bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of end-stage renal disease on long-term survival after major amputation
Authors: Meyer Alexander , Griesbach Colin , Maudanz Nils , Lang Werner , Almasi-Sperling Veronika , Rother Ulrich
Published: March 2020

Summary: Background: To analyze long-term outcomes and possible influencing factors in patients with endstage renal disease (ESRD) and critical limb ischemia (CLI) after major amputation compared to patients with normal renal function and non-dialysis-dependent chronic kidney disease. Patients and methods: Abstraction of single-center medical records of patients undergoing above knee (AKA) and below knee (BKA) amputation over a 10 years period (n = 436; 2009–2018). Excluded were amputations due to trauma or tumor. Patients were subdivided according to renal function in three categories: ESRD patients (n = 98), non-dialysis dependent chronic kidney disease (CKD, n = 98) and normal renal function (NF, n = 240). Predefined endpoints were survival and postoperative complications. Cox-regression models were built to analyze independent risk factors for outcome parameters. Results: In total, 298 AKA, 133 BKA and 5 knee joint exarticulations were performed. ESRD patients showed inferior in-hospital results as to death (ESRD 36.7 % vs. CKD 19.4 % and NF 20.0 %, P = .002). Similarly, long-term survival rates (6 months: ESRD 55.0 % vs. CKD 69.4 %, NF 67.9 % 1 year: ESRD 48.6 %, CKD 60.2 %, NF 60.8 % 5 years: ESRD 9.9 %, CKD 31.8 %, NF 37.1 %, P < .001) were significantly decreased for ESRD patients. Median postoperative survival was 10 months in ERSD, and 22 months in CKD and NF, respectively. Analysis of postoperative surgical complications revealed no differences between groups (ESRD 19.4 %, CKD 17.3 %, NF 17.0 %; P = 0.433). Cox regression analysis indicated that dialysis (HR 1.63; 95 % CI 1.22–2.16; P = .001), hypertension (HR 1.59; 95 % CI 0.99–2.54) and smoking (HR 1.22; 95 % CI 1.03–1.44; P = .022) was associated with increased risk of death during follow-up. Conclusions: Mortality after limb amputation in ERSD patients remains high. Survival of ERSD patients is lower in relation to chronic kidney disease and patients with normal renal function. Due to poor in hospital outcomes and absent long-term survival, benefit of primary amputation in ERSD seems scarce.
Global Climate and Human Health Effects of the Gasoline and Diesel Vehicle Fleets
Authors: Huang Yaoxian , Unger Nadine , Harper Kandice , Heyes Chris
Published: March 2020

The global gasoline and diesel fuel vehicle fleets impose substantial impacts on air quality, human health, and climate change. Here we quantify the global radiative forcing and human health impacts of the global gasoline and diesel sectors using the NCAR CESM global chemistry‐climate model for year 2015 emissions from the IIASA GAINS inventory. Net global radiative effects of short‐lived climate forcers (including aerosols, ozone, and methane) from the gasoline and diesel sectors are +13.6 and +9.4 mW m−2, respectively. The annual mean net aerosol contributions to the net radiative effects of gasoline and diesel are −9.6 ± 2.0 and +8.8 ± 5.8 mW m−2. Aerosol indirect effects for the gasoline and diesel road vehicle sectors are −16.6 ± 2.1 and −40.6 ± 4.0 mW m−2. The fractional contributions of short‐lived climate forcers to the total global climate impact including carbon dioxide on the 20‐year time scale are similar, 14.9% and 14.4% for gasoline and diesel, respectively. Global annual total PM2.5‐ and ozone‐induced premature deaths for gasoline and diesel sectors approach 115,000 (95% CI: 69,000–153,600) and 122,100 (95% CI: 78,500–157,500), with corresponding years of life lost of 2.10 (95% CI: 1.23–2.66) and 2.21 (95% CI: 1.47–2.85) million years. Substantial regional variability of premature death rates is found for the diesel sector when the regional health effects are normalized by the annual total regional vehicle distance traveled. Regional premature death rates for the gasoline and diesel sectors, respectively, vary by a factor of eight and two orders of magnitude, with India showing the highest for both gasoline and diesel sectors.
Frequency‐Dependent Behavior of Zonal Jet Variability
Authors: Lindgren Erik A. , Sheshadri Aditi , Plumb R. Alan
Published: March 2020

Recent work suggests that storm track diagnostics such as eddy heat fluxes and eddy kinetic energies have very small signatures in the first annular mode of zonal mean zonal wind, suggesting a lack of co‐variability between the locations of the extratropical jet and storm tracks. The frequency‐dependence of this apparent decoupling is explored in ERA‐Interim reanalysis data. The annular modes show similar spatial characteristics in the different frequency ranges considered. Cancellation between the signatures of storm track diagnostics in the leading low‐pass and high‐pass filtered annular modes is evident, partly explaining their small signature in the total. It is shown that at timescales greater than 30 days, the first zonal wind mode describes latitudinal shifts of both the midlatitude jet and its associated storm tracks, and it appears that the persistence of zonal wind anomalies is sustained primarily by a baroclinic feedback.
Polar Amplification as an Inherent Response of a Circulating Atmosphere: Results From the TRACMIP Aquaplanets
Authors: Russotto Rick D. , Biasutti Michela
Published: March 2020

In the Tropical Rain belts with an Annual cycle and Continent Model Intercomparison Project (TRACMIP) ensemble of aquaplanet climate model experiments, CO2‐induced warming is amplified in the poles in 10 out of 12 models, despite the lack of sea ice. We attribute causes of this amplification by perturbing individual radiative forcing and feedback components in a moist energy balance model. We find a strikingly linear pattern of tropical versus polar warming contributions across models and processes, implying that polar amplification is an inherent consequence of diffusion of moist static energy by the atmosphere. The largest contributor to polar amplification is the instantaneous CO2 forcing, followed by the water vapor feedback and, for some models, cloud feedbacks. Extratropical feedbacks affect polar amplification more strongly, but even feedbacks confined to the tropics can cause polar amplification. Our results contradict studies inferring warming contributions directly from the meridional gradient of radiative perturbations, highlighting the importance of interactions between feedbacks and moisture transport for polar amplification.
Lateral Variations of Shear‐Wave Velocity in the D″ Layer Beneath the Indian‐Eurasian Plate Collision Zone
Authors: Li Guohui , Bai Ling , Ritsema Jeroen
Published: March 2020

Seismic tomography has demonstrated that the shear‐wave velocity is relatively high over a 3,000‐km wide region in the lowermost mantle beneath southern and eastern Asia. This seismic anomaly demarcates the current position of slab remnants that may have subducted in the Cretaceous. To further characterize the seismic structure at smaller scales, we measure 929 residual travel time differences (δt) between the phases ScS and S using recordings of eight earthquakes beneath the Indian Ocean at stations from the Chinese Digital Seismic Network. We interpret variations of δt up to 10 s as due to horizontal shear‐velocity variations in D″ beneath northern India, Nepal, and southwestern China. The shear velocity can vary by as much as 7% over distances shorter than 300 km. Our observations provide additional observational evidence that compositional heterogeneity and possibly melt contribute to the seismic structure of the lower mantle characterized by long‐term subduction and mantle downwelling.
Particle Ejection Contributions to the Rotational Acceleration and Orbit Evolution of Asteroid (101955) Bennu
Authors: Scheeres D. J. , McMahon J. W. , Brack D. N. , French A. S. , Chesley S. R. , Farnocchia D. , Vokrouhlický D. , Ballouz R.‐L. , Emery J. P. , Rozitis B. , Nolan M. C. , Hergenrother C. W. , Lauretta D. S.
Published: March 2020

This paper explores the implications of the observed Bennu particle ejection events for that asteroid's spin rate and orbit evolution, which could complicate interpretation of the Yarkovsky‐O'Keefe‐Radzievskii‐Paddack (YORP) and Yarkovsky effects on this body's spin rate and orbital evolution. Based on current estimates of particle ejection rates, we find that the overall contribution to Bennu's spin and orbital drift is small or negligible as compared to the Yarkovsky and YORP effects. However, if there is a large unseen component of smaller mass ejections or a strong directionality in the ejection events, it could constitute a significant contribution that could mask the overall YORP effect. This means that the YORP effect may be stronger than currently assumed. The analysis is generalized so that the particle ejection effect can be assessed for other bodies that may be subject to similar mass loss events. Further, our model can be modified to address different potential mechanisms of particle ejection, which are a topic of ongoing study.
Crustal Thickness Beneath the Dinarides and Surrounding Areas From Receiver Functions
Authors: Stipčević Josip , Herak Marijan , Molinari Irene , Dasović Iva , Tkalčić Hrvoje , Gosar Andrej
Published: March 2020

Knowledge about the crustal thickness is one of the key elements in the reconstruction of the regional tectonic history. The Dinaric mountain belt is one of the most enigmatic segments of the Alpine‐Mediterranean collision zone, characterized by large variations in crustal thickness and not studied sufficiently. We present a new Moho depth map for the wider Dinarides region which was created using teleseismic earthquake recordings from 87 permanent and temporary seismic stations in the region. Teleseismic data were analyzed using the receiver function method to extract converted P to S waves.

The resulting Moho topography fits well within a structural framework comprising a thicker crust under the Dinarides, which gradually becomes thinner toward the Pannonian and Adriatic domains. The profiles crossing the northwestern Dinarides are marked by a relatively sharp decrease in crustal thickness north of the main thrust front. This transition is followed by significant crustal thinning toward the Pannonian basin. The Mohorovičić discontinuity lies the deepest in the central and southern Dinarides, at depths of over 55 km. Here similarly to the northwestern segment we observe a jump in the crustal thickness when transitioning toward the Internal Dinarides, which hints at possible underthrusting (or subduction) of the Adria plate in this region. Moho depths in the transition zone toward the Pannonian basin and in the Pannonian basin proper vary between 25 and 35 km. In the Adriatic domain, we find crustal thickness ranging from 30 km to more than 45 km around the Central Adriatic islands.
Ann Gibbons Receives 2019 David Perlman Award for Excellence in Science Journalism–News
Authors:   AGU
Published: March 2020

Ann Gibbons was awarded the 2019 David Perlman Award for Excellence in Science Journalism–News at the AGU Fall Meeting Honors Ceremony, held on 11 December 2019 in San Francisco, Calif. The award is given “for excellence in news reporting about the Earth and space sciences, with a deadline of one week or less.”
Intensified Investigations of East Asian Aerosols and Climate
Authors: Li Zhanqing
Published: March 2020

Three special collections in JGR: Atmospheres present a fast-growing body of literature on atmospheric aerosols and their impact on the regional climate in East Asia.
Human Composting Is a Greener Way to Go
Authors: Cartier Kimberly
Published: March 2020

Our environmental impact doesn’t go away when we die, but there’s a way to make that impact a positive one.
A Machine‐Learning Approach to Derive Long‐Term Trends of Thermospheric Density
Authors: Weng Libin , Lei Jiuhou , Zhong Jiahao , Dou Xiankang , Fang Hanxian
Published: March 2020

Key Points

The Artificial Neural Network Model (ANNM) has good capability of characterizing the variability of the satellite drag‐derived densities

The density data during either 1967–2005 or 1967–2013 intervals are used to give a similar long‐term trend from the ANNM

The thermospheric density trend relative to the ANNM from 250 to 575 km is about −1.5% to −2.0% per decade without obvious solar flux dependence
Molecular principles of metastasis: a hallmark of cancer revisited
Authors: Fares Jawad , Fares Mohamad Y. , Khachfe Hussein H. , Salhab Hamza A. , Fares Youssef
Published: March 2020

Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.
Taxon-specific microbial growth and mortality patterns reveal distinct temporal population responses to rewetting in a California grassland soil
Authors: Blazewicz Steven J , Hungate Bruce A , Koch Benjamin J , Nuccio Erin E , Morrissey Ember , Brodie Eoin L , Schwartz Egbert , Pett-Ridge Jennifer , Firestone Mary K
Published: March 2020

Microbial activity increases after rewetting dry soil, resulting in a pulse of carbon mineralization and nutrient availability. The biogeochemical responses to wet-up are reasonably well understood and known to be microbially mediated. Yet, the population level dynamics, and the resulting changes in microbial community patterns, are not well understood as ecological phenomena. Here, we used sequencing of 16S rRNA genes coupled with heavy water (H218O) DNA quantitative stable isotope probing to estimate population-specific rates of growth and mortality in response to a simulated wet-up event in a California annual grassland soil. Bacterial growth and mortality responded rapidly to wet-up, within 3 h, and continued throughout the 168 h incubation, with patterns of sequential growth observed at the phylum level. Of the 37 phyla detected in the prewet community, growth was found in 18 phyla while mortality was measured in 26 phyla. Rapid growth and mortality rates were measurable within 3 h of wet-up but had contrasting characteristics; growth at 3 h was dominated by select taxa within the Proteobacteria and Firmicutes, whereas mortality was taxonomically widespread. Furthermore, across the community, mortality exhibited density-independence, consistent with the indiscriminate shock resulting from dry-down and wet-up, whereas growth was density-dependent, consistent with control by competition or predation. Total aggregated growth across the community was highly correlated with total soil CO2 production. Together, these results illustrate how previously “invisible” population responses can translate quantitatively to emergent observations of ecosystem-scale biogeochemistry.
Autophagy-dependent filopodial kinetics restrict synaptic partner choice during Drosophila brain wiring
Authors: Kiral Ferdi Ridvan , Linneweber Gerit Arne , Mathejczyk Thomas , Georgiev Svilen Veselinov , Wernet Mathias F. , Hassan Bassem A. , von Kleist Max , Hiesinger Peter Robin
Published: March 2020

Brain wiring is remarkably precise, yet most neurons readily form synapses with incorrect partners when given the opportunity. Dynamic axon-dendritic positioning can restrict synaptogenic encounters, but the spatiotemporal interaction kinetics and their regulation remain essentially unknown inside developing brains. Here we show that the kinetics of axonal filopodia restrict synapse formation and partner choice for neurons that are not otherwise prevented from making incorrect synapses. Using 4D imaging in developing Drosophila brains, we show that filopodial kinetics are regulated by autophagy, a prevalent degradation mechanism whose role in brain development remains poorly understood. With surprising specificity, autophagosomes form in synaptogenic filopodia, followed by filopodial collapse. Altered autophagic degradation of synaptic building material quantitatively regulates synapse formation as shown by computational modeling and genetic experiments. Increased filopodial stability enables incorrect synaptic partnerships. Hence, filopodial autophagy restricts inappropriate partner choice through a process of kinetic exclusion that critically contributes to wiring specificity.
Cancer immune control needs senescence induction by interferon-dependent cell cycle regulator pathways in tumours
Authors: Brenner Ellen , Schörg Barbara F. , Ahmetlić Fatima , Wieder Thomas , Hilke Franz Joachim , Simon Nadine , Schroeder Christopher , Demidov German , Riedel Tanja , Fehrenbacher Birgit , Schaller Martin , Forschner Andrea , Eigentler Thomas , Niessner Heike , Sinnberg Tobias , Böhm Katharina S. , Hömberg Nadine , Braumüller Heidi , Dauch Daniel , Zwirner Stefan , Zender Lars , Sonanini Dominik , Geishauser Albert , Bauer Jürgen , Eichner Martin , Jarick Katja J. , Beilhack Andreas , Biskup Saskia , Döcker Dennis , Schadendorf Dirk , Quintanilla-Martinez Leticia , Pichler Bernd J. , Kneilling Manfred , Mocikat Ralph , Röcken Martin
Published: March 2020

Immune checkpoint blockade (ICB)-based or natural cancer immune responses largely eliminate tumours. Yet, they require additional mechanisms to arrest those cancer cells that are not rejected. Cytokine-induced senescence (CIS) can stably arrest cancer cells, suggesting that interferon-dependent induction of senescence-inducing cell cycle regulators is needed to control those cancer cells that escape from killing. Here we report in two different cancers sensitive to T cell-mediated rejection, that deletion of the senescence-inducing cell cycle regulators p16Ink4a/p19Arf(Cdkn2a) or p21Cip1(Cdkn1a) in the tumour cells abrogates both the natural and the ICB-induced cancer immune control. Also in humans, melanoma metastases that progressed rapidly during ICB have losses of senescence-inducing genes and amplifications of senescence inhibitors. Metastatic cells also resist CIS. Such genetic and functional alterations are infrequent in metastatic melanomas regressing during ICB. Thus, activation of tumour-intrinsic, senescence-inducing cell cycle regulators is required to stably arrest cancer cells that escape from eradication.
Global plant trait relationships extend to the climatic extremes of the tundra biome
Authors: Thomas H. J. D. , Bjorkman A. D. , Myers-Smith I. H. , Elmendorf S. C. , Kattge J. , Diaz S. , Vellend M. , Blok D. , Cornelissen J. H. C. , Forbes B. C. , Henry G. H. R. , Hollister R. D. , Normand S. , Prevéy J. S. , Rixen C. , Schaepman-Strub G. , Wilmking M. , Wipf S. , Cornwell W. K. , Beck P. S. A. , Georges D. , Goetz S. J. , Guay K. C. , Rüger N. , Soudzilovskaia N. A. , Spasojevic M. J. , Alatalo J. M. , Alexander H. D. , Anadon-Rosell A. , Angers-Blondin S. , te Beest M. , Berner L. T. , Björk R. G. , Buchwal A. , Buras A. , Carbognani M. , Christie K. S. , Collier L. S. , Cooper E. J. , Elberling B. , Eskelinen A. , Frei E. R. , Grau O. , Grogan P. , Hallinger M. , Heijmans M. M. P. D. , Hermanutz L. , Hudson J. M. G. , Johnstone J. F. , Hülber K. , Iturrate-Garcia M. , Iversen C. M. , Jaroszynska F. , Kaarlejarvi E. , Kulonen A. , Lamarque L. J. , Lantz T. C. , Lévesque E. , Little C. J. , Michelsen A. , Milbau A. , Nabe-Nielsen J. , Nielsen S. S. , Ninot J. M. , Oberbauer S. F. , Olofsson J. , Onipchenko V. G. , Petraglia A. , Rumpf S. B. , Shetti R. , Speed J. D. M. , Suding K. N. , Tape K. D. , Tomaselli M. , Trant A. J. , Treier U. A. , Tremblay M. , Venn S. E. , Vowles T. , Weijers S. , Wookey P. A. , Zamin T. J. , Bahn M. , Blonder B. , van Bodegom P. M. , Bond-Lamberty B. , Campetella G. , Cerabolini B. E. L. , Chapin F. S. , Craine J. M. , Dainese M. , Green W. A. , Jansen S. , Kleyer M. , Manning P. , Niinemets Ü. , Onoda Y. , Ozinga W. A. , Peñuelas J. , Poschlod P. , Reich P. B. , Sandel B. , Schamp B. S. , Sheremetiev S. N. , de Vries F. T.
Published: March 2020

The majority of variation in six traits critical to the growth, survival and reproduction of plant species is thought to be organised along just two dimensions, corresponding to strategies of plant size and resource acquisition. However, it is unknown whether global plant trait relationships extend to climatic extremes, and if these interspecific relationships are confounded by trait variation within species. We test whether trait relationships extend to the cold extremes of life on Earth using the largest database of tundra plant traits yet compiled. We show that tundra plants demonstrate remarkably similar resource economic traits, but not size traits, compared to global distributions, and exhibit the same two dimensions of trait variation. Three quarters of trait variation occurs among species, mirroring global estimates of interspecific trait variation. Plant trait relationships are thus generalizable to the edge of global trait-space, informing prediction of plant community change in a warming world.
Piezo-catalysis for nondestructive tooth whitening
Authors: Wang Yang , Wen Xinrong , Jia Yanmin , Huang Ming , Wang Feifei , Zhang Xuehui , Bai Yunyang , Yuan Guoliang , Wang Yaojin
Published: March 2020

The increasing demand for a whiter smile has resulted in an increased popularity for tooth whitening procedures. The most classic hydrogen peroxide-based whitening agents are effective, but can lead to enamel demineralization, gingival irritation, or cytotoxicity. Furthermore, these techniques are excessively time-consuming. Here, we report a nondestructive, harmless and convenient tooth whitening strategy based on a piezo-catalysis effect realized by replacement of abrasives traditionally used in toothpaste with piezoelectric particles. Degradation of organic dyes via piezo-catalysis of BaTiO3 (BTO) nanoparticles was performed under ultrasonic vibration to simulate daily tooth brushing. Teeth stained with black tea, blueberry juice, wine or a combination thereof can be notably whitened by the poled BTO turbid liquid after vibration for 3 h. A similar treatment using unpoled or cubic BTO show negligible tooth whitening effect. Furthermore, the BTO nanoparticle-based piezo-catalysis tooth whitening procedure exhibits remarkably less damage to both enamel and biological cells.
Perivascular localization of macrophages in the intestinal mucosa is regulated by Nr4a1 and the microbiome
Authors: Honda Masaki , Surewaard Bas G. J. , Watanabe Mayuki , Hedrick Catherine C. , Lee Woo-Yong , Brown Kirsty , McCoy Kathy D. , Kubes Paul
Published: March 2020

While the ontogeny and recruitment of the intestinal monocyte/macrophage lineage has been studied extensively, their precise localization and function has been overlooked. Here we show by imaging the murine small and large intestines in steady-state that intestinal CX3CR1+ macrophages form an interdigitated network intimately adherent to the entire mucosal lamina propria vasculature. The macrophages form contacts with each other, which are disrupted in the absence of microbiome, monocyte recruitment (Ccr2−/−), or monocyte conversion (Nr4a1−/−). In dysbiosis, gaps exist between the perivascular macrophages correlating with increased bacterial translocation from the lamina propria into the bloodstream. The recruitment of monocytes and conversion to macrophages during intestinal injury is also dependent upon CCR2, Nr4a1 and the microbiome. These findings demonstrate a relationship between microbiome and the maturation of lamina propria perivascular macrophages into a tight anatomical barrier that might function to prevent bacterial translocation. These cells are also critical for emergency vascular repair.
Slow-to-fast transition of giant creeping rockslides modulated by undrained loading in basal shear zones
Authors: Agliardi Federico , Scuderi Marco M. , Fusi Nicoletta , Collettini Cristiano
Published: March 2020

Giant rockslides are widespread and sensitive to hydrological forcing, especially in climate change scenarios. They creep slowly for centuries and then can fail catastrophically posing major threats to society. However, the mechanisms regulating the slow-to-fast transition toward their catastrophic collapse remain elusive. We couple laboratory experiments on natural rockslide shear zone material and in situ observations to provide a scale-independent demonstration that short-term pore fluid pressure variations originate a full spectrum of creep styles, modulated by slip-induced undrained conditions. Shear zones respond to pore pressure increments by impulsive acceleration and dilatancy, causing spontaneous deceleration followed by sustained steady-rate creep. Increasing pore pressure results in high creep rates and eventual collapse. Laboratory experiments quantitatively capture the in situ behavior of giant rockslides and lay physically-based foundations to understand the collapse of giant rockslides.
A receptor for the complement regulator factor H increases transmission of trypanosomes to tsetse flies
Authors: Macleod Olivia J. S. , Bart Jean-Mathieu , MacGregor Paula , Peacock Lori , Savill Nicholas J. , Hester Svenja , Ravel Sophie , Sunter Jack D. , Trevor Camilla , Rust Steven , Vaughan Tristan J. , Minter Ralph , Mohammed Shabaz , Gibson Wendy , Taylor Martin C. , Higgins Matthew K. , Carrington Mark
Published: March 2020

Persistent pathogens have evolved to avoid elimination by the mammalian immune system including mechanisms to evade complement. Infections with African trypanosomes can persist for years and cause human and animal disease throughout sub-Saharan Africa. It is not known how trypanosomes limit the action of the alternative complement pathway. Here we identify an African trypanosome receptor for mammalian factor H, a negative regulator of the alternative pathway. Structural studies show how the receptor binds ligand, leaving inhibitory domains of factor H free to inactivate complement C3b deposited on the trypanosome surface. Receptor expression is highest in developmental stages transmitted to the tsetse fly vector and those exposed to blood meals in the tsetse gut. Receptor gene deletion reduced tsetse infection, identifying this receptor as a virulence factor for transmission. This demonstrates how a pathogen evolved a molecular mechanism to increase transmission to an insect vector by exploitation of a mammalian complement regulator.
Impact of the gut microbiota on the m6A epitranscriptome of mouse cecum and liver
Authors: Jabs Sabrina , Biton Anne , Bécavin Christophe , Nahori Marie-Anne , Ghozlane Amine , Pagliuso Alessandro , Spanò Giulia , Guérineau Vincent , Touboul David , Giai Gianetto Quentin , Chaze Thibault , Matondo Mariette , Dillies Marie-Agnès , Cossart Pascale
Published: March 2020

The intestinal microbiota modulates host physiology and gene expression via mechanisms that are not fully understood. Here we examine whether host epitranscriptomic marks are affected by the gut microbiota. We use methylated RNA-immunoprecipitation and sequencing (MeRIP-seq) to identify N6-methyladenosine (m6A) modifications in mRNA of mice carrying conventional, modified, or no microbiota. We find that variations in the gut microbiota correlate with m6A modifications in the cecum, and to a lesser extent in the liver, affecting pathways related to metabolism, inflammation and antimicrobial responses. We analyze expression levels of several known writer and eraser enzymes, and find that the methyltransferase Mettl16 is downregulated in absence of a microbiota, and one of its target mRNAs, encoding S-adenosylmethionine synthase Mat2a, is less methylated. We furthermore show thatAkkermansia muciniphilaandLactobacillus plantarumaffect specific m6A modifications in mono-associated mice. Our results highlight epitranscriptomic modifications as an additional level of interaction between commensal bacteria and their host.
Complex microparticle architectures from stimuli-responsive intrinsically disordered proteins
Authors: Roberts Stefan , Miao Vincent , Costa Simone , Simon Joseph , Kelly Garrett , Shah Tejank , Zauscher Stefan , Chilkoti Ashutosh
Published: March 2020

The controllable production of microparticles with complex geometries is useful for a variety of applications in materials science and bioengineering. The formation of intricate microarchitectures typically requires sophisticated fabrication techniques such as flow lithography or multiple-emulsion microfluidics. By harnessing the molecular interactions of a set of artificial intrinsically disordered proteins (IDPs), we have created complex microparticle geometries, including porous particles, core-shell and hollow shell structures, and a unique ‘fruits-on-a-vine’ arrangement, by exploiting the metastable region of the phase diagram of thermally responsive IDPs within microdroplets. Through multi-site unnatural amino acid (UAA) incorporation, these protein microparticles can also be photo-crosslinked and stably extracted to an all-aqueous environment. This work expands the functional utility of artificial IDPs as well as the available microarchitectures of this class of biocompatible IDPs, with potential applications in drug delivery and tissue engineering.
Electrical monitoring of photoisomerization of block copolymers intercalated into graphene sheets
Authors: Kim Semin , Le Thanh-Hai , Choi Yunseok , Lee Haney , Heo Eunseo , Lee Unhan , Kim Saerona , Chae Subin , Kim Yoong Ahm , Yoon Hyeonseok
Published: March 2020

Insulating polymers have received little attention in electronic applications. Here, we synthesize a photoresponsive, amphiphilic block copolymer (PEO-b-PVBO) and further control the chain growth of the block segment (PVBO) to obtain different degrees of polymerization (DPs). The benzylidene oxazolone moiety in PEO-b-PVBO facilitated chain-conformational changes due to photoisomerization under visible/ultraviolet (UV) light illumination. Intercalation of the photoresponsive but electrically insulating PEO-b-PVBO into graphene sheets enabled electrical monitoring of the conformational change of the block copolymer at the molecular level. The current change at the microampere level was proportional to the DP of PVBO, demonstrating that the PEO-b-PVBO-intercalated graphene nanohybrid (PGNH) can be used in UV sensors. Additionally, discrete signals at the nanoampere level were separated from the first derivative of the time-dependent current using the fast Fourier transform (FFT). Analysis of the harmonic frequencies using the FFT revealed that the PGNH afforded sawtooth-type current flow mediated by Coulomb blockade oscillation.
Cryptochrome-mediated blue-light signalling modulates UVR8 photoreceptor activity and contributes to UV-B tolerance in Arabidopsis
Authors: Tissot Nicolas , Ulm Roman
Published: March 2020

UV-B constitutes a critical part of the sunlight reaching the earth surface. The homodimeric plant UV-B photoreceptor UV RESISTANCE LOCUS 8 (UVR8) monomerizes in response to UV-B and induces photomorphogenic responses, including UV-B acclimation and tolerance. REPRESSOR OF UV-B PHOTOMORPHOGENESIS 1 (RUP1) and RUP2 are negative feedback regulators that operate by facilitating UVR8 ground state reversion through re-dimerization. Here we show that RUP1 and RUP2 are transcriptionally induced by cryptochrome photoreceptors in response to blue light, which is dependent on the bZIP transcriptional regulator ELONGATED HYPOCOTYL 5 (HY5). Elevated RUP1 and RUP2 levels under blue light enhance UVR8 re-dimerization, thereby negatively regulating UVR8 signalling and providing photoreceptor pathway cross-regulation in a polychromatic light environment, as is the case in nature. We further show that cryptochrome 1, as well as the red-light photoreceptor phytochrome B, contribute to UV-B tolerance redundantly with UVR8. Thus, photoreceptors for both visible light and UV-B regulate UV-B tolerance through an intricate interplay allowing the integration of diverse sunlight signals.
FAM111A protects replication forks from protein obstacles via its trypsin-like domain
Authors: Kojima Yusuke , Machida Yuka , Palani Sowmiya , Caulfield Thomas R. , Radisky Evette S. , Kaufmann Scott H. , Machida Yuichi J.
Published: March 2020

Persistent protein obstacles on genomic DNA, such as DNA-protein crosslinks (DPCs) and tight nucleoprotein complexes, can block replication forks. DPCs can be removed by the proteolytic activities of the metalloprotease SPRTN or the proteasome in a replication-coupled manner; however, additional proteolytic mechanisms may exist to cope with the diversity of protein obstacles. Here, we show that FAM111A, a PCNA-interacting protein, plays an important role in mitigating the effect of protein obstacles on replication forks. This function of FAM111A requires an intact trypsin-like protease domain, the PCNA interaction, and the DNA-binding domain that is necessary for protease activity in vivo. FAM111A, but not SPRTN, protects replication forks from stalling at poly(ADP-ribose) polymerase 1 (PARP1)-DNA complexes trapped by PARP inhibitors, thereby promoting cell survival after drug treatment. Altogether, our findings reveal a role of FAM111A in overcoming protein obstacles to replication forks, shedding light on cellular responses to anti-cancer therapies.
SSRP1-mediated histone H1 eviction promotes replication origin assembly and accelerated development
Authors: Falbo Lucia , Raspelli Erica , Romeo Francesco , Fiorani Simona , Pezzimenti Federica , Casagrande Francesca , Costa Ilaria , Parazzoli Dario , Costanzo Vincenzo
Published: March 2020

In several metazoans, the number of active replication origins in embryonic nuclei is higher than in somatic ones, ensuring rapid genome duplication during synchronous embryonic cell divisions. High replication origin density can be restored by somatic nuclear reprogramming. However, mechanisms underlying high replication origin density formation coupled to rapid cell cycles are poorly understood. Here, using Xenopus laevis, we show that SSRP1 stimulates replication origin assembly on somatic chromatin by promoting eviction of histone H1 through its N-terminal domain. Histone H1 removal derepresses ORC and MCM chromatin binding, allowing efficient replication origin assembly. SSRP1 protein decays at mid-blastula transition (MBT) when asynchronous somatic cell cycles start. Increasing levels of SSRP1 delay MBT and, surprisingly, accelerate post-MBT cell cycle speed and embryo development. These findings identify a major epigenetic mechanism regulating DNA replication and directly linking replication origin assembly, cell cycle duration and embryo development in vertebrates.
Lipidomic and biophysical homeostasis of mammalian membranes counteracts dietary lipid perturbations to maintain cellular fitness
Authors: Levental Kandice R. , Malmberg Eric , Symons Jessica L. , Fan Yang-Yi , Chapkin Robert S. , Ernst Robert , Levental Ilya
Published: March 2020

Proper membrane physiology requires maintenance of biophysical properties, which must be buffered from external perturbations. While homeostatic adaptation of membrane fluidity to temperature variation is a ubiquitous feature of ectothermic organisms, such responsive membrane adaptation to external inputs has not been directly observed in mammals. Here, we report that challenging mammalian membranes by dietary lipids leads to robust lipidomic remodeling to preserve membrane physical properties. Specifically, exogenous polyunsaturated fatty acids are rapidly incorporated into membrane lipids, inducing a reduction in membrane packing. These effects are rapidly compensated both in culture and in vivo by lipidome-wide remodeling, most notably upregulation of saturated lipids and cholesterol, resulting in recovery of membrane packing and permeability. Abrogation of this response results in cytotoxicity when membrane homeostasis is challenged by dietary lipids. These results reveal an essential mammalian mechanism for membrane homeostasis wherein lipidome remodeling in response to dietary lipid inputs preserves functional membrane phenotypes.
Boron-mediated directed aromatic C–H hydroxylation
Authors: Lv Jiahang , Zhao Binlin , Yuan Yu , Han Ying , Shi Zhuangzhi
Published: March 2020

Transition metal-catalysed C–H hydroxylation is one of the most notable advances in synthetic chemistry during the past few decades and it has been widely employed in the preparation of alcohols and phenols. The site-selective hydroxylation of aromatic C–H bonds under mild conditions, especially in the context of substituted (hetero)arenes with diverse functional groups, remains a challenge. Here, we report a general and mild chelation-assisted C–H hydroxylation of (hetero)arenes mediated by boron species without the use of any transition metals. Diverse (hetero)arenes bearing amide directing groups can be utilized for ortho C–H hydroxylation under mild reaction conditions and with broad functional group compatibility. Additionally, this transition metal-free strategy can be extended to synthesize C7 and C4-hydroxylated indoles. By utilizing the present method, the formal synthesis of several phenol intermediates to bioactive molecules is demonstrated.
The genetic architecture of breast papillary lesions as a predictor of progression to carcinoma
Authors: Kader Tanjina , Elder Kenneth , Zethoven Magnus , Semple Timothy , Hill Prue , Goode David L. , Thio Niko , Cheasley Dane , Rowley Simone M. , Byrne David J. , Pang Jia-Min , Miligy Islam M. , Green Andrew R. , Rakha Emad A. , Fox Stephen B. , Mann G. Bruce , Campbell Ian G. , Gorringe Kylie L.
Published: March 2020

Intraductal papillomas (IDP) are challenging breast findings because of their variable risk of progression to malignancy. The molecular events driving IDP development and genomic features of malignant progression are poorly understood. In this study, genome-wide CNA and/or targeted mutation analysis was performed on 44 cases of IDP, of which 20 cases had coexisting ductal carcinoma in situ (DCIS), papillary DCIS or invasive ductal carcinoma (IDC). CNA were rare in pure IDP, but 69% carried an activatingPIK3CAmutation. Among the synchronous IDP cases, 55% (11/20) were clonally related to the synchronous DCIS and/or IDC, only one of which had papillary histology. In contrast to pure IDP,PIK3CAmutations were absent from clonal cases. CNAs in any of chromosomes 1, 16 or 11 were significantly enriched in clonal IDP lesions compared to pure and non-clonal IDP. The observation that 55% of IDP are clonal to DCIS/IDC indicates that IDP can be a direct precursor for breast carcinoma, not limited to the papillary type. The absence ofPIK3CAmutations and presence of CNAs in IDP could be used clinically to identify patients at high risk of progression to carcinoma.
Tuneable topological domain wall states in engineered atomic chains
Authors: Huda Md Nurul , Kezilebieke Shawulienu , Ojanen Teemu , Drost Robert , Liljeroth Peter
Published: March 2020

Topological modes in one- and two-dimensional systems have been proposed for numerous applications utilizing their exotic electronic responses. The 1D, zero-energy, topologically protected end modes can be realized in structures implementing the Su–Schrieffer–Heeger (SSH) model. While the edge modes in the SSH model are at exactly the mid-gap energy, other paradigmatic 1D models such as trimer and coupled dimer chains have non-zero energy boundary states. However, these structures have not been realized in an atomically tuneable system that would allow explicit control of the edge modes. Here, we demonstrate atomically controlled trimer and coupled dimer chains realized using chlorine vacancies in the c(2 × 2) adsorption layer on Cu(100). This system allows wide tuneability of the domain wall modes that we experimentally demonstrate using low-temperature scanning tunneling microscopy (STM).
An optimized purified inactivated Zika vaccine provides sustained immunogenicity and protection in cynomolgus macaques
Authors: Lecouturier Valérie , Pavot Vincent , Berry Catherine , Donadieu Arnaud , de Montfort Aymeric , Boudet Florence , Rokbi Bachra , Jackson Nicolas , Heinrichs Jon
Published: March 2020

The recent spread of Zika virus (ZIKV) through the Americas and Caribbean and its devastating consequences for pregnant women and their babies have driven the search for a safe and efficacious ZIKV vaccine. Among the vaccine candidates, a first-generation ZIKV purified inactivated vaccine (ZPIV), adjuvanted with aluminum hydroxide, developed by the Walter Reed Army Institute of Research (WRAIR), has elicited high seroconversion rates in participants in three phase-I clinical trials. In collaboration with the WRAIR, Sanofi Pasteur (SP) optimized the production scale, culture and purification conditions, and increased the regulatory compliance, both of which are critical for clinical development and licensure of this vaccine. Using a clinical batch of the first-generation ZPIV as a benchmark, we report that different doses of the optimized vaccine (ZPIV-SP) elicited sustained neutralizing antibodies, specific T- and memory B-cells, and provided complete protection against a ZIKV challenge in cynomolgus macaques. These data provide evidence that the ZPIV-SP vaccine performs at least as well as the ZPIV vaccine, and provide support for continued development in the event of future ZIKV outbreaks.
BCG and BCGΔBCG1419c protect type 2 diabetic mice against tuberculosis via different participation of T and B lymphocytes, dendritic cells and pro-inflammatory cytokines
Authors: Segura-Cerda Cristian Alfredo , Marquina-Castillo Brenda , Lozano-Ordaz Vasti , Mata-Espinosa Dulce , Barrios-Payán Jorge Alberto , López-Torres Manuel O. , Aceves-Sánchez Michel de Jesús , Bielefeldt-Ohmann Helle , Hernández-Pando Rogelio , Flores-Valdez Mario Alberto
Published: March 2020

Comorbidity between Tuberculosis (TB) and type 2 diabetes (T2D) is one of the greatest contributors to the spread ofMycobacterium tuberculosis (M. tuberculosis)in low- and middle-income countries. T2D compromises key steps of immune responses againstM. tuberculosisand it might affect the protection afforded by vaccine candidates against TB. We compared the protection and immune response afforded by the BCGΔBCG1419c vaccine candidate versus that of wild-type BCG in mice with T2D. Vaccination with both BCGΔBCG1419c, BCG or infection withM. tuberculosisreduced weight loss, hyperglycemia, and insulin resistance during T2D progression, suggesting that metabolic changes affecting these parameters were affected by mycobacteria. For control of acute TB, and compared with non-vaccinated controls, BCG showed a dominant T CD4+response whereas BCGΔBCG1419c showed a dominant T CD8+/B lymphocyte response. Moreover, BCG maintained an increased response in lung cells via IFN-γ, TNF-α, and IL-4, while BCGΔBCG1419c increased IFN-γ but reduced IL-4 production. As for chronic TB, and compared with non-vaccinated controls, both BCG strains had a predominant presence of T CD4+lymphocytes. In counterpart, BCGΔBCG1419c led to increased presence of dendritic cells and an increased production of IL-1 β. Overall, while BCG effectively reduced pneumonia in acute infection, it failed to reduce it in chronic infection, whereas we hypothesize that increased production of IL-1 β induced by BCGΔBCG1419c contributed to reduced pneumonia and alveolitis in chronic TB. Our results show that BCG and BCGΔBCG1419c protect T2D mice against TB via different participation of T and B lymphocytes, dendritic cells, and pro-inflammatory cytokines.
Syngeneic Mesenchymal Stem Cells Reduce Immune Rejection After Induced Pluripotent Stem Cell-Derived Allogeneic Cardiomyocyte Transplantation
Authors: Yoshida Shohei , Miyagawa Shigeru , Toyofuku Toshihiko , Fukushima Satsuki , Kawamura Takuji , Kawamura Ai , Kashiyama Noriyuki , Nakamura Yuki , Toda Koichi , Sawa Yoshiki
Published: March 2020

Avoiding immune rejection after allogeneic induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) transplantation is a concern. However, mesenchymal stem cells (MSCs) can suppress immune rejection. To determine whether MSC co-transplantation can reduce immune rejection after allogeneic iPSC-CM transplantation, the latter cell type, harbouring a luciferase transgene, was subcutaneously transplanted alone or together with syngeneic MSCs into BALB/c mice. Bioluminescence imaging revealed that MSC co-transplantation significantly improved graft survival (day 7: iPSC-CMs alone 34 ± 5%; iPSC-CMs with MSCs, 61 ± 7%; P = 0.008). MSC co-transplantation increased CD4 + CD25 + FOXP3 + regulatory T cell numbers, apoptotic CD8-positive T cells, and IL-10 and TGF-beta expression at the implantation site. Analysis using a regulatory T cell depletion model indicated that enhanced regulatory T cell populations in the iPSC-CM with MSC group partially contributed to the extended iPSC-CM survival. Further, MSCs affected activated lymphocytes directly through cell–cell contact, which reduced the CD8/CD4 ratio, the proportion of Th1-positive cells among CD4-positive cells, and the secretion of several inflammation-related cytokines. Syngeneic MSC co-transplantation might thus control allogeneic iPSC-CM rejection by mediating immune tolerance via regulatory T cells and cell–cell contact with activated lymphocytes; this approach has promise for cardiomyogenesis-based therapy using allogeneic iPSC-CMs for severe heart failure.
Metabolomic-guided discovery of cyclic nonribosomal peptides from Xylaria ellisii sp. nov., a leaf and stem endophyte of Vaccinium angustifolium
Authors: Ibrahim Ashraf , Tanney Joey B. , Fei Fan , Seifert Keith A. , Cutler G. Christopher , Capretta Alfredo , Miller J. David , Sumarah Mark W.
Published: March 2020

Fungal endophytes are sources of novel bioactive compounds but relatively few agriculturally important fruiting plants harboring endophytes have been carefully studied. Previously, we identified a griseofulvin-producing Xylaria species isolated from Vaccinium angustifolium, V. corymbosum, and Pinus strobus. Morphological and genomic analysis determined that it was a new species, described here as Xylaria ellisii. Untargeted high-resolution LC-MS metabolomic analysis of the extracted filtrates and mycelium from 15 blueberry isolates of this endophyte revealed differences in their metabolite profiles. Toxicity screening of the extracts showed that bioactivity was not linked to production of griseofulvin, indicating this species was making additional bioactive compounds. Multivariate statistical analysis of LC-MS data was used to identify key outlier features in the spectra. This allowed potentially new compounds to be targeted for isolation and characterization. This approach resulted in the discovery of eight new proline-containing cyclic nonribosomal peptides, which we have given the trivial names ellisiiamides A-H. Three of these peptides were purified and their structures elucidated by one and two-dimensional nuclear magnetic resonance spectroscopy (1D and 2D NMR) and high-resolution tandem mass spectrometry (HRMS/MS) analysis. The remaining five new compounds were identified and annotated by high-resolution mass spectrometry. Ellisiiamide A demonstrated Gram-negative activity against Escherichia coli BW25113, which is the first reported for this scaffold. Additionally, several known natural products including griseofulvin, dechlorogriseofulvin, epoxy/cytochalasin D, zygosporin E, hirsutatin A, cyclic pentapeptides #1–2 and xylariotide A were also characterized from this species.