bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulation of design changes impact in healthcare construction projects using system dynamics
Authors: Saad Dina A. , Gharib Farouk , El-Said Moheeb
Published: April 2020

Design changes (DC) contribute significantly to construction projects’ delays and cost overruns. Many research efforts tackled DC management, yet with less efforts in healthcare construction (HC) projects which involve multiple stakeholders including medical users and require meeting engineering and medical specifications. Therefore, a new system dynamics (SD) model that simulates HC environment, considering engineering and medical factors that can potentially trigger DCs, was developed. It simulates, as well, DCs’ ripple effect in inducing further DCs due to errors encountered while processing the DCs, and time extension that make the project vulnerable to DCs to catch up with the latest medical advancements. Using a real HC project, the proposed model is validated, and a sensitivity analysis has been conducted to identify the most sensitive factors to DCs. Thus, the new SD model is a useful tool to allow proactive DC management and sound decision-making to maintain the planned project performance.
Transversity and heavy quark production on hadron colliders
Authors: Zhang G. P.
Published: April 2020

The azimuthal asymmetry of heavy quarks production on double polarized proton–proton and proton–antiproton colliders are studied in this work at next-to-leading order in $$\alpha _s$$αs, with some details included. The purpose is to see whether the effect of extracted transversity distribution functions can be seen on present and near future colliders. All analytic one-loop hard coefficients are given. Numerical results for the asymmetry on proton–(anti)proton colliders are presented.
Strange particle effective temperatures in relativistic nuclear collisions
Authors: Ristea Oana , Ristea Catalin , Jipa Alexandru
Published: April 2020

The energy dependence of the effective temperatures of charged kaons, [Formula: see text] and [Formula: see text] produced in Au[Formula: see text]Au collisions at the Relativistic Heavy Ion Collider (RHIC) Beam Energy Scan (BES) energies are presented. At energies around [Formula: see text][Formula: see text]GeV, there is a sudden change in the energy dependence of [Formula: see text] and [Formula: see text] effective temperatures, while at higher energies a slower, continuous rise up to [Formula: see text][Formula: see text]TeV is observed. This behavior is similar with previous SPS results and could indicate the onset of deconfinement in this energy range. The [Formula: see text] effective temperatures increase with energy and no plateau-like behavior is evidenced by the data.
The nature and origins of decametre-scale porosity in Ordovician carbonate rocks, Halahatang oilfield, Tarim Basin, China
Authors: Ukar Estibalitz , Baqués Vinyet , Laubach Stephen E. , Marrett Randall
Published: April 2020

At >7 km depths in the Tarim Basin, hydrocarbon reservoirs in Ordovician rocks of the Yijianfang Formation contain large cavities (
c
. 10 m or more), vugs, fractures and porous fault rocks. Although some Yijianfang Formation outcrops contain shallow (formed near surface) palaeokarst features, cores from the Halahatang oilfield lack penetrative palaeokarst evidence. Outcrop palaeokarst cavities and opening-mode fractures are mostly mineral filled but some show evidence of secondary dissolution and fault rocks are locally highly (
c
. 30%) porous. Cores contain textural evidence of repeated formation of dissolution cavities and subsequent filling by cement. Calcite isotopic analyses indicate depths between
c
. 220 and 2000 m. Correlation of core and image logs shows abundant cement-filled vugs associated with decametre-scale fractured zones with open cavities that host hydrocarbons. A Sm–Nd isochron age of 400 ± 37 Ma for fracture-filling fluorite indicates that cavities in core formed and were partially cemented prior to the Carboniferous, predating Permian oil emplacement. Repeated creation and filling of vugs, timing constraints and the association of vugs with large cavities suggest dissolution related to fractures and faults. In the current high-strain-rate regime, corroborated by velocity gradient tensor analysis of global positioning system (GPS) data, rapid horizontal extension could promote connection of porous and/or solution-enlarged fault rock, fractures and cavities.

Supplementary material:
Stable isotopic analyses and the velocity gradient tensor and principal direction and magnitude calculation are available at
https://doi.org/10.6084/m9.figshare.c.4946046

Thematic collection:
This article is part of the The Geology of Fractured Reservoirs collection available at:
https://www.lyellcollection.org/cc/the-geology-of-fractured-reservoirs
Technologies and Health Inequities
Authors: Timmermans Stefan , Kaufman Rebecca
Published: April 2020

Health technologies aim to improve individual and population health, but they may also exacerbate health disparities. Focusing on the specific design features of technologies, their availability, and their use, we present a conceptual framework to examine how health technologies may benefit some groups more than others by combining the theory of fundamental causes with a technology-in-practice approach. We examine three classes of technologies that have been associated with health inequities: once-advanced technologies such as kidney dialysis and transplantation for end-stage renal disease, which have been plagued by issues of scarcity and fair distribution, generating racial disparities; the highly anticipated precision medicine promising to change the focus from population to individualized medicine; and digital technologies, which may herald a democratization of health care.
Enabling High Power Density Fuel Cells by Evaporative Cooling with Advanced Porous Media
Authors: Cochet M. , Forner-Cuenca A. , Manzi-Orezzoli V. , Siegwart M. , Scheuble D. , Boillat P.
Published: April 2020

Despite being a promising technology for automotive applications, polymer electrolyte fuel cells still face challenges to reduce their complexity and cost. One challenge is to achieve good humidification, which is essential for a fuel cell membrane, without expensive external humidifiers. Here we present an evaporative cooling concept that manages humidification and cooling simultaneously, and does not require any additional layer to the structure of the cell. To this aim, water flows in the fuel cell itself through a small number of the flowfields’ channels. Modified gas diffusion layers, with separate parallel hydrophilic regions, are capable of wicking the water from these supply channels and bring it in contact to the gas flow to evaporate, thus providing cooling and humidification. Our results show that this concept can provide the necessary cooling power and humidification for a cell with completely dry inlet gases at 80 °C, and has the potential for working at higher temperatures.
Hepatocyte nuclear factor-4α regulates expression of the serotonin transporter in intestinal epithelial cells
Authors: Holton Nathaniel W. , Singhal Megha , Kumar Anoop , Ticho Alexander L. , Manzella Christopher R. , Malhotra Pooja , Jarava David , Saksena Seema , Dudeja Pradeep K. , Alrefai Waddah A. , Gill Ravinder K.
Published: April 2020

The serotonin transporter (SERT) functions to regulate the availability of serotonin (5-HT) in the brain and intestine. An intestine-specific mRNA variant arising from a unique transcription start site and alternative promoter in the SERT gene has been identified (iSERT; spanning exon 1C). A decrease in SERT is implicated in several gut disorders, including inflammatory bowel diseases (IBD). However, little is known about mechanisms regulating the iSERT variant, and a clearer understanding is warranted for targeting SERT for the treatment of gut disorders. The current studies examined the expression of iSERT across different human intestinal regions and investigated its regulation by HNF4α (hepatic nuclear factor-4α), a transcription factor important for diverse cellular functions. iSERT mRNA abundance was highest in the human ileum and Caco-2 cell line. iSERT mRNA expression was downregulated by loss of HNF4α (but not HNF1α, HNF1β, or FOXA1) in Caco-2 cells. Overexpression of HNF4α increased iSERT mRNA concomitant with an increase in SERT protein. Progressive promoter deletion and site-directed mutagenesis revealed that the HNF4α response element spans nucleotides −1,163 to −1150 relative to the translation start site. SERT mRNA levels in the intestine were drastically reduced in the intestine-specific HNF4α-knockout mice relative to HNF4αFL/FL mice. Both HNF4α and SERT mRNA levels were also downregulated in mouse model of ileitis (SAMP) compared with AKR control mice. These results establish the transcriptional regulation of iSERT at the gut-specific internal promoter (hSERTp2) and have identified HNF4α as a critical modulator of basal SERT expression in the intestine.
Circadian clock genes and respiratory neuroplasticity genes oscillate in the phrenic motor system
Authors: Kelly Mia N. , Smith Danelle N. , Sunshine Michael D. , Ross Ashley , Zhang Xiping , Gumz Michelle L. , Esser Karyn A. , Mitchell Gordon S.
Published: April 2020

Circadian rhythms are endogenous and entrainable daily patterns of physiology and behavior. Molecular mechanisms underlie circadian rhythms, characterized by an ~24-h pattern of gene expression of core clock genes. Although it has long been known that breathing exhibits circadian rhythms, little is known concerning clock gene expression in any element of the neuromuscular system controlling breathing. Furthermore, we know little concerning gene expression necessary for specific respiratory functions, such as phrenic motor plasticity. Thus, we tested the hypotheses that transcripts for clock genes ( Bmal1, Clock, Per1, and Per2) and molecules necessary for phrenic motor plasticity ( Htr2a, Htr2b, Bdnf, and Ntrk2) oscillate in regions critical for phrenic/diaphragm motor function via RT-PCR. Tissues were collected from male Sprague-Dawley rats entrained to a 12-h light-dark cycle at 4 zeitgeber times (ZT; n = 8 rats/group): ZT5, ZT11, ZT17, and ZT23; ZT0 = lights on. Here, we demonstrate that 1) circadian clock genes ( Bmal1, Clock, Per1, and Per2) oscillate in regions critical for phrenic/diaphragm function, including the caudal medulla, ventral C3–C5 cervical spinal cord, and diaphragm; 2) the clock protein BMAL1 is localized within CtB-labeled phrenic motor neurons; 3) genes necessary for intermittent hypoxia-induced phrenic/diaphragm motor plasticity ( Htr2b and Bdnf) oscillate in the caudal medulla and ventral C3–C5 spinal cord; and 4) there is higher intensity of immunofluorescent BDNF protein within phrenic motor neurons at ZT23 compared with ZT11 ( n = 11 rats/group). These results suggest local circadian clocks exist in the phrenic motor system and confirm the potential for local circadian regulation of neuroplasticity and other elements of the neural network controlling breathing.
The gravitational imprint on sensorimotor planning and control
Authors: White O. , Gaveau J. , Bringoux L. , Crevecoeur F.
Published: April 2020

Humans excel at learning complex tasks, and elite performers such as musicians or athletes develop motor skills that defy biomechanical constraints. All actions require the movement of massive bodies. Of particular interest in the process of sensorimotor learning and control is the impact of gravitational forces on the body. Indeed, efficient control and accurate internal representations of the body configuration in space depend on our ability to feel and anticipate the action of gravity. Here we review studies on perception and sensorimotor control in both normal and altered gravity. Behavioral and modeling studies together suggested that the nervous system develops efficient strategies to take advantage of gravitational forces across a wide variety of tasks. However, when the body was exposed to altered gravity, the rate and amount of adaptation exhibited substantial variation from one experiment to another and sometimes led to partial adjustment only. Overall, these results support the hypothesis that the brain uses a multimodal and flexible representation of the effect of gravity on our body and movements. Future work is necessary to better characterize the nature of this internal representation and the extent to which it can adapt to novel contexts.
The Renal Physiology of Pendrin-Positive Intercalated Cells
Authors: Wall Susan M. , Verlander Jill W. , Romero Cesar A.
Published: April 2020

Intercalated cells (ICs) are found in the connecting tubule and the collecting duct. Of the three IC subtypes identified, type B intercalated cells are one of the best characterized and known to mediate Cl−absorption and HCO3−secretion, largely through the anion exchanger pendrin. This exchanger is thought to act in tandem with the Na+-dependent Cl−/HCO3−exchanger, NDCBE, to mediate net NaCl absorption. Pendrin is stimulated by angiotensin II and aldosterone administration via the angiotensin type 1a and the mineralocorticoid receptors, respectively. It is also stimulated in models of metabolic alkalosis, such as with NaHCO3administration. In some rodent models, pendrin-mediated HCO3−secretion modulates acid-base balance. However, of probably more physiological or clinical significance is the role of these pendrin-positive ICs in blood pressure regulation, which occurs, at least in part, through pendrin-mediated renal Cl−absorption, as well as their effect on the epithelial Na+channel, ENaC. Aldosterone stimulates ENaC directly through principal cell mineralocorticoid hormone receptor (ligand) binding and also indirectly through its effect on pendrin expression and function. In so doing, pendrin contributes to the aldosterone pressor response. Pendrin may also modulate blood pressure in part through its action in the adrenal medulla, where it modulates the release of catecholamines, or through an indirect effect on vascular contractile force. In addition to its role in Na+and Cl−balance, pendrin affects the balance of other ions, such as K+and I−. This review describes how aldosterone and angiotensin II-induced signaling regulate pendrin and the contribution of pendrin-positive ICs in the kidney to distal nephron function and blood pressure.
Phonetics and Ambiguity Comprehension Gated Attention Network for Humor Recognition
Authors: Fan Xiaochao , Lin Hongfei , Yang Liang , Diao Yufeng , Shen Chen , Chu Yonghe , Zhang Tongxuan
Published: April 2020

Humor refers to the quality of being amusing. With the development of artificial intelligence, humor recognition is attracting a lot of research attention. Although phonetics and ambiguity have been introduced by previous studies, existing recognition methods still lack suitable feature design for neural networks. In this paper, we illustrate that phonetics structure and ambiguity associated with confusing words need to be learned for their own representations via the neural network. Then, we propose the Phonetics and Ambiguity Comprehension Gated Attention network (PACGA) to learn phonetic structures and semantic representation for humor recognition. The PACGA model can well represent phonetic information and semantic information with ambiguous words, which is of great benefit to humor recognition. Experimental results on two public datasets demonstrate the effectiveness of our model.
Ethanol Extract of the Infructescence of Platycarya strobilacea Sieb. et Zucc. Induces Methuosis of Human Nasopharyngeal Carcinoma Cells
Authors: Liu Jinkun , Ying Min , Wu Bin , Fu Chaomei
Published: April 2020

The infructescence of Platycarya strobilacea Sieb. et Zucc. (PS) has been used in the treatment of rhinitis and sinusitis in clinical practice. Our preliminary study showed that an ethanol extract of the infructescence of PS (EPS) had significant antinasopharyngeal carcinoma (NPC) effects in vitro. However, the mechanism underlying the NPS cell death induced by EPS remains unclear. The aim of the present study was to investigate the inhibitory effects of EPS on NPC cells and to elucidate the underlying mechanism. The effects of EPS on NPC cells were investigated in CNE1 and CNE2 cells in vitro. In EPS‐treated cells, the cell morphological changes were evaluated through fluorescence microscope, transmission electron microscopy, and flow cytometry. The underlying mechanism was analyzed via network pharmacology and further verified by western blot analysis. The anticancer effects of EPS were associated with the generation of CNE1 and CNE2 cell fusion and vacuoles, the perturbation of lysosomal vesicle transportation, and the induction of methuosis. The network pharmacology and western blot results indicated that the effect of EPS in NPC cells might be achieved via regulation of the Ras proto‐oncogene (RAS)/mitogen‐activated protein kinase (MAPK) signaling pathway and the transcription factor c‐Fos proto‐oncogene (c‐FOS) and its downstream genes. EPS induces NPC cell death through methuosis. The mechanism might be related to regulation of the transcription factor c‐FOS and its downstream genes.
Periodic Attitudes of Libration Point Spacecrafts in the Earth-Moon System
Authors: Guo Qiwei , Xu Bo , Lei Hanlun
Published: April 2020

The attitude motion of a rigid spacecraft is studied in the Earth-Moon circular restricted three-body problem. Firstly, the equilibrium attitude and its stability as functions of the moments of inertia are discussed when the spacecraft is assumed at the libration points. Then, periodic attitudes of a spacecraft with mass distribution given in the stable regions are obtained. Regarding space mission applications, the Sun orientation is discussed, and the orbit-attitude resonances are constructed for spacecrafts working on the libration point orbits by means of a continuation procedure.
Characterization of Graphs with an Eigenvalue of Large Multiplicity
Authors: Qi Linming , Miao Lianying , Zhao Weiliang , Liu Lu
Published: April 2020

Let G be a simple and undirected graph. The eigenvalues of the adjacency matrix of G are called the eigenvalues of G. In this paper, we characterize all the n-vertex graphs with some eigenvalue of multiplicity n−2 and n−3, respectively. Moreover, as an application of the main result, we present a family of nonregular graphs with four distinct eigenvalues.
Chinese Herbal Medicines for Rheumatoid Arthritis: Text‐Mining the Classical Literature for Potentially Effective Natural Products
Authors: Xia Xuan , May Brian H. , Zhang Anthony Lin , Guo Xinfeng , Lu Chuanjian , Xue Charlie C. , Huang Qingchun
Published: April 2020

Background. Rheumatoid arthritis (RA) is an autoimmune disease characterized by multijoint swelling, pain, and destruction of the synovial joints. Treatments are available but new therapies are still required. One source of new therapies is natural products, including herbs used in traditional medicines. In China and neighbouring countries, natural products have been used throughout recorded history and are still in use for RA and its symptoms. This study used text‐mining of a database of classical Chinese medical books to identify candidates for future clinical and experimental investigations of therapeutics for RA. Methods. The database Encyclopaedia of Traditional Chinese Medicine (Zhong Hua Yi Dian) includes the full texts of over 1,150 classical books. Eight traditional terms were searched. All citations were assessed for relevance to RA. Results and Conclusions. After removal of duplications, 3,174 citations were considered. After applying the exclusion and inclusion criteria, 548 citations of traditional formulas were included. These derived from 138 books written from 206 CE to 1948. These formulas included 5,018 ingredients (mean, 9 ingredients/formula) comprising 243 different natural products. When these text‐mining results were compared to the 18 formulas recommended in a modern Chinese Medicine clinical practice guideline, 44% of the herbal formulas were the same. This suggests considerable continuity in the clinical application of these herbs between classical and modern Chinese medicine practice. Of the 15 herbs most frequently used as ingredients of the classical formulas, all have received research attention, and all have been reported to have anti‐inflammatory effects. Two of these 15 herbs have already been developed into new anti‐RA therapeutics—sinomenine from Sinomenium acutum (Thunb.) Rehd. & Wils and total glucosides of peony from Paeonia lactiflora Pall. Nevertheless, there remains considerable scope for further research. This text‐mining approach was effective in identifying multiple natural product candidates for future research.
Dynamical System Analysis and Optimal Control Measures of Lassa Fever Disease Model
Authors: Onah Ifeanyi Sunday , Collins Obiora Cornelius , Madueme Praise-God Uchechukwu , Mbah Godwin Christopher Ezike
Published: April 2020

Lassa fever is an animal-borne acute viral illness caused by the Lassa virus. This disease is endemic in parts of West Africa including Benin, Ghana, Guinea, Liberia, Mali, Sierra Leone, and Nigeria. We formulate a mathematical model for Lassa fever disease transmission under the assumption of a homogeneously mixed population. We highlighted the basic factors influencing the transmission of Lassa fever and also determined and analyzed the important mathematical features of the model. We extended the model by introducing various control intervention measures, like external protection, isolation, treatment, and rodent control. The extended model was analyzed and compared with the basic model by appropriate qualitative analysis and numerical simulation approach. We invoked the optimal control theory so as to determine how to reduce the spread of the disease with minimum cost.
Fault Detection of Reciprocating Compressor Valve Based on One-Dimensional Convolutional Neural Network
Authors: Guo Fu-yan , Zhang Yan-chao , Wang Yue , Wang Ping , Ren Pei-jun , Guo Rui , Wang Xin-Yi
Published: April 2020

Reciprocating compressors are important equipment in oil and gas industries which closely relate with the healthy development of the enterprise. It is essential to detect the valve fault because valve failures account for 60% in total failures. For this field, an artificial neural network (ANN) is widely used, but a complex network is not suitable for its low accuracy and easy overfitting. This paper proposes a fault diagnosis model of a reciprocating compressor valve based on a one-dimensional convolutional neural network (1DCNN). This method takes the differential pressure and differential temperature of each compressor stage as the input of 1DCNN, using the characteristics of the CNN to extract the features and finally using Softmax to classify the fault. In order to verify this method, it is compared with LM-BP, RBF, and BP neural networks. The results show that the fault recognition rate of 1DCNN reaches 100%, which proves the effectiveness and feasibility of the proposed method.
Chitosan-Based Nanoparticles for Intracellular Delivery of ISAV Fusion Protein cDNA into Melanoma Cells: A Path to Develop Oncolytic Anticancer Therapies
Authors: Robles-Planells Claudia , Sánchez-Guerrero Giselle , Barrera-Avalos Carlos , Matiacevich Silvia , Rojo Leonel E. , Pavez Jorge , Salas-Huenuleo Edison , Kogan Marcelo J. , Escobar Alejandro , Milla Luis A. , Fernandez Ricardo , Imarai Mónica , Spencer Eugenio , Huidobro-Toro Juan Pablo , Acuña-Castillo Claudio
Published: April 2020

Oncolytic virus therapy has been tested against cancer in preclinical models and clinical assays. Current evidence shows that viruses induce cytopathic effects associated with fusogenic protein-mediated syncytium formation and immunogenic cell death of eukaryotic cells. We have previously demonstrated that tumor cell bodies generated from cells expressing the fusogenic protein of the infectious salmon anemia virus (ISAV-F) enhance crosspriming and display prophylactic antitumor activity against melanoma tumors. In this work, we evaluated the effects of the expression of ISAV-F on the B16 melanoma model, both in vitro and in vivo, using chitosan nanoparticles as transfection vehicle. We confirmed that the transfection of B16 tumor cells with chitosan nanoparticles (NP-ISAV) allows the expression of a fusogenically active ISAV-F protein and decreases cell viability because of syncytium formation in vitro. However, the in vivo transfection induces a delay in tumor growth, without inducing changes on the lymphoid populations in the tumor and the spleen. Altogether, our observations show that expression of ISAV fusion protein using chitosan nanoparticles induces cell fusion in melanoma cells and slight antitumor response.
Sex Differences in Cancer Incidence and Survival: A Pan-Cancer Analysis
Authors: Dong Michelle , Cioffi Gino , Wang Jacqueline , Waite Kristin A. , Ostrom Quinn T. , Kruchko Carol , Lathia Justin D. , Rubin Joshua B. , Berens Michael E. , Connor James , Barnholtz-Sloan Jill S.
Published: April 2020

Background:

Sex plays an important role in the incidence, prognosis, and mortality of cancers, but often is not considered in disease treatment.

Methods:

We quantified sex differences in cancer incidence using the United States Cancer Statistics (USCS) public use database and sex differences in cancer survival using Surveillance, Epidemiology, and End Results (SEER) public use data from 2001 to 2016. Age-adjusted male-to-female incidence rate ratios (IRR) with 95% confidence intervals (CI) were generated by primary cancer site, race, and age groups. In addition, age-adjusted hazard ratios with 95% CI by sex within site were generated.

Results:

In general, cancer incidence and overall survival were lower in males than females, with Kaposi sarcoma (IRR: 9.751; 95% CI, 9.287–10.242; P < 0.001) having highest male-to-female incidence, and thyroid cancers (HR, 1.774; 95% CI, 1.707–1.845) having largest male-to-female survival difference. Asian or Pacific Islanders had particularly high male-to-female incidence in larynx cancers (IRR: 8.199; 95% CI, 7.203–9.363; P < 0.001), relative to other races. Among primary brain tumors, germ cell tumors had the largest male-to-female incidence (IRR: 3.03; 95% CI, 2.798–3.284, P < 0.001).

Conclusions:

Overall, incidence and survival of cancer vary significantly by sex, with males generally having lower incidence and survival compared with females. Male-to-female incidence differences were also noted across race and age groups. These results provide strong evidence that the fundamental biology of sex differences affects cancers of all types.

Impact:

This study represents the most recent and comprehensive reporting of sex differences in cancer incidence and survival in the United States. Identifying disadvantaged groups is critical as it can provide useful information to improve cancer survival, as well as to better understand the etiology and pathogenesis of specific cancers.
EZH2-Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress
Authors: León Theresa E. , Rapoz-D'Silva Tanya , Bertoli Cosetta , Rahman Sunniyat , Magnussen Michael , Philip Brian , Farah Nadine , Richardson Simon E. , Ahrabi Sara , Guerra-Assunção José Afonso , Gupta Rajeev , Nacheva Elisabeth P. , Henderson Stephen , Herrero Javier , Linch David C. , de Bruin Robertus A.M. , Mansour Marc R.
Published: April 2020

Loss-of-function mutations of EZH2, the enzymatic component of PRC2, have been associated with poor outcome and chemotherapy resistance in T-cell acute lymphoblastic leukemia (T-ALL). Using isogenic T-ALL cells, with and without CRISPR/Cas9–induced EZH2-inactivating mutations, we performed a cell-based synthetic lethal drug screen. EZH2-deficient cells exhibited increased sensitivity to structurally diverse inhibitors of CHK1, an interaction that could be validated genetically. Furthermore, small-molecule inhibition of CHK1 had efficacy in delaying tumor progression in isogenic EZH2-deficient, but not EZH2 wild-type, T-ALL cells in vivo, as well as in a primary cell model of PRC2-mutant ALL. Mechanistically, EZH2 deficiency resulted in a gene-expression signature of immature T-ALL cells, marked transcriptional upregulation of MYCN, increased replication stress, and enhanced dependency on CHK1 for cell survival. Finally, we demonstrate this phenotype is mediated through derepression of a distal PRC2-regulated MYCN enhancer. In conclusion, we highlight a novel and clinically exploitable pathway in high-risk EZH2-mutated T-ALL.

Significance:

Loss-of-function mutations of PRC2 genes are associated with chemotherapy resistance in T-ALL, yet no specific therapy for this aggressive subtype is currently clinically available. Our work demonstrates that loss of EZH2 activity leads to MYCN-driven replication stress, resulting in increased sensitivity to CHK1 inhibition, a finding with immediate clinical relevance.

This article is highlighted in the In This Issue feature, p. 890
Respiratory Syncytial Virus in Greece, 2016–2018
Authors: Tsergouli Katerina , Pappa Styliani , Haidopoulou Katerina , Gogou Maria , Giannopoulos Andreas , Papa Anna
Published: April 2020

Human respiratory syncytial virus (RSV) is the leading cause of acute bronchiolitis in infants and young children. Children under the age of 2 years, hospitalized for bronchiolitis in the pediatric clinic of a tertiary hospital in northern Greece, were tested for RSV infection during two RSV seasons (2016–2017 and 2017–2018). RSV was detected in 37 of 71 (52.1%) patients, most of them younger than 6 months. Both RSV subtypes were detected – RSV-A (54.1%) and RSV-B (45.9%) – with predominance of RSV-A during the 2016–2017 and RSV-B during the 2017–2018 season. RSV-A and RSV-B sequences clustered within the ON1 and BA genotypes, respectively. Compared to the prototype strains, several amino acid substitutions were observed in the duplication region of the G gene. The study provides a first insight into the molecular epidemiology of RSV in Greece.
Belinostat in Relapsed/Refractory T-Cell Large Granular Lymphocyte Leukemia
Authors: Poh Christina , Arora Mili , Ghuman Sudeep , Tuscano Joseph
Published: April 2020

T-cell large granular lymphocyte (LGL) leukemia is a rare indolent neoplasm primarily treated with immunosuppression. Few therapies and no consensus exist for the optimal treatment of T-cell LGL leukemia refractory to immunosuppressive therapy. Here, we report a case of relapsed/refractory T-cell LGL treated with belinostat. A 57-year-old male presented with lymphocytosis and anemia and was found to have T-cell LGL, requiring frequent packed red blood cell transfusions. He was initially treated with methotrexate with no response after 7 months. He was then switched to cyclosporine and cyclophosphamide and experienced transfusion independence for 42 months before disease relapse. He was then started on belinostat with noted subsequent transfusion independence for greater than 15 months to date and decreased disease involvement on bone marrow biopsy. To our knowledge, this is the first reported case of belinostat use in relapsed/refractory T-cell LGL leukemia which resulted in a durable clinical and biologic response.
Histone Deacetylases Take Center Stage on Regulation of Podocyte Function
Authors: Liu Min , Qiao Zhe , Zhang Yang , Zhan Ping , Yi Fan
Published: April 2020

Background: Podocytes (highly specialized and terminally differentiated epithelial cells) are integral components of the glomerular filtration barrier that are vulnerable to a variety of injuries and, as a result, they undergo a series of changes ranging from hypertrophy to detachment and apoptosis. Podocyte injury is a major determinant in proteinuric kidney disease and identification of potential therapeutic targets for preventing podocyte injury has clinical importance. Although numerous studies have achieved dramatic advances in the understanding of podocyte biology and its relevance to renal injury, few effective and specific therapies are available. Summary: Epigenetic modifications have been proven to play important roles in the pathogenesis of kidney diseases. Among them, histone deacetylase (HDAC)-mediated epigenetic acetylation in the kidney has attracted much attention, which may play multiple roles in both kidney development and the pathogenesis of kidney disease. Recent studies have demonstrated that HDAC protect against podocyte injury by regulation of inflammation, apoptosis, autophagy, mitochondrial function, and insulin resistance. In this review, we summarize recent advances in the understanding of the functions and regulatory mechanisms of HDAC in podocytes and associated proteinuric kidney diseases. In addition, we provide evidence of the potential therapeutic effects of HDAC inhibitors for proteinuric kidney disease. Key Messages: Pharmacological targeting of HDAC-mediated epigenetic processes may open new therapeutic avenues for chronic kidney disease.
No lugar dos pastores
Authors: Oliveira Fábio José Santos de
Published: April 2020

Poucos sabem que o escritor Ariano Suassuna (1927-2014) era também artista plástico, tendo, inclusive, ilustrado algumas de suas próprias obras e produzido gravuras divulgadas e/ou vendidas esparsamente. Este ensaio tem o objetivo, justamente, de analisar algumas dessas gravuras de Suassuna, principalmente uma intitulada “O presépio e nós – Poema de Natal”, que o escritor produziu seguindo os moldes do que ele mesmo nomeava como iluminogravura. Ainda que sejam produções curtas, essas obras ilustram bem as fontes envolvidas no processo criativo de Ariano Suassuna.
Procedural Volume and Outcomes After Percutaneous Coronary Intervention for Unprotected Left Main Coronary Artery Disease
—
Report From the National Clinical Data (J‐PCI Registry)
Authors: Aikawa Tadao , Yamaji Kyohei , Nagai Toshiyuki , Kohsaka Shun , Kamiya Kiwamu , Omote Kazunori , Inohara Taku , Numasawa Yohei , Tsujita Kenichi , Amano Tetsuya , Ikari Yuji , Anzai Toshihisa
Published: April 2020

Background

There is a limited evidence base to support the volume‐outcome relationship in patients undergoing percutaneous coronary intervention (
PCI
) for unprotected left main coronary artery disease (
UPLMD
). This study aimed to evaluate the relationship between institutional and operator volume and in‐hospital outcomes in patients undergoing
PCI
for unprotected left main coronary artery disease.

Methods and Results

We analyzed characteristics and clinical outcomes of 24 320 patients undergoing
PCI
for unprotected left main coronary artery disease at 1102 hospitals by 7244 operators using data from the Japanese nationwide J‐PCI Registry (National PCI Data Registry) between January 2014 and December 2017. We classified institutions and operators into quartiles based on the mean annual volume of
PCI
. A generalized linear mixed‐effects model was used to evaluate the association between institutional and operator
PCI
volume and in‐hospital outcomes. Among the 24 320 patients, 4027 (16.6%), 6147 (25.3%), and 14 146 (58.2%) presented with
ST
‐segment–elevation myocardial infarction, non–
ST
‐segment–elevation acute coronary syndrome, and stable ischemic heart disease; their crude in‐hospital mortality was 15%, 3.1%, and 0.3%, respectively. Compared with patients in the lowest quartile of institutional volume (1–216
PCI
s/y), the adjusted odds ratio of in‐hospital death in patients in the second (217–323
PCI
s/y), third (324–487
PCI
s/y), and fourth (488–3015
PCI
s/y) quartile of institutional volume was 0.75 (95% CI, 0.51–1.10;
P
=0.14), 0.87 (95%
CI
, 0.57–1.34;
P
=0.54), and 0.51 (95%
CI
, 0.30–0.86;
P
=0.01), respectively. These findings were consistent in rates of in‐hospital death or any complication. Conversely, operator
PCI
volume was not significantly associated with in‐hospital outcomes.

Conclusions

Institutional rather than operator‐based
PCI
volume was associated with better in‐hospital outcomes in patients undergoing
PCI
for unprotected left main coronary artery disease.
Assessment of knowledge and perceptions of medical radiation among caregivers and adolescent patients in the paediatric emergency department
Authors: Chew SY , Ang WLI , Lim XYD , Tan QSM , Wee ZY
Published: April 2020

INTRODUCTION This study aimed to assess understanding of the potential risks associated with medical imaging among caregivers and adolescent patients in a paediatric emergency department (PED) in Singapore. METHODS A prospective convenience sample survey was performed involving adolescents and caregivers presenting to our PED from December 2015 to May 2016. The questionnaire examined demographic data, knowledge of imaging procedures and radiation risks, and expectations regarding information provided about medical radiation. RESULTS A total of 349 questionnaires were returned (caregivers 82.5%, adolescents 17.5%). A mean of 6.2 ± 2.4 (out of 11) questions were correctly answered. Those who had tertiary education fared better than those who did not (36.4% vs. 17.2% scoring above the mean, p = 0.001). Age, gender, history of previous imaging and imaging performed during the visit did not affect the score. Two-thirds of the participants did not associate medical radiation with any negative lifetime risk of cancers or know that different scans entailed differing amounts of radiation. Most were unaware that the radiation dose in medical imaging is adjusted to a child’s size. Among patients who underwent imaging, 90.1% received explanations on the need for scans, and 26.5% were informed of the risks involved. Almost all participants wished to be informed of imaging indications and risks. More preferred to learn this from physicians (75.6%) or technicians (51.6%) rather than through educational pamphlets (34.4%) or Internet resources (22.9%). CONCLUSION Awareness regarding medical radiation needs to be improved in our patient population. A mismatch exists between caregiver expectations and the actual procedure of disclosure of the risk associated with radiation.
Advancing Ethical Principles for Non-Invasive, Respectful Research with Nonhuman Animal Participants
Authors: Van Patter Lauren E. , Blattner Charlotte
Published: April 2020

Animal studies scholars are increasingly engaging with nonhuman animals firsthand to better understand their lifeworlds and interests. The current 3R framework is inadequate to guide respectful, non-invasive research relations that aim to encounter animals as meaningful participants and safeguard their well-being. This article responds to this gap by advancing ethical principles for research with animals guided by respect, justice, and reflexivity. It centers around three core principles: non-maleficence (including duties around vulnerability and confidentiality); beneficence (including duties around reciprocity and representation); and voluntary participation (involving mediated informed consent and ongoing embodied assent). We discuss three areas (inducements, privacy, and refusing research) that merit further consideration. The principles we advance serve as a starting point for further discussions as researchers across disciplines strive to conduct multispecies research that is guided by respect for otherness, geared to ensuring animals’ flourishing, and committed to a nonviolent ethic.
Investigations on the Use of Limitations to Freedom of Religion or Belief in Brazil
Authors: Alves Pinto Thiago , Souza Alves Rodrigo Vitorino
Published: April 2020

The present article analyses cases from top Brazilian courts and has received contributions from several scholars, practitioners, and public officials to better understand the use of limitations to freedom of religion or belief in the country. The Brazilian Constitution provides for the right to freedom of religion or belief as a fundamental right, and other domestic legislation regulate the right, including those implementing international human rights treaties that Brazil has ratified. These laws are easily accessible. Nevertheless, domestic courts seldom rely on such international instruments or the case-law of international bodies in their judgments. Therefore, although these instruments are in force in Brazil, domestic courts do not expressly use or refer to the clauses of permissible limitations of the relevant international and regional human rights instruments, creating a scenario with low levels of legal certainty for those seeking the protection of the right to freedom of religion or belief.
Permissible Limitations to Freedom of Religion and Belief in Nigeria
Authors: Garba Ahmed Salisu
Published: April 2020

The application of permissible limitations to restrict freedom of religion and belief in Nigeria continues to generate debate among scholars. This article applies a socio-legal methodology to analyse the legal rationale that Nigerian courts have used in cases concerning limitations to freedom of religion or belief. First, the article explores the history of the legal frameworks for the protection of freedom of religion and belief including its limitation in Nigeria. Second, the article analyses Nigerian courts’ interpretation of the concept with specific reference to the legal rational used. Third, the article investigates the application of the proportionality test to balance the regulatory power of the state and citizens’ right to practice their religion. The article engages with case-law on freedom of religion, mostly from High courts and Court of Appeal in Nigeria. The article contains contributions from several scholars, religious groups, public officials, Non-Governmental Organisations obtained through interviews at their various offices.
Are Turkey’s Restrictions on Freedom of Religion or Belief Permissible?
Authors: Yıldırım Mine
Published: April 2020

This article constitutes a summary of the findings of an inquiry into the utilization of the restriction clause of freedom of religion or belief in the course of restriction of this right in Turkey. It demonstrates that FoRB is restricted in various ways by public authorities which rarely involve a systematic application of the FoRB restriction clause. Despite Turkey’s human rights obligations in the area of freedom of religion or belief and the high status conferred to international human rights law under Article 90 of the Turkish Constitution the impact of international provisions on the protection of FoRB in Turkey remains insufficient and inconsistent. The right to freedom of religion or belief has been restricted through measures based on “established practice”, decisions of public authorities based on laws and regulations not directly dealing with this right and court decisions that are not in full compliance with international law.
Yue Ren, Luli, and Anlu: the Tomb Occupant of Yunmeng Shuihudi Han Tomb No. 77 and the Village Where He Resided
Authors: Wei Chen , Dan Cai
Published: April 2020

By examining the excavated bamboo slips and boards of Shuihudi 睡虎地 Western Han tomb no. 77 in Yunmeng 雲夢, it is possible to know that the name of the tomb occupant was Yue Ren 越人 and that he served as an Office Assistant 官佐 in Anlu 安陸 County from the ninth year (171 bce.) of the reign of Western Han Emperor Wendi 文帝 (r. 180–157 bce.) to the seventh year (157 bce.) of the Houyuan 後元 era (163–157 bce.) of his reign. In addition, we can understand a number of the actions and life events of Yue Ren and his colleagues and family members, and know that in the tenth month of the third year of the Houyuan era of Wendi’s reign (161 bce.), Yue Ren and his family moved their residence to Luli 路里. Moreover, by analyzing the slips and boards of tomb no. 77, and viewing these in connection with lacquerware items on which are inscribed two graphs spelling out “Luli” 路里 excavated from the Shuihudi Qin tombs, it can be concluded that from the Qin dynasty to the early Western Han dynasty, residents of Luli were entombed in the cemetery at Shuihudi. This provides what is currently the strongest evidence for arguing that the ancient walled town at Yunmeng 雲夢古城—also referred to as the “Walled Town of the Chu King” 楚王城—is the ruins of the walled town that was seat of Anlu County in the Qin and Han periods.
Three new species of the genus Homaloxestis Meyrick, 1910 (Lepidoptera, Lecithoceridae) from China
Authors: YU SHUAI , WANG SHUXIA
Published: April 2020

Three new species of the genus Homaloxestis Meyrick are described from China: H. trapezialis sp. nov., H. longicornuta sp. nov., and H. rotundisigna sp. nov. The female of H. miscogana Wu, 1997 is described for the first time. Photographs of adults and genitalia are provided.
Quantification of the Radiative Effect of Aerosol–Cloud Interactions in Shallow Continental Cumulus Clouds
Authors: Glenn Ian B. , Feingold Graham , Gristey Jake J. , Yamaguchi Takanobu
Published: April 2020

The indirect radiative effect of aerosol variability on shallow cumulus clouds is realized in nature with considerable concurrent meteorological variability. Large-eddy simulations constrained by observations at a continental site in Oklahoma are performed to represent the variability of different meteorological states on days with different aerosol conditions. The total radiative effect of this natural covariation between aerosol and other meteorological drivers of total cloud amount and albedo is quantified. The changes to these bulk quantities are used to understand the response of the cloud radiative effect to aerosol–cloud interactions (ACI) in the context of concurrent processes, as opposed to attempting to untangle the effect of individual processes on a case-by-case basis. Mutual information (MI) analysis suggests that meteorological variability masks the strength of the relationship between cloud drop number concentration and the cloud radiative effect. This is shown to be mostly due to variation in solar zenith angle and cloud field horizontal heterogeneity masking the relationship between cloud drop number and cloud albedo. By combining MI and more traditional differential analyses, a framework to identify important modes of covariation between aerosol, clouds, and meteorological conditions is developed. This shows that accounting for solar zenith angle variation and implementing an albedo bias correction increases the detectability of the radiative effects of ACI in simulations of shallow cumulus.
Observation of Jet Stream Winds during NAWDEX and Characterization of Systematic Meteorological Analysis Errors
Authors: Schäfler Andreas , Harvey Ben , Methven John , Doyle James D. , Rahm Stephan , Reitebuch Oliver , Weiler Fabian , Witschas Benjamin
Published: April 2020

Observations across the North Atlantic jet stream with high vertical resolution are used to explore the structure of the jet stream, including the sharpness of vertical wind shear changes across the tropopause and the wind speed. Data were obtained during the North Atlantic Waveguide and Downstream Impact Experiment (NAWDEX) by an airborne Doppler wind lidar, dropsondes, and a ground-based stratosphere–troposphere radar. During the campaign, small wind speed biases throughout the troposphere and lower stratosphere of only −0.41 and −0.15 m s−1 are found, respectively, in the ECMWF and Met Office analyses and short-term forecasts. However, this study finds large and spatially coherent wind errors up to ±10 m s−1 for individual cases, with the strongest errors occurring above the tropopause in upper-level ridges. ECMWF and Met Office analyses indicate similar spatial structures in wind errors, even though their forecast models and data assimilation schemes differ greatly. The assimilation of operational observational data brings the analyses closer to the independent verifying observations, but it cannot fully compensate for the forecast error. Models tend to underestimate the peak jet stream wind, the vertical wind shear (by a factor of 2–5), and the abruptness of the change in wind shear across the tropopause, which is a major contribution to the meridional potential vorticity gradient. The differences are large enough to influence forecasts of Rossby wave disturbances to the jet stream with an anticipated effect on weather forecast skill even on large scales.