bluuebunny/crossref_metadata_2025 huggingface dataset:
Pluralism and the General Will: The Roman and Spartan Models in Rousseau'sSocial Contract
Authors: Oprea Alexandra
Published: September 2019

How should institutions be designed so that the votes of the people reflect the general will and not the corporate will of the politically powerful? Rousseau'sSocial Contractprovides us with two mutually exclusive solutions. The first is the more commonly discussed Spartan model where an encompassing public education system eliminates pluralism through social engineering. The second is the often overlooked Roman model of organizing the population into multiple overlapping electoral divisions and checking the power of various interest groups. Rousseau's discussion of Servius's electoral reforms anticipates Madison's arguments about controlling the effects of factions. By distinguishing these two institutional solutions, the article challenges the dominance of Sparta in readings of theSocial Contractand supports the broader antiutopian turn in Rousseau scholarship.
Aristotelian Realism: Political Friendship and the Problem of Stability
Authors: Cheng Eric
Published: September 2019

This paper argues that the pursuit of stability is the primary concern of Aristotle's understanding of political friendship. Specifically, I argue that Aristotle chooses to understand political friendship to be a “special sort” of utility/advantage friendship, applicable to multiple regime types of varying degrees of (in)equality, because he fears what might happen when citizens in any polity develop mutual animosity. Turning to the contemporary liberal democratic context, I note that Aristotle provides us with a strong positive argument for why we ought to take political friendship seriously. However, I stipulate that contemporary liberal democracies present obstacles to the realization of classical political friendship. I thereby conclude by suggesting that citizens can potentially be political friends when they understand politics and their social relations through the “metaphor” of political friendship.
The Reader and the Resurrection in Prudentius
Authors: Pelttari Aaron
Published: September 2019

In Prudentius, the bodily resurrection becomes a figure for poetic immortality. Just as the author believes that his God will one day raise him from the dead, he expects and invokes a Christian reader to authenticate and authorise the fragile verbal records of a poetry that is insistently human and fallen. In other words, Prudentius’ metapoetics are perfectly in sync with his theology. After (I) presenting Prudentius’ transformation at the end of hisPraefatioand setting out the terms and scope of the argument, this article (II) shows how the author puts himself at the mercy of his readers and patrons in thePeristefanonpoems and then (III) considers the body and the resurrection in theLiber Cathemerinon. A short section (IV) on fictionality and belief opens up the argument, and a conclusion (V) advances it through a reading of the end ofDe opusculis suis. This metapoetic reading of Prudentius reveals that the author's hopes for an afterlife are expressed in and through the creative imagining of poetic and fictional scenes.
Moral reasoning is the process of asking moral questions and answering them
Authors: Alfano Mark
Published: September 2019

Reasoning is the iterative, path-dependent process of asking questions and answering them. Moral reasoning is a species of such reasoning, so it is a matter of asking and answering moral questions, which requires both creativity and curiosity. As such, interventions and practices that help people ask more and better moral questions promise to improve moral reasoning.
Moral judgment as reasoning by constraint satisfaction
Authors: Holyoak Keith J. , Powell Derek
Published: September 2019

May's careful examination of empirical evidence makes a compelling case against the primacy of emotion in driving moral judgments. At the same time, emotion certainly is involved in moral judgments. We argue that emotion interacts with beliefs, values, and moral principles through a process of coherence-based reasoning (operating at least partially below the level of conscious awareness) in generating moral judgments and decisions.
Optimism in unconscious, intuitive morality
Authors: Clark Cory J. , Winegard Bo M.
Published: September 2019

Moral cognition, by its very nature, stems from intuitions about what is good and bad, and these intuitions influence moral assessments outside of conscious awareness. However, because humans evolved a shared set of moral intuitions, and are compelled to justify their moral assessments as good and rational (even erroneously) to others, moral virtue and moral progress are still possible.
Baselines for human morality should include species typicality, inheritances, culture, practice, and ecological attachment
Authors: Narvaez Darcia
Published: September 2019

Empirical studies involve WEIRD (Western, European, industrialized, rich, democratic) but also un-nested (raised outside humanity's evolved nest) and underdeveloped participants. Assessing human moral potential needs to integrate a transdisciplinary approach to understanding species typicality and baselines, relevant evolutionary inheritances beyond genes, assessment of cultures and practices that foster (or not) virtue, and ecological morality. Human moral reason (nous) emerges from all of these.
The space between rationalism and sentimentalism: A perspective from moral development
Authors: Rottman Joshua
Published: September 2019

May interprets the prevalence of non-emotional moral intuitions as indicating support for rationalism. However, research in developmental psychology indicates that the mechanisms underlying these intuitions are not always rational in nature. Specifically, automatic intuitions can emerge passively, through processes such as evolutionary preparedness and enculturation. Although these intuitions are not always emotional, they are not clearly indicative of reason.
Moral foundations are not moral propositions
Authors: Haas Daniel
Published: September 2019

Joshua May responds to skepticism about moral knowledge via appeal to empirical work on moral foundations. I demonstrate that the moral foundations literature is not able to do the work May needs. It demonstrates shared moral cognition, not shared moral judgment, and therefore, May's attempt to defeat general skepticism fails.
HEARING THE BODY OF CHRIST IN EARLY MODERN PRAGUE
Authors: Honisch Erika Supria
Published: September 2019

The multi-confessional cities of early modern Central Europe resounded with sacred music. People sang to express faith, to challenge the beliefs of others, and to lay claim to shared urban spaces. This study considers how such music was heard in Prague, the capital of the Holy Roman Empire, during the reign of the Habsburg Emperor Rudolf II (1576–1612). During this period, the city’s Catholics jostled for supremacy with Czech-speaking Utraquists (followers of Jan Hus), who vastly outnumbered them, and a growing population of German-speaking Lutherans. Focusing on the sonically rich Corpus Christi processions held by Prague’s Jesuits, this article examines how sounds that aggressively promoted Catholic Eucharistic doctrine were received by those who were––by chance or by design––within earshot. Viewing Catholic claims alongside non-Catholic resistance suggests that music’s power lay as much in the fact of its performance as in its deployment of specific texts and sounds.
An “Untrammeled Right”? The McCarran Immigration Subcommittee and the Origins of Presidential Authority to Suspend and Restrict Alien Entry Under §1182(f)
Authors: Friman H. Richard
Published: September 2019

The language of Section 212(e) of the 1952 Immigration and Nationality Act, 8 U.S.C. §1182(f), contains a sweeping authorization of presidential discretion to suspend and restrict alien entry into the United States. Senator Pat McCarran (D-NV) first introduced the subsection in 1950 as part of the omnibus immigration bill drafted by his Judiciary Committee’s immigration subcommittee. The specific origins of the language and the original intent behind the subsection remain missing pieces in the extensive scholarly literature on the 1952 INA and legislative history as explored by the courts. This article reveals that the subcommittee modeled the subsection on the sixth proviso of the 1917 Immigration Act, the May 1918 Wartime Measure, and a selective interpretation of Supreme Court precedent. The article reveals further that the original intent behind the subsection was to close perceived loopholes in existing law enabling entry by displaced persons and Communist governmental officials.
Urban Regimes and the Policing of Strikes in Two Gilded Age Cities: New York and Chicago
Authors: Schneirov Richard
Published: September 2019

Since the 1980s, scholars have argued that during the Gilded Age urban party machines incorporated working people through the use of patronage, informal provision of personal welfare, and limited concessions, thereby eliminating sustained labor and Socialist Party alternatives and keeping workers’ militancy and assertiveness confined to the workplace. That view is challenged by a historical comparison of the policing of labor disputes in New York and Chicago. In New York, organized workers were eliminated from the governing coalition of the Swallowtail-Kelly regime that succeeded the Tweed Ring, and police routinely used coercion to defeat strikes and intimidate Socialists. In Chicago, however, labor and Socialists were part of the governing coalition of the Carter Harrison regime, and the police took a hands-off stance in many strikes. This article explores the contrast in policing and the balance of social forces in the two cities and seeks to explain the differences by examining the political settlements that concluded Reconstruction, the ethnic makeup of each city's working classes, the different characteristics of each city's labor movement, and labor's ability to mount third-party challenges—all in the context of regional variations. It concludes that historians cannot assume that workers were incorporated into machines in this period.
How to evaluate machine translation: A review of automated and human metrics
Authors: Chatzikoumi Eirini
Published: September 2019

This article presents the most up-to-date, influential automated, semiautomated and human metrics used to evaluate the quality of machine translation (MT) output and provides the necessary background for MT evaluation projects. Evaluation is, as repeatedly admitted, highly relevant for the improvement of MT. This article is divided into three parts: the first one is dedicated to automated metrics; the second, to human metrics; and the last, to the challenges posed by neural machine translation (NMT) regarding its evaluation. The first part includes reference translation–based metrics; confidence or quality estimation (QE) metrics, which are used as alternatives for quality assessment; and diagnostic evaluation based on linguistic checkpoints. Human evaluation metrics are classified according to the criterion of whether human judges directly express a so-called subjective evaluation judgment, such as ‘good’ or ‘better than’, or not, as is the case in error classification. The former methods are based on directly expressed judgment (DEJ); therefore, they are called ‘DEJ-based evaluation methods’, while the latter are called ‘non-DEJ-based evaluation methods’. In the DEJ-based evaluation section, tasks such as fluency and adequacy annotation, ranking and direct assessment (DA) are presented, whereas in the non-DEJ-based evaluation section, tasks such as error classification and postediting are detailed, with definitions and guidelines, thus rendering this article a useful guide for evaluation projects. Following the detailed presentation of the previously mentioned metrics, the specificities of NMT are set forth along with suggestions for its evaluation, according to the latest studies. As human translators are the most adequate judges of the quality of a translation, emphasis is placed on the human metrics seen from a translator-judge perspective to provide useful methodology tools for interdisciplinary research groups that evaluate MT systems.
Discovering multiword expressions
Authors: Villavicencio Aline , Idiart Marco
Published: September 2019

In this paper, we provide an overview of research on multiword expressions (MWEs), from a natural language processing perspective. We examine methods developed for modelling MWEs that capture some of their linguistic properties, discussing their use for MWE discovery and for idiomaticity detection. We concentrate on their collocational and contextual preferences, along with their fixedness in terms of canonical forms and their lack of word-for-word translatatibility. We also discuss a sample of the MWE resources that have been used in intrinsic evaluation setups for these methods.
The Influence of Premorbid Adjustment and Autistic Traits on Social Cognitive Dysfunction in Schizophrenia
Authors: Bechi Margherita , Agostoni Giulia , Buonocore Mariachiara , Bosinelli Francesca , Spangaro Marco , Bianchi Laura , Cocchi Federica , Guglielmino Carmelo , Cavallaro Roberto , Bosia Marta
Published: September 2019

Objectives:

Premorbid dysfunction during childhood and adolescence is well documented in patients with schizophrenia. Literature pointed out multiple premorbid trajectories leading to different patients’ cognitive status, symptomatology, and global functioning after disease onset. This study aimed at identifying groups of premorbid trajectories and disentangling between group differences in clinical and cognitive measures, focusing on theory of mind (ToM) and autistic traits (ATs).

Methods:

Ninety-seven patients with schizophrenia were recruited and assessed for cognitive and ToM abilities, psychopathology, and ATs. A two-step cluster analysis identified three different groups of patients based on premorbid adjustment during childhood, adolescence, and late adolescence (i.e., stable-good, stable-poor, and “deteriorating”).

Results:

Compared to 66 healthy controls, results showed a widespread impairment in cognitive and ToM abilities among all groups of patients, except for affective ToM and executive functions in the stable-good group. Moreover, the stable-poor group exhibited more pronounced ATs and a more severe ToM impairment, compared to the other two groups of patients.

Conclusions:

Our findings highlight the existence of a group of patients with poor premorbid adjustment since childhood, more pronounced ATs and a severe ToM impairment affecting those basic mentalizing skills that are usually preserved in schizophrenia. Results might have intriguing implications in identifying underpinning endophenotypes and implementing cutting-edge rehabilitation programs.
Farmer perspectives and experiences introducing the novel perennial grain Kernza intermediate wheatgrass in the US Midwest
Authors: Lanker Marisa , Bell Michael , Picasso Valentin D.
Published: September 2019

Kernza® intermediate wheatgrass (Thinopyrum intermedium) is a novel perennial grain and forage crop with the potential to provide multiple ecosystem services, which recently became commercially available to farmers in the USA. The viability and further expansion of this promising crop require understanding how it may fit the needs of farmers’ livelihoods and the structure of their farming systems. However, no prior research has studied the perceptions and experiences of Kernza growers. The goals of this research were to understand why farmers grow Kernza, how Kernza fits into their systems and identify challenges for future research. We conducted in-depth interviews with ten growers in the North Central USA during the summer of 2017, who accounted for a third of the Kernza farmers in the USA at the time. All farmers had a positive attitude toward experimentation and trying new practices, and they were interested in Kernza for its simultaneous ecological and economic benefits. Kernza was marginal in terms of area, quality of fields and resources allocated in the farm systems, which also meant that farmers maintained low costs and risks. Growers utilized and valued Kernza as a dual-use crop (grain and forage), sometimes not harvesting grain but almost always grazing or harvesting hay and straw for bedding. Weeds were perceived as a challenge in some cases, but Kernza was valued as a highly weed-suppressive crop in others. Farmers requested information on optimal establishment practices, assessment of forage nutritive value, how to maintain grain yields over years, weed management, markets and economic assessment of Kernza systems. These results agree with other cases on sustainable practices adoption showing that engaging farmers in the research process from the beginning, identifying knowledge gaps and testing management alternatives are critical for the success and expansion of novel agricultural technologies.
Elite collective agency and the state
Authors: Ertürk Korkut Alp
Published: September 2019

The paper explores how elites can develop capacity for collective agency through coordination.. The challenge for elites is to simultaneously deter the state from abusing power while at the same time relying on it to discipline defectors in their midst..The basic insight holds that the credibility of the state's threats depends on the cost of carrying them out, which elites can control. The elites can coordinate by being compliant when the ruler's threats serve their collective interest, which by reducing the cost of carrying them out make them more credible. On the other hand, their coordinated non-compliance has the opposite effect...
Characteristic mode-based compact circularly polarized metasurface antenna for in-band RCS reduction
Authors: Rajanna Puneeth Kumar , Rudramuni Karthik , Kandasamy Krishnamoorthy
Published: September 2019

This paper presents a novel design of a low profile circularly polarized (CP) metasurface (MTS) antenna with in-band radar cross-section (RCS) reduction property. The MTS is loaded as a superstrate on slot antenna and it can be viewed as a polarization-dependent MTS (PDMTS). The rectangular patch-based PDMTS is analyzed using characteristic mode analysis to find two orthogonal degenerate modes, which produces CP waves. Linearly polarized slot antenna is used to excite the PDMTS. The performance of PDMTS loaded slot antenna is analyzed numerically using full-wave analysis method. The PDMTS CP antenna is fabricated and its performance is tested experimentally. The proposed antenna has a compact structure and it has an overall size of $0.52{\lambda _0}\times 0.52{\lambda _0} \times 0.078{\lambda _0}$ (where ${\lambda _0}$ is the free space wavelength). The measured results show that the PDMTS antenna achieves $-10\,{\rm dB}$ impedance bandwidth of 29.41$\%$, 3-dB axial ratio bandwidth of 9.05$\%$, broadside gain of 6.34 dB, and monostatic RCS reduction of $-30.2\,{\rm dBsm}$ at the resonant frequency of 5.86 GHz. The simulated results are in well agreement with the measured results and it is well suited for C-band Radar and Satellite communication.
Bermudagrass tolerance of indaziflam PRE applications in forage production
Authors: Hurdle Nicholas L. , Grey Timothy L. , McCullough Patrick E. , Shilling Donn , Belcher Jason
Published: September 2019

Bermudagrass is a major forage species throughout Georgia and the Southeast. An essential part of achieving high-yielding, top-quality forages is proper weed control. Indaziflam is a residual herbicide that controls many broadleaf and grass species by inhibiting cellulose biosynthesis. Research conducted in Tift and Colquitt counties in Georgia determined optimal PRE rates for indaziflam for bermudagrass forage production. Treatments applied at spring greenup of established ‘Alicia’ bermudagrass included indaziflam at 47, 77, 155, or 234 g ai ha−1 PRE, pendimethalin at 4,480 g ha−1 PRE, a split application of indaziflam at 47 g ha−1 PRE followed by the same rate applied POST after the first cutting, and a nontreated control (seven treatments in all). Forages were machine harvested three times each year for each location beginning at least 47 d after treatment (DAT), with final cuttings up to 168 DAT. For all treatments, fresh- and dry-weight yields at each harvest and totals for the season did not differ from the nontreated control. Indaziflam at 155 and 234 g ha−1 did cause minor stunting at 44 DAT, but this was transient and not observed at the second harvest. Indaziflam applied PRE has the potential to provide residual control of troublesome weeds in bermudagrass forage and hay production, with ephemeral stunting at the recommended application rates.
Ge/Si Partitioning in Igneous Systems: Constraints From Laser Ablation ICP‐MS Measurements on Natural Samples
Authors: He Detao , Lee Cin‐Ty A. , Yu Xun , Farner Michael
Published: September 2019

Mineral/melt and intermineral Ge/Si exchange coefficients for nine common rock‐forming silicate minerals were determined by Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA‐ICP‐MS). Ge/Si mineral/melt exchange coefficients were found to vary by up to a factor of 10. In mafic and ultramafic systems, Ge/Si mineral/melt exchange coefficients are less than 1 for plagioclase (0.48) and olivine (0.72), close to 1 for clinopyroxene (1.17) and orthopyroxene (1.07), and greater than 1 for garnet (2.69). In felsic and silicic systems, the Ge/Si mineral/melt exchange coefficient is less than 1 for quartz (0.23), plagioclase (0.67), and potassium feldspar (0.67) but much greater than 1 for biotite (4.80) and hornblende (3.95). We show that early, olivine‐dominated fractionation of primitive basalts does not fractionate Ge/Si significantly, but subsequent cotectic crystallization of plagioclase and pyroxene can increase the Ge/Si ratio from 6 × 10−6 to 7 × 10−6. We show that the only way to decrease Ge/Si during magmatic differentiation is by crystallization of hornblende or biotite (though biotite is typically a late crystallizing phase), consistent with hornblende being a major fractionating phase in hydrous intermediate magmas. The high compatibility of Ge in hornblende makes this element, in conjunction with Si, a potentially useful approach for distinguishing between hornblende and garnet in the source regions of intermediate magmas. The high compatibility of Ge in micas suggests that Ge/Si systematics may also be useful in understanding the origin of ultrapotassic magmas, which are often thought to derive from phlogopite‐rich sources.
Distinct Ultrafine‐ and Accumulation‐Mode Particle Properties in Clean and Polluted Urban Environments
Authors: Wang Yuying , Li Zhanqing , Zhang Renyi , Jin Xiaoai , Xu Weiqi , Fan Xinxin , Wu Hao , Zhang Fang , Sun Yele , Wang Qiuyan , Cribb Maureen , Hu Dawei
Published: September 2019

In this study, we report the phenomenon of fast changes in aerosol hygroscopicity between clean and polluted periods observed frequently in urban Beijing during winter using a hygroscopicity tandem mobility analyzer. The cause of this phenomenon and the formation process of particles in different modes are discussed. During clean periods, ultrafine‐mode particles (i.e., nucleation and Aitken modes) stem mainly from nucleation events with subsequent growth. During heavily polluted periods, ultrafine‐mode particles originate chiefly from primary emissions. Larger‐mode particles like accumulation‐mode particles are mainly from primary emissions during clean periods and aqueous reactions during polluted periods. This finding based on hygroscopicity tandem mobility analyzer measurements can make up the deficiency of mass‐dependent instruments in analyzing sources and chemical processes of ultrafine‐mode particles.
Modeling the Electron Flux Enhancement and Butterfly Pitch Angle Distributions on L Shells <2.5
Authors: Hua Man , Li Wen , Ma Qianli , Ni Binbin , Nishimura Yukitoshi , Shen Xiao‐Chen , Li Haimeng
Published: September 2019

We analyze an energetic electron flux enhancement event in the inner radiation belt observed by Van Allen Probes during an intense geomagnetic storm. The energetic electron flux at L~1.5 increased by a factor of 3 with pronounced butterfly pitch angle distributions (PADs). Using a three‐dimensional radiation belt model, we simulate the electron evolution under the impact of radial diffusion, local wave‐particle interactions including hiss, very low frequency transmitters, and magnetosonic waves, as well as Coulomb scattering. Consistency between observation and simulation suggests that inward radial diffusion plays a dominant role in accelerating electrons up to 900 keV and transporting the butterfly PADs from higher L shells to form the butterfly PADs at L~1.5. However, local wave‐particle interactions also contribute to drive butterfly PADs at L ≳ 1.9. Our study provides a feasible mechanism to explain the electron flux enhancement in the inner belt and the persistent presence of the butterfly PADs at L~1.5.
Persistent Supercooled Drizzle at Temperatures Below −25 °C Observed at McMurdo Station, Antarctica
Authors: Silber Israel , Fridlind Ann M. , Verlinde Johannes , Ackerman Andrew S. , Chen Yao‐Sheng , Bromwich David H. , Wang Sheng‐Hung , Cadeddu Maria , Eloranta Edwin W.
Published: September 2019

The rarity of reports in the literature of brief and spatially limited observations of drizzle at temperatures below −20 °C suggest that riming and other temperature‐dependent cloud microphysical processes such as heterogeneous ice nucleation and ice crystal depositional growth prevent drizzle persistence in cold environments. In this study, we report on a persistent drizzle event observed by ground‐based remote sensing measurements at McMurdo Station, Antarctica. The temperatures in the drizzle‐producing cloud were below −25 °C and the drizzle persisted for a period exceeding 7.5 hr. Using ground‐based, satellite, and reanalysis data, we conclude that drizzle was likely present in parts of a widespread cloud field, which stretched more than ~1,000 km along the Ross Ice Shelf coast. Parameter space sensitivity tests using two‐moment bulk microphysics in large eddy simulations constrained by the observations suggest that activated ice freezing nuclei and accumulation‐mode aerosol number concentrations aloft during this persistent drizzle period were likely on the order of 0.2 L−1and 20 cm−3, respectively. In such constrained simulations, the drizzle moisture flux through cloud base exceeds that of ice. The simulations also indicate that drizzle can lead to the formation of multiple peaks in cloud water content profiles. This study suggests that persistent drizzle at these low temperatures may be common at the low aerosol concentrations typical of the Antarctic and Southern Ocean atmospheres.
Systematic Analysis of Machine Learning and Feature Selection Techniques for Prediction of the Kp Index
Authors: Zhelavskaya I. S. , Vasile R. , Shprits Y. Y. , Stolle C. , Matzka J.
Published: September 2019

The Kp index is a measure of the midlatitude global geomagnetic activity and represents short‐term magnetic variations driven by solar wind plasma and interplanetary magnetic field. The Kp index is one of the most widely used indicators for space weather alerts and serves as input to various models, such as for the thermosphere and the radiation belts. It is therefore crucial to predict the Kp index accurately. Previous work in this area has mostly employed artificial neural networks to nowcast Kp, based their inferences on the recent history of Kp and on solar wind measurements at L1. In this study, we systematically test how different machine learning techniques perform on the task of nowcasting and forecasting Kp for prediction horizons of up to 12 hr. Additionally, we investigate different methods of machine learning and information theory for selecting the optimal inputs to a predictive model. We illustrate how these methods can be applied to select the most important inputs to a predictive model of Kp and to significantly reduce input dimensionality. We compare our best performing models based on a reduced set of optimal inputs with the existing models of Kp, using different test intervals, and show how this selection can affect model performance.
Myelofibrosis in 2019: moving beyond JAK2 inhibition
Authors: Schieber Michael , Crispino John D. , Stein Brady
Published: September 2019

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by ineffective clonal hematopoiesis, splenomegaly, bone marrow fibrosis, and the propensity for transformation to acute myeloid leukemia. The discovery of mutations in JAK2, CALR, and MPL have uncovered activated JAK-STAT signaling as a primary driver of MF, supporting a rationale for JAK inhibition. However, JAK inhibition alone is insufficient for long-term remission and offers modest, if any, disease-modifying effects. Given this, there is great interest in identifying mechanisms that cooperate with JAK-STAT signaling to predict disease progression and rationally guide the development of novel therapies. This review outlines the latest discoveries in the biology of MF, discusses current clinical management of patients with MF, and summarizes the ongoing clinical trials that hope to change the landscape of MF treatment.
Inhibition of cyclooxygenase-2 activity in subchondral bone modifies a subtype of osteoarthritis
Authors: Tu Manli , Yang Mi , Yu Nanxi , Zhen Gehua , Wan Mei , Liu Wenlong , Ji Baochao , Ma Hairong , Guo Qiaoyue , Tong Peijian , Cao Li , Luo Xianghang , Cao Xu
Published: September 2019

Osteoarthritis (OA) causes the destruction of joints. Its pathogenesis is still under investigation, and there is no effective disease-modifying therapy. Here, we report that elevated cyclooxygenase-2 (COX-2) expression in the osteocytes of subchondral bone causes both spontaneous OA and rheumatoid arthritis (RA). The knockout of COX-2 in osteocytes or treatment with a COX-2 inhibitor effectively rescues the structure of subchondral bone and attenuates cartilage degeneration in spontaneous OA (STR/Ort) mice and tumor necrosis factor-α transgenic RA mice. Thus, elevated COX-2 expression in subchondral bone induces both OA-associated and RA-associated joint cartilage degeneration. The inhibition of COX-2 expression can potentially modify joint destruction in patients with arthritis.
The transcription factor Zfp281 sustains CD4+ T lymphocyte activation through directly repressing Ctla-4 transcription
Authors: Guo Jing , Xue Zhonghui , Ma Ruoyu , Yi Weiwei , Hui Zhaoyuan , Guo Yixin , Yao Yuxi , Cao Wenqiang , Wang Jianli , Ju Zhenyu , Lu Linrong , Wang Lie
Published: September 2019

The expression of coinhibitory receptors, such as CTLA-4, on effector T cells is a key mechanism for the negative regulation of T-cell activation. However, the transcriptional regulation of CTLA-4 is not well understood. Zfp281, a C2H2 zinc finger protein, is a negative regulator of pluripotency maintenance of embryonic stem cells. Nevertheless, the function of Zfp281 in differentiated cells has not been studied. We generated Zfp281 conditional knockout mice in which the function of the Zfp281 gene was conditionally disrupted by the Cd4
Cre transgene to study its impact on T cell function. Zfp281 had no effect on T-cell development, but CD4+ T cell activation and cytokine production were impaired due to diminished T-cell receptor signaling. Furthermore, Zfp281 deficiency inhibited in vivo T cell responses to Listeria monocytogenes infection. Using genome-wide expression profiling assays, we determined that Zfp281 repressed Ctla-4 expression by directly binding to GC-rich sites in its promoter, which inhibited the negative feedback of T cell activation. In line with this result, CTLA-4 blockade and shRNA knockdown partly rescued the reduced cytokine production caused by Zfp281 deficiency. These findings indicate that Zfp281 sustains CD4+ T lymphocyte activation by directly repressing Ctla-4 transcription.
TGFβ blocks IFNα/β release and tumor rejection in spontaneous mammary tumors
Authors: Guerin Marion V. , Regnier Fabienne , Feuillet Vincent , Vimeux Lene , Weiss Julia M. , Bismuth Georges , Altan-Bonnet Gregoire , Guilbert Thomas , Thoreau Maxime , Finisguerra Veronica , Donnadieu Emmanuel , Trautmann Alain , Bercovici Nadège
Published: September 2019

Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA (5,6-dimethylxanthenone-4-acetic acid) can induce strong production of IFNα/β and rejection of transplanted primary tumors. In the present study, we address whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFNα/β production. Mechanistically, we identify TGFβ, which is abundant in spontaneous tumors, as a key molecule limiting this IFN-induced tumor regression by DMXAA. Finally, blocking TGFβ restores the production of IFNα by activated MHCII+tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGFβ.
Bacterial co-culture with cell signaling translator and growth controller modules for autonomously regulated culture composition
Authors: Stephens Kristina , Pozo Maria , Tsao Chen-Yu , Hauk Pricila , Bentley William E.
Published: September 2019

Synthetic biology and metabolic engineering have expanded the possibilities for engineered cell-based systems. The addition of non-native biosynthetic and regulatory components can, however, overburden the reprogrammed cells. In order to avoid metabolic overload, an emerging area of focus is on engineering consortia, wherein cell subpopulations work together to carry out a desired function. This strategy requires regulation of the cell populations. Here, we design a synthetic co-culture controller consisting of cell-based signal translator and growth-controller modules that, when implemented, provide for autonomous regulation of the consortia composition. The system co-opts the orthogonal autoinducer AI-1 and AI-2 cell-cell signaling mechanisms of bacterial quorum sensing (QS) to enable cross-talk between strains and a QS signal-controlled growth rate controller to modulate relative population densities. We further develop a simple mathematical model that enables cell and system design for autonomous closed-loop control of population trajectories.
Aluminum with dispersed nanoparticles by laser additive manufacturing
Authors: Lin Ting-Chiang , Cao Chezheng , Sokoluk Maximilian , Jiang Lin , Wang Xin , Schoenung Julie M. , Lavernia Enrique J. , Li Xiaochun
Published: September 2019

While laser-printed metals do not tend to match the mechanical properties and thermal stability of conventionally-processed metals, incorporating and dispersing nanoparticles in them should enhance their performance. However, this remains difficult to do during laser additive manufacturing. Here, we show that aluminum reinforced by nanoparticles can be deposited layer-by-layer via laser melting of nanocomposite powders, which enhance the laser absorption by almost one order of magnitude compared to pure aluminum powders. The laser printed nanocomposite delivers a yield strength of up to 1000 MPa, plasticity over 10%, and Young’s modulus of approximately 200 GPa, offering one of the highest specific Young’s modulus and specific yield strengths among structural metals, as well as an improved specific strength and thermal stability up to 400 °C compared to other aluminum-based materials. The improved performance is attributed to a high density of well-dispersed nanoparticles, strong interfacial bonding between nanoparticles and Al matrix, and ultrafine grain sizes.
Cooperation of cancer drivers with regulatory germline variants shapes clinical outcomes
Authors: Musa Julian , Cidre-Aranaz Florencia , Aynaud Marie-Ming , Orth Martin F. , Knott Maximilian M. L. , Mirabeau Olivier , Mazor Gal , Varon Mor , Hölting Tilman L. B. , Grossetête Sandrine , Gartlgruber Moritz , Surdez Didier , Gerke Julia S. , Ohmura Shunya , Marchetto Aruna , Dallmayer Marlene , Baldauf Michaela C. , Stein Stefanie , Sannino Giuseppina , Li Jing , Romero-Pérez Laura , Westermann Frank , Hartmann Wolfgang , Dirksen Uta , Gymrek Melissa , Anderson Nathaniel D. , Shlien Adam , Rotblat Barak , Kirchner Thomas , Delattre Olivier , Grünewald Thomas G. P.
Published: September 2019

Pediatric malignancies including Ewing sarcoma (EwS) feature a paucity of somatic alterations except for pathognomonic driver-mutations that cannot explain overt variations in clinical outcome. Here, we demonstrate in EwS how cooperation of dominant oncogenes and regulatory germline variants determine tumor growth, patient survival and drug response. Binding of the oncogenic EWSR1-FLI1 fusion transcription factor to a polymorphic enhancer-like DNA element controls expression of the transcription factor MYBL2 mediating these phenotypes. Whole-genome and RNA sequencing reveals that variability at this locus is inherited via the germline and is associated with variable inter-tumoral MYBL2 expression. High MYBL2 levels sensitize EwS cells for inhibition of its upstream activating kinase CDK2 in vitro and in vivo, suggesting MYBL2 as a putative biomarker for anti-CDK2-therapy. Collectively, we establish cooperation of somatic mutations and regulatory germline variants as a major determinant of tumor progression and highlight the importance of integrating the regulatory genome in precision medicine.
Reaction selectivity of homochiral versus heterochiral intermolecular reactions of prochiral terminal alkynes on surfaces
Authors: Wang Tao , Lv Haifeng , Huang Jianmin , Shan Huan , Feng Lin , Mao Yahui , Wang Jinyi , Zhang Wenzhao , Han Dong , Xu Qian , Du Pingwu , Zhao Aidi , Wu Xiaojun , Tait Steven L. , Zhu Junfa
Published: September 2019

Controlling selectivity between homochiral and heterochiral reaction pathways on surfaces remains a great challenge. Here, competing reactions of a prochiral alkyne on Ag(111): two-dimensional (2D) homochiral Glaser coupling and heterochiral cross-coupling with a Bergman cyclization step have been examined. We demonstrate control strategies in steering the reactions between the homochiral and heterochiral pathways by tuning the precursor substituents and the kinetic parameters, as confirmed by high-resolution scanning probe microscopy (SPM). Control experiments and density functional theory (DFT) calculations reveal that the template effect of organometallic chains obtained under specific kinetic conditions enhances Glaser coupling between homochiral molecules. In contrast, for the reaction of free monomers, the kinetically favorable reaction pathway is the cross-coupling between two heterochiral molecules (one of them involving cyclization). This work demonstrates the application of kinetic control to steer chiral organic coupling pathways at surfaces.
Visible light induced alkene aminopyridylation using N-aminopyridinium salts as bifunctional reagents
Authors: Moon Yonghoon , Park Bohyun , Kim Inwon , Kang Gyumin , Shin Sanghoon , Kang Dahye , Baik Mu-Hyun , Hong Sungwoo
Published: September 2019

The development of intermolecular alkene aminopyridylation has great potential for quickly increasing molecular complexity with two valuable groups. Here we report a strategy for the photocatalytic aminopyridylation of alkenes using a variety of N-aminopyridinium salts as both aminating and pyridylating reagents. Using Eosin Y as a photocatalyst, amino and pyridyl groups are simultaneously incorporated into alkenes, affording synthetically useful aminoethyl pyridine derivatives under mild reaction conditions. Remarkably, the C4-regioselectivity in radical trapping with N-aminopyridinium salt can be controlled by electrostatic interaction between the pyridinium nitrogen and sulfonyl group of β-amino radical. This transformation is characterized by a broad substrate scope, good functional group compatibility, and the utility of this transformation was further demonstrated by late-stage functionalization of complex biorelevant molecules. Combining experiments and DFT calculations on the mechanism of the reaction is investigated to propose a complete mechanism and regioselectivity.
Early induction of C/EBPβ expression as a potential marker of steroid responsive colitis
Authors: Assas Mushref Bakri , Levison Scott , Pennock Joanne L.
Published: September 2019

The precise mechanism of hydrocortisone immune regulation in the management of colitis is poorly understood. Whilst not without limitations, its ability to suppress pathology and rapidly improve patient clinical outcome is key. We were interested in identifying early markers of therapeutic responsiveness in order to identify patients’ refractory to therapy. Chronic Th1-driven colitis was induced in AKR/J mice using a parasite infection,Trichuris muris. 35 days post infection, mice were treated with low dose hydrocortisone (2 mg/kg/) i.p. on alternate days. Response to therapy was assessed at a systemic and tissue level day 45 post infection. Histopathology, gene and protein analysis was conducted to determine cytokine and transcriptional profiles. The colonic transcriptional profile in steroid treated mice showed significant upregulation of a small subset of T cell associated genes, in particular C/EBPβ, CD4, IL7R and STAT5a. Despite no change in either transcription or protein production in downstream cytokines IFN γ, TNFα IL-17 and IL-10, hydrocortisone treatment significantly reduced colonic pathology and restored colonic length to naïve levels. As expected, steroid treatment of chronic gut inflammation generated significant immunosuppressive effects characterized by histological improvement. Low dose hydrocortisone induced significant upregulation of a subset of genes associated with T cell maintenance and regulation, including C/EBPβ. These data suggest that enhanced expression of C/EBPβ may be one of a subset of early markers demonstrating an immune regulatory response to hydrocortisone therapy, potentially by stabilization of Treg function. These observations contribute to our understanding of the immune landscape after steroid therapy, providing a potential markers of therapeutic responders and those refractory to hydrocortisone treatment.
E40, a novel microbial protease efficiently detoxifying gluten proteins, for the dietary management of gluten intolerance
Authors: Cavaletti Linda , Taravella Anna , Carrano Lucia , Carenzi Giacomo , Sigurtà Alessandro , Solinas Nicola , Caro Salvatore De , Stasio Luigia Di , Picascia Stefania , Laezza Mariavittoria , Troncone Riccardo , Gianfrani Carmen , Mamone Gianfranco
Published: September 2019

Gluten proteins are the causative agent of Celiac Disease (CD), a life-long food intolerance characterized by an autoimmune enteropathy. Inadvertent gluten exposure is frequent even in celiac patients complying with a gluten-free diet, and the supplementation of exogenous gluten-digestive enzymes (glutenases) is indeed a promising approach to reduce the risk of dietary gluten boost. Here we describe Endopeptidase 40, a novel glutenase discovered as secreted protein from the soil actinomycete Actinoallomurus A8, and its recombinant active form produced by Streptomyces lividans TK24. E40 is resistant to pepsin and trypsin, and active in the acidic pH range 3 to 6. E40 efficiently degrades the most immunogenic 33-mer as well as the whole gliadin proteins, as demonstrated by SDS-PAGE, HPLC, LC-MS/MS, and ELISA. T lymphocytes from duodenal biopsies of celiac patients showed a strongly reduced or absent release of IFN-γ when exposed to gluten digested with E40. Data in gastrointestinal simulated conditions suggest that no toxic peptides are freed during gluten digestion by E40 into the stomach to enter the small intestine, thus counteracting the intestinal inflammatory cascade to occur in CD patients. E40 is proposed as a novel candidate in Oral Enzymatic Therapy for the dietary management of gluten toxicity.
Ecological modeling of Cistanche deserticola Y.C. Ma in Alxa, China
Authors: Li Ziyan , Zhang Chunhong , Ren Guanyao , Yang Min , Zhu Shoudong , Li Minhui
Published: September 2019

Cistanche deserticola Y.C. Ma has long been used for medical purposes in China. It mainly grows in the Chinese provinces of Inner Mongolia, Ningxia, Gansu, and Xinjiang, and the species in the Alxa region of northwest China, have the most distinct qualities. To explain the geoherbalism quality and geographical distribution of C. deserticola, we sampled 65 wild plants in Alxa, determined their echinacoside and acteoside content, and assessed the relationship between the ecological environment and quality of C. deserticola through maximum entropy modeling and geographic information system. We identified the areas suitable for the growth of high-quality C. deserticola species. The regionalization analysis of growth suitability showed that the most influential ecological factors for the growth of C. deserticola are soil type, annual sunshine duration, altitude, temperature seasonality (standard deviation ×100), vegetation type, sunshine duration in the growing season, mean precipitation in August and mean temperature in July. The most suitable areas for growing C. deserticola are southeast of Ejin Banner, central Alxa Right Banner, and north of Alxa Left Banner. The regionalization analysis of quality suitability showeds that the most influential ecological factors for glycosides in C. deserticola are sunshine duration in June, average precipitation in May, and average temperature in March, and the best-quality C. deserticola grows in Dalaihob Town, Ejin Banner. Upon inspection, the result of the experiment reached a high accuracy of 0.994, which indicates that these results are consistent with the actual distribution of C. deserticola in Alxa. The results of this study may serve as a scientific basis for site selection of artificial planting bases for C. deserticola.
Fluidized landslides triggered by the liquefaction of subsurface volcanic deposits during the 2018 Iburi–Tobu earthquake, Hokkaido
Authors: Kameda Jun , Kamiya Hiro , Masumoto Hirokazu , Morisaki Tomonori , Hiratsuka Toru , Inaoi Chisaki
Published: September 2019

The 6.6 Mw Iburi–Tobu earthquake struck southern Hokkaido, Japan on 6 September 2018. The earthquake triggered widespread slope collapses in the hills near the epicenter, resulting in destructive landslides that killed 36 people. Volcanic deposits covering the region slid downhill in a flow-like manner suggestive of fluidized landslides. Here, we report a distinctive example of liquefaction in the field, which could be a prerequisite for the generation of fluidized landslides triggered by large earthquakes. In the scarp of a typical landslide, an altered halloysite-bearing volcanic layer is observed at a level almost coincident with the sliding surface. The layer is intensely undulating and can be divided into an upper clay-rich layer and a lower pumice-rich layer, suggesting that the altered layer had liquefied as a result of the strong coseismic ground motion. The layer had been soaked by heavy rainfall just one day before the earthquake and could have liquefied, producing a weak and slippery plane, resulting in the catastrophic landslides in this area.