bluuebunny/crossref_metadata_2025 huggingface dataset:
Moving Engagement Theory Forward: My Practical Insights on Activation's Centrality to Understanding Gender Differences in Discretionary Workplace Commitment
Authors: Westover Jonathan
Published: September 2024

This article explores the concept of activation as a missing theoretical link for understanding gender differences in discretionary workplace commitment. Activation refers to an individual's readiness to take action and has been shown to influence engagement outcomes through its impact on effort and attention levels. The article first reviews key academic literature establishing engagement theory and the role of activation. It then shares real-world examples where activation helps explain observed gender differences in discretionary behaviors beyond basic job duties. Differences in situational job demands and available resources that differentially impact women's activation reserves are also examined. The article argues that conceptualizing engagement through an activation lens can help address why discrepancies occur and suggest impactful job redesign strategies. Recommendations focus on boosting activation for all employees through initiatives like flexible scheduling, social support programs, and inclusive cultures. The discussion proposes advancing engagement theory by considering the understudied yet important role of activation, particularly regarding gender.
Impact of Using Big Data Analisys in Increasing Personalization of Learning
Authors: Rahmawati Rahmawati , Nursalim Nursalim , Alfiah Agry , Hasyim Andi , Fawait Aldi Bastiatul
Published: September 2024

In today’s digital era, big data analytics has become a very relevant topic to improve learning personalisation as it can collect and analyse very large and complex data. Big data analytics can lead to a more efficient learning system by collecting and analysing huge and complex data. In education, big data analytics can be used to understand students’ learning behaviour, their needs and preferences, so that learning and learning outcomes can be improved. This research is conducted with the aim of using big data analytics to improve learning personalisation. It also aims to find out the challenges of using big data analytics to improve learning personalisation. The method used in this research is quantitative method. This method is a way of collecting numerical data that can be tested. Data is collected through the distribution of questionnaires addressed to students. Furthermore, the data that has been collected from the distribution of the questionnaire, will be accessible in Excel format which can then be processed with SPSS. From the research results, it can be seen that the big data analysis has shown that the use of more detailed and accurate data can help teachers find students’ special needs and improve learning effectiveness. As a result, teachers can create learning strategies that are better suited to students’ needs and improve their learning outcomes. From this study, we can conclude that the use of big data analytics in improving personalisation allows teachers to understand better the individual needs and preferences of students, so that more suitable learning plans can be developed and student engagement can be improved.
Cognitive Frailty in Older Adult Patients with Coronary Heart Disease During Hospitalization
Authors: Wang Min , Diva Mary Beth
Published: September 2024

Cognitive frailty, characterized by physical weakness and impaired cognitive function, has garnered increasing attention with the global aging population. The study aimed to identify independent risk factors and their implications for developing personalized intervention strategies. A quantitative descriptive design among 564 participants utilizing a survey instrument was conducted among the elderly with congestive heart disease during hospitalization. This study focused on elderly patients with coronary heart disease (CHD), investigating the interplay between age, duration of disease, and C-reactive protein as potential independent risk factors for cognitive frailty. Results showed that age emerged as a significant independent risk factor for cognitive frailty in elderly patients with coronary heart disease, with a direct correlation between age and cognitive frailty. The duration of the disease and elevated C-reactive protein levels were identified as independent risk factors, highlighting the cumulative effects of chronic conditions on cognitive function. The findings emphasized the need for a comprehensive approach to intervention. The cumulative defect model was invoked to explain how chronic conditions and associated complications contribute to cognitive frailty. Age, duration of disease, and C-reactive protein levels independently contribute to cognitive frailty. The study advocates for a holistic approach to intervention, encompassing physical, psychological, and social aspects. A cognitive frailty management model is recommended for hospitalized older adult patients with coronary heart disease to provide multidisciplinary key areas interventions, activities, assessment, and evaluation. Keywords: cognitive frailty, coronary heart disease, older adult patients, disease duration, C-reactive protein
Status Sosial Ekonomi Orang Tua, Lingkungan Belajar Terhadap Hasil Belajar Siswa
Authors: Sudirman  , Wisnawati Budi
Published: September 2024

Tujuan Penelitian ini adalah untuk mengetahui pengaruh status sosial ekonomi orang tua dan lingkungan terhadap hasil belajar siswa pada mata pelajaran IPS Terpadu di SMP Negeri 3 Dulupi Kabupaten Boalemo Provinsi Gorontalo. Metode penelitian yang digunakan adalah metode kuantitatif, dengan sampel sebanyak 83 siswa kelas VII, VIII dan kelas IX. Metode analisis yang digunakan adalah analisis regresi berganda dengan bantuan program SPSS 23. Hasil penelitian menunjukan: 1) Terdapat pengaruh positif dan signifikan Status Sosial Ekonomi Orang Tua terhadap hasil belajar siswa sebesar 25,2%. 2) Terdapat pengaruh positif dan signifikan Lingkungan terdahap hasil belajar siswa sebesar 42,4%. 3) Status Sosial Ekonomi Orang Tua dan Lingkungan berpengaruh positif dan signifikan terhadap hasil belajar siswa sebesar 46,1%. Hasil ini mengindikasi bahwa Hasil Belajar dapat dipengaruhi oleh variable Status Sosial Ekonomi Orang Tua dan Lingkungan sebesar 46,1% sedangkan sisanya 53,9% dipengaruhi faktor lain yang tidak diteliti dalam penelitian ini
The Impact of Artificial Intelligence on Academic Research
Authors: Rolnik Zachary
Published: September 2024

Artificial Intelligence (AI) has revolutionized various sectors, including academic research. This article examines the transformative effects of AI on academic research across different disciplines. We explore how AI enhances data analysis, automates repetitive tasks, enables new research methodologies, and addresses ethical considerations. By reviewing recent advancements and case studies, we provide a comprehensive overview of AI’s impact on the efficiency, scope, and quality of academic research.
Modeling and Solving the Problem of Location of Facilities in the Distribution Sector of the Supply Chain in Multi-Product and Multi-Period Mode
Authors: Taleghani Mohammad , Taleghani Ataollah
Published: September 2024

Location of facilities is an integral part of organizational strategy that can play an essential role in the strategic direction of the organization. This activity includes many factors that may be in conflict in nature, so that if the necessary checks are not carried out when choosing a location, this can affect the life of the organization in the long term. The purpose of this research is to investigate the problem of location of facilities in the supply chain distribution sector and to develop a new mathematical model for this problem. One of the important limitations of this mathematical model is the capacity limitations. Also, this issue is investigated for multi-product and multi-period distribution planning. Therefore, while defining and modeling this problem, a numerical example is also analyzed to solve the results.
Hjemlige duft- og lydmiljøer: Et interventionsstudie på aarhusianske plejehjem
Authors: Wilms Sofie Kønig , Lundgård Sissel Raahede , Dahl Mads Duevang , Udsen Anne-Sofie , Birch Amalie Rævsbæk , Højlund Susanne , Sørensen Johanne Korsdal , Højlund Marie Koldkjær
Published: September 2024

Nærværende rapport er udarbejdet i forsommeren 2023 på baggrund af kvalitative og kvantitative data indsamlet på otte plejehjem i Aarhus Kommune ifm. projektet: ”Lyd- og duftmiljøer på aarhusianske plejehjem.” Projektet udspringer af en indsats, der har eksisteret i Aarhus Kommune de sidste ti år under betegnelsen hjemliggørelse. Denne indsats fokuserer på forbedring af fysiske og sansemæssige rammer på kommunens plejehjem og folkehuse. Målsætninger er især mindskning af miljøernes institutionelle aspekter, hvilket skaber rum og plads til hjemlige kvaliteter.
Associations’ involvement in preserving and developing local communities in rural areas
Authors: Ibsen Bjarne , Iversen Evald Bundgård
Published: September 2024

How much do associations in rural districts involve themselves in the local community, and what can explain differences their involvement? The analysis of this issue is based on data from a survey in 2022 of all types of associations in four rural municipalities. The analysis, which is inspired by theories of new institutionalism, shows that most associations are involved in tasks that aim to preserve or develop local conditions and institutions, and that the associations have a positive attitude towards contributing to develop the local community. The associations’ involvement in the local community depends in particular on the number of inhabitants in the local community, what their primary goals are and their size, while the associations’ age, municipal context and public support have little significance.
Vertical interaction between village councils, citizen associations, and the municipality: the associations’ perspective
Authors: Bavnbæk Kasper Friis , Thuesen Annette Aagaard
Published: September 2024

Based on deliberative democracy theory, this article examines differences between village councils and citizen associations in terms of their interests and interaction with the municipality. Survey data shows that they are engaged with many issues that municipalities are responsible for, and that distance to the municipality’s town hall affects their engagement. Survey data also shows that local councils occupy a position closer to the municipality than citizen associations. The two types of associations are satisfied with their interaction with the municipality but based on different parameters. Regular meetings where the associations have access to direct conversations with politicians and administration and the opportunity to access municipal funds are some of the things that mean most for perceptions of positive interaction.
ERT field survey supported with numerical and analogue modeling applied to study a fragment of the Pieniny Klippen Belt (Spisz Pieniny Mountains, southern Poland)
Authors: Bania Grzegorz , Mościcki Włodzimierz Jerzy , Golonka Jan
Published: September 2024

Electrical Resistivity Tomography (ERT) method was applied to study a fragment of the Pieniny Klippen Belt (PKB), which has been investigated for more than 100 years. The study area is located in the Spisz Pieniny Mountains of southern Poland. The PKB in this region includes a characteristic belt of limestone outcrops. ERT turned out to be an effective method to determine the structure of this part of the PKB, revealing its zonal nature and documenting the presence of limestone olistoliths and allowing estimates of their sizes. Moreover, we show that proper planning and conducting of ERT measurements in the field is critical to the effective use of resistivity data for geological inference and interpretation. This has been demonstrated by performing appropriate numerical and analogue ERT modeling that shows possible ambiguous results arising from the field ERT survey. Awareness of this issue can help researchers avoid and minimize false interpretation of ERT data.
The theory of massively repeated evolution and full identifications of cancer-driving nucleotides (CDNs)
Authors: Zhang Lingjie , Deng Tong , Liufu Zhongqi , Liu Xueyu , Chen Bingjie , Hu Zheng , Liu Chenli , Tracy Miles E , Lu Xuemei , Wen Hai-Jun , Wu Chung-I
Published: September 2024

Tumorigenesis, like most complex genetic traits, is driven by the joint actions of many mutations. At the nucleotide level, such mutations are cancer-driving nucleotides (CDNs). The full sets of CDNs are necessary, and perhaps even sufficient, for the understanding and treatment of each cancer patient. Currently, only a small fraction of CDNs is known as most mutations accrued in tumors are not drivers. We now develop the theory of CDNs on the basis that cancer evolution is massively repeated in millions of individuals. Hence, any advantageous mutation should recur frequently and, conversely, any mutation that does not is either a passenger or deleterious mutation. In the TCGA cancer database (sample size n=300–1000), point mutations may recur in i out of n patients. This study explores a wide range of mutation characteristics to determine the limit of recurrences (i*) driven solely by neutral evolution. Since no neutral mutation can reach i*=3, all mutations recurring at i≥3 are CDNs. The theory shows the feasibility of identifying almost all CDNs if n increases to 100,000 for each cancer type. At present, only <10% of CDNs have been identified. When the full sets of CDNs are identified, the evolutionary mechanism of tumorigenesis in each case can be known and, importantly, gene targeted therapy will be far more effective in treatment and robust against drug resistance.
Måleegenskaper ved norsk kort- og fullversjon av Revised Children´s Anxiety and Depression Scale (RCADS)
Authors: Elvsåshagen Mari , Neumer Simon-Peter , Eidet Lise Mette , Lisøy Carina
Published: September 2024

Beskrivelse: The Revised Child Anxiety and Depression Scale (RCADS) er et spørreskjema utviklet av Bruce F. Chorpita og kollegaer. Spørreskjemaet er oversatt til norsk av Marianne A. Villabø og Hanne Kristensen. Instrumentet er tilgjengelig i en fullversjon med 47 ledd og i en kortversjon med 25 ledd. Begge versjonene kartlegger kliniske symptomer på både angst og depresjon. RCADS er tilgjengelig i barne- og foreldreversjon. RCADS er gratis tilgjengelig på rcads.ucla.edu, men bruk av testen i en tjeneste eller til forskning krever skriftlig avtale. 
Litteratursøk: Litteratursøket ga 691 treff etter dublettsjekk. Fjorten publikasjoner oppfylte kriteriene og ble inkluderte (2 norske og 12 svenske eller danske studier). Antall deltakere i studiene varierte fra 92 til 667. Barnas alder varierte fra 1 til 22 år, og fem av studiene inkluderte foreldre. Seks av studiene hadde utvalg fra den generelle populasjonen, mens to studier hadde utvalg med både en klinisk gruppe og en kontrollgruppe. Seks studier undersøkte kun kliniske populasjoner.
Psykometri: For barneversjonen var reliabilitet dokumentert i form av indre konsistens i ni studier for RCADS-47, og i to publikasjoner for RCADS-25. For foreldreversjonen av RCADS-47 rapporterte tre publikasjoner indre konsistens. Skalaene hadde tilfredsstillende til utmerket indre konsistens i alle publikasjoner. Flere publikasjoner rapporterte også funn som støttet opp om RCADS´ begrepsvaliditet. Middelverdier var rapportert i 10 publikasjoner, men vi fant ingen skandinaviske normer. Ingen publikasjoner rapporterte kriterievaliditet, test-retest reliabilitet eller mål på endringssensitivitet.
Konklusjon: Måleegenskaper for skandinaviske full- og kort barneversjoner av RCADS var gode, og samsvarte med funn fra internasjonale studier. Men klinikere bør benytte den norske versjonen med forsiktighet ettersom skandinaviske normer ikke foreligger. Kunnskapsgrunnlaget for måleegenskapene ved den norske foreldreversjonen av RCADS-47 og RCADS-25 er foreløpig mangelfullt og det er et behov for studier som undersøker disse.
Evaluating the Forensic Inferences of Oral Nicotine Ingestion: Autopsy Case Review, Animal Experimentation, and Legal Implications
Authors: Yoo Seong Ho , Lee Won Tae , Lee Jung-bin
Published: September 2024

Nicotine, a highly lipophilic alkaloid derived from Nicotiana tabacum and Nicotiana rustica, can be lethal even in small doses when ingested in concentrated forms like e-cigarette liquids. This study examined a murder case in South Korea where a 52-year-old man was allegedly killed by oral administration of nicotine. Despite the absence of typical signs, such as chemical burns or vomiting, the case posed questions about the lethal concentration of nicotine and the presence of gastrointestinal symptoms in nicotine poisoning. Through literature review, autopsy analysis, and animal experiments, this study evaluated the forensic evidence presented in court. The results indicated that lethal nicotine levels could be lower than established previously, and death could occur without gastrointestinal injury or vomiting. Our findings supported the court's conviction decision, emphasizing the variability of symptoms in nicotine toxicity and the importance of scientific evidence in legal proceedings. The results of this study highlight the role of forensic medicine in clarifying scientific uncertainties in judicial contexts, particularly in cases involving toxic substances.
Lethal Hemorrhage Following Laparoscopic Cholecystectomy Complicated with Medicolegal Issues
Authors: Park Sohyung , Choi Seung Gyu
Published: September 2024

This is a case study of unexpected death after laparoscopic cholecystectomy for acute calculous cholecystitis, complicated with medicolegal issues including chronic methamphetamine use and alleged medicolegal malpractice. The deceased underwent a laparoscopic cholecystectomy following acute calculous cholecystitis, and died on the fourth day after the surgery. Postmortem examination revealed massive peritoneal hemorrhage and the cystic artery on the surgical site was cauterized but unligated. Histopathology of the gallbladder revealed acute inflammation due to gall stones but also ischemic change. As the investigation progressed, a history of chronic methamphetamine use was discovered, however, acute methamphetamine toxicity was excluded by toxicological test. Thus, we suggest forensic considerations based on a review of the literature in the interpretation of the pathology of the gallbladder, the unligated cystic artery and cholecystectomy, and chronic methamphetamine use.
Postmortem Computed Tomography – Based Body Weight Estimation in Korean Infants Using Volume and Multiplication Factors
Authors: Heo Jin-Haeng , Jang Seon Jung , Kwon Jeong-hwa , Im Sang-Beom , Na Joo-Young , Yoon Yongsu , Ko Young San , Lee Minju , Oh Se-Min , Choi Sung Wook , Lee Sookyoung
Published: September 2024

Postmortem computed tomography (PMCT) is used in forensic medicine worldwide due to its ability to non-invasively visualize injuries, hemorrhage, and estimate volume. In the autopsy of infants, assessing nutritional conditions such as weight is crucial for identifying neglect. This study aims to evaluate the usefulness of retrospectively estimating the weight of Korean infants using PMCT-based volume and multiplication factors, even when the body has been cremated. A total of 44 cases of infant death (under 12 months) were analyzed. PMCT images were obtained before autopsy. Autopsy records and documentation provided by the police at the time of autopsy were reviewed to determine the weight (g) of the infant. PMCT-based infant volumes (mL) were estimated using a three-dimensional semi-automatic segmentation method. Multiplication factors (g/mL) were calculated by dividing the weight recorded at autopsy by the PMCT-based volume, yielding a mean of 1.047 g/mL, ranging from 1.014 g/mL to 1.085 g/mL. The mean absolute error compared to weights recorded at autopsy was 95 g. Significant discrepancies were observed between weights recorded at the scene or medical center and those measured at autopsy. This study demonstrates that PMCT-based weight estimation for Korean infants is a reliable method and has the potential for retrospectively validating incorrect weight measurements and addressing inconsistencies in recorded weight data.
Mechanical properties of cement-based composites incorporating eco-friendly aggregate of waste rubber
Authors: Alperen Bulut H. , Kandil Ufuk
Published: September 2024

The purpose of this study is to evaluate the waste tires that harm the environment as aggregate in concrete and to examine the effect on the mechanical properties of concrete. Three different classes (powder, crumb and chips) of waste rubber with seven different ratios (0%, 4%, 8%, 12%, 16%, 20% and 24%) and two different water to cement ratio (0.4 and 0.5) were used in concrete production. In this regard, this study conducted various experiments consisting of 28 and 90 days of the curing process to determine the properties of unit weight, compressive, flexural, and splitting tensile strength, along with ultrasonic pulse velocity (UPV) and dynamic modulus of elasticity. The waste rubber concrete with the highest compressive strength at the end of 90 days is the concrete that includes 4% waste rubber (0.4WR4) with 58.81 MPa. Concrete containing 8% waste rubber has the highest UPV of 5660 m/s after 90 days. The increase in the water/cement ratio from 0.4 to 0.5 and the waste rubber ratio cause deterioration in the mechanical properties of concrete. Although the use of waste rubbers does not bring an increase in strength, it is feasible to produce high strength concretes with 4% and 8% waste rubber substitution ratios. The water/cement ratio and curing time were highly effective on the mechanical properties of rubberized concrete.
Investigation of the earthquake behavior of the historical Adana great clock tower using FEM updated based on environmental vibration data
Authors: Erkek Hakan , Yetkin Musa , Calayır Yusuf
Published: September 2024

In this study, the historical Adana great clock tower's dynamic characteristics (natural frequencies and mode shapes) were determined using the operational modal analysis (OMA) method. The finite element model (FEM) of the Clock Tower was updated based on the experimentally obtained dynamic characteristics. The update process was performed manually using the material properties of the Clock Tower. Linear dynamic analyses of the structures under earthquake loadings were performed using its updated finite element model. The acceleration records of the 1998 Adana-Ceyhan earthquake, scaled according to the horizontal elastic design spectrum defined in TBEC (2018) were used for dynamic input. The displacements, maximum and minimum principal stresses of the Clock Tower were obtained and evaluated. As a result of the analyses, it was determined that there was a potential for damage to the Clock Tower due to exceeding the tensile strength of the walls, but the potential for damage to the Clock Tower due to exceeding the compressive strength of the walls is weak.
Attitudes toward Learning Mathematics and Performance of Grade 11 Students in the New Normal
Authors: Sabanal Chabelita S. , Bago Jelyan S. , Balandra Carlito B. , Miranda Aldwin T.
Published: September 2024

This study aimed to determine the relationship between students' attitudes toward learning mathematics and their mathematical performance in the New Normal at a secondary school in Davao region. Descriptive-correlational research design was used. With the stratified random sampling technique, 286 out of 1000 students were selected as respondents. Quantitative data were gathered using an adopted questionnaire and the data were analyzed using mean and Spearman correlation analysis. Results indicate that students’ confidence in learning mathematics is moderate and occasionally felt. Engagement in mathematics is frequently observed. Students place importance on mathematics and understand its purpose in their lives. The mathematics performance of the students is approaching proficiency level, indicating they require minimal guidance from teachers and assistance from peers. The students' overall attitude toward learning mathematics is high, and their mathematics performance in the New Normal is satisfactory. Among the indicators, only confidence in mathematics showed a significant correlation with mathematics performance. This finding highlights the important role of confidence in shaping students' success in mathematics during the New Normal, suggesting that interventions aimed at boosting confidence could further enhance their performance.
Effect of Cumulative Amendment of Soil with Fly Ash in Combination with Other Nutrients on Change in Grain Yield, Crude Protein, NPN and True Protein Contents of Rice
Authors: Muni Sachidananda
Published: September 2024

An experiment was planned and conducted at Instructional Farm (IF), Odisha University of Agriculture & Technology (OUAT), Bhubaneswar in the years 2022 and 2023 during the Kharif seasons to study the effect of the cumulative addition of nine varieties of nutrients on the yield and protein contents of two varieties of rice namely Gayatri and Vandana. The applied fly ash (FA) was alkaline in nature whereas the soil was acidic. The grain yield of the Kharif crop in 2022 (Gayatri) varied from the lowest of 31.56 qha-1 to the highest of 37.21 qha-1. It varied from the lowest of 38.66 qha-1 to the highest of 43.82 qha-1 in 2023. The crude protein content varied from the lowest of 7.97% to the highest of 9.16% in 2022 but it varied from the lowest of 7.31% to the highest of 8.39% in 2023. The non-protein nitrogen (NPN) content varied from the lowest of 7.97% to the highest of 9.16% in 2022 but it varied from the lowest of 7.31% to the highest of 8.39% in 2023. The true protein content varied from the lowest of 6.90% to the highest of 7.97% in 2022 but it varied from the lowest of 6.12% to the highest of 7.50% in 2023. It was observed that the grain yield, crude protein, non-protein nitrogen (NPN) and true protein content decreased by the application of FA over control (only NPK fertilizer). The crude protein content decreased in all the treatments in 2023 over its 2022 counterpart whereas NPN increased by the cumulative addition of nutrients. This resulted in higher values of true protein content in the grains in the year 2023. Grain yield increased in all the treatments in 2023 over the previous year resulting in higher yield of true protein content. Hence more amount of protein rich grains per hectare can be obtained by the cumulative addition of nutrients in spite of varietal difference of the grains.
The need for accurate long‐term measurements of water vapor in the upper troposphere and lower stratosphere with global coverage
Authors: Müller Rolf , Kunz Anne , Hurst Dale F. , Rolf Christian , Krämer Martina , Riese Martin
Published: December 2015

Water vapor is the most important greenhouse gas in the atmosphere although changes in carbon dioxide constitute the “control knob” for surface temperatures. While the latter fact is well recognized, resulting in extensive space‐borne and ground‐based measurement programs for carbon dioxide as detailed in the studies by Keeling et al. (1996), Kuze et al. (2009), and Liu et al. (2014), the need for an accurate characterization of the long‐term changes in upper tropospheric and lower stratospheric (UTLS) water vapor has not yet resulted in sufficiently extensive long‐term international measurement programs (although first steps have been taken). Here, we argue for the implementation of a long‐term balloon‐borne measurement program for UTLS water vapor covering the entire globe that will likely have to be sustained for hundreds of years.
Faulting structure above the Main Himalayan Thrust as shown by relocated aftershocks of the 2015 Mw7.8 Gorkha, Nepal, earthquake
Authors: Bai Ling , Liu Hongbing , Ritsema Jeroen , Mori James , Zhang Tianzhong , Ishikawa Yuzo , Li Guohui
Published: December 2015

The 25 April 2015, Mw7.8 Gorkha, Nepal, earthquake ruptured a shallow section of the Indian‐Eurasian plate boundary by reverse faulting with NNE‐SSW compression, consistent with the direction of current Indian‐Eurasian continental collision. The Gorkha main shock and aftershocks were recorded by permanent global and regional arrays and by a temporary local broadband array near the China‐Nepal border deployed prior to the Gorkha main shock. We relocate 272 earthquakes with Mw>3.5 by applying a multiscale double‐difference earthquake relocation technique to arrival times of direct and depth phases recorded globally and locally. We determine a well‐constrained depth of 18.5 km for the main shock hypocenter which places it on the Main Himalayan Thrust (MHT). Many of the aftershocks at shallower depths illuminate faulting structure in the hanging wall with dip angles that are steeper than the MHT. This system of thrust faults of the Lesser Himalaya may accommodate most of the elastic strain of the Himalayan orogeny.
Segmented Hellenic slab rollback driving Aegean deformation and seismicity
Authors: Sachpazi M. , Laigle M. , Charalampakis M. , Diaz J. , Kissling E. , Gesret A. , Becel A. , Flueh E. , Miles P. , Hirn A.
Published: December 2015

The NE dipping slab of the Hellenic subduction is imaged in unprecedented detail using teleseismic receiver function analysis on a dense 2‐D seismic array. Mapping of slab geometry for over 300 km along strike and down to 100 km depth reveals a segmentation into dipping panels by along‐dip faults. Resolved intermediate‐depth seismicity commonly attributed to dehydration embrittlement is shown to be clustered along these faults. Large earthquakes occurrence within the upper and lower plate and at the interplate megathrust boundary show a striking correlation with the slab faults suggesting high mechanical coupling between the two plates. Our results imply that the general slab rollback occurs here in a differential piecewise manner imposing its specific stress and deformation pattern onto the overriding Aegean plate.
The 2015 Illapel earthquake, central Chile: A type case for a characteristic earthquake?
Authors: Tilmann F. , Zhang Y. , Moreno M. , Saul J. , Eckelmann F. , Palo M. , Deng Z. , Babeyko A. , Chen K. , Baez J. C. , Schurr B. , Wang R. , Dahm T.
Published: December 2015

On 16 September 2015, the MW = 8.2 Illapel megathrust earthquake ruptured the Central Chilean margin. Combining inversions of displacement measurements and seismic waveforms with high frequency (HF) teleseismic backprojection, we derive a comprehensive description of the rupture, which also predicts deep ocean tsunami wave heights. We further determine moment tensors and obtain accurate depth estimates for the aftershock sequence. The earthquake nucleated near the coast but then propagated to the north and updip, attaining a peak slip of 5–6 m. In contrast, HF seismic radiation is mostly emitted downdip of the region of intense slip and arrests earlier than the long period rupture, indicating smooth slip along the shallow plate interface in the final phase. A superficially similar earthquake in 1943 with a similar aftershock zone had a much shorter source time function, which matches the duration of HF seismic radiation in the recent event, indicating that the 1943 event lacked the shallow slip.
Source model of the 16 September 2015 Illapel, Chile, Mw 8.4 earthquake based on teleseismic and tsunami data
Authors: Heidarzadeh Mohammad , Murotani Satoko , Satake Kenji , Ishibe Takeo , Gusman Aditya Riadi
Published: December 2015

We proposed a source model for the 16 September 2015 Illapel (Chile) tsunamigenic earthquake using teleseismic and tsunami data. The 2015 epicenter was at the northernmost of the aftershocks zone of the 2010 Mw 8.8 Maule earthquake. Teleseismic body wave inversions and tsunami simulations showed optimum rupture velocities of 1.5–2.0 km/s. The agreement between observed and synthetic waveforms was quantified using normalized root‐mean‐square (NRMS) misfit. The variations of NRMS misfits were larger for tsunami data compared to the teleseismic data, because tsunami waveforms are more sensitive to the spatial distribution of slip. The large‐slip area was 80 km (along strike) × 100 km (along dip) with an average slip of 5.0 m and depth of 12–33 km, located ~70 km to the northwest of the epicenter. We obtained a seismic moment of 4.42 × 1021 Nm equivalent to Mw 8.4. Results may indicate a northward stress transfer from the 2010 Maule earthquake.
Viscous flow rates of icy topography on the north polar layered deposits of Mars
Authors: Sori Michael M. , Byrne Shane , Hamilton Christopher W. , Landis Margaret E.
Published: December 2015

We investigate the importance of viscous flow in shaping topography at the north polar layered deposits (NPLD) of Mars by using finite element modeling to calculate the distribution of stresses and flow velocities. Present‐day impact craters on the NPLD are too small and cold for viscous relaxation to have been an important mechanism in controlling their current dimensions; this effect may be ignored when analyzing crater size‐frequency distributions. Scarps at the NPLD margins, where avalanches of dust and carbon dioxide frost occur, are sufficiently steep, high, and warm to experience significant viscous flow. We find flow velocities at the base of these steep scarps on the order of tens to hundreds of cm/yr, which are fast enough to significantly affect their slope over kiloyear timescales. Alternatively, the scarps could be close to steady state in which observed block falls provide a competing effect to viscous flow.
Survey of radiation belt energetic electron pitch angle distributions based on the Van Allen Probes MagEIS measurements
Authors: Shi Run , Summers Danny , Ni Binbin , Fennell Joseph F. , Blake J. Bernard , Spence Harlan E. , Reeves Geoffrey D.
Published: December 2015

A statistical survey of electron pitch angle distributions (PADs) is performed based on the pitch angle‐resolved flux observations from the Magnetic Electron Ion Spectrometer (MagEIS) instrument on board the Van Allen Probes during the period from 1 October 2012 to 1 May 2015. By fitting the measured PADs to a sinnα form, where α is the local pitch angle and n is the power law index, we investigate the dependence of PADs on electron kinetic energy, magnetic local time (MLT), the geomagnetic Kp index, and L shell. The difference in electron PADs between the inner and outer belt is distinct. In the outer belt, the common averaged n values are less than 1.5, except for large values of the Kp index and high electron energies. The averaged n values vary considerably with MLT, with a peak in the afternoon sector and an increase with increasing L shell. In the inner belt, the averaged n values are much larger, with a common value greater than 2. The PADs show a slight dependence on MLT, with a weak maximum at noon. A distinct region with steep PADs lies in the outer edge of the inner belt where the electron flux is relatively low. The distance between the inner and outer belt and the intensity of the geomagnetic activity together determine the variation of PADs in the inner belt. Besides being dependent on electron energy, magnetic activity, and L shell, the results show a clear dependence on MLT, with higher n values on the dayside.
Ion heating by Alfvén waves associated with dipolarization in the magnetotail: Two‐dimensional global hybrid simulation
Authors: Guo Zhifang , Wu Mingyu , Du Aimin
Published: December 2015

In this paper, ion heating by Alfvén waves associated with dipolarization in the near‐Earth magnetotail is investigated by performing a two‐dimensional (2‐D) global‐scale hybrid simulation. In our simulation, the earthward propagating plasma flow is initialized by the E × B drift near the equatorial plane due to the existence of the dawn‐dusk convection electric field. When the earthward flow reaches the strong dipole field region, it is braked by the geomagnetic field and simultaneously leads to the pileup of the magnetic flux. This continuous pileup finally results in the formation of the large‐scale dipolarization. Dipolarization first appears around (x, z) = (−10.5, 0.3)RE (where RE is the radius of Earth) and subsequently spreads tailward. In the dipolarization region, Alfvén waves are excited and cause the scattering and heating of ions. The heating is mainly on the perpendicular direction. Therefore, the ion temperature anisotropy can be formed in the dipolarization region. Our work provides one possible mechanism for the ion heating and anisotropic distributions observed near the dipolarization region.
Rising and falling diapirs, shifting depocenters, and flap overturning in the Cretaceous Sopeira and Sant Gervàs subbasins (Ribagorça Basin, southern Pyrenees)
Authors: Saura Eduard , Ardèvol i Oró Lluís , Teixell Antonio , Vergés Jaume
Published: December 2015

The halokinetic structure of inverted salt‐related continental margins is frequently obliterated by compressional overprinting. The Cretaceous Sopeira and Sant Gervàs subbasins of the Ribagorça Basin (south central Pyrenees) show evidence of salt‐related extensional tectonics and diapiric growth along the Iberian Margin of the Mesozoic Pyrenean rift. We present an integrated field‐based tectonic‐sedimentary study to reconstruct the evolution of the Ribagorça Basin system previous to, and in the early stages of, the Pyrenean orogeny. The ~4 km thick Albian‐Cenomanian Sopeira minibasin infill thins toward the basin borders, especially toward the eastern, N‐S trending, Llastarri salt weld. The 90° tilt to the south of the Sopeira basin bottom records the growth of the buried north dipping Sopeira listric fault from Albian to Santonian times, when it evolved as an extensional rollover associated with the Aulet salt roller. The ~3 km thick Cenomanian‐Campanian succession filling the Sant Gervàs flap displays 130° bed fanning attitude from overturned Cenomanian carbonate platform strata to upright Campanian turbidite beds. The Sant Gervàs flap development since Cenomanian times was related to the fall of a large salt pillow after the main Soperia minibasin stage. Jurassic‐Campanian diachronous subsidence is also observed in the adjacent Montiberri, Faiada, and Tamurcia depocenters. Correlation with the Pedraforca, Cotiella, and Basque‐Cantabrian Basins along the southern Pyrenees suggests that a significant segment of the Iberian side of the Pyrenean rift experienced a gravity‐driven extension from Albian to late Santonian. The Ribagorça Basin provides an excellent field analogue for presently buried salt‐related structures of extended passive margins.
miRNA expression profiling of Epstein–Barr virus‐associated NKTL cell lines by Illumina deep sequencing
Authors: Alles Julia , Menegatti Jennifer , Motsch Natalie , Hart Martin , Eichner Norbert , Reinhardt Richard , Meister Gunter , Grässer Friedrich A.
Published: December 2015

The aim of this work was to establish the microRNA profile of SNK6 and SNT16, two Epstein–Barr virus (EBV)‐infected cell lines derived from nasal NK/T‐cell lymphoma (NKTL). The oncogenic EBV is strongly associated with the pathogenesis of nasal and extranodal NK/T‐cell lymphoma and expresses 44 mature microRNAs and two noncoding EBV‐encoded RNAs (EBERs). miRNAs are 19‐25nt noncoding RNAs that affect host and viral gene expression post‐transcriptionally. Deregulated miRNA patterns are frequently linked to a variety of human cancers including lymphomas. miRNA profiling of the two NK/T cell lines vs. primary cells revealed 10 and 4 up‐regulated and 10 and 12 down‐regulated miRNAs in SNK6 and SNT16 cells respectively. The results were validated by qRT‐PCR for selected miRNAs. Target gene analyses confirmed cullin 5 (CUL5) and sphingosin‐1‐phosphate receptor 1 (S1PR1) as targets for the down‐regulated hsa‐miR‐148a and viral ebv‐miR‐BART16 respectively. As recently demonstrated for the regulation of IL1‐alpha by miR‐142‐3p, coexpression of the EBERs selectively exerted corepression of S1PR1 by BART16 but not of CUL5 by miR‐148a, indicating selective corepression by the EBERs.
Protein Engineering: Applications to Therapeutic Proteins and Antibodies
Authors: Popplewell Andrew G.
Published: December 2015

The development of recombinant DNA methodology and genetic engineering from the late 1970s onwards opened up a range of possibilities for making specific changes to primary protein sequences. This chapter serves as an introduction to protein engineering, briefly explaining the basic concepts and methods before exemplifying with some success stories of applications to therapeutic proteins. The examples are somewhat biased toward therapeutic antibodies, in part because of the author's own area of expertise and also because antibodies are the leading class of biological drugs. The chapter also mentions the contribution to other non‐antibody approved biologics. Fast‐acting forms include insulin lispro, engineered by point mutation of two adjacent residues of the beta chain (proline (Pro‐28) to lysine (Lys) and Lys‐29 to Pro) to de‐stabilize dimerization of the B‐subunit facilitating rapid capillary absorption of active monomer.
Therapeutic Antibodies—Protein Engineering to InfluenceADME,PK, and Efficacy
Authors: Tachibana Tatsuhiko , Haraya Kenta , Iwayanagi Yuki , Igawa Tomoyuki
Published: December 2015

This chapter focuses on protein engineering strategies to reduce nonspecific uptake. One of those strategies tries to reduce the isoelectric point (pI) of the antibody by protein engineering, which can be an effective way to reduce nonspecific cellular uptake as well as improve various pharmacokinetic properties of the antibody. The authors have developed a technology to reduce target‐mediated clearance by adding a pH‐dependent antigen binding property to the therapeutic antibody, thereby increasing its chances of being recycled. For antibodies targeting soluble antigens, conventional antibodies still face significant drawbacks even if their pharmacokinetic profile is in the acceptable range. In some cases, higher concentrations of the therapeutic antibody are needed due to this accumulation of antigen, which may require substantially higher dose levels. The authors have also developed a technology to reduce antigen accumulation by optimized pH‐dependent antigen binding and increased affinity to neonatal Fc receptor (FcRn) or Fcγ receptors (FcγRs).
Role of Lymphatic System in Subcutaneous Absorption of Therapeutic Proteins
Authors: Lin Jiunn H. , Wang Weirong
Published: December 2015

Therapeutic proteins can only be injected by parenteral routes, including intravenous (IV) and subcutaneous (SC) injection. It is highly desirable for therapeutic proteins to be self‐administered SC, than by IV injection, by patient themselves, thus providing convenience for patients, and improving the quality of life and treatment adherence. Bioavailability of protein drugs after SC administration is quite variable ranging from 20% to 95%. One possible source of the variation in the bioavailability of protein drugs is the difference in presystemic catabolism of proteins in the interstitial space and/or during the transport in lymphatic vessels after SC administration. This chapter provides an overview of current knowledge of the processes of protein absorption after SC administration. In addition, the underlying mechanisms that govern the SC absorption as well as the factors that influence the SC absorption will also be discussed.
Biodistribution of Therapeutic Biologics: Methods and Applications in Informing Target Biology, Pharmacokinetics, and Dosing Strategies
Authors: Joseph Sean B. , Prabhu Saileta , Boswell C. Andrew
Published: December 2015

This chapter first provides an overview of the biodistribution of antibodies including biological determinants and available technologies for measurement. Antibody biodistribution is governed by various molecular and physiological factors, many of which also affect systemic pharmacokinetic (PK) exposure. The chapter then discusses the molecular (e.g., antigen binding, Fc receptor binding, and physicochemical attributes) and physiological (e.g., tissue‐specific blood flow, vascular volume, and interstitial volume) properties that govern antibody biodistribution. It also presents technical considerations for
in vivo
studies (e.g., labeling techniques, time point selection, organ harvest strategies, dosing, and euthanasia techniques) and tissue analysis (e.g., gamma counting, scintillation counting, and imaging techniques). Finally, the chapter provides helpful tips for data interpretation including calculations and units, blood correction, derivation of interstitial concentrations, confirmation of receptor occupancy, explaining unexpectedly rapid clearance, and assisting in clinical dose selection.
Immunogenicity: Its Impact onADMEof Therapeutic Biologics
Authors: Kropshofer Harald , Richter Wolfgang F.
Published: December 2015

The immunogenicity of therapeutic biologics is an intensively studied feature shared by almost all biologics that have been developed. This chapter addresses essentially three aspects: which factors are key in initiating and orchestrating an anti‐drug antibody (ADA) response; the impact of ADA (both neutralizing and nonneutralizing) on the absorption, distribution, and clearance of biologics, such as monoclonal antibodies (mAbs) and other protein drugs; and how to deal with ADA responses in nonclinical and clinical studies in the establishment of a pharmacokinetic/pharmacodynamic (PK/PD) relationship. The impact of ADA on absorption, distribution, and clearance are discussed mainly based on nonclinical data. To establish a causal relationship between unexpected PK/ PD profiles and unwanted immune responses, PK/PD sampling needs to be accompanied by sampling for immunogenicity/ ADA testing and vice versa‐in both nonclinical and clinical studies.
Mechanistic Physiologically Based Pharmacokinetic Models in Development of Therapeutic Monoclonal Antibodies
Authors: Cao Yanguang , Jusko William J.
Published: December 2015

Physiologically based pharmacokinetic (PBPK) models, with integrating the structural,
in silico
, and
in vitro
physicochemical data of drugs and the physiological and anatomical features of the body, provide a realistic characterization of the systemic disposition of drugs. Therapeutic monoclonal antibodies (mAbs), as the fastest growing class of new therapeutic molecules, hold great promise for the treatment of a variety of diseases. This chapter first presents the background and history of PBPK models, and then details the principles and methods of PBPK modelling for mAbs. A number of factors should be particularly considered for antibodies in developing PBPK models: distribution space, extravasation, lymphatic distribution, and specific target binding. Then, the chapter discusses the challenges in PBPK modelling, by considering the physiological parameters, extravasation mechanisms, and FcRn function. The chapter also highlights two situations where the minimal PBPK model enacts target‐mediated drug disposition (TMDD) in either plasma or interstitial space.
Tumor Effect‐Site Pharmacokinetics: Mechanisms and Impact on Efficacy
Authors: Thurber Greg M.
Published: December 2015

Biologics, particularly monoclonal antibodies, form a rapidly growing field of cancer therapeutics. These molecules have exquisite specificity for their targets, thereby reducing off‐target effects. However, there are inherent challenges in managing the pharmacokinetics of biologics. In this chapter, focus on how mechanisms of distribution and efficacy play out at the site of action for cancer biologics: the tumor. The chapter first describes the distribution of antibodies and other macromolecules in tumors comprising the effects of tissue physiology, drug properties, and their interaction. A brief review of fluid transport in healthy and tumor tissues is followed by mechanisms that determine antibody distribution. The chapter details how this distribution ultimately impacts efficacy. It overviews cell‐killing mechanisms leading into a discussion on how particular delivery issues impact each of these strategies.