bluuebunny/crossref_metadata_2025 huggingface dataset:
Parallelae Vitae: Antiquities Smuggling and Hidden Incomes in Greece
Authors: Sotiriou Konstantinos-Orfeas
Published: November 2020

Nowadays, the antiquities-smuggling phenomenon seems more complicated than many researchers thought before. Antiquity looting is delinquent behaviour and a criminal activity. Hence, it is closely connected to many of the other problems that Greece is currently facing. This article tries to set the smuggling problem in a wider frame. More specifically, many researchers have pointed to the long-term inability of Greece’s tax services to detect income hiding. This has led to increased tax evasion and a shadow economic phenomenon. Moreover, researchers and institutions have made the conclusion that self-employed persons / freelancers in Greece have an increased capability for income hiding, irrespective of the origin of the money. A thorough examination of the occupations of 497 arrested people in Greece revealed that, indeed, the majority of them fall in the self-employed/freelance category. The results of this article are based on the 291 official arrests that took place from 1999 to 2015.
Reconstructing the Sacred: The Controversial Process of Bagrati Cathedral’s Full-scale Restoration and Its World Heritage Delisting
Authors: Meladze Tamar , Uekita Yasufumi
Published: November 2020

This article unfolds around the controversial case of Georgia’s eleventh-century Bagrati Cathedral, which represents the only site to be removed from the World Heritage List as a result of its full-scale reconstruction. After its destruction in armed conflict by the end of the seventeenth century, the first conservation-restoration works on the monument were carried out in the 1950s. In 1994, partially reconstructed but still without a roof, Bagrati Cathedral had no issues in meeting the conditions of authenticity when the nomination was made for inscription in the World Heritage List. The conflict arose further when the conservation experts did not endorse the state party’s intention to fully rebuild the cathedral, notwithstanding the fact it was stated to be crucial for its functional continuity. The International Council on Monuments and Sites and the United Nations Educational, Scientific and Cultural Organization took the view that this scale intervention would compromise the cathedral’s outstanding universal value and authenticity. This article offers a closer look at the decision-making process, from the nomination to the delisting of Bagrati Cathedral, and analyzes the factors contributing to the conflicting interpretations of the monument’s fundamental values among stakeholders. It addresses the issues from a broader perspective to include the historical-cultural background of Georgia and local approaches to preserving the religious sites, which tend to be overlooked in the discourse.
A Second-Personal Solution to the Paradox of Moral Complaint
Authors: Piovarchy Adam
Published: November 2020

Smilansky (2006) notes that wrongdoers seem to lack any entitlement to complain about being treated in the ways that they have treated others. However, it also seems impermissible to treat agents in certain ways, and this impermissibility would give wrongdoers who are themselves wronged grounds for complaint. This article solves this apparent paradox by arguing that what is at issue is not the right simply to make complaints, but the right to have one's demands respected. Agents must accept the authority of others to make second-personal demands on them before they can expect others to treat their own demands (or complaints) as legitimate. Wrongdoers’ previous wrongdoing shows they do not treat others’ demands as authoritative. However, as they are still beings with dignity, which acts as a source of moral reasons for others, wronging them remains impermissible.
Cardiac strangulation after epicardial pacing: the importance of non-specific symptoms and a low index of suspicion
Authors: Morrison Margaret L. , Karayiannis Steven , Speggiorin Simone , Sands Andrew J. , Rosenthal Eric
Published: November 2020

Cardiac strangulation is a rare and potentially deadly complication of epicardial pacemaker implantation. A young boy presenting with chest pain and tiredness almost 7 years after pacemaker implantation was found to have cardiac strangulation. Literature review revealed 22 cases reported to date with a worrying rise in the number of reports over the past 3 years. Strangulation is associated with implantation of leads at a young age and appears to be related to somatic growth. Serial assessment with chest X-ray and echocardiogram is recommended, at least until full adult growth is attained with further coronary artery imaging reserved for symptoms or suspicious echocardiographic findings. If cardiac strangulation is diagnosed prompt replacement of the offending system is needed.
The intraoperative use of recombinant activated factor VII in arterial switch operations
Authors: Zink Jessica , Spigel Zachary A. , Ibarra Christopher , Gottlieb Erin A. , Adachi Iki , Mery Carlos M. , Imamura Michiaki , Heinle Jeffrey S. , McKenzie Emmett Dean , Fraser Charles D. , Binsalamah Ziyad M.
Published: November 2020

Background:

The rate of bleeding complications following arterial switch operation is too low to independently justify a prospective randomised study for benefit from recombinant factor VIIa. We aimed to evaluate factor VIIa in a pilot study.

Methods:

We performed a retrospective cohort study of patients undergoing arterial switch operation from 2012 to 2017. Nearest-neighbour propensity score matching on age, gender, weight, and associated cardiac defects was used to match 27 controls not receiving recombinant factor VIIa to 30 patients receiving recombinant factor VIIa. Fisher’s exact test was performed to compare categorical variables. Wilcoxon’s rank-sum test was used to compare continuous variables between cohorts.

Results:

Post-operative thrombotic complications were not associated with factor VIIa administration (Odds Ratio (OR) 0.28, 95% CI 0.005–3.77, p = 0.336), nor was factor VIIa administration associated with any re-explorations for bleeding. No intraoperative transfusion volumes were different between the recombinant factor VIIa cohort and controls. Post-operative prothrombin time (10.8 [10.3–12.3] versus 15.9 [15.1–17.2], p < 0.001) and international normalised ratio (0.8 [0.73–0.90] versus 1.3 [1.2–1.4], p < 0.001]) were lower in recombinant factor VIIa cohort relative to controls.

Conclusions:

In spite of a higher post-bypass packed red blood cell transfusion requirement, patients receiving recombinant factor VIIa had a similar incidence of bleeding post-operatively. With no difference in thrombotic complications, and with improved post-operative laboratory haemostasis, a prospective randomised study is warranted to evaluate recombinant factor VIIa.
The Intersection of ‘English Use’ Liturgy and Social Justice: Snapshots of Augustus Pugin, Percy Dearmer, Conrad Noel and William Palmer Ladd
Authors: Spinks Bryan D.
Published: November 2020

The thought of Percy Dearmer was related to that of Augustus Pugin and Daniel Rock, Roman Catholics seeking to revive English medieval forms, and to his Anglican near-contemporaries Conrad Noel and William Palmer Ladd. In England, Noel was more ideologically committed than Dearmer and his imagined medieval society and the English Use were given applied expression at Thaxted. In the USA, William Palmer Ladd was a congenial colleague to Dearmer but his liturgical ideals were of the 1930s, and not an outcome of the nineteenth-century English ritual controversies. Dearmer, Ladd and Noel were all grounded in what has been called Sacramental Socialism, which saw a unity between the Eucharist, the corporate church, and its mission as part of the Kingdom of God.
Club Petroushka, Émigré Performance, and New York's Russian Nightclubs of the Roaring Twenties
Authors: ZELENSKY NATALIE K.
Published: November 2020

In the midst of the Prohibition era, New York City proliferated with nightclubs that presented patrons with imagined worlds of music and entertainment. This essay explores the role of music in creating such imagined worlds, looking specifically at the Russian-themed nightclubs founded by and employing émigrés recently exiled from Bolshevik Russia. Examining Midtown's Club Petroushka as a prime example of such a space, this essay focuses on the so-called “Russian Gypsy” entertainment that caught the eye and ear of the club's patrons, whose ranks included Charlie Chaplin, Harpo Marx, and the Gershwin brothers. Based on an examination of archival material—including memoirs, compositions, and extant recordings of Club Petroushka's musicians and photographs detailing its interior—as well as on advertisements and reviews from Russian American and other newspapers and magazines, this essay contends that the “Russian Gypsy” music presented at Club Petroushka enabled a transformative experience for patrons while providing a performative space for its recently exiled musicians. I argue that two aspects of this music in particular enabled the transformative process as it was delineated in contemporary discourses: 1) heightened emotionality; and 2) playing with a sense of time (a musical attribute I call “achronality”). Examining the complex cultural entanglements at work in the performance of “Russian Gypsy” music and situating my analysis within a theoretical framework of night cultures proposed by Brian D. Palmer and mimesis proposed by Michael Taussig, this essay illuminates the multivalent role of this musical trope for the different constituencies comprising Club Petroushka, while it also documents the largely overlooked Russian-Romani musical tradition as it took shape in the anti-Bolshevik, first wave Russian diaspora.
A Shallow Seabed Dynamic Gas Hydrate System off SW Taiwan: Results From 3‐D Seismic, Thermal, and Fluid Migration Analyses
Authors: Kunath Pascal , Chi Wu‐Cheng , Berndt Christian , Chen Liwen , Liu Char‐Shine , Kläschen Dirk , Muff Sina
Published: November 2020

Large amounts of methane, a potent greenhouse gas, are stored in hydrates beneath the seafloor. Sea level changes can trigger massive methane release into the ocean. It is not clear, however, whether surficial seafloor processes can cause comparable discharge. Previously, fluid migration was difficult to study due to a lack of spatially dense seismic and thermal observations. Here we examine a gas hydrate site at Four‐Way‐Closure Ridge off SW Taiwan using a high‐resolution 3‐D seismic cube, together with bottom‐simulating reflections (BSRs) mapped in the cube, a thermal probe data set, and 3‐D thermal modeling results. We document, on a scale of tens of meters, the interaction between surficial sedimentary processes, fluid flow, and a dynamic gas hydrate system. Fluid migrates upward through dipping permeable strata in the limb, the slope basin, and along thrust faults and ridge‐top normal faults. The seismic data also reveal several double BSRs that underlie seabed sedimentary sliding and depositional features. Abrupt changes in subsurface pressure and temperature due to the rapid seabed sedimentary processes can cause a rapid shift of the base of the gas hydrate stability zone. This shift may be either downward or upward and would result in the accumulation or dissociation of hydrate in sediments sandwiched by the double BSRs, respectively. We propose that dynamic surficial processes on the seafloor together with shallow focused fluid flow affect hydrate distribution and saturation at depth and may even result in methane expulsion into the ocean if such localized features are common along convergent plate boundaries.
Affordable Clean Energy Rule Threatens Progress of Clean Air Act
Authors: Benish Sarah , Fiffer Melissa
Published: November 2020

The scientific community must act to minimize the adverse air quality and health impacts of relaxed EPA regulation.
Stochastic Inversion of Gaussian Random Media Using Transverse Coherence Functions for Reflected Waves: Theory and Method
Authors: Hu Hao , Zheng Yingcai
Published: November 2020

The transverse coherence functions (TCFs) of phase and amplitude fluctuations of a seismic wave are powerful to estimate the spatial distribution, length scales, and strength of random heterogeneities. However, TCFs have been formulated for transmitted waves only, not for reflected waves. In this paper, we derive reflection TCFs for Gaussian random media using the mirror reflection principle. Furthermore, we propose to invert for Gaussian random media using the reflection TCFs based on a grid search. We validate the new reflection TCF formulas using 2‐D elastic finite‐difference numerically modeled seismic data. We also show the feasibility and efficiency of the inverse problem. The stochastic inversion using reflected waves can be used in both exploration and global seismology.
Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis
Authors: Nothdurft Silke , Thumser-Henner Clotilde , Breitenbücher Frank , Okimoto Ross A. , Dorsch Madeleine , Opitz Christiane A. , Sadik Ahmed , Esser Charlotte , Hölzel Michael , Asthana Saurabh , Forster Jan , Beisser Daniela , Kalmbach Sophie , Grüner Barbara M. , Bivona Trever G. , Schramm Alexander , Schuler Martin
Published: November 2020

Lung cancer mortality largely results from metastasis. Despite curative surgery many patients with early-stage non-small cell lung cancer ultimately succumb to metastatic relapse. Current risk reduction strategies based on cytotoxic chemotherapy and radiation have only modest activity. Against this background, we functionally screened for novel metastasis modulators using a barcoded shRNA library and an orthotopic lung cancer model. We identified aryl hydrocarbon receptor (AHR), a sensor of xenobiotic chemicals and transcription factor, as suppressor of lung cancer metastasis. Knockdown of endogenous AHR induces epithelial–mesenchymal transition signatures, increases invasiveness of lung cancer cells in vitro and metastasis formation in vivo. Low intratumoral AHR expression associates with inferior outcome of patients with resected lung adenocarcinomas. Mechanistically, AHR triggers ATF4 signaling and represses matrix metalloproteinase activity, both counteracting metastatic programs. These findings link the xenobiotic defense system with control of lung cancer progression. AHR-regulated pathways are promising targets for innovative anti-metastatic strategies.
Tumor necrosis factor α inhibition overcomes immunosuppressive M2b macrophage-induced bevacizumab resistance in triple-negative breast cancer
Authors: Liu Yu , Ji Xuemei , Kang Nannan , Zhou Junfei , Liang Xue , Li Jiaxin , Han Tianzhen , Zhao Chen , Yang Tianwu
Published: November 2020

Bevacizumab in neoadjuvant therapy provides a new hope of improved survival for patients with triple-negative breast cancer (TNBC) by targeting vascular endothelial growth factor in combination with chemotherapy, but curative effect is limited by bevacizumab’s continuous use while mechanisms remain incompletely understood. More and more researches reported that tumor-associated macrophages mediate resistance to chemotherapy and radiotherapy in various tumors. Here we developed a TNBC model resistant to bevacizumab under bevacizumab continuous administration. It was found that proportion of a specific subset of tumor-associated macrophages characterized as M2b (CD11b+ CD86high IL10high) increased and responsible for acquired resistance to bevacizumab. Then, we showed that RAW264.7 macrophages could be polarized to M2b subtype on simultaneous exposure to bevacizumab and TLR4 ligands as occurs in the context of continuous bevacizumab treatment. Concordantly, in TLR4-deleted C57BL/10ScNJNju (TLR4lps–del) mut/mut mice with bevacizumab treatment model, it was verified that the M2b macrophage could be induced by Fc gamma receptor-TLR4 cross-talk. In MDA-MB-231-resistant tumor-bearing mice, the content of TNFα in serum kept going up consistent with CCL1, a chemokine of M2b macrophage. In vitro neutralizing tumor necrosis factor α (TNFα) could inhibit the tumor progression caused by M2b culture medium and tumor IDO1 expression. Therefore, we thought that TNFα is a key tumor-promoting effector molecule secreted by M2b macrophage. Accordingly, the curative effect of bevacizumab was proved to be significantly improved by neutralizing TNFα with anti-TNFα nanobody. This study is expected to provide theoretical and clinical evidence elucidating the drug resistance in patients receiving bevacizumab.
NQO1 protects obese mice through improvements in glucose and lipid metabolism
Authors: Di Francesco Andrea , Choi Youngshim , Bernier Michel , Zhang Yingchun , Diaz-Ruiz Alberto , Aon Miguel A. , Kalafut Krystle , Ehrlich Margaux R. , Murt Kelsey , Ali Ahmed , Pearson Kevin J. , Levan Sophie , Preston Joshua D. , Martin-Montalvo Alejandro , Martindale Jennifer L. , Abdelmohsen Kotb , Michel Cole R. , Willmes Diana M. , Henke Christine , Navas Placido , Villalba Jose Manuel , Siegel David , Gorospe Myriam , Fritz Kristofer , Biswal Shyam , Ross David , de Cabo Rafael
Published: November 2020

Chronic nutrient excess leads to metabolic disorders and insulin resistance. Activation of stress-responsive pathways via Nrf2 activation contributes to energy metabolism regulation. Here, inducible activation of Nrf2 in mice and transgenesis of the Nrf2 target, NQO1, conferred protection from diet-induced metabolic defects through preservation of glucose homeostasis, insulin sensitivity, and lipid handling with improved physiological outcomes. NQO1-RNA interaction mediated the association with and inhibition of the translational machinery in skeletal muscle of NQO1 transgenic mice. NQO1-Tg mice on high-fat diet had lower adipose tissue macrophages and enhanced expression of lipogenic enzymes coincident with reduction in circulating and hepatic lipids. Metabolomics data revealed a systemic metabolic signature of improved glucose handling, cellular redox, and NAD+ metabolism while label-free quantitative mass spectrometry in skeletal muscle uncovered a distinct diet- and genotype-dependent acetylation pattern of SIRT3 targets across the core of intermediary metabolism. Thus, under nutritional excess, NQO1 transgenesis preserves healthful benefits.
Effectiveness of antipsychotic drugs in schizophrenia: a 10-year retrospective study in a Korean tertiary hospital
Authors: Oh Sanghoon , Lee Tae Young , Kim Minah , Kim Se Hyun , Lee Suehyun , Cho Sunwoo , Kim Ju Han , Kwon Jun Soo
Published: November 2020

Extensive research has been carried out on the comparative effectiveness of antipsychotic medications. Most studies, however, have been performed in Western countries. The purpose of this study was to compare the effectiveness, indicated by time to any-cause discontinuation, of antipsychotic drugs in a large number of patients with schizophrenia in South Korea. We identified 1458 patients with schizophrenia or schizophreniform disorder who were treated with antipsychotic medications using a clinical data warehouse at the Seoul National University Hospital between March 2005 and February 2014. Kaplan–Meier survival analyses were used to estimate the time to discontinuation of antipsychotic drugs. We compared the survival curves of different antipsychotics using log-rank tests. Overall, the median time to discontinuation for any cause was 133 days (95% CI, 126–147). The longest time to discontinuation was observed for clozapine, followed by aripiprazole, paliperidone, olanzapine, amisulpride, risperidone, quetiapine, ziprasidone, and haloperidol. Specifically, clozapine was significantly different from all other antipsychotic drugs (allp < 0.001). Aripiprazole also had a significantly longer time to discontinuation than amisulpride (p = 0.001), risperidone (p < 0.001), quetiapine (p < 0.001), ziprasidone (p < 0.001), and haloperidol (p < 0.001). In Asian patients with schizophrenia, clozapine was the most effective antipsychotic in terms of time to discontinuation, followed by aripiprazole. This study extends the findings of previous effectiveness studies from Western populations and suggests the need to develop guidelines for the pharmacotherapy of schizophrenia tailored to Asian individuals.
Episiotomy practices in France: epidemiology and risk factors in non-operative vaginal deliveries
Authors: Clesse Christophe , Cottenet Jonathan , Lighezzolo-Alnot Joelle , Goueslard Karine , Scheffler Michele , Sagot Paul , Quantin Catherine
Published: November 2020

Episiotomy use has decreased due to the lack of evidence on its protective effects from maternal obstetric anal sphincter injuries. Indications for episiotomy vary considerably and there are a great variety of factors associated with its use. The aim of this article is to describe the episiotomy rate in France between 2013 and 2017 and the factors associated with its use in non-operative vaginal deliveries. In this retrospective population-based cohort study, we included vaginal deliveries performed in French hospitals (N = 584) and for which parity was coded. The variable of interest was the rate of episiotomy, particularly for non-operative vaginal deliveries. Trends in the episiotomy rates were studied using the Cochran-Armitage test. Hierarchical logistic regression was used to identify variables associated with episiotomy according to maternal age and parity. Between 2013 and 2017, French episiotomy rates fell from 21.6 to 14.3% for all vaginal deliveries (p < 0.01), and from 15.5 to 9.3% (p < 0.01) for all non-operative vaginal deliveries. Among non-operative vaginal deliveries, epidural analgesia, non-reassuring fetal heart rate, meconium in the amniotic fluid, shoulder dystocia, and newborn weight (≥ 4,000 g) were risk factors for episiotomy, both for nulliparous and multiparous women. On the contrary, prematurity reduced the risk of its use. For nulliparous women, breech presentation was also a risk factor for episiotomy, and for multiparous women, scarred uterus and multiple pregnancies were risk factors. In France, despite a reduction in episiotomy use over the last few years, the factors associated with episiotomy have not changed and are similar to the literature. This suggests that the decrease in episiotomies in France is an overall tendency which is probably related to improved care strategies that have been relayed by hospital teams and perinatal networks.
Evaluation of right ventricular performance and impact of continuous positive airway pressure therapy in patients with obstructive sleep apnea living at high altitude
Authors: Chu Ai-Ai , Yu Hong-Mei , Yang Hui , Tian Li-Min , Hu Zhong-Yuan , Jiang Na , Xie Wan-Xia , Huang Yan
Published: November 2020

Obstructive sleep apnea syndrome (OSAS) can lead to alterations in right ventricular (RV) performance and pulmonary vascular haemodynamics. Additionally, altitude-related hypoxia is associated with pulmonary vasoconstriction, and the effect of high-altitude on the pulmonary circulation in OSAS patients can be further altered. We sought to assess alterations in RV morphology and function in OSAS patients living at high altitude by way of 2-dimensional speckle tracking echocardiography (2D-STE), real-time 3- dimensional echocardiography (RT-3DE) and cardiac biomarkers. We also evaluate the impact of continuous positive airway pressure (CPAP) treatment on RV performance. Seventy-one patients with newly diagnosed OSAS and thirty-one controls were included in this study. All individuals were assessed for cardiac biomarkers as well as underwent 2D-STE and RT-3DE. Forty-five OSAS patients underwent CPAP therapy for at least 24 weeks and were studied before and after CPAP treatment. RT-3DE was used to measure RV volume, and calculate RV 3D ejection fraction (3D RVEF). Peak systolic strain was determined. Cardiac biomarkers, including C-reactive protein (CRP), N-terminal pro-B-type natriuretic peptide, and cardiac troponin T were also measured. Right atrium volume index, RV volume, RV volume index, systolic pulmonary artery pressure (sPAP), pulmonary vascular resistance (PVR) and level of serum CRP were significantly higher in OSAS group, while OSAS patients showed lower 3D RVEF and RV longitudinal strains. Compared to the patients with sPAP < 40 mmHg, RV longitudinal strains in patients with sPAP ≥ 40 mmHg were lower. Both RV global longitudinal strain and sPAP were associated with apnea–hypopnea index. Patients treated with 6 months of CPAP therapy had significant improvement in RV geometry and performance. RV structural abnormalities and RV function impairments were observed in OSAS patients living at moderate high altitude compared to control highlanders. The reversibility of these changes after application of CPAP were further confirmed.
Full wave 3D inverse scattering transmission ultrasound tomography in the presence of high contrast
Authors: Wiskin James , Malik Bilal , Borup David , Pirshafiey Nasser , Klock John
Published: November 2020

We present here a quantitative ultrasound tomographic method yielding a sub-mm resolution, quantitative 3D representation of tissue characteristics in the presence of high contrast media. This result is a generalization of previous work where high impedance contrast was not present and may provide a clinically and laboratory relevant, relatively inexpensive, high resolution imaging method for imaging in the presence of bone. This allows tumor, muscle, tendon, ligament or cartilage disease monitoring for therapy and general laboratory or clinical settings. The method has proven useful in breast imaging and is generalized here to high-resolution quantitative imaging in the presence of bone. The laboratory data are acquired in ~ 12 min and the reconstruction in ~ 24 min—approximately 200 times faster than previously reported simulations in the literature. Such fast reconstructions with real data require careful calibration, adequate data redundancy from a 2D array of 2048 elements and a paraxial approximation. The imaging results show that tissue surrounding the high impedance region is artifact free and has correct speed of sound at sub-mm resolution.
Investigating the origin and authenticity of Victoria Cross medals using X-ray fluorescence spectrometry
Authors: Marriott Andrew , Prendergast James G. D.
Published: November 2020

The Victoria Cross is the United Kingdom’s premier military award for bravery, presented for gallantry during active operations. Since its inception in 1856 just 1358 have been awarded, and, due to their rarity and historic interest, have become highly prized amongst private and public collections. Unresolved, however, is a debate about the source material of the medals. Some authorities adhere to a traditional belief that all medals have been cast from the bronze of guns captured from the Russians at Sebastopol. Furthermore, controversy is attached to the authenticity of some VCs. In this study we used X-ray fluorescence spectrometry data to compare the metal compositions of 100 Victoria Crosses, covering 7% of those ever issued. Using Gaussian mixture modelling we identify that Victoria Crosses fall into four distinct clusters, confirming that the primary split occurred between medals issued prior to and after 1914. Using these data we investigate the potential of X-ray fluorescence to inform the study of medals whose authenticity have been queried, showing some have unusually similar compositions to other VCs. This paper highlights how X-ray fluorescence data in conjunction with clustering approaches can be used to effectively and non-destructively investigate the authenticity and history of Victoria Crosses.
DNA damage induced by KP372-1 hyperactivates PARP1 and enhances lethality of pancreatic cancer cells with PARP inhibition
Authors: Viera Talysa , Patidar Praveen L.
Published: November 2020

The overall prognosis for pancreatic cancer remains dismal and potent chemotherapeutic agents that selectively target this cancer are critically needed. Elevated expression of NAD(P)H:quinone oxidoreductase 1 (NQO1) is frequent in pancreatic cancer, and it offers promising tumor-selective targeting. Recently, KP372-1 was identified as a novel NQO1 redox cycling agent that induces cytotoxicity in cancer cells by creating redox imbalance; however, the mechanistic basis of KP372-1-induced cytotoxicity remains elusive. Here, we show that KP372-1 sensitizes NQO1-expressing pancreatic cancer cells and spares immortalized normal pancreatic duct cells, hTERT-HPNE. Notably, we found that KP372-1 is ~ 10- to 20-fold more potent than β-lapachone, another NQO1 substrate, against pancreatic cancer cells. Mechanistically, our data strongly suggest that reactive oxygen species produced by NQO1-dependent redox cycling of KP372-1 cause robust DNA damage, including DNA breaks. Furthermore, we found that KP372-1-induced DNA damage hyperactivates the central DNA damage sensor protein poly(ADP-ribose) polymerase 1 (PARP1) and activates caspase-3 to initiate cell death. Our data also show that the combination of KP372-1 with PARP inhibition creates enhanced cytotoxicity in pancreatic cancer cells. Collectively, our study provides mechanistic insights into the cytotoxicity instigated by KP372-1 and lays an essential foundation to establish it as a promising chemotherapeutic agent against cancer.
Neutrophil extracellular traps are induced in a psoriasis model of interleukin-36 receptor antagonist-deficient mice
Authors: Watanabe Soichiro , Iwata Yohei , Fukushima Hidehiko , Saito Kenta , Tanaka Yoshihito , Hasegawa Yurie , Akiyama Masashi , Sugiura Kazumitsu
Published: November 2020

Loss-of-function mutations in the interleukin (IL)-36 gene IL36RN are associated with psoriasis. The importance of neutrophil extracellular traps (NETs), web-like structures composed of neutrophil DNA, in the pathogenesis of psoriasis has been unclear. Here, we aimed to clarify the role of NET signaling in the deficiency of IL36 receptor antagonist (DITRA). We evaluated the severity of psoriasis-like lesions induced by imiquimod cream treatment in Il36rn−/− mice. The mRNA levels of psoriasis-related cytokines were measured via real-time reverse transcription polymerase chain reaction, and the effects of Cl-amidine, a peptidyl arginine deiminase 4 (PAD4) inhibitor, on psoriasis-like lesions were evaluated. PAD4 is a histone-modifying enzyme that is involved in NET formation. Psoriasis area and severity index scores, epidermal thickness, and infiltrated neutrophil counts were significantly increased in Il36rn−/− mice; NET formation was confirmed pathologically. Several cytokines and chemokines were upregulated in the skin lesions of Il36rn−/− mice and Cl-amidine treatment improved these psoriasis-like lesions. These results suggest that NET formation plays an important role in the pathology of psoriasis-like lesions in these mice and might represent a promising therapeutic target for DITRA.
Earthquakes and extreme rainfall induce long term permeability enhancement of volcanic island hydrogeological systems
Authors: Vittecoq B. , Fortin J. , Maury J. , Violette S.
Published: November 2020

Earthquakes affect near-surface permeability, however temporal permeability evolution quantification is challenging due to the scarcity of observations data. Using thirteen years of groundwater level observations, we highlight clear permeability variations induced by earthquakes in an aquifer and overlaying aquitard. Dynamic stresses, above a threshold value PGV > 0.5 cm s−1, were mostly responsible for these variations. We develop a new model using earth tides responses of water levels between earthquakes. We demonstrate a clear permeability increase of the hydrogeological system, with the permeability of the aquifer increasing 20-fold and that of the aquitard 300-fold over 12 years, induced by fracture creation or fracture unclogging. In addition, we demonstrate unprecedented observations of increase in permeability due to the effect of extreme tropical deluges of rainfall and hurricanes. The water pressure increase induced by the exceptional rainfall events thus act as piston strokes strong enough to unclog congested fractures by colloids, particles or precipitates. Lastly, an analysis of regional permeabilities also highlights a permeability increase over geological timeframes (× 40 per million years), corroborating the trend observed over the last decade. This demonstrates that permeability of aquifers of andesitic volcanic islands, such as the Lesser Antilles, significantly evolve with time due to seismic activity and extreme rainfall.
Characterization of Plasmodium falciparum NEDD8 and identification of cullins as its substrates
Authors: Bhattacharjee Manish , Adhikari Navin , Sudhakar Renu , Rizvi Zeba , Das Divya , Palanimurugan R. , Sijwali Puran Singh
Published: November 2020

A variety of post-translational modifications of Plasmodium falciparum proteins, including phosphorylation and ubiquitination, are shown to have key regulatory roles during parasite development. NEDD8 is a ubiquitin-like modifier of cullin-RING E3 ubiquitin ligases, which regulates diverse cellular processes. Although neddylation is conserved in eukaryotes, it is yet to be characterized in Plasmodium and related apicomplexan parasites. We characterized P. falciparum NEDD8 (PfNEDD8) and identified cullins as its physiological substrates. PfNEDD8 is a 76 amino acid residue protein without the C-terminal tail, indicating that it can be readily conjugated. The wild type and mutant (Gly75Ala/Gly76Ala) PfNEDD8 were expressed in P. falciparum. Western blot of wild type PfNEDD8-expressing parasites indicated multiple high molecular weight conjugates, which were absent in the parasites expressing the mutant, indicating conjugation of NEDD8 through Gly76. Immunoprecipitation followed by mass spectrometry of wild type PfNEDD8-expressing parasites identified two putative cullins. Furthermore, we expressed PfNEDD8 in mutant S. cerevisiae strains that lacked endogenous NEDD8 (rub1Δ) or NEDD8 conjugating E2 enzyme (ubc12Δ). The PfNEDD8 immunoprecipitate also contained S. cerevisiae cullin cdc53, further substantiating cullins as physiological substrates of PfNEDD8. Our findings lay ground for investigation of specific roles and drug target potential of neddylation in malaria parasites.
Strategies to produce T-DNA free CRISPRed fruit trees via Agrobacterium tumefaciens stable gene transfer
Authors: Dalla Costa Lorenza , Piazza Stefano , Pompili Valerio , Salvagnin Umberto , Cestaro Alessandro , Moffa Loredana , Vittani Lorenzo , Moser Claudio , Malnoy Mickael
Published: November 2020

Genome editing via CRISPR/Cas9 is a powerful technology, which has been widely applied to improve traits in cereals, vegetables and even fruit trees. For the delivery of CRISPR/Cas9 components into dicotyledonous plants, Agrobacterium tumefaciens mediated gene transfer is still the prevalent method, although editing is often accompanied by the integration of the bacterial T-DNA into the host genome. We assessed two approaches in order to achieve T-DNA excision from the plant genome, minimizing the extent of foreign DNA left behind. The first is based on the Flp/FRT system and the second on Cas9 and synthetic cleavage target sites (CTS) close to T-DNA borders, which are recognized by the sgRNA. Several grapevine and apple lines, transformed with a panel of CRISPR/SpCas9 binary vectors, were regenerated and characterized for T-DNA copy number and for the rate of targeted editing. As detected by an optimized NGS-based sequencing method, trimming at T-DNA borders occurred in 100% of the lines, impairing in most cases the excision. Another observation was the leakage activity of Cas9 which produced pierced and therefore non-functional CTS. Deletions of genomic DNA and presence of filler DNA were also noticed at the junctions between T-DNA and genomic DNA. This study proved that many factors must be considered for designing efficient binary vectors capable of minimizing the presence of exogenous DNA in CRISPRed fruit trees.
Loss of the spectraplakin gene Short stop induces a DNA damage response in Drosophila epithelia
Authors: Dewey Evan B. , Parra Amalia S. , Johnston Christopher A.
Published: November 2020

Epithelia are an eminent tissue type and a common driver of tumorigenesis, requiring continual precision in cell division to maintain tissue structure and genome integrity. Mitotic defects often trigger apoptosis, impairing cell viability as a tradeoff for tumor suppression. Identifying conditions that lead to cell death and understanding the mechanisms behind this response are therefore of considerable importance. Here we investigated how epithelia of the Drosophila wing disc respond to loss of Short stop (Shot), a cytoskeletal crosslinking spectraplakin protein that we previously found to control mitotic spindle assembly and chromosome dynamics. In contrast to other known spindle-regulating genes, Shot knockdown induces apoptosis in the absence of Jun kinase (JNK) activation, but instead leads to elevated levels of active p38 kinase. Shot loss leads to double-strand break (DSB) DNA damage, and the apoptotic response is exacerbated by concomitant loss of p53. DSB accumulation is increased by suppression of the spindle assembly checkpoint, suggesting this effect results from chromosome damage during error-prone mitoses. Consistent with DSB induction, we found that the DNA damage and stress response genes, Growth arrest and DNA damage (GADD45) and Apoptosis signal-regulating kinase 1 (Ask1), are transcriptionally upregulated as part of the shot-induced apoptotic response. Finally, co-depletion of Shot and GADD45 induced significantly higher rates of chromosome segregation errors in cultured cells and suppressed shot-induced mitotic arrest. Our results demonstrate that epithelia are capable of mounting molecularly distinct responses to loss of different spindle-associated genes and underscore the importance of proper cytoskeletal organization in tissue homeostasis.
Retraction Note: Silencing of Glutathione S-Transferase Pi Inhibits Cancer Cell Growth via Oxidative Stress Induced by Mitochondria Dysfunction
Authors: Fujitani Naoki , Yoneda Akihiro , Takahashi Motoko , Takasawa Akira , Aoyama Tomoyuki , Miyazaki Tadaaki
Published: November 2020

Editor's Note: this Article has been retracted; the Retraction Note is available at https://www.nature.com/articles/s41598-020-77205-9
Inverse sex-based expression profiles of PTEN and Klotho in mice
Authors: de Mello Natalia Prudente , Andreotti Diana Zukas , Orellana Ana Maria , Scavone Cristoforo , Kawamoto Elisa Mitiko
Published: November 2020

Sex differences are considered predictive factors in the development of several neurological diseases, which are also known to coincide with impaired phosphoinositide 3-kinase (PI3K)-AKT pathway activity, an essential signaling cascade involved in the control of several cellular functions such as autophagy and apoptosis. Here, under physiological conditions, we show important sex differences in the underlying balancing mechanisms that lead to similar AKT activity levels and autophagy and apoptosis processes in the two sexes. We demonstrate inverse sex-based expression of PTEN and Klotho, two important proteins that are known to negatively regulate the AKT pathway, and inverse sex-dependent levels of mTOR and FoxO3a activity. Taken together, our findings indicate that inverse sex-based regulation may be one of the underlying balancing mechanisms that differ between the sexes and a possible cause of sex-based autophagic and apoptotic responses to triggering situations that can lead to a sex-based predisposition to some neurological diseases.
Combined light- and heat-induced shape memory behavior of anthracene-based epoxy elastomers
Authors: Li Yuzhan , Goswami Monojoy , Zhang Yuehong , Liu Tuan , Zhang Jinwen , Kessler Michael R. , Wang Liwei , Rios Orlando
Published: November 2020

The development of multi-stimuli-responsive shape memory polymers has received increasing attention because of its scientific and technological significance. In this work, epoxy elastomers with reversible crosslinks are synthesized by polymerizing an anthracene-functionalized epoxy monomer, a diepoxy comonomer, and a dicarboxylic acid curing agent. The synthesized elastomers exhibit active responses to both light and heat enabled by the incorporated anthracene groups. When exposed to 365 nm UV light, additional crosslinking points are created by the photo-induced dimerization of pendant anthracene groups. The formation of the crosslinking points increases modulus and glass transition temperature of the elastomers, allowing for the fixation of a temporary shape at room temperature. The temporary shape remains stable until an external heat stimulus is applied to trigger the scission of the dimerized anthracene, which reduces the modulus and glass transition temperature and allows the elastomers to recover their original shapes. The effects of external stimuli on the thermal and dynamic mechanical properties of the elastomers are investigated experimentally and are correlated with molecular dynamics simulations that reveal the changes of structure and dynamics of the anthracene molecules and flexible chains.
Serum trace metal association with response to erythropoiesis stimulating agents in incident and prevalent hemodialysis patients
Authors: Brier Michael E. , Gooding Jessica R. , Harrington James M. , Burgess Jason P. , McRitchie Susan L. , Zhang Xiaolan , Rovin Brad H. , Klein Jon B. , Himmelfarb Jonathan , Sumner Susan J. , Merchant Michael L.
Published: November 2020

Alterations in hemodialysis patients’ serum trace metals have been documented. Early studies addressing associations levels of serum trace metals with erythropoietic responses and/or hematocrit generated mixed results. These studies were conducted prior to current approaches for erythropoiesis stimulating agent (ESA) drug dosing guidelines or without consideration of inflammation markers (e.g. hepcidin) important for regulation of iron availability. This study sought to determine if the serum trace metal concentrations of incident or chronic hemodialysis patients associated with the observed ESA response variability and with consideration to ESA dose response, hepcidin, and high sensitivity C-reactive protein levels. Inductively-coupled plasma-mass spectrometry was used to measure 14 serum trace metals in 29 incident and 79 prevalent dialysis patients recruited prospectively. We compared these data to three measures of ESA dose response, sex, and dialysis incidence versus dialysis prevalence. Hemoglobin was negatively associated with ESA dose and cadmium while positively associated with antimony, arsenic and lead. ESA dose was negatively associated with achieved hemoglobin and vanadium while positively associated with arsenic. ESA response was positively associated with arsenic. Vanadium, nickel, cadmium, and tin were increased in prevalent patients. Manganese was increased in incident patients. Vanadium, nickel, and arsenic increased with time on dialysis while manganese decreased. Changes in vanadium and manganese were largest and appeared to have some effect on anemia. Incident and prevalent patients’ chromium and antimony levels exceeded established accepted upper limits of normal.
Inhibitory effects of astaxanthin on postovulatory porcine oocyte aging in vitro
Authors: Jia Bao-Yu , Xiang De-Cai , Shao Qing-Yong , Zhang Bin , Liu Shao-Na , Hong Qiong-Hua , Quan Guo-Bo , Wu Guo-Quan
Published: November 2020

Mammalian oocytes represent impaired quality after undergoing a process of postovulatory aging, which can be alleviated through various effective ways such as reagent treatment. Accumulating evidences have revealed the beneficial effects of astaxanthin (Ax) as a potential antioxidant on reproductive biology. Here, porcine matured oocytes were used as a model to explore whether Ax supplement can protect against oocyte aging in vitro and the underlying mechanism, and therefore they were cultured with or without 2.5 μM Ax for an additional 24 h. Aged oocytes treated with Ax showed improved yield and quality of blastocysts as well as recovered expression of maternal genes. Importantly, oxidative stress in aged oocytes was relieved through Ax treatment, based on reduced reactive oxygen species and enhanced glutathione and antioxidant gene expression. Moreover, inhibition in apoptosis and autophagy of aged oocyte by Ax was confirmed through decreased caspase-3, cathepsin B and autophagic activities. Ax could also maintain spindle organization and actin expression, and rescue functional status of organelles including mitochondria, endoplasmic reticulum, Golgi apparatus and lysosomes according to restored fluorescence intensity. In conclusion, Ax might provide an alternative for ameliorating the oocyte quality following aging in vitro, through the mechanisms mediated by its antioxidant properties.
COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1
Authors: Dankel Simon N. , Grytten Elise , Bjune Jan-Inge , Nielsen Hans Jørgen , Dietrich Arne , Blüher Matthias , Sagen Jørn V. , Mellgren Gunnar
Published: November 2020

Fibrillar collagen COL6α3 in adipose tissue has been associated with obesity, inflammation, insulin resistance and cancer. We here aimed to identify novel transcriptional regulators of COL6A3 expression. Based on a transcriptome dataset of adipose tissue, we identified strong correlations for 56 genes with COL6A3 mRNA, including targets of TGF-β/SMAD signaling. Among the identified candidates, the homeobox transcription factor PRRX1 showed a particularly striking co-expression with COL6A3, validated across several different cohorts, including patients with extreme obesity, insulin sensitive and resistant obesity (subcutaneous and omental), after profound fat loss (subcutaneous), and lean controls (subcutaneous). In human and mouse adipose cells, PRRX1 knockdown reduced COL6A3 mRNA and PRRX1 overexpression transactivated a reporter construct with the endogenous human COL6A3 promoter. Stable PRRX1 overexpression in 3T3-L1 cells induced Col6a3 mRNA threefold specifically after adipogenic induction, whereas TGF-β1 treatment upregulated Col6a3 mRNA also in the preadipocyte state. Interestingly, pro-inflammatory stimulus (i.e., TNF-α treatment) decreased PRRX1-mediated Col6a3 transactivation and mRNA expression, supporting a role for this mechanism in the regulation of adipose tissue inflammation. In conclusion, we identified the homeobox factor PRRX1 as a novel transcriptional regulator associated with COL6A3 expression, providing new insight into the regulatory mechanisms of altered adipose tissue function in obesity and insulin resistance.
Super-enhancer in prostate cancer: transcriptional disorders and therapeutic targets
Authors: Chen Xuanrong , Ma Qianwang , Shang Zhiqun , Niu Yuanjie
Published: November 2020

Abnormal activity of oncogenic and tumor-suppressor signaling pathways contributes to cancer and cancer risk in humans. Transcriptional dysregulation of these pathways is commonly associated with tumorigenesis and the development of cancer. Genetic and epigenetic alterations may mediate dysregulated transcriptional activity. One of the most important epigenetic alternations is the non-coding regulatory element, which includes both enhancers and super-enhancers (SEs). SEs, characterized as large clusters of enhancers with aberrant high levels of transcription factor binding, have been considered as key drivers of gene expression in controlling and maintaining cancer cell identity. In cancer cells, oncogenes acquire SEs and the cancer phenotype relies on these abnormal transcription programs driven by SEs, which leads to cancer cells often becoming addicted to the SEs-related transcription programs, including prostate cancer. Here, we summarize recent findings of SEs and SEs-related gene regulation in prostate cancer and review the potential pharmacological inhibitors in basic research and clinical trials.