bluuebunny/crossref_metadata_2025 huggingface dataset:
Two-Stage Structural Damage Assessment by Combining Modal Kinetic Energy Change with Symbiotic Organisms Search
Authors: Dinh-Cong D. , Nguyen-Thoi T. , Vinyas M. , Nguyen Duc T.
Published: June 2019

In the literature, modal kinetic energy (MKE) has been commonly utilized for optimal sensor placement strategies. However, there have been very few studies on its application to structural damage detection. This paper introduces a new two-stage structural damage assessment method by combining the modal kinetic energy change ratio (MKECR) and symbiotic organisms search (SOS) algorithm. In the first stage, an efficient damage indicator, named MKECR, is used to locate the potential damaged sites. Meanwhile, for the purpose of comparison with MKECR, three other indices are also used. In the second stage, an SOS-based finite element (FE) model updating strategy is adopted to estimate the damage magnitude of identified sites, while excluding false warnings (if any), where an objective function is proposed using a combination of the flexibility matrix and modal assurance criterion (MAC). The performance of the SOS algorithm is also verified by comparing with four other meta-heuristic algorithms. Finally, three numerical examples of 2D truss and frame structures with various hypothetical damage scenarios are carried out to investigate the capability of the proposed method. The numerical results indicate that the proposed method not only can accurately locate and quantify single- and multi-damage in the structures, but also shows a great saving in computational cost.
Cosmological Tests of Gravity
Authors: Ferreira Pedro G.
Published: June 2019

Cosmological observations are beginning to reach a level of precision that allows us to test some of the most fundamental assumptions in our working model of the Universe. One such assumption is that gravity is governed by the theory of general relativity. In this review, we discuss how one might go about extending general relativity and how such extensions can be described in a unified way on large scales. This allows us to describe the phenomenology of modified gravity in the growth and morphology of the large-scale structure of the Universe. On smaller scales, we explore the physics of gravitational screening and how it might manifest itself in galaxies, clusters, and, more generally, in the cosmic web. We then analyze the current constraints from large-scale structure and conclude by discussing the future prospects of the field in light of the plethora of surveys currently being planned. Key results include the following: ▪ There are a plethora of alternative theories of gravity that are restricted by fundamental physics considerations. ▪ There is now a well-established formalism for describing cosmological perturbations in the linear regime for general theories of gravity. ▪ Gravitational screening can mask modifications to general relativity on small scales but may, itself, lead to distinctive signatures in the large-scale structure of the Universe. ▪ Current constraints on both linear and nonlinear scales may be affected by systematic uncertainties that limit our ability to rule out alternatives to general relativity. ▪ The next generation of cosmological surveys will dramatically improve constraints on general relativity, by up to two orders of magnitude.
Moving Through Barriers in Science and Life
Authors: Klinman Judith P.
Published: June 2019

This first serious attempt at an autobiographical accounting has forced me to sit still long enough to compile my thoughts about a long personal and scientific journey. I especially hope that my trajectory will be of interest and perhaps beneficial to much younger women who are just getting started in their careers. To paraphrase from Virginia Woolf's writings in A Room of One's Own at the beginning of the 20th century, “for most of history Anonymous was a Woman.” However, Ms. Woolf is also quoted as saying “nothing has really happened until it has been described,” a harbinger of the enormous historical changes that were about to be enacted and recorded by women in the sciences and other disciplines. The progress in my chosen field of study—the chemical basis of enzyme action—has also been remarkable, from the first description of an enzyme's 3D structure to a growing and deep understanding of the origins of enzyme catalysis.
Eukaryotic Base Excision Repair: New Approaches Shine Light on Mechanism
Authors: Beard William A. , Horton Julie K. , Prasad Rajendra , Wilson Samuel H.
Published: June 2019

Genomic DNA is susceptible to endogenous and environmental stresses that modify DNA structure and its coding potential. Correspondingly, cells have evolved intricate DNA repair systems to deter changes to their genetic material. Base excision DNA repair involves a number of enzymes and protein cofactors that hasten repair of damaged DNA bases. Recent advances have identified macromolecular complexes that assemble at the DNA lesion and mediate repair. The repair of base lesions generally requires five enzymatic activities: glycosylase, endonuclease, lyase, polymerase, and ligase. The protein cofactors and mechanisms for coordinating the sequential enzymatic steps of repair are being revealed through a range of experimental approaches. We discuss the enzymes and protein cofactors involved in eukaryotic base excision repair, emphasizing the challenge of integrating findings from multiple methodologies. The results provide an opportunity to assimilate biochemical findings with cell-based assays to uncover new insights into this deceptively complex repair pathway.
Exosomes
Authors: Pegtel D. Michiel , Gould Stephen J.
Published: June 2019

Exosomes are small, single-membrane, secreted organelles of ∼30 to ∼200 nm in diameter that have the same topology as the cell and are enriched in selected proteins, lipids, nucleic acids, and glycoconjugates. Exosomes contain an array of membrane-associated, high-order oligomeric protein complexes, display pronounced molecular heterogeneity, and are created by budding at both plasma and endosome membranes. Exosome biogenesis is a mechanism of protein quality control, and once released, exosomes have activities as diverse as remodeling the extracellular matrix and transmitting signals and molecules to other cells. This pathway of intercellular vesicle traffic plays important roles in many aspects of human health and disease, including development, immunity, tissue homeostasis, cancer, and neurodegenerative diseases. In addition, viruses co-opt exosome biogenesis pathways both for assembling infectious particles and for establishing host permissiveness. On the basis of these and other properties, exosomes are being developed as therapeutic agents in multiple disease models.
Human Coronavirus: Host-Pathogen Interaction
Authors: Fung To Sing , Liu Ding Xiang
Published: June 2019

Human coronavirus (HCoV) infection causes respiratory diseases with mild to severe outcomes. In the last 15 years, we have witnessed the emergence of two zoonotic, highly pathogenic HCoVs: severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Replication of HCoV is regulated by a diversity of host factors and induces drastic alterations in cellular structure and physiology. Activation of critical signaling pathways during HCoV infection modulates the induction of antiviral immune response and contributes to the pathogenesis of HCoV. Recent studies have begun to reveal some fundamental aspects of the intricate HCoV-host interaction in mechanistic detail. In this review, we summarize the current knowledge of host factors co-opted and signaling pathways activated during HCoV infection, with an emphasis on HCoV-infection-induced stress response, autophagy, apoptosis, and innate immunity. The cross talk among these pathways, as well as the modulatory strategies utilized by HCoV, is also discussed.
Defense and Counterdefense During Plant-Pathogenic Oomycete Infection
Authors: Wang Yan , Tyler Brett M. , Wang Yuanchao
Published: June 2019

Plant-pathogenic oomycetes include numerous species that are ongoing threats to agriculture and natural ecosystems. Understanding the molecular dialogs between oomycetes and plants is instrumental for sustaining effective disease control. Plants respond to oomycete infection by multiple defense actions including strengthening of physical barriers, production of antimicrobial molecules, and programmed cell death. These responses are tightly controlled and integrated via a three-layered immune system consisting of a multiplex recognition layer, a resilient signal-integration layer, and a diverse defense-action layer. Adapted oomycete pathogens utilize apoplastic and intracellular effector arsenals to counter plant immunity mechanisms within each layer, including by evasion or suppression of recognition, interference with numerous signaling components, and neutralization or suppression of defense actions. A coevolutionary arms race continually drives the emergence of new mechanisms of plant defense and oomycete counterdefense.
Vascular Inflammation Risk Factors in Retinal Disease
Authors: Soto Ileana , Krebs Mark P. , Reagan Alaina M. , Howell Gareth R.
Published: June 2019

Inflammation of the blood vessels that serve the central nervous system has been increasingly identified as an early and possibly initiating event among neurodegenerative conditions such as Alzheimer's disease and related dementias. However, the causal relevance of vascular inflammation to major retinal degenerative diseases is unresolved. Here, we describe how genetics, aging-associated changes, and environmental factors contribute to vascular inflammation in age-related macular degeneration, diabetic retinopathy, and glaucoma. We highlight the importance of mouse models in studying the underlying mechanisms and possible treatments for these diseases. We conclude that data support vascular inflammation playing a central if not primary role in retinal degenerative diseases, and this association should be a focus of future research.
Methods for Assessing Quantity and Quality of Illumination
Authors: David Aurelien , Smet Kevin A.G. , Whitehead Lorne
Published: June 2019

Human vision provides useful information about the shape and color of the objects around us. It works well in many, but not all, lighting conditions. Since the advent of human-made light sources, it has been important to understand how illumination affects vision quality, but this has been surprisingly difficult. The widespread introduction of solid-state light emitters has increased the urgency of this problem. Experts still debate how lighting can best enable high-quality vision—a key issue since about one-fifth of global electrical power production is used to make light. Photometry, the measurement of the visual quantity of light, is well established, yet significant uncertainties remain. Colorimetry, the measurement of color, has achieved good reproducibility, but researchers still struggle to understand how illumination can best enable high-quality color vision. Fortunately, in recent years, considerable progress has been made. Here, we summarize the current understanding and discuss key areas for future study.
Dynamic signatures of gut microbiota and influences of delivery and feeding modes during the first 6 months of life
Authors: Yang Rong , Gao Renyuan , Cui Sainan , Zhong Hui , Zhang Xiaohui , Chen Yanjie , Wang Jing , Qin Huanlong
Published: June 2019

The gut microbiota of infants changes over time and is affected by various factors during early life. However, rarely have studies explored the gut microbiota development and affecting factors in the Chinese infant population. We enrolled 102 infants and collected stool samples from them at birth, 42 days, 3 mo, and 6 mo after delivery to characterize the microbiota signatures and the effects of different factors that modulate the gut microbiota diversity, composition, and function over time. DNA extracted from the bacteria in the stool samples was subjected to high-throughput sequencing and bioinformatics analysis. Microbial richness and diversity increased significantly during the first 6 mo of life. Beneficial microbes such as Bifidobacterium, Lactobacillus, and Blautia were found to be increased in the infant’s gut at 6 mo, while pathological bacteria such as Escherichia-Shigella, Enterobacter, Staphylococcus, and Klebsiella decreased over time. The changes in the infant delivery mode and infant-feeding mode only produced changes in the microbial composition, whereas changes in bacterial richness, diversity and effects sizes on the microbial architecture were all time dependent. A comparison of infant delivery modes conveyed a decrease in abundance of Bacteroidetes over time in the gut of infants born via C-section, while the Bifidobacterium was the most dominant genus in the vaginal delivery group. The gut microbiota of infants changed extensively during the first 6 mo of life. Delivery and feeding modes were strong factors that significantly affected microbial architecture and functions.
HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma
Authors: Faião-Flores Fernanda , Emmons Michael F. , Durante Michael A. , Kinose Fumi , Saha Biswarup , Fang Bin , Koomen John M. , Chellappan Srikumar P. , Maria-Engler Silvya Stuchi , Rix Uwe , Licht Jonathan D. , Harbour J. William , Smalley Keiran S.M.
Published: June 2019

Purpose:

The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. This study has used multiomics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance.

Experimental Design: Mass spectrometry–based proteomics and RNA-Seq were used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified, and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo models of uveal melanoma.

Results:

We identified a number of putative escape pathways that were upregulated following MEK inhibition, including the PI3K/AKT pathway, ROR1/2, and IGF-1R signaling. MEK inhibition was also associated with increased GPCR expression, particularly the endothelin B receptor, and this contributed to therapeutic escape through ET-3–mediated YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo, the MEK-HDAC inhibitor combination outperformed either agent alone, leading to a long-term decrease of tumor growth in both subcutaneous and liver metastasis models and the suppression of adaptive PI3K/AKT and YAP signaling.

Conclusions:

Together, our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in advanced uveal melanoma.
Dual Farnesyl and Geranylgeranyl Transferase Inhibitor Thwarts Mutant KRAS-Driven Patient-Derived Pancreatic Tumors
Authors: Kazi Aslamuzzaman , Xiang Shengyan , Yang Hua , Chen Liwei , Kennedy Perry , Ayaz Muhammad , Fletcher Steven , Cummings Christopher , Lawrence Harshani R. , Beato Francisca , Kang Ya'an , Kim Michael P. , Delitto Andrea , Underwood Patrick W. , Fleming Jason B. , Trevino Jose G. , Hamilton Andrew D. , Sebti Said M.
Published: June 2019

Purpose:

Mutant KRAS is a major driver of pancreatic oncogenesis and therapy resistance, yet KRAS inhibitors are lacking in the clinic. KRAS requires farnesylation for membrane localization and cancer-causing activity prompting the development of farnesyltransferase inhibitors (FTIs) as anticancer agents. However, KRAS becomes geranylgeranylated and active when cancer cells are treated with FTIs. To overcome this geranylgeranylation-dependent resistance to FTIs, we designed FGTI-2734, a RAS C-terminal mimetic dual FT and geranylgeranyltransferase-1 inhibitor (GGTI).

Experimental Design:

Immunofluorescence, cellular fractionation, and gel shift assays were used to assess RAS membrane association, Western blotting to evaluate FGTI-2734 effects on signaling, and mouse models to demonstrate its antitumor activity.

Results:

FGTI-2734, but not the selective FTI-2148 and GGTI-2418, inhibited membrane localization of KRAS in pancreatic, lung, and colon human cancer cells. FGTI-2734 induced apoptosis and inhibited the growth in mice of mutant KRAS–dependent but not mutant KRAS–independent human tumors. Importantly, FGTI-2734 inhibited the growth of xenografts derived from four patients with pancreatic cancer with mutant KRAS (2 G12D and 2 G12V) tumors. FGTI-2734 was also highly effective at inhibiting, in three-dimensional cocultures with resistance promoting pancreatic stellate cells, the viability of primary and metastatic mutant KRAS tumor cells derived from eight patients with pancreatic cancer. Finally, FGTI-2734 suppressed oncogenic pathways mediated by AKT, mTOR, and cMYC while upregulating p53 and inducing apoptosis in patient-derived xenografts in vivo.

Conclusions:

The development of this novel dual FGTI overcomes a major hurdle in KRAS resistance, thwarting growth of patient-derived mutant KRAS–driven xenografts from patients with pancreatic cancer, and as such it warrants further preclinical and clinical studies.
Cytotoxic T Cells and their Activation Status are Independent Prognostic Markers in Meningiomas
Authors: Rapp Carmen , Dettling Steffen , Liu Fang , Ull Anna Theresa , Warta Rolf , Jungk Christine , Roesch Saskia , Mock Andreas , Sahm Felix , Schmidt Melissa , Jungwirth Gerhard , Zweckberger Klaus , Lamszus Katrin , Gousias Konstaninos , Kessler Almuth F. , Grabe Niels , Loehr Mario , Ketter Ralf , Urbschat Steffi , Senft Christian , Westphal Manfred , Abdollahi Amir , Debus Juergen , von Deimling Andreas , Unterberg Andreas , Simon Matthias , Herold-Mende Christel C.
Published: June 2019

Purpose:

Clinically aggressive meningiomas (MGMs) are rare but treatment-resistant tumors in need for more effective therapies. Because tumor-infiltrating T lymphocytes (TILs) are essential for successful immunotherapy, we assessed TIL numbers and their activation status in primary (p-) and recurrent (r-) meningiomas and their impact on survival.

Experimental Design:

Presence of TILs was analyzed in 202 clinically well-annotated cases (n = 123 pMGMs and n = 79 rMGMs) focusing on higher-grade meningiomas [n = 97 World Health Organization (WHO) °II, n = 62 WHO°III]. TILs were quantified by a semiautomated analysis on whole-tissue sections stained by multicolor immunofluorescence for CD3, CD8, FOXP3, and programmed cell death protein 1 (PD-1).

Results:

Median T-cell infiltration accounted for 0.59% TILs per total cell count. Although there were no significant WHO°-dependent changes regarding helper (CD3+CD8−FOXP3−) and cytotoxic (CD3+CD8+FOXP3−) TILs in pMGMs, higher number of cytotoxic TILs were associated with an improved progression-free survival (PFS) independent of prognostic confounders. rMGMs were characterized by lower numbers of TILs in general, helper, and cytotoxic TILs. The additional analysis of their activation status revealed that a proportion of PD-1+CD8+ TILs within the TIL population was significantly decreased with higher WHO grade and in rMGMs. Furthermore, lower proportions of PD-1+CD8+ TILs were associated with inferior PFS in multivariate analyses, arguing for PD-1 as activation rather than exhaustion marker.

Conclusions:

We identified higher numbers of CD3+CD8+FOXP3− TILs and proportions of PD-1–expressing CD3+CD8+FOXP3− TILs as novel biomarkers for better survival. These findings might facilitate the selection of patients who may benefit from immunotherapy and argue in favor of an intervention in primary rather than recurrent tumors.
First-in-Class, First-in-Human Study Evaluating LV305, a Dendritic-Cell Tropic Lentiviral Vector, in Sarcoma and Other Solid Tumors Expressing NY-ESO-1
Authors: Somaiah Neeta , Block Matthew S. , Kim Joseph W. , Shapiro Geoffrey I. , Do Khanh T. , Hwu Patrick , Eder Joseph P. , Jones Robin L. , Lu Hailing , ter Meulen Jan H. , Bohac Chet , Chen Michael , Hsu Frank J. , Gnjatic Sacha , Pollack Seth M.
Published: June 2019

Purpose:

LV305 is a modified, third-generation, nonreplicating, integration-deficient lentivirus-based vector designed to selectively transduce dendritic cells in vivo. LV305 induces expression of the New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) cancer testis antigen in dendritic cells, promoting immune responses against NY-ESO-1–expressing tumors. This phase I study evaluated the safety, immunogenicity, and preliminary efficacy of LV305 in patients with sarcoma or other solid tumors.

Patients and Methods:

Adults with previously treated, advanced, NY-ESO-1–positive solid tumors and limited tumor burden were eligible. LV305 was administered every 3 weeks by intradermal injection in four dose cohorts (Cohort 1: 108 vector genomes (vg) x 3 doses; Cohorts 1A, 2, and 3: 108 vg, 109 vg, 1010 vg x 4 doses).

Results:

Thirty-nine patients were enrolled: 3 patients each in Cohorts 1, 1A, and 2, and 30 patients in Cohort 3. No dose-limiting toxicities were observed. Tumor types included sarcoma (n = 24), ovarian (n = 8), melanoma (n = 6), and lung cancer (n = 1). All treatment-related adverse events were grade 1 or 2. Common treatment-related adverse events were fatigue (49%), injection site reactions (46%), and myalgia (21%). The disease control rate was 56.4% in all patients and 62.5% in sarcoma patients. One patient with synovial sarcoma achieved a partial response lasting >36 months. Anti–NY-ESO-1-specific CD4+ and/or CD8+ T cells were induced in 57% of evaluable sarcoma patients. Induction of an anti–NY-ESO-1 immune response was associated with improved 1-year survival in an exploratory analysis.

Conclusions:

This first-in-class, first-in-human study of LV305 demonstrated a favorable safety profile, induction of antigen-specific responses, and potential clinical activity in patients with advanced cancer.
Evolutionary Routes in Metastatic Uveal Melanomas Depend on MBD4 Alterations
Authors: Rodrigues Manuel , Mobuchon Lenha , Houy Alexandre , Alsafadi Samar , Baulande Sylvain , Mariani Odette , Marande Benjamin , Ait Rais Khadija , Van der Kooij Monique K. , Kapiteijn Ellen , Gassama Sieta , Gardrat Sophie , Barnhill Raymond L. , Servois Vincent , Dendale Rémi , Putterman Marc , Tick Sarah , Piperno-Neumann Sophie , Cassoux Nathalie , Pierron Gaëlle , Waterfall Joshua J. , Roman-Roman Sergio , Mariani Pascale , Stern Marc-Henri
Published: June 2019

Purpose:

Uveal melanomas (UM) are genetically simple tumors carrying few copy number alterations (CNA) and a low mutation burden, except in rare MBD4-deficient, hypermutated cases. The genomics of uveal melanoma metastatic progression has not been described. We assessed the genetic heterogeneity of primary and metastatic MBD4-proficient and -deficient uveal melanomas.

Experimental Design: We prospectively collected 75 metastatic and 16 primary samples from 25 consecutive uveal melanoma patients, and performed whole-exome sequencing.

Results:

MBD4-proficient uveal melanomas contained stable genomes at the nucleotide level, acquiring few new single nucleotide variants (SNVs; 16 vs. 13 in metastases and primary tumors, respectively), and no new driver mutation. Five CNAs were recurrently acquired in metastases (losses of 1p, 6q, gains of 1q, 8q, and isodisomy 3). In contrast, MBD4-deficient uveal melanomas carried more than 266 SNVs per sample, with high genetic heterogeneity and TP53, SMARCA4, and GNAS new driver mutations. SNVs in MBD4-deficient contexts were exploited to unveil the timeline of oncogenic events, revealing that metastatic clones arose early after tumor onset. Surprisingly, metastases were not enriched in monosomy 3, a previously defined metastatic risk genomic feature. Monosomy 3 was associated with shorter metastatic-free interval compared with disomy 3 rather than higher rate of relapse.

Conclusions:

MBD4-proficient uveal melanomas are stable at the nucleotide level, without new actionable alterations when metastatic. In contrast, MBD4 deficiency is associated with high genetic heterogeneity and acquisition of new driver mutations. Monosomy 3 is associated with time to relapse rather than rate of relapse, thus opening avenues for a new genetic prognostic classification of uveal melanomas.
When Cancer Vaccines Go Viral
Authors: Repáraz David , Llopiz Diana , Sarobe Pablo
Published: June 2019

Induction of antitumor responses by vaccines requires strong immunogens. Heterologous viral prime/boost immunization with the BN-CV301 vaccine promotes activation of immune responses that provide a clinical benefit to patients with cancer. This viral platform may be used to harbor different antigens and prime tumor immunity potentially useful for combinatorial strategies.

See related article by Gatti-Mays et al., p. 4933
Caspase-11 Mediates Pyroptosis of Tubular Epithelial Cells and Septic Acute Kidney Injury
Authors: Ye Zhiming , Zhang Li , Li Ruizhao , Dong Wei , Liu Shuangxin , Li Zhilian , Liang Huaban , Wang Lifen , Shi Wei , Malik Asrar B. , Cheng Kwong Tai , Liang Xinling
Published: June 2019

Background/Aims: Acute kidney injury (AKI) is a serious complication of sepsis and has a high morbidity and mortality rate. Caspase-11 induces pyroptosis, a form of programmed cell death that plays a critical role in endotoxic shock, but its role in tubular epithelial cell death and whether it contributes to sepsis-associated AKI remains unknown. Methods: The caspase-11–/– mouse received an intraperitoneal injection of lipopolysaccharide (LPS, 40 mg/kg body weight). Caspase-11–/– renal tubular epithelial cells (RTECs) form C57BL caspase-11–/– mice were treated with LPS in vitro. The IL-1β ELISA kit and Scr assay kit were used to measure the level of interleukin-1β and serum creatinine. Annexin V-FITC assay and TUNEL staining assay were used to detect the cell death in different groups in vitro and in vivo. Western blot was performed to analyze the protein expression of caspase-11 and Gsdmdc1. Results: LPS-induced sepsis results in lytic death of RTECs, accompanied by increased expression of the pyroptosis-related proteins caspase-11 and Gsdmd. However, the increase in pyroptosis-related protein expression induced by LPS was attenuated with caspase-11 knockout, both in vitro and in vivo. Furthermore, when challenged with lethal doses of systemic LPS, pathologic abnormalities in renal structure, increased serum and kidney interleukin-1β, increased serum creatinine, and animal death were observed in wild-type mice but prevented in caspase-11–/– mice. Conclusions: Caspase-11-induced pyroptosis of RTECs is a key event during septic AKI, and targeting of caspase-11 in RTECs may serve as a novel therapeutic target in septic AKI.
Evaluation of Activities of Daily Living/Instrumental Activities of Daily Living to Accurately Determine Severity of Moderate and Severe Alzheimer’s Disease: Comparison of Assessments by Receiver Operating Characteristic Curve and Discriminant Analyses
Authors: Suzuki Yukiko , Teruya Koji , Mochizuki Hideki , Nagasawa Akira , Kondo Tomoko , Shimoda Nobuaki
Published: June 2019

Aim: The aim of this study was to determine Activities of Daily Living/Instrumental Activities of Daily Living (ADL/IADL) evaluations that will enable better understanding of the severity of Alzheimer’s disease (AD). Methods: AD patients were evaluated by Functional Independence Measure (FIM), Hyogo Activities of Daily Living Scale (HADLS), and Assessment of Motor and Process Skills (AMPS) to identify the assessments that will enable highly precise discrimination of AD Clinical Dementia Rating (CDR) 2 (moderate) and CDR3 (severe) using receiver operating characteristic (ROC) curve and discriminant analyses. Results: The participants were 75 AD patients (CDR2 = 50, mean age = 80.3 ± 5.9 years; CDR3 = 25, mean age = 78.3 ± 9.0 years). The evaluation methods consisted of FIM, HADLS, and AMPS. The results were divided into FIM-M, FIM-C, HADLS-ADL, HADLS-IADL, AMPS-motor skills, and AMPS-process skills. The values for the area under the curve (AUC) were compared by ROC curve and discriminant analyses. AUC values for FIM-C and AMPS-process skills were 0.956 and 0.947, respectively. With these two evaluations only, values ≥0.9 were shown. Moreover, the AUC of the discrimination score (combination of the FIM-C and AMPS-process skills) was significantly higher than those for FIM-M, FIM-C, HADLS-ADL, HADLS-IADL, and AMPS-motor skills. Conclusions: The results demonstrated that evaluation by FIM-C and AMPS-process skills methods was useful for discriminating between CDR2 (moderate) and CDR3 (severe) AD. Moreover, the results indicated that these two evaluation methods enabled more accurate determination of severity and the spared capabilities of AD patients.
A Phase 1b/2 Study of the Bruton Tyrosine Kinase Inhibitor Ibrutinib and the PD-L1 Inhibitor Durvalumab in Patients with Pretreated Solid Tumors
Authors: Hong David , Rasco Drew , Veeder Michael , Luke Jason J. , Chandler Jason , Balmanoukian Ani , George Thomas J. , Munster Pamela , Berlin Jordan D. , Gutierrez Martin , Mita Alain , Wakelee Heather , Samakoglu Selda , Guan Shanhong , Dimery Isaiah , Graef Thorsten , Borazanci Erkut
Published: June 2019

Background: Ibrutinib, a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is approved in the United States for the treatment of various B-cell malignancies. Preclinical data suggest synergistic antitumor activity of ibrutinib with programmed death-ligand 1 (PD-L1) inhibitors in solid tumors. This study evaluated ibrutinib plus durvalumab, a PD-L1-targeting antibody, in patients with relapsed/refractory solid tumors. Methods: This open-label, multicenter, phase 1b/2 study enrolled previously treated patients with stage III/IV pancreatic adenocarcinoma, breast cancer, or non-small cell lung cancer (NSCLC). Phase 1b determined the recommended phase 2 dose (RP2D). In phase 2, patients were treated at the RP2D to evaluate the safety and antitumor activity of ibrutinib plus durvalumab. Results: The RP2D was identified as ibrutinib 560 mg p.o. daily and durvalumab 10 mg/kg i.v. every 2 weeks, with 122 patients treated at the RP2D. Median age was 61 years, and the majority of patients (94%) had stage IV disease. Overall response rates (complete or partial responses) were 2% for pancreatic cancer, 3% for breast cancer, and 0% for NSCLC. Median progression-free survival was 1.7, 1.7, and 2.0 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. Median overall survival was 4.2, 4.2, and 7.9 months in the pancreatic cancer, breast cancer, and NSCLC cohorts, respectively. The safety profiles observed across tumor types were consistent with the known safety profiles for ibrutinib and durvalumab. Grade ≥3 adverse events in ≥5% of all patients were hyponatremia (10%), dyspnea (7%), maculopapular rash (7%), pneumonia (7%), anemia (6%), and diarrhea (6%). Conclusions: The combination of ibrutinib 560 mg daily and durvalumab 10 mg/kg every 2 weeks had an acceptable safety profile. The antitumor activity of the ibrutinib-durvalumab combination was limited in our study population.
Syntax-aware Semantic Role Labeling without Parsing
Authors: Cai Rui , Lapata Mirella
Published: June 2019

In this paper we focus on learning dependency aware representations for semantic role labeling without recourse to an external parser. The backbone of our model is an LSTM-based semantic role labeler jointly trained with two auxiliary tasks: predicting the dependency label of a word and whether there exists an arc linking it to the predicate. The auxiliary tasks provide syntactic information that is specific to semantic role labeling and are learned from training data (dependency annotations) without relying on existing dependency parsers, which can be noisy (e.g., on out-of-domain data or infrequent constructions). Experimental results on the CoNLL-2009 benchmark dataset show that our model outperforms the state of the art in English, and consistently improves performance in other languages, including Chinese, German, and Spanish.
Review of the caddisfly genus Tagalopsyche with the description of new species and a related new genus (Trichoptera: Leptoceridae: Mystacidini)
Authors: HOLZENTHAL RALPH W. , ANDERSEN TROND
Published: June 2019

The long-horned caddisfly genus Tagalopsyche Banks, 1913 (Leptoceridae: Mystacidini) is reviewed and 4 new species are described and illustrated: T. apratita, new species (India), T. jolandae, new species (Brunei, Malaysia), T. kjaerandseni, new species (Ghana), and T. udagama, new species (India, Sri Lanka). The 4 previously described species are redescribed and illustrated: T. aethiopica Kimmins, 1963a (Ethiopia), T. brunnea (Ulmer, 1905) (Indonesia), T. fletcheri Kimmins, 1963b (India), and T. sisyroides Banks, 1913 (Indonesia, Philippines). A related new genus, Fernandoschmidia, new genus, and 2 new species, F. amudita, new species, and F. aramaniya, new species, from India are described and illustrated. The phylogenetic position of the new genus is assessed; it is sister to a clade formed by Tagalopsyche and Mystacides Berthold, 1827, the only other genus in the Mystacidini.
Ascid mites (Acari: Mesostigmata: Ascidae) from Costa Rican hummingbirds (Aves: Trochilidae), with description of three new species and a key to the Proctolaelaps belemensis species group
Authors: DUSBABEK FRANTISEK , LITERAK IVAN , CAPEK MIROSLAV , HAVLICEK MARTIN
Published: June 2019

Eleven species of hummingbird flower mites of the genera Proctolaelaps Berlese, 1923, Tropicoseius Baker & Yunker, 1964 and Rhinoseius Baker & Yunker, 1964 were recorded from hummingbirds in Costa Rica. Three new species of the genus Proctolaelaps are described and figured, i.e. P. threnetes Dusbabek & Literak, sp. nov., P. naskreckii Dusbabek & Havlicek, sp. nov. and P. chalybura Dusbabek & Capek, sp. nov. A key for identification of females and males of the P. belemensis species group is included. Five species of the genus Tropicoseius and three species of the genus Rhinoseius are recorded, three of these species are recorded from Costa Rica for the first time.
Staphylinidae (Insecta: Coleoptera) in Latin America: synopsis, annotated catalog, diversity and distribution
Authors: ASENJO ANGÉLICO , KLIMASZEWSKI JAN , CHANDLER DONALD S. , FIERROS-LÓPEZ HUGO EDUARDO , VIEIRA JULIANA S.
Published: June 2019

The taxonomic diversity of species and genera of Staphylinidae and their distribution in Latin America are discussed and listed/tabulated based on published literature. In total, 11,675 species in 1075 genera are reported from Latin America. South America has the most recorded species for Latin America, 7773 including 7079 endemic species. The four subfamilies with the highest total number of genera including endemic genera are Aleocharinae, Staphylininae, Pselaphinae, and Paederinae. All recorded genera and their synonyms are listed alphabetically within the subfamilies of Staphylinidae, providing a catalog of published genera for Latin America. Two hundred forty-four color or black and white images of species representing different genera are provided.
Longitudinal evaluation of the Teen Outreach Programme: Impacts of a health promotion programme on risky sexual behaviours
Authors: Daley Ellen M , Marhefka Stephanie L , Wang Wei , Noble Charlotte A , Mahony Helen , Arzola Saba , Singleton Ashley , Malmi Markku , Ziemba Robert , Turner DeAnne , Marwah Elizabeth , Walsh-Buhi Eric R
Published: June 2019

Objective:

This study evaluated the longitudinal impact of the Teen Outreach Programme (TOP) on adolescent pregnancy, sexual behaviour, risky sex and sexual intentions in non-metropolitan high schools.

Design:

Pair-matched, cluster randomised controlled trial.

Setting:

Non-metropolitan public high schools in Florida, USA.

Methods:

TOP was evaluated against the standard school health curriculum content. Young people ( N = 3,836) enrolled in 26 schools were surveyed at baseline (2012), immediate post-programme (2013) and at 1-year follow-up (2014). Most youth were 14 years old and in ninth grade at baseline. Missing data were imputed using a sequential imputation procedure and analysis took place using generalised linear mixed-effects models with logit link function.

Results:

Post-programme, young people in the treatment group were less likely to report ever having sex, recent sex, recent sex without a condom or intention to have sex in the next year. At 1-year follow-up, programme participants were less likely to report ever having been pregnant or having got someone pregnant. When examining treatment effects by gender, statistically significant differences were found only for female programme participants.

Conclusion:

Although many protective factors dissipated by second follow-up and were primarily found among female programme participants, TOP has the potential to decrease risky sexual behaviour.
Automatic visual inspection system for quality control of the sandwich panel and detecting the dipping and buckling of the surfaces
Authors: Torkzadeh Vahid , Toosizadeh Saeed
Published: June 2019

In this paper, an automated inspection system is proposed for detecting the location and measuring the size of existing dipping or buckling on the sandwich panel surface using an RGB camera and an inexpensive linear laser. The proposed method, by observing the radiated laser beams on the sandwich panel surface, can localize and calculate the level of dipping and buckling with acceptable accuracy while being robust to vibrations of moving sandwich panel on the production line conveyor. After a complete processing of the panel by the system, a three-dimensional (surface plot) or two-dimensional (heat map) output is produced to assist the production line supervisor to easily inspect the surface quality of the sandwich panels. Our experimental results show that the proposed system can detect and measure the surface defects including dipping and buckling with a high accuracy and performance.
Legal recognition of same-sex partnerships: A comparative study of Hong Kong, Taiwan and Japan
Authors: Tang Denise Tse-Shang , Khor Diana , Chen Yi-Chien
Published: June 2019

Legal recognition of same-sex partnerships and marriages has been at the forefront of media attention in East Asian societies. For our comparative study, we carried out qualitative in-depth interviews with 31 gay men and lesbians to investigate the nuanced understanding of marriage, family and sexual citizenship within the context of debates on marriage equality across Hong Kong, Japan and Taiwan. Expanding on the theoretical concepts in Chen’s ‘Asia as method’, Iwabuchi’s ‘inter-Asian referencing’ and Yue and Leung’s ‘queer Asia as method’, we aim to understand how the act of marriage is defined, conducted and rationalized amidst a web of social relations within each research locale. We argue that despite the variations in the structure and practice of kin relations, same-sex unions cannot be detached from the kinship institution in the three research sites. Our study points to a different perspective on same-sex marriage that goes beyond the binary of assimilation to/dismantling of the heterosexual marriage institution by attending to the structural and symbolic significance of the family and community.
Parents’ post-traumatic growth and spirituality post-neonatal intensive care unit discharge
Authors: Brelsford Gina M. , Doheny Kim K. , Nestler Lisa
Published: June 2019

Parents of preterm infants often experience high levels of stress resulting in feelings of trauma after discharge from the neonatal intensive care unit (NICU). However, post-traumatic growth can occur after a stressful incident resulting in more favorable individual outcomes. One predictor of post-traumatic growth that has not been studied in relation to the NICU is parents’ religiousness and spirituality. This study focused on filling this gap in the literature by conducting a pilot study comprised of 25 parents’ reports on their experiences of post-traumatic growth post-NICU discharge. Specifically, we explored associations between parents’ reports on religiousness and spirituality through measures of parent–child sanctification, religious coping, and spiritual disclosure in relation to parents’ distress and their post-traumatic growth. We found that parents who sanctified their parent–child relationship experienced higher levels of post-traumatic growth even in the presence of stress. Parents who reported increased use of positive forms of religious coping and open spiritual disclosure with their spouse/partner also reported higher levels of post-traumatic growth. Results support a continued focus on family-centered NICU care during and after discharge with the caveat of also considering parents’ spiritual and religious worldviews.
Interpersonal stress in ministry: The lived experiences of female clergy cancer survivors
Authors: Moss Latoya , Snodgrass Jill L
Published: June 2019

Ministry is a unique vocation that often requires self-sacrifice to meet the needs of others. Navigating interpersonal relationships can be a difficult aspect of ministry, and this challenge is even more pronounced if the clergy is female and battling cancer. This article reports a sub-set of findings from a qualitative study that utilized interpretative phenomenological analysis to uncover the lived experiences of six female clergy cancer survivors. The findings revealed that congregants, and participants’ relationships with congregants, influenced participants’ cancer experience in three key ways. First, participants experienced stress and loneliness based on their own and others’ unrealistic expectations associated with a career in ministry. Second, participants learned to don a figurative mask and to selectively reveal and guard their emotions about cancer and cancer treatment from those they were called to serve. Third, participants’ experience of cancer and their commitment to their calling required both reliance on God and self-care. Implications for career counseling and coaching with clergy in adverse situations are offered.
Comparison of neural network and neurofuzzy identification of vehicle handling under uncertainties
Authors: Aalizadeh Bagher
Published: June 2019

In this study, two adaptive neural network and neurofuzzy identification models are proposed to identify vehicle handling under uncertainties. These models are used to identify vehicle handling in different road friction coefficients and velocities. These two identification models modify their weights to cope with uncertainties using back propagation of error as a learning algorithm. However, an adaptive model has some limitations to identify real systems. The ability of adaptation is not the same for all identification models; some models are more robust to cope with a specific uncertainty or a wider range of uncertainties. In this study, adaptiveness of two identification models are compared under two different uncertainties. First, a precise model in CARSIM software is simulated and a set of input/output data of vehicle response are collected. Then an initial three-layer neural network is trained in MATLAB software. In addition, a Neurofuzzy model is also trained in ANFIS (adaptive neurofuzzy inference system) toolbox of MATLAB software. Then this trained model is applied to the vehicle in different maneuvers, velocities and road friction coefficients. Results show that proposed neural network identifies the vehicle handling more efficiently than neurofuzzy model in conditions that are away from training condition. However, proposed neurofuzzy model is more precise and accurate than neural network in the training condition.
Impact of the InferCabulary App on Vocabulary Knowledge of Fifth-Grade Students With Disabilities
Authors: Kennedy Michael J. , Romig John Elwood , VanUitert Victoria J. , Rodgers Wendy J.
Published: June 2019

There are multiple pathways for students with and without disabilities to learn new vocabulary terms. However, the number of empirically tested and validated multimedia options is surprisingly limited. In this study, researchers tested a commercially available app (InferCabulary) to evaluate the impact on vocabulary performance of fifth-grade students with and without disabilities. A key practice that can take many forms while maintaining its core characteristics is explicit instruction. Therefore, researchers paired the functionality of the app with explicit instruction to evaluate its impact on student learning. Based on a counterbalanced design across 6 alternating weeks accessing the app or teacher-led business-as-usual instruction, students scored higher on weeks when they used the app plus explicit instruction to learn new terms. Implications for future research are included.
Constraining political extremism and legal revolution
Authors: Schupmann Benjamin A.
Published: June 2019

Recently, extremist ‘populist’ parties have succeeded in obtaining large enough democratic electoral mandates both to legally make substantive changes to the law and constitution and to legally eliminate avenues to challenge their control over the government. Extremists place committed liberal democrats in an awkward position as they work to legally revolutionize their constitutions and turn them into ‘illiberal democracies’. This article analyses political responses to this problem. It argues that the twin phenomena of legal revolution and illiberal democracy reveal a latent tension between the constitutional commitments to democracy and liberalism, that is, the equal chance to have one’s political goals enacted into law and individual basic rights. Political extremists make the latent tension real when they use the procedures of democratic legal change to abrogate constitutional commitments to liberalism, among other things. Although the two commitments normally coexist side by side, exceptional times raise an existential dilemma for liberal democracies: is it constitutional to democratically amend liberalism out of the constitution? After analysing the moral legitimacy of both the democratic and liberal arguments, this article concludes that liberal constitutionalism is constitutive of genuine democracy. In other words, it is unconstitutional to abrogate basic liberal commitments and it is legitimate to adopt constitutional mechanisms to guarantee liberalism – even if it means constraining democracy to do so. This article then situates ‘constrained democracy’ within the liberal current as a way to conceive of and respond to this pressing problem. It concludes by discussing four constitutional mechanisms – inspired by the German Grundgesetz – to guarantee liberalism: unambiguous lexically prior commitment to liberalism, limits on negative majorities, the eternity clause and party bans. It concludes that constrained democracy is an important constitutional guarantee of liberal democracy and that the four mechanisms, among others, are essential to enact constrained democracy.