous last level cache (LLC) architecture for 3D embedded chip-multiprocessors (3D eCMPs) which employs two types of STT-RAM memory banks with retention time of 1s and 10ms to provide a beneficial trade-off between reliability, energy consumption, and performance. To this end, we also propose a convex optimization model to find the optimal configurations for these two kinds of memory banks. In parallel with hybrid memory architecting, optimizing the number and placement of through silicon vias (TSVs) as a main component of on-chip interconnection for building 3D CMPs is another important target of the proposed optimization approach. Experimental results show that the proposed method improves the energy-delay products and throughput by about 69% and 34.5% on average compared with SRAM configurations.
A New CPFSK Demodulation Approach for Software Defined Radio
Authors: Mayer Kayol Soares , Müller Candice , de Castro Fernando Cesar Comparsi , de Castro Maria Cristina Felippetto
Published: February 2019

This paper proposes a new coherent Frequency-Shift Keying (FSK) demodulation technique for software defined radio platform, based on a new Digital Phase Locked Loop (DPLL) architecture. The proposed DPLL addresses the frequency dependence on classic DPLL architectures found in the literature. In classical approaches, the loop filter constants are dependent on the frequency level of the FSK transmitted symbols. The proposed approach applies a simpler feedback loop, with a single integrator and a phase detector architecture based on the small-angle approximation [Formula: see text], which resulted in a DPLL totally independent of frequency. The proposed demodulator has been implemented in Very High Speed Integrated Circuits (VHSIC) Hardware Description Language (VHDL) and evaluated for continuous-phase frequency shift keying (CPFSK) and Gaussian minimum shift keying (GMSK) signals. For CPFSK signals, the demodulator has been evaluated for 2, 4 and 8 frequency levels, with modulation indexes [Formula: see text], [Formula: see text] and [Formula: see text], respectively. For evaluation of GMSK signals, several Gaussian filter bandwidths were considered. In addition, a brief analysis for 2-CPFSK and GMSK is presented over multipath and carrier frequency offset. Results show that the proposed method presents a significantly reduced bit error rate when compared to other coherent methods presented in the literature.
A Memetic Algorithm-Based Design Space Exploration for Datapath Resource Allocation During High-Level Synthesis
Authors: Rajmohan Shathanaa , Ramasubramanian N.
Published: February 2019

System designers have started adopting high-level synthesis (HLS) for architectural design because of the higher levels of abstraction offered. The HLS tools provide multiple design choices with tradeoff among different design parameters. Design Space Exploration (DSE) involves optimizing the synthesis options to achieve best tradeoffs among the metrics of interest. With the aim of exploring the design space in a feasible amount of time, we present a novel automated DSE approach. In particular, meeting the constraints presented by different parameters of interest is modeled as a multi-objective problem and solved using Memetic algorithm. The effectiveness of different variations of the Memetic algorithm in solving the DSE problem is studied and a Firefly algorithm-based solution is proposed with a novel probabilistic local search mechanism. The proposed approach is compared with existing solutions and the results prove that the proposed approach outperforms both existing solutions and other variations of Memetic algorithms in terms of convergence time and quality of results. In addition to that, a case study has been included to demonstrate the applicability of the approach. Results show that the proposed approach achieves a 33% improvement in cost, [Formula: see text] improvement in speed and [Formula: see text] improvement in hypervolume.
New Hardware Architecture for Self-Organizing Map Used for Color Vector Quantization
Authors: Khalifa Khaled Ben , Blaiech Ahmed Ghazi , Abadi Mehdi , Bedoui Mohamed Hedi
Published: February 2019

In this paper, we present a new generic architectural approach of a Self-Organizing Map (SOM). The proposed architecture, called the Diagonal-SOM (D-SOM), is described as an Hardware–Description-Language as an intellectual property kernel with easily adjustable parameters.The D-SOM architecture is based on a generic formalism that exploits two levels of the nested parallelism of neurons and connections. This solution is therefore considered as a system based on the cooperation of a distributed set of independent computations. The organization and structure of these calculations process an oriented data flow in order to find a better treatment distribution between different neuroprocessors. To validate the D-SOM architecture, we evaluate the performance of several SOM network architectures after their integration on a Xilinx Virtex-7 Field Programmable Gate Array support. The proposed solution allows the easy adaptation of learning to a large number of SOM topologies without any considerable design effort. [Formula: see text] SOM hardware is validated through FPGA implementation, where temporal performance is almost twice as fast as that obtained in the recent literature. The suggested D-SOM architecture is also validated through simulation on variable-sized SOM networks applied to color vector quantization.
An Efficient Load Forecasting in Predictive Control Strategy Using Hybrid Neural Network
Authors: Sengar Shweta , Liu Xiaodong
Published: February 2019

Load forecasting is a difficult task, because the load series is complex and exhibits several levels of seasonality. The load at a given hour is dependent not only on the load at the previous day, but also on the load at the same hour on the previous day and previous week, and because there are many important exogenous variables that must be considered. Most of the researches were simultaneously concentrated on the number of input variables to be considered for the load forecasting problem. In this paper, we concentrate on optimizing the load demand using forecasting of the weather conditions, water consumption, and electrical load. Here, the neural network (NN) power load forecasting model clubbed with Levy-flight from cuckoo search algorithm is proposed, i.e., called hybrid neural network (HNN), and named as LF-HNN, where the Levy-flight is used to automatically select the appropriate spread parameter value for the NN power load forecasting model. The results from the simulation work have demonstrated the value of the LF-HNN approach successfully selected the appropriate operating mode to achieve optimization of the overall energy efficiency of the system using all available energy resources.
Reliability-Equivalent Field Reference Usage Level When Both Field Usage and Usage to Failure are Random
Authors: Sun Fengbin
Published: February 2019

This paper provides a practical engineering insight for product reliability design when both the field usage and usage to failure (life or strength) are a random variable. Especially, what percentile for the usage should one use in order to meet the same level of population reliability target.
Two-Dimensional NHPP Models Based on Several Testing-Time Functions and Their Applications
Authors: Minamino Yuka , Sakaguchi Shunichi , Inoue Shinji , Yamada Shigeru
Published: February 2019

Enormous testing-time and testing-effort (central processing unit (CPU) time, execution time, man-hour, test coverage, executed test case, and so forth) are invested in testing-phase for enhancing software reliability. Although they are software reliability growth factors, existing software reliability growth models (SRGMs) are not introduced simultaneously. Also, the software reliability growth factors enable to substitute each other partly. Therefore, we develop new bivariate nonhomogeneous Poisson process (NHPP) models based on two types of testing-time functions in this paper. Concretely, we assume that the testing-time as a software reliability growth factor is composed of the testing-time and testing-effort factors. Then, the testing-time as the software reliability growth factor is expressed by the Cobb–Douglas and constant elasticity of substitution (CES) type testing-time functions. We conduct goodness-of-fit comparisons of existing models with proposed bivariate models. Also, we discuss estimation method of the optimal software release time and optimal amount of testing-effort as an application. Finally, we show numerical examples by using actual datasets.
The manipulation of second-order nonlinear harmonic wave by structured material and structured light
Authors: Liu Haigang , Chen Xianfeng
Published: February 2019

Nonlinear frequency conversion is the important method to get coherent radiation in all-optical waveband. The intentional manipulation of nonlinear harmonic wave, which has some special phase, amplitude, polarization, and so on, is also important to realize all kinds of optical micro-manipulation, optical micro-fabrication, and optical communication in all-optical waveband. There are three methods to manipulate such nonlinear harmonic wave, which are tailoring the functional facet, the structure of crystals, and the structure of the incident light. In this review, we will systematically introduce the fundamental principle and latest advances in this field and summarize the respective characteristics of these three methods.
VARIANCE AND VOLATILITY SWAPS UNDER A TWO-FACTOR STOCHASTIC VOLATILITY MODEL WITH REGIME SWITCHING
Authors: HE XIN-JIANG , ZHU SONG-PING
Published: February 2019

In this paper, the pricing problem of variance and volatility swaps is discussed under a two-factor stochastic volatility model. This model can be treated as a two-factor Heston model with one factor following the CIR process and another characterized by a Markov chain, with the motivation originating from the popularity of the Heston model and the strong evidence of the existence of regime switching in real markets. Based on the derived forward characteristic function of the underlying price, analytical pricing formulae for variance and volatility swaps are presented, and numerical experiments are also conducted to compare swap prices calculated through our formulae and those obtained under the Heston model to show whether the introduction of the regime switching factor would lead to any significant difference.
ℵ0-Injective group rings
Authors: Shen Liang
Published: February 2019

Recall that a ring [Formula: see text] is called right [Formula: see text]-injective if every homomorphism from a countably generated right ideal of [Formula: see text] to [Formula: see text] can be extended to a homomorphism from [Formula: see text] to [Formula: see text]. These rings are not only a natural generalization of self-injective rings but also strongly connected with regularities of rings. Let [Formula: see text] be the group ring of a group [Formula: see text] over a ring [Formula: see text]. It is proved that [Formula: see text] is right [Formula: see text]-injective if and only if (i) [Formula: see text] is right [Formula: see text]-injective; (ii) [Formula: see text] is finite; (iii) for each countably generated right ideal [Formula: see text] of [Formula: see text], any right [Formula: see text]-homomorphism from [Formula: see text] to [Formula: see text] can be extended to a right [Formula: see text]-homomorphism from [Formula: see text] to [Formula: see text].
Localization operators, time frequency concentration and quantitative-type uncertainty for the continuous wavelet transform associated with spherical mean operator
Authors: Mejjaoli Hatem , Hamadi Nadia Ben , Omri Slim
Published: February 2019

We consider the continuous wavelet transform [Formula: see text] associated with the spherical mean operator. We investigate the localization operators for [Formula: see text], in particular, we prove that they are in the Schatten-von Neumann class. Next, we analyze the concentration of this transform on sets of finite measure. In particular, Donoho-Stark and Benedicks-type uncertainty principles are given. Finally, we prove many versions of quantitative uncertainty principles for [Formula: see text].
Beyond Independence: CEO Influence and the Internal Operations of the Board
Authors: Horstmeyer Derek
Published: February 2019

Using a detailed dataset on the meeting sub-structure of the board, this paper investigates the time trends and cross-sectional determinants of internal boardroom control. First, I document that the principal governance reform following Sarbanes–Oxley was the removal of the CEO as a participating member in board monitoring and investment decisions. Consistent with this being against the preferences of the average CEO, I find that CEO power is negatively related to monitoring work handled outside of the CEO’s presence and positively related to board-time spent in the executive committee. Together the results highlight internal operations as governance concerns of the modern board.
Advances and Challenges in Log Analysis
Authors: Oliner Adam , Ganapathi Archana , Xu Wei
Published: February 2019

Computer-system logs provide a glimpse into the states of a running system. Instrumentation occasionally generates short messages that are collected in a system-specific log. The content and format of logs can vary widely from one system to another and even among components within a system. A printer driver might generate messages indicating that it had trouble communicating with the printer, while a Web server might record which pages were requested and when.
You Don’t Know Jack about Shared Variables or Memory Models
Authors: Boehm Hans-J , Adve Sarita V.
Published: February 2019

A Google search for "Threads are evil" generates 18,000 hits, but threads are ubiquitous. Almost all of the processes running on a modern Windows PC use them. Software threads are typically how programmers get machines with multiple cores to work together to solve problems faster. And often they are what allow user interfaces to remain responsive while the application performs a background calculation.
Social Networks under Stress
Authors: Romero Daniel M. , Uzzi Brian , Kleinberg Jon
Published: February 2019

Social network research has begun to take advantage of fine-grained communications regarding coordination, decision-making, and knowledge sharing. These studies, however, have not generally analyzed how external events are associated with a social network’s structure and communicative properties. Here, we study how external events are associated with a network’s change in structure and communications. Analyzing a complete dataset of millions of instant messages among the decision-makers with different roles in a large hedge fund and their network of outside contacts, we investigate the link between price shocks, network structure, and change in the affect and cognition of decision-makers embedded in the network. We also analyze the communication dynamics among specialized teams in the organization. When price shocks occur the communication network tends not to display structural changes associated with adaptiveness such as the activation of weak ties to obtain novel information. Rather, the network “turtles up.” It displays a propensity for higher clustering, strong tie interaction, and an intensification of insider vs. outsider and within-role vs. between-role communication. Further, we find changes in network structure predict shifts in cognitive and affective processes, execution of new transactions, and local optimality of transactions better than prices, revealing the important predictive relationship between network structure and collective behavior within a social network.
News from the SIGs
Authors: Walker Ellen , Settle Amber , Lunt Barry
Published: February 2019

This issue celebrates outstanding members of SIGs and ACM. Amber Settle of SIGCSE highlights recent award winners from SIGCSE, and our newest correspondent, Barry Lunt of SIGITE sends an appreciation of SIG and ACM volunteers.
Unified Classification of Molecular, Network, and Endocrine Features of Hypothalamic Neurons
Authors: Romanov Roman A. , Alpár Alán , Hökfelt Tomas , Harkany Tibor
Published: February 2019

Peripheral endocrine output relies on either direct or feed-forward multi-order command from the hypothalamus. Efficient coding of endocrine responses is made possible by the many neuronal cell types that coexist in intercalated hypothalamic nuclei and communicate through extensive synaptic connectivity. Although general anatomical and neurochemical features of hypothalamic neurons were described during the past decades, they have yet to be reconciled with recently discovered molecular classifiers and neurogenetic function determination. By interrogating magnocellular as well as parvocellular dopamine, GABA, glutamate, and phenotypically mixed neurons, we integrate available information at the molecular, cellular, network, and endocrine output levels to propose a framework for the comprehensive classification of hypothalamic neurons. Simultaneously, we single out putative neuronal subclasses for which future research can fill in existing gaps of knowledge to rationalize cellular diversity through function-determinant molecular marks in the hypothalamus.
lncRNA GAS5 restrains CCl4-induced hepatic fibrosis by targeting miR-23a through the PTEN/PI3K/Akt signaling pathway
Authors: Dong Zhiheng , Li Sha , Wang Xiaohui , Si Lengge , Ma Ruilian , Bao Lidao , Bo Agula
Published: February 2019

Hepatic fibrosis is chronic liver damage with many causes that has a relatively high death rate. The current study showed that long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5), microRNA-23a (miR-23a), and phosphatase and tensin homolog (PTEN) play important roles in the pathological process of hepatic fibrosis but have a relatively unclear regulatory mechanism. This study aimed to investigate the roles of lncRNA GAS5, miR-23a, and PTEN in the pathological process of hepatic fibrosis and hepatic stellate cell (HSC) activation. We used carbon tetrachloride (CCl4) intraperitoneal injections to establish a rat hepatic fibrosis model and exogenous transforming growth factor-β1 to establish an HSC activation model. Quantitative RT-PCR, Western blot, dual-luciferase reporter system, and RNA pull-down assays were used to investigate which microRNAs and lncRNAs participate in the process of hepatic fibrosis and HSC activation. miR-23a expression increased significantly in hepatic fibrosis tissues and activated HSCs. miR-23a interaction with and degradation of PTEN further influenced the downstream signaling pathway phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin/Snail (PI3K/Akt/mTOR/Snail), causing E-cadherin expression levels to decrease and α-smooth muscle actin and collagen I expression levels to increase. lncRNA GAS5 can be used as a sponge platform for miR-23a to decrease miR-23a expression levels competitively. We revealed the role of the lncRNA GAS5/miR-23a/PTEN/PI3K/Akt/mTOR/Snail signaling pathway in hepatic fibrosis, providing molecular targets for the treatment of hepatic fibrosis.

NEW & NOTEWORTHY This is the first study revealing that microRNA-23a (miR-23a) promotes hepatic fibrosis through the phosphatase and tensin homolog/phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin/Snail signaling pathway, and long noncoding RNA (lncRNA) growth arrest-specific transcript 5 (GAS5) can act as a sponge platform for miR-23a. Therefore, lncRNA GAS5/miR-23a may bring molecular targets for hepatic fibrosis therapy.
Docosahexaenoic acid reduces resting blood pressure but increases muscle sympathetic outflow compared with eicosapentaenoic acid in healthy men and women
Authors: Lee Jordan B. , Notay Karambir , Klingel Shannon L. , Chabowski Adrian , Mutch David M. , Millar Philip J.
Published: February 2019

Supplementation with monounsaturated or ω-3 polyunsaturated fatty acids ( n-3 PUFA) can lower resting blood pressure (BP) and reduce the risk of cardiovascular events. The independent contributions of the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on BP, and the mechanisms responsible, are unclear. We tested whether EPA, DHA, and olive oil (OO), a source of monounsaturated fat, differentially affect resting hemodynamics and muscle sympathetic nerve activity (MSNA). Eighty-six healthy young men and women were recruited to participate in a 12-wk, randomized, double-blind trial examining the effects of orally supplementing ~3 g/day of EPA ( n = 28), DHA ( n = 28), or OO ( n = 30) on resting hemodynamics; MSNA was examined in a subset of participants ( n = 31). Both EPA and DHA supplements increased the ω-3 index ( P < 0.01). Reductions in systolic BP were greater [adjusted intergroup mean difference (95% confidence interval)] after DHA [−3.4 mmHg (−0.9, −5.9), P = 0.008] and OO [−3.0 mmHg (−0.5, −5.4), P = 0.01] compared with EPA, with no difference between DHA and OO ( P = 0.74). Reductions in diastolic BP were greater following DHA [−3.4 mmHg (−1.3,−5.6), P = 0.002] and OO [−2.2 mmHg (0.08,−4.3), P = 0.04] compared with EPA. EPA increased heart rate compared with DHA [4.2 beats/min (−0.009, 8.4), P = 0.05] and OO [4.2 beats/min, (0.08, 8.3), P = 0.04]. MSNA burst frequency was higher after DHA [4 bursts/min (0.5, 8.3), P = 0.02] but not OO [−3 bursts/min (−6, 0.6), P = 0.2] compared with EPA. Overall, DHA and OO evoked similar responses in resting BP; however, DHA, but not OO, increased peripheral vasoconstrictor outflow. These findings may have implications for fatty acid supplementation in clinical populations characterized by chronic high BP and sympathetic overactivation.

NEW & NOTEWORTHY We studied the effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and olive oil supplementation on blood pressure (BP) and muscle sympathetic nerve activity (MSNA). After 12 wk of 3 g/day supplementation, DHA and olive oil were associated with lower resting systolic and diastolic BPs than EPA. However, DHA increased MSNA compared with EPA. The reductions in BP with DHA likely occur via a vascular mechanism and evoke a baroreflex-mediated increase in sympathetic activity.
EZH2 Inhibitor GSK126 Suppresses Antitumor Immunity by Driving Production of Myeloid-Derived Suppressor Cells
Authors: Huang Shuo , Wang Zhongyu , Zhou Jie , Huang Jiani , Zhou Li , Luo Jing , Wan Yisong Y. , Long Haixia , Zhu Bo
Published: February 2019

Enhancer of zeste homolog (EZH2) is a key epigenetic regulator of gene expression and is frequently overexpressed in various cancer types, suggesting a role in oncogenesis. The therapeutic potential of EZH2 inhibitors is currently being explored, but their effect on antitumor immunity is largely unknown. Here we report that suppressing EZH2 activity using EZH2 inhibitor GSK126 resulted in increased numbers of myeloid-derived suppressor cells (MDSC) and fewer CD4+ and IFNγ+CD8+ T cells, which are involved in antitumor immunity. Addition of a neutralizing antibody against the myeloid differentiation antigen GR-1 or gemcitabine/5-fluorouracil–depleted MDSCs alleviated MDSC-mediated immunosuppression and increased CD4+ and CD8+ T-cell tumor infiltration and GSK126 therapeutic efficacy. Mechanistically, we identified a novel pathway of MDSC production in cancer in which EZH2 inhibition directs myeloid differentiation from primitive hematopoietic progenitor cells. These findings suggest that modulating the tumor immune microenvironment may improve the efficacy of EZH2 inhibitors.

Significance:

This study uncovers a potential mechanism behind disappointing results of a phase I clinical trial of EZH2 inhibitor GSK126 and identifies a translatable combinational strategy to overcome it.
Upregulation of PD-L1 via HMGB1-Activated IRF3 and NF-κB Contributes to UV Radiation-Induced Immune Suppression
Authors: Wang Wei , Chapman Nicole M. , Zhang Bo , Li Mingqi , Fan Meiyun , Laribee R. Nicholas , Zaidi M. Raza , Pfeffer Lawrence M. , Chi Hongbo , Wu Zhao-Hui
Published: February 2019

Solar ultraviolet radiation (UVR) suppresses skin immunity, which facilitates initiation of skin lesions and establishment of tumors by promoting immune evasion. It is unclear whether immune checkpoints are involved in the modulation of skin immunity by UVR. Here, we report that UVR exposure significantly increased expression of immune checkpoint molecule PD-L1 in melanoma cells. The damage-associated molecular patterns molecule HMGB1 was secreted by melanocytes and keratinocytes upon UVR, which subsequently activated the receptor for advanced glycation endproducts (RAGE) receptor to promote NF-κB– and IRF3-dependent transcription of PD-L1 in melanocytes. UVR exposure significantly reduced the susceptibility of melanoma cells to CD8+ T-cell–dependent cytotoxicity, which was mitigated by inhibiting the HMGB1/TBK1/IRF3/NF-κB cascade or by blocking the PD-1/PD-L1 checkpoint. Taken together, our findings demonstrate that UVR-induced upregulation of PD-L1 contributes to immune suppression in the skin microenvironment, which may promote immune evasion of oncogenic cells and drive melanoma initiation and progression.

Significance:

These findings identify PD-L1 as a critical component of UV-induced immune suppression in the skin, which facilitates immunoevasion of oncogenic melanocytes and development of melanoma.

See related commentary by Sahu, p. 2805
A T-cell–engaging B7-H4/CD3-bispecific Fab-scFv Antibody Targets Human Breast Cancer
Authors: Iizuka Akira , Nonomura Chizu , Ashizawa Tadashi , Kondou Ryota , Ohshima Keiichi , Sugino Takashi , Mitsuya Koichi , Hayashi Nakamasa , Nakasu Yoko , Maruyama Kouji , Yamaguchi Ken , Akiyama Yasuto
Published: February 2019

Purpose:

The B7 homolog 4 (B7-H4, VTCN1) is an immune checkpoint molecule that negatively regulates immune responses and is known to be overexpressed in many human cancers. Previously, we generated a mouse anti-human B7-H4 mAb that did not have a significant antitumor effect in vivo probably because of molecule instability. In this study, we designed a B7-H4/CD3-bispecific antibody (BsAb) and investigated its antitumor activity in vitro and in vivo using a humanized mouse model.

Experimental Design:

cDNAs of the antibody-binding fragment (Fab)–single-chain variable fragment (scFv) and scFv-scFv of the anti-B7-H4/CD3 BsAb were synthesized, and the BsAb antibodies were produced in HEK293 cells. The antitumor activity against human breast cancer cells by human peripheral blood mononuclear cells (hPBMC) with BsAb was measured by lactate dehydrogenase release in vitro, and in vivo using hPBMC-transplanted MHC class I- and class II–deficient NOG mice.

Results:

hPBMCs with anti-B7-H4/CD3 BsAbs successfully lysed the human breast cancer cell line MDA-MB-468 (EC50: 0.2 ng/mL) and other B7-H4+ cell lines in vitro. When BsAb was injected in a humanized mouse model, there was an immediate and strong antitumor activity against MDA-MB-468, HCC-1954, and HCC-1569 tumors and CD8+ and granzyme B+ CTL infiltration into the tumor, and there were no adverse effects after long-term observation. CD8+ T-cell depletion by an anti-CD8 antibody mostly reduced the antitumor effect of BsAb in vivo.

Conclusions:

An anti-B7-H4/CD3 BsAb may be a good therapeutic tool for patients with B7-H4+ breast cancers.
Drugging RB1 Deficiency: Synthetic Lethality with Aurora Kinases
Authors: Dick Frederick A. , Li Shawn Shun-Cheng
Published: February 2019

Two recent reports describe pharmacologic approaches to specifically treat RB1-mutant cancers. The basis of this approach is a synthetic lethal relationship between RB1 mutations and inhibition of Aurora kinases A or B.

See related article by Oser et al., p. 230.

See related article by Gong et al., p. 248.
Acoustic Discriminability of the Complex Phonation System in !Xóõ
Authors: Garellek Marc
Published: February 2019

Phonation types, or contrastive voice qualities, are minimally produced using complex movements of the vocal folds, but may additionally involve constriction in the supraglottal and pharyngeal cavities. These complex articulations in turn produce a multidimensional acoustic output that can be modeled in various ways. In this study, I investigate whether the psychoacoustic model of voice by Kreiman et al. (2014) succeeds at distinguishing six phonation types of !Xóõ. Linear discriminant analysis is performed using parameters from the model averaged over the entire vowel as well as for the first and final halves of the vowel. The results indicate very high classification accuracy for all phonation types. Measures averaged over the vowel’s entire duration are closely correlated with the discriminant functions, suggesting that they are sufficient for distinguishing even dynamic phonation types. Measures from all classes of parameters are correlated with the linear discriminant functions; in particular, the “strident” vowels, which are harsh in quality, are characterized by their noise, changes in spectral tilt, decrease in voicing amplitude and frequency, and raising of the first formant. Despite the large number of contrasts and the time-varying characteristics of many of the phonation types, the phonation contrasts in !Xóõ remain well differentiated acoustically.
Validation of the Malay Version of Addenbrooke’s Cognitive Examination III in Detecting Mild Cognitive Impairment and Dementia
Authors: Kan Kwai Ching , Subramaniam Ponnusamy , Shahrizaila Nortina , Kamaruzzaman Shahrul Bahyah , Razali Rosdinom  , Ghazali Shazli Ezzat
Published: February 2019

Background/Aims: This study aimed to investigate the validity and reliability of the Malay version of Addenbrooke’s Cognitive Examination III (ACE-III) for detecting mild cognitive impairment (MCI) and dementia. Methods: A total of 152 participants (dementia = 53, MCI = 38, controls = 61) were recruited from two teaching hospitals. The Malay version of ACE-III was translated following the standard guidelines for cross-cultural adaptation of measure. All the participants were assessed with the Malay version of ACE-III and Mini-Mental State Examination (MMSE). Results: The reliability of the Malay version of ACE-III was good with Cronbach’s α coefficient of 0.829 and intraclass correlation coefficient of 0.959. There was a strong positive correlation between the Malay version of ACE-III and MMSE (r = 0.806). Age (r = –0.335) and years of education (r = 0.536) exerted a significant correlation with total score performance. The cutoff score to discriminate dementia from healthy controls was 74/75 (sensitivity = 90.6%, specificity = 82.0%) whereas to discriminate MCI, the cutoff score was 77/78 (sensitivity = 63.2%, specificity = 63.9%). The diagnostic accuracy of ACE-III was higher than that of MMSE in the detection of dementia (area under the curve: ACE-III = 0.929 vs. MMSE = 0.915). Conclusions: The Malay version of ACE-III demonstrated to be a reliable and valid screening tool for dementia.
Idiopathic Generalized Exfoliative Dermatitis and Association with Antihypertensive Drugs and Statins: A Retrospective Case-Control Study
Authors: Cheong Kah Wai , Yew Yik Weng , Tey Hong Liang
Published: February 2019

Background/Aims: We aim to examine the hypothesis that antihypertensive drugs and statins may be responsible for the development of idiopathic generalized exfoliative dermatitis (GED) with a case-control study. Methods: All inpatients who were hospitalized under the dermatology service at the Tan Tock Seng Hospital, Singapore, between 1 May 2013 and 31 May 2015, were analysed. Idiopathic GED cases had consistent clinical and histological features but no apparent cause despite comprehensive evaluation. Controls were randomly selected from inpatients with other dermatological conditions in a 1: 1 ratio during the same period. Their relationship was analysed using univariate (χ2 or Fisher exact tests) and multivariate logistic regression analysis. Results: There were 78 cases and 83 controls. Of the 78 cases, 42 patients had a history of treatment with antihypertensive drugs or statins. Cases were not found to be more likely on angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, calcium channel blockers, thiazides or statins compared to controls (OR: 0.81; 95% CI: 0.43–1.51; p = 0.507). Conclusions: There was insufficient evidence to suggest a significant relationship between the chronic use of antihypertensive drugs or statins and idiopathic GED in this study, despite previous evidence reporting this might be so. Further case-control studies with larger sample sizes are needed to evaluate this association.
The Rationale for Endoscopic Inferior Meatal Antrostomy
Authors: Landsberg Roee , Warman Meir , Margulis Ariel , Masalha Muhamed
Published: February 2019

Background: Complete removal of some maxillary sinus pathologies may be challenging. We describe our experience in performing endoscopic inferior meatal antrostomy (EIMA) when approaching certain chronic maxillary sinus disease. Methods: Retrospectively reviewing charts of all patients whose surgery included EIMA between the years 2012 and 2015. EIMA was performed either after routine endoscopic middle meatal antrostomy (EMMA) failed to completely resect the lesion, or as the sole selected approach for specific maxillary pathologies. Results: A total of 56 patients were included in the study. Indications for EIMA included antrochoanal polyps (ACP), maxillary sinus chronic inflammatory disease, maxillary sinus pathology before sinus lift, and odontogenic maxillary sinusitis. In nearly one third of the patients, sinus surgery included only EIMA, of which, the majority were resection of ACP. Follow-up time ranged between 12 and 34 months (mean 14). Residual EIMA opening was variable in size. In the vast majority of our patients, the maxillary sinus cavities were cleared of disease. No major complications and no recirculation were observed in any of the patients. Conclusion: EIMA should be considered for various maxillary sinus pathologies. It provides better access to anteroinferior lesions of the maxillary sinus. EMMA is not mandatory for every maxillary sinus disease.
Molecular Network Analysis of the Urinary Proteome of Alzheimer’s Disease Patients
Authors: Watanabe Yumi , Hirao Yoshitoshi , Kasuga Kensaku , Tokutake Takayoshi , Semizu Yuka , Kitamura Kaori , Ikeuchi Takeshi , Nakamura Kazutoshi , Yamamoto Tadashi
Published: February 2019

Background/Aims: The identification of predictive biomarkers for Alzheimer’s disease (AD) from urine would aid in screening for the disease, but information about biological and pathophysiological changes in the urine of AD patients is limited. This study aimed to explore the comprehensive profile and molecular network relations of urinary proteins in AD patients. Methods: Urine samples collected from 18 AD patients and 18 age- and sex-matched cognitively normal controls were analyzed by mass spectrometry and semiquantified with the normalized spectral index method. Bioinformatics analyses were performed on proteins which significantly increased by more than 2-fold or decreased by less than 0.5-fold compared to the control (p < 0.05) using DAVID bioinformatics resources and KeyMolnet software. Results: The levels of 109 proteins significantly differed between AD patients and controls. Among these, annotation clusters related to lysosomes, complement activation, and gluconeogenesis were significantly enriched. The molecular relation networks derived from these proteins were mainly associated with pathways of lipoprotein metabolism, heat shock protein 90 signaling, matrix metalloproteinase signaling, and redox regulation by thioredoxin. Conclusion: Our findings suggest that changes in the urinary proteome of AD patients reflect systemic changes related to AD pathophysiology.
Acute Ischemic Stroke in Pregnancy
Authors: Rodrigues Rita , Silva Renata , Fontão Luís , Ruano Luís , Roriz José Mário
Published: February 2019

Stroke is an uncommon but serious potential complication of pregnancy. The management of acute ischemic stroke in pregnant women remains a complex challenge that extends beyond the limits of clinical trial evidence. Patient 1 was a 29-year-old woman 27 weeks into her first pregnancy, without remarkable past medical history or vascular risk factors. She was admitted 1 h after sudden onset of a left total anterior circulation syndrome (National Institute of Health Stroke Scale [NIHSS] score of 23). CT and angio-CT scans were normal. Thrombolysis was performed, with mild clinical improvement. Brain MRI showed multi-territorial embolic events. Extended blood panel, cervical-transcranial ultrasound, 48-h ECG monitoring, and transthoracic echocardiogram were unremarkable. She was started on aspirin and low-molecular-weight heparin (LMWH), giving birth to a healthy child 10 weeks later. Patient 2 was a 45-year-old woman 34 weeks into her pregnancy, without remarkable past medical history or vascular risk factors. She was admitted 30 min after sudden onset of a left partial anterior circulation syndrome, already partially recovered (NIHSS score of 4). The CT scan showed only a subacute right incidental middle cerebral artery infarct, while the angio-CT confirmed a left M3 branch occlusion. Thrombolysis and thrombectomy were contraindicated by the recent contralateral infarct, mild deficits, and distal occlusion site. Brain MRI also suggested an embolic etiology and LMWH was started. Extended blood panel, 48-h ECG monitoring, and transthoracic echocardiogram were normal. She gave birth to a healthy baby 4 weeks later. These cases emphasize the growing real-world evidence of the emergent use of CT, IV contrast, and recombinant tissue plasminogen activator in pregnant women with acute stroke, while also illustrating the importance of an individualized management, accounting for the safety of both mother and child.
Implications of Immunotherapy in Hepatobiliary Tumors
Authors: Gottlieb Aline , Best Jan , Canbay Ali
Published: February 2019

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death worldwide. Upon ineligibility for resection, liver transplantation, or locoregional therapies, sorafenib has been the only systemic treatment option of advanced HCC for more than a decade. Immunotherapy is an evolving HCC treatment option that has shown promise in treatment efficacy at an acceptable safety profile during several preceding phase I/II trials. Numerous clinical trials of immune checkpoint inhibitors (ICPIs) alone, in combination of two, or combined with other targeted or locoregional therapies are ongoing. Encouraging results of two-phase III trials testing pembrolizumab or nivolumab versus standard care therapy even resulted in Food and Drug Administration approval for second-line treatment of advanced HCC. ICPIs may open new avenues to the treatment of hepatobiliary tumors, alone or in combination.
Sequence Variants in TBX6 Are Associated with Disorders of the Müllerian Ducts: An Update
Authors: Tewes Ann-Christin , Hucke Jürgen , Römer Thomas , Kapczuk Karina , Schippert Cordula , Hillemanns Peter , Wieacker Peter , Ledig Susanne
Published: February 2019

Müllerian anomalies comprise the Mayer-Rokitansky-Küster-Hauser syndrome as well as fusion defects of the müllerian ducts. Recurrent micro-aberrations like deletions in 16p11.2 encompassing TBX6 were found to be causative in these patients. TBX6 encodes a transcription factor which plays a role in paraxial mesoderm differentiation/specification. In previous studies, we and other groups found possibly pathogenic variants in TBX6 in patients with müllerian anomalies. Since we suggested TBX6 as a strong candidate, we performed sequential analysis of the TBX6 gene in additional 125 patients with müllerian anomalies, and 2 possibly pathogenic missense variants and 1 nonsense substitution in TBX6 in 4/125 patients were found. The missense variant c.484G>A, which we have described in a previous study, was reidentified but with no higher frequency as in our controls. We detected 3 possibly pathogenic variants in TBX6 and could show that the variant c.484G>A is not causative for disorders of the müllerian ducts in the non-Finnish European population. In summary, we present increasing evidence for association of variants in TBX6 with malformations of the müllerian ducts.
THREE DIFFERENT TYPES OF PLASTIC PACKAGING MATERIALS: THEIR EFFECTS ON MOULD INFECTION AND AFLATOXIN CONTAMINATION IN PEANUTS.
Authors: Dharmaputra Okky Setyawati , Retnowati Ina , Ambarwati Santi
Published: February 2019

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NOTES ON THE PROFILE OF INDONESIAN INVASIVE ALIEN PLANT SPECIES
Authors: Tjitrosoedirjo Sri Sudarmiyati
Published: February 2019

An alien species, which becomes established in natural or semi-natural ecosystems or habitas, is an agent of change and threatens native biological diversity.Â  The Convention on Biological Diversity (CBD) declared in 1992, in which the issue on invasive alien species was raised, was ratified by the Indonesian Government in 1994.Â  Protecting our biodiversity will be our moral obligation to comply with CBD.Â  Inventory on the invasive alien plant species in Indonesia should be done by field surveys aside from the data collected from the references and herbarium specimens.Â  Field studies should be carried out to get complete figures, to identify the new ones, to determine their distributions, to plan their management including prevention to spread, containment and movement or mitigate their impact to environment.Â  Sometimes it is difficult in determining whether the plants are aliens or not. Cooperation with botanists and taxonomists in other parts of the world is necessary.Â  There are some species of invasive aliens plant in Indonesia, which have to be watched for their aggressiveness i.e. Acasia nilotica (L.) Willd. ex Del., Eupatorium sordidum Less., Jatropa gossipifolia L., Mikania micrantha Kunth, Mimosa pigra L., Opuntia sp., and Piper aduncum L. have to be watch for their aggressiveness.Â  Notes on some important invasive alien plant species are discussed.
THE QUALITY OF PHYSIC NUT(Jatropha curcas L.) SEEDS PACKED IN PLASTIC MATERIAL DURING STORAGE
Authors: Worang Rantje Lilly , Dharmaputra Okky Setyawati , Syarief Rizal , Miftahuddin
Published: February 2019

The effect of storage duration on fungal population, moisture content, lipid and free fatty acid contents, lipase activity, viability and vigor of physic nut seeds was investigated. Physic nut seeds with initial moisture content of 7.9% were stored in plastic bags under warehouse conditions. Samples of physic nut were collected before storage, and subsequently after one to six months of storage. The results showed that the moisture contents increased after one month of storage, and became relatively constant up to six months of storage. The range of moisture contents (7.9 â€“ 8.4%) was safe for storage of physic nut seeds. Sixteen fungal species were isolated from physic nut seeds during six months of storage. Fungal population decreased with the increase of storage duration. At the beginning of storage, most of the fungi that infected the seeds were classified as field fungi, such as Colletotrichum sp., Cladosporium spp., and Fusarium spp.. Their populations decreased with the increase of storage duration. After three months of storage, the existence of field fungi was generally replaced by storage fungi, such as Aspergillus spp., and Penicillium spp. dominate the population. Lipid contents, viabilities and vigors decreased with the increase of storage duration, while free fatty acids and lipase activities increased. Under uncontrolled condiÂ­tions, physic nut seeds packed in plastic material can be stored up to one month for seeds to be planted, while it can be stored up to five months for producing oil.