bluuebunny/crossref_metadata_2025 huggingface dataset:
GENRE, ATTRIBUTION AND AUTHORSHIP IN THE THIRTEENTH CENTURY: ROBERT DE REIMS VS ‘ROBERT DE RAINS’
Authors: Saint-Cricq Gaël
Published: September 2019

This article presents a textbook case for the examination of generic interplay in the thirteenth century, investigating four works that offer transgeneric reworkings relating polyphony to trouvère song. These works are found as anonymous motets and clausulae in polyphonic gatherings, but their upper voices are also copied as multi-strophic songs in songbooks, where they are attributed to the trouvère Robert de Reims. This case therefore touches on the issues of generic borders and mixing, on trouvère involvement in this generic interplay, and on the relationships between attribution and authorship in the Middle Ages. The investigation has important outcomes for the reconstruction of the genetic map of the motet, revealing works playing havoc with the vectors of transmission customarily established in the interplay of motet, chanson and clausula, and revealing early trouvère involvement in the repertoire as an essential key to the comprehension of cross-over activity between song and polyphony.
Mass separated particle flux from a laser-ablation metal cluster source
Authors: Ishikawa Yuta , Hasegawa Jun , Horioka Kazuhiko
Published: September 2019

Flux waveforms of aluminum cluster beams supplied from a laser-ablation cluster source were precisely investigated under various source conditions such as background pressure, ablation laser intensity, and nozzle structure. A time-of-flight mass spectroscopy revealed that aluminum clusters with sizes up to 200 were generated and the amount of the clusters could be maximized by choosing a proper background pressure (~2 MPa) and an ablation laser fluence (~40 mJ/cm2). Flux waveforms of clusters having specific sizes were carefully reconstructed from the observed mass spectra. It is found that the pulse widths of the aluminum cluster beams were typically about 100 µs and much smaller than that of the monoatomic aluminum beam, indicating that the cluster formation was limited in a relatively small volume in the laser-ablated vapor. Introducing a conical nozzle having a large open angle was also found to enhance the cluster beam velocity and reduce its pulse width. A velocity measurement of particles in the cluster beam was conducted to examine the velocity spread of the supplied clusters. We found that the aluminum clusters were continuously released from the source for about 100 µs and this release time mainly determined the pulse width of the cluster beam, suggesting that controlling the behavior of an ablated vapor plume in the waiting room of the cluster source holds the key to drastically improving the cluster beam flux.
“Put the Gangsters Out of Business”: Gambling Legalization and the War on Organized Crime
Authors: Cohen Jonathan D.
Published: September 2019

From the 1950s through the 1970s, American policymakers engaged in an extensive campaign against illegal gambling in an effort to turn the tide in the government’s crusade against organized crime. At the grassroots, however, voters endorsed a different form of state expansion to beat back the mob menace. Between 1963 and 1977, fourteen northeastern and Rust Belt states enacted the first government-run lotteries in the twentieth-century United States on the belief that legalized gambling would undercut the mob’s gambling profits. While gambling opponents pointed to Las Vegas as proof that organized crime would flourish following legalization, supporters argued that illegal gambling was already pervasive, so the state may as well profit from this irrepressible activity. The history of gambling legalization challenges narratives on the popularity of law-and-order politics and offers a new perspective on crime policy in the post–World War II period.
General international law in the relations between international organizations and their members
Authors: Bordin Fernando Lusa
Published: September 2019

To what extent do rules of general international law apply between international organizations and their members? The article tackles this question by distinguishing between two categories of relations: those that take place on the international plane and those that are, rather, situated on the institutional plane constituted by the organization’s internal law. I argue that general international law applies by default to relations belonging to the first category, only being displaced when the internal law of an organization contains applicable lex specialis, but that it cannot claim a similar role at the level of internal institutional relations. The question there becomes one concerning the dialogue between relatively autonomous international legal orders, so that it is the internal law of each organization that defines the terms on which rules of international law are allowed in. At the same time, a normative argument can be made for a ‘monistic presumption’ for the application of general international law in cases where the rules of the organization are silent. By delving into such questions of applicable law and identifying the relevant analytical frameworks, the article aims to help international lawyers dealing with complex disputes opposing international organizations and their members to structure the legal analysis.
Incorporating calendar effects to predict influenza seasonality in Milwaukee, Wisconsin
Authors: Simpson Ryan B. , Alarcon Falconi Tania M. , Venkat Aishwarya , Chui Kenneth H. H. , Navidad Jose , Naumov Yuri N. , Gorski Jack , Bhattacharyya Sanjib , Naumova Elena N.
Published: September 2019

Social outings can trigger influenza transmission, especially in children and elderly. In contrast, school closures are associated with reduced influenza incidence in school-aged children. While influenza surveillance modelling studies typically account for holidays and mass gatherings, age-specific effects of school breaks, sporting events and commonly celebrated observances are not fully explored. We examined the impact of school holidays, social events and religious observances for six age groups (all ages, ⩽4, 5–24, 25–44, 45–64, ⩾65 years) on four influenza outcomes (tests, positives, influenza A and influenza B) as reported by the City of Milwaukee Health Department Laboratory, Milwaukee, Wisconsin from 2004 to 2009. We characterised holiday effects by analysing average weekly counts in negative binomial regression models controlling for weather and seasonal incidence fluctuations. We estimated age-specific annual peak timing and compared influenza outcomes before, during and after school breaks. During the 118 university holiday weeks, average weekly tests were lower than in 140 school term weeks (5.93 vs. 11.99 cases/week, P < 0.005). The dampening of tests during Winter Break was evident in all ages and in those 5–24 years (RR = 0.31; 95% CI 0.22–0.41 vs. RR = 0.14; 95% CI 0.09–0.22, respectively). A significant increase in tests was observed during Spring Break in 45–64 years old adults (RR = 2.12; 95% CI 1.14–3.96). Milwaukee Public Schools holiday breaks showed similar amplification and dampening effects. Overall, calendar effects depend on the proximity and alignment of an individual holiday to age-specific and influenza outcome-specific peak timing. Better quantification of individual holiday effects, tailored to specific age groups, should improve influenza prevention measures.
Prevalence and risk factors of pulmonary nontuberculous mycobacterial infections in the Zhejiang Province of China
Authors: Xu Jintian , Li Ping , Zheng Shengchao , Shu Wei , Pang Yu
Published: September 2019

Risk factors and prevalence of pulmonary nontuberculous mycobacterial (NTM) diseases were retrospectively evaluated in 1208 suspected pulmonary TB patients seeking care at the Affiliated Hospital of Hangzhou Normal University between July 2018 and December 2018. Further analysis of 390 culture-positive cases demonstrated that 358 (358/390, 91.8%) were infected with Mycobacterium tuberculosis (MTB), 24 (24/390, 6.2%) with NTM and eight (8/390, 2.0%) with both MTB and NTM. M. intracellulare was the most prevalent NTM isolated (16/24, 66.7%), followed by M. abscessus (3/24), M. kansasii (2/24), M. avium (1/24), M. szulgai (1/24) and M. fortuitum (1/24). The difference between NTM and TB case rates for the ⩾65-year-old age group significantly exceeded the difference for the reference group (patients aged 25–44 years) (OR (95% CI): 4.63 (1.03–20.90)). Pulmonary NTM diseases incidence positively correlated with prior TB history (OR (95% CI): 12.92 (3.24–31.82)). Moreover, pulmonary NTM patients were significantly more likely to exhibit underlying bronchiectasis than pulmonary TB patients (OR (95% CI): 18.89 (7.54–47.88)). In conclusion, approximately one-tenth of culture-positive suspected pulmonary TB patients are infected with NTM (most frequently M. intracellulare) in Zhejiang Province, China. The elderly and those with bronchiectasis or a history of TB are at the greatest risk of contracting pulmonary NTM disease.
Extremely short setting of optimal sensed atrioventricular interval in patients after Fontan procedure with implanted dual-chamber pacemaker
Authors: Miyazaki Aya , Yoshimura Shin-ichiro , Matsutani Hayato , Miyake Makoto , Negishi Jun , Yamanaka Kazuo , Yamada Osamu , Doi Hiraku , Ohuchi Hideo
Published: September 2019

Background:

Atrioventricular interval optimisation is important in patients with dual-chamber pacing, especially with heart failure. In patients with CHD, especially in those with Fontan circulation, the systemic atrial contraction is supposed to be more important than in patients without structural heart disease.

Methods:

We retrospectively evaluated two patients after Fontan procedure with dual-chamber pacemaker with a unique setting of optimal sensed atrioventricular interval.

Results:

The optimal sensed atrioventricular interval determined by echocardiogram was extremely short sensed atrioventricular interval at 25 and 30 ms in both cases; however, the actual P wave and ventricular pacing interval showed 180 and 140 ms, respectively. In both cases, the atrial epicardial leads were implanted on the opposite site of the origin of their own atrial rhythm. The time differences between sensed atrioventricular interval and actual P wave and ventricular pacing interval occurred because of the site of the epicardial atrial pacing leads and the intra-atrial conduction delay.

Conclusion:

We need to consider the origin of the atrial rhythm, the site of the epicardial atrial lead, and the atrial conduction delay by using electrocardiogram and X-ray when we set the optimal sensed atrioventricular interval in complicated CHD.
Present‐Day Subsidence in the Ganges‐Brahmaputra‐Meghna Delta: Eastern Amplification of the Holocene Sediment Loading Contribution
Authors: Krien Y. , Karpytchev M. , Ballu V. , Becker M. , Grall C. , Goodbred S. , Calmant S. , Shum C. K. , Khan Z.
Published: September 2019

The subsidence of the Ganges‐Brahmaputra‐Meghna Delta (GBMD) drastically increases the adverse impacts of coastal flooding and exacerbates the vulnerability of populations from ongoing rapid sea level rise. We focus here on estimating the present‐day subsidence rates induced by the loading of sediments continuously deposited within the GBMD over the past 11,000 years. By constructing a realistic GBMD 3‐D numerical model with laterally variable mantle and lithospheric structure, we demonstrate for the first time that the presence of the strong Indian Craton and the weakened Indo‐Burma margin results in significant amplification of subsidence driven by sediment loading in the eastern part of the delta, where the population density is the highest (>1,000 habitants per km2). Although uncertainties remain regarding the amplitude of subsidence, the rate estimates (2–3 mm/year) are found to be comparable to the present‐day global mean sea level rise.
Strength Profile of the Inner Nankai Accretionary Prism at IODP Site C0002
Authors: Kitamura Manami , Kitajima Hiroko , Sone Hiroki , Hamada Yohei , Hirose Takehiro
Published: September 2019

The strength of accretionary prisms is important for understanding their formation and the generation of earthquakes along the underlying plate boundary faults. We establish a continuous depth profile of rock strength and possible ranges of the minimum and maximum horizontal stresses (Shmin and SHmax) based on indentation tests on cuttings samples at the Integrated Ocean Drilling Program (IODP) Site C0002 in the Nankai accretionary prism. The rock strength (i.e., differential stress) increases with depth from 5.1 and 11.0 MPa at 975 meters below the seafloor (mbsf) to 22.8 and 59.6 MPa at 3005 mbsf in normal and reverse faulting regimes, respectively. The minimum value of Shmin and the maximum value of SHmax range from 33.2 and 49.4 MPa at 975 mbsf to 57.1 and 139.6 MPa at 3005 mbsf, respectively. Our estimated strength, in combination with Coulomb wedge model, may improve understanding of the evolution of accretionary prisms.
Forced Subduction Initiation at Passive Continental Margins: Velocity‐Driven Versus Stress‐Driven
Authors: Zhong Xinyi , Li Zhong‐Hai
Published: September 2019

Subduction initiation (SI) at passive continental margin plays a key role in the Wilson cycle of plate tectonics; however, the long‐lived, stable Atlantic‐type margin challenges this hypothesis. The spontaneous SI at passive margin is difficult, which could be instead induced by far‐field tectonic forces. Previous analog and numerical models are generally conducted with constant convergent velocity, which may lead to extremely large boundary force in order for SI. In this study, we focus on numerical models with constant convergent force/stress to investigate the conditions for SI at typical passive margin without any type of prescribed weak zones. The result indicates that the SI at young passive margins with thin oceanic lithosphere is much easier than that at old margins. It reveals the dynamics of multiple newly formed subduction zones in the young oceanic plates of Southeast Asia and Southwest Pacific, but generally no SI for the old Atlantic‐type passive margin.
Large Summer Contribution of Organic Biogenic Aerosols to Arctic Cloud Condensation Nuclei
Authors: Lange Robert , Dall'Osto Manuel , Wex Heike , Skov Henrik , Massling Andreas
Published: September 2019

A k‐means cluster analysis of a 5‐year aerosol particle size distribution data set from northeast Greenland is combined with measurements of coincident shorter field studies of aerosol equivalent black carbon (eBC) content, hygroscopic growth factor (HGF), and cloud condensation nuclei (CCN) concentrations. This led to five clusters strongly controlled by natural emissions (eBC 8–15 ng/m3) and three anthropogenic clusters with larger particle concentrations in the accumulation mode (eBC 29–77 ng/m3). The HGF and CCN properties of the eight aerosol clusters differ drastically. Anthropogenic clusters feature high growth factors (1.62–1.81) and low CCN κ values (0.10–0.46), while natural clusters show lower HGF (1.38–1.70) but remarkably higher κ values (0.35–0.51). Extrapolating the CCN properties on the basis of the cluster analysis to annual timescales suggests that biogenic organic aerosol may drive Arctic aerosol production during summer.
Physical Weathering Intensity Controls Bioavailable Primary Iron(II) Silicate Content in Major Global Dust Sources
Authors: Shoenfelt Elizabeth M. , Winckler Gisela , Annett Amber L. , Hendry Katharine R. , Bostick Benjamin C.
Published: September 2019

The speciation of iron (Fe) reaching the ocean, for instance in wind‐blown dust and coastal sediments, impacts its bioavailability to phytoplankton and its impact on atmospheric carbon dioxide (CO2) and climate. For dust reaching the Southern Ocean, primary Fe(II) silicates that are physically weathered from bedrock are highly bioavailable compared to more chemically weathered, Fe(III)‐rich species, suggesting that weathering in dust source regions impacts the bioavailable Fe supply. However, this phenomenon has not been studied in other important terrestrial Fe sources, where weathering regimes and source geology vary. Here, we use Fe X‐ray absorption spectroscopy on marine sediment cores to show that major global dust and sediment sources impacted by high physical weathering contain abundant primary minerals and thus are overlooked as a source of highly bioavailable Fe globally. Thus, it is important to consider the role of physical versus chemical weathering in Fe fertilization and biotic CO2 cycling.
Buoyancy Effect on the Winter South China Sea Western Boundary Current
Authors: Yan Yunwei , Wang Guihua , Xue Huijie , Chai Fei
Published: September 2019

The month‐to‐month variation of the winter South China Sea (SCS) western boundary current (WBC) along the western slope is examined using drifter observations, satellite altimetry data, and an ocean reanalysis. The most surprising phenomenon is that the WBC velocity at the sea surface reaches the maxima in November–December, which cannot be explained by wind forcing and Kuroshio intrusion alone. Analysis results demonstrate that buoyancy effect should be considered to explain the month‐to‐month variation besides wind‐Kuroshio effects. In winter, cold‐and‐salty advection by the WBC from the north decreases/reverses the zonal density gradient in the seasonal pycnocline induced by wind forcing and Kuroshio intrusion and therefore weakens wind‐Kuroshio‐induced WBC. Buoyancy effect on the winter SCS WBC is opposite to wind‐Kuroshio effects. In addition, buoyancy effect reaches the maximum in January, which is concurrent with wind‐Kuroshio effects. As a result of their competition, the zonal density gradient in the seasonal pycnocline is maximum in November–December, resulting in the maximum surface velocity along the western slope occurring in November‐December. This study demonstrates the importance of buoyancy forcing to the winter SCS WBC.
Understanding Monsoonal Water Cycle Changes in a Warmer Climate in E3SMv1 Using a Normalized Gross Moist Stability Framework
Authors: Harrop Bryce E. , Ma Po‐Lun , Rasch Philip J. , Qian Yun , Lin Guangxing , Hannay Cecile
Published: September 2019

One of the grand challenges of climate science is understanding the changes of the tropical rain belts and monsoon systems owing to CO2‐induced warming. A promising path forward links the fluxes of energy and moisture to tropical circulation features. To this end, we make use of the Energy Exascale Earth System Model version 1, where the divergence of moist static energy and moisture have been calculated online, and employ a normalized gross moist stability (NGMS) diagnostic framework to understand the linkages between changes in the flow of energy and moisture within the monsoons. We focus on the Asian Summer Monsoon system and utilize a series of atmosphere‐land and atmosphere‐land‐ocean simulations to understand the connection between fluxes and monsoons. Uncoupled simulations with prescribed sea surface temperatures indicate that decreases in NGMS over land are important in explaining precipitation increases in response to both sea surface temperature and CO2 increases. In fully coupled experiments, NGMS decreases remain an important contributor to the increase in P‐E, but the coupled simulations highlight the importance of consistent ocean and land responses in interpreting the monsoon changes. This study indicates that transient eddy fluxes play an important role in NGMS decreases and that a time‐mean view of the monsoon circulations is insufficient to quantify the link between future changes in the fluxes of energy and moisture. Compensation between dynamic and thermodynamic components of vertical moist static energy advection occurs, with the thermodynamic contribution dominating. The compensation is shown to be sensitive to relative humidity, with higher relative humidity leading to a stronger thermodynamic component.
The Epstein–Barr virus nuclear antigen-1 upregulates the cellular antioxidant defense to enable B-cell growth transformation and immortalization
Authors: Wang Jiayu , Nagy Noemi , Masucci Maria G.
Published: September 2019

Epstein–Barr virus (EBV) immortalizes human B-lymphocytes and is implicated in the pathogenesis of lymphoid and epithelial cell malignancies. The EBV nuclear antigen (EBNA)-1 induces the accumulation of reactive oxygen species (ROS), which enables B-cell immortalization but causes oxidative DNA damage and triggers antiproliferative DNA damage responses. By comparing pairs of EBV-negative and -positive tumor cell lines we found that, while associated with the accumulation of oxidized nucleotides, EBV carriage promotes the concomitant activation of oxo-dNTP sanitization and purging pathways, including upregulation of the nucleoside triphosphatase mut-T homolog 1 (MTH1) and the DNA glycosylases 8-oxoguanine-glycosylase-1 (OGG1) and mut-Y homolog (MUTYH). Expression of EBNA1 was reversibly associated with transcriptional activation of this cellular response. DNA damage and apoptosis were preferentially induced in EBNA1-positive cell lines by treatment with MTH1 inhibitors, suggesting that virus carriage is linked to enhanced vulnerability to oxidative stress. MTH1, OGG1, and MUTYH were upregulated upon EBV infection in primary B-cells and treatment with MTH1 inhibitors prevented B-cell immortalization. These findings highlight an important role of the cellular antioxidant response in sustaining EBV infection, and suggests that targeting this cellular defense may offer a novel approach to antiviral therapy and could reduce the burden of EBV associated cancer.
Correction: Synergistic anti-AML effects of the LSD1 inhibitor T-3775440 and the NEDD8-activating enzyme inhibitor pevonedistat via transdifferentiation and DNA rereplication
Authors: Ishikawa Y. , Nakayama K. , Morimoto M. , Mizutani A. , Nakayama A. , Toyoshima K. , Hayashi A. , Takagi S. , Dairiki R. , Miyashita H. , Matsumoto S. , Gamo K. , Nomura T. , Nakamura K.
Published: September 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Fibroblast growth factor 21 Ameliorates diabetes-induced endothelial dysfunction in mouse aorta via activation of the CaMKK2/AMPKα signaling pathway
Authors: Ying Lei , Li Na , He Zhengyue , Zeng Xueqin , Nan Yan , Chen Jiantong , Miao Peipei , Ying Yunyun , Lin Wei , Zhao Xinyu , Lu Lu , Chen Mengke , Cen Wei , Guo Tonglin , Li Xiaokun , Huang Zhifeng , Wang Yang
Published: September 2019

Endothelial dysfunction initiates and exacerbates hypertension, atherosclerosis and other cardiovascular complications in diabetic mellitus. FGF21 is a hormone that mediates a number of beneficial effects relevant to metabolic disorders and their associated complications. Nevertheless, it remains unclear as to whether FGF21 ameliorates endothelial dysfunction. Therefore, we investigated the effect of FGF21 on endothelial function in both type 1 and type 2 diabetes. We found that FGF21 reduced hyperglycemia and ameliorated insulin resistance in type 2 diabetic mice, an effect that was totally lost in type 1 diabetic mice. However, FGF21 activated AMPKα, suppressing oxidative stress and enhancing endothelium-dependent vasorelaxation of aorta in both types, suggesting a mechanism that is independent of its glucose-lowering and insulin-sensitizing effects. In vitro, we identified a direct action of FGF21 on endothelial cells of the aorta, in which it bounds to FGF receptors to alleviate impaired endothelial function challenged with high glucose. Furthermore, the CaMKK2-AMPKα signaling pathway was activated to suppress oxidative stress. Apart from its anti-oxidative capacity, FGF21 activated eNOS to dilate the aorta via CaMKK2/AMPKα activation. Our data suggest expanded potential uses of FGF21 for the treatment of vascular diseases in diabetes.
Efficacy of pulmonary transplantation of engineered macrophages secreting IL-4 on acute lung injury in C57BL/6J mice
Authors: Liu Huiying , He Yuan , Lu Cheng , Zhang Pengfei , Zhou Chenchen , Ni Yanli , Niu Wenkai , Yuan Xin , Li Puyuan , Zheng Jing , Qin Yanhong , Zhang Luo , Bai Changqing
Published: September 2019

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of respiratory failure, but currently, no effective pharmacotherapy exists for these disorders. Alveolar macrophages play a critical role in both the acute/initial phase and chronic/resolving phase of ALI, rendering them a potential therapeutic target. Interleukin-4 (IL-4), a Th2 cytokine, not only directly inhibits the secretion of pro-inflammatory factors from macrophages but also drives macrophages to the anti-inflammatory and tissue remodeling M2 type. However, the short half-life of IL-4 in vivo hampers its effect on disease treatment. In this study, macrophages secreting IL-4 (M-IL-4) were established and used to treat ALI through pulmonary macrophage transplantation (PMT). The results showed that highly sustained levels of IL-4 and M2 macrophage markers were detected in mice lungs following pulmonary M-IL-4 transplantation. Furthermore, PMT improved the therapeutic effect by reducing lung inflammation, alleviating tissue injury, reducing alveolar macrophages necrotic cell death, and decreasing mortality in mice with ALI. These results suggest an efficient macrophage-based protein drug delivery strategy, and for the first time, prove the feasibility and efficacy of PMT in ALI treatment.
SNRPB promotes the tumorigenic potential of NSCLC in part by regulating RAB26
Authors: Liu Nianli , Wu Zhiyuan , Chen Aoxing , Wang Yuqi , Cai Dafei , Zheng Junian , Liu Yong , Zhang Longzhen
Published: September 2019

SNRPB is a core component of spliceosome and plays a major role in regulating alternative splicing of the pre-mRNA. However, little is known about its role in cancer to date. In this study, we observe that SNRPB is overexpressed in NSCLC and correlated with poor prognosis in patients with NSCLC. We demonstrate that SNRPB promotes NSCLC tumorigenesis both in vitro and in vivo. Mechanistically, we reveal that RAB26 is a critical target of SNRPB. Suppression of SNRPB leads to retention of intron seven in the RAB26 mRNA and reduced RAB26 mRNA through activation of nonsense-mediated RNA decay (NMD). Moreover, forced expression of RAB26 partially restores the decreased tumorigenicity in NSCLC cells with SNRPB depletion. Our study unveils a novel role of SNRPB in facilitating NSCLC tumorigenesis via regulation of RAB26 expression and proposes that the SNRPB/RAB26 pathway may offer a therapeutic vulnerability in NSCLC.
Circadian control of lung inflammation in influenza infection
Authors: Sengupta Shaon , Tang Soon Y. , Devine Jill C. , Anderson Seán T. , Nayak Soumyashant , Zhang Shirley L. , Valenzuela Alex , Fisher Devin G. , Grant Gregory R. , López Carolina B. , FitzGerald Garret A.
Published: September 2019

Influenza is a leading cause of respiratory mortality and morbidity. While inflammation is essential for fighting infection, a balance of anti-viral defense and host tolerance is necessary for recovery. Circadian rhythms have been shown to modulate inflammation. However, the importance of diurnal variability in the timing of influenza infection is not well understood. Here we demonstrate that endogenous rhythms affect survival in influenza infection. Circadian control of influenza infection is mediated by enhanced inflammation as proven by increased cellularity in bronchoalveolar lavage (BAL), pulmonary transcriptomic profile and histology and is not attributable to viral burden. Better survival is associated with a time dependent preponderance of NK and NKT cells and lower proportion of inflammatory monocytes in the lung. Further, using a series of genetic mouse mutants, we elucidate cellular mechanisms underlying circadian gating of influenza infection.
Engineered triple inhibitory receptor resistance improves anti-tumor CAR-T cell performance via CD56
Authors: Zou Fan , Lu Lijuan , Liu Jun , Xia Baijin , Zhang Wanying , Hu Qifei , Liu Weiwei , Zhang Yiwen , Lin Yingtong , Jing Shuliang , Huang Mei , Huang Bifen , Liu Bingfeng , Zhang Hui
Published: September 2019

The inhibitory receptors PD-1, Tim-3, and Lag-3 are highly expressed on tumor-infiltrating lymphocytes and compromise their antitumor activity. For efficient cancer immunotherapy, it is important to prevent chimeric antigen receptor T (CAR-T)-cell exhaustion. Here we downregulate these three checkpoint receptors simultaneously on CAR-T cells and that show the resulting PTL-CAR-T cells undergo epigenetic modifications and better control tumor growth. Furthermore, we unexpectedly find increased tumor infiltration by PTL-CAR-T cells and their clustering between the living and necrotic tumor tissue. Mechanistically, PTL-CAR-T cells upregulate CD56 (NCAM), which is essential for their effector function. The homophilic interaction between intercellular CD56 molecules correlates with enhanced infiltration of CAR-T cells, increased secretion of interferon-γ, and the prolonged survival of CAR-T cells. Ectopically expressed CD56 promotes CAR-T cell survival and antitumor response. Our findings demonstrate that genetic blockade of three checkpoint inhibitory receptors and the resulting high expression of CD56 on CAR-T cells enhances the inhibition of tumor growth.
Molecular basis for metabolite channeling in a ring opening enzyme of the phenylacetate degradation pathway
Authors: Sathyanarayanan Nitish , Cannone Giuseppe , Gakhar Lokesh , Katagihallimath Nainesh , Sowdhamini Ramanathan , Ramaswamy Subramanian , Vinothkumar Kutti R.
Published: September 2019

Substrate channeling is a mechanism for the internal transfer of hydrophobic, unstable or toxic intermediates from the active site of one enzyme to another. Such transfer has previously been described to be mediated by a hydrophobic tunnel, the use of electrostatic highways or pivoting and by conformational changes. The enzyme PaaZ is used by many bacteria to degrade environmental pollutants. PaaZ is a bifunctional enzyme that catalyzes the ring opening of oxepin-CoA and converts it to 3-oxo-5,6-dehydrosuberyl-CoA. Here we report the structures of PaaZ determined by electron cryomicroscopy with and without bound ligands. The structures reveal that three domain-swapped dimers of the enzyme form a trilobed structure. A combination of small-angle X-ray scattering (SAXS), computational studies, mutagenesis and microbial growth experiments suggests that the key intermediate is transferred from one active site to the other by a mechanism of electrostatic pivoting of the CoA moiety, mediated by a set of conserved positively charged residues.
Artificial colloidal liquid metacrystals by shearing microlithography
Authors: Jiang Yanqiu , Guo Fan , Xu Zhen , Gao Weiwei , Gao Chao
Published: September 2019

Meta-periodicity beyond intrinsic atomic and molecular order, such as metacrystalline and quasicrystalline lattices, exists in solids, but is usually elusive in lyotropic liquid crystals for its energetic instability. The stable meta-periodicity in lyotropic liquid crystals in the absence of external stimuli remains unexplored, and how to achieve it keeps a great challenge. Here we create lyotropic liquid crystals with stable meta-periodicity in a free state, coined as liquid metacrystals, in colloidal systems by an invented shearing microlithography. The meta-periodicity is dynamically stabilized by the giant molecular size and strong excluded volume repulsion. Liquid metacrystals are designed to completely cover a library of symmetries, including five Bravais and six quasicrystalline lattices. Liquid metacrystal promises an extended form of liquid crystals with rich meta-periodicity and the shearing microlithography emerges as a facile technology to fabricate liquid meta-structures and metamaterials, enabling the digital design of structures and functionalities of liquid crystalline materials.
The WT1-like transcription factor Klumpfuss maintains lineage commitment of enterocyte progenitors in the Drosophila intestine
Authors: Korzelius Jerome , Azami Sina , Ronnen-Oron Tal , Koch Philipp , Baldauf Maik , Meier Elke , Rodriguez-Fernandez Imilce A. , Groth Marco , Sousa-Victor Pedro , Jasper Heinrich
Published: September 2019

In adult epithelial stem cell lineages, the precise differentiation of daughter cells is critical to maintain tissue homeostasis. Notch signaling controls the choice between absorptive and entero-endocrine cell differentiation in both the mammalian small intestine and the Drosophila midgut, yet how Notch promotes lineage restriction remains unclear. Here, we describe a role for the transcription factor Klumpfuss (Klu) in restricting the fate of enteroblasts (EBs) in the Drosophila intestine. Klu is induced in Notch-positive EBs and its activity restricts cell fate towards the enterocyte (EC) lineage. Transcriptomics and DamID profiling show that Klu suppresses enteroendocrine (EE) fate by repressing the action of the proneural gene Scute, which is essential for EE differentiation. Loss of Klu results in differentiation of EBs into EE cells. Our findings provide mechanistic insight into how lineage commitment in progenitor cell differentiation can be ensured downstream of initial specification cues.
In vivo epigenetic editing of Sema6a promoter reverses transcallosal dysconnectivity caused by C11orf46/Arl14ep risk gene
Authors: Peter Cyril J. , Saito Atsushi , Hasegawa Yuto , Tanaka Yuya , Nagpal Mohika , Perez Gabriel , Alway Emily , Espeso-Gil Sergio , Fayyad Tariq , Ratner Chana , Dincer Aslihan , Gupta Achla , Devi Lakshmi , Pappas John G. , Lalonde François M. , Butman John A. , Han Joan C. , Akbarian Schahram , Kamiya Atsushi
Published: September 2019

Many neuropsychiatric risk genes contribute to epigenetic regulation but little is known about specific chromatin-associated mechanisms governing the formation of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46, a nuclear protein encoded in the chromosome 11p13 WAGR risk locus. C11orf46 haploinsufficiency was associated with hypoplasia of the corpus callosum. C11orf46 knockdown disrupted transcallosal projections and was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with intellectual disability. Multiple genes encoding key regulators of axonal development, including Sema6a, were hyperexpressed in C11orf46-knockdown neurons. RNA-guided epigenetic editing of Sema6a gene promoters via a dCas9-SunTag system with C11orf46 binding normalized SEMA6A expression and rescued transcallosal dysconnectivity via repressive chromatin remodeling by the SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain’s connectome via gene-targeted designer activators and repressor proteins.
Spontaneous whole-genome duplication restores fertility in interspecific hybrids
Authors: Charron Guillaume , Marsit Souhir , Hénault Mathieu , Martin Hélène , Landry Christian R.
Published: September 2019

Interspecies hybrids often show some advantages over parents but also frequently suffer from reduced fertility, which can sometimes be overcome through sexual reproduction that sorts out genetic incompatibilities. Sex is however inefficient due to the low viability or fertility of hybrid offspring and thus limits their evolutionary potential. Mitotic cell division could be an alternative to fertility recovery in species such as fungi that can also propagate asexually. Here, to test this, we evolve in parallel and under relaxed selection more than 600 diploid yeast inter-specific hybrids that span from 100,000 to 15 M years of divergence. We find that hybrids can recover fertility spontaneously and rapidly through whole-genome duplication. These events occur in both hybrids between young and well-established species. Our results show that the instability of ploidy in hybrid is an accessible path to spontaneous fertility recovery.
CircAnks1a in the spinal cord regulates hypersensitivity in a rodent model of neuropathic pain
Authors: Zhang Su-Bo , Lin Su-Yan , Liu Meng , Liu Cui-Cui , Ding Huan-Huan , Sun Yang , Ma Chao , Guo Rui-Xian , Lv You-You , Wu Shao-Ling , Xu Ting , Xin Wen-Jun
Published: September 2019

Circular RNAs are non-coding RNAs, and are enriched in the CNS. Dorsal horn neurons of the spinal cord contribute to pain-like hypersensitivity after nerve injury in rodents. Here we show that spinal nerve ligation is associated with an increase in expression of circAnks1a in dorsal horn neurons, in both the cytoplasm and the nucleus. Downregulation of circAnks1a by siRNA attenuates pain-like behaviour induced by nerve injury. In the cytoplasm, we show that circAnks1a promotes the interaction between transcription factor YBX1 and transportin-1, thus facilitating the nucleus translocation of YBX1. In the nucleus, circAnks1a binds directly to the Vegfb promoter, increases YBX1 recruitment to the Vegfb promoter, thereby facilitating transcription. Furthermore, cytoplasmic circAnks1a acts as a miRNA sponge in miR-324-3p-mediated posttranscriptional regulation of VEGFB expression. The upregulation of VEGFB contributes to increased excitability of dorsal horn neurons and pain behaviour induced by nerve injury. We propose that circAnks1a and VEGFB are regulators of neuropathic pain.
Biomechanical signaling within the developing zebrafish heart attunes endocardial growth to myocardial chamber dimensions
Authors: Bornhorst Dorothee , Xia Peng , Nakajima Hiroyuki , Dingare Chaitanya , Herzog Wiebke , Lecaudey Virginie , Mochizuki Naoki , Heisenberg Carl-Philipp , Yelon Deborah , Abdelilah-Seyfried Salim
Published: September 2019

Intra-organ communication guides morphogenetic processes that are essential for an organ to carry out complex physiological functions. In the heart, the growth of the myocardium is tightly coupled to that of the endocardium, a specialized endothelial tissue that lines its interior. Several molecular pathways have been implicated in the communication between these tissues including secreted factors, components of the extracellular matrix, or proteins involved in cell-cell communication. Yet, it is unknown how the growth of the endocardium is coordinated with that of the myocardium. Here, we show that an increased expansion of the myocardial atrial chamber volume generates higher junctional forces within endocardial cells. This leads to biomechanical signaling involving VE-cadherin, triggering nuclear localization of the Hippo pathway transcriptional regulator Yap1 and endocardial proliferation. Our work suggests that the growth of the endocardium results from myocardial chamber volume expansion and ends when the tension on the tissue is relaxed.
Conscious perception of natural images is constrained by category-related visual features
Authors: Lindh Daniel , Sligte Ilja G. , Assecondi Sara , Shapiro Kimron L. , Charest Ian
Published: September 2019

Conscious perception is crucial for adaptive behaviour yet access to consciousness varies for different types of objects. The visual system comprises regions with widely distributed category information and exemplar-level representations that cluster according to category. Does this categorical organisation in the brain provide insight into object-specific access to consciousness? We address this question using the Attentional Blink approach with visual objects as targets. We find large differences across categories in the attentional blink. We then employ activation patterns extracted from a deep convolutional neural network to reveal that these differences depend on mid- to high-level, rather than low-level, visual features. We further show that these visual features can be used to explain variance in performance across trials. Taken together, our results suggest that the specific organisation of the higher-tier visual system underlies important functions relevant for conscious perception of differing natural images.
Surface association sensitizes Pseudomonas aeruginosa to quorum sensing
Authors: Chuang Sara K. , Vrla Geoffrey D. , Fröhlich Kathrin S. , Gitai Zemer
Published: September 2019

In the pathogen Pseudomonas aeruginosa, LasR is a quorum sensing (QS) master regulator that senses the concentration of secreted autoinducers as a proxy for bacterial cell density. Counterintuitively, previous studies showed that saturating amounts of the LasR ligand, 3OC12-HSL, fail to induce the full LasR regulon in low-density liquid cultures. Here we demonstrate that surface association, which is necessary for many of the same group behaviors as QS, promotes stronger QS responses. We show that lasR is upregulated upon surface association, and that surface-associated bacteria induce LasR targets more strongly in response to autoinducer than planktonic cultures. This increased sensitivity may be due to surface-dependent lasR induction initiating a positive feedback loop through the small RNA, Lrs1. The increased sensitivity of surface-associated cells to QS is affected by the type IV pilus (TFP) retraction motors and the minor pilins. The coupling of physical surface responses and chemical QS responses could enable these bacteria to trigger community behaviors more robustly when they are more beneficial.
Author Correction: Structural basis for delta cell paracrine regulation in pancreatic islets
Authors: e Drigo Rafael Arrojo , Jacob Stefan , García-Prieto Concha F. , Zheng Xiaofeng , Fukuda Masahiro , Nhu Hoa Tran Thi , Stelmashenko Olga , Peçanha Flavia Letícia Martins , Rodriguez-Diaz Rayner , Bushong Eric , Deerinck Thomas , Phan Sebastien , Ali Yusuf , Leibiger Ingo , Chua Minni , Boudier Thomas , Song Sang-Ho , Graf Martin , Augustine George J. , Ellisman Mark H. , Berggren Per-Olof
Published: September 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Performance analysis of 349-element adaptive optics unit for a coherent free space optical communication system
Authors: Yang Leqiang , Yao Kainan , Wang Jianli , Cao Jingtai , Lin Xudong , Liu Xinyue , Liu Wei , Gu Haijun
Published: September 2019

As a continuation of our previous work [Optics Express.25, 15229(2017)] in which we have verified the performance of a coherent free space optical communication (FSOC) system with a 97-element adaptive optics (AO) system, in this paper, we evaluated the performance improvement of the coherent FSOC system using a large-scale high-speed AO system with a 349-element continuous surface deformable mirror. The mixing efficiency (ME) and bit-error-rate (BER) under different Greenwood frequency (GF) were calculated as the performance metric of coherent FSOC system. The performance of FSOC system using such a large-scale AO system was quantitatively verified for the first time. The obtained results showed that the performance was obviously improved when a larger-scale high-speed AO system is employed in coherent FSOC system. This analysis result provides a performance verification for large-scale high-speed AO systems used in FSOC system which is beneficial for coherent FSOC system parameters design.
HIV-1 Vpr mediates the depletion of the cellular repressor CTIP2 to counteract viral gene silencing
Authors: Forouzanfar F. , Ali S. , Wallet C. , De Rovere M. , Ducloy C. , El Mekdad H. , El Maassarani M. , Aït-Ammar A. , Van Assche J. , Boutant E. , Daouad F. , Margottin-Goguet F. , Moog C. , Van Lint C. , Schwartz C. , Rohr O.
Published: September 2019

Mammals have evolved many antiviral factors impacting different steps of the viral life cycle. Associated with chromatin-modifying enzymes, the cellular cofactor CTIP2 contributes to HIV-1 gene silencing in latently infected reservoirs that constitute the major block toward an HIV cure. We report, for the first time, that the virus has developed a strategy to overcome this major transcriptional block. Productive HIV-1 infection results in a Vpr-mediated depletion of CTIP2 in microglial cells and CD4+ T cells, two of the major viral reservoirs. Associated to the Cul4A-DDB1-DCAF1 ubiquitin ligase complex, Vpr promotes CTIP2 degradation via the proteasome pathway in the nuclei of target cells and notably at the latent HIV-1 promoter. Importantly, Vpr targets CTIP2 associated with heterochromatin-promoting enzymes dedicated to HIV-1 gene silencing. Thereby, Vpr reactivates HIV-1 expression in a microglial model of HIV-1 latency. Altogether our results suggest that HIV-1 Vpr mediates the depletion of the cellular repressor CTIP2 to counteract viral gene silencing.
Epidemiology and Diversity of Rickettsiales Bacteria in Humans and Animals in Jiangsu and Jiangxi provinces, China
Authors: Lu Miao , Li Feng , Liao Yong , Shen Jin-Jin , Xu Jian-Min , Chen Yin-Zhong , Li Jian-Hua , Holmes Edward C. , Zhang Yong-Zhen
Published: September 2019

Diseases caused by Rickettsiales bacteria are a global public health problem. To better understand the diversity and origins of Rickettsiales infection in humans and animals, we sampled 134 febrile patients, 173 rodents and 43 shrews, as well as 358 ticks, from two cities in Jiangsu and Jiangxi provinces, China. Our data revealed a relatively high prevalence of scrub typhus cases in both localities. In addition, both serological tests and genetic analysis identified three patients infected with Anaplasma bovis, Rickettsia monacensis, and Orientia tsutsugamushi bacteria. Molecular epidemiological investigation revealed the co-circulation of multiple species of Rickettsiales bacteria in small mammals and ticks in both provinces, potentially including novel bacterial species. In sum, these data demonstrate the ongoing importance of Rickettsiales infection in China and highlight the need for the regular surveillance of local arthropods, mammals and humans.
A genome-wide screen for human salicylic acid (SA)-binding proteins reveals targets through which SA may influence development of various diseases
Authors: Choi Hyong Woo , Wang Lei , Powell Adrian F. , Strickler Susan R. , Wang Dekai , Dempsey D’Maris A. , Schroeder Frank C. , Klessig Daniel F.
Published: September 2019

Salicylic acid (SA) is the major metabolite and active ingredient of aspirin; both compounds reduce pain, fever, and inflammation. Despite over a century of research, aspirin/SA’s mechanism(s) of action is still only partially understood. Here we report the results of a genome-wide, high-throughput screen to identify potential SA-binding proteins (SABPs) in human HEK293 cells. Following photo-affinity crosslinking to 4-azidoSA and immuno-selection with an anti-SA antibody, approximately 2,000 proteins were identified. Among these, 95 were enriched more than 10-fold. Pathway enrichment analysis with these 95 candidate SABPs (cSABPs) revealed possible involvement of SA in multiple biological pathways, including (i) glycolysis, (ii) cytoskeletal assembly and/or signaling, and (iii) NF-κB-mediated immune signaling. The two most enriched cSABPs, which corresponded to the glycolytic enzymes alpha-enolase (ENO1) and pyruvate kinase isozyme M2 (PKM2), were assessed for their ability to bind SA and SA’s more potent derivative amorfrutin B1 (amoB1). SA and amoB1 bound recombinant ENO1 and PKM2 at low millimolar and micromolar concentrations, respectively, and inhibited their enzymatic activities in vitro. Consistent with these results, low millimolar concentrations of SA suppressed glycolytic activity in HEK293 cells. To provide insights into how SA might affect various human diseases, a cSABP-human disorder/disease network map was also generated.