bluuebunny/crossref_metadata_2025 huggingface dataset:
Germany and the Papacy in the Late Middle Ages
Authors: D'AVRAY DAVID
Published: January 2020

Towards the end of the twentieth century much UK public money for research was diverted to collaborative projects with specific research objectives, notably in the field of history. This distinguished the UK from other countries on the cutting edge of historical research, notably the USA which lags far behind, but not from Germany, which had long led the way when it comes to teamwork with a clearly defined theme, and where average budgets for historical research projects are still on a scale unimaginable on this side of the Channel. One of the greatest German historical enterprises is the Repertorium Germanicum. The project was conceived in the 1890s, and linked from the start with the German Historical Institute in Rome, from which so much fine work on papal history has emerged, notably by Protestant scholars. The first secretary of the DHI (Deutsches Historisches Institut) had the idea of creating a ‘search engine’ (Suchmaschine). It was to be and is organised within pontificates by the names of individuals who appear in documents in the Vatican Archives: a prosopographical structure. Though the individuals need a ‘German’ connection to be included, that is interpreted in the broadest sense, so that dioceses from Poland to Belgium find a place, as do any Germans who turn up in any other region, if the team happened upon them. Consultation online is now also possible, at < http://194.242.233.132/denqRG/index.htm>, though the volumes under review did not seem to have been made available electronically at time of writing – and many will find the paper volumes easier to manage, where they are available. Ludwig Quidde, who conceived of the project, thought that it could be completed up to the end of the fifteenth century by a team of five within three years. He had no idea of the scale of the holdings in the archive. Furthermore, alongside the Repertorium Germanicum one must now place its precocious younger sister, the Repertorium Poenitentiariae Germanicum, which has (thanks to Ludwig Schmugge and his team) already overtaken the elder sibling with Repertorium Poenitentiariae Germanicum, XI: Hadrian VI,1522–1523, ed. Ludwig Schmugge (Tübingen 2018).
Vitamin supplementation increases the virulence ofEntamoeba histolyticagrown axenically
Authors: Vargas-Villareal Javier , Lozano-Garza Gerardo , Said-Fernández Salvador Luis , González-Salazar Francisco , Moreno-Treviño María Guadalupe , Monsiváis-Diaz Ofelia , Lozano-Alanís Alan Giresse , Guzmán-de la Garza Francisco Javier
Published: January 2020

As a consequence of axenic growth and the elimination of accompanying bacterial flora,Entamoeba histolyticavirulence decreases rapidly, and pathogenicity is lost. This paper evaluated the impact of vitamin supplementation on the pathogenicity ofE. histolytica.Growth ofE. histolyticatrophozoites, cultured axenically in PEHPS (a Spanish acronym for the main ingredients – casein peptone, liver, pancreas extract and bovine serum) medium, with or without vitamins, exhibited a similar growth rate. However, the vitamin-enriched PEHPS preparations expressed 2.65 times more haemolytic activity (at 60 min: 98vs48%,P< 0.05), 2.5 times more phospholipase A2activity at 150 min of incubation and generated more hepatic abscesses (88vs60%,P= 0.05) than the preparations without vitamins. The haemolytic and phospholipase A2activity for the PEHPS − V preparations were restored following vitamin supplementation with A and D. These data highlight, for the first time, that vitamins and specifically vitamin A and D were essential for the recovery of amoebic virulence, lost through axenic growth.
The use of antipsychotic agents during pregnancy and the risk of gestational diabetes mellitus: a systematic review and meta-analysis
Authors: Wang Z. , Wong I.C.K. , Man K.K.C. , Alfageh B.H. , Mongkhon P. , Brauer R.
Published: January 2020

Background

Previous studies have found contradicting results with regard to the use of antipsychotics during pregnancy and the risk of gestational diabetes mellitus (GDM). We aimed to evaluate the association between antipsychotic use in pregnancy and GDM.

Methods

A systematic literature search was conducted in PubMed, EMBASE, PsycINFO and Cochrane Library databases up to March 2019, for data from observational studies assessing the association between gestational antipsychotic use and GDM. Non-English studies, animal studies, case reports, conference abstracts, book chapters, reviews and summaries were excluded. The primary outcome was GDM. Estimates were pooled using a random effect model, with the I2 statistic used to estimate heterogeneity of results. Our study protocol was registered with PROSPERO number: CRD42018095014.

Results

In total 10 cohort studies met the inclusion criteria in our systematic review with 6642 exposed and 1 860 290 unexposed pregnancies. Six studies were included in the meta-analysis with a pooled adjusted relative risk of 1.24 overall [95% confidence interval (CI) 1.09–1.42]. The I2 result suggested low heterogeneity between studies (I2 = 6.7%, p = 0.373).

Conclusion

We found that the use of antipsychotic medications during pregnancy is associated with an increased risk of GDM in mothers. However, the evidence is still insufficient, especially for specific drug classes. We recommend more studies to investigate this association for specific drug classes, dosages and comorbidities to help clinicians to manage the risk of GDM if initiation or continuation of antipsychotic prescriptions during pregnancy is needed.
Can the migration process influence the clinical expression of heroin use disorder in migrants to Italy?
Authors: Maremmani Icro , Carbone Manuel G. , Tagliarini Claudia , Ricci Marina , Lupi Anna M. , Sarandrea Lucia , Ceban Angela , Maremmani Angelo G.I. , Casella Pietro
Published: January 2020

Background

For some time now, there has been a strong consensus that the migration process can influence the onset, course, development, outcome, and clinical aspects of psychiatric pathologies.

Methods

In this study, we have analyzed the influence of the migration process on the clinical expression of heroin use disorder (HUD). In a naturalistic case–control study, we compared, both at univariate and multivariate level, 30 migrant HUD (M-HUD) patients with 30 age/gender-matched Italian HUD (IT-HUD) patients. We also analyzed demographic data, drug addiction history, psychopathological symptoms, addictive behavior, and emotional reactivity to life events.

Results

Compared with IT-HUD pairs, at HUD Agonist Opioid Treatment, M-HUD patients were characterized by inadequate income and the presence of legal problems. They were more frequently at stage 3 of heroin addiction, with a concomitantly less frequent use of stimulants. Their age at the onset of heroin use was greater than that of subjects in the IT-HUD group. HUD post-traumatic stress disorder spectrum was present and was more severe in all M-HUD patients, but grief reactions and maladaptive behavior were the most discriminant traits. No differences were found in terms of addictive behaviors related to heroin craving or with respect to the severity/typology of psychopathology specific to HUD.

Conclusions

The migratory process does not seem to be correlated with addictive behaviors or with psychopathology specific to HUD. It partly affects HUD history, and specifically correlates with emotional reactivity to loss and traumatic life events, so suggesting that in M-HUD individuals, the link between the migratory syndrome and HUD is very close.
Testing Theories about Advocacy and Public Policy
Authors: Burstein Paul
Published: January 2020

One critical way that social scientists contribute to our understanding of policy change is developing and testing theories to explain the impact of advocacy efforts by nonparty organizations and activists to influence policy. What does the theory testing discover? To find out, this article analyzes all tests of such theories published in 25 major journals in political science and sociology between 2000 and 2018. Nineteen theories were tested and are generally quite similar, proposing that advocacy will affect policy and seeing electoral concerns as the basis of that influence. But they differ in terms of whose impact they seek to explain: there are different theories for interest groups, social movement organizations, and nongovernmental organizations. Predictions made by the theories are consistent with the data just over half the time. The theory-testing articles fail to show what their findings add to the weight of evidence for or against their theories, rarely test competing theories against each other, and seldom generalize or make specific suggestions for future work. This article highlights the most constructive suggestions for future work and argues for breaking down barriers between subdisciplines and systematically spelling out the value added by each new test of theory.
A corrugated G-shaped grounded ring slot antenna for wideband circular polarization
Authors: Saraswat Kapil , Kumar Trivesh , Harish A. R.
Published: January 2020

In this paper, a wideband circularly polarized corrugated G-shaped grounded ring slot antenna is presented. The proposed antenna structure is excited using a coplanar waveguide-fed monopole antenna, which is placed inside a corrugated G-shaped grounded ring. Due to the asymmetry in the ground plane, two orthogonal modes, having equal magnitude and out of phase by 90° are excited, resulting in circular polarization (CP). The generation of the CP in the proposed antenna structure is explained using thin dipole current element approximation. A prototype of the proposed antenna is fabricated and tested. The measured results exhibit a 3 dB axial ratio bandwidth of 37.6% (2.22–3.25 GHz), and reflection coefficient bandwidth (|S11| ≤ −10 dB) of 47.91% (2.13–3.47 GHz). Additionally, the design guidelines are also presented for G-shaped grounded ring slot antennas.
Openness to Experience Moderates the Association Between Problem-Solving Style and Negative Affect
Authors: Sanatkar Samineh , Rubin Mark
Published: January 2020

Abstract. Everyday problem-solving situations can be approached on an independent or interdependent basis. The current article investigated the moderating effects of openness to experience and self-efficacy on the relation between an independent versus interdependent problem-solving style and negative affect (stress, anxiety, depression, and neuroticism). Australian university students ( Ns = 399, 186, 337, and 248) and international academic researchers ( N = 199) took part in research studies examining the relations between personality, problem-solving-style, and mental health. Openness to experience moderated the association between problem-solving style and negative affect in all five studies. When openness was low, independent problem-solvers reported greater negative emotionality compared to interdependent problem-solvers. Further, the moderating effect of openness to experience on trait-based negative affectivity (i.e., neuroticism) was mediated by state-based negative emotional experiences of anxiety and stress. The moderating effect of self-efficacy appraisals was only statistically significant on specific anxiety about solving problems. Openness to experience seems to help alleviate the negative mental consequences of independent problem-solvers. These findings have implications for clinical practice with regard to building a therapeutic relationship and retaining clients.
Earthquake Declustering Using the Nearest‐Neighbor Approach in Space‐Time‐Magnitude Domain
Authors: Zaliapin Ilya , Ben‐Zion Yehuda
Published: January 2020

We introduce an algorithm for declustering earthquake catalogs based on the nearest‐neighbor analysis of seismicity. The algorithm discriminates between background and clustered events by random thinning that removes events according to a space‐varying threshold. The threshold is estimated using randomized‐reshuffled catalogs that are stationary, have independent space and time components, and preserve the space distribution of the original catalog. Analysis of catalog produced by the Epidemic Type Aftershock Sequence model demonstrates that the algorithm correctly classifies over 80% of background and clustered events, correctly reconstructs the stationary and space‐dependent background intensity, and shows high stability with respect to random realizations (over 75% of events have the same estimated type in over 90% of random realizations). The declustering algorithm is applied to the global Northern California Earthquake Data Center catalog with magnitudes m ≥ 4 during 2000–2015; a Southern California catalog with m ≥ 2.5, 3.5 during 1981–2017; an area around the 1992 Landers rupture zone with m ≥ 0.0 during 1981–2015; and the Parkfield segment of San Andreas fault with m ≥ 1.0 during 1984–2014. The null hypotheses of stationarity and space‐time independence are not rejected by several tests applied to the estimated background events of the global and Southern California catalogs with magnitude ranges Δm < 4. However, both hypotheses are rejected for catalogs with larger range of magnitudes Δm > 4. The deviations from the nulls are mainly due to local temporal fluctuations of seismicity and activity switching among subregions; they can be traced back to the original catalogs and represent genuine features of background seismicity.
Why Do the Maximum Intensities in Modeled Tropical Cyclones Vary Under the Same Environmental Conditions?
Authors: Tao Dandan , Bell Michael , Rotunno Richard , van Leeuwen Peter Jan
Published: January 2020

In this study w e explored why the different initial tropical cyclone structures can result in different steady‐state maximum intensities in model simulations with the same environmental conditions. We discovered a linear relationsh ip between the radius of maximum wind (rm) and the absolute angular momentum that passes through rm (Mm) in the model simulated steady‐state tropical cyclones that rm = aMm+b. This nonnegligible intercept b is found to be the key to making a steady‐state storm with a larger Mm more intense. The sensitivity experiments show that this nonzero b results mainly from horizontal turbulent mixing and decreases with decreased horizontal mixing. Using this linear relationship from the simulations, it is also found that the degree of supergradient wind is a function of Mm as well as the turbulent mixing length such that both a larger Mm and/or a reduced turbulent mixing length result in larger supergradient winds.
Charge Separation in Collisions Between Ice Crystals and a Spherical Simulated Graupel of Centimeter Size
Authors: Luque Melina Y. , Nollas Fernando , Pereyra Rodolfo G. , Bürgesser Rodrigo E. , Ávila Eldo E.
Published: January 2020

This work reports a new laboratory study of the electric charge separated in collisions between a spherical target of 1 cm in diameter growing by riming and vapor‐grown ice crystals, with the objective of studying the charging behavior of the larger ice precipitation particles in thunderstorms in terms of the noninductive mechanism. A series of experiments was conducte d for a wide range of environmental conditions; the measurements were performed for effective liquid water content between 0.5 and 5 g m−3, for ambient temperatures between −5 and −30 °C and at air speed of 11 m s−1. The magnitude and sign of the electric charge transfer on the ice sphere as a function of the ambient temperature and the effective liquid water content is presented. The results show a charge reversal temperature for the riming target, which is roughly independent of liquid water concentration in the measured range. The simulated graupel charges negatively for temperatures below −15 °C, and positively at temperatures above −15 °C.
Exploring Impacts of Size‐Dependent Evaporation and Entrainment in a Global Model
Authors: Karset I. H. H. , Gettelman A. , Storelvmo T. , Alterskjær K. , Berntsen T. K.
Published: January 2020

While most observations indicate well‐buffered clouds to aerosol perturbations, global models do not. Among the suggested mechanisms for this discrepancy is the models' lack of connections between cloud droplet size and two processes that can contribute to reduced cloudiness when droplets become more numerous and smaller: evaporation and entrainment. In this study, we explore different implementations of size‐dependent evaporation and entrainment in the global atmospheric model CAM5.3‐Oslo. We study their impact on the preindustrial‐to‐present day change in liquid water path (
) and the corresponding aerosol indirect effect (
). Impacts of the 2014–2015 fissure eruption in Holuhraun, Iceland, are also presented. Our entrainment modifications only have a moderate effect on
(changes from
1.07 W m
to
0.98 W m
), and a small impact on the signal from the Holuhraun eruption compared to other suggested compensating mechanisms. Simulations with added size‐dependent evaporation in the top of the stratiform clouds also show small evaporation differences between PI and PD. Moderate changes in
were achieved when also including an entrainment feedback to the evaporation changes, mixing air between the cloudtop layer and the layer above. These changes were not associated with the size dependency, but changes in the cloud susceptibility to aerosols in both PI and PD when adding evaporation. We find that increased evaporation of smaller droplets at stratiform cloud tops can reduce
, but can increase
in some areas due to enhanced shallow convection caused by destabilization.
Real‐Time Thermospheric Density Estimation via Two‐Line Element Data Assimilation
Authors: Gondelach David J. , Linares Richard
Published: January 2020

Inaccurate estimates of the thermospheric density are a major source of error in low Earth orbit prediction. Therefore, real‐time density estimation is required to improve orbit prediction. In this work, we develop a dynamic reduced‐order model for the thermospheric density that enables real‐time density estimation using two‐line element (TLE) data. For this, the global thermospheric density is represented by the main spatial modes of the atmosphere and a time‐varying low‐dimensional state and a linear model is derived for the dynamics. Three different models are developed based on density data from the TIE‐GCM, NRLMSISE‐00, and JB2008 thermosphere models and are valid from 100 to maximum 800 km altitude. Using the models and TLE data, the global density is estimated by simultaneously estimating the density and the orbits and ballistic coefficients of several objects using a Kalman filter. The sequential estimation provides both estimates of the density and corresponding uncertainty. Accurate density estimation using the TLEs of 17 objects is demonstrated and validated against CHAMP and GRACE accelerometer‐derived densities. The estimated densities are shown to be significantly more accurate and less biased than NRLMSISE‐00 and JB2008 modeled densities. The uncertainty in the density estimates is quantified and shown to be dependent on the geographical location, solar activity, and objects used for estimation. In addition, the data assimilation capability of the model is highlighted by assimilating CHAMP accelerometer‐derived density data together with TLE data to obtain more accurate global density estimates. Finally, the dynamic thermosphere model is used to forecast the density.
Mantle Structure and Flow Beneath an Early‐Stage Continental Rift: Constraints From P Wave Anisotropic Tomography
Authors: Yu Youqiang , Gao Stephen S. , Zhao Dapeng , Liu Kelly H.
Published: January 2020

To explore 3‐D seismic velocity and radial anisotropy structures of the upper mantle and mantle transition zone beneath the Malawi and Luangwa rift zones of the East African Rift System, we conduct the first study of P wave anisotropic tomography using data recorded at 75 seismic stations including 34 stations that we installed along two profiles as part of the Seismic Arrays for African Rift Initiation experiment. Both rift zones are revealed to have normal or slightly low velocity anomalies in the lithosphere and upper asthenosphere. The surrounding cratonic lithosphere is characterized by high‐velocity anomalies with amplitudes ranging from +1.0% to +2.0%. Negative radial anisotropy, which is indicative of upwelling or downwelling in the mantle, is mainly distributed beneath the rift zones, whereas the other areas mostly feature positive radial anisotropy that implies horizontal flow. A prominent circular low‐velocity anomaly exists in the top 200 km of the upper mantle beneath the Rungwe Volcanic Province without obvious connections to the lower mantle. Combining the present findings with previous geodetic and tomography results, we interpret the Rungwe Volcanic Province magmatism as primarily due to decompression melting in response to lithospheric extension induced by the counterclockwise and clockwise rotations of the Victoria and Rovuma microplates, respectively, with respect to the Nubian plate. Isolated mantle upwelling, which is indicated by scattered low‐velocity anomalies and negative radial anisotropy beneath the Malawi rift zone, may contribute to the incipient rifting.
Reconciling Orogenic Drivers for the Evolution of the Bangong‐Nujiang Tethys During Middle‐Late Jurassic
Authors: Li Shi‐Min , Wang Qing , Zhu Di‐Cheng , Cawood Peter A. , Stern Robert J. , Weinberg Roberto , Zhao Zhidan , Mo Xuan‐Xue
Published: January 2020

Identifying arc‐trench systems along with spatial and temporal variations in their record of tectono‐magmatic events is crucial for determining the orogenic divers and evolution of orogenic systems. New geochronological and geochemical data of Jurassic igneous rocks, as well as detrital zircon data from contemporaneous sedimentary units, within the eastern Bangong‐Nujiang suture in central Tibet indicate the existence of an approximately 1,200‐km Middle‐Late Jurassic magmatic arc system. This arc system can be divided into two distinct along‐strike segments, which are characterized by magmatic activity extending from 166 to 160 Ma in the east and 170–148 Ma in the west, followed by magmatic gaps at 160–120 and 148–125 Ma, respectively. An accretionary prism, magmatic arc, and retro‐arc sedimentary units are identified from south to north in the eastern segment. The 166–160 Ma arc includes high‐K calc‐alkaline granitoids, and high‐Mg andesites, dacites, and rhyolites, which collectively can be interpreted to originate from partial melting of ancient lower crust and mélange diapirs above a north dipping subduction zone. Our analysis reveals the existence of an overall compressional arc‐trench system along strike, which overlaps with a phase of 170–160 Ma ophiolite generation and a rock association of 160–148 Ma slab‐derived adakites and oceanic island basalt‐type rocks, and is followed by an overall magmatic gap during 148–125 Ma with subsequent 125–105 Ma extensive magmatism. We infer that these records may reflect sequential tectonic events, including subparallel ridge‐trench collision (170–160 Ma), slab window formation (160–148 Ma), subsequent subduction termination (148–125 Ma), and final Lhasa‐Qiangtang amalgamation (125–105 Ma).
B7-H3 promotes colorectal cancer angiogenesis through activating the NF-κB pathway to induce VEGFA expression
Authors: Wang Ruoqin , Ma Yanchao , Zhan Shenghua , Zhang Guangbo , Cao Lei , Zhang Xueguang , Shi Tongguo , Chen Weichang
Published: January 2020

Tumor angiogenesis is a hallmark of cancer and is involved in the tumorigenesis of solid tumors. B7-H3, an immune checkpoint molecule, plays critical roles in proliferation, metastasis and tumorigenesis in diverse tumors; however, little is known about the biological functions and molecular mechanism underlying B7-H3 in regulating colorectal cancer (CRC) angiogenesis. In this study, we first demonstrated that the expression of B7-H3 was significantly upregulated and was positively associated with platelet endothelial cell adhesion molecule-1 (CD31) level in tissue samples from patients with CRC. In addition, a series of in vitro and in vivo experiments showed that conditioned medium from B7-H3 knockdown CRC cells significantly inhibited the migration, invasion, and tube formation of human umbilical vein endothelial cells (HUVECs), whereas overexpression of B7-H3 had the opposite effect. Furthermore, B7-H3 promoted tumor angiogenesis by upregulating VEGFA expression. Recombinant VEGFA abolished the inhibitory effects of conditioned medium from shB7-H3 CRC cells on HUVEC angiogenesis, while VEGFA siRNA or a VEGFA-neutralizing antibody reversed the effects of conditioned medium from B7-H3-overexpressing CRC cells on HUVEC angiogenesis. Moreover, we verified that B7-H3 upregulated VEGFA expression and angiogenesis by activating the NF-κB pathway. Collectively, our findings identify the B7-H3/NF-κB/VEGFA axis in promoting CRC angiogenesis, which serves as a promising approach for CRC treatment.
Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue
Authors: Turchi Riccardo , Tortolici Flavia , Guidobaldi Giulio , Iacovelli Federico , Falconi Mattia , Rufini Stefano , Faraonio Raffaella , Casagrande Viviana , Federici Massimo , De Angelis Lorenzo , Carotti Simone , Francesconi Maria , Zingariello Maria , Morini Sergio , Bernardini Roberta , Mattei Maurizio , La Rosa Piergiorgio , Piemonte Fiorella , Lettieri-Barbato Daniele , Aquilano Katia
Published: January 2020

Decreased expression of mitochondrial frataxin (FXN) causes Friedreich’s ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.
Correction: Generation of qualified clinical-grade functional hepatocytes from human embryonic stem cells in chemically defined conditions
Authors: Li Zhongwen , Wu Jun , Wang Lei , Han Weifang , Yu Juan , Liu Xin , Wang Yukai , Zhang Ying , Feng Guihai , Li Wei , Stacey Glyn Nigel , Gu Qi , Hu Baoyang , Wang Liu , Zhou Qi , Hao Jie
Published: January 2020

The original version of this article contained an error in the name of one of the co-authors (Glyn Nigel Stacey). This has been corrected in the PDF and HTML versions of the article.
The yin and yang of co-inhibitory receptors: toward anti-tumor immunity without autoimmunity
Authors: Schnell Alexandra , Bod Lloyd , Madi Asaf , Kuchroo Vijay K.
Published: January 2020

Co-inhibitory receptors are important regulators of T-cell function that define the balance between tolerance and autoimmunity. The immune regulatory function of co-inhibitory receptors, including CTLA-4, PD-1, TIM-3, TIGIT, and LAG-3, was first discovered in the setting of autoimmune disease models, in which their blockade or deficiency resulted in induction or exacerbation of the disease. Later on, co-inhibitory receptors on lymphocytes have also been found to influence outcomes in tumor and chronic viral infection settings. These receptors suppress T-cell function in the tumor microenvironment (TME), thereby making the T cells dysfunctional. Based on this observation, blockade of co-inhibitory receptors (also known as checkpoint molecules) has emerged as a successful treatment option for a number of human cancers. However, severe autoimmune-like side effects limit the use of therapeutics that block individual or combinations of co-inhibitory receptors for cancer treatment. In this review we provide an overview of the role of co-inhibitory receptors in autoimmunity and anti-tumor immunity. We then discuss current approaches and future directions to leverage our knowledge of co-inhibitory receptors to target them in tumor immunity without inducing autoimmunity.
Chaperone mediated detection of small molecule target binding in cells
Authors: Cho Kelvin F. , Ma Taylur P. , Rose Christopher M. , Kirkpatrick Donald S. , Yu Kebing , Blake Robert A.
Published: January 2020

The ability to quantitatively measure a small molecule’s interactions with its protein target(s) is crucial for both mechanistic studies of signaling pathways and in drug discovery. However, current methods to achieve this have specific requirements that can limit their application or interpretation. Here we describe a complementary target-engagement method, HIPStA (Heat Shock Protein Inhibition Protein Stability Assay), a high-throughput method to assess small molecule binding to endogenous, unmodified target protein(s) in cells. The methodology relies on the change in protein turnover when chaperones, such as HSP90, are inhibited and the stabilization effect that drug-target binding has on this change. We use HIPStA to measure drug binding to three different classes of drug targets (receptor tyrosine kinases, nuclear hormone receptors, and cytoplasmic protein kinases), via quantitative fluorescence imaging. We further demonstrate its utility by pairing the method with quantitative mass spectrometry to identify previously unknown targets of a receptor tyrosine kinase inhibitor.
Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1
Authors: Imbert Caroline , Montfort Anne , Fraisse Marine , Marcheteau Elie , Gilhodes Julia , Martin Elodie , Bertrand Florie , Marcellin Marlène , Burlet-Schiltz Odile , Peredo Anne Gonzalez de , Garcia Virginie , Carpentier Stéphane , Tartare-Deckert Sophie , Brousset Pierre , Rochaix Philippe , Puisset Florent , Filleron Thomas , Meyer Nicolas , Lamant Laurence , Levade Thierry , Ségui Bruno , Andrieu-Abadie Nathalie , Colacios Céline
Published: January 2020

Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.
Regenerable and stable sp2 carbon-conjugated covalent organic frameworks for selective detection and extraction of uranium
Authors: Cui Wei-Rong , Zhang Cheng-Rong , Jiang Wei , Li Fang-Fang , Liang Ru-Ping , Liu Juewen , Qiu Jian-Ding
Published: January 2020

Uranium is a key element in the nuclear industry, but its unintended leakage has caused health and environmental concerns. Here we report asp2carbon-conjugated fluorescent covalent organic framework (COF) named TFPT-BTAN-AO with excellent chemical, thermal and radiation stability is synthesized by integrating triazine-based building blocks with amidoxime-substituted linkers. TFPT-BTAN-AO shows an exceptional UO22+adsorption capacity of 427 mg g−1attributable to the abundant selective uranium-binding groups on the highly accessible pore walls of open 1D channels. In addition, it has an ultra-fast response time (2 s) and an ultra-low detection limit of 6.7 nM UO22+suitable for on-site and real-time monitoring of UO22+, allowing not only extraction but also monitoring the quality of the extracted water. This study demonstrates great potential of fluorescent COFs for radionuclide detection and extraction. By rational designing target ligands, this strategy can be extended to the detection and extraction of other contaminants.
NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons
Authors: Engström Ruud Linda , Pereira Mafalda M. A. , de Solis Alain J. , Fenselau Henning , Brüning Jens C.
Published: January 2020

Activation of Agouti-Related Peptide (AgRP)-expressing neurons promotes feeding and insulin resistance. Here, we examine the contribution of neuropeptide Y (NPY)-dependent signaling to the diverse physiological consequences of activating AgRP neurons. NPY-deficient mice fail to rapidly increase food intake during the first hour of either chemo- or optogenetic activation of AgRP neurons, while the delayed increase in feeding is comparable between control and NPY-deficient mice. Acutely stimulating AgRP neurons fails to induce systemic insulin resistance in NPY-deficient mice, while increased locomotor activity upon AgRP neuron stimulation in the absence of food remains unaffected in these animals. Selective re-expression of NPY in AgRP neurons attenuates the reduced feeding response and reverses the protection from insulin resistance upon optogenetic activation of AgRP neurons in NPY-deficient mice. Collectively, these experiments reveal a pivotal role of NPY-dependent signaling in mediating the rapid feeding inducing effect and the acute glucose regulatory function governed by AgRP neurons.
Nedd4 ubiquitylates VDAC2/3 to suppress erastin-induced ferroptosis in melanoma
Authors: Yang Yongfei , Luo Meiying , Zhang Kexin , Zhang Jun , Gao Tongtong , Connell Douglas O’ , Yao Fengping , Mu Changwen , Cai Bingyu , Shang Yuxue , Chen Wei
Published: January 2020

Ferroptosis is a newly defined form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Erastin, the ferroptosis activator, binds to voltage-dependent anion channels VDAC2 and VDCA3, but treatment with erastin can result in the degradation of the channels. Here, the authors show that Nedd4 is induced following erastin treatment, which leads to the ubiquitination and subsequent degradation of the channels. Depletion of Nedd4 limits the protein degradation of VDAC2/3, which increases the sensitivity of cancer cells to erastin. By understanding the molecular mechanism of erastin-induced cellular resistance, we can discover how cells adapt to new molecules to maintain homeostasis. Furthermore, erastin-induced resistance mediated by FOXM1-Nedd4-VDAC2/3 negative feedback loop provides an initial framework for creating avenues to overcome the drug resistance of ferroptosis activators.
A meta-analysis of the efficacy of HAART on HIV transmission and its impact on sexual risk behaviours among men who have sex with men
Authors: Jiang Ying , Su Shu , Borné Yan
Published: January 2020

Evidence showed preventive impacts of the highly active antiretroviral therapy (HAART) on the Human Immunodeficiency Virus (HIV) transmission amomg heterosexual population, however, that is of deficit among men who have sex with men (MSM). The aim was to systematically examine the efficacy of HAART on HIV transmission and the association between the HAART initiation and unprotected anal intercourse (UAI) in MSM population. Three electronic databases were fully searched for articles published in peer-reviewed journals between 1996 and 2017. Of 1616 identified articles, fifteen articles were eligible for meta-analyses. The summary incidence rate (IR) of HIV was 6.63/100 person-year (95%CI 2.06–11.20/100 person-year)(p = 0.004). The pooled per-contact rate (PCR) of HIV was 0.42% (95% CI 0.21–0.63%)(p < 0.05). The HAART initiation (vs non-HAART) was not associated with engaging in UAI, with odds ratio (OR) 1.09 (95% CI 0.90–1.34)(p > 0.05). In the stratified analysis, participants with no less than 6 months recall period was slightly more likely to engage in UAI (OR 1.32; 95% CI 1.01–1.74)(p < 0.05). It indicated that HAART has potential efficacy on reducing infectivity of HIV positive individuals in anal intercourses. The relationship between the HAART initiation and UAI was not significant and may be influenced by some social-demographic factors. Consistent condom use and education on safe sex among MSM are crucial.
Restoring Wnt6 signaling ameliorates behavioral deficits in MeCP2 T158A mouse model of Rett syndrome
Authors: Hsu Wei-Lun , Ma Yun-Li , Liu Yen-Chen , Tai Derek J. C. , Lee Eminy H. Y.
Published: January 2020

The methyl-CpG-binding protein 2 gene, MECP2, is an X chromosome-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). Previous study has shown that re-expression of SUMO-modified MeCP2 in Mecp2-null neurons rescues synaptic and behavioral deficits in Mecp2 conditional knockout mice, whereas about 12-fold decrease in Wnt6 mRNA level was found in MeCP2K412R sumo-mutant mice. Here, we examined the role of Wnt6 in MeCP2 T158A mouse model of RTT. Results show that lentiviral delivery of Wnt6 to the amygdala ameliorates locomotor impairment and social behavioral deficits in these animals. MeCP2 T158A mice show decreased level of GSK-3β phosphorylation and increased level of β-catenin phosphorylation. They also show reduced level of MeCP2 SUMOylation. These alterations were also restored by lenti-Wnt6 transduction. Further, both BDNF and IGF-1 expressions are decreased in MeCP2 T158A mice. Overexpression of Wnt6 increases Bdnf and Igf-1 promoter activity in HEK293T cells in a dose-dependent manner. Lenti-Wnt6 transduction to the amygdala similarly increases the mRNA level and protein expression of BDNF and IGF-1 in MeCP2 T158A mice. Moreover, environmental enrichment (EE) similarly ameliorates the locomotor and social behavioral deficits in MeCP2 T158A mice. One of the mechanisms underlying EE is mediated through enhanced MeCP2 SUMOylation and increased Wnt6 expression in these animals by EE.
Gender-based pairings influence cooperative expectations and behaviours
Authors: Cigarini Anna , Vicens Julián , Perelló Josep
Published: January 2020

The study explores the expectations and cooperative behaviours of men and women in a lab-in-the-field experiment by means of citizen science practices in the public space. It specifically examines the influence of gender-based pairings on the decisions to cooperate or defect in a framed and discrete Prisoner’s Dilemma game after visual contact. Overall, we found that when gender is considered behavioural differences emerge in expectations of cooperation, cooperative behaviours, and their decision time depending on whom the partner is. Men pairs are the ones with the lowest expectations and cooperation rates. After visual contact women infer men’s behaviour with the highest accuracy. Also, women take significantly more time to defect than to cooperate, compared to men. Finally, when the interacting partners have the opposite gender they expect significantly more cooperation and they achieve the best collective outcome. Together, the findings suggest that non verbal signals may influence men and women differently, offering novel interpretations to the context-dependence of gender differences in social decision tasks.
Linking Small-Scale Flight Manoeuvers and Density Profiles to the Vertical Movement of Insects in the Nocturnal Stable Boundary Layer
Authors: Wainwright Charlotte E. , Reynolds Don R. , Reynolds Andy M.
Published: January 2020

Huge numbers of insects migrate over considerable distances in the stably-stratified night-time atmosphere with great consequences for ecological processes, biodiversity, ecosystem services and pest management. We used a combination of meteorological radar and lidar instrumentation at a site in Oklahoma, USA, to take a new look at the general assistance migrants receive from both vertical and horizontal airstreams during their long-distance flights. Movement in the nocturnal boundary layer (NBL) presents very different challenges for migrants compared to those prevailing in the daytime convective boundary layer, but we found that Lagrangian stochastic modelling is effective at predicting flight manoeuvers in both cases. A key feature for insect transport in the NBL is the frequent formation of a thin layer of fast-moving air – the low-level jet. Modelling suggests that insects can react rapidly to counteract vertical air movements and this mechanism explains how migrants are retained in the jet for long periods (e.g. overnight, and perhaps for several hours early in the morning). This results in movements over much longer distances than are likely in convective conditions, and is particularly significant for the reintroduction of pests to northern regions where they are seasonally absent due to low winter temperatures.
Structural, optical, thermal and conducting properties of V2−xLixO5−δ (0.15 ≤ x ≤ 0.30) systems
Authors: Khan Savidh , Singh K.
Published: January 2020

Lithium-doped vanadates (V2−xLixO5−δ (0.15 ≤ x ≤ 0.30)) are synthesized by melt-quench method. The physical, structural, optical, thermal and conducting properties of as-quenched samples are investigated using various experimental techniques to study their suitability for electrolyte in battery/solid oxide fuel cell application. X-ray diffraction (XRD) patterns confirm the formation of three different crystalline phases. FTIR and Raman spectra indicate that the doping of Li2O into V2O5 leads to a transition from VO5 into VO4 structural unit. The optical diffused reflectance spectra revealed that the optical band gap (Eg) decreases from 2.2 to 2.08 eV while Urbach energy (EU) increases (0.31–0.41 eV) with the addition of Li2O content in place of vanadium. The thermal stability is studied by thermogravimetric analyser (TGA). The DC conductivity of the present samples is increased from 0.08 to 0.12 Scm−1 at 450 °C with Li2O doping. These materials can be used as electrolyte for battery/solid oxide fuel cell due to their good conductivity (~0.12 Scm−1) at 450 °C.
Thermostabilization of VPR, a kinetically stable cold adapted subtilase, via multiple proline substitutions into surface loops
Authors: Óskarsson K. R. , Sævarsson A. F. , Kristjánsson M. M.
Published: January 2020

Protein stability is a widely studied topic, there are still aspects however that need addressing. In this paper we examined the effects of multiple proline substitutions into loop regions of the kinetically stable proteinase K-like serine protease VPR, using the thermostable structural homologue AQUI as a template. Four locations for proline substitutions were chosen to imitate the structure of AQUI. Variants were produced and characterized using differential scanning calorimetry (DSC), circular dichroism (CD), steady state fluorescence, acrylamide fluorescence quenching and thermal inactivation experiments. The final product VPRΔC_N3P/I5P/N238P/T265P was greatly stabilized which was achieved without any noticeable detrimental effects to the catalytic efficiency of the enzyme. This stabilization seems to be derived from the conformation restrictive properties of the proline residue in its ability to act as an anchor point and strengthen pre-existing interactions within the protein and allowing for these interactions to prevail when thermal energy is applied to the system. In addition, the results underline the importance of the synergy between distant local protein motions needed to result in stabilizing effects and thus giving an insight into the nature of the stability of VPR, its unfolding landscape and how proline residues can infer kinetic stability onto protein structures.
A facile and efficient method for the synthesis of crystalline tetrahydro-β-carbolines via the Pictet-Spengler reaction in water
Authors: Byeon Hong-Ju , Jung Kyung-Hwan , Moon Gi-Seong , Moon Sung-Kwon , Lee Hyang-Yeol
Published: January 2020

A facile and efficient synthesis of tetrahydro-β-carbolines (tryptolines) in one step from tryptamine and aldehydes, in an environmentally friendly water solvent, has been investigated. This convenient and clean synthesis of various tryptolines was facilitated by l-tartaric acid, a natural compound, to obtain the desired products as clear crystals. Among the four crystalline products, the most substituted tryptoline 2 showed the best inhibitory activity against EJ cells and the least cytotoxicity, with an LC50 value of 1.49 mg/mL, against brine shrimp larvae.
Centre of Rotation of the Human Subtalar Joint Using Weight-Bearing Clinical Computed Tomography
Authors: Peña Fernández Marta , Hoxha Dorela , Chan Oliver , Mordecai Simon , Blunn Gordon W. , Tozzi Gianluca , Goldberg Andy
Published: January 2020

Accurate in vivo quantification of subtalar joint kinematics can provide important information for the clinical evaluation of subtalar joint function; the analysis of outcome of surgical procedures of the hindfoot; and the design of a replacement subtalar joint prosthesis. The objective of the current study was to explore the potential of full weight-bearing clinical computed tomography (CT) to evaluate the helical axis and centre of rotation of the subtalar joint during inversion and eversion motion. A subject specific methodology was proposed for the definition of the subtalar joint motion combining three-dimensional (3D) weight-bearing imaging at different joint positions with digital volume correlation (DVC). The computed subtalar joint helical axis parameters showed consistency across all healthy subjects and in line with previous data under simulated loads. A sphere fitting approach was introduced for the computation of subtalar joint centre of rotation, which allows to demonstrate that this centre of rotation is located in the middle facet of the subtalar joint. Some translation along the helical axis was also observed, reflecting the elasticity of the soft-tissue restraints. This study showed a novel technique for non-invasive quantitative analysis of bone-to-bone motion under full weight-bearing of the hindfoot. Identifying different joint kinematics in patients with ligamentous laxity and instability, or in the presence of stiffness and arthritis, could help clinicians to define optimal patient-specific treatments.