bluuebunny/crossref_metadata_2025 huggingface dataset:
Push, Pull, or Inform - an Empirical Taxonomy of Environmental Policy Support in Sweden
Authors: Ejelöv Emma , Harring Niklas , Hansla André , Jagers Sverker , Nilsson Andreas
Published: February 2022

Research on environmental policy support utilises different categorisations of policies, for example, differentiating between policies assumed to be perceived as rewarding or punishing. Do citizens’ perception of environmental policies also lend itself to this categorisation? Based on an exhaustive sample of active policies in Sweden, this study presents a taxonomy of environmental policy support in Sweden. A fairly representative Swedish sample (N = 2911) rated the acceptability of 44 environmental policies. Exploratory factor analysis indicated that participants’ acceptability of policies forms three categories: push policies consisting of regulatory and market-based disincentives, pull policies consisting mainly of market-based incentives, and informational policies, such as ecolabeling. Sociodemographics had small but consistent effects on attitudes towards the three categories, while political ideology had a larger effect across the categories. This study indicates that current academic categorisations may not adequately capture laypeople’s perceptions, and discusses the importance of research on driving mechanisms behind the current taxonomy.
Control of flexible knee joint exoskeleton robot based on dynamic model
Authors: Liu Biao , Liu YouWei , Zhou Zikang , Xie Longhan
Published: February 2022

The knee joint plays a significant role in ground clearness, which is a crucial subtask of normal walking and avoiding falls. While post-stroke survivors are often faced with muscle weakness during walking, which leads to inadequate knee flexion. The lack of ground clearance caused by inadequate knee flexion will severely impede walking, increase metabolic exertion, and increase the risk of falls. A compliant exoskeleton robot possesses more favorable edges than other rigid ones in lightweight, safety, sense of comfort, and so on. We developed a new type of soft exoskeleton robot to assist the knee joint to achieve desired movements with Bowden cable transmitting force and torque. With the agonist–antagonist driving method, like a group of muscles working, we have explored dual-motors structure to realize the knee flexion function. It has built a standard dynamic model to analyze stability and realize the control law. We have conducted simulation and prototype experiments to verify the feasibility and usefulness of our method. The results show that the device can compensate for the lack of the knee joint driving force and realize the reference movement. Finally, we concluded that our method is a desirable way, and the scheme could improve the knee flexion ability and clearing ground.
Raging in Delhi and Rajasthan: Post-show Audience Discussions of Medea
Authors: Marwah Anuradha
Published: February 2022

From April to November 2019, eight members of the pandies’ theatre, a Delhi-based activist theatre group, toured Delhi and Rajasthan with a fifty-five-minute version of Euripides’ Medea, in Hindustani. The group gave fifteen performances in the round, in spaces ranging from a tin shed to a plush air-conditioned conference room, addressing diverse audiences. During post-performance discussions in four spaces – Ambedkar University of Delhi, the village of Mangliawas in Rajasthan, the India Habitat Centre, and Studio Safdar in New Delhi – spontaneous debates arose between women on the one side and men on the other in which the women expressed their understanding of Medea’s actions or their ‘identification’ with her character. Anuradha Marwah, the director of the play, discusses these debates with reference to the ‘agonistic’ character of Medea (431 BCE) while framing the tour as a feminist activist endeavour in India today, where the condition of abandoned women and those considered to be outsiders has become even more precarious due to increasing divisiveness and chauvinism. Anuradha Marwah is a theatre activist and a Professor in the Department of English at Zakir Husain Delhi College, Delhi University. She was a Fulbright-Nehru Academic and Professional Excellence Fellow at the Interdisciplinary Centre for Study of Global Change, University of Minnesota-Twin Cities in 2017. Her publications include two plays, A Pipe Dream in Delhi and Ismat’s Love Stories, three novels, and several academic and popular articles.
Stability of maritime boundaries and the challenge of geographical change: A reply to Snjólaug Árnadóttir
Authors: Lando Massimo
Published: February 2022

Geographical phenomena impacting the shape of coastlines may have implications for the stability of maritime boundaries delimited by agreement or judicial process. Sea level rise resulting from human-caused climate change has recently arisen as an additional phenomenon compelling the re-assessment of the stability of maritime boundaries over time. In a recent article published in this Journal, Dr. Snjólaug Árnadóttir has argued that a solution to the challenges of coastline change could be for maritime boundaries to fluctuate following the fluctuation of the baselines on which their course depends. By way of reply to Dr. Árnadóttir’s suggestion, this article argues that fluctuating boundaries have no legal basis either in the United Nations Convention on the Law of the Sea or in judicial decisions. Moreover, the delimitation process in three stages, commonly applied by international courts and tribunals since the Black Sea judgment, appears to be ill-suited for establishing fluctuating boundaries. There seems to be other solutions to the problem of coastline change, which this article also briefly explores.
Three improvements to the top-down solver
Authors: Seidl Helmut , Vogler Ralf
Published: February 2022

The local solver TD is a generic fixpoint engine which explores a given system of equations on demand. It has been successfully applied to the interprocedural analysis of procedural languages. The solver TD gains efficiency by detecting dependencies between unknowns on the fly. This algorithm has been recently extended to deal with widening and narrowing as well. In particular, it has been equipped with an automatic detection of widening and narrowing points. That version, however, is only guaranteed to terminate under two conditions: only finitely many unknowns are encountered, and all right-hand sides are monotonic. While the first condition is unavoidable, the second limits the applicability of the solver. Another limitation is that the solver maintains the current abstract values of all encountered unknowns instead of a minimal set sufficient for performing the iteration. By consuming unnecessarily much space, interprocedural analyses may not succeed on seemingly small programs. In the present paper, we therefore extend the top-down solver TD in three ways. First, we indicate how the restriction to monotonic right-hand sides can be lifted without compromising termination. We then show how the solver can be tuned to store abstract values only when their preservation is inevitable. Finally, we also show how the solver can be extended to side-effecting equation systems. Right-hand sides of these may not only provide values for the corresponding left-hand side unknowns but at the same time produce contributions to other unknowns. This practical extension has successfully been used for a seamless combination of context-sensitive analyses (e.g., of local states) with flow-insensitive analyses (e.g., of globals).
Bayesian vine copulas for modelling dependence in data breach losses
Authors: Liu Jia , Li Jackie , Daly Kevin
Published: February 2022

Potentialdata breach losses represent a significant part of operational risk and can be a serious concern for risk managers and insurers. In this paper, we employ the vine copulas under a Bayesian framework to co-model incidences from different data breach types. A full Bayesian approach can allow one to select both the copulas and margins and estimate their parameters in a coherent fashion. In particular, it can incorporate process, parameter, and model uncertainties, and this is very important for applications in risk management under current regulations. We also conduct a series of sensitivity tests on the Bayesian modelling results. Using two public data sets of data breach losses, we find that the overall dependency structure and tail dependence vary significantly between different types of data breaches. The optimally selected vine structure and pairwise copulas suggest more conservative value-at-risk estimates when compared to the other suboptimal copula models.
Decrypting Log Data
Authors: Klose Maria , Steger Diana , Fick Julian , Artelt Cordula
Published: February 2022

Abstract. Analyzing log data from digital learning environments provides information about online learning. However, it remains unclear how this information can be transferred to psychologically meaningful variables or how it is linked to learning outcomes. The present study summarizes findings on correlations between general online activity and learning outcomes in university settings. The course format, instructions to engage in online discussions, requirements, operationalization of general online activity, and publication year are considered moderators. A multi-source search provided 41 studies ( N = 28,986) reporting 69 independent samples and 104 effect sizes. The three-level random-effects meta-analysis identified a pooled effect of r = .25 p = .003, 95% CI [.09, .41], indicating that students who are more active online have better grades. Despite high heterogeneity, Q(103) = 3,960.04, p < .001, moderator analyses showed no statistically significant effect. We discuss further potential influencing factors in online courses and highlight the potential of learning analytics.
Dealing With Dependent Effect Sizes in MASEM
Authors: Stolwijk Isidora , Jak Suzanne , Eichelsheim Veroni , Hoeve Machteld
Published: February 2022

Abstract. The objective of the present study was to examine whether different methods for dealing with dependency in meta-analytic structural equation modeling (MASEM) lead to different results. Four different methods for dealing with dependent effect sizes in MASEM were applied to empirical data, including: (1) ignoring dependency; (2) aggregation; (3) elimination; and (4) a multilevel approach. Random-effects two-stage structural equation modeling was conducted for each method separately, and potential moderators were examined using subgroup analysis. Results demonstrated that the different methods of dealing with dependency in MASEM lead to different results. Thus, the decision on which approach should be used in MASEM-analysis should be carefully considered. Given that the multilevel approach is the only approach that includes all available information while explicitly modeling dependency, it is currently the theoretically preferred approach for dealing with dependency in MASEM. Future research should evaluate the multilevel approach with simulated data.
Effect of the Intensified Sub‐Thermocline Eddy on Strengthening the Mindanao Undercurrent in 2019
Authors: Azminuddin Fuad , Lee Jae Hak , Jeon Dongchull , Shin Chang‐Woong , Villanoy Cesar , Lee Seok , Min Hong Sik , Kim Dong Guk
Published: February 2022

The northward‐flowing Mindanao Undercurrent (MUC) was directly measured by acoustic Doppler current profilers from a subsurface mooring at about 8°N, 127°E during 2 years (November 2017–December 2019). Its depth covers a range from 400 m to deeper than 1,000 m with its core appearing at around 900 m. The mean velocity of MUC's core was approximately 5.8 cm s−1 with a maximum speed of about 47.6 cm s−1. The MUC was observed as a quasi‐permanent current with strong intraseasonal variability (ISV) with a period of 70–80 days. Further analyses with an eddy‐resolving circulation model output suggest that the ISV is closely related to sub‐thermocline eddies (SEs). In this study, two types of SEs near the Philippine coast are disclosed: the westward propagating SE (SE‐1) and the quasi‐stational SE southeast of Mindanao Island (SE‐2). The SE‐1 has both cyclonic and anticyclonic polarities with the propagation speed of 7–8 cm s−1, while the SE‐2 is an anticyclonic eddy that moves erratically within 4–8°N, 127–130°E with the mean translation speed of about 11 cm s−1. Even though the SE‐1 plays an important role in modulating the MUC, our results show that the observed strong MUC event (May–July 2019) is evidently induced by the intensified SE‐2 that moves northwestward. This study emphasizes that the SE‐2 when intensified, receives more energy from the strengthened New Guinea Coastal Undercurrent and loses the energy northward along the Philippine coast by intensifying the MUC.
Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity
Authors: Griesius Simonas , O’Donnell Cian , Waldron Sophie , Thomas Kerrie L. , Dwyer Dominic M. , Wilkinson Lawrence S. , Hall Jeremy , Robinson Emma S. J. , Mellor Jack R.
Published: February 2022

Copy number variants indicating loss of function in the DLG2 gene have been associated with markedly increased risk for schizophrenia, autism spectrum disorder, and intellectual disability. DLG2 encodes the postsynaptic scaffolding protein DLG2 (PSD93) that interacts with NMDA receptors, potassium channels, and cytoskeletal regulators but the net impact of these interactions on synaptic plasticity, likely underpinning cognitive impairments associated with these conditions, remains unclear. Here, hippocampal CA1 neuronal excitability and synaptic function were investigated in a novel clinically relevant heterozygous Dlg2+/− rat model using ex vivo patch-clamp electrophysiology, pharmacology, and computational modelling. Dlg2+/− rats had reduced supra-linear dendritic integration of synaptic inputs resulting in impaired associative long-term potentiation. This impairment was not caused by a change in synaptic input since NMDA receptor-mediated synaptic currents were, conversely, increased and AMPA receptor-mediated currents were unaffected. Instead, the impairment in associative long-term potentiation resulted from an increase in potassium channel function leading to a decrease in input resistance, which reduced supra-linear dendritic integration. Enhancement of dendritic excitability by blockade of potassium channels or activation of muscarinic M1 receptors with selective allosteric agonist 77-LH-28-1 reduced the threshold for dendritic integration and 77-LH-28-1 rescued the associative long-term potentiation impairment in the Dlg2+/− rats. These findings demonstrate a biological phenotype that can be reversed by compound classes used clinically, such as muscarinic M1 receptor agonists, and is therefore a potential target for therapeutic intervention.
Selective induction of human gut-associated acetogenic/butyrogenic microbiota based on specific microbial colonization of indigestible starch granules
Authors: Nagara Yusuke , Fujii Daichi , Takada Toshihiko , Sato-Yamazaki Mikiko , Odani Toru , Oishi Kenji
Published: February 2022

Prediction of individualized responses is one of biggest challenges in dietary intervention to modulate human gut microbiota. Bacterial interspecies competition for dietary factors should underlie the inter-subject heterogeneity of microbial responses. Microscale localization of bacterial species around intestinal food structures could provide direct evidence for understanding this, however, little information is currently available. Here we analyzed human fecal sections and found multiple types of bacterial colonization of food structures. The most eminent one was dense and frequent colonization of starch granules by Bifidobacterium adolescentis. After intake of raw potato starch (pSt), B. adolescentis dramatically increased in every carrier of the species, accompanied by an increase in bifidobacterial metabolite acetate. In the other subjects, Eubacterium rectale and its metabolite butyrate increased, but it was suppressed in B. adolescentis carriers. A correlation analysis indicated the contribution of these species to respective metabolites. In vitro analyses of isolates of major gut bacterial species confirmed that these species are major colonizers of pSt and that B. adolescentis can colonize pSt even in the presence of the known starch granule–degrading bacterium Ruminococcus bromii. Collectively, we propose that specific binding of B. adolescentis or E. rectale to pSt selectively induces acetogenic or butyrogenic response of gut microbiota, where the former determines the response of the latter.
Compromised mammillary body connectivity and psychotic symptoms in mice with di- and mesencephalic ablation of ST8SIA2
Authors: Küçükerden Melike , Schuster Ute E. , Röckle Iris , Alvarez-Bolado Gonzalo , Schwabe Kerstin , Hildebrandt Herbert
Published: February 2022

Altered long-range connectivity is a common finding across neurodevelopmental psychiatric disorders, but causes and consequences are not well understood. Genetic variation in ST8SIA2 has been associated with schizophrenia, autism, and bipolar disorder, and St8sia2−/− mice show a number of related neurodevelopmental and behavioral phenotypes. In the present study, we use conditional knockout (cKO) to dissect neurodevelopmental defects and behavioral consequences of St8sia2 deficiency in cortical interneurons, their cortical environment, or in the di- and mesencephalon. Neither separate nor combined cortical and diencephalic ablation of St8sia2 caused the disturbed thalamus-cortex connectivity observed in St8sia2−/− mice. However, cortical ablation reproduced hypoplasia of corpus callosum and fornix and mice with di- and mesencephalic ablation displayed smaller mammillary bodies with a prominent loss of parvalbumin-positive projection neurons and size reductions of the mammillothalamic tract. In addition, the mammillotegmental tract and the mammillary peduncle, forming the reciprocal connections between mammillary bodies and Gudden’s tegmental nuclei, as well as the size of Gudden’s ventral tegmental nucleus were affected. Only mice with these mammillary deficits displayed enhanced MK-801-induced locomotor activity, exacerbated impairment of prepulse inhibition in response to apomorphine, and hypoanxiety in the elevated plus maze. We therefore propose that compromised mammillary body connectivity, independent from hippocampal input, leads to these psychotic-like responses of St8sia2-deficient mice.
LINC01123 promotes immune escape by sponging miR-214-3p to regulate B7–H3 in head and neck squamous-cell carcinoma
Authors: Li Huan , Yang Zihui , Yang Xiangming , Zhang Fengrui , Wang Jun , Wu Zhongming , Wanyan Chaojie , Meng Qingzhe , Gao Wanpeng , Yang Xinjie , Wei Jianhua
Published: February 2022

Numerous studies have shown that long noncoding RNAs (LncRNAs) are involved in the development and immune escape of head and neck squamous-cell carcinoma (HNSCC). However, the specific regulatory mechanisms by which LINC01123 regulates HNSCC and its correlation with immunity remain unclear. Therefore, this study’s primary purpose was to explore the mechanisms by which LINC01123 regulates the immune escape and progression of HNSCC. This study confirmed that LINC01123 is competitively bound to miR-214-3p, and miR-214-3p specifically targets B7–H3. The effects of LINC01123, B7–H3, and miR-214-3p on tumor progression, CD8+T-cell-mediated immune response, and the tumorigenicity of HNSCC in vitro and in vivo were examined through the downregulation or upregulation of LINC01123, B7–H3, and miR-214-3p. Our results indicated that LINC01123 and B7–H3 were highly expressed in HNSCC and are associated with poor prognosis in patients. Notably, overexpression of LINC01123 or B7–H3 or downregulation of miR-214-3p inhibited the function of CD8+T cells and promoted the progression of HNSCC. Therefore, LINC01123 acts as a miR-214-3p sponge to inhibit the activation of CD8+T cells and promote the progression of HNSCC by upregulating B7–H3.
E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis
Authors: Shi Yuhua , Yang Yang , Xu Weilv , Shi Dongyun , Xu Wei , Fu Xinyu , Lv Qian , Xia Jie , Shi Fushan
Published: February 2022

Gasdermin D (GSDMD) participates in the activation of inflammasomes and pyroptosis. Meanwhile, ubiquitination strictly regulates inflammatory responses. However, how ubiquitination regulates Gasdermin D activity is not well understood. In this study, we show that pyroptosis triggered by Gasdermin D is regulated through ubiquitination. Specifically, SYVN1, an E3 ubiquitin ligase of gasdermin D, promotes GSDMD-mediated pyroptosis. SYVN1 deficiency inhibits pyroptosis and subsequent LDH release and PI uptake. SYVN1 directly interacts with GSDMD, and mediates K27-linked polyubiquitination of GSDMD on K203 and K204 residues, promoting GSDMD-induced pyroptotic cell death. Thus, our findings revealed the essential role of SYVN1 in GSDMD-mediated pyroptosis. Overall, GSDMD ubiquitination is a potential therapeutic module for inflammatory diseases.
The anthelmintic drug niclosamide induces GSK-β-mediated β-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability and suppress pancreatic cancer progression
Authors: Guo Yangyang , Zhu Hengyue , Xiao Yanyi , Guo Hangcheng , Lin Miaomiao , Yuan Ziwei , Yang Xuejia , Huang Youze , Zhang Qiyu , Bai Yongheng
Published: February 2022

Niclosamide, a cell-permeable salicylanilide, was approved by the Food and Drug Administration for its anthelmintic efficiency. A growing body of evidence in recent years suggests that niclosamide exhibits potential tumor-suppressive activity. However, the role and molecular mechanism of niclosamide in pancreatic cancer remain unclear. In this study, niclosamide inhibited proliferation of pancreatic cancer cells (PCCs), induced apoptosis via the mitochondrial-mediated pathway, and suppressed cell migration and invasion by antagonizing epithelial-to-mesenchymal transition. Also, niclosamide inhibited tumor growth and metastasis in pancreatic cancer xenograft mouse models. Mechanistically, niclosamide exerted these therapeutic effects via targeting β-catenin. Niclosamide did not reduce β-catenin mRNA expression in PCCs, but significantly downregulated its protein level. Moreover, niclosamide induced β-catenin phosphorylation and protein degradation. Interestingly, niclosamide also induced GSK-3β phosphorylation, which is involved in the ubiquitination degradation of β-catenin. Pharmacological activation of β-catenin by methyl vanillate and β-catenin overexpression abolished the inhibitory effects of niclosamide. Furthermore, niclosamide potentiated the antitumor effect of the chemotherapy drug gemcitabine and reduced the ability of cancer immune evasion by downregulating the expression levels of PD-L1, which is involved in T cell immunity. Thus, our study indicated that niclosamide induces GSK-β-mediated β-catenin degradation to potentiate gemcitabine activity, reduce immune evasion ability, and suppress pancreatic cancer progression. Niclosamide may be a potential therapeutic candidate for pancreatic cancer.
Distinct molecular phenotypes involving several human diseases are induced by IFN-λ3 and IFN-λ4 in monocyte-derived macrophages
Authors: De Manjarika , Bhushan Anand , Grubbe William S. , Roy Subhajit , Mendoza Juan L. , Chinnaswamy Sreedhar
Published: February 2022

Human Interferon (IFN) lambda 3 (IFN-λ3) and IFN-λ4 are closely linked at the IFNL locus and show association with several diseases in genetic studies. Since they are only ~30% identical to each other, to better understand their roles in disease phenotypes, comparative studies are needed. Monocytes are precursors to macrophages (monocyte-derived macrophages; MDMs) that get differentiated under the influence of various immune factors, including IFNs. In a recent study, we characterized lipopolysaccharide-activated M1 and M2-MDMs that were differentiated in presence of IFN-λ3 or IFN-λ4. In this study, we performed transcriptomics on these M1 and M2-MDMs to further understand their molecular phenotypes. We identified over 760 genes that were reciprocally regulated by IFN-λ3 and IFN-λ4, additionally we identified over 240 genes that are significantly affected by IFN-λ4 but not IFN-λ3. We observed that IFN-λ3 was more active in M2-MDMs while IFN-λ4 showed superior response in M1-MDMs. Providing a structural explanation for these functional differences, molecular modeling showed differences in expected interactions of IFN-λ3 and IFN-λ4 with the extracellular domain of IFN-λR1. Further, pathway analysis showed several human infectious diseases and even cancer-related pathways being significantly affected by IFN-λ3 and/or IFN-λ4 in both M1 and M2-MDMs.
Sculpting tissues by phase transitions
Authors: Lenne Pierre-François , Trivedi Vikas
Published: February 2022

Biological systems display a rich phenomenology of states that resemble the physical states of matter - solid, liquid and gas. These phases result from the interactions between the microscopic constituent components - the cells - that manifest in macroscopic properties such as fluidity, rigidity and resistance to changes in shape and volume. Looked at from such a perspective, phase transitions from a rigid to a flowing state or vice versa define much of what happens in many biological processes especially during early development and diseases such as cancer. Additionally, collectively moving confluent cells can also lead to kinematic phase transitions in biological systems similar to multi-particle systems where the particles can interact and show sub-populations characterised by specific velocities. In this Perspective we discuss the similarities and limitations of the analogy between biological and inert physical systems both from theoretical perspective as well as experimental evidence in biological systems. In understanding such transitions, it is crucial to acknowledge that the macroscopic properties of biological materials and their modifications result from the complex interplay between the microscopic properties of cells including growth or death, neighbour interactions and secretion of matrix, phenomena unique to biological systems. Detecting phase transitions in vivo is technically difficult. We present emerging approaches that address this challenge and may guide our understanding of the organization and macroscopic behaviour of biological tissues.
Contrasting impacts of forests on cloud cover based on satellite observations
Authors: Xu Ru , Li Yan , Teuling Adriaan J. , Zhao Lei , Spracklen Dominick V. , Garcia-Carreras Luis , Meier Ronny , Chen Liang , Zheng Youtong , Lin Huiqing , Fu Bojie
Published: February 2022

Forests play a pivotal role in regulating climate and sustaining the hydrological cycle. The biophysical impacts of forests on clouds, however, remain unclear. Here, we use satellite data to show that forests in different regions have opposite effects on summer cloud cover. We find enhanced clouds over most temperate and boreal forests but inhibited clouds over Amazon, Central Africa, and Southeast US. The spatial variation in the sign of cloud effects is driven by sensible heating, where cloud enhancement is more likely to occur over forests with larger sensible heat, and cloud inhibition over forests with smaller sensible heat. Ongoing forest cover loss has led to cloud increase over forest loss hotspots in the Amazon (+0.78%), Indonesia (+1.19%), and Southeast US (+ 0.09%), but cloud reduction in East Siberia (-0.20%) from 2002-2018. Our data-driven assessment improves mechanistic understanding of forest-cloud interactions, which remain uncertain in Earth system models.
Carbon-coated MoS1.5Te0.5 nanocables for efficient sodium-ion storage in non-aqueous dual-ion batteries
Authors: Liu Yangjie , Hu Xiang , Li Junwei , Zhong Guobao , Yuan Jun , Zhan Hongbing , Tang Yongbing , Wen Zhenhai
Published: February 2022

Sodium-based dual-ion batteries have received increased attention owing to their appealing cell voltage (i.e., >3 V) and cost-effective features. However, the development of high-performance anode materials is one of the key elements for exploiting this electrochemical energy storage system at practical levels. Here, we report a source-template synthetic strategy for fabricating a variety of nanowire-in-nanotube MSxTey@C (M = Mo, W, Re) structures with an in situ-grown carbon film coating, termed as nanocables. Among the various materials prepared, the MoS1.5Te0.5@C nanocables are investigated as negative electrode active material in combination with expanded graphite at the positive electrode and NaPF6-based non-aqueous electrolyte solutions for dual-ion storage in coin cell configuration. As a result, the dual-ion lab-scale cells demonstrate a prolonged cycling lifespan with 97% capacity retention over 1500 cycles and a reversible capacity of about 101 mAh g−1 at specific capacities (based on the mass of the anode) of 1.0 A g−1 and 5.0 A g−1, respectively.
Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice
Authors: De Logu Francesco , Nassini Romina , Hegron Alan , Landini Lorenzo , Jensen Dane D. , Latorre Rocco , Ding Julia , Marini Matilde , Souza Monteiro de Araujo Daniel , Ramírez-Garcia Paulina , Whittaker Michael , Retamal Jeffri , Titiz Mustafa , Innocenti Alessandro , Davis Thomas P. , Veldhuis Nicholas , Schmidt Brian L. , Bunnett Nigel W. , Geppetti Pierangelo
Published: February 2022

Efficacy of monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor (calcitonin receptor-like receptor/receptor activity modifying protein-1, CLR/RAMP1) implicates peripherally-released CGRP in migraine pain. However, the site and mechanism of CGRP-evoked peripheral pain remain unclear. By cell-selective RAMP1 gene deletion, we reveal that CGRP released from mouse cutaneous trigeminal fibers targets CLR/RAMP1 on surrounding Schwann cells to evoke periorbital mechanical allodynia. CLR/RAMP1 activation in human and mouse Schwann cells generates long-lasting signals from endosomes that evoke cAMP-dependent formation of NO. NO, by gating Schwann cell transient receptor potential ankyrin 1 (TRPA1), releases ROS, which in a feed-forward manner sustain allodynia via nociceptor TRPA1. When encapsulated into nanoparticles that release cargo in acidified endosomes, a CLR/RAMP1 antagonist provides superior inhibition of CGRP signaling and allodynia in mice. Our data suggest that the CGRP-mediated neuronal/Schwann cell pathway mediates allodynia associated with neurogenic inflammation, contributing to the algesic action of CGRP in mice.
Direct-laser writing for subnanometer focusing and single-molecule imaging
Authors: Coelho Simao , Baek Jongho , Walsh James , Justin Gooding J. , Gaus Katharina
Published: February 2022

Two-photon direct laser writing is an additive fabrication process that utilizes two-photon absorption of tightly focused femtosecond laser pulses to implement spatially controlled polymerization of a liquid-phase photoresist. Two-photon direct laser writing is capable of nanofabricating arbitrary three-dimensional structures with nanometer accuracy. Here, we explore direct laser writing for high-resolution optical microscopy by fabricating unique 3D optical fiducials for single-molecule tracking and 3D single-molecule localization microscopy. By having control over the position and three-dimensional architecture of the fiducials, we improve axial discrimination and demonstrate isotropic subnanometer 3D focusing (<0.8 nm) over tens of micrometers using a standard inverted microscope. We perform 3D single-molecule acquisitions over cellular volumes, unsupervised data acquisition and live-cell single-particle tracking with nanometer accuracy.
The selection force weakens with age because ageing evolves and not vice versa
Authors: Giaimo Stefano , Traulsen Arne
Published: February 2022

According to the classic theory of life history evolution, ageing evolves because selection on traits necessarily weakens throughout reproductive life. But this inexorable decline of the selection force with adult age was shown to crucially depend on specific assumptions that are not necessarily fulfilled. Whether ageing still evolves upon their relaxation remains an open problem. Here, we propose a fully dynamical model of life history evolution that does not presuppose any specific pattern the force of selection should follow. The model shows: (i) ageing can stably evolve, but negative ageing cannot; (ii) when ageing is a stable equilibrium, the associated selection force decreases with reproductive age; (iii) non-decreasing selection is either a transient or an unstable phenomenon. Thus, we generalize the classic theory of the evolution of ageing while overturning its logic: the decline of selection with age evolves dynamically, and is not an implicit consequence of certain assumptions.
Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis
Authors: Lionaki Eirini , Gkikas Ilias , Daskalaki Ioanna , Ioannidi Maria-Konstantina , Klapa Maria I. , Tavernarakis Nektarios
Published: February 2022

Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.
Inferring protein expression changes from mRNA in Alzheimer’s dementia using deep neural networks
Authors: Tasaki Shinya , Xu Jishu , Avey Denis R. , Johnson Lynnaun , Petyuk Vladislav A. , Dawe Robert J. , Bennett David A. , Wang Yanling , Gaiteri Chris
Published: February 2022

Identifying the molecular systems and proteins that modify the progression of Alzheimer’s disease and related dementias (ADRD) is central to drug target selection. However, discordance between mRNA and protein abundance, and the scarcity of proteomic data, has limited our ability to advance candidate targets that are mainly based on gene expression. Therefore, by using a deep neural network that predicts protein abundance from mRNA expression, here we attempt to track the early protein drivers of ADRD. Specifically, by applying the clei2block deep learning model to 1192 brain RNA-seq samples, we identify protein modules and disease-associated expression changes that were not directly observed at the mRNA level. Moreover, pseudo-temporal trajectory inference based on the predicted proteome became more closely correlated with cognitive decline and hippocampal atrophy compared to RNA-based trajectories. This suggests that the predicted changes in protein expression could provide a better molecular representation of ADRD progression. Furthermore, overlaying clinical traits on protein pseudotime trajectory identifies protein modules altered before cognitive impairment. These results demonstrate how our method can be used to identify potential early protein drivers and possible drug targets for treating and/or preventing ADRD.
Ligand relay catalysis for cobalt-catalyzed sequential hydrosilylation and hydrohydrazidation of terminal alkynes
Authors: Sun Yufeng , Guo Jun , Shen Xuzhong , Lu Zhan
Published: February 2022

Sequential double hydrofunctionalizationalization of alkynes is a powerful method to construct useful vicinal compounds. Herein, we report a cobalt-catalyzed sequential hydrosilylation/hydrohydrazidation of alkynes to afford 1,2-N,Si compounds via ligand relay catalysis. A phenomenon of ligand relay is found that the tridentate anionic N-ligand (OPAQ) could capture the cobalt ion from bidentate neutral P-ligand (Xantphos) cobalt complex. This protocol uses three abundant chemical feedstocks, alkynes, silanes, and diazo compounds, and also features operationally simple, mild conditions, low catalyst loading (1 mol%), and excellent functional group tolerance. The 1,2-N,Si compounds can be easily further derivatized to afford various substituted silane derivatives via Si-H functionalization, alcohols via Fleming-Tamao oxidation, free amines and amides via N-N bond cleavage and protection. The asymmetric reaction could also be carried out to afford chiral products with up to 86% ee. The ligand relay has been supported by control experiments and absorption spectra.
Gαi2-induced conductin/axin2 condensates inhibit Wnt/β-catenin signaling and suppress cancer growth
Authors: Miete Cezanne , Solis Gonzalo P. , Koval Alexey , Brückner Martina , Katanaev Vladimir L. , Behrens Jürgen , Bernkopf Dominic B.
Published: February 2022

Conductin/axin2 is a scaffold protein negatively regulating the pro-proliferative Wnt/β-catenin signaling pathway. Accumulation of scaffold proteins in condensates frequently increases their activity, but whether condensation contributes to Wnt pathway inhibition by conductin remains unclear. Here, we show that the Gαi2 subunit of trimeric G-proteins induces conductin condensation by targeting a polymerization-inhibiting aggregon in its RGS domain, thereby promoting conductin-mediated β-catenin degradation. Consistently, transient Gαi2 expression inhibited, whereas knockdown activated Wnt signaling via conductin. Colorectal cancers appear to evade Gαi2-induced Wnt pathway suppression by decreased Gαi2 expression and inactivating mutations, associated with shorter patient survival. Notably, the Gαi2-activating drug guanabenz inhibited Wnt signaling via conductin, consequently reducing colorectal cancer growth in vitro and in mouse models. In summary, we demonstrate Wnt pathway inhibition via Gαi2-triggered conductin condensation, suggesting a tumor suppressor function for Gαi2 in colorectal cancer, and pointing to the FDA-approved drug guanabenz for targeted cancer therapy.
Characterising within-hospital SARS-CoV-2 transmission events using epidemiological and viral genomic data across two pandemic waves
Authors: Lindsey Benjamin B. , Villabona-Arenas Ch. Julián , Campbell Finlay , Keeley Alexander J. , Parker Matthew D. , Shah Dhruv R. , Parsons Helena , Zhang Peijun , Kakkar Nishchay , Gallis Marta , Foulkes Benjamin H. , Wolverson Paige , Louka Stavroula F. , Christou Stella , State Amy , Johnson Katie , Raza Mohammad , Hsu Sharon , Jombart Thibaut , Cori Anne ,   Sheffield COVID-19 Genomics Group, Shah Dhruv R. , Johnson Katie , Hsu Sharon , de Silva Thushan I. , Cope Alison , Ali Nasar , Raghei Rasha , Heffer Joe , Smith Nikki , Whiteley Max , Pohare Manoj , Hansford Samantha E. , Green Luke R. , Wang Dennis , Anckorn Michael , Angyal Adrienn , Brown Rebecca , Hornsby Hailey , Yavuz Mehmet , Groves Danielle C. , Parsons Paul J. , Tucker Rachel M. , Dabrowska Magdalena B. , Saville Thomas , Schutter Jose , Wyles Matthew D. ,   The COVID-19 Genomics UK (COG-UK) consortium, Evans Cariad ,   CMMID COVID-19 working group, Davies Nicholas G. , Pearson Carl A. B. , Quaife Matthew , Tully Damien C. , Abbott Sam , Evans Cariad M. , Partridge David G. , Atkins Katherine E. , Hué Stéphane , de Silva Thushan I.
Published: February 2022

Hospital outbreaks of COVID19 result in considerable mortality and disruption to healthcare services and yet little is known about transmission within this setting. We characterise within hospital transmission by combining viral genomic and epidemiological data using Bayesian modelling amongst 2181 patients and healthcare workers from a large UK NHS Trust. Transmission events were compared between Wave 1 (1st March to 25th July 2020) and Wave 2 (30th November 2020 to 24th January 2021). We show that staff-to-staff transmissions reduced from 31.6% to 12.9% of all infections. Patient-to-patient transmissions increased from 27.1% to 52.1%. 40%-50% of hospital-onset patient cases resulted in onward transmission compared to 4% of community-acquired cases. Control measures introduced during the pandemic likely reduced transmissions between healthcare workers but were insufficient to prevent increasing numbers of patient-to-patient transmissions. As hospital-acquired cases drive most onward transmission, earlier identification of nosocomial cases will be required to break hospital transmission chains.
Endothelial cell-specific expression of serine/threonine kinase 11 modulates dendritic cell differentiation
Authors: Zhao Qiang , Han Young-Min , Song Ping , Liu Zhixue , Yuan Zuyi , Zou Ming-Hui
Published: February 2022

In the bone marrow, classical and plasmacytoid dendritic cells (DC) develop from the macrophage-DC precursor (MDP) through a common DC precursor (CDP) step. This developmental process receives essential input from the niche in which it takes place, containing endothelial cells (EC) among other cell types. Here we show that targeted deletion of serine/threonine kinase 11 (Stk11) encoding tumor suppressor liver kinase b1 (Lkb1) in mouse ECs but not DCs, results in disrupted differentiation of MDPs to CDPs, severe reduction in mature DC numbers and spontaneous tumorigenesis. In wild type ECs, Lkb1 phosphorylates polypyrimidine tract binding protein 1 (Ptbp1) at threonine 138, which regulates stem cell factor (Scf) pre-mRNA splicing. In the absence of Lkb1, exon 6 of Scf is spliced out, leading to the loss of Scf secretion. Adeno-associated-virus-mediated delivery of genes encoding either soluble Scf or the phosphomimetic mutant Ptbp1T138E proteins rescued the defects of MDP to CDP differentiation and DC shortage in the endothelium specific Stk11 knockout mice. In summary, endothelial Stk11 expression regulates DC differentiation via modulation of Scf splicing, marking the Stk11-soluble-Scf axis as a potential cause of DC deficiency syndromes.
Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis
Authors: Yan Yiwu , Zhou Bo , Qian Chen , Vasquez Alex , Kamra Mohini , Chatterjee Avradip , Lee Yeon-Joo , Yuan Xiaopu , Ellis Leigh , Di Vizio Dolores , Posadas Edwin M. , Kyprianou Natasha , Knudsen Beatrice S. , Shah Kavita , Murali Ramachandran , Gertych Arkadiusz , You Sungyong , Freeman Michael R. , Yang Wei
Published: February 2022

Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality from PC. Thus, there is growing recognition that preventing or delaying PC metastasis holds great potential for substantially improving patient outcomes. Here we show receptor-interacting protein kinase 2 (RIPK2) is a clinically actionable target for inhibiting PC metastasis. RIPK2 is amplified/gained in ~65% of lethal metastatic castration-resistant PC. Its overexpression is associated with disease progression and poor prognosis, and its genetic knockout substantially reduces PC metastasis. Multi-level proteomics analyses reveal that RIPK2 strongly regulates the stability and activity of c-Myc (a driver of metastasis), largely via binding to and activating mitogen-activated protein kinase kinase 7 (MKK7), which we identify as a direct c-Myc-S62 kinase. RIPK2 inhibition by preclinical and clinical drugs inactivates the noncanonical RIPK2/MKK7/c-Myc pathway and effectively impairs PC metastatic outgrowth. These results support targeting RIPK2 signaling to extend metastasis-free and overall survival.
A role for ColV plasmids in the evolution of pathogenic Escherichia coli ST58
Authors: Reid Cameron J. , Cummins Max L. , Börjesson Stefan , Brouwer Michael S. M. , Hasman Henrik , Hammerum Anette M. , Roer Louise , Hess Stefanie , Berendonk Thomas , Nešporová Kristina , Haenni Marisa , Madec Jean-Yves , Bethe Astrid , Michael Geovana B. , Schink Anne-Kathrin , Schwarz Stefan , Dolejska Monika , Djordjevic Steven P.
Published: February 2022

Escherichia coli ST58 has recently emerged as a globally disseminated uropathogen that often progresses to sepsis. Unlike most pandemic extra-intestinal pathogenic E. coli (ExPEC), which belong to pathogenic phylogroup B2, ST58 belongs to the environmental/commensal phylogroup B1. Here, we present a pan-genomic analysis of a global collection of 752 ST58 isolates from diverse sources. We identify a large ST58 sub-lineage characterized by near ubiquitous carriage of ColV plasmids, which carry genes encoding virulence factors, and by a distinct accessory genome including genes typical of the Yersiniabactin High Pathogenicity Island. This sub-lineage includes three-quarters of all ExPEC sequences in our study and has a broad host range, although poultry and porcine sources predominate. By contrast, strains isolated from cattle often lack ColV plasmids. Our data indicate that ColV plasmid acquisition contributed to the divergence of the major ST58 sub-lineage, and different sub-lineages inhabit poultry, swine and cattle.
Manipulating the oxygen reduction reaction pathway on Pt-coordinated motifs
Authors: Zhao Jiajun , Fu Cehuang , Ye Ke , Liang Zheng , Jiang Fangling , Shen Shuiyun , Zhao Xiaoran , Ma Lu , Shadike Zulipiya , Wang Xiaoming , Zhang Junliang , Jiang Kun
Published: February 2022

Electrochemical oxygen reduction could proceed via either 4e−-pathway toward maximum chemical-to-electric energy conversion or 2e−-pathway toward onsite H2O2 production. Bulk Pt catalysts are known as the best monometallic materials catalyzing O2-to-H2O conversion, however, controversies on the reduction product selectivity are noted for atomic dispersed Pt catalysts. Here, we prepare a series of carbon supported Pt single atom catalyst with varied neighboring dopants and Pt site densities to investigate the local coordination environment effect on branching oxygen reduction pathway. Manipulation of 2e− or 4e− reduction pathways is demonstrated through modification of the Pt coordination environment from Pt-C to Pt-N-C and Pt-S-C, giving rise to a controlled H2O2 selectivity from 23.3% to 81.4% and a turnover frequency ratio of H2O2/H2O from 0.30 to 2.67 at 0.4 V versus reversible hydrogen electrode. Energetic analysis suggests both 2e− and 4e− pathways share a common intermediate of *OOH, Pt-C motif favors its dissociative reduction while Pt-S and Pt-N motifs prefer its direct protonation into H2O2. By taking the Pt-N-C catalyst as a stereotype, we further demonstrate that the maximum H2O2 selectivity can be manipulated from 70 to 20% with increasing Pt site density, providing hints for regulating the stepwise oxygen reduction in different application scenarios.