bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploiting Usage to Predict Instantaneous App Popularity
Authors: Sigg Stephan , Lagerspetz Eemil , Peltonen Ella , Nurmi Petteri , Tarkoma Sasu
Published: April 2019

Popularity of mobile apps is traditionally measured by metrics such as the number of downloads, installations, or user ratings. A problem with these measures is that they reflect usage only indirectly. Indeed, retention rates, i.e., the number of days users continue to interact with an installed app, have been suggested to predict successful app lifecycles. We conduct the first independent and large-scale study of retention rates and usage trends on a dataset of app-usage data from a community of 339,842 users and more than 213,667 apps. Our analysis shows that, on average, applications lose 65% of their users in the first week, while very popular applications (top 100) lose only 35%. It also reveals, however, that many applications have more complex usage behaviour patterns due to seasonality, marketing, or other factors. To capture such effects, we develop a novel app-usage trend measure which provides instantaneous information about the popularity of an application. Analysis of our data using this trend filter shows that roughly 40% of all apps never gain more than a handful of users (
Marginal
apps). Less than 0.1% of the remaining 60% are constantly popular (
Dominant
apps), 1% have a quick drain of usage after an initial steep rise (
Expired
apps), and 6% continuously rise in popularity (
Hot
apps). From these, we can distinguish, for instance, trendsetters from copycat apps. We conclude by demonstrating that usage behaviour trend information can be used to develop better mobile app recommendations.
Beyond Control
Authors: Jain Milan , Gupta Mridula , Singh Amarjeet , Chandan Vikas
Published: April 2019

Smart thermostats, with multiple sensory abilities, are becoming pervasive and ubiquitous, in both residential and commercial buildings. By analyzing occupants' behavior, adjusting set temperature automatically, and adapting to temporal and spatial changes in the atmosphere, smart thermostats can maximize both - energy savings and user comfort. In this paper, we study smart thermostats for refrigerant leakage detection. Retail outlets, such as milk-booths and quick service restaurants set up cold-rooms to store perishable items. In each room, a refrigeration unit (akin to air-conditioners) is used to maintain a suitable temperature for the stored products. Often, refrigerant leaks through the coils (or valves) of the refrigeration unit which slowly diminishes the cooling capacity of the refrigeration unit while allowing it to be functional. Such leaks waste significant energy, risk occupants' health, and impact the quality of stored perishable products. While store managers usually fail to sense the early symptoms of such leaks, current techniques to report refrigerant leakage are often not scalable. We propose Greina - to continuously monitor the readily available ambient information from the thermostat and timely report such leaks. We evaluate our approach on 74 outlets of a retail enterprise and results indicate that Greina can report the leakage a week in advance when compared to manual reporting.
Animo
Authors: Liu Fannie , Esparza Mario , Pavlovskaia Maria , Kaufman Geoff , Dabbish Laura , Monroy-Hernández Andrés
Published: April 2019

We present Animo, a smartwatch app that enables people to share and view each other's biosignals. We designed and engineered Animo to explore new ground for smartwatch-based biosignals social computing systems: identifying opportunities where these systems can support lightweight and mood-centric interactions. In our work we develop, explore, and evaluate several innovative features designed for dyadic communication of heart rate. We discuss the results of a two-week study (N=34), including new communication patterns participants engaged in, and outline the design landscape for communicating with biosignals on smartwatches.
Understanding Cycling Trip Purpose and Route Choice Using GPS Traces and Open Data
Authors: Nair Suraj , Javkar Kiran , Wu Jiahui , Frias-Martinez Vanessa
Published: April 2019

Many mobile applications such as Strava or Mapmyride allow cyclists to collect detailed GPS traces of their trips for health or route sharing purposes. However, cycling GPS traces also have a lot of potential from an urban planning perspective. In this paper, we focus on two important issues to characterize urban cyclist behavior: trip purpose and route choice. Cycling trip purpose has been typically analyzed using survey data. Here, we present a method to automatically infer the purpose of a cycling trip using cyclists' personal data, GPS traces and a variety of built-in and social environment features extracted from open datasets characterizing the streets cycled. We evaluate the proposed method using GPS traces from over 7, 000 cycling routes in the city of Philadelphia and report F1 scores of up to 86% when four trip purposes are considered. On the other hand, we also present a novel statistical method to identify the role that certain variables characterizing the built-in and social environment play in the selection of a specific cycling route. Our results show that cyclists in Philadelphia tend to favor routes with green areas, safety and centrality.
Clinical Data in Context
Authors: Raj Shriti , Lee Joyce M. , Garrity Ashley , Newman Mark W.
Published: April 2019

Clinical data augmented with contextual data can help patients with chronic conditions make sense of their disease. However, existing tools do not support interpretation of multiple data streams. To better understand how individuals make sense of clinical and contextual data, we interviewed patients with Type 1 diabetes and their caregivers using context-enhanced visualizations of patients' data as probes to facilitate interpretation activities. We observed that our participants performed four analytical activities when interpreting their data -- finding context-based trends and explaining them, triangulating multiple factors, suggesting context-specific actions, and hypothesizing about alternate contextual factors affecting outcomes. We also observed two challenges encountered during analysis -- the inability to identify clear trends challenged action planning and counterintuitive insights compromised trust in data. Situating our findings within the existing sensemaking frameworks, we demonstrate that sensemaking can not only inform action but can guide the discovery of information needs for exploration. We further argue that sensemaking is a valuable approach for exploring contextual data. Informed by our findings and our reflection on existing sensemaking frameworks, we provide design guidelines for sensemaking tools to improve awareness of contextual factors affecting patients and to support patients' agency in making sense of health data.
Electrochemiluminescence Imaging for Bioanalysis
Authors: Zhang Jingjing , Arbault Stéphane , Sojic Neso , Jiang Dechen
Published: April 2019

Electrochemiluminescence (ECL) is a widely used analytical technique with the advantages of high sensitivity and low background signal. The recent and rapid development of electrochemical materials, luminophores, and optical elements significantly increases the ECL signals and, thus, ECL imaging with enhanced spatial and temporal resolutions is realized. Currently, ECL imaging is successfully applied to high-throughput bioanalysis and to visualize the distribution of molecules at single cells. Compared with other optical bioassays, no optical excitation is involved in imaging, so the approach avoids a background signal from illumination and increases the detection sensitivity. This review highlights some of the most exciting developments in this field, including the mechanisms, electrode designs, and the applications of ECL imaging in bioanalysis and at single cells and particles.
Emerging Analytical Techniques for Rapid Pathogen Identification and Susceptibility Testing
Authors: Shin Dong Jin , Andini Nadya , Hsieh Kuangwen , Yang Samuel , Wang Tza-Huei
Published: April 2019

In the face of looming threats from multi-drug resistant microorganisms, there is a growing need for technologies that will enable rapid identification and drug susceptibility profiling of these pathogens in health care settings. In particular, recent progress in microfluidics and nucleic acid amplification is pushing the boundaries of timescale for diagnosing bacterial infections. With a diverse range of techniques and parallel developments in the field of analytical chemistry, an integrative perspective is needed to understand the significance of these developments. This review examines the scope of new developments in assay technologies grouped by key enabling domains of research. First, we examine recent development in nucleic acid amplification assays for rapid identification and drug susceptibility testing in bacterial infections. Next, we examine advances in microfluidics that facilitate acceleration of diagnostic assays via integration and scale. Lastly, recentdevelopments in biosensor technologies are reviewed. We conclude this review with perspectives on the use of emerging concepts to develop paradigm-changing assays.
Understanding the Role of Lipids in Signaling Through Atomistic and Multiscale Simulations of Cell Membranes
Authors: Manna Moutusi , Nieminen Tuomo , Vattulainen Ilpo
Published: April 2019

Cell signaling controls essentially all cellular processes. While it is often assumed that proteins are the key architects coordinating cell signaling, recent studies have shown more and more clearly that lipids are also involved in signaling processes in a number of ways. Lipids do, for instance, act as messengers, modulate membrane receptor conformation and dynamics, and control membrane receptor partitioning. Further, through structural modifications such as oxidation, the functions of lipids as part of signaling processes can be modified. In this context, in this article we discuss the understanding recently revealed by atomistic and coarse-grained computer simulations of nanoscale processes and underlying physicochemical principles related to lipids’ functions in cellular signaling.
The Theory and Neuroscience of Cerebellar Cognition
Authors: Schmahmann Jeremy D. , Guell Xavier , Stoodley Catherine J. , Halko Mark A.
Published: April 2019

Cerebellar neuroscience has undergone a paradigm shift. The theories of the universal cerebellar transform and dysmetria of thought and the principles of organization of cerebral cortical connections, together with neuroanatomical, brain imaging, and clinical observations, have recontextualized the cerebellum as a critical node in the distributed neural circuits subserving behavior. The framework for cerebellar cognition stems from the identification of three cognitive representations in the posterior lobe, which are interconnected with cerebral association areas and distinct from the primary and secondary cerebellar sensorimotor representations linked with the spinal cord and cerebral motor areas. Lesions of the anterior lobe primary sensorimotor representations produce dysmetria of movement, the cerebellar motor syndrome. Lesions of the posterior lobe cognitive-emotional cerebellum produce dysmetria of thought and emotion, the cerebellar cognitive affective/Schmahmann syndrome. The notion that the cerebellum modulates thought and emotion in the same way that it modulates motor control advances the understanding of the mechanisms of cognition and opens new therapeutic opportunities in behavioral neurology and neuropsychiatry.
Sexual and Romantic Relationships in Young Adulthood
Authors: Tillman Kathryn Harker , Brewster Karin L. , Holway Giuseppina Valle
Published: April 2019

Sociological research has long recognized the important role that intimate relationships play in young people's lives. In recent decades, relationship formation patterns and relationship trajectories during the early years of adulthood have become increasingly diverse and complex. In recognition of this, we review contemporary research on sexual and romantic relationships among young adults in the United States, noting how relationship attitudes, expectations, and experiences have changed in response to broader social and economic developments and how they vary by gender, socioeconomic status, race/ethnicity, and sexual identity. Data and methodological limitations are also considered. We conclude by identifying promising directions for future sociological research and data collection efforts.
Loss of the glucocorticoid receptor in zebrafish improves muscle glucose availability and increases growth
Authors: Faught Erin , Vijayan Mathilakath M.
Published: April 2019

Chronic stress and the associated elevation in corticosteroid levels increase muscle protein catabolism. We hypothesized that the glucocorticoid receptor (GR)-regulated restriction of muscle glucose availability may play a role in the increased protein catabolism during chronic stress. To test this, we generated a ubiquitous GR knockout (GRKO) zebrafish to determine the physiological consequence of glucocorticoid stimulation on muscle metabolism and growth. Adult GRKO zebrafish had higher body mass, and this corresponded to an increased protein and lipid, but not carbohydrate, content. GRKO fish were hypercortisolemic, but they elicited a higher cortisol response to an acute stressor. However, the stressor-induced increase in plasma glucose level observed in the wild type was completely abolished in the GRKO fish. Also, the muscle, but not liver, capacity for glucose uptake was enhanced in the GRKO fish, and this corresponded with a higher hexokinase activity in the mutants. Zebrafish lacking GR also showed a higher capacity for protein synthesis, including increased phosphorylation of eukaryotic initiation factor 4B, higher expression of heat shock protein cognate 70, and total protein content. A chronic fasting stressor reduced body mass and muscle protein content in adult zebrafish, but this decrease was attenuated in the GRKO compared with the wild-type fish. Metabolomics analysis revealed that the free pool of amino acid substrates used for oxidation and gluconeogenesis were lower in the fasted GRKO fish muscle compared with the wild type. Altogether, chronic stressor-mediated GR signaling limits muscle glucose uptake, and this may play a role in protein catabolism, leading to the growth suppression in fish.
Krüppel-like factor 4 plays a role in the luteal transition in steroidogenesis by downregulating Cyp19A1 expression
Authors: Choi Hyeonhae , Ryu Ki-Young , Roh Jaesook
Published: April 2019

The transition from granulosa cell (GC) to luteal cell involves a change from estrogen production to predominantly progesterone production. We analyzed the role of Krüppel-like factor 4 ( Klf4), a transcriptional repressor used to generate pluripotent cells, in that transition. After luteinizing hormone (LH)/human chorionic gonadotropin treatment of preovulatory follicles, a major but transient increase in Klf4 transcript levels was detected. Therefore, we enquired whether Klf4 is involved in the rapid decline of aromatase, the key estrogen-producing enzyme, using preovulatory GCs obtained from pregnant mare serum gonadotropin-primed immature rat ovaries. Cyp19A1 expression in GCs transfected with FLAG- Klf4 or Klf4-specific siRNA was analyzed by real-time PCR and immunofluorescence staining. Cyp19A1 decreased when Klf4 was overexpressed, and Cyp19A1 and estradiol biosynthesis increased when Klf4 was knocked down. The mechanism by which Klf4 regulates Cyp19A1 expression was investigated using Cyp19A1 promoter-luciferase reporter assays and chromatin immunoprecipitation assays. The results revealed that the steroidogenic factor-1 (SF1)-binding motif, but not the specificity protein 1 (Sp1) binding element or the CACCC motif, was required for Klf4-mediated repression of Cyp19A1 promoter activity. Here we showed that Klf4 suppressed endogenous Cyp19A1 transcript and protein production, and this resulted from direct binding of Klf4 to the SF1 recognition motif in the Cyp19A1 promoter. These findings suggest that Klf4 is a physiologic regulator of Cyp19A1 expression in response to the LH surge in preovulatory GCs and that it has an essential role in the luteal transition in steroidogenesis.
Quantifying the contribution of dietary protein to whole body protein kinetics: examination of the intrinsically labeled proteins method
Authors: Wolfe Robert R. , Park Sanghee , Kim Il-Young , Starck Carlene , Marquis Bryce J. , Ferrando Arny A. , Moughan Paul J.
Published: April 2019

Intrinsically labeled dietary proteins have been used to trace various aspects of digestion and absorption, including quantifying the contribution of dietary protein to observed postprandial amino acid and protein kinetics in human subjects. Quantification of the rate of appearance in peripheral blood of an unlabeled (tracee) amino acid originating from an intrinsically labeled protein (exogenous Ra) requires the assumption that there is no dilution of the isotope enrichment of the protein-bound amino acid in the gastrointestinal tract or across the splanchnic bed. It must also be assumed that the effective volume of distribution into which the tracer and tracee appear can be reasonably estimated by a single value and that any recycling of the tracer is minimal and thus does not affect calculated rates. We have assessed these assumptions quantitatively using values from published studies. We conclude that the use of intrinsically labeled proteins as currently described to quantify exogenous Ra systematically underestimates the true value. When used with the tracer-determined rates of amino acid kinetics, underestimation of exogenous Ra from the intrinsically labeled protein method likely translates to incorrect conclusions regarding protein breakdown, including the effect of a protein meal and the anabolic impact of the speed of digestion and absorption of amino acids. Estimation of exogenous Ra from the bioavailability of ingested protein has some advantages as compared with the intrinsically labeled protein method. We therefore conclude that the bioavailability method for estimating exogenous Ra is preferable to the intrinsically labeled protein method.
Evaluation of Fatty Acid Waste in the Synthesis of Oligo(Ether-Ester)s
Authors: Kocaman S. , Cerit A. , Soydal U. , Marti M. E. , Ahmetli G.
Published: April 2019

In this study, the waste of sunflower oil refinement was converted to a fatty acid glycidyl ester (FAGE). An unsaturated oligo(ether-ester) (OEE) was synthesized by ring-opening polymerization using propylene oxide (PO) and FAGE. Oligo(ether-ester) production was achieved with a high yield of 80% at 5 h and 0°C when the mole ratio of PO : FAGE was 1 : 1. Synthesized OEE was characterized by FTIR and several chemical analysis methods. According to the TGA results, T5, T10, and T50 values of OEE-styrene copolymers increased up to a 7 : 3 mole ratio then decreased. The weight losses of these copolymers changed in the range of 3-5%. The data of longitudinal and transversal wave velocities showed that copolymers with styrene had better elastic properties and impact resistances compared to those with pure polystyrene.
Access Time Analysis of MCPTT Off-Network Mode over LTE
Authors: Sun Yishen , Garey Wesley , Rouil Richard , Varin Priam
Published: April 2019

Public safety organizations around the world started migrating toward Long-Term Evolution (LTE) networks to support the increasing needs for video and data. To address the unique voice communication requirements of first responders, the 3rd Generation Partnership Project (3GPP) introduced new capabilities that aim at providing similar functionalities as the traditional Land Mobile Radio (LMR) systems, namely, Direct Mode communication and mission critical push-to-talk (MCPTT). Direct Mode communication, also called Proximity Services (ProSe), allows public safety users to communicate directly with each other regardless of the network status. MCPTT was the first mission critical service, and first application, standardized by 3GPP to provide both on- and off-network voice capability. Assessing the performance of those capabilities is critical to accelerate their deployment and adoption by first responders. In this study, we evaluate the performance of an off-network mode MCPTT device over ProSe by focusing on the access time, a measure of the delay incurred before a user can talk. We develop analytical models for various types of calls and verify the accuracy of the predicted access time using ns-3 simulations. We perform sensitivity analysis to show the validity of the models for various scenarios. Finally, we show how the models can be used to guide parameter configuration for both MCPTT and ProSe to optimize the performance.
Transient Dyschromatopsia, Static Form Agnosia, and Prosopagnosia Observed in a Patient with Anti-NMDA Receptor Encephalitis
Authors: Hashimoto Ritsuo , Tagawa Asako , Komori Noriyo , Ogawa Tomoko , Kato Hiroyuki
Published: April 2019

We presented a case of a 19-year-old woman who suffered from anti-N-methyl-D-aspartate (NMDA) receptor encephalitis associated with ovarian teratoma. The patient showed a variety of higher visual symptoms which changed over the recovery phase of the disease. In chronological order, she experienced cortical blindness, amblyopia, dyschromatopsia, static form agnosia, and prosopagnosia. Among these symptoms, the most intriguing was the static form agnosia. Although she could recognize the forms of moving objects, she could not make out those of stationary ones. All of these visual symptoms were transient, implying that she might have incidentally regained the function of the distinct cortical visual areas in the time course of follow-up. This case further suggests that visual functions concerned with the perceptions of static form and form-from-motion could be dissociable and may rely on distinct brain regions.
Effect of Measurement of Dew Point Temperature in Moist Air on the Absorption Line at 1392.53 nm of Water Vapor
Authors: Khelifa N.
Published: April 2019

The HITRAN database (High-Resolution Transmission molecular absorption database) is an extremely helpful reference for selecting lines of molecular species. In the case of water vapor, a particular strong absorption line around λ ≈ 1392.5 nm is suitable for the detection of molecules, not only because of its high strength but also because it is well separated from the neighboring transitions, thus avoiding any overlap. First, we present the optical system that uses a distributed feedback (DFB) laser diode, emitting around λ ≈ 1392.5 nm with a power ≈ 3 mW and linewidth ≤ 10 MHz. For metrological needs, we are looking for a means to control the water vapor concentration in ambient air in near real time and especially when an optical chilled mirror hygrometer is used. The latter instrument is widely used due to its performance with regard to both accuracy and repeatability of measurements. Here, using the molecular absorption device the use of such an instrument is examined from the point of view of its impact on the measurement of relative humidity. This paper reports the measured frequency positions of the observed line at λ = 1392.5337 nm for different air pressures and compares them with the values given in the HITRAN database. In addition, we discuss the possibility of using water vapor detection by spectroscopy to observe the change of the shape and the position of the absorption line produced during measurements of the dew point temperature by the optical chilled mirror hygrometer.
Yiqi Yangyin Huoxue Method in Treating Diabetic Retinopathy: A Systematic Review and Meta-Analysis
Authors: Ou Chen , Yang Yi Jing , Peng Qing Hua
Published: April 2019

Objective. To evaluate the efficacy of Yiqi Yangyin Huoxue method in the treatment of diabetic retinopathy (DR) with meta-analysis. Method. A randomized controlled trial of Yiqi Yangyin Huoxue method in the treatment of diabetic retinopathy in PubMed, Medline, Cochrane Library, Weipu Journal, China Knowledge Network, and Wanfang database was conducted. Two reviewers independently extracted data and methodological quality assessment. Data analysis was performed using Rev Man 5.3 software for statistical analysis. Results. A total of 10 randomized controlled trials, including 661 patients, were included. The results showed that Yiqi Yangyin Huoxue method could significantly improve the vision [risk ratio (RR)=1.32, 95% confidence interval (CI) (1.18, 1.47), P<0.00001] and change the eye fundus [RR=1.23, 95% CI (1.10, 1.37), P=0.0002], fundus fluorescence angiography (FFA) [RR=1.33, 95% CI (1.11, 1.60), P=0.002], traditional Chinese medicine syndromes [RR=1.31, 95% CI (1.15, 1.49), P<0.0001], and hemorheological parameters [mean difference (MD) =-0.37, 95% CI (-0.41, -0.32), P<0.00001]. Conclusion. Yiqi Yangyin Huoxue method showed beneficial effects for DR on improving vision, eye fundus, FFA, TCM syndromes, and hemorheological parameters.
The Effect of Leucocytosis, Gender Difference, and Ultrasound in the Diagnosis of Acute Cholecystitis in the Elderly Population
Authors: Demirkan Arda , Tanrıverdi Ayça Koca , Çetinkaya Arda , Polat Onur , Günalp Müge
Published: April 2019

Introduction. Acute cholecystitis is one of the most common reasons of acute abdominal pain for older patients to present to the emergency department (ED). Presentation may differ from that of the younger patient and is often complicated by coexistent disease due to elderliness. In this study, we aimed to evaluate the clinical presentation of acute cholecystitis, with special focus on comparision between elderly and young patients. Materials and Methods. This study included 318 patients who were admitted to the emergency department with right upper quadrant pain during a period of determined 8 months. After retrospective data collection, patients were groupped in accordance with their age, <65 and ≥65 years. Those who had ultrasonographic signs such as wall thickening and fluid collection were diagnosed as acute cholecystitis. Results. The young group (Group I) consisted of 225 patients, 132 females and 93 males. In Group I, 39 patients were diagnosed as acute cholecystitis of whom 27 were females and 15 were males. The elderly group (Group II) consisted of 93 patients 48 females and 45 males. In Group II, 36 patients were diagnosed as acute cholecystitis of whom 15 were females and 21 were males. Regarding the diagnosis of acute cholecystitis, the female to male ratio is 2.25 in Group I and 0.71 in Group II (p=0.016). The average white blood cells counts of patients with acute cholecystitis in Group I and in Group II were 9907x109/L(±4.437) and 17083x109/L(±7485), respectively (p<0,001). Conclusions. Acute cholecystitis is a common diagnosis in elderly patients with right upper quadrant pain. It is more frequent in female in the early ages, but the gender difference tends to change with age. Elderly patients demonstrate a higher level of white blood cells when compared to young patients in acute cholecystitis. Clinicians must maintain a degree of awareness in the evaluation of geriatric patients with right upper quadrant abdominal pain.
Photosynthetic Pigments with Potential for a Photosynthetic Antenna: A DFT Analysis
Authors: Monzón-Bensojo Jesús Francisco , Flores-Hidalgo Manuel A. , Barraza-Jiménez Diana
Published: April 2019

Geometrical and electronic properties of the main photosynthetic pigments in higher plants such as chlorophylls and xanthophylls were studied to find potential candidates that were able to participate in an eventual zeolite-dye artificial antenna. CRDFT (chemical reactivity density functional theory) and TD-DFT (time-dependent DFT) methods were employed in ground-state and excited-state calculations, respectively. The evaluated electronic properties at the gas phase included (a) energies such as HOMO-LUMO band gap (H-L, ranging from 2.168 to 2.504 eV), adiabatic ionization potential (I, ranging from 5.964 to 7.207 eV), and adiabatic electronic affinity (A, ranging from 2.176 to 2.741 eV); (b) global chemical reactivity indexes such as electronegativity (χ, ranging from 4.121 to 4.974 eV), hardness (η, ranging from 1.812 to 2.233 eV), electrophilicity index (ω, ranging from 4.365 to 5.541 eV), and electroaccepting-electrodonating powers (ω+, ranging from 1.671 to 2.115 eV, and ω−, ranging from 4.375 to 5.273 eV); (c) electron-hole reorganization energies (λ, ranging from 0.225 to 0.519 eV and ranging from 0.168 to 0.425 eV, respectively) and electron-hole extraction potentials (EEP, ranging from 2.570 to 2.966 eV, and HEP, ranging from 5.538 to 7.012 eV, respectively); and (d) local chemical reactivity indexes like condensed Fukui functions (fk), condensed dual descriptor (f2r), and condensed local softness (sk). These electronic properties allowed the association between molecules and reactivity-selectivity criteria, under the context of charge transfer and electronic transitions. Also, the aforementioned electronic properties were determined for combinations made with the selected molecules (β-cryptoxanthin and zeaxanthin) and 5 solvents (n-hexane, diethyl ether, acetone, ethanol, and methanol) with upward dielectric constants (ε). From frequency calculations, IR spectra were obtained for combinations. Finally, excited-state computations were carried out to acquire UV-Vis spectra of the combinations. We conclude that the selection of dyes is controlled mainly by geometrical constraints rather than by electronic properties.
Gut Microbiota-Mediated NLRP12 Expression Drives the Attenuation of Dextran Sulphate Sodium-Induced Ulcerative Colitis by Qingchang Wenzhong Decoction
Authors: Sun Zhongmei , Pei Wenjing , Guo Yi , Wang Zhibin , Shi Rui , Chen Xiaowei , Zhao Xingjie , Chen Chen , Liu Jiali , Tan Xiang , Yuan Wenjing , Mao Tangyou
Published: April 2019

Qingchang Wenzhong Decoction (QCWZD) is a newly developed, effective traditional Chinese herbal formulation for ulcerative colitis (UC). In earlier studies, we found that QCWZD could relieve the clinical symptoms of UC patients, reduce inflammation, and improve the intestinal barrier function in dextran sulphate sodium (DSS)-induced UC rats. However, the relationship between QCWZD and the gut microbiota in colitis was not clarified. In this study, we established a rat model of DSS-induced UC and then investigated the regulatory effects of QCWZD on the gut microbiota using 16S rRNA analysis. We also determined the expression of NLRP12 after QCWZD administration. Our findings suggested that QCWZD administration could modulate gut microbiota composition and selectively promote the protective strains such asButyricimonas,Blautia,andOdoribacter,whereas the enteric pathogens includingClostridiumandDoreawere significantly reduced after QCWZD treatment. It is noteworthy that QCWZD administration was identified to promote gut microbiota-mediated NLRP12 expression by inhibiting the activity of the TLR4/Blimp-1 axis. In conclusion, our study supports the potential of QCWZD administration as a beneficial therapeutic strategy for UC.
Hemap: An Interactive Online Resource for Characterizing Molecular Phenotypes across Hematologic Malignancies
Authors: Pölönen Petri , Mehtonen Juha , Lin Jake , Liuksiala Thomas , Häyrynen Sergei , Teppo Susanna , Mäkinen Artturi , Kumar Ashwini , Malani Disha , Pohjolainen Virva , Porkka Kimmo , Heckman Caroline A. , May Patrick , Hautamäki Ville , Granberg Kirsi J. , Lohi Olli , Nykter Matti , Heinäniemi Merja
Published: April 2019

Large collections of genome-wide data can facilitate the characterization of disease states and subtypes, permitting pan-cancer analysis of molecular phenotypes and evaluation of disease context for new therapeutic approaches. We analyzed 9,544 transcriptomes from more than 30 hematologic malignancies, normal blood cell types, and cell lines, and showed that disease types could be stratified in a data-driven manner. We then identified cluster-specific pathway activity, new biomarkers, and in silico drug target prioritization through interrogation of drug target databases. Using known vulnerabilities and available drug screens, we highlighted the importance of integrating molecular phenotype with drug target expression for in silico prediction of drug responsiveness. Our analysis implicated BCL2 expression level as an important indicator of venetoclax responsiveness and provided a rationale for its targeting in specific leukemia subtypes and multiple myeloma, linked several polycomb group proteins that could be targeted by small molecules (SFMBT1, CBX7, and EZH1) with chronic lymphocytic leukemia, and supported CDK6 as a disease-specific target in acute myeloid leukemia. Through integration with proteomics data, we characterized target protein expression for pre-B leukemia immunotherapy candidates, including DPEP1. These molecular data can be explored using our publicly available interactive resource, Hemap, for expediting therapeutic innovations in hematologic malignancies.

Significance:

This study describes a data resource for researching derailed cellular pathways and candidate drug targets across hematologic malignancies.
NFAT1-Mediated Regulation of NDEL1 Promotes Growth and Invasion of Glioma Stem-like Cells
Authors: Jiang Yang , Song Yifu , Wang Run , Hu Tianhao , Zhang Di , Wang Zixun , Tie Xinxin , Wang Minghao , Han Sheng
Published: April 2019

Glioma stem-like cells (GSC) promote tumor generation and progression. However, the mechanism of GSC induction or maintenance is largely unknown. We previously demonstrated that the calcium-responsive transcription factor nuclear factor of activated T cells-1 (NFAT1) is activated in glioblastomas and regulates the invasion of tumor cells. In this study, we further explored the role of NFAT1 in GSC. We found that NFAT1 expression was associated with an aggressive phenotype and predicted poor survival in gliomas. Compared with normal glioma cells, NFAT1 was upregulated in GSC. NFAT1 knockdown reduced GSC viability, invasion, and self-renewal in vitro and inhibited tumorigenesis in vivo, whereas NFAT1 overexpression enhanced the growth and invasion of GSCs. RNA sequencing showed that NFAT1 depletion was associated with reduced neurodevelopment protein 1-like 1 (NDEL1, a potential downstream target of NFAT1) expression, whereas NFAT1 overexpression induced NDEL1 expression. In addition, NFAT1 regulated the promoter activities of NDEL1, whereas rescue of NDEL1 in NFAT1-silenced GSC partially restored tumor growth and invasion. Upregulation of NFAT1–NDEL1 signaling elevated Erk activation, increased protein levels of stemness markers in GSC, and resulted in de-differentiation of normal neuronal cells and astrocytes. Our results indicate that NFAT1 controls the growth and invasion of GSC partially through regulation of NDEL1. Targeting the NFAT1–NDEL1 axis therefore might be of potential benefit in the treatment of patients with glioma.

Significance:

NFAT1 controls the growth and invasion of GSCs, partially by regulating NDEL1. Targeting the NFAT1–NDEL1 axis might provide opportunities in treating patients with glioma.
Epigenetic Regulation of NAMPT by NAMPT-ASDrives Metastatic Progression in Triple-Negative Breast Cancer
Authors: Zhang Hanwen , Zhang Ning , Liu Ying , Su Peng , Liang Yiran , Li Yaming , Wang Xiaolong , Chen Tong , Song Xiaojin , Sang Yuting , Duan Yi , Zhang Jiashu , Wang Lijuan , Chen Bing , Zhao Wenjing , Guo Haiyang , Liu Zhaojian , Hu Guohong , Yang Qifeng
Published: April 2019

Triple-negative breast cancer (TNBC) is highly heterogeneous and has a poor prognosis. It is therefore important to identify the underlying molecular mechanisms in order to develop novel therapeutic strategies. Although emerging research has revealed long noncoding RNAs (lncRNA) as vital to carcinogenesis and cancer progression, their functional involvement in TNBC has not been well defined. In this study, we utilized the The Cancer Genome Atlas (TCGA) database and analyzed clinical samples to show that the long noncoding antisense transcript of nicotinamide phosphoribosyltransferase (NAMPT), NAMPT-AS, is upregulated in TNBC and is associated with poor prognosis, lymph node involvement, metastasis, and advanced stage. NAMPT-AS was cotranscribed with NAMPT from a bidirectional promoter, where the distributions of H3K4me3 and H3K27Ac chromatin modifications were enriched based on ENCODE and FANTOM5, suggesting the potential enhancer-RNA characteristics of NAMPT-AS. NAMPT-AS epigenetically regulated the expression of NAMPT in two divergent ways: NAMPT-AS recruited POU2F2 to activate the transcription of NAMPT, and NAMPT-AS acted as a competing endogenous RNA to rescue NAMPT degradation from miR-548b-3p. NAMPT-AS/NAMPT promoted tumor progression and regulated autophagy through the mTOR pathway in vitro and in vivo. In a cohort of 480 breast cancer patients, NAMPT was associated with breast cancer–specific survival and overall survival. These results demonstrate that NAMPT-AS is an oncogenic lncRNA in TNBC that epigenetically activates NAMPT to promote tumor progression and metastasis. Furthermore, these data identify NAMPT-AS/NAMPT as promising therapeutic targets in patients with TNBC.

Significance:

Upregulation of the long noncoding antisense RNA of NAMPT gene (NAMPT-AS) is associated with metastasis and poor prognosis in TNBC.
Auranofin Protects Intestine against Radiation Injury by Modulating p53/p21 Pathway and Radiosensitizes Human Colon Tumor
Authors: Nag Dhrubajyoti , Bhanja Payel , Riha Randal , Sanchez-Guerrero Giselle , Kimler Bruce F. , Tsue Terance T. , Lominska Chris , Saha Subhrajit
Published: April 2019

Purpose:

The radiosensitivity of the normal intestinal epithelium is the major limiting factor for definitive radiotherapy against abdominal malignancies. Radiosensitizers, which can be used without augmenting radiation toxicity to normal tissue, are still an unmet need. Inhibition of proteosomal degradation is being developed as a major therapeutic strategy for anticancer therapy as cancer cells are more susceptible to proteasomal inhibition–induced cytotoxicity compared with normal cells. Auranofin, a gold-containing antirheumatoid drug, blocks proteosomal degradation by inhibiting deubiquitinase inhibitors. In this study, we have examined whether auranofin selectively radiosensitizes colon tumors without promoting radiation toxicity in normal intestine.

Experimental Design:

The effect of auranofin (10 mg/kg i.p.) on the radiation response of subcutaneous CT26 colon tumors and the normal gastrointestinal epithelium was determined using a mouse model of abdominal radiation. The effect of auranofin was also examined in a paired human colonic organoid system using malignant and nonmalignant tissues from the same patient.

Results:

Both in the mouse model of intestinal injury and in the human nonmalignant colon organoid culture, auranofin pretreatment prevented radiation toxicity and improved survival with the activation of p53/p21–mediated reversible cell-cycle arrest. However, in a mouse model of abdominal tumor and in human malignant colonic organoids, auranofin inhibited malignant tissue growth with inhibition of proteosomal degradation, induction of endoplasmic reticulum stress/unfolded protein response, and apoptosis.

Conclusions:

Our data suggest that auranofin is a potential candidate to be considered as a combination therapy with radiation to improve therapeutic efficacy against abdominal malignancies.
Combination of Trastuzumab Emtansine and Stereotactic Radiosurgery Results in High Rates of Clinically Significant Radionecrosis and Dysregulation of Aquaporin-4
Authors: Stumpf Priscilla K. , Cittelly Diana M. , Robin Tyler P. , Carlson Julie A. , Stuhr Kelly A. , Contreras-Zarate Maria Jose , Lai Steven , Ormond D. Ryan , Rusthoven Chad G. , Gaspar Laurie E. , Rabinovitch Rachel , Kavanagh Brian D. , Liu Arthur , Diamond Jennifer R. , Kabos Peter , Fisher Christine M.
Published: April 2019

Purpose:

Patients with human EGFR2-positive (HER2+) breast cancer have a high incidence of brain metastases, and trastuzumab emtansine (T-DM1) is often employed. Stereotactic radiosurgery (SRS) is frequently utilized, and case series report increased toxicity with combination SRS and T-DM1. We provide an update of our experience of T-DM1 and SRS evaluating risk of clinically significant radionecrosis (CSRN) and propose a mechanism for this toxicity.

Experimental Design:

Patients with breast cancer who were ≤45 years regardless of HER2 status or had HER2+ disease regardless of age and underwent SRS for brain metastases were included. Rates of CSRN, SRS data, and details of T-DM1 administration were recorded. Proliferation and astrocytic swelling studies were performed to elucidate mechanisms of toxicity.

Results:

A total of 45 patients were identified; 66.7% were HER2+, and 60.0% were ≤ 45 years old. Of the entire cohort, 10 patients (22.2%) developed CSRN, 9 of whom received T-DM1. CSRN was observed in 39.1% of patients who received T-DM1 versus 4.5% of patients who did not. Receipt of T-DM1 was associated with a 13.5-fold (P = 0.02) increase in CSRN. Mechanistically, T-DM1 targeted reactive astrocytes and increased radiation-induced cytotoxicity and astrocytic swelling via upregulation of Aquaporin-4 (Aqp4).

Conclusions:

The strong correlation between development of CSRN after SRS and T-DM1 warrants prospective studies controlling for variations in timing of T-DM1 and radiation dosing to further stratify risk of CSRN and mitigate toxicity. Until such studies are completed, we advise caution in the combination of SRS and T-DM1.
Targeting Glutamine Metabolism and Redox State for Leukemia Therapy
Authors: Gregory Mark A. , Nemkov Travis , Park Hae J. , Zaberezhnyy Vadym , Gehrke Sarah , Adane Biniam , Jordan Craig T. , Hansen Kirk C. , D’Alessandro Angelo , DeGregori James
Published: April 2019

Purpose:

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. These studies were directed at determining the effects of glutaminase inhibition on metabolism in AML and identifying general weaknesses that can be exploited therapeutically.

Experimental Design:

AML cancer cell lines, primary AML cells, and mouse models of AML and acute lymphoblastic leukemia (ALL) were utilized.

Results:

We show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples, and in vivo using mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating ALL cells in vitro and in vivo.

Conclusions:

Targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.
Targeting CD38 Enhances the Antileukemic Activity of Ibrutinib in Chronic Lymphocytic Leukemia
Authors: Manna Alak , Aulakh Sonikpreet , Jani Prachi , Ahmed Salman , Akhtar Sharoon , Coignet Marie , Heckman Michael , Meghji Zahara , Bhatia Kirtipal , Sharma Aarushi , Sher Taimur , Alegria Victoria , Malavasi Fabio , Chini Eduardo N. , Chanan-Khan Asher , Ailawadhi Sikander , Paulus Aneel
Published: April 2019

Purpose:

CD38 has emerged as a high-impact therapeutic target in multiple myeloma, with the approval of daratumumab (anti-CD38 mAb). The clinical importance of CD38 in patients with chronic lymphocytic leukemia (CLL) has been known for over 2 decades, although it's relevance as a therapeutic target in CLL remains understudied.

Experimental Design:

We investigated the biological effects and antitumor mechanisms engaged by daratumumab in primary CLL cells. Besides its known immune-effector mechanisms (antibody-dependent cell-mediated cytotoxicity, complement-dependent death, and antibody-dependent cellular phagocytosis), we also measured direct apoptotic effects of daratumumab alone or in combination with ibrutinib. In vivo antileukemic activity was assessed in a partially humanized xenograft model. The influence of CD38 on B-cell receptor (BCR) signaling was measured via immunoblotting of Lyn, Syk, BTK, PLCγ2, ERK1/2, and AKT.

Results:

In addition to immune-effector mechanisms; daratumumab also induced direct apoptosis of primary CLL cells, which was partially dependent on FcγR cross-linking. For the first time, we demonstrated the influence of CD38 on BCR signaling where interference of CD38 downregulated Syk, BTK, PLCγ2, ERK1/2, and AKT; effects that were further enhanced by addition of ibrutinib. In comparison to single-agent treatment, the combination of ibrutinib and daratumumab resulted in significantly enhanced anti-CLL activity in vitro and significantly decreased tumor growth and prolonged survival in the in vivo CLL xenograft model.

Conclusions:

Overall, our data demonstrate the antitumor mechanisms of daratumumab in CLL; furthermore, we show how cotargeting BTK and CD38 lead to a robust anti-CLL effect, which has clinical implications.
Radiotherapy in Periocular Cutaneous Malignancies: A Retrospective Study
Authors: Lazarevic Diana , Ramelyte Egle , Dummer Reinhard , Imhof Laurence
Published: April 2019

Background: Due to the importance of function and cosmetics, periocular skin malignancies represent a therapeutic challenge. Objective: To evaluate the safety and efficacy of radiotherapy (RT) treating periocular skin tumors. Methods: Data of patients with periocular tumors treated with grenz or soft X-rays at the University Hospital Zurich, Switzerland, between 2009 and 2014 were reviewed. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with associated in situ lesions, cutaneous melanoma, lentigo maligna (LM), cutaneous lymphoma and Kaposi’s sarcoma were included in the analysis. Results: We found 159 periocular lesions in 145 patients. Overall recurrence was highest for actinic keratosis and Bowen’s disease (27%), melanoma (17%) and LM (15%), whereas SCC and BCC showed recurrence in 11 and 10%, respectively. 45% of all recurrences occurred within 12 months after treatment, with a median time to recurrence of 13 months (range 3–73). Conclusion: RT, which provides a good therapeutic response with minimal adverse events, is a therapy option for periocular cutaneous malignancies.
Electroconvulsive Therapy and Schizophrenia: A Systematic Review
Authors: Ali Sana A. , Mathur  Nandita , Malhotra Anil K. , Braga Raphael J.
Published: April 2019

Electroconvulsive therapy (ECT) is a remarkably effective treatment for major depressive disorder, but is less commonly utilized for treatment of psychotic disorders. Recent literature indicates that ECT can be a useful strategy for a wide range of psychotic disorders, including treatment-resistant schizophrenia. The purpose of this review is to examine the extant literature on ECT in schizophrenia with a primary focus on its efficacy, its impact on cognitive function, the role of maintenance ECT, and the potential role of neuroimaging biomarkers to provide more precise ECT treatment strategies. We evaluated the available literature, with a particular focus on prospective, randomized trials. Our review suggests that ECT can be an effective treatment strategy in this severely ill patient population. Studies suggest that while ECT in schizophrenia is a safe treatment modality, the potential for cognitive impairment must always be carefully weighed. The use and investigation of new biomarker strategies for the pharmacological treatment of schizophrenia, and the extension of these approaches to ECT are also discussed.