bluuebunny/crossref_metadata_2025 huggingface dataset:
Incorporating Stakeholder Perspectives on Scarce Resource Allocation: Lessons Learned from Policymaking in a Time of Crisis
Authors: BRUNO BETHANY , HURWITZ HEATHER MCKEE , MERCER MARYBETH , MABEL HILARY , SANKARY LAUREN , MORLEY GEORGINA , FORD PAUL J. , HORSBURGH CRISTIE COLE , ROSE SUSANNAH L.
Published: March 2021

The coronavirus disease (COVID-19) crisis provoked an organizational ethics dilemma: how to develop ethical pandemic policy while upholding our organizational mission to deliver relationship- and patient-centered care. Tasked with producing a recommendation about whether healthcare workers and essential personnel should receive priority access to limited medical resources during the pandemic, the bioethics department and survey and interview methodologists at our institution implemented a deliberative approach that included the perspectives of healthcare professionals and patient stakeholders in the policy development process. Involving the community more, not less, during a crisis required balancing the need to act quickly to garner stakeholder perspectives, uncertainty about the extent and duration of the pandemic, and disagreement among ethicists about the most ethically supportable way to allocate scarce resources. This article explains the process undertaken to garner stakeholder input as it relates to organizational ethics, recounts the stakeholder perspectives shared and how they informed the triage policy developed, and offers suggestions for how other organizations may integrate stakeholder involvement in ethical decision-making as well as directions for future research and public health work.
NONCLASSICAL TRUTH WITH CLASSICAL STRENGTH. A PROOF-THEORETIC ANALYSIS OF COMPOSITIONAL TRUTH OVER HYPE
Authors: FISCHER MARTIN , NICOLAI CARLO , DOPICO PABLO
Published: March 2021

Questions concerning the proof-theoretic strength of classical versus nonclassical theories of truth have received some attention recently. A particularly convenient case study concerns classical and nonclassical axiomatizations of fixed-point semantics. It is known that nonclassical axiomatizations in four- or three-valued logics are substantially weaker than their classical counterparts. In this paper we consider the addition of a suitable conditional to First-Degree Entailment—a logic recently studied by Hannes Leitgeb under the label HYPE. We show in particular that, by formulating the theory PKF over HYPE, one obtains a theory that is sound with respect to fixed-point models, while being proof-theoretically on a par with its classical counterpart KF. Moreover, we establish that also its schematic extension—in the sense of Feferman—is as strong as the schematic extension of KF, thus matching the strength of predicative analysis.
Coastal Wetland Resilience, Accelerated Sea‐Level Rise, and the Importance of Timescale
Authors: Törnqvist Torbjörn E. , Cahoon Donald R. , Morris James T. , Day John W.
Published: March 2021

Recent studies have produced conflicting results as to whether coastal wetlands can keep up with present‐day and future sea‐level rise. The stratigraphic record shows that threshold rates for coastal wetland submergence or retreat are lower than what instrumental records suggest, with wetland extent that shrinks considerably under high rates of sea‐level rise. These apparent conflicts can be reconciled by recognizing that many coastal wetlands still possess sufficient elevation capital to cope with sea‐level rise, and that processes like sediment compaction, ponding, and wave erosion require multidecadal or longer timescales to drive wetland loss that is in many cases inevitable.
Comment on “An Active Plume Eruption on Europa During Galileo Flyby E26 as Indicated by Energetic Proton Depletions” by Huybrighs et al.
Authors: Jia Xianzhe , Kivelson Margaret G. , Paranicas Christopher
Published: March 2021

The Galileo spacecraft passed close to Europa on 11 encounters, two of which (E12 and E26) came within 400 km of the surface. In E12 data, there are perturbations in field and plasma data consistent with effects of a nearby plume (Jia et al., 2018). Huybrighs et al. (2020, https://doi.org/10.1029/2020GL087806) report depletions of proton flux in one channel of the Galileo Energetic Particle Detector (EPD) as Galileo passed close to Europa on E26. They trace particle trajectories in the magnetic field provided by a magnetohydrodynamic simulation and conclude that the spacecraft probably also passed through or close to a vapor plume on E26. However, the absence of a related signature in the measured magnetic field led us to question this conclusion. Examination of the EPD data remote from Europa on the E26 flyby reveals that the putative plume signature in the EPD data is an artifact.
How a Small Reef in the Kuroshio Cultivates the Ocean
Authors: Hasegawa D. , Matsuno T. , Tsutsumi E. , Senjyu T. , Endoh T. , Tanaka T. , Yoshie N. , Nakamura H. , Nishina A. , Kobari T. , Nagai T. , Guo X.
Published: March 2021

Vertical nitrate fluxes associated with turbulent mixing and upwelling around a small reef in the Kuroshio are quantified by continuously deploying a turbulence microstructure profiler with an attached submersible ultraviolet nitrate analyzer while drifting from the upstream to the downstream of the reef. Flow separations and trains of Kelvin‐Helmholtz billows (thickness = 60 m) are identified using a shipboard ADCP and an echo‐sounder. The turbulence diffusivity associated with the vigorous turbulent mixing reaches up to O(10−1 m2 s−1), resulting in strong nitrate fluxes of O(1–103 mmol m−2 day−1). In addition, large differences between the upstream and downstream density profiles suggest a strong upwelling velocity of O(10−3 m s−1), as well as an upwelling nitrate flux of O(102 mmol m−2 day−1) in the entire subsurface layer.
Crossing the Shoreline
Authors: Goss Heather
Published: March 2021

As the decade-long GeoPRISMS program comes to an end this spring, Eos’s April issue features just a few its accomplishments.
Pharmacological targeting of the novel β-catenin chromatin-associated kinase p38α in colorectal cancer stem cell tumorspheres and organoids
Authors: Lepore Signorile Martina , Grossi Valentina , Di Franco Simone , Forte Giovanna , Disciglio Vittoria , Fasano Candida , Sanese Paola , De Marco Katia , Susca Francesco Claudio , Mangiapane Laura Rosa , Nicotra Annalisa , Di Carlo Gabriella , Dituri Francesco , Giannelli Gianluigi , Ingravallo Giuseppe , Canettieri Gianluca , Stassi Giorgio , Simone Cristiano
Published: March 2021

The prognosis of locally advanced colorectal cancer (CRC) is currently unsatisfactory. This is mainly due to drug resistance, recurrence, and subsequent metastatic dissemination, which are sustained by the cancer stem cell (CSC) population. The main driver of the CSC gene expression program is Wnt signaling, and previous reports indicate that Wnt3a can activate p38 MAPK. Besides, p38 was shown to feed into the canonical Wnt/β-catenin pathway. Here we show that patient-derived locally advanced CRC stem cells (CRC-SCs) are characterized by increased expression of p38α and are “addicted” to its kinase activity. Of note, we found that stage III CRC patients with high p38α levels display reduced disease-free and progression-free survival. Extensive molecular analysis in patient-derived CRC-SC tumorspheres and APCMin/+ mice intestinal organoids revealed that p38α acts as a β-catenin chromatin-associated kinase required for the regulation of a signaling platform involved in tumor proliferation, metastatic dissemination, and chemoresistance in these CRC model systems. In particular, the p38α kinase inhibitor ralimetinib, which has already entered clinical trials, promoted sensitization of patient-derived CRC-SCs to chemotherapeutic agents commonly used for CRC treatment and showed a synthetic lethality effect when used in combination with the MEK1 inhibitor trametinib. Taken together, these results suggest that p38α may be targeted in CSCs to devise new personalized CRC treatment strategies.
A Zic2/Runx2/NOLC1 signaling axis mediates tumor growth and metastasis in clear cell renal cell carcinoma
Authors: Wu Chen-Yan , Li Lei , Chen Shi-Lu , Yang Xia , Zhang Chris Zhiyi , Cao Yun
Published: March 2021

Clear cell renal cell carcinoma (ccRCC) is one of the most common malignancies with rapid growth and high metastasis, but lacks effective therapeutic targets. Here, using public sequencing data analyses, quantitative real-time PCR assay, western blotting, and IHC staining, we characterized that runt-related transcription factor 2 (Runx2) was significantly upregulated in ccRCC tissues than that in normal renal tissues, which was associated with the worse survival of ccRCC patients. Overexpression of Runx2 promoted malignant proliferation and migration of ccRCC cells, and inversely, interfering Runx2 with siRNA attenuates its oncogenic ability. RNA sequencing and functional studies revealed that Runx2 enhanced ccRCC cell growth and metastasis via downregulation of tumor suppressor nucleolar and coiled-body phosphoprotein 1 (NOLC1). Moreover, increased Zic family member 2 (Zic2) was responsible for the upregulation of Runx2 and its oncogenic functions in ccRCC. Kaplan–Meier survival analyses indicated that ccRCC patients with high Zic2/Runx2 and low NOLC1 had the worst outcome. Therefore, our study demonstrates that Zic2/Runx2/NOLC1 signaling axis promotes ccRCC progression, providing a set of potential targets and prognostic indicators for patients with ccRCC.
The critical role of FXR is associated with the regulation of autophagy and apoptosis in the progression of AKI to CKD
Authors: Kim Dong-Hyun , Park Jung Sun , Choi Hoon-In , Kim Chang Seong , Bae Eun Hui , Ma Seong Kwon , Kim Soo Wan
Published: March 2021

Autophagy is important for cells to break down and recycle cellular proteins, remove damaged organelles, and especially, for recovery from acute kidney injury (AKI). Despite research on the role and cellular mechanism of autophagy in AKI, the role of autophagy in the progression to chronic kidney disease (CKD) remains poorly understood. Here, using farnesoid X receptor (FXR) knockout (KO) mice, we determined whether FXR prevents the progression of AKI to CKD after renal ischemic-reperfusion (such as I/R) injury through the regulation of renal autophagy and apoptosis. FXR regulated genes that participate in renal autophagy under feeding and fasting conditions, such as hepatic autophagy, and the activation of FXR by agonists, such as GW4064 and INT-747, attenuated the increased autophagy and apoptosis of hypoxia-induced human renal proximal tubule epithelial (HK2) cells. The expression levels of autophagy-related and apoptosis-related proteins in FXR KO mice were increased compared with those in wild-type (WT) mice. We also showed that the increase in reactive oxidative species (ROS) in hypoxia-treated HK2 cells was attenuated by treatment with FXR agonist or by FXR overexpression, and that the level of ROS was elevated in FXR-deficient cells and mice. At 28 days after I/R injury, the autophagy levels were still elevated in FXR KO mice, and the expression levels of fibrosis-related proteins and ROS deposits were higher than those in WT mice. In conclusion, the regulation of renal autophagy and apoptosis by FXR may be a therapeutic target for the early stages of kidney damage, and the progression of AKI to CKD.
A general approach to high-efficiency perovskite solar cells by any antisolvent
Authors: Taylor Alexander D. , Sun Qing , Goetz Katelyn P. , An Qingzhi , Schramm Tim , Hofstetter Yvonne , Litterst Maximillian , Paulus Fabian , Vaynzof Yana
Published: March 2021

Deposition of perovskite films by antisolvent engineering is a highly common method employed in perovskite photovoltaics research. Herein, we report on a general method that allows for the fabrication of highly efficient perovskite solar cells by any antisolvent via manipulation of the antisolvent application rate. Through detailed structural, compositional, and microstructural characterization of perovskite layers fabricated by 14 different antisolvents, we identify two key factors that influence the quality of the perovskite layer: the solubility of the organic precursors in the antisolvent and its miscibility with the host solvent(s) of the perovskite precursor solution, which combine to produce rate-dependent behavior during the antisolvent application step. Leveraging this, we produce devices with power conversion efficiencies (PCEs) that exceed 21% using a wide range of antisolvents. Moreover, we demonstrate that employing the optimal antisolvent application procedure allows for highly efficient solar cells to be fabricated from a broad range of precursor stoichiometries.
Engineering and characterization of gymnosperm sapwood toward enabling the design of water filtration devices
Authors: Ramchander Krithika , Hegde Megha , Antony Anish Paul , Wang Luda , Leith Kendra , Smith Amy , Karnik Rohit
Published: March 2021

Naturally-occurring membranes in the xylem tissue of gymnosperm sapwood enable its use as an abundantly-available material to construct filters, with potential to facilitate access to safe drinking water in resource-constrained settings. However, the material’s behavior as a filter is poorly understood, and challenges such as short shelf life have not been addressed. Here, we characterize the operational attributes of xylem filters and show that the material exhibits a highly non-linear dependence of flow resistance on thickness upon drying, and a tendency for self-blocking. We develop guidelines for the design and fabrication of xylem filters, demonstrate gravity-operated filters with shelf life >2 years, and show that the filters can provide >3 log removal of E. coli, MS-2 phage, and rotavirus from synthetic test waters and coliform bacteria from contaminated spring, tap, and ground waters. Through interviews and workshops in India, we use a user-centric approach to design a prototype filtration device with daily- to weekly-replaceable xylem filters, and uncover indicators of social acceptance of xylem as a natural water filter. Our work enhances the understanding of xylem as a filtration material, and opens opportunities for engineering a diverse range of low-cost, biodegradable xylem-based filtration products on a global scale.
High-fidelity spatial mode transmission through a 1-km-long multimode fiber via vectorial time reversal
Authors: Zhou Yiyu , Braverman Boris , Fyffe Alexander , Zhang Runzhou , Zhao Jiapeng , Willner Alan E. , Shi Zhimin , Boyd Robert W.
Published: March 2021

The large number of spatial modes supported by standard multimode fibers is a promising platform for boosting the channel capacity of quantum and classical communications by orders of magnitude. However, the practical use of long multimode fibers is severely hampered by modal crosstalk and polarization mixing. To overcome these challenges, we develop and experimentally demonstrate a vectorial time reversal technique, which is accomplished by digitally pre-shaping the wavefront and polarization of the forward-propagating signal beam to be the phase conjugate of an auxiliary, backward-propagating probe beam. Here, we report an average modal fidelity above 80% for 210 Laguerre-Gauss and Hermite-Gauss modes by using vectorial time reversal over an unstabilized 1-km-long fiber. We also propose a practical and scalable spatial-mode-multiplexed quantum communication protocol over long multimode fibers to illustrate potential applications that can be enabled by our technique.
Enhancing stability by trapping palladium inside N-heterocyclic carbene-functionalized hypercrosslinked polymers for heterogeneous C-C bond formations
Authors: Yue Chengtao , Xing Qi , Sun Peng , Zhao Zelun , Lv Hui , Li Fuwei
Published: March 2021

Catalyst deactivation caused by the aggregation of active metal species in the reaction process poses great challenges for practical applications of supported metal catalysts in solid-liquid catalysis. Herein, we develop a hypercrosslinked polymer integrated with N-heterocyclic carbene (NHC) as bifunctional support to stabilize palladium in heterogeneous C-C bond formations. This polymer supported palladium catalyst exhibits excellent stability in the one-pot fluorocarbonylation of indoles to four kinds of valuable indole-derived carbonyl compounds in cascade or sequential manner, as well as the representative Suzuki-Miyaura coupling reaction. Investigations on stabilizing effect disclose that this catalyst displays a molecular fence effect in which the coordination of NHC sites and confinement of polymer skeleton contribute together to stabilize the active palladium species in the reaction process. This work provides new insight into the development of supported metal catalysts with high stability and will also boost their efficient applications in advanced synthesis.
The actomyosin interface contains an evolutionary conserved core and an ancillary interface involved in specificity
Authors: Robert-Paganin Julien , Xu Xiao-Ping , Swift Mark F. , Auguin Daniel , Robblee James P. , Lu Hailong , Fagnant Patricia M. , Krementsova Elena B. , Trybus Kathleen M. , Houdusse Anne , Volkmann Niels , Hanein Dorit
Published: March 2021

Plasmodium falciparum, the causative agent of malaria, moves by an atypical process called gliding motility. Actomyosin interactions are central to gliding motility. However, the details of these interactions remained elusive until now. Here, we report an atomic structure of the divergent Plasmodium falciparum actomyosin system determined by electron cryomicroscopy at the end of the powerstroke (Rigor state). The structure provides insights into the detailed interactions that are required for the parasite to produce the force and motion required for infectivity. Remarkably, the footprint of the myosin motor on filamentous actin is conserved with respect to higher eukaryotes, despite important variability in the Plasmodium falciparum myosin and actin elements that make up the interface. Comparison with other actomyosin complexes reveals a conserved core interface common to all actomyosin complexes, with an ancillary interface involved in defining the spatial positioning of the motor on actin filaments.
Embedding atomic cobalt into graphene lattices to activate room-temperature ferromagnetism
Authors: Hu Wei , Wang Chao , Tan Hao , Duan Hengli , Li Guinan , Li Na , Ji Qianqian , Lu Ying , Wang Yao , Sun Zhihu , Hu Fengchun , Yan Wensheng
Published: March 2021

Graphene is extremely promising for next-generation spintronics applications; however, realizing graphene-based room-temperature magnets remains a great challenge. Here, we demonstrate that robust room-temperature ferromagnetism with TC up to ∼400 K and saturation magnetization of 0.11 emu g−1 (300 K) can be achieved in graphene by embedding isolated Co atoms with the aid of coordinated N atoms. Extensive structural characterizations show that square-planar Co-N4 moieties were formed in the graphene lattices, where atomically dispersed Co atoms provide local magnetic moments. Detailed electronic structure calculations reveal that the hybridization between the d electrons of Co atoms and delocalized pz electrons of N/C atoms enhances the conduction-electron mediated long-range magnetic coupling. This work provides an effective means to induce room-temperature ferromagnetism in graphene and may open possibilities for developing graphene-based spintronics devices.
Combination therapy protects macaques against advanced Marburg virus disease
Authors: Cross Robert W. , Bornholdt Zachary A. , Prasad Abhishek N. , Borisevich Viktoriya , Agans Krystle N. , Deer Daniel J. , Abelson Dafna M. , Kim Do H. , Shestowsky William S. , Campbell Lioudmila A. , Bunyan Elaine , Geisbert Joan B. , Fenton Karla A. , Zeitlin Larry , Porter Danielle P. , Geisbert Thomas W.
Published: March 2021

Monoclonal antibodies (mAbs) and remdesivir, a small-molecule antiviral, are promising monotherapies for many viruses, including members of the genera Marburgvirus and Ebolavirus (family Filoviridae), and more recently, SARS-CoV-2. One of the major challenges of acute viral infections is the treatment of advanced disease. Thus, extending the window of therapeutic intervention is critical. Here, we explore the benefit of combination therapy with a mAb and remdesivir in a non-human primate model of Marburg virus (MARV) disease. While rhesus monkeys are protected against lethal infection when treatment with either a human mAb (MR186-YTE; 100%), or remdesivir (80%), is initiated 5 days post-inoculation (dpi) with MARV, no animals survive when either treatment is initiated alone beginning 6 dpi. However, by combining MR186-YTE with remdesivir beginning 6 dpi, significant protection (80%) is achieved, thereby extending the therapeutic window. These results suggest value in exploring combination therapy in patients presenting with advanced filovirus disease.
Selective electrochemical reduction of nitric oxide to hydroxylamine by atomically dispersed iron catalyst
Authors: Kim Dong Hyun , Ringe Stefan , Kim Haesol , Kim Sejun , Kim Bupmo , Bae Geunsu , Oh Hyung-Suk , Jaouen Frédéric , Kim Wooyul , Kim Hyungjun , Choi Chang Hyuck
Published: March 2021

Electrocatalytic conversion of nitrogen oxides to value-added chemicals is a promising strategy for mitigating the human-caused unbalance of the global nitrogen-cycle, but controlling product selectivity remains a great challenge. Here we show iron–nitrogen-doped carbon as an efficient and durable electrocatalyst for selective nitric oxide reduction into hydroxylamine. Using in operando spectroscopic techniques, the catalytic site is identified as isolated ferrous moieties, at which the rate for hydroxylamine production increases in a super-Nernstian way upon pH decrease. Computational multiscale modelling attributes the origin of unconventional pH dependence to the redox active (non-innocent) property of NO. This makes the rate-limiting NO adsorbate state more sensitive to surface charge which varies with the pH-dependent overpotential. Guided by these fundamental insights, we achieve a Faradaic efficiency of 71% and an unprecedented production rate of 215 μmol cm−2 h−1 at a short-circuit mode in a flow-type fuel cell without significant catalytic deactivation over 50 h operation.
Experimental evidence of mosaic structure in strongly supercooled molecular liquids
Authors: Caporaletti F. , Capaccioli S. , Valenti S. , Mikolasek M. , Chumakov A. I. , Monaco G.
Published: March 2021

When a liquid is cooled to produce a glass its dynamics, dominated by the structural relaxation, become very slow, and at the glass-transition temperature Tg its characteristic relaxation time is about 100 s. At slightly elevated temperatures (~1.2 Tg) however, a second process known as the Johari-Goldstein relaxation, βJG, decouples from the structural one and remains much faster than it down to Tg. While it is known that the βJG-process is strongly coupled to the structural relaxation, its dedicated role in the glass-transition remains under debate. Here we use an experimental technique that permits us to investigate the spatial and temporal properties of the βJG relaxation, and give evidence that the molecules participating in it are highly mobile and spatially connected in a system-spanning, percolating cluster. This correlation of structural and dynamical properties provides strong experimental support for a picture, drawn from theoretical studies, of an intermittent mosaic structure in the deeply supercooled liquid phase.
Electrocatalytic synthesis of heterocycles from biomass-derived furfuryl alcohols
Authors: Liu Xuan , Li Bo , Han Guanqun , Liu Xingwu , Cao Zhi , Jiang De-en , Sun Yujie
Published: March 2021

It is very attractive yet underexplored to synthesize heterocyclic moieties pertaining to biologically active molecules from biomass-based starting compounds. Herein, we report an electrocatalytic Achmatowicz reaction for the synthesis of hydropyranones from furfuryl alcohols, which can be readily produced from biomass-derived and industrially available furfural. Taking advantage of photo-induced polymerization of a bipyridyl ligand, we demonstrate the facile preparation of a heterogenized nickel electrocatalyst, which effectively drives the Achmatowicz reaction electrochemically. A suite of characterization techniques and density functional theory computations were performed to aid the understanding of the reaction mechanism. It is rationalized that the unsaturated coordination sphere of nickel sites in our electrocatalyst plays an important role at low applied potential, not only allowing the intimate interaction between the nickel center and furfuryl alcohol but also enabling the transfer of hydroxide from nickel to the bound furfuryl alcohol.
Measuring inequality in community resilience to natural disasters using large-scale mobility data
Authors: Hong Boyeong , Bonczak Bartosz J. , Gupta Arpit , Kontokosta Constantine E.
Published: March 2021

While conceptual definitions provide a foundation for the study of disasters and their impacts, the challenge for researchers and practitioners alike has been to develop objective and rigorous measures of resilience that are generalizable and scalable, taking into account spatiotemporal dynamics in the response and recovery of localized communities. In this paper, we analyze mobility patterns of more than 800,000 anonymized mobile devices in Houston, Texas, representing approximately 35% of the local population, in response to Hurricane Harvey in 2017. Using changes in mobility behavior before, during, and after the disaster, we empirically define community resilience capacity as a function of the magnitude of impact and time-to-recovery. Overall, we find clear socioeconomic and racial disparities in resilience capacity and evacuation patterns. Our work provides new insight into the behavioral response to disasters and provides the basis for data-driven public sector decisions that prioritize the equitable allocation of resources to vulnerable neighborhoods.
Drug ranking using machine learning systematically predicts the efficacy of anti-cancer drugs
Authors: Gerdes Henry , Casado Pedro , Dokal Arran , Hijazi Maruan , Akhtar Nosheen , Osuntola Ruth , Rajeeve Vinothini , Fitzgibbon Jude , Travers Jon , Britton David , Khorsandi Shirin , Cutillas Pedro R.
Published: March 2021

Artificial intelligence and machine learning (ML) promise to transform cancer therapies by accurately predicting the most appropriate therapies to treat individual patients. Here, we present an approach, named Drug Ranking Using ML (DRUML), which uses omics data to produce ordered lists of >400 drugs based on their anti-proliferative efficacy in cancer cells. To reduce noise and increase predictive robustness, instead of individual features, DRUML uses internally normalized distance metrics of drug response as features for ML model generation. DRUML is trained using in-house proteomics and phosphoproteomics data derived from 48 cell lines, and it is verified with data comprised of 53 cellular models from 12 independent laboratories. We show that DRUML predicts drug responses in independent verification datasets with low error (mean squared error < 0.1 and mean Spearman’s rank 0.7). In addition, we demonstrate that DRUML predictions of cytarabine sensitivity in clinical leukemia samples are prognostic of patient survival (Log rankp < 0.005). Our results indicate that DRUML accurately ranks anti-cancer drugs by their efficacy across a wide range of pathologies.
Controlling network ensembles
Authors: Klickstein Isaac , Sorrentino Francesco
Published: March 2021

The field of optimal control typically requires the assumption of perfect knowledge of the system one desires to control, which is an unrealistic assumption for biological systems, or networks, typically affected by high levels of uncertainty. Here, we investigate the minimum energy control of network ensembles, which may take one of a number of possible realizations. We ensure the controller derived can perform the desired control with a tunable amount of accuracy and we study how the control energy and the overall control cost scale with the number of possible realizations. Our focus is in characterizing the solution of the optimal control problem in the limit in which the systems are drawn from a continuous distribution, and in particular, how to properly pose the weighting terms in the objective function. We verify the theory in three examples of interest: a unidirectional chain network with uncertain edge weights and self-loop weights, a network where each edge weight is drawn from a given distribution, and the Jacobian of the dynamics corresponding to the cell signaling network of autophagy in the presence of uncertain parameters.
Polariton-assisted excitation energy channeling in organic heterojunctions
Authors: Wang Mao , Hertzog Manuel , Börjesson Karl
Published: March 2021

Exciton-polaritons are hybrid light-matter states resulting from strong exciton-photon coupling. The wave function of the polariton is a mixture of light and matter, enabling long-range energy transfer between spatially separated chromophores. Moreover, their delocalized nature, inherited from the photon component, has been predicted to enhance exciton transport. Here, we strongly couple an organic heterojunction consisting of energy/electron donor and acceptor materials to the same cavity mode. Using time-resolved spectroscopy and optoelectrical characterization, we show that the rate of exciton harvesting is enhanced with one order of magnitude and the rate of energy transfer in the system is increased two- to threefold in the strong coupling regime. Our results exemplify two means of efficiently channeling excitation energy to a heterojunction interface, where charge separation can occur. This study opens a new door to increase the overall efficiency of light harvesting systems using the tool of strong light-matter interactions.
Non-Hermitian route to higher-order topology in an acoustic crystal
Authors: Gao He , Xue Haoran , Gu Zhongming , Liu Tuo , Zhu Jie , Zhang Baile
Published: March 2021

Topological phases of matter are classified based on their Hermitian Hamiltonians, whose real-valued dispersions together with orthogonal eigenstates form nontrivial topology. In the recently discovered higher-order topological insulators (TIs), the bulk topology can even exhibit hierarchical features, leading to topological corner states, as demonstrated in many photonic and acoustic artificial materials. Naturally, the intrinsic loss in these artificial materials has been omitted in the topology definition, due to its non-Hermitian nature; in practice, the presence of loss is generally considered harmful to the topological corner states. Here, we report the experimental realization of a higher-order TI in an acoustic crystal, whose nontrivial topology is induced by deliberately introduced losses. With local acoustic measurements, we identify a topological bulk bandgap that is populated with gapped edge states and in-gap corner states, as the hallmark signatures of hierarchical higher-order topology. Our work establishes the non-Hermitian route to higher-order topology, and paves the way to exploring various exotic non-Hermiticity-induced topological phases.
The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5
Authors: Radomir Lihi , Kramer Matthias P. , Perpinial Michal , Schottlender Nofar , Rabani Stav , David Keren , Wiener Anna , Lewinsky Hadas , Becker-Herman Shirly , Aharoni Rina , Milo Ron , Mauri Claudia , Shachar Idit
Published: March 2021

B cells have essential functions in multiple sclerosis and in its mouse model, experimental autoimmune encephalomyelitis, both as drivers and suppressors of the disease. The suppressive effects are driven by a regulatory B cell (Breg) population that functions, primarily but not exclusively, via the production of IL-10. However, the mechanisms modulating IL-10-producing Breg abundance are poorly understood. Here we identify SLAMF5 for controlling IL-10+ Breg maintenance and function. In EAE, the deficiency of SLAMF5 in B cells causes accumulation of IL10+ Bregs in the central nervous system and periphery. Blocking SLAMF5 in vitro induces both human and mouse IL-10-producing Breg cells and increases their survival with a concomitant increase of a transcription factor, c-Maf. Finally, in vivo SLAMF5 blocking in EAE elevates IL-10+ Breg levels and ameliorates disease severity. Our results suggest that SLAMF5 is a negative moderator of IL-10+ Breg cells, and may serve as a therapeutic target in MS and other autoimmune diseases.
Author Correction: Discovery of fungal surface NADases predominantly present in pathogenic species
Authors: Strømland Øyvind , Kallio Juha P. , Pschibul Annica , Skoge Renate H. , Harðardóttir Hulda M. , Sverkeli Lars J. , Heinekamp Thorsten , Kniemeyer Olaf , Migaud Marie , Makarov Mikhail V. , Gossmann Toni I. , Brakhage Axel A. , Ziegler Mathias
Published: March 2021

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22476-7
An acidic morpholine derivative containing glyceride from thraustochytrid, Aurantiochytrium
Authors: Kaya Kunimitsu , Shiraishi Fujio , Iida Tetsuo , Yamada Masaki , Sano Tomoharu
Published: March 2021

A novel acidic morpholine-derivative containing glyceride (M-glyceride) was isolated from the cells of two strains of the thraustochytrid, Aurantiochytrium. The glyceride accounted for approximately 0.1 -0.4% of the lyophilized cells. The glyceride consisted of peaks I (85%) and II (15%). The structures of the intact and acetylated glycerides were elucidated by liquid chromatography-quadrupole time-of-flight chromatograph mass spectrometer (LC–Q/TOF) and NMR spectroscopy. The hydrate type of M-glyceride was detected as a minor component by LC–MS/MS. By 2D-NMR experiments, peaks I of the intact M-glyceride were elucidated as 1,2-didocosapentaenoyl-glyceryl-2′-oxy-3′-oxomorpholino propionic acid, and peak II was estimated 1,2-palmitoyldocosapentaenoyl- and/or 1,2-docosapentaenoylpalmitoyl-glyceryl-2′-oxy-3′-oxomorpholino propionic acid. The double bond position of docosapentaenoic acid was of the ω − 6 type (C22 = 5.ω − 6). The M-glyceride content varied by the cell cycle. The content was 0.4% of lyophilized cells at the mid logarithmic phase, and decreased to 0.1% at the mid stationary phase. When cells were grown in 1.0 µM M-glyceride-containing growth media, cell growth was stimulated to 110% of the control. With 0.1 µM acetyl M-glyceride, stimulation of 113% of the control was observed. Finding morpholine derivatives in biological components is rare, and 2-hydroxy-3-oxomorpholino propionic acid (auranic acid) is a novel morpholine derivative.
Chopstick technique used in laparoendoscopic single site radical hysterectomy for early stage cervical cancer
Authors: Wang Yanzhou , Yao Yuanyang , Dou Yuya , Tang Shuai , Chen Cheng , Li Yudi , Chen Yong , Deng Li , Liang Zhiqing
Published: March 2021

Laparoendoscopic single-site surgery (LESS) further minimizes the invasiveness of traditional laparoscopic surgery. However, the "chopstick" effect caused by the parallel arrangement of the instruments in the umbilicus is considered an obstacle indelicate operations. The purpose of this study was to introduce a new technique characterized by a double fulcrum formed by instruments, named the "chopstick" technique, which facilitates the expedient accomplishment of complicated surgeries such as LESS radical hysterectomy (LESS-RH). Seventy-three patients who underwent LESS-RH using the "chopstick" technique were retrospectively analyzed. The procedure was performed successfully in 72 patients. The median operative duration was 225 min, and the median intraoperative blood loss was 200 ml. Among the operations in the first 20 patients, intraoperative vascular injuries and bladder injury occurred in two patients and were repaired by LESS. Patients responded positively regarding minimal postoperative pain control. The score of satisfaction with the cosmetic outcome expressed by the patients was eight at discharge and nine 30 days later. In conclusion, this study presents the feasibility of accomplishing complicated procedures, such as radical hysterectomy, by LESS using the “chopstick” technique. This approach provides more options for both selected patients and surgeons.
Comprehensive verbal fluency features predict executive function performance
Authors: Amunts Julia , Camilleri Julia A. , Eickhoff Simon B. , Patil Kaustubh R. , Heim Stefan , von Polier Georg G. , Weis Susanne
Published: March 2021

Semantic verbal fluency (sVF) tasks are commonly used in clinical diagnostic batteries as well as in a research context. When performing sVF tasks to assess executive functions (EFs) the sum of correctly produced words is the main measure. Although previous research indicates potentially better insights into EF performance by the use of finer grained sVF information, this has not yet been objectively evaluated. To investigate the potential of employing a finer grained sVF feature set to predict EF performance, healthy monolingual German speaking participants (n = 230) were tested with a comprehensive EF test battery and sVF tasks, from which features including sum scores, error types, speech breaks and semantic relatedness were extracted. A machine learning method was applied to predict EF scores from sVF features in previously unseen subjects. To investigate the predictive power of the advanced sVF feature set, we compared it to the commonly used sum score analysis. Results revealed that 8 / 14 EF tests were predicted significantly using the comprehensive sVF feature set, which outperformed sum scores particularly in predicting cognitive flexibility and inhibitory processes. These findings highlight the predictive potential of a comprehensive evaluation of sVF tasks which might be used as diagnostic screening of EFs.
Degradation of insulin amyloid by antibiotic minocycline and formation of toxic intermediates
Authors: Mori Wakako , Yuzu Keisuke , Lobsiger Nadine , Nishioka Hideo , Sato Hisako , Nagase Terumasa , Iwaya Keiichi , Lindgren Mikael , Zako Tamotsu
Published: March 2021

Insulin balls, localized insulin amyloids formed at subcutaneous insulin-injection sites in patients with diabetes, cause poor glycemic control owing to impairments in insulin absorption. Our previous study has shown that some insulin balls are cytotoxic, but others are not, implying amyloid polymorphism. Interestingly, the patient with toxic insulin balls had been treated with antibiotic minocycline, suggesting a possible relationship between toxicity of insulin balls and minocycline. However, the direct effect of minocycline on the structure and cytotoxicity of the insulin amyloid is still unclear. Herein, we demonstrated that that minocycline at physiological concentrations induced degradation of insulin amyloids formed from human insulin and insulin drug preparations used for diabetes patients. Interestingly, the process involved the initial appearance of the toxic species, which subsequently changed into less-toxic species. It is also shown that the structure of the toxic species was similar to that of sonicated fragments of human insulin amyloids. Our study shed new light on the clarification of the revelation of insulin balls and the development of the insulin analogs for diabetes therapy.
Potential chemopreventive, anticancer and anti-inflammatory properties of a refined artocarpin-rich wood extract of Artocarpus heterophyllus Lam.
Authors: Morrison Isaac J. , Zhang Jianan , Lin Jingwen , Murray JeAnn E. , Porter Roy , Langat Moses K. , Sadgrove Nicholas J. , Barker James , Zhang Guodong , Delgoda Rupika
Published: March 2021

Colorectal cancer (CRC) represents the third leading cause of death among cancer patients below the age of 50, necessitating improved treatment and prevention initiatives. A crude methanol extract from the wood pulp of Artocarpus heterophyllus was found to be the most bioactive among multiple others, and an enriched extract containing 84% (w/v) artocarpin (determined by HPLC–MS–DAD) was prepared. The enriched extract irreversibly inhibited the activity of human cytochrome P450 CYP2C9, an enzyme previously shown to be overexpressed in CRC models. In vitro evaluations on heterologously expressed microsomes, revealed irreversible inhibitory kinetics with an IC50 value of 0.46 µg/mL. Time- and concentration-dependent cytotoxicity was observed on human cancerous HCT116 cells with an IC50 value of 4.23 mg/L in 72 h. We then employed the azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-induced model in C57BL/6 mice, which revealed that the enriched extract suppressed tumor multiplicity, reduced the protein expression of proliferating cell nuclear antigen, and attenuated the gene expression of proinflammatory cytokines (Il-6 and Ifn-γ) and protumorigenic markers (Pcna, Axin2, Vegf, and Myc). The extract significantly (p = 0.03) attenuated (threefold) the gene expression of murine Cyp2c37, an enzyme homologous to the human CYP2C9 enzyme. These promising chemopreventive, cytotoxic, anticancer and anti-inflammatory responses, combined with an absence of toxicity, validate further evaluation of A. heterophyllus extract as a therapeutic agent.
SPINK7 expression changes accompanied by HER2, P53 and RB1 can be relevant in predicting oral squamous cell carcinoma at a molecular level
Authors: Pennacchiotti Gina , Valdés-Gutiérrez Fabio , González-Arriagada Wilfredo Alejandro , Montes Héctor Federico , Parra Judith Maria Roxana , Guida Valeria Andrea , Gómez Silvina Esther , Guerrero-Gimenez Martin Eduardo , Fernandez-Muñoz Juan Manuel , Zoppino Felipe Carlos Martin , Carón Rubén Walter , Ezquer Marcelo Eduardo , Fernández-Ramires Ricardo , Bruna Flavia Alejandra
Published: March 2021

The oral squamous cell carcinoma (OSCC), which has a high morbidity rate, affects patients worldwide. Changes in SPINK7 in precancerous lesions could promote oncogenesis. Our aim was to evaluate SPINK7 as a potential molecular biomarker which predicts OSCC stages, compared to: HER2, TP53, RB1, NFKB and CYP4B1. This study used oral biopsies from three patient groups: dysplasia (n = 33), less invasive (n = 28) and highly invasive OSCC (n = 18). The control group consisted of clinically suspicious cases later to be confirmed as normal mucosa (n = 20). Gene levels of SPINK7, P53, RB, NFKB and CYP4B1 were quantified by qPCR. SPINK7 levels were correlated with a cohort of 330 patients from the TCGA. Also, SPINK7, HER2, TP53, and RB1, were evaluated by immunohistofluorescence. One-way Kruskal–Wallis test and Dunn's post-hoc with a p < 0.05 significance was used to analyze data. In OSCC, the SPINK7 expression had down regulated while P53, RB, NFKB and CYP4B1 had up regulated (p < 0.001). SPINK7 had also diminished in TCGA patients (p = 2.10e-6). In less invasive OSCC, SPINK7 and HER2 proteins had decreased while TP53 and RB1 had increased with respect to the other groups (p < 0.05). The changes of SPINK7 accompanied by HER2, P53 and RB1 can be used to classify the molecular stage of OSCC lesions allowing a diagnosis at molecular and histopathological levels.
An entropic associative memory
Authors: Pineda Luis A. , Fuentes Gibrán , Morales Rafael
Published: March 2021

Natural memories are associative, declarative and distributed, and memory retrieval is a constructive operation. In addition, cues of objects that are not contained in the memory are rejected directly. Symbolic computing memories resemble natural memories in their declarative character, and information can be stored and recovered explicitly; however, they are reproductive rather than constructive, and lack the associative and distributed properties. Sub-symbolic memories developed within the connectionist or artificial neural networks paradigm are associative and distributed, but lack the declarative property, the capability of rejecting objects that are not included in the memory, and memory retrieval is also reproductive. In this paper we present a memory model that sustains the five properties of natural memories. We use Relational-Indeterminate Computing to model associative memory registers that hold distributed representations of individual objects. This mode of computing has an intrinsic computing entropy which measures the indeterminacy of representations. This parameter determines the operational characteristics of the memory. Associative registers are embedded in an architecture that maps concrete images expressed in modality specific buffers into abstract representations and vice versa. The framework has been used to model a visual memory holding the representations of hand-written digits. The system has been tested with a set of memory recognition and retrieval experiments with complete and severely occluded images. The results show that there is a range of entropy values, not too low and not too high, in which associative memory registers have a satisfactory performance. The experiments were implemented in a simulation using a standard computer with a GPU, but a parallel architecture may be built where the memory operations would take a very reduced number of computing steps.
The effect of off-center placement of twisted tape on flow and heat transfer characteristics in a circular tube
Authors: Wang Li , Ni Peiyong , Xi Guannan
Published: March 2021

This study is conducted to investigate the effect of off-center placement of twisted tape on flow distribution and heat transfer in a circular tube. The effect of tape width of 20, 18, 16, 14 and 12 mm on the heat transfer performance is discussed under the same twist ratio of 2.0. The numerical analysis of the flow field, average Nusselt number, friction factor and thermo-hydraulic performance parameter of the tube are discussed with Reynolds number ranged from 2600 to 8760. The results indicate that the Nusselt number of the tube fitted with center-placed twisted tapes at various width is 7–51% higher than the plain tube, and performance in low Reynolds region was found more effective than that in high Reynolds region. The heat transfer for circular tube with twisted tape attached to the wall shows better performance than that for the tube with center-placed twisted tape. With a smaller tape width, a higher increasing ratio of Nu-wall/Nu-center is obtained. The increasing ratio for Nusselt number ranged from 3 to 18%. However, the use of twisted tape inserts is not beneficial for energy saving. The thermo-hydraulic performance parameters for convective heat transfer of helium gas flowing in a circular tube are below unity for the calculated Reynolds region.
Hemodynamic analysis for stenosis microfluidic model of thrombosis with refined computational fluid dynamics simulation
Authors: Zhao Yunduo Charles , Vatankhah Parham , Goh Tiffany , Michelis Rhys , Kyanian Kiarash , Zhang Yingqi , Li Zhiyong , Ju Lining Arnold
Published: March 2021

Disturbed blood flow has been increasingly recognized for its critical role in platelet aggregation and thrombosis. Microfluidics with hump shaped contractions have been developed to mimic microvascular stenosis and recapitulate the prothrombotic effect of flow disturbance. However the physical determinants of microfluidic hemodynamics are not completely defined. Here, we report a refined computational fluid dynamics (CFD) simulation approach to map the shear rate (γ) and wall shear stress (τ) distribution in the stenotic region at high accuracy. Using ultra-fine meshing with sensitivity verification, our CFD results show that the stenosis level (S) is dominant over the bulk shear rate (γ0) and contraction angle (α) in determining γ and τ distribution at stenosis. In contrast, α plays a significant role in governing the shear rate gradient (γ′) distribution while it exhibits subtle effects on the peak γ. To investigate the viscosity effect, we employ a Generalized Power-Law model to simulate blood flow as a non-Newtonian fluid, showing negligible difference in the γ distribution when compared with Newtonian simulation with water medium. Together, our refined CFD method represents a comprehensive approach to examine microfluidic hemodynamics in three dimensions and guide microfabrication designs. Combining this with hematological experiments promises to advance understandings of the rheological effect in thrombosis and platelet mechanobiology.