bluuebunny/crossref_metadata_2025 huggingface dataset:
Frank Knight and the cognitive diversity of entrepreneurship
Authors: Dold Malte F. , Rizzo Mario J.
Published: May 2021

InRisk, Uncertainty and Profit(RUP), Knight (1921) develops a theory of the firm that stresses the important role of entrepreneurial judgment for a firm's success. For Knight, entrepreneurial judgment is first and foremost the selection of ‘proxy entrepreneurs’ who are capable of making good judgments under uncertainty. In this sense, entrepreneurial judgment is essentially ‘judgment of judgment’. An overlooked implication of Knight's position is the fact that it leads to an endorsement of distributed entrepreneurship and responsibility. We deem this a very modern idea that challenges a completely hierarchical understanding of the firm. Knight himself does not thoroughly examine the institutional implications of the analytical framework he sets up in RUP. In this paper, we summarize the ‘philosophical vision’ of Knight's framework and illustrate his rationale behind the distribution of entrepreneurship. We conclude the paper with a discussion of potential institutional implications by referring to the danger ofmonocultures, the additional value created bycognitively diverse teams, and the effectiveness ofventure capitalists.
Mitigation and Adaptation through Environmental Impact Assessment Litigation: Rethinking the Prospect of Climate Change Litigation in China
Authors: He Xiangbai
Published: May 2021

There are two general pathways towards climate change litigation in China: tort-based litigation to hold carbon emitters accountable in civil law, and administrative litigation against the government to demand better climate regulation. While the first pathway is gaining momentum among Chinese scholars, this article argues that legal barriers to applying tort-based rules to climate change should be fairly acknowledged. The article argues that China's legal framework for environmental impact assessment (EIA) provides more openness and flexibility for the resolution of climate change disputes. Therefore, EIA-based climate lawsuits, which challenge environmental authorities for not adequately taking climate change factors into account in decision-making processes, encounter relatively fewer legal barriers, require less radical legal or institutional reform, and have greater potential to maintain existing legal orders. The regulatory effects produced by EIA-based litigation suggest that the scholarship on climate change litigation in China should take such litigation seriously because it could influence both governments and emitters in undertaking more proactive efforts. This China-based study, with a special focus on judicial practice in the largest developing country, will shine a light on China's contribution to transnational climate litigation.
The role of surgical and total endovascular techniques in the	treatment of ruptured juxtarenal aortic aneurysms
Authors: Keschenau Paula R. , Beropoulis Efthymios , Gombert Alexander , Jacobs Michael J. , Torsello Giovanni , Austermann Martin , Kotelis Drosos , Donas Konstantinos P.
Published: May 2021

Summary: Background: Ruptured juxtarenal aortic aneurysms (RJAAA) represent a special challenge in clinical practice, but the evidence to guide therapeutic decision-making is scarce. The aim of this study was to present two different approaches, open surgical (OAR) and chimney endovascular repair (CHEVAR), for treating patients with RJAAA. Patients and methods: This retrospective two-center study included all patients per center undergoing OAR or CHEVAR for RJAAA between February 2008 and January 2020. Juxtarenal aortic aneurysms were defined as having an infrarenal neck of 2–5 mm, measured after three-dimensional reconstruction of the computed tomography angiography scan. Results: 12 OAR patients (10 male, median age 73 years [58–90 years]) and 6 CHEVAR patients (all male, median age 74 years [59–83 years]) were included. In the OAR group, the proximal aortic clamping was suprarenal in 7 and interrenal in 5 patients. Cold renal perfusion was used in 4 patients, in 2 with suprarenal aortic clamping and in 2 with interrenal aortic clamping. 3 CHEVAR patients received a single renal chimney, the other 3 received double renal chimneys. Technical success was 12/12 in the OAR group 5/6 in the CHEVAR group. In-hospital mortality and 30-day mortality were 3/12 after OAR and 0/6 after CHEVAR. 2 OAR patients required transient dialysis. Median in-hospital stay was 14 (10–63) and 8 (6–21) days and median follow-up (FU) was 20 (3–37) and 30 (7–101) months, respectively. No further deaths occurred during FU. One OAR patient and 4 CHEVAR patients required aortic reinterventions. Conclusions: RJAAAs are rare. Both OAR and CHEVAR can represent adequate treatments for RJAAAs. OAR is the traditional approach, but CHEVAR has - in a high-volume center - promising early results with nonetheless a need for continuous FU to prevent reinterventions. Defining the studied aortic pathology precisely is essential for future research in order to draw valid conclusions.
Quantifying Global Power Plant Carbon Dioxide Emissions With Imaging Spectroscopy
Authors: Cusworth Daniel H. , Duren Riley M. , Thorpe Andrew K. , Eastwood Michael L. , Green Robert O. , Dennison Philip E. , Frankenberg Christian , Heckler Joseph W. , Asner Gregory P. , Miller Charles E.
Published: May 2021

Anthropogenic carbon dioxide (CO2) emissions dominate uncertainties in the global carbon budget. Global inventories, such as the National Greenhouse Gas Inventories, have latencies of 12–24 months and may not keep pace with rapidly changing infrastructure, particularly in the developing world. Our work reveals that airborne and satellite imaging spectrometers provide 3–30 m spatial resolution and accurate quantification of CO2 emissions at the facility scale. Examples from 17 coal and gas fired power plants across the United States demonstrate robust correlation and 21% agreement on average between our remotely sensed estimates and simultaneous in situ measured emissions. We highlight four examples of coal‐fired power plants in India, Poland, and South Korea, where we quantify significant carbon dioxide emissions from power plants where limited public emissions data exist. Leveraging previous work on methane (CH4) plume detection, we present a strategy to exploit joint CO2 and CH4 plume imaging to quantify carbon emissions across widely distributed industrial infrastructure, including facilities that co‐emit CO2 and CH4. We show an example of a coal operation, where we attribute 25% of greenhouse gas emissions to coal extraction (CH4) and the remaining 75% to energy generation (CO2). Satellite spectrometers could track high emitting coal‐fired power plants that collectively contribute to 60% or more of global coal CO2 emissions. Multiple revisits and coordinated targeting of these high emitting facilities by multiple spaceborne instruments will be key to reducing uncertainties in global anthropogenic CO2 emissions and supporting emissions mitigation strategies.
Regional Probabilistic Tsunami Hazard Analysis for the Mexican Subduction Zone From Stochastic Slip Models
Authors: Salazar‐Monroy E. F. , Melgar D. , Jaimes M. A. , Ramirez‐Guzman L.
Published: May 2021

The Mexican subduction zone is prone to large earthquakes that impact populated coastal and inland cities due to strong shaking and can generate potentially disastrous tsunamis. Even though the population and infrastructure on the Mexican Pacific coast may experience tsunamis, only sparse instrumentation and scarce tsunami observations exist for both, historical and instrumental, records. This study presents a probabilistic tsunami hazard analysis that can provide information for managing and assessing risks in the region. We use ensembles of numerical tsunami simulations to estimate the probability of exceedance of the maximum tsunami amplitudes, considering the contribution of near sources and slip heterogeneities, for return periods of 100, 500, and 1,000 years. According to 7,946 simulated scenarios, the amplitudes can reach up to 9.5 m along the shoreline. Moreover, tsunami hazard maps, curves, and disaggregation analyses reveal critical hazard points along the coasts of the states of Jalisco, Colima, Michoacán, Guerrero, and Oaxaca.
GRACEfully Closing the Water Balance: A Data‐Driven Probabilistic Approach Applied to River Basins in Iran
Authors: Schoups Gerrit , Nasseri Mohsen
Published: May 2021

To fully benefit from remotely sensed observations of the terrestrial water cycle, bias and random errors in these data sets need to be quantified. This paper presents a Bayesian hierarchical model that fuses monthly water balance data and estimates the corresponding data errors and error‐corrected water balance components (precipitation, evaporation, river discharge, and water storage). The model combines monthly basin‐scale water balance constraints with probabilistic data error models for each water balance variable. Each data error model includes parameters that are in turn treated as unknown random variables to reflect uncertainty in the errors. Errors in precipitation and evaporation data are parameterized as a function of multiple data sources, while errors in GRACE storage observations are described by a noisy sine wave model with parameters controlling the phase, amplitude, and randomness of the sine wave. Error parameters and water balance variables are estimated using a combination of Markov Chain Monte Carlo sampling and iterative smoothing. Application to semiarid river basins in Iran yields (a) significant reductions in evaporation uncertainty during water‐stressed summers, (b) basin‐specific timing and amplitude corrections of the GRACE water storage dynamics, and (c) posterior water balance estimates with average standard errors of 4–12 mm/month for water storage, 3.5–7 mm/month for precipitation, 2–6 mm/month for evaporation, and 0–2 mm/month for river discharge. The approach is readily extended to other data sets and other (gauged) basins around the world, possibly using customized data error models. The resulting error‐filtered and bias‐corrected water balance estimates can be used to evaluate hydrological models.
Observations of Closed Magnetic Flux Embedded in the Lobes During Periods of Northward IMF
Authors: Fryer L. J. , Fear R. C. , Coxon J. C. , Gingell I. L.
Published: May 2021

The high latitude, lobe regions of the magnetosphere are often assumed to contain cool, low energy plasma populations. However, during periods of northward Interplanetary Magnetic Field, energetic plasma populations have occasionally been observed. We present three cases when Cluster observed uncharacteristically “hot” plasma populations in the lobe. For two of the three events, we present simultaneous observations of the plasma sheet observed by Double Star. The similarity between the plasma in the lobe and the plasma sheet suggests that the mechanism that produces plasma at high latitudes is likely to be tail reconnection, resulting in a trapped “wedge” of closed flux about the noon‐midnight meridian. Complementary images from Imager for Magnetopause to Aurora Global Exploration and DMSP/Special Sensor Ultraviolet Spectrographic Imager show that transpolar arcs, which form in each event in at least one hemisphere, directly intersect the footprint of the Cluster spacecraft in all three events. The intersection of the Cluster footprint with the transpolar arcs is synchronous with the observation of the energetic plasma populations in the lobe. This further supports the conclusion that it is likely this energetic plasma observed in the high latitude lobe regions of magnetosphere is on closed field lines.
PER2-mediated ameloblast differentiation via PPARγ/AKT1/β-catenin axis
Authors: Huang Wushuang , Zheng Xueqing , Yang Mei , Li Ruiqi , Song Yaling
Published: May 2021

Circadian rhythm is involved in the development and diseases of many tissues. However, as an essential environmental regulating factor, its effect on amelogenesis has not been fully elucidated. The present study aims to investigate the correlation between circadian rhythm and ameloblast differentiation and to explore the mechanism by which circadian genes regulate ameloblast differentiation. Circadian disruption models were constructed in mice for in vivo experiments. An ameloblast-lineage cell (ALC) line was used for in vitro studies. As essential molecules of the circadian system, Bmal1 and Per2 exhibited circadian expression in ALCs. Circadian disruption mice showed reduced amelogenin (AMELX) expression and enamel matrix secretion and downregulated expression of BMAL1, PER2, PPARγ, phosphorylated AKT1 and β-catenin, cytokeratin-14 and F-actin in ameloblasts. According to previous findings and our study, BMAL1 positively regulated PER2. Therefore, the present study focused on PER2-mediated ameloblast differentiation and enamel formation. Per2 knockdown decreased the expression of AMELX, PPARγ, phosphorylated AKT1 and β-catenin, promoted nuclear β-catenin accumulation, inhibited mineralization and altered the subcellular localization of E-cadherin in ALCs. Overexpression of PPARγ partially reversed the above results in Per2-knockdown ALCs. Furthermore, in in vivo experiments, the length of incisor eruption was significantly decreased in the circadian disturbance group compared to that in the control group, which was rescued by using a PPARγ agonist in circadian disturbance mice. In conclusion, through regulation of the PPARγ/AKT1/β-catenin signalling axis, PER2 played roles in amelogenin expression, cell junctions and arrangement, enamel matrix secretion and mineralization during ameloblast differentiation, which exert effects on enamel formation.
Metastasis-suppressor NME1 controls the invasive switch of breast cancer by regulating MT1-MMP surface clearance
Authors: Lodillinsky Catalina , Fuhrmann Laetitia , Irondelle Marie , Pylypenko Olena , Li Xiao-Yan , Bonsang-Kitzis Hélène , Reyal Fabien , Vacher Sophie , Calmel Claire , De Wever Olivier , Bièche Ivan , Lacombe Marie-Lise , Eiján Ana Maria , Houdusse Anne , Vincent-Salomon Anne , Weiss Stephen J. , Chavrier Philippe , Boissan Mathieu
Published: May 2021

Membrane Type 1 Matrix Metalloprotease (MT1-MMP) contributes to the invasive progression of breast cancers by degrading extracellular matrix tissues. Nucleoside diphosphate kinase, NME1/NM23-H1, has been identified as a metastasis suppressor; however, its contribution to local invasion in breast cancer is not known. Here, we report that NME1 is up-regulated in ductal carcinoma in situ (DCIS) as compared to normal breast epithelial tissues. NME1 levels drop in microinvasive and invasive components of breast tumor cells relative to synchronous DCIS foci. We find a strong anti-correlation between NME1 and plasma membrane MT1-MMP levels in the invasive components of breast tumors, particularly in aggressive histological grade III and triple-negative breast cancers. Knockout of NME1 accelerates the invasive transition of breast tumors in the intraductal xenograft model. At the mechanistic level, we find that MT1-MMP, NME1 and dynamin-2, a GTPase known to require GTP production by NME1 for its membrane fission activity in the endocytic pathway, interact in clathrin-coated vesicles at the plasma membrane. Loss of NME1 function increases MT1-MMP surface levels by inhibiting endocytic clearance. As a consequence, the ECM degradation and invasive potentials of breast cancer cells are enhanced. This study identifies the down-modulation of NME1 as a potent driver of the in situ-to invasive transition during breast cancer progression.
18F-Fluciclovine PET/CT performance in biochemical recurrence of prostate cancer: a systematic review
Authors: Rais-Bahrami Soroush , Efstathiou Jason A. , Turnbull Catriona M. , Camper Stephen B. , Kenwright Andy , Schuster David M. , Scarsbrook Andrew F.
Published: May 2021

Background

A systematic literature review of the performance of 18Fluorine-fluciclovine PET/CT for imaging of men with recurrent prostate cancer was performed.

Methods

Scientific literature databases (MEDLINE, ScienceDirect and Cochrane Libraries) were searched systematically during Oct 2020 using PRISMA criteria. No limit was put on the date of publication. Prospective studies reporting a patient-level 18F-fluciclovine detection rate (DR) from ≥25 patients with recurrent prostate cancer were sought. Proceedings of relevant meetings held from 2018 through Oct 2020 were searched for abstracts meeting criteria.

Results

Searches identified 321 unique articles. In total, nine articles (six papers and three conference abstracts), comprising a total of 850 patients met inclusion criteria. Most studies (n = 6) relied on ASTRO-Phoenix Criteria, EAU-ESTRO-SIOG, and/or ASTRO-AUA guidelines to identify patients with biochemical recurrence. Patients’ PSA levels ranged from 0.02–301.7 ng/mL (median level per study, 0.34–4.10 ng/mL [n = 8]). Approximately 64% of patients had undergone prostatectomy, but three studies focused solely on post-prostatectomy patients. Adherence to imaging protocol guidelines was heterogeneous, with variance seen in administered activity, uptake and scan times. Overall patient-level DR varied between studies from 26% to 83%, with 78% of studies reporting a DR > 50%. DR was proportional to PSA, but even at PSA < 0.5 ng/mL DR of up to 53% were reported. Prostate/bed DR (n = 7) ranged from 18% to 78% and extra-prostatic rates (n = 6) from 8% to 72%. Pelvic node and bone lesion DR ranged from 8% to 47% and 0% to 26%, respectively (n = 5). 18F-Fluciclovine PET/CT was shown to impact patient management and outcomes. Two studies reported 59–63% of patients to have a management change post-scan. A further study showed significant increase in failure-free survival following 18F-fluciclovine-guided compared with conventional imaging-guided radiotherapy planning.

Conclusions

18F-Fluciclovine PET/CT shows good performance in patients with recurrent prostate cancer leading to measurable clinical benefits. Careful adherence to recommended imaging protocols may help optimize DR.
RNAi and chemogenetic reporter co-regulation in primate striatal interneurons
Authors: Lerchner Walter , Adil Abdullah A. , Mumuney Sekinat , Wang Wenliang , Falcone Rossella , Turchi Janita , Richmond Barry J.
Published: May 2021

Using genetic tools to study the functional roles of molecularly specified neuronal populations in the primate brain is challenging, primarily because of specificity and verification of virus-mediated targeting. Here, we report a lentivirus-based system that helps improve specificity and verification by (a) targeting a selected molecular mechanism, (b) in vivo reporting of expression, and (c) allowing the option to independently silence all regional neural activity. Specifically, we modulate cholinergic signaling of striatal interneurons by shRNAmir and pair it with hM4Di_CFP, a chemogenetic receptor that can function as an in vivo and in situ reporter. Quantitative analyses by visual and deep-learning assisted methods show an inverse linear relation between hM4Di_CFP and ChAT protein expression for several shRNAmir constructs. This approach successfully applies shRNAmir to modulating gene expression in the primate brain and shows that hM4Di_CFP can act as a readout for this modulation.
A small climate-amplifying effect of climate-carbon cycle feedback
Authors: Zhang Xuanze , Wang Ying-Ping , Rayner Peter J. , Ciais Philippe , Huang Kun , Luo Yiqi , Piao Shilong , Wang Zhonglei , Xia Jianyang , Zhao Wei , Zheng Xiaogu , Tian Jing , Zhang Yongqiang
Published: May 2021

The climate-carbon cycle feedback is one of the most important climate-amplifying feedbacks of the Earth system, and is quantified as a function of carbon-concentration feedback parameter (β) and carbon-climate feedback parameter (γ). However, the global climate-amplifying effect from this feedback loop (determined by the gain factor, g) has not been quantified from observations. Here we apply a Fourier analysis-based carbon cycle feedback framework to the reconstructed records from 1850 to 2017 and 1000 to 1850 to estimate β and γ. We show that the β-feedback varies by less than 10% with an average of 3.22 ± 0.32 GtC ppm−1 for 1880–2017, whereas the γ-feedback increases from −33 ± 14 GtC K−1 on a decadal scale to −122 ± 60 GtC K−1 on a centennial scale for 1000–1850. Feedback analysis further reveals that the current amplification effect from the carbon cycle feedback is small (g is 0.01 ± 0.05), which is much lower than the estimates by the advanced Earth system models (g is 0.09 ± 0.04 for the historical period and is 0.15 ± 0.08 for the RCP8.5 scenario), implying that the future allowable CO2 emissions could be 9 ± 7% more. Therefore, our findings provide new insights about the strength of climate-carbon cycle feedback and about observational constraints on models for projecting future climate.
Nanostructure-specific X-ray tomography reveals myelin levels, integrity and axon orientations in mouse and human nervous tissue
Authors: Georgiadis Marios , Schroeter Aileen , Gao Zirui , Guizar-Sicairos Manuel , Liebi Marianne , Leuze Christoph , McNab Jennifer A. , Balolia Aleezah , Veraart Jelle , Ades-Aron Benjamin , Kim Sunglyoung , Shepherd Timothy , Lee Choong H. , Walczak Piotr , Chodankar Shirish , DiGiacomo Phillip , David Gergely , Augath Mark , Zerbi Valerio , Sommer Stefan , Rajkovic Ivan , Weiss Thomas , Bunk Oliver , Yang Lin , Zhang Jiangyang , Novikov Dmitry S. , Zeineh Michael , Fieremans Els , Rudin Markus
Published: May 2021

Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains a challenge. Here, we exploit myelin’s nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method’s sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures.
A trimethoprim derivative impedes antibiotic resistance evolution
Authors: Manna Madhu Sudan , Tamer Yusuf Talha , Gaszek Ilona , Poulides Nicole , Ahmed Ayesha , Wang Xiaoyu , Toprak Furkan C. R. , Woodard DaNae R. , Koh Andrew Y. , Williams Noelle S. , Borek Dominika , Atilgan Ali Rana , Hulleman John D. , Atilgan Canan , Tambar Uttam , Toprak Erdal
Published: May 2021

The antibiotic trimethoprim (TMP) is used to treat a variety of Escherichia coli infections, but its efficacy is limited by the rapid emergence of TMP-resistant bacteria. Previous laboratory evolution experiments have identified resistance-conferring mutations in the gene encoding the TMP target, bacterial dihydrofolate reductase (DHFR), in particular mutation L28R. Here, we show that 4’-desmethyltrimethoprim (4’-DTMP) inhibits both DHFR and its L28R variant, and selects against the emergence of TMP-resistant bacteria that carry the L28R mutation in laboratory experiments. Furthermore, antibiotic-sensitive E. coli populations acquire antibiotic resistance at a substantially slower rate when grown in the presence of 4’-DTMP than in the presence of TMP. We find that 4’-DTMP impedes evolution of resistance by selecting against resistant genotypes with the L28R mutation and diverting genetic trajectories to other resistance-conferring DHFR mutations with catalytic deficiencies. Our results demonstrate how a detailed characterization of resistance-conferring mutations in a target enzyme can help identify potential drugs against antibiotic-resistant bacteria, which may ultimately increase long-term efficacy of antimicrobial therapies by modulating evolutionary trajectories that lead to resistance.
FKRP-dependent glycosylation of fibronectin regulates muscle pathology in muscular dystrophy
Authors: Wood A. J. , Lin C. H. , Li M. , Nishtala K. , Alaei S. , Rossello F. , Sonntag C. , Hersey L. , Miles L. B. , Krisp C. , Dudczig S. , Fulcher A. J. , Gibertini S. , Conroy P. J. , Siegel A. , Mora M. , Jusuf P. , Packer N. H. , Currie P. D.
Published: May 2021

The muscular dystrophies encompass a broad range of pathologies with varied clinical outcomes. In the case of patients carrying defects in fukutin-related protein (FKRP), these diverse pathologies arise from mutations within the same gene. This is surprising as FKRP is a glycosyltransferase, whose only identified function is to transfer ribitol-5-phosphate to α-dystroglycan (α-DG). Although this modification is critical for extracellular matrix attachment, α-DG’s glycosylation status relates poorly to disease severity, suggesting the existence of unidentified FKRP targets. Here we reveal that FKRP directs sialylation of fibronectin, a process essential for collagen recruitment to the muscle basement membrane. Thus, our results reveal that FKRP simultaneously regulates the two major muscle-ECM linkages essential for fibre survival, and establishes a new disease axis for the muscular dystrophies.
Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding
Authors: Wang Kaituo , Dagil Robert , Lavstsen Thomas , Misra Sandeep K. , Spliid Charlotte B. , Wang Yong , Gustavsson Tobias , Sandoval Daniel R. , Vidal-Calvo Elena Ethel , Choudhary Swati , Agerbaek Mette Ø , Lindorff-Larsen Kresten , Nielsen Morten A. , Theander Thor G. , Sharp Joshua S. , Clausen Thomas Mandel , Gourdon Pontus , Salanti Ali
Published: May 2021

Placental malaria can have severe consequences for both mother and child and effective vaccines are lacking. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA and the glycosaminoglycan chondroitin sulfate A (CS) abundantly present in the intervillous space. Here, we report cryo-EM structures of the VAR2CSA ectodomain at up to 3.1 Å resolution revealing an overall V-shaped architecture and a complex domain organization. Notably, the surface displays a single significantly electropositive patch, compatible with binding of negatively charged CS. Using molecular docking and molecular dynamics simulations as well as comparative hydroxyl radical protein foot-printing of VAR2CSA in complex with placental CS, we identify the CS-binding groove, intersecting with the positively charged patch of the central VAR2CSA structure. We identify distinctive conserved structural features upholding the macro-molecular domain complex and CS binding capacity of VAR2CSA as well as divergent elements possibly allowing immune escape at or near the CS binding site. These observations will support rational design of second-generation placental malaria vaccines.
Mechanism for DPY30 and ASH2L intrinsically disordered regions to modulate the MLL/SET1 activity on chromatin
Authors: Lee Young-Tae , Ayoub Alex , Park Sang-Ho , Sha Liang , Xu Jing , Mao Fengbiao , Zheng Wei , Zhang Yang , Cho Uhn-Soo , Dou Yali
Published: May 2021

Recent cryo-EM structures show the highly dynamic nature of the MLL1-NCP (nucleosome core particle) interaction. Functional implication and regulation of such dynamics remain unclear. Here we show that DPY30 and the intrinsically disordered regions (IDRs) of ASH2L work together in restricting the rotational dynamics of the MLL1 complex on the NCP. We show that DPY30 binding to ASH2L leads to stabilization and integration of ASH2L IDRs into the MLL1 complex and establishes new ASH2L-NCP contacts. The significance of ASH2L-DPY30 interactions is demonstrated by requirement of both ASH2L IDRs and DPY30 for dramatic increase of processivity and activity of the MLL1 complex. This DPY30 and ASH2L-IDR dependent regulation is NCP-specific and applies to all members of the MLL/SET1 family of enzymes. We further show that DPY30 is causal for de novo establishment of H3K4me3 in ESCs. Our study provides a paradigm of how H3K4me3 is regulated on chromatin and how H3K4me3 heterogeneity can be modulated by ASH2L IDR interacting proteins.
Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover
Authors: Martin Thomas G. , Myers Valerie D. , Dubey Praveen , Dubey Shubham , Perez Edith , Moravec Christine S. , Willis Monte S. , Feldman Arthur M. , Kirk Jonathan A.
Published: May 2021

The association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired Fmax arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with Fmax. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced Fmax and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/Fmax, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued Fmax and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.
The kaolinite shuttle links the Great Oxidation and Lomagundi events
Authors: Hao Weiduo , Mänd Kaarel , Li Yuhao , Alessi Daniel S. , Somelar Peeter , Moussavou Mathieu , Romashkin Alexander E. , Lepland Aivo , Kirsimäe Kalle , Planavsky Noah J. , Konhauser Kurt O.
Published: May 2021

The ~2.22–2.06 Ga Lomagundi Event was the longest positive carbon isotope excursion in Earth’s history and is commonly interpreted to reflect perturbations in continental weathering and the phosphorous cycle. Previous models have focused on mechanisms of increasing phosphorous solubilization during weathering without focusing on transport to the oceans and its dispersion in seawater. Building from new experimental results, here we report kaolinite readily absorbs phosphorous under acidic freshwater conditions, but quantitatively releases phosphorous under seawater conditions where it becomes bioavailable to phytoplankton. The strong likelihood of high weathering intensities and associated high kaolinite content in post-Great-Oxidation-Event paleosols suggests there would have been enhanced phosphorus shuttling from the continents into marine environments. A kaolinite phosphorous shuttle introduces the potential for nonlinearity in the fluxes of phosphorous to the oceans with increases in chemical weathering intensity.
In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels
Authors: Rothgangl Tanja , Dennis Melissa K. , Lin Paulo J. C. , Oka Rurika , Witzigmann Dominik , Villiger Lukas , Qi Weihong , Hruzova Martina , Kissling Lucas , Lenggenhager Daniela , Borrelli Costanza , Egli Sabina , Frey Nina , Bakker Noëlle , Walker John A. , Kadina Anastasia P. , Victorov Denis V. , Pacesa Martin , Kreutzer Susanne , Kontarakis Zacharias , Moor Andreas , Jinek Martin , Weissman Drew , Stoffel Markus , van Boxtel Ruben , Holden Kevin , Pardi Norbert , Thöny Beat , Häberle Johannes , Tam Ying K. , Semple Sean C. , Schwank Gerald
Published: May 2021

Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle–based delivery of mRNA encoding an ABE and a single-guide RNA targetingPCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases.
COVID-19 non-pharmaceutical intervention portfolio effectiveness and risk communication predominance
Authors: Chan Louis Yat Hin , Yuan Baoyin , Convertino Matteo
Published: May 2021

Non-pharmaceutical interventions (NPIs) including resource allocation, risk communication, social distancing and travel restriction, are mainstream actions to control the spreading of Coronavirus disease 2019 (COVID-19) worldwide. Different countries implemented their own combinations of NPIs to prevent local epidemics and healthcare system overloaded. Portfolios, as temporal sets of NPIs have various systemic impacts on preventing cases in populations. Here, we developed a probabilistic modeling framework to evaluate the effectiveness of NPI portfolios at the macroscale. We employed a deconvolution method to back-calculate incidence of infections and estimate the effective reproduction number by using the package EpiEstim. We then evaluated the effectiveness of NPIs using ratios of the reproduction numbers and considered them individually and as a portfolio systemically. Based on estimates from Japan, we estimated time delays of symptomatic-to-confirmation and infection-to-confirmation as 7.4 and 11.4 days, respectively. These were used to correct surveillance data of other countries. Considering 50 countries, risk communication and returning to normal life were the most and least effective yielding the aggregated effectiveness of 0.11 and − 0.05 that correspond to a 22.4% and 12.2% reduction and increase in case growth. The latter is quantified by the change in reproduction number before and after intervention implementation. Countries with the optimal NPI portfolio are along an empirical Pareto frontier where mean and variance of effectiveness are maximized and minimized independently of incidence levels. Results indicate that implemented interventions, regardless of NPI portfolios, had distinct incidence reductions and a clear timing effect on infection dynamics measured by sequences of reproduction numbers. Overall, the successful suppression of the epidemic cannot work without the non-linear effect of NPI portfolios whose effectiveness optimality may relate to country-specific socio-environmental factors.
Involvement of the dopaminergic system in the reward-related behavior of pregabalin
Authors: Althobaiti Yusuf S. , Almutairi Farooq M. , Alshehri Fahad S. , Altowairqi Ebtehal , Marghalani Aliyah M. , Alghorabi Amal A. , Alsanie Walaa F. , Gaber Ahmed , Alsaab Hashem O. , Almalki Atiah H. , Hakami Alqassem Y. , Alkhalifa Turki , Almalki Ahmad D. , Hardy Ana M. G. , Shah Zahoor A.
Published: May 2021

There has been an increase in cases of drug addiction and prescription drug abuse worldwide. Recently, pregabalin abuse has been a focus for many healthcare agencies, as highlighted by epidemiological studies. We previously evaluated the possibility of pregabalin abuse using the conditioned place preference (CPP) paradigm. We observed that a 60 mg/kg dose could induce CPP in mice and that pregabalin-rewarding properties were mediated through glutamate neurotransmission. Notably, the dopaminergic reward circuitry is also known to play a crucial role in medication-seeking behavior. Therefore, this study aimed to explore the possible involvement of dopaminergic receptor-1 in pregabalin-induced CPP. Mice were randomly allocated to receive saline or the dopamine-1 receptor antagonist SKF-83566 (0.03 mg/kg, intraperitoneal). After 30 min, the mice received either saline or pregabalin (60 mg/kg) during the conditioning phase. Among the control groups that received saline or SKF-83566, the time spent in the two conditioning chambers was not significantly altered. However, among the pregabalin-treated group, there was a marked increase in the time spent in the drug-paired chamber compared to the time spent in the vehicle-paired chamber. Notably, blocking dopamine-1 receptors with SKF-83566 completely prevented pregabalin-induced place preference, thus demonstrating the engagement of the dopaminergic system in pregabalin-induced reward-related behavior.
Hidden order across online extremist movements can be disrupted by nudging collective chemistry
Authors: Velásquez N. , Manrique P. , Sear R. , Leahy R. , Restrepo N. Johnson , Illari L. , Lupu Y. , Johnson N. F.
Published: May 2021

Disrupting the emergence and evolution of potentially violent online extremist movements is a crucial challenge. Extremism research has analyzed such movements in detail, focusing on individual- and movement-level characteristics. But are there system-level commonalities in the ways these movements emerge and grow? Here we compare the growth of the Boogaloos, a new and increasingly prominent U.S. extremist movement, to the growth of online support for ISIS, a militant, terrorist organization based in the Middle East that follows a radical version of Islam. We show that the early dynamics of these two online movements follow the same mathematical order despite their stark ideological, geographical, and cultural differences. The evolution of both movements, across scales, follows a single shockwave equation that accounts for heterogeneity in online interactions. These scientific properties suggest specific policies to address online extremism and radicalization. We show how actions by social media platforms could disrupt the onset and ‘flatten the curve’ of such online extremism by nudging its collective chemistry. Our results provide a system-level understanding of the emergence of extremist movements that yields fresh insight into their evolution and possible interventions to limit their growth.
Recognising the dynamic form of fire
Authors: Nagle Fintan , Johnston Alan
Published: May 2021

Encoding and recognising complex natural sequences provides a challenge for human vision. We found that observers could recognise a previously presented segment of a video of a hearth fire when embedded in a longer sequence. Recognition performance declined when the test video was spatially inverted, but not when it was hue reversed or temporally reversed. Sampled motion degraded forwards/reversed playback discrimination, indicating observers were sensitive to the asymmetric pattern of motion of flames. For brief targets, performance increased with target length. More generally, performance depended on the relative lengths of the target and embedding sequence. Increased errors with embedded sequence length were driven by positive responses to non-target sequences (false alarms) rather than omissions. Taken together these observations favour interpreting performance in terms of an incremental decision-making model based on a sequential statistical analysis in which evidence accrues for one of two alternatives. We also suggest that prediction could provide a means of providing and evaluating evidence in a sequential analysis model.
Flux-pinning behaviors and mechanism according to dopant level in (Fe, Ti) particle-doped $$\text {MgB}_2$$ superconductor
Authors: Lee H. B. , Kim G. C. , Shon Young Jin , Kim Dongjin , Kim Y. C.
Published: May 2021

We have studied flux-pinning effects of $$\text {MgB}_2$$

MgB
2

superconductor by doping (Fe, Ti) particles of which radius is 163 nm on average. 5 wt.% (Fe, Ti) doped $$\text {MgB}_2$$

MgB
2

among the specimens showed the best field dependence of magnetization and 25 wt.% one did the worst at 5 K. The difference of field dependence of magnetization of the two specimens increased as temperature increased. Here we show experimental results of (Fe, Ti) particle-doped $$\text {MgB}_2$$

MgB
2

specimens according to dopant level and the causes of the behaviors. Flux-pinning effect of volume defects-doped superconductor was modeled in ideal state and relative equations were derived. During the study, we had to divide M-H curve of volume defect-dominating superconductor as three discreet regions for analyzing flux-pinning effects, which are diamagnetic increase region after $$\text {H}_{c1}$$

H

c
1

, $$\Delta \text {H}=\Delta \text {B}$$

Δ
H
=
Δ
B

region, and diamagnetic decrease region. As a result, flux-pinning effects of volume defects decreased as dopant level increased over the optimal dopant level, which was caused by decrease of flux-pinning limit of a volume defect. And similar behaviors are obtained as dopant level decreased below the optimal dopant level, which was caused by the decreased number of volume defects. Comparing the model with experimental results, deviations increased as dopant level increased over the optimal dopant level, whereas the two was well matched on less dopant level. The behavior is considered to be caused by the segregation of the volume defects. On the other hand, the cause that diamagnetic properties of over-doped $$\text {MgB}_2$$

MgB
2

specimens dramatically decreased as temperature increased was the double decreases of flux-pinning limit of a volume defect and the segregation effect, which are caused by over-doping and temperature increase.
En route to single-step, two-phase purification of carbon nanotubes facilitated by high-throughput spectroscopy
Authors: Podlesny Blazej , Olszewska Barbara , Yaari Zvi , Jena Prakrit V. , Ghahramani Gregory , Feiner Ron , Heller Daniel A. , Janas Dawid
Published: May 2021

Chirality purification of single-walled carbon nanotubes (SWCNTs) is desirable for applications in many fields, but general utility is currently hampered by low throughput. We discovered a method to obtain single-chirality SWCNT enrichment by the aqueous two-phase extraction (ATPE) method in a single step. To achieve appropriate resolution, a biphasic system of non-ionic tri-block copolymer surfactant is varied with an ionic surfactant. A nearly-monochiral fraction of SWCNTs can then be harvested from the top phase. We also found, via high-throughput, near-infrared excitation-emission photoluminescence spectroscopy, that the parameter space of ATPE can be mapped to probe the mechanics of the separation process. Finally, we found that optimized conditions can be used for sorting of SWCNTs wrapped with ssDNA as well. Elimination of the need for surfactant exchange and simplicity of the separation process make the approach promising for high-yield generation of purified single-chirality SWCNT preparations.
Towards water-soluble [60]fullerenes for the delivery of siRNA in a prostate cancer model
Authors: Korzuch Julia , Rak Monika , Balin Katarzyna , Zubko Maciej , Głowacka Olga , Dulski Mateusz , Musioł Robert , Madeja Zbigniew , Serda Maciej
Published: May 2021

This paper presents two water-soluble fullerene nanomaterials (HexakisaminoC60 and monoglucosamineC60, which is called here JK39) that were developed and synthesized as non-viral siRNA transfection nanosystems. The developed two-step Bingel–Hirsch reaction enables the chemical modification of the fullerene scaffold with the desired bioactive fragments such as d-glucosamine while keeping the crucial positive charged ethylenediamine based malonate. The ESI–MS and 13C-NMR analyses of JK39 confirmed its high Th symmetry, while X-ray photoelectron spectroscopy revealed the presence of nitrogen and oxygen-containing C–O or C–N bonds. The efficiency of both fullerenes as siRNA vehicles was tested in vitro using the prostate cancer cell line DU145 expressing the GFP protein. The HexakisaminoC60 fullerene was an efficient siRNA transfection agent, and decreased the GFP fluorescence signal significantly in the DU145 cells. Surprisingly, the glycofullerene JK39 was inactive in the transfection experiments, probably due to its high zeta potential and the formation of an extremely stable complex with siRNA.
A physicochemical assessment of the thermal stability of dextrin–colistin conjugates
Authors: Chiron Emilie , Varache Mathieu , Stokniene Joana , Thomas David W. , Ferguson Elaine L.
Published: May 2021

Attachment of polysaccharide carriers is increasingly being used to achieve precision delivery and improved effectiveness of protein and peptide drugs. Although it is clear that their clinical effectiveness relies on the purity and integrity of the conjugate in storage, as well as following administration, instability of polysaccharide-based conjugates can reduce the protective efficacy of the polymer, which may adversely affect the bioactive’s potency. As a model, these studies used dextrin–colistin conjugates, with varying degrees of polymer modification (1, 2.5 and 7.5 mol% succinoylation) to assess the effect of storage temperature (− 20, 4, 21 and 37 °C) and duration (up to 12 months) on saccharide and colistin release and antimicrobial activity. Estimation of the proportion of saccharide release (by comparison of area under the curve from size exclusion chromatograms) was more pronounced at higher temperatures (up to 3 and 35% at − 20 °C and 37 °C, respectively after 12 months), however, repeated freeze–thaw did not produce any measurable release of saccharides, while addition of amylase (20, 100, 500 IU/L) caused rapid release of saccharides (> 70% total within 24 h). At all temperatures, conjugates containing the lowest degree of succinoylation released the highest proportion of free colistin, which increased with storage temperature, however no trend in saccharide release was observed. Despite the clear physical effects of prolonged storage, antimicrobial activity of all samples was only altered after storage at 37 °C for 12 months (> threefold decreased activity). These results demonstrate significant release of saccharides from dextrin–colistin conjugates during prolonged storage in buffered solution, especially at elevated temperature, which, in most cases, did not affect antimicrobial activity. These findings provide vital information about the structure–activity relationship of dextrin–colistin conjugates, prior to full-scale commercial development, which can subsequently be applied to other polysaccharide-protein and -peptide conjugates.
Profiling of tumour-associated microbiota in human hepatocellular carcinoma
Authors: Komiyama Seiga , Yamada Takahiro , Takemura Nobuyuki , Kokudo Norihiro , Hase Koji , Kawamura Yuki I.
Published: May 2021

Liver cancer is the fourth leading cause of cancer-related death. Hepatocellular carcinoma (HCC) is a primary liver cancer that results from chronic hepatitis caused by multiple predisposing factors such as viral infection, alcohol consumption, and non-alcoholic fatty liver disease. Accumulating studies have indicated that dysfunction of the gut epithelial barrier and hepatic translocation of gut microbes may be implicated in the pathogenesis of HCC. However, the translocated bacteria in HCC patients remains unclear. Here, we characterised tumour-associated microbiota in patients with liver cancer and focused on HCC. We observed that the number of amplicon sequence variants in tumour-associated microbiota was significantly higher compared with that in non-tumour regions of the liver. The tumour-associated microbiota consisted of Bacteroidetes, Firmicutes, and Proteobacteria as the dominant phyla. We identified an unclassified genus that belonged to the Bacteroides, Romboutsia, uncultured bacterium of Lachnospiraceae as a signature taxon for primary liver cancer. Additionally, we identified Ruminococcus gnavus as a signature taxon for HCC patients infected with hepatitis B and/or hepatitis C viruses. This study suggests that tumour microbiota may contribute to the pathology of HCC.