bluuebunny/crossref_metadata_2025 huggingface dataset:
Noncommutative correction to the entropy of Schwarzschild black hole with GUP
Authors: Anacleto M. A. , Brito F. A. , Cruz S. S. , Passos E.
Published: January 2021

In this paper we study through tunneling formalism, the effect of noncommutativity to Hawking radiation and the entropy of the noncommutative Schwarzschild black hole. In our model we have considered the noncommutativity implemented via the Lorentzian distribution. We obtain noncommutative corrections to the Hawking temperature using the Hamilton–Jacobi method and the Wentzel–Kramers–Brillouin (WKB) approximation. In addition, we found corrections of the logarithmic and other types due to noncommutativity and quantum corrections from the generalized uncertainty principle (GUP) for the entropy of the Schwarzschild black hole.
Paleoproterozoic metaluminous syenites synchronous with the
c.
2.21 Ga mafic dyke swarms from the Eastern Dharwar Craton, India: implications for alkaline magmatism associated with the breakup of supercraton Superia
Authors: Pandey Ashutosh , Rao N. V. Chalapathi , Rahaman Waliur , Seth Vikas , Sahoo Samarendra
Published: January 2021

The Eastern Dharwar Craton (EDC) hosts numerous Late Neoarchean to Paleoproterozoic syenites whose genesis remains unclear. Here we present a petrological and geochemical study on the syenites from Peddavaduguru, Danduvaripalle and Vannedoddi, towards the western margin of the Paleo-Mesoproterozoic Cuddapah Basin in the EDC. These syenite bodies constitute a part of the Paleoproterozoic (2210 ± 110 Ma) Dancherla alkaline complex and are contemporaneous with a mafic dyke swarm emplacement in the EDC. The Danduvaripalle and Vannedoddi syenites display geochemical affinities to adakites. The Peddavaduguru syenite shows a negative Eu anomaly and relatively gentle chondrite-normalized rare earth element (REE) pattern, suggesting an origin by a different process. The
ɛ
Nd
values range between 0.5 and 0.8 for the Peddavaduguru syenite, − 5.2 and − 4.2 for the Danduvaripalle syenite, and − 6.0 and − 1.0 for the Vannedoddi syenite. In tectonic discrimination diagrams, the Peddavaduguru syenite shows affinities to within-plate granitoids similar to syenites from the Deccan large igneous province whereas the others show geochemical similarities to arc-related alkaline rocks and volcanic arc granitoids. The adakitic syenites show deficiency of MgO, Ni, Cr and Sc, highly fractionated REE patterns and negative Nb–Ta–Ti anomalies along with low Nb/U and high Th/U ratios. These geochemical traits are compatible with their origin by the partial melting of a mafic crustal source that subsequently underwent fractionation of amphibole and garnet responsible to impart an adakitic character. We suggest that the crustal source of these syenites underwent partial melting by heat from the rising plume during the Paleoproterozoic extension of the Superia supercraton. The non-adakitic Peddavaduguru syenite, on the other hand, is suggested to have originated from direct fractionation of mafic magma.
GDPR anti-patterns
Authors: Shastri Supreeth , Wasserman Melissa , Chidambaram Vijay
Published: January 2021

How design and operation of modern cloud-scale systems conflict with GDPR.
Keeping science on keel when software moves
Authors: Ahn Dong H. , Baker Allison H. , Bentley Michael , Briggs Ian , Gopalakrishnan Ganesh , Hammerling Dorit M. , Laguna Ignacio , Lee Gregory L. , Milroy Daniel J. , Vertenstein Mariana
Published: January 2021

An approach to reproducibility problems related to porting software across machines and compilers.
CAPE
Authors: Fletcher Carol L. , Warner Jayce R.
Published: January 2021

Examining both the leading indicators of equity in CS and the lagging indicators of student outcomes.
The 1st ACM SIGSPATIAL International Workshop on Modeling and Understanding the Spread of COVID-19
Authors: Anderson Taylor , Yu Jia , Züfle Andreas
Published: January 2021

In response to the COVID-19 pandemic, a number of spatially-explicit models have been developed to better explain the pathways of the disease, to predict the trajectory of the disease, and to test the effect of different health guidelines and policies on the number of cases and deaths. The 1st ACM SIGSPATIAL International Workshop on Modeling and Understanding the Spread of COVID-19 workshop (COVID'2020) featured research efforts that aim to understand the spatial processes and patterns of COVID-19 spread using a variety of spatial modeling, simulation, and mining approaches. The goal of this workshop was to bring together a range of interdisciplinary researchers in the SIGSPATIAL community in the fields of computer science, spatial modeling, social sciences, and epidemiology. Also, this workshop was advertised for anyone interested in infectious disease data and modelling, including but not limited to COVID-19.
Isoprostanes evoke contraction of the murine and human detrusor muscle via activation of the thromboxane prostanoid TP receptor and Rho kinase
Authors: Molnár Péter József , Dér Bálint , Borsodi Kinga , Balla Helga , Borbás Zsófia , Molnár Krisztina , Ruisanchez Éva , Kenessey István , Horváth András , Keszthelyi Attila , Majoros Attila , Nyirády Péter , Offermanns Stefan , Benyó Zoltán
Published: January 2021

Voiding disorders affect millions of people worldwide. Inflammation can impair urinary bladder functions and contribute to the development of detrusor overactivity. The effects and signal transduction of inflammatory lipid mediator isoprostanes were studied in human and murine urinary bladders ex vivo. We found that isoprostanes evoke contraction, an effect mediated by thromboxane prostanoid receptors. The G12/13-Rho-Rho kinase signaling pathway plays a significant role in mediating the contraction and therefore may be a potential therapeutic target.
Nrf2 mediates hypoxia-inducible HIF1α activation in kidney tubular epithelial cells
Authors: Potteti Haranatha R. , Noone Patrick M. , Tamatam Chandramohan R. , Ankireddy Aparna , Noel Sanjeev , Rabb Hamid , Reddy Sekhar P.
Published: January 2021

Nuclear factor erythroid 2-related factor 2 (Nrf2) and hypoxia-inducible factor-1α (HIF1α) transcription factors protect against ischemic acute kidney injury (AKI) by upregulating metabolic and cytoprotective gene expression. In this study, we tested the hypothesis that Nrf2 is required for HIF1α-mediated hypoxic responses using Nrf2-sufficient (wild-type) and Nrf2-deficient ( Nrf2–/–) primary murine renal/kidney tubular epithelial cells (RTECs) and human immortalized tubular epithelial cells (HK2 cells) with HIF1 inhibition and activation. The HIF1 pathway inhibitor digoxin blocked hypoxia-stimulated HIF1α activation and heme oxygenase ( HMOX1) expression in HK2 cells. Hypoxia-mimicking cobalt (II) chloride-stimulated HMOX1 expression was significantly lower in Nrf2–/– RTECs than in wild-type counterparts. Similarly, hypoxia-stimulated HIF1α-dependent metabolic gene expression was markedly impaired in Nrf2–/– RTECs. Nrf2 deficiency impaired hypoxia-induced HIF1α stabilization independent of increased prolyl 4-hydroxylase gene expression. We found decreased HIF1α mRNA levels in Nrf2–/– RTECs under both normoxia and hypoxia-reoxygenation conditions. In silico analysis and chromatin immunoprecipitation assays demonstrated Nrf2 binding to the HIF1α promoter in normoxia, but its binding decreased in hypoxia-exposed HK2 cells. However, Nrf2 binding at the HIF1α promoter was enriched following reoxygenation, demonstrating that Nrf2 maintains constitutive HIF1α expression. Consistent with this result, we found decreased levels of Nrf2 in hypoxia and that were restored following reoxygenation. Inhibition of mitochondrial complex I prevented hypoxia-induced Nrf2 downregulation and also increased basal Nrf2 levels. These results demonstrate a crucial role for Nrf2 in optimal HIF1α activation in hypoxia and that mitochondrial signaling downregulates Nrf2 levels in hypoxia, whereas reoxygenation restores it. Nrf2 and HIF1α interact to provide optimal metabolic and cytoprotective responses in ischemic AKI.
Gestational gut microbial remodeling is impaired in a rat model of preeclampsia superimposed on chronic hypertension
Authors: Ishimwe Jeanne A. , Akinleye Adesanya , Johnson Ashley C. , Garrett Michael R. , Sasser Jennifer M.
Published: January 2021

Preeclampsia is a progressive hypertensive disorder of pregnancy affecting 2%–8% of pregnancies globally. Preexisting chronic hypertension is a major risk factor associated with developing preeclampsia, and growing evidence suggests a role for the gut microbiome in the development of preeclampsia. However, neither alterations in the gut microbiome associated with preeclampsia nor the mechanisms involved are fully understood. In this study, we tested the hypothesis that normal gestational maternal gut microbiome remodeling is impaired in the Dahl salt-sensitive (Dahl S) rat model of superimposed preeclampsia. Gut microbiome profiles of pregnant Dahl S, normal pregnant Sprague–Dawley (SD), and matched virgin controls were assessed by 16S rRNA gene sequencing at baseline; during early, middle, and late pregnancy; and 1-wk postpartum. Dahl S rats had significantly higher abundance in Proteobacteria, and multiple genera were significantly different from SD rats at baseline. The pregnant SD displayed a significant increase in Proteobacteria and genera such as Helicobacter, but these were not different between pregnant and virgin Dahl S rats. By late pregnancy, Dahl S rats had significantly lower α-diversity and Firmicutes compared with their virgin Dahl S controls. β-diversity was significantly different among groups ( P < 0.001). KEGG metabolic pathways including those associated with short-chain fatty acids were different in Dahl S pregnancy but not in SD pregnancy. These results reveal an association between chronic hypertension and gut microbiome dysbiosis which may hinder pregnancy-specific remodeling in the gut microbial composition during superimposed preeclampsia.
Theoretical Study and Application of Rate Transient Analysis on Complex Fractured-Caved Carbonate Reservoirs
Authors: Yu Qingyan , Wang Qi , Liu Pengcheng , Zhang Jing , Zhang Qi , Deng Xiaojuan , Feng Kai
Published: January 2021

Carbonate reservoirs are mainly fractured-caved reservoirs with very well-developed dissolved pores, fractures, and caves. They have strong heterogeneity with various types of reservoir pore spaces. Using seismic inversion and reservoir static characterization, the result shows that the fractured-caved carbonate rocks in China are mainly caves with poor connectivity and complex oil-water distribution. Large-scale dissolved caves are mostly discrete and isolated, while the fractures are complex and various. The fracture features are observed either as a single large fractures or as a local fracture network. The characteristics of fluid flow in fracture-caved reservoirs vary as a result of the different combinations of fractures and caves. Currently, the static characterization technology of fractured-caved reservoirs is influenced by the limited resolution of seismic data, leading to large interpretation errors. In contrast, the dynamic method is a more reliable and effective method to determine reservoir parameters. However, traditional seepage equations cannot accurately characterize the flow pattern of fractured-caved carbonate reservoirs. In the case of a single large-scale dissolved fractured-caved reservoir, oil wells are usually connected to large caves through large fractures or directly drilled into large dissolved caves. In this study, the large-scale dissolved caved reservoir is simplified into two cases: (1) a single-cave and single-fracture series model composed of a single-cave and a single-fracture and (2) a composite model of dissolved caves and surrounding fracture networks. Note that the flow in a large cave is considered as free flow due to its large scale. The flow in a large fracture connected to the cave is considered as flow through porous media, and the flow in the reservoir surrounding the fracture network is considered as multiple-porosity model seepage flow. The corresponding seepage-free flow coupling mathematical model of different fractured-caved reservoirs has been established on this basis. We also obtained the rate transient analysis type curves of the oil well, conducted sensitivity analysis of each parameter, constructed the corresponding rate transient analysis curves, analyzed sensitivities of each parameter, and finally designed a dynamic evaluation method of well and reservoir parameters for different types of fractured-caved carbonate reservoirs. This study extensively applies this method in the Halahatang Oilfield of China and evaluates parameters such as reservoir reserves and physical properties to provide rational guidance for developing fractured-caved carbonate reservoirs.
Iterative Sliding Mode and Increment Feedback Attitude Control for On-Orbit Capturing Process of Spacecraft
Authors: Yin ChunWu , Ding YouJun , Song LiJun , Li ZhaoQiang , He Xing
Published: January 2021

According to the characteristics of spacecraft capturing noncooperative targets in orbit, an increment feedback controller based on nonlinear iterative sliding mode is presented. Firstly, the attitude tracking error equation is established, and then, an increment feedback control law based on bounded iterative sliding modes is proposed, which does not need to estimate the uncertain moment of inertia and external disturbances. For comparing, an adaptive sliding mode controller has been designed in the paper. Some numerical simulations have been given in the presence of spacecraft on-orbit capturing noncooperative target, and the simulation results show that the increment feedback controller has strong robustness to the unknown parametric variations and external disturbances and has a smaller control input torque in control process.
Factors Associated with Adherence to the Mediterranean Diet and Dietary Habits among University Students in Lebanon
Authors: El Hajj Jennifer S. , Julien Sofi G.
Published: January 2021

Although the Mediterranean Diet has been acknowledged as the best overall diet for the year 2020, it has seen a decrease in its adherence over the past years. This is due to several reasons, one of which is the gradual shift to a more westernized diet with all the influences that occur especially on university students whose dietary choices set a path for future dietary habits. The aim of this study is to check the level of adherence to the Mediterranean Diet and frequency of breakfast consumption among university students in Lebanon and check whether they are influenced by sociodemographic, anthropometric, dietary knowledge, or academic data. A cross-sectional questionnaire was electronically sent to randomly selected students (210 females and 93 males) from different universities across Lebanon, aged between 18 and 25 years old. The questionnaire was filled online, and all data were self-reported. The Mediterranean Diet Quality Index (KIDMED) was used as a tool to evaluate adherence to the Mediterranean Diet. The results showed that 18.8% of respondents had high adherence to the Mediterranean Diet. Students who reported always consuming breakfast and not skipping meals had significantly higher adherence to the MD. Furthermore, students with lower BMI and higher KIDMED scores had significantly more correct answers on the nutritional knowledge questions. In addition, there was a significant difference in the average KIDMED scores between different GPA categories, most notably when comparing high and poor MD adherence; students with excellent GPA scores had higher adherence to the MD than those with poor GPA scores. In conclusion, nutrition awareness in a university setting is very important since it may positively affect academic outcomes and may be the last chance to teach and engrave healthy eating patterns to a large scale of students.
Glycolysis‐Related Genes Serve as Potential Prognostic Biomarkers in Clear Cell Renal Cell Carcinoma
Authors: Zhang Yan , Chen Mingying , Liu Meihong , Xu Yingkun , Wu Guangzhen
Published: January 2021

Metabolic rearrangement is a marker of cancer that has been widely studied in recent years. One of the major metabolic characteristics of tumor cells is the high levels of glycolysis, even under aerobic conditions, a phenomenon that is called the “Warburg effect.” We investigated the expression and copy number variation (CNV) frequency of all glycolysis‐related genes in multiple cancer types and found many differentially expressed genes, particularly in clear cell renal cell carcinoma (ccRCC). Single nucleotide variants (SNVs) showed that the overall average mutation frequency for all genes was low. The purpose of this study was to establish a predictive model by studying glycolysis‐related genes in ccRCC. We compared the expression of glycolysis‐related genes in 539 ccRCC tissues and 72 normal renal tissues from The Cancer Genome Atlas dataset and identified 17 upregulated and 26 downregulated genes. Pathway analysis revealed that PSAT1 and SDHB could activate the cell cycle, RPIA could activate the DNA damage response, and HK3 could activate apoptosis and EMT signaling, while PDK2 could inhibit apoptosis. The results of the drug sensitivity analysis suggested that some of these differentially expressed genes were positively correlated with drug sensitivity. Thirteen genes were selected from the gene coexpression network and the LASSO regression analysis. The Kaplan‐Meier overall survival curves showed that the expression of upregulated genes in ccRCC patients was associated with lower overall survival. We established a predictive model consisting of 13 genes (RPIA, G6PD, PSAT1, ENO2, HK3, IDH1, PDK4, PGM2, PGK1, FBP1, OGDH, SUCLA2, and SUCLG2). This predictive model correlated well with the development and progression of ccRCC. Thus, it is of great value in the diagnosis and prognostic evaluation of ccRCC and may aid the identification of potential prognostic biomarkers and drug targets.
Nutritional Properties and In Vitro Antidiabetic Activities of Blue and Yellow Corn Extracts: A Comparative Study
Authors: Smorowska Aleksandra J. , Żołnierczyk Anna K. , Nawirska-Olszańska Agnieszka , Sowiński Józef , Szumny Antoni
Published: January 2021

The objective of this research was to designate and identify the profile of fatty acids, sterols, and polyphenol compounds and to demonstrate the antidiabetic activity, in blue corn extracts (BCE) in comparison with the yellow variant of this raw material. All of the maize lines, including the blue corn, were grown in Europe (southwestern part of Poland) and not in the place of origin (South America). In the extracts of the blue corn variety, eight anthocyanin compounds were isolated. The compound found in the largest amount was pelargonidin, followed by cyanidin-3-glucoside and other glycoside derivatives. Unsaturated fatty acids were the main ones found in the lipid fraction of blue and yellow corn, including linoleic acid and oleic acid. Saturated fatty acids, such as stearic and palmitic acid, were present in smaller amounts. The blue corn’s sterol profile was similar to other varieties of this corn, with β-sitosterol and campesterol occurring in the largest amount, alongside smaller amounts of stigmastanol and stigmasterol. The blue corn variety was characterized by a high content of polyphenolic compounds, which show several biological activities, including antidiabetic activity. The strongest in vitro antidiabetic effect was found in the blue corn lines. Among the polyphenolic compounds in both the blue and yellow corn varieties, in the largest amounts, were caffeic acid, procyanidin B2, and gallic acid. Despite the known and proven biological activity of polyphenolic compounds, the fat fraction showed the highest in vitro antidiabetic activity in the BCE studied.
Enhancing Hyperheuristics for the Knapsack Problem through Fuzzy Logic
Authors: Olivas Frumen , Amaya Ivan , Ortiz-Bayliss José Carlos , Conant-Pablos Santiago E. , Terashima-Marín Hugo
Published: January 2021

Hyperheuristics rise as powerful techniques that get good results in less computational time than exact methods like dynamic programming or branch and bound. These exact methods promise the global best solution, but with a high computational time. In this matter, hyperheuristics do not promise the global best solution, but they promise a good solution in a lot less computational time. On the contrary, fuzzy logic provides the tools to model complex problems in a more natural way. With this in mind, this paper proposes a fuzzy hyperheuristic approach, which is a combination of a fuzzy inference system with a selection hyperheuristic. The fuzzy system needs the optimization of its fuzzy rules due to the lack of expert knowledge; indeed, traditional hyperheuristics also need an optimization of their rules. The fuzzy rules are optimized by genetic algorithms, and for the rules of the traditional methods, we use particle swarm optimization. The genetic algorithm will also reduce the number of fuzzy rules, in order to find the best minimal fuzzy rules, whereas traditional methods already use very few rules. Experimental results show the advantage of using our approach instead of a traditional selection hyperheuristic in 3200 instances of the 0/1 knapsack problem.
Finite-Time Stability and Stabilization of Switched Linear Time-Varying Systems with Time-Varying Delay
Authors: Feng Lulu , Zhao Ping
Published: January 2021

This paper deals with the finite-time stability (FTS) of switched linear time-varying (SLTV) systems with time-varying delay. Firstly, based on Lyapunov–Krasovskii functional technique and average dwell time (ADT) approach, a sufficient criterion on FTS for SLTV systems with time-varying delay is obtained. For the SLTV system with delay and control input, based on the criterion, a state feedback controller is designed such that the closed-loop system is finite-time stable (FTS). Finally, an example is employed to illustrate the validity of our results.
Evasion of Innate Immunity Contributes to Small Cell Lung Cancer Progression and Metastasis
Authors: Zhu Mingrui , Huang Yi , Bender Matthew E. , Girard Luc , Kollipara Rahul , Eglenen-Polat Buse , Naito Yujiro , Savage Trisha K. , Huffman Kenneth E. , Koyama Shohei , Kumanogoh Atsushi , Minna John D. , Johnson Jane E. , Akbay Esra A.
Published: January 2021

Small cell lung cancer (SCLC) is a pulmonary neuroendocrine cancer with very poor prognosis and limited effective therapeutic options. Most patients are diagnosed at advanced stages, and the exact reason for the aggressive and metastatic phenotype of SCLC is completely unknown. Despite a high tumor mutational burden, responses to immune checkpoint blockade are minimal in patients with SCLC. This may reflect defects in immune surveillance. Here we illustrate that evading natural killer (NK) surveillance contributes to SCLC aggressiveness and metastasis, primarily through loss of NK-cell recognition of these tumors by reduction of NK-activating ligands (NKG2DL). SCLC primary tumors expressed very low level of NKG2DL mRNA and SCLC lines express little to no surface NKG2DL at the protein level. Chromatin immunoprecipitation sequencing showed NKG2DL loci in SCLC are inaccessible compared with NSCLC, with few H3K27Ac signals. Restoring NKG2DL in preclinical models suppressed tumor growth and metastasis in an NK cell–dependent manner. Likewise, histone deacetylase inhibitor treatment induced NKG2DL expression and led to tumor suppression by inducing infiltration and activation of NK and T cells. Among all the common tumor types, SCLC and neuroblastoma were the lowest NKG2DL-expressing tumors, highlighting a lineage dependency of this phenotype. In conclusion, these data show that epigenetic silencing of NKG2DL results in a lack of stimulatory signals to engage and activate NK cells, highlighting the underlying immune avoidance of SCLC and neuroblastoma.

Significance:

This study discovers in SCLC and neuroblastoma impairment of an inherent mechanism of recognition of tumor cells by innate immunity and proposes that this mechanism can be reactivated to promote immune surveillance.
The Use of Serial Circulating Tumor DNA to Detect Resistance Alterations in Progressive Metastatic Breast Cancer
Authors: Jacob Saya , Davis Andrew A. , Gerratana Lorenzo , Velimirovic Marko , Shah Ami N. , Wehbe Firas , Katam Neelima , Zhang Qiang , Flaum Lisa , Siziopikou Kalliopi P. , Platanias Leonidas C. , Gradishar William J. , Behdad Amir , Bardia Aditya , Cristofanilli Massimo
Published: January 2021

Purpose:

Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer.

Experimental Design:

This was a retrospective cohort between 2015 and 2019 obtained under an Institutional Review Board–approved protocol at Northwestern University (Chicago, IL). ctDNA samples were analyzed with Guardant360 next-generation sequencing (NGS) assay. A total of 86 patients had at least two serial ctDNA collections with the second drawn at first post-NGS progression (PN1) by imaging and clinical assessment. A total of 27 participants had ctDNA drawn at second post-NGS clinical progression (PN2). We analyzed alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs' variations in MAF, NOA, and alterations at progression were tested through Wilcoxon test. We identified an independent control cohort at Massachusetts General Hospital (Boston, MA) of 63 patients with serial ctDNA sampling and no evidence of progression.

Results:

We identified 44 hormone receptor–positive, 20 HER2+, and 22 triple-negative breast cancer cases. The significant alterations observed between baseline and PN1 were TP53 (P < 0.0075), PIK3CA (P < 0.0126), AR (P < 0.0126), FGFR1 (P < 0.0455), and ESR1 (P < 0.0143). Paired analyses revealed increased MAF and NOA from baseline to PN1 (P = 0.0026, and P < 0.0001, respectively). When compared with controls without progression, patients with ctDNA collection at times of progression were associated with increased MAF and NOA (P = 0.0042 and P < 0.0001, respectively).

Conclusions:

Serial ctDNA testing identified resistance alterations and increased NOA and MAF were associated with disease progression. Prospective longitudinal ctDNA evaluation could potentially monitor tumor genomic evolution.
Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies
Authors: Tayari Mina M. , Santos Helena G. Dos , Kwon Deukwoo , Bradley Terrence J. , Thomassen Amber , Chen Charles , Dinh Yvonne , Perez Aymee , Zelent Arthur , Morey Lluis , Cimmino Luisa , Shiekhattar Ramin , Swords Ronan T. , Watts Justin M.
Published: January 2021

Purpose:

In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS).

Patients and Methods:

Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily).

Results:

ATRA-TCP had an acceptable safety profile. The MTD of TCP was 20 mg twice daily. Best responses included one morphologic leukemia-free state, one marrow complete remission with hematologic improvement, two stable disease with hematologic improvement, and two stable disease. By intention to treat, the overall response rate was 23.5% and clinical benefit rate was 35.3%. Gene expression profiling of patient blasts showed that responding patients had a more quiescent CD34+ cell phenotype at baseline, including decreased MYC and RARA expression, compared with nonresponders that exhibited a more proliferative CD34+ phenotype, with gene expression enrichment for cell growth signaling. Upon ATRA-TCP treatment, we observed significant induction of retinoic acid–target genes in responders but not nonresponders. We corroborated this in AML cell lines, showing that ATRA-TCP synergistically increased differentiation capacity and cell death by regulating the expression of key gene sets that segregate patients by their clinical response.

Conclusions:

These data indicate that LSD1 inhibition sensitizes AML cells to ATRA and may restore ATRA responsiveness in subsets of patients with MDS and AML.
TNIK Is a Therapeutic Target in Lung Squamous Cell Carcinoma and Regulates FAK Activation through Merlin
Authors: Torres-Ayuso Pedro , An Elvira , Nyswaner Katherine M. , Bensen Ryan C. , Ritt Daniel A. , Specht Suzanne I. , Das Sudipto , Andresson Thorkell , Cachau Raul E. , Liang Roger J. , Ries Amy L. , Robinson Christina M. , Difilippantonio Simone , Gouker Brad , Bassel Laura , Karim Baktiar O. , Miller Chad J. , Turk Benjamin E. , Morrison Deborah K. , Brognard John
Published: January 2021

Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer. Despite extensive genomic characterization, no targeted therapies are approved for the treatment of LSCC. Distal amplification of the 3q chromosome is the most frequent genomic alteration in LSCC, and there is an urgent need to identify efficacious druggable targets within this amplicon. We identify the protein kinase TNIK as a therapeutic target in LSCC. TNIK is amplified in approximately 50% of LSCC cases. TNIK genetic depletion or pharmacologic inhibition reduces the growth of LSCC cells in vitro and in vivo. In addition, TNIK inhibition showed antitumor activity and increased apoptosis in established LSCC patient-derived xenografts. Mechanistically, we identified the tumor suppressor Merlin/NF2 as a novel TNIK substrate and showed that TNIK and Merlin are required for the activation of focal adhesion kinase. In conclusion, our data identify targeting TNIK as a potential therapeutic strategy in LSCC.

Significance:

Targeted therapies have not yet been approved for the treatment of LSCC, due to lack of identification of actionable cancer drivers. We define TNIK catalytic activity as essential for maintaining LSCC viability and validate the antitumor efficacy of TNIK inhibition in preclinical models of LSCC.

This article is highlighted in the In This Issue feature, p. 1307
Evaluation of Mathematical Arterialization of Venous Blood in Intensive Care and Pulmonary Ward Patients
Authors: Thomsen Lars Pilegaard , Klein Anne-Christin , Vitali-Serdoz Laura , Bastian Dirk , Shastri Lisha , Rees Stephen Edward , Rittger Harald
Published: January 2021

Background: Arterial blood gases are important when assessing acute or critically ill patients. Capillary blood and mathematical arterialization of venous blood have been proposed as alternative methods, eliminating pain and complications of arterial puncture. Objectives: This study compares the arterial samples, arterialized venous samples, and capillary samples in ICU and pulmonary ward patients. Method: Ninety-one adult patients with respiratory failure were included in the analysis. Arterial, peripheral venous, and mathematically arterialized venous samples were compared in all patients using Bland-Altman analysis, with capillary samples included in 36 patients. Results: Overall for pH and PCO2, arterialized venous values, and in the subset of 36 patients, capillary values, compared well to arterial values and were within the pre-defined clinically acceptable differences (pH ± 0.05 and PCO2 ± 0.88 kPa). For PO2, arterialized or capillary values describe arterial with similar precision (PO2 arterialized −0.03, LoA −1.48 to 1.42 kPa and PO2 capillary 0.82, LoA −1.36 to 3 kPa), with capillary values underestimating arterial. Conclusions: Mathematical arterialization functions well in a range of patients in an ICU and ward outside the country of development of the method. Furthermore, accuracy and precision are similar to capillary blood samples. When considering a replacement for arterial sampling in ward patients, using capillary sampling or mathematical arterialization should depend on logistic ease of implementation and use rather than improved measurements of using either technique.
Performance analysis of power generation by wood and woody biomass gasification in a downdraft gasifier
Authors: Safarian Sahar , Unnthorsson Runar , Richter Christiaan
Published: January 2021

An equilibrium simulation model was developed by applying Aspen Plus to evaluate the performance of 28 wood and woody biomass (W&WB) gasification in a downdraft gasifier integrated with power production unit. The developed simulation model does not focus the gasification process as a closed box, it considers important processes in gasification like drying, pyrolysis, combustion, gasification and integrated with power production plant (combustion chamber plus gas turbine). The results for the 28 W&WB alternatives show that the net power produced from 1-ton feedstock entering to the gasification system is between the interval [0-400 kW/ton] and among them, gasification system derived from Tamarack bark biomass significantly outranks all other systems by producing 363 kW/ton, owing to the favorable results obtained in the performance analysis. Moreover, effect of various operating parameters such as gasification temperature and air to fuel ratio (AFR) on the system performance was carried out. Finally, the developed model is applied as an effective tool to assess the impact of so many biomasses and operating parameters on output power.
Urinary- and Plasma-Derived Exosomes Reveal a Distinct MicroRNA Signature Associated With Albuminuria in Hypertension
Authors: Perez-Hernandez Javier , Riffo-Campos Angela L. , Ortega Ana , Martinez-Arroyo Olga , Perez-Gil Daniel , Olivares Dolores , Solaz Elena , Martinez Fernando , Martínez-Hervás Sergio , Chaves Felipe J. , Redon Josep , Cortes Raquel
Published: January 2021

Urinary albumin excretion (UAE) is a marker of cardiovascular risk and renal damage in hypertension. MicroRNAs (miRNAs) packaged into exosomes function as paracrine effectors in cell communication and the kidney is not exempt. This study aimed to state an exosomal miRNA profile/signature associated to hypertension with increased UAE and the impact of profibrotic TGF-β1 (transforming growth factor β1) on exosomes miRNA release. Therefore, exosomes samples from patients with hypertension with/without UAE were isolated and characterized. Three individual and unique small RNA libraries from each subject were prepared (total plasma, urinary, and plasma-derived exosomes) for next-generation sequencing profiling. Differentially expressed miRNAs were over-represented in Kyoto Encyclopedia of Genes and Genomes pathways, and selected miRNAs were validated by real-time quantitative polymerase chain reaction in a confirmation cohort. Thus, a signature of 29 dysregulated circulating miRNAs was identified in UAE hypertensive subjects, regulating 21 pathways. Moreover, changes in the levels of 4 exosomes-miRNAs were validated in a confirmation cohort and found associated with albuminuria. In particular miR-26a, major regulator of TGF-β signaling, was found downregulated in both type of exosomes when compared with healthy controls and to hypertension normoalbuminurics (
P
<0.01). Similarly, decreased miR-26a levels were found in podocyte-derived exosomes after TGF-β stress. Our results revealed an exosomes miRNA signature associated to albuminuria in hypertension. In particular, exosomes miR-26a seemed to play a key role in the regulation of TGF-β, a relevant effector in podocyte damage. These findings support the use of exosomes miRNAs as biomarkers of cardiovascular risk progression and therapeutic tools in early kidney damage.
Hypertension Burden and the Risk of New-Onset Atrial Fibrillation
Authors: Lee So-Ryoung , Park Chan Soon , Choi Eue-Keun , Ahn Hyo-Jeong , Han Kyung-Do , Oh Seil , Lip Gregory Y.H.
Published: January 2021

The association between the cumulative hypertension burden and the development of atrial fibrillation (AF) is unclear. We aimed to investigate the relationship between hypertension burden and the development of incident AF. Using the Korean National Health Insurance Service database, we identified 3 726 172 subjects who underwent 4 consecutive annual health checkups between 2009 and 2013, with no history of AF. During the median follow-up of 5.2 years, AF was newly diagnosed in 22 012 patients (0.59% of the total study population; 1.168 per 1000 person-years). Using the blood pressure (BP) values at each health checkup, we determined the burden of hypertension (systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg), stratified as 0 to 4 per the hypertension criteria. The subjects were grouped according to hypertension burden scale 1 to 4: 20% (n=742 806), 19% (n=704 623), 19% (n=713 258), 21% (n=766 204), and 21% (n=799 281). Compared with normal people, subjects with hypertension burdens of 1, 2, 3, and 4 were associated with an 8%, 18%, 26%, and 27% increased risk of incident AF, respectively. On semiquantitative analyses with further stratification of stage 1 (systolic BP of 130–139 mm Hg or diastolic BP of 80–89 mm Hg) and stage 2 (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) hypertension, the risk of AF increased with the hypertension burden by up to 71%. In this study, both a sustained exposure and the degree of increased BP were associated with an increased risk of incident AF. Tailored BP management should be emphasized to reduce the risk of AF.
Good Clinical Outcome Decreases With Number of Retrieval Attempts in Stroke Thrombectomy
Authors: Flottmann Fabian , Brekenfeld Caspar , Broocks Gabriel , Leischner Hannes , McDonough Rosalie , Faizy Tobias D. , Deb-Chatterji Milani , Alegiani Anna , Thomalla Götz , Mpotsaris Anastasios , Nolte Christian H. , Fiehler Jens , Maros Máté E. , Boeckh-Behrens Tobias , Wunderlich Silke , Wiesmann Martin , Ernemann Ulrike , Hauser Till-Karsten , Siebert Eberhard , Zweynert Sarah , Bohner Georg , Ludolph Alexander , Henn Karl-Heinz , Pfeilschifter Waltraud , Wagner Marlis , Röther Joachim , Eckert Bernd , Berrouschot Jörg , Bormann Albrecht , Gerloff Christian , Hattingen Elke , Petzold Gabor , Thonke Sven , Bangard Christopher , Kraemer Christoffer , Dichgans Martin , Wollenwebe Frank , Kellert Lars , Dorn Franziska , Herzberg Moriz , Psychogios Marios , Liman Jan , Petersen Martina , Stögbauer Florian , Kraft Peter , Pham Mirko , Braun Michael , Hamann Gerhard F. , Kastrup Andreas , Roth Christian , Gröschel Klaus , Uphaus Timo , Limmroth Volker
Published: January 2021

Background and Purpose:

Endovascular therapy is the standard of care in the treatment of acute ischemic stroke due to large-vessel occlusion. Often, more than one retrieval attempt is needed to achieve reperfusion. We aimed to quantify the influence of endovascular therapy on clinical outcome depending on the number of retrievals needed for successful reperfusion in a large multi-center cohort.

Methods:

For this observational cohort study, 2611 patients from the prospective German Stroke Registry included between June 2015 and April 2018 were analyzed. Patients who received endovascular therapy for acute anterior circulation stroke with known admission National Institutes of Health Stroke Scale score and Alberta Stroke Program Early CT Score, final Thrombolysis in Cerebral Infarction score, and number of retrievals were included. Successful reperfusion was defined as a Thrombolysis in Cerebral Infarction score of 2b or 3. The primary outcome was defined as functional independence (modified Rankin Scale score of 0–2) at day 90. Multivariate mixed-effects models were used to adjust for cluster effects of the participating centers and confounders.

Results:

The inclusion criteria were met by 1225 patients. The odds of good clinical outcome decreased with every retrieval attempt required for successful reperfusion: the first retrieval had the highest odds of good clinical outcome (adjusted odds ratio, 6.45 [95% CI, 4.0–10.4]), followed by the second attempt (adjusted odds ratio, 4.56 [95% CI, 2.7–7.7]), and finally the third (adjusted odds ratio, 3.16 [95% CI, 1.8–5.6]).

Conclusions:

Successful reperfusion within the first 3 retrieval attempts is associated with improved clinical outcome compared with patients without reperfusion. We conclude that at least 3 retrieval attempts should be performed in endovascular therapy of anterior circulation strokes.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT03356392.
To Disclose or Deceive? Sharing Secret Information between Aligned States
Authors: Haas Melinda , Yarhi-Milo Keren
Published: January 2021

Why do aligned states sometimes disclose secret information about their miitary plans to use force, whereas other times they choose to deceive their partners? The state initiating these plans may choose among four information-sharing strategies: collusion, compartmentalization, concealment, and lying. Three main considerations shape its decision: the state's assessment of whether it needs its partner's capabilities to succeed at the military mission, the state's perception of whether the partner will be willing to support the state in the requested role, and the state's anticipated deception costs for not fully informing its partner state. Several cases illustrate how these strategies are chosen: Israel, Britain, and France's decision to use force against Egypt during the Suez Crisis (collusion between France and Israel, and concealment vis-à-vis the United States); Israel's 2007 bombing of Syria's al Kibar reactor (compartmentalization); and Israel's deliberations whether to attack Iran's nuclear reactor (lying). These strategies have implications for intra-alliance restraint and contribute to understanding deception and secrecy between allies.
Read between the lineata: A revision of the tattooed wasps, Zagrammosoma Ashmead (Hymenoptera: Eulophidae), with descriptions of eleven new species
Authors: PERRY RYAN K. , HERATY JOHN M.
Published: January 2021

The genus Zagrammosoma Ashmead (Hymenoptera: Eulophidae) is revised. Twenty-six species are recognized, of which 23 have been molecularly verified in a phylogenetic context using 28S, ITS2, and COI. Zagrammosoma is recovered as monophyletic, worldwide in distribution, and morphologically distinct from Cirrospilus Westwood. Zagrammosoma interlineatum Girault stat. rev. is elevated from synonymy. The following synonymies are proposed: Zagrammosoma mirum Girault under Zagrammosoma flavolineatum Crawford n. syn., Zagrammosoma dulanense Cao & Zhu under Zagrammosoma talitzkii Bouček n. syn. The following species are described as new: Zagrammosoma calvini Perry n. sp. (Argentina, Chile), Zagrammosoma deliae Perry n. sp. (Peru), Zagrammosoma fisheri Perry n. sp. (USA), Zagrammosoma galapagoense Perry n. sp. (Ecuador: Galapagos Islands), Zagrammosoma headricki Perry n. sp. (Mexico, USA), Zagrammosoma metallicum Perry n. sp. (USA), Zagrammosoma occidentale Perry n. sp. (Mexico, USA), Zagrammosoma triangulum Perry n. sp. (USA), Zagrammosoma trifurcatum Perry n. sp. (Belize, USA), Zagrammosoma villosum Perry n. sp. (Nearctic, Neotropical), Zagrammosoma yanegai Perry n. sp. (Thailand). The following new combination is proposed: Cirrospilus variegatus (Masi) n. comb, from Zagrammosoma. Descriptions, distribution maps, host associations, and a key to all known species are provided.
Catalogue of the Australian Eumeninae (Hymenoptera: Vespidae)
Authors: CARPENTER JAMES M. , BROWN GRAHAM R.
Published: January 2021

A catalogue of Eumeninae occurring in Australia is presented. The genus Lissodynerus Giordani Soika is synonymized with Pararrhynchium de Saussure. Species placed in the genus Pseudepipona de Saussure, by Giordani Soika and Borsato are transferred to Euodynerus Dalla Torre, and species placed in the genus Syneuodynerus Blüthgen, by Giordani Soika are transferred to Stenodyneriellus Giordani Soika. New combinations are Anterhynchium decoratum (de Saussure), A. tamarinum inviolatum (Giordani Soika), Australodynerus flavoniger (Giordani Soika), Deuterodiscoelius confusus (Giordani Soika), D. ephippium (de Saussure), D. insignis (de Saussure), D. spinosus (de Saussure), Euodynerus aborigenus (Borsato), E. alaris (de Saussure), E. angulatus alexandriae (Giordani Soika), E. angulatus angulatus (de Saussure), E. aspra (Giordani Soika), E. clypalaris (Giordani Soika), E. flavus (Giordani Soika), E. pallidus (Giordani Soika), E. succinctus purgatus(Giordani Soika), E. succinctus succinctus (de Saussure), Pararrhynchium desaussurei (Borsato), P. kurandensis (Giordani Soika), Pseudalastor aurantiacus (Borsato), P. pecularis (Borsato), Stenodyneriellus aurantiacus (Giordani Soika), S. aurantiopilosella (Giordani Soika), S. cylindrellus (Giordani Soika), S. longebispinosa (Giordani Soika) and S. occidentatus (Giordani Soika). Revised combinations are Australodynerus yanchepensis nigrithorax Giordani Soika and A. yanchepensis yanchepensis Giordani Soika, which are returned to that genus. Other new synonymies are Anterhynchium tamarinum septentrionale Giordani Soika = Anterhynchium tamarinum tamarinum (de Saussure), Ischnocoelia robusta analis Giordani Soika = I. robusta robusta (Meade-Waldo), Pseudabispa bicolor flavescentula (Giordani Soika) = P bicolor bicolor (de Saussure), Pseudalastor tridentatus septentrionalis Giordani Soika = P. tridentatus tridentatus Giordani Soika and Rhynchium australense Perkins = R. magnificum Smith.
2. Sense and Sensibility
Authors: Bartlett Nora
Published: January 2021

In this chapter, Bartlett shares why Sense and Sensibility is her favourite among Jane Austen's novels. Discussed are this novel's history and criticism; the role of Austen's early manuscripts in her family life; and the role of her plays in her writing (particularly Sense and Sensibility). Next, Bartlett takes a look at humour, as well as mourning, in this novel. She further examines the novel's narration; "silence"; and Dashwood sisters, including a contrast to one another, in terms of desire for control of feeling. The impact that a concern for certain details (of money, food, clothing, or health) has on Austen’s characters is also discussed. Next, a look at Mrs. Dashwood; and comparisons of this novel to Pride and Prejudice. There is an examination of the importance of the two scenes that end Volume I and begin Volume II, including a closer look at Lucy and Anne. Bartlett discusses "sense and sensibility"; comic misapprehension; and the subject of the novel. Finally, she ends her examination with a look at the impact of Edward's announcement.