A Novel Method for Automatic Detection and Elimination of the Jumps Caused by the Instantaneous Disturbance Torque in the Maglev Gyro Signal

Yiwen Wang, Zhiqiang Yang, Ji Ma, Zhen Shi, Di Liu, Ling Shi, Hang Li

School of Geology Engineering and Geomatics, Chang’an University, 126 Yanta Road, Xi’an 710054, China

National Natural Science Foundation of China, Natural Science Basic Research Program of Shaanxi, Fundamental Research Funds for the Central Universities, CHD, Key Laboratory of Geospace Environment and Geodesy, Ministry of Education, Wuhan University, Guangxi Young and Middle-aged Teachers’ Basic Scientific Research Ability Improvement Project, Natural Science Foundation of Guangxi

Abstract: The signal measured by the maglev gyro sensor is sensitive to the influence of the instantaneous disturbance torque caused by the instantaneous strong wind or the ground vibration, which reduced the north-seeking accuracy of the instrument. To address this issue, we proposed a novel method combining the heuristic segmentation algorithm (HSA) and the two-sample Kolmogorov-Smirnov (KS) test (named HSA-KS method) to process the gyro signals and improve the north-seeking accuracy of the gyro. There were two key steps in the HSA-KS method: (i) all the potential change points were automatically and accurately detected by HSA, and (ii) the jumps in the signal caused by the instantaneous disturbance torque were quickly located and eliminated by the two-sample KS test. The effectiveness of our method was verified through a field experiment on a high-precision global positioning system (GPS) baseline at the 5th sub-tunnel of the Qinling water conveyance tunnel of the Hanjiang-to-Weihe River Diversion Project in Shaanxi Province, China. Our results from the autocorrelograms indicated that the jumps in the gyro signals can be automatically and accurately eliminated by the HSA-KS method. After processing, the absolute difference between the gyro and high-precision GPS north azimuths was enhanced by 53.5%, which was superior to the optimized wavelet transform and the optimized Hilbert-Huang transform.


Joint Video Super-Resolution and Frame Interpolation via Permutation Invariance

Department of Electrical Engineering, KAIST, Daejeon 34141, Republic of Korea

National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT), Institute of Information & communications Technology Planning & Evaluation (IITP) grant funded by the Korea government (MSIT), National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT)

Abstract: We propose a joint super resolution (SR) and frame interpolation framework that can perform both spatial and temporal super resolution. We identify performance variation according to permutation of inputs in video super-resolution and video frame interpolation. We postulate that favorable features extracted from multiple frames should be consistent regardless of input order if the features are optimally complementary for respective frames. With this motivation, we propose a permutation invariant deep architecture that makes use of the multi-frame SR principles by virtue of our order (permutation) invariant network. Specifically, given two adjacent frames, our model employs a permutation invariant convolutional neural network module to extract “complementary” feature representations facilitating both the SR and temporal interpolation tasks. We demonstrate the effectiveness of our end-to-end joint method against various combinations of the competing SR and frame interpolation methods on challenging video datasets, and thereby we verify our hypothesis.


Editorial for the Special Issue on Electronics for Sensors II

Giuseppe Ferri, Gianluca Barile, Alfiero Leoni

Department of Industrial and Information Engineering and Economics, University of L’Aquila, 67100 L’Aquila, Italy

Abstract: Sensor signals are physical, chemical, or biological quantities that evolve over time [...]


Erratum: Han, D.-H.; Kang, L.-H. Terahertz Displacement and Thickness Sensor with Micrometer Resolution and Centimeter Dynamic Range

Department of Mechatronics Engineering, and LANL-JBNU Engineering Institute-Korea, Jeonbuk National University, 567 Baekje-daero, Duckjin-gu, Jeonju-si, Jeonbuk 54896, Korea

Abstract: The authors wish to make the following erratum to this paper [...]


Tracking Control of a Magnetic Shape Memory Actuator Using an Inverse Preisach Model with Modified Fuzzy Sliding Mode Control

Department of Engineering Science and Ocean Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 106, Taiwan

Ministry of Science and Technology, Taiwan

Abstract: Magnetic shape memory (MSM) alloys are a new class of smart materials with extraordinary strains up to 12% and frequencies in the range of 1 to 2 kHz. The MSM actuator is a potential device which can achieve high performance electromagnetic actuation by using the properties of MSM alloys. However, significant non-linear hysteresis behavior is a significant barrier to control the MSM actuator. In this paper, the Preisach model was used, by capturing experiments from different input signals and output responses, to model the hysteresis of MSM actuator, and the inverse Preisach model, as a feedforward control, provided compensational signals to the MSM actuator to linearize the hysteresis non-linearity. The control strategy for path tracking combined the hysteresis compensator and the modified fuzzy sliding mode control (MFSMC) which served as a path controller. Based on the experimental results, it was verified that a tracking error in the order of micrometers was achieved.


Coded Cooperation for Multiway Relaying in Wireless Sensor Networks

Zhongwei Si, Junyang Ma, Ragnar Thobaben

Key Lab of Universal Wireless Communications, Ministry of Education, Beijing University of Posts and Telecommunications (BUPT), 100876 Beijing, China

Abstract: Wireless sensor networks have been considered as an enabling technology for constructing smart cities. One important feature of wireless sensor networks is that the sensor nodes collaborate in some manner for communications. In this manuscript, we focus on the model of multiway relaying with full data exchange where each user wants to transmit and receive data to and from all other users in the network. We derive the capacity region for this specific model and propose a coding strategy through coset encoding. To obtain good performance with practical codes, we choose spatially-coupled LDPC (SC-LDPC) codes for the coded cooperation. In particular, for the message broadcasting from the relay, we construct multi-edge-type (MET) SC-LDPC codes by repeatedly applying coset encoding. Due to the capacity-achieving property of the SC-LDPC codes, we prove that the capacity region can theoretically be achieved by the proposed MET SC-LDPC codes. Numerical results with finite node degrees are provided, which show that the achievable rates approach the boundary of the capacity region in both binary erasure channels and additive white Gaussian channels.


Systematic Analysis of Randomization-based Protected Cache Architectures

2021 IEEE Symposium on Security and Privacy (SP)

Antoon Purnal, Lukas Giner, Daniel Gruss, Ingrid Verbauwhede


Stronger bounds for weak epsilon-nets in higher dimensions

Proceedings of the 53rd Annual ACM SIGACT Symposium on Theory of Computing

Ben-Gurion University of the Negev, Israel


The critical O(N) CFT: Methods and conformal data

European Research Council, European Research Council, Horizon 2020 Framework Programme, Horizon 2020


Turbulent shear flow without vortex shedding, Reynolds shear stress and small-scale intermittency

K. Steiros, M. Obligado, P. Bragança, C. Cuvier, J.C. Vassilicos

Abstract: This work presents an experimental investigation of the effects of vortex shedding suppression on the properties and recovery of turbulent wakes. Four plates, properly modified so that they produce different vortex shedding strengths, are tested using high speed particle image velocimetry and hot-wire anemometry, and analysed using spectral proper orthogonal decomposition, mean-flow linear stability analysis and various turbulence statistics. When present, vortex shedding is found to exhibit a characteristic frequency that scales with the mean shear, providing a link between the mean flow and the main turbulent motion. To achieve full suppression of shedding, we combine the effects of porosity and fractal perimeter. The mean shear is then decreased to the point where the flow becomes convectively unstable and shedding vanishes. In that case, the onset of self-similarity is delayed, compared with the case with vortex shedding, and appears after another large-scale structure, the secondary vortex street, emerges. It is also found that both large- and small-scale intermittency are starkly reduced when shedding is absent. A simple theoretical representation of the wake dynamics explains the evolution of the wake properties and its connection to the coherent structures in the flow.


Evolution of Multicellular Complexity in The Dictyostelid Social Amoebas

School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK

European Research Council, Wellcome Trust, European Molecular Biology Organization, Japanese Organisation for the Promotion of Science

Abstract: Multicellularity evolved repeatedly in the history of life, but how it unfolded varies greatly between different lineages. Dictyostelid social amoebas offer a good system to study the evolution of multicellular complexity, with a well-resolved phylogeny and molecular genetic tools being available. We compare the life cycles of the Dictyostelids with closely related amoebozoans to show that complex life cycles were already present in the unicellular common ancestor of Dictyostelids. We propose frost resistance as an early driver of multicellular evolution in Dictyostelids and show that the cell signalling pathways for differentiating spore and stalk cells evolved from that for encystation. The stalk cell differentiation program was further modified, possibly through gene duplication, to evolve a new cell type, cup cells, in Group 4 Dictyostelids. Studies in various multicellular organisms, including Dictyostelids, volvocine algae, and metazoans, suggest as a common principle in the evolution of multicellular complexity that unicellular regulatory programs for adapting to environmental change serve as “proto-cell types” for subsequent evolution of multicellular organisms. Later, new cell types could further evolve by duplicating and diversifying the “proto-cell type” gene regulatory networks.


X-SSD: A Storage System with Native Support for Database Logging and Replication

Proceedings of the 2022 International Conference on Management of Data

Sangjin Lee, Alberto Lerner, André Ryser, Kibin Park, Chanyoung Jeon, Jinsub Park, Yong Ho Song, Philippe Cudré-Mauroux

Hanyang University, Seoul, Republic of Korea


Disrupting Epileptiform Activity by Preventing Parvalbumin Interneuron Depolarization Block

Alexandru Călin, Andrei S. Ilie, Colin J. Akerman

Wellcome Trust, EC | European Research Council, EC | European Research Council, University College Oxford

Abstract: Inhibitory synaptic mechanisms oppose epileptic network activity in the brain. The breakdown in this inhibitory restraint and propagation of seizure activity has been linked to the overwhelming of feedforward inhibition, which is provided in large part by parvalbumin-expressing (PV) interneurons in the cortex. The underlying cellular processes therefore represent potential targets for understanding and preventing the propagation of seizure activity. Here we use an optogenetic strategy to test the hypothesis that depolarization block in PV interneurons is a significant factor during the loss of inhibitory restraint. Depolarization block results from the inactivation of voltage-gated sodium channels and leads to impaired action potential firing. We used focal NMDA stimulation to elicit reproducible epileptiform discharges in hippocampal organotypic brain slices from male and female mice and combined this with targeted recordings from defined neuronal populations. Simultaneous patch-clamp recordings from PV interneurons and pyramidal neurons revealed epileptiform activity that was associated with an overwhelming of inhibitory synaptic mechanisms and the emergence of a partial, and then complete, depolarization block in PV interneurons. To counteract this depolarization block, we developed protocols for eliciting pulsed membrane hyperpolarization via the inhibitory opsin, archaerhodopsin. This optical approach was effective in counteracting cumulative inactivation of voltage-gated channels, maintaining PV interneuron action potential firing properties during the inhibitory restraint period, and reducing the probability of initiating epileptiform activity. These experiments support the idea that depolarization block is a point of weakness in feedforward inhibitory synaptic mechanisms and represents a target for preventing the initiation and spread of seizure activity.SIGNIFICANCE STATEMENTGABAAreceptor-mediated synaptic transmission opposes seizure activity by establishing an inhibitory restraint against spreading excitation. Parvalbumin-expressing (PV) interneurons contribute significantly to this inhibitory restraint, but it has been suggested that these cells are overwhelmed as they enter a state of “depolarization block.” Here we test the importance of this process by devising an optogenetic strategy to selectively relieve depolarization block in PV interneurons. By inducing brief membrane hyperpolarization, we show that it is possible to reduce depolarization block in PV interneurons, maintain their action potential firing in the face of strong excitation, and disrupt epileptiform activity in anin vitromodel. This represents a proof of principle that targeting rate-limiting processes can strengthen the inhibitory restraint of epileptiform activity.


Effect of AZD4017, a Selective 11β-HSD1 Inhibitor, on Bone Turnover Markers in Postmenopausal Osteopenia

The Journal of Clinical Endocrinology & Metabolism

Afroze Abbas, Marian Schini, Gemma Ainsworth, Sarah R Brown, Jamie Oughton, Rachel K Crowley, Mark S Cooper, Rebecca J Fairclough, Richard Eastell, Paul M Stewart

Faculty of Medicine and Health, University of Leeds, and Leeds Teaching Hospitals NHS Trust , Leeds LS9 7TF , UK

Medical Research Council, European Research Council, NIHR, NIHR

Abstract: Abstract Context The causative link between circulating glucocorticoid excess and osteoporosis is well-established. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which increases local cortisol production, is expressed in human osteoblasts and its activity increases with age. Objective We hypothesized that local 11β-HSD1 might mediate an age-related decrease in bone formation and that selective 11β-HSD1 inhibition may enhance bone formation. Methods A dual-center, phase II, randomized, double-blind, placebo-controlled trial of 90 days’ treatment with AZD4017 (a selective 11β-HSD1 inhibitor) was conducted in 55 postmenopausal women with osteopenia. Participants received 400 mg oral AZD4017 twice daily vs matched placebo over 90 days. The primary outcome measure was the impact on the bone formation marker osteocalcin. Secondary objectives included correlation with 11β-HSD1 activity. Results At 90 days, osteocalcin levels did not differ between treatment groups: active (mean 22.3 [SD 8.6] ng/mL, n = 22) and placebo (21.7 [SD 9.2] ng/mL, n = 24), with a baseline-adjusted treatment effect of 0.95 (95% CI: −2.69, 4.60). The results from the urinary [THF + alloTHF]/THE ratio (index of 11β-HSD1 activity) and the urinary cortisol/cortisone ratio (index of 11β-HSD2 activity) confirmed a &gt; 90% inhibition of 11β-HSD1 but no change in activity of 11β-HSD2. Conclusion This trial demonstrates that AZD4017 selectively inhibits 11β-HSD1 activity in vivo in a safe and reversible manner. Following 90 days of treatment, there is no effect on bone formation, indicating that the relative impairment of bone mineral density in postmenopausal women is not mediated by local intracellular production of cortisol under normal physiological concentrations.


The protein kinases of Dictyostelia and their incorporation into a signalome

Koryu Kin, Zhi-hui Chen, Gillian Forbes, Hajara Lawal, Christina Schilde, Reema Singh, Christian Cole, Geoffrey J. Barton, Pauline Schaap

European Molecular Biology Organization, Wellcome Trust, Wellcome Trust, European Research Council, Biotechnology and Biological Sciences Research Council, Japan Society for the Promotion of Science London, European Research Council


Soil microbial carbon consumption is affected by tree and mammal diversity

María LOSADA, Mar SOBRAL, Antonio M. MARTÍNEZ CORTIZAS, Carlos E.P. CERRI, Kristen M. DEANGELIS, Sara VARELA, José M.V. FRAGOSO, Kirsten M. SILVIUS

Xunta de Galicia, Xunta de Galicia, Xunta de Galicia, European Research Council, Gordon and Betty Moore Foundation, National Science Foundation, Stanford University, Universidade de Santiago de Compostela


Chaos, coherence, and turbulence

Abstract: This paper is a personal overview of the efforts over the past half century to understand fluid turbulence in terms of simpler coherent units. The consequences of chaos and the concept of coherence are first reviewed, using examples from free-shear and wall-bounded shear flows, and including how the simplifications due to coherent structures have been useful in the conceptualization and control of turbulence. It is remarked that, even if this approach has revolutionized our understanding of the flow, most of turbulence cannot yet be described by structures. This includes cascades, both direct and inverse, and possibly junk turbulence, whose role, if any, is currently unknown. This part of the paper is mostly a catalog of questions, some of them answered and others still open. A second part of the paper examines which new techniques can be expected to help in attacking the open questions and which, in the opinion of the author, are the strengths and limitations of current approaches, such as data-driven science and causal inference.


The chemical interaction between plants and the rhizosphere microbiome

Harro Bouwmeester, Lemeng Dong, Kathrin Wippel, Twan Hofland, Age Smilde

Deutsche Forschungsgemeinschaft, Deutsche Forschungsgemeinschaft, Technology Foundation STW, HORIZON EUROPE European Research Council, European Research Council, University of Amsterdam, EU Framework Programme for Research and Innovation Marie Skłodowska-Curie Actions, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Toegepaste en Technische Wetenschappen, NWO, European Research Council


Monitoring mitochondrial translation in living cells

Roya Yousefi, Eugenio F Fornasiero, Lukas Cyganek, Julio Montoya, Stefan Jakobs, Silvio O Rizzoli, Peter Rehling, David Pacheu-Grau

European Research Council, European Research Council, Sonderforschungsbereiche, Sonderforschungsbereiche, Deutsche Forschungsgemeinschaft, Deutsche Forschungsgemeinschaft, Germany’s Excellence Strategy, German Federal Ministry of Education and Research (BMBF)/DZHK, Instituto de Salud Carlos III, Max Planck Institute for Biophysical Chemistry


Morphological transitions of flexible fibers in viscous flows

Institut Pierre-Gilles de Gennes, European Research Council, Tulane University


Bridging the gap: When transcription meets translation

Department of Integrated Structural Biology Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC)  Illkirch France

European Research Council, Fondation pour la Recherche Médicale, Agence Nationale de la Recherche, Agence Nationale de la Recherche, Agence Nationale de la Recherche, Agence Nationale de la Recherche

Abstract: Recruitment of the small ribosomal subunit (30S) to messenger RNA (mRNA) marks a key step in bacterial translation initiation. Recruitment begins with a 30S standby site binding single‐stranded mRNA regions at or near the translation initiation region (TIR). Subsequently, the mRNA is accommodated into the 30S mRNA binding channel to initiate translation. An essential part of accommodation is the recognition and proper positioning of the start codon to establish the correct reading frame. This is often facilitated by the Shine–Dalgarno (SD) sequence. Recent structural and biochemical studies provided snapshots of the first steps of 30S recruitment to a nascent mRNA preceding accommodation, which likely reflect similar events for fully transcribed mRNAs. These studies suggest that a transcribing RNA polymerase (RNAP) promotes 30S recruitment to the nascent mRNA via two distinct pathways. In one, RNAP cooperates with ribosomal protein bS1, which captures the mRNA and channels it toward the anti‐Shine–Dalgarno (aSD) sequence for base pairing. In the other, direct coupling between RNAP and the 30S, mediated by transcription factor NusG, facilitates an alternative mRNA delivery pathway. We explore the current understanding of mRNA delivery, highlighting different modes of 30S recruitment to the nascent mRNA, the role of bS1, and how this leads to the establishment of transcription–translation coupling.


Reconstruction of Residential Land Cover and Spatial Analysis of Population in Bursa Region (Turkey) in the Mid-Nineteenth Century

College of Social Sciences and Humanities, Koc University, Istanbul 34450, Turkey

Abstract: The historic reconstruction of residential land cover is of significance to uncover the human-environment relationship and its changing dynamics. Taking into account the historical census data and cadastral maps of seven villages, this study generated residential land cover maps for the Bursa Region in the 1850s using a model based on natural constraints, land zoning, socio-economic factors and residential suitability. Two different historical reconstructions were generated; one based on a high density residential model and another based on a low density model. The simulated landcover information was used as an ancillary data to redistribute aggregated census counts to fine scale raster cells. Two different statistical models were developed; one based on probability maps and the other applying regression models including Ordinary Least Squares (OLS) and Geographically Weighted Regression (GWR) models. The regression models were validated with historical census data of the 1840s. From regression models, socio-economic and physical characteristics, accessibility and natural amenities showed significant impacts on the distribution of population. Model validation analysis revealed that GWR is more accurate than OLS models. The generated residential land cover and gridded population datasets can provide a basis for the historical study of population and land use.


Nanotechnology‐Based Strategies to Evaluate and Counteract Cancer Metastasis and Neoangiogenesis

Istituto Italiano di Tecnologia Smart Bio‐Interfaces  Viale Rinaldo Piaggio 34 Pontedera Pisa 56025 Italy

Abstract: AbstractCancer metastasis is the major cause of cancer‐related morbidity and mortality. It represents one of the greatest challenges in cancer therapy, both because of the ability of metastatic cells to spread into different organs, and because of the consequent heterogeneity that characterizes primary and metastatic tumors. Nanomaterials can potentially be used as targeting or detection agents owing to unique chemical and physical features that allow tailored and tunable theranostic functions. This review highlights nanomaterial‐based approaches in the detection and treatment of cancer metastasis, with a special focus on the evaluation of nanostructure effects on cell migration, invasion, and angiogenesis in the tumor microenvironment.


Role of fluorocarbons in PUR foams: a cryo-SEM study

Martin Hamann, Alain Carvalho, Marc Schmutz, Luca Fiorucci, Daniel Telkemeyer, Markus Schütte, Wiebke Drenckhan-Andreatta

European Research Council, European Research Council, European Research Council, European Research Council, European Research Council, Agence Nationale de la Recherche, Agence Nationale de la Recherche, Agence Nationale de la Recherche, Agence Nationale de la Recherche, Agence Nationale de la Recherche, BASF


Incomplete lytic cycle of a widespread Bacteroides bacteriophage leads to the formation of defective viral particles

Sol Vendrell-Fernández, Beatriz Beamud, Yasmina Abou Haydar, Jorge Am de Sousa, Julien Burlaud-Gaillard, Etienne Kornobis, Bertrand Raynal, Joelle Vinh, David Bikard, Jean-Marc Ghigo

Agence Nationale de la Recherche, Agence Nationale de la Recherche, Agence Nationale de la Recherche, Agence Nationale de la Recherche, Agence Nationale de la Recherche, European Research Council, Agence Nationale de la Recherche

Abstract: Advances in metagenomics have led to the identification of new intestinal temperate bacteriophages. However, their experimental characterization remains challenging due to a limited understanding of their lysogenic-lytic cycle and the common lack of plaque formation in vitro. In this study, we investigated the hankyphage, a widespread transposable phage of prominent Bacteroides symbionts. Hankyphages spontaneously produced virions in laboratory conditions even in the absence of inducer, but virions did not show any evidence of infectivity. To increase virion production and raise the chances of observing infection events, we identified a master repressor of the hankyphage lytic cycle, RepC HP , whose silencing amplified hankyphage gene expression, and enhanced replicative transposition and virion production. However, attempts to infect or lysogenize new host cells with different capsular types remained unsuccessful. Transmission electron microscopy and capsid DNA sequencing revealed an abnormal virion morphology and incomplete DNA packaging of the hankyphage, suggesting that it cannot complete its assembly in laboratory conditions for reasons that are yet to be identified. Still, metavirome and phylogenetic analyses were suggestive of hankyphage horizontal transmission. We could also detect the activity of diversity-generating retroelements (DGRs) that mutagenize the hankyphage tail fiber, and likely contribute to its broad host range. This study sheds light on the life cycle of this abundant intestinal bacteriophage and highlights important gaps in our understanding of the factors required for the completion of its life cycle. Elucidating this puzzle will be critical to gain a better understanding of the hankyphage biology and ecological role.


Generation of a Biotin-Tagged Dual-Display Phage

Laura Maria De Plano, Salvatore Oddo, David Bikard, Antonella Caccamo, Sabrina Conoci

Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy

European Union’s Horizon Europe EICPathfinder Open Programme “ECLIPSE project”, European Research Council, Agence Nationale de la Recherche

Abstract: Phage display is widely used in biomedical research. One of the great advantages of phage display is the specificity of the connection of a foreign peptide exposed outside the capsid to the intended target. Secondary detection systems, which are often laborious and costly, are required to identify and quantify the peptide/target interaction. In this study, we generated a novel dual-display phage to facilitate the detection and quantification of the peptide/target interaction. First, we generated a biotin-tagged phage by adding a small biotin-accepting peptide (sBT) to gene-3 of the M13K07 helper phage. Subsequently, we enhanced the M13K07 biotin-tagged phage by incorporating a selective peptide on gene-8, which is then exposed to the phage capsid. The exposed peptide acts as a probe to bind to a selective molecular target, whose interaction can be readily visualized thanks to the biotinylated phage. Our versatile dual-display phage exhibits high flexibility; by swapping the displayed peptide/probe, one can change the phage target while retaining the sBT gene in-frame with the pIII. We expect the generated biotin-tagged dual phages to be used as a multifunctional probe to couple with several streptavidin-biotin-based systems.


Codifying and Commodifying Nature: Narratives on Forest Property Rights and the Implementation of Tenure Regularization Policies in Northwestern Argentina

Carla Inguaggiato, Michele Graziano Ceddia, Maurice Tschopp, Dimitris Christopoulos

Centre for Development and Environment (CDE), University of Bern, 3012 Bern, Switzerland

Abstract: Environmental resource management requires negotiation among state and non-state actors with conflicting goals and different levels of influence. In northwestern Argentina, forest policy implementation is described as weak, due to governance structure and ambiguities in the law. We studied how policy actors’ attitudes and their positions in the forest governance network relate to the implementation of land tenure regularization in a context where land tenure regularization is at the core of struggles over environmental policies. We focused on the Chaco Salteño part of the Gran Chaco ecosystem, one of the world’s major deforestation frontiers. We argue that the presence of weak advocacy coalitions requires an analysis of agency to understand this policy process. Our policy network analysis revealed a lack of clear contrasting factions, due to a core–periphery structure. The core of the network brings together all core beliefs but not all of the most influential actors. Assessing network centrality and reputational influence enabled us to identify actors with exceptional agency. We contribute to the debates on advocacy coalitions and on land tenure by distinguishing between attitudes toward tenure regularization policies and their actual implementation in a context where actors have diverging interests and objectives.


Calcium dependence of neurotransmitter release at a high fidelity synapse

Abdelmoneim Eshra, Hartmut Schmidt, Jens Eilers, Stefan Hallermann

Carl-Ludwig-Institute for Physiology, Medical Faculty, University of Leipzig, Leipzig, Germany

Deutsche Forschungsgemeinschaft, Deutsche Forschungsgemeinschaft, European Research Council

Abstract: The Ca 2+ -dependence of the priming, fusion, and replenishment of synaptic vesicles are fundamental parameters controlling neurotransmitter release and synaptic plasticity. Despite intense efforts, these important steps in the synaptic vesicles’ cycle remain poorly understood due to the technical challenge in disentangling vesicle priming, fusion, and replenishment. Here, we investigated the Ca 2+ -sensitivity of these steps at mossy fiber synapses in the rodent cerebellum, which are characterized by fast vesicle replenishment mediating high-frequency signaling. We found that the basal free Ca 2+ concentration (<200 nM) critically controls action potential-evoked release, indicating a high-affinity Ca 2+ sensor for vesicle priming. Ca 2+ uncaging experiments revealed a surprisingly shallow and non-saturating relationship between release rate and intracellular Ca 2+ concentration up to 50 μM. The rate of vesicle replenishment during sustained elevated intracellular Ca 2+ concentration exhibited little Ca 2+ -dependence. Finally, quantitative mechanistic release schemes with five Ca 2+ binding steps incorporating rapid vesicle replenishment via parallel or sequential vesicle pools could explain our data. We thus show that co-existing high- and low-affinity Ca 2+ sensors mediate priming, fusion, and replenishment of synaptic vesicles at a high-fidelity synapse.


An Immunomodulatory Miniaturized 3D Screening Platform Using Liquefied Capsules

Sara Nadine, Clara R. Correia, João F. Mano

CICECO – Aveiro Institute of Materials Department of Chemistry University of Aveiro Campus Universitário de Santiago  Aveiro 3810‐193 Portugal

Abstract: AbstractA critical determinant of successful clinical outcomes is the host's response to the biomaterial. Therefore, the prediction of the immunomodulatory bioperformance of biomedical devices following implantation is of utmost importance. Herein, liquefied capsules are proposed as immunomodulatory miniaturized 3D platforms for the high‐content combinatorial screening of different polymers that could be used generically in scaffolds. Additionally, the confined and liquefied core of capsules affords a cell‐mediated 3D assembly with bioinstructive microplatforms, allowing to study the potential synergistic effect that cells in tissue engineering therapies have on the immunological environment before implantation. As a proof‐of‐concept, three different polyelectrolytes, ranging in charge density and source, are used. Poly(L‐lysine)‐, alginate‐, and chitosan‐ending capsules with or without encapsulated mesenchymal stem/stromal cells (MSCs) are placed on top of a 2D culture of macrophages. Results show that chitosan‐ending capsules, as well as the presence of MSCs, favor the balance of macrophage polarization toward a more regenerative profile, through the up‐regulation of anti‐inflammatory markers, and the release of pro‐regenerative cytokines. Overall, the developed system enables the study of the immunomodulatory bioperformance of several polymers in a cost‐effective and scalable fashion, while the paracrine signaling between encapsulated cells and the immunological environment can be simultaneously evaluated.


Antiviral Function of NKEF against VHSV in Rainbow Trout

Veronica Chico, Maria Elizabhet Salvador-Mira, Ivan Nombela, Sara Puente-Marin, Luis Perez, Luis Mercado, Maria del Mar Ortega-Villaizan

Instituto de Biología Molecular y Celular (IBMC), Universidad Miguel Hernández (IBMC-UMH), 03202 Elche, Spain

Abstract: Natural killer enhancing factor (NKEF) belongs to the peroxiredoxin family of proteins, a group of antioxidants that has been extensively studied in mammals. Recently, we identified NKEF in the immunoprecipitated proteome of rainbow trout red blood cells (RBCs) exposed to viral hemorrhagic septicemia virus (VHSV). In the present study, we evaluated the role of NKEF in the antiviral response of rainbow trout against VHSV by examining the expression profile of NKEF in VHSV-exposed RBCs and rainbow trout gonad-2 (RTG-2) cell line. We found an in vitro correlation between decreased VHSV replication and increased NKEF expression after RBCs were exposed to VHSV, however this was not found in RTG-2 cells where the infection highly increased and nkef transcripts remained almost unchanged. In addition, siRNA silencing of the nkef gene in rainbow trout RBCs and RTG-2 cells resulted in increased VHSV replication. We also found a correlation between nkef gene silencing and a decrease in the expression of genes related to type 1 interferon (IFN1) pathway. These findings indicated that NKEF is involved in the antiviral mechanisms of rainbow trout RBCs against VHSV and thus support its antiviral role and implication in the modulation of their immune response. Finally, overexpression of NKEF in an EPC cell line significantly reduced VHSV infectivity and was coupled to an increment in IFN1-related genes. In conclusion, NKEF may be a potential target for new therapeutic strategies against viral infections.


Spider mite genotypes with higher growth rate suffer more from competition but exert stronger reproductive interference

Miguel A. Cruz, Flore Zélé, Raquel Gaspar, Ricardo Santos, Leonor R. Rodrigues, Vitor C. Sousa, Sara Magalhães

Centre for Ecology, Evolution and Environmental Changes (CE3C) & CHANGE ‐ Global Change and Sustainability Institute Faculdade de Ciências da Universidade de Lisboa  Lisbon Portugal

European Research Council, Fundação para a Ciência e a Tecnologia, Fundação para a Ciência e a Tecnologia, Fundação para a Ciência e a Tecnologia, Fundação para a Ciência e a Tecnologia, Fundação para a Ciência e a Tecnologia

Abstract: Abstract Within‐species individual variation has been gaining increased attention in ecological studies of species interactions. Yet, these studies rarely consider genetic variation and potential genetic correlations among traits. Moreover, traits beyond those associated with trophic interactions are mostly overlooked. Filling these gaps is important to fully understand the relevance of trait variation in both the ecology and evolution of species interactions. We addressed this using inbred lines of Tetranychus cinnabarinus , a spider mite species that often engages in antagonistic interactions with its congeneric T. urticae . Specifically, we measured (a) the intrinsic growth rate and the sex ratio in the absence of food competition and reproductive interference; (b) food competition against a density gradient of conspecific or heterospecific competitors in the absence of reproductive interference; (c) reproductive interference in the absence of food competition; and (d) the body size of adult females and males. We found significant genetic variance (i.e. broad‐sense heritability) among lines for all variables except for the effect of T. cinnabarinus on its heterospecific competitor via food competition. Moreover, we showed that lines with higher intrinsic growth were more sensitive to intra‐ and interspecific competition for food but exerted stronger reproductive interference on heterospecifics. In addition, the higher the proportion of sons produced by a line, the more resilient it was to reproductive interference but also the lower its growth rate. No genetic correlations were found between any variable and body size. Our results indicate that considering genetic correlations among traits involved in both trophic and sexual interactions is key to understanding the role of individual variation in species interactions and their evolution.


Discovery of dynamical heterogeneity in a supercooled magnetic monopole fluid

Proceedings of the National Academy of Sciences

Jahnatta Dasini, Chaia Carroll, Jack Murphy, Catherine Dawson, Hiroto Takahashi, Sudarshan Sharma, Fabian Jerzembeck, Stephen J. Blundell, Graeme M. Luke, J. C. Séamus Davis, Jonathan Ward

Department of Physics, University College Cork

Research Ireland, Research Ireland, International Max Planck Research School for Chemistry and Physics of Quantum Materials, UK Research and Innovation, Gordon and Betty Moore Foundation, EC | European Research Council, Royal Society, Research Ireland, Royal Society

Abstract: Dynamical heterogeneity, in which transitory local fluctuations occur in the conformation and dynamics of constituent particles, is widely hypothesized to be essential to the evolution of supercooled liquids into the structural glass state. Yet its microscopic spatiotemporal phenomenology is challenging to detect directly in molecular glass forming liquids. Because recent theoretical advances predict that corresponding dynamical heterogeneity could occur in supercooled magnetic monopole fluids (Proc. Nat. Acad. Sci. 112, 8549 (2015)), we searched for such phenomena in Dy 2 Ti 2 O 7 . By measuring its microsecond-resolved spontaneous magnetization fluctuations M ( t , T ) we detected a sharp bifurcation in monopole noise characteristics below T ≈ 1,500 mK , with the appearance of powerful spontaneous monopole current bursts. This intense dynamics emerges upon entering the supercooled monopole fluid regime, reaches maximum strength near T ≈ 750 mK and then collapses along with coincident loss of ergodicity approaching T g ≈ 250 mK . Moreover, when the four-point dynamical susceptibility χ 4 ( τ , T ) is determined directly from temperature dependence of correlations in M ( t , T ) , it evolves as predicted when dynamical heterogeneity is present, revealing its simultaneously and rapidly escalating length and time scales, ξ ( T ) and τ 4 ( T ) . This overall phenomenology greatly expands our empirical knowledge of supercooled monopole fluids and, more generally, demonstrates techniques for detection of the time sequence, magnitude, statistics, and correlations of dynamical heterogeneity, access to which may greatly accelerate fundamental vitrification studies.


Genome Editing for β-Hemoglobinopathies: Advances and Challenges

Laboratory of Chromatin and Gene Regulation during Development, Imagine Institute, Université de Paris, INSERM UMR 1163, F-75015 Paris, France

Agence Nationale de la Recherche, European Research Council, French Muscular Dystrophy Association

Abstract: β-hemoglobinopathies are the most common genetic disorders worldwide and are caused by mutations affecting the production or the structure of adult hemoglobin. Patients affected by these diseases suffer from anemia, impaired oxygen delivery to tissues, and multi-organ damage. In the absence of a compatible donor for allogeneic bone marrow transplantation, the lifelong therapeutic options are symptomatic care, red blood cell transfusions and pharmacological treatments. The last decades of research established lentiviral-mediated gene therapy as an efficacious therapeutic strategy. However, this approach is highly expensive and associated with a variable outcome depending on the effectiveness of the viral vector and the quality of the cell product. In the last years, genome editing emerged as a valuable tool for the development of curative strategies for β-hemoglobinopathies. Moreover, due to the wide range of its applications, genome editing has been extensively used to study regulatory mechanisms underlying globin gene regulation allowing the identification of novel genetic and pharmacological targets. In this work, we review the current advances and challenges of genome editing approaches to β-hemoglobinopathies. Special focus has been directed towards strategies aimed at correcting the defective β-globin gene or at inducing fetal hemoglobin (HbF), which are in an advanced state of clinical development.


Towards a complex systems model of evidence for public health

Karien Stronks, Morten Hulvej Rod, Harry Rutter, Naja Hulvej Rod

Department of Public and Occupational Health, Amsterdam UMC/University of Amsterdam, Amsterdam, The Netherlands

Abstract: There has been growing interest in the adoption of complex systems approaches to tackle major public health challenges such as obesity. This perspective redirects focus from individually oriented and narrowly focused interventions towards strategies that reshape structural drivers of health and disease across multiple levels, offering novel avenues for enhancing population health and tackling health inequalities. Despite growing consensus on the use of a complex systems model of evidence to support these kinds of approaches, there remains limited agreement on the types of evidence required both to understand and to tackle complex public health problems. In this paper, we propose a complex systems model of evidence that combines three types of evidence—causal, intervention, implementation—across three dimensions of complex systems—mechanisms, dynamics and patterns. This model thus identifies nine categories of evidence: causal evidence , which explains the mechanisms behind public health problems, the dynamics driving changes therein and emerging health patterns; intervention evidence, which focuses on the set of actions that can modify these mechanisms and dynamics, including their intended and unintended consequences on health outcomes and implementation evidence, which addresses what is needed to implement systems change effectively, how systems adapt to these changes and how systems changes contribute to changes in health patterns. This complex systems model of evidence may serve as a guide to researchers and decision-makers when designing research programmes and evidence-based policies in response to complex public health problems.


Synchrony and Stability in Trophic Metacommunities: When Top Predators Navigate in a Heterogeneous World

European Research Council, Laboratoire d'Excellence TULIP

Abstract: Ecosystem stability strongly depends on spatial aspects since localized perturbations spread across an entire region through species dispersal. Assessing the synchrony of the response of connected populations is fundamental to understand stability at different scales because if populations fluctuate asynchronously, the risk of their simultaneous extinction is low, thus reducing the species' regional extinction risk. Here, we consider a metacommunity model consisting of two food chains connected by dispersal and we review the various mechanisms governing the transmission of small perturbations affecting populations in the vicinity of equilibrium. First, we describe how perturbations propagate vertically (i.e., within food chains through trophic interactions) and horizontally (i.e., between food chains through dispersal) in metacommunities. Then, we discuss the mechanisms susceptible to alter synchrony patterns such as density-depend dispersal or spatial heterogeneity. Density-dependent dispersal, which is the influence of prey or predator abundance on dispersal, has a major impact because the species with the highest coefficient of variation of biomass governs the dispersal rate of the dispersing species and determines the synchrony of its populations, thus bypassing the classic vertical transmission of perturbations. Spatial heterogeneity, which is a disparity between patches of the attack rate of predators on prey in our model, alters the vertical transmission of perturbations in each patch, thus making synchrony dependent on which patch is perturbed. Finally, by combining our understanding of the impact of each of these mechanisms on synchrony, we are able to full explain the response of realistic metacommunities such as the model developed by Rooney et al. (2006). By disentangling the main mechanisms governing synchrony, our metacommunity model provides a broad insight into the consequences of spacial aspects on food web stability.


The Emerging Role of IL-9 in the Anticancer Effects of Anti-PD-1 Therapy

UMR 1231, Lipides Nutrition Cancer, INSERM, 21000 Dijon, France

Fondation de France, Fondation de France, Fondation de France, Fondation de France, Fondation pour la Recherche Médicale, Fondation pour la Recherche Médicale, Fondation pour la Recherche Médicale, Fondation pour la Recherche Médicale, Conseil Régional de Bourgogne, Conseil Régional de Bourgogne, Conseil Régional de Bourgogne, Conseil Régional de Bourgogne, FEDER, FEDER, FEDER, FEDER, LabEx LipSTIC, LabEx LipSTIC, LabEx LipSTIC, LabEx LipSTIC, LabEx MAbImprove, LabEx MAbImprove, LabEx MAbImprove, LabEx MAbImprove, European Research Council, European Research Council, European Research Council, European Research Council, Brown Center for Immunotherapy at Indiana University Melvin, Brown Center for Immunotherapy at Indiana University Melvin, Brown Center for Immunotherapy at Indiana University Melvin, Brown Center for Immunotherapy at Indiana University Melvin, Bren Simon Comprehensive Cancer Center, Bren Simon Comprehensive Cancer Center, Bren Simon Comprehensive Cancer Center, Bren Simon Comprehensive Cancer Center

Abstract: PD-1 blockade rescues failing anticancer immune responses, resulting in durable remissions in some cancer patients. Cytokines such as IFNγ and IL-2 contribute to the anti-tumor effect of PD-1 blockade. IL-9 was identified over the last decade as a cytokine demonstrating a potent ability to harness the anticancer functions of innate and adaptive immune cells in mice. Recent translational investigations suggest that the anticancer activity of IL-9 also extends to some human cancers. Increased T cell-derived IL-9 was proposed to predict the response to anti-PD-1 therapy. Preclinical investigations accordingly revealed that IL-9 could synergize with anti-PD-1 therapy in eliciting anticancer responses. Here, we review the findings suggesting an important contribution of IL-9 in the efficacy of anti-PD-1 therapy and discuss their clinical relevance. We will also discuss the role of host factors like the microbiota and TGFβ in the tumor microenvironment (TME) in the regulation of IL-9 secretion and anti-PD-1 treatment efficacy.


Rapid Manufacturing of High‐Permittivity Dielectric Elastomer Actuator Fibers

Patrick M. Danner, Tazio Pleij, Florent Liechti, Jana Wolf, Alexandra V. Bayles, Jan Vermant, Dorina M. Opris

Swiss Federal Laboratories for Materials Science and Technology – Empa Laboratory for Functional Polymers  Ueberlandstr. 129 Dübendorf CH‐8600 Switzerland

Abstract: Abstract The fast and scalable production of dielectric elastomer actuators (DEAs) remains the major bottleneck preventing the widespread use of DEAs. In this work, an ultra‐fast production method is presented for dielectric elastomer fibers which can reach industrial‐like extrusion speeds of up to 60 mm s −1 of fiber, leading to a production speed of up to 16.7 m of fiber per second or 216 m per hour. Electrode and high permittivity (' = 11.2) dielectric inks are used with a long pot life, but ultra‐fast cross‐linking at elevated temperatures. The process eliminates the need for tedious and time‐consuming post‐processing, as simple co‐extrusion and laser ablation enable the production of fully functional, high‐permittivity DEA fibers within seconds. This work represents a significant advancement in DEA manufacturing, transitioning from conventional layer‐by‐layer batch production to continuous co‐extrusion‐based manufacturing. To the best of the knowledge, this is currently the fastest method for fabricating fully functional DEAs in a single processing step.


Integration Strategies and Formats in Field-Effect Transistor Chemo- and Biosensors: A Critical Review

Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf e. V. (HZDR)

European Research Council, Deutsche Forschungsgemeinschaft, Deutsche Forschungsgemeinschaft


Distinct gene programs underpinning disease tolerance and resistance in influenza virus infection

Ofir Cohn, Gal Yankovitz, Naama Peshes-Yaloz, Yael Steuerman, Amit Frishberg, Rachel Brandes, Michal Mandelboim, Jennifer R. Hamilton, Tzachi Hagai, Ido Amit, Mihai G. Netea, Nir Hacohen, Fuad A. Iraqi, Eran Bacharach, Irit Gat-Viks

Chan Zuckerberg Initiative, Chan Zuckerberg Initiative, United States-Israel Binational Science Foundation, United States-Israel Binational Science Foundation, United States-Israel Binational Science Foundation, United States-Israel Binational Science Foundation, Horizon 2020, Horizon 2020, ERC, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Tel Aviv University, European Research Council


Plasmon-Induced Graphene/Silicon Schottky Junctions for Ultrasensitive Gas Sensing

Katarzyna Drozdowska, Janusz Smulko, Tesfalem Welearegay, Lars Österlund, Sergey Rumyantsev

Department of Metrology and Electronic Systems, Faculty of Electronics, Telecommunications, and Informatics, Gdańsk University of Technology, G. Narutowicza 11/12, 80-233 Gdańsk, Poland

European Research Council, Narodowe Centrum Nauki


Deformation under flow and morphological recovery of cancer cells

Emile Gasser, Emilie Su, Kotryna Vaidžiulytė, Nassiba Abbade, Hamizah Cognart, Jean-Baptiste Manneville, Jean-Louis Viovy, Matthieu Piel, Jean-Yves Pierga, Kyohei Terao, Catherine Villard

Institut Curie and Institut Pierre Gilles de Gennes, Physique des Cellules et Cancer, CNRS UMR168, Université PSL, F-75005 Paris, France

European Research Council, Institut Pierre-Gilles de Gennes, Institut Pierre-Gilles de Gennes, Institut Pierre-Gilles de Gennes, Japan Science and Technology Agency

Abstract: A novel microfluidic device dedicated to cell rheology after flow-induced deformation in constricted channel: a focus on the recovery properties of circulating tumor cells.


Macromolecular assemblies supporting transcription-translation coupling

Institut de Gé né tique et de Biologie Molé culaire et Cellulaire (IGBMC)

Agence Nationale de la Recherche, Agence Nationale de la Recherche, European Research Council, European molecular biology organization


In vivo autofluorescence lifetime imaging of spatial metabolic heterogeneities and learning-induced changes in the Drosophila mushroom body

Philémon Roussel, Mingyi Zhou, Chiara Stringari, Thomas Preat, Pierre-Yves Plaçais, Auguste Genovesio

Computational Bioimaging and Bioinformatics, IBENS, École normale supérieure, CNRS, INSERM, Université PSL

Agence Nationale de la Recherche, Agence Nationale de la Recherche, Agence Nationale de la Recherche, Agence Nationale de la Recherche, Agence Nationale de la Recherche, EC | European Research Council

Abstract: Neuronal energy regulation is increasingly recognized as a critical factor underlying brain functions and their pathological alterations, yet the metabolic dynamics that accompany cognitive processes remain poorly understood. As a label-free and minimally invasive technique, fluorescence lifetime imaging (FLIM) of coenzymes NADH and NADPH (collectively referred to as NAD(P)H) offers the possibility to resolve cellular metabolic profiles with high spatial precision. However, NAD(P)H FLIM’s capacity to detect subtle variations in neuronal metabolism has not been demonstrated. In this study, we applied NAD(P)H FLIM to map the metabolic profiles of Drosophila neurons in vivo across multiple scales, focusing on the primary centers for associative memory: the mushroom bodies (MBs). At a broad scale, we obtained an overview of the metabolic signatures of the main brain tissue and identified a marked difference between neuropil and cortex areas. At a finer scale, our findings revealed notable heterogeneity in the basal metabolic profiles of distinct MB neuron subtypes. Measurements performed after associative olfactory learning also uncovered a low-magnitude subtype-specific metabolic shift associated with memory formation, suggesting the utility of NAD(P)H FLIM in detecting physiology-driven changes linked to brain function. These results establish a promising framework for studying the spatial heterogeneities and the dynamics of cerebral energy metabolism in vivo.


Speckle spatial correlations aiding optical transmission matrix retrieval: the smoothed Gerchberg–Saxton single-iteration algorithm

Daniele Ancora, Lorenzo Dominici, Antonio Gianfrate, Paolo Cazzato, Milena De Giorgi, Dario Ballarini, Daniele Sanvitto, Luca Leuzzi

Abstract: The estimation of the transmission matrix of a disordered medium is a challenging problem in disordered photonics. Usually, its reconstruction relies on a complex inversion that aims at connecting a fully controlled input to the deterministic interference of the light field scrambled by the device. At the moment, iterative phase retrieval protocols provide the fastest reconstructing frameworks, converging in a few tens of iterations. Exploiting the knowledge of speckle correlations, we construct a new phase retrieval algorithm that reduces the computational cost to a single iteration. Besides being faster, our method is practical because it accepts fewer measurements than state-of-the-art protocols. Thanks to reducing computation time by one order of magnitude, our result can be a step forward toward real-time optical imaging that exploits disordered devices.


Federated mmWave Beam Selection Utilizing LIDAR Data

Institute of Electrical and Electronics Engineers (IEEE)

Mahdi Boloursaz Mashhadi, Mikolaj Jankowski, Tze-Yang Tung, Szymon Kobus, Deniz Gunduz

European Research Council, Engineering and Physical Sciences Research Council


Partial Exchangeability for Contingency Tables

Department of Mathematics and Statistics, Sequoia Hall, Stanford University, Stanford, CA 94305, USA

Abstract: A parameter free version of classical models for contingency tables is developed along the lines of de Finetti’s notions of partial exchangeability.


Rapidly Degrading Hydrogels to Support Biofabrication and 3D Bioprinting Using Cartilage Microtissues

Gabriela S. Kronemberger, Francesca D. Spagnuolo, Aliaa S. Karam, Kaoutar Chattahy, Kyle J. Storey, Daniel J. Kelly

Trinity Centre for Biomedical Engineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin D02 R590, Ireland


Steering Stem Cell Fate within 3D Living Composite Tissues Using Stimuli‐Responsive Cell‐Adhesive Micromaterials

Tom Kamperman, Niels G. A. Willemen, Cindy Kelder, Michelle Koerselman, Malin Becker, Luanda Lins, Castro Johnbosco, Marcel Karperien, Jeroen Leijten

Department of Developmental BioEngineering Faculty of Science and Technology Technical Medical Centre University of Twente  Drienerlolaan 5 Enschede 7522NB The Netherlands

Abstract: AbstractEngineered living microtissues such as cellular spheroids and organoids have enormous potential for the study and regeneration of tissues and organs. Microtissues are typically engineered via self‐assembly of adherent cells into cellular spheroids, which are characterized by little to no cell–material interactions. Consequently, 3D microtissue models currently lack structural biomechanical and biochemical control over their internal microenvironment resulting in suboptimal functional performance such as limited stem cell differentiation potential. Here, this work report on stimuli‐responsive cell‐adhesive micromaterials (SCMs) that can self‐assemble with cells into 3D living composite microtissues through integrin binding, even under serum‐free conditions. It is demonstrated that SCMs homogeneously distribute within engineered microtissues and act as biomechanically and biochemically tunable designer materials that can alter the composite tissue microenvironment on demand. Specifically, cell behavior is controlled based on the size, stiffness, number ratio, and biofunctionalization of SCMs in a temporal manner via orthogonal secondary crosslinking strategies. Photo‐based mechanical tuning of SCMs reveals early onset stiffness‐controlled lineage commitment of differentiating stem cell spheroids. In contrast to conventional encapsulation of stem cell spheroids within bulk hydrogel, incorporating cell‐sized SCMs within stem cell spheroids uniquely provides biomechanical cues throughout the composite microtissues’ volume, which is demonstrated to be essential for osteogenic differentiation.


Entanglement gap, corners, and symmetry breaking

Institute of Physics, University of Amsterdam

Abstract: We investigate the finite-size scaling of the lowest entanglement gap \delta\xi δ ξ in the ordered phase of the two-dimensional quantum spherical model (QSM). The entanglement gap decays as \delta\xi=\Omega/\sqrt{L\ln(L)} δ ξ = Ω / L ln ( L ) . This is in contrast with the purely logarithmic behaviour as \delta\xi=\pi^2/\ln(L) δ ξ = π 2 / ln ( L ) at the critical point. The faster decay in the ordered phase reflects the presence of magnetic order. We analytically determine the constant \Omega Ω , which depends on the low-energy part of the model dispersion and on the geometry of the bipartition. In particular, we are able to compute the corner contribution to \Omega Ω , at least for the case of a square corner.


Architecture and assembly dynamics of the essential mitochondrial chaperone complex TIM9·10·12

Katharina Weinhäupl, Yong Wang, Audrey Hessel, Martha Brennich, Kresten Lindorff-Larsen, Paul Schanda

Lundbeckfonden, European Research Council, French Infrastructure for Integrated Structural Biology, European Research Council, Agence nationale de la recherche, Agence nationale de la recherche, Agence nationale de la recherche


Stoechiometric and dynamical autocatalysis for diluted chemical reaction networks

European Research Council, Fondation Pierre-Gilles de Gennes pour la recherche, Fondation Pierre-Gilles de Gennes pour la recherche


Elucidating Mechanisms of Hypomorphic WDR19-Related Kidney Failure

Omer Shlomovitz, Yam Ben-Haim, Netanel Eisenstein, Leah Armon, Igor Grinberg, Sylvie Polak-Charcon, Danit Atias-Varon, Guy Chowers, Dror Ben-Ruby, Achia Urbach, Asaf Vivante

ISF, ERC, Tel Aviv University, European Research Council


Sweet taste and obesity

Gabriela Ribeiro, Albino J. Oliveira-Maia

Fundação para a Ciência e a Tecnologia, Fundação Bial, Universidade de Lisboa, Horizon 2020, European Research Council, Horizon 2020 Framework Programme


Metabolic response of a chemolithoautotrophic archaeon to carbon limitation

Logan H. Hodgskiss, Melina Kerou, Zhen-Hao Luo, Barbara Bayer, Andreas Maier, Wolfram Weckwerth, Thomas Nägele, Christa Schleper

Department of Functional and Evolutionary Ecology, Archaea Biology and Ecogenomics Unit, University of Vienna

Austrian Science Fund, European Research Council, PRIORITY 'Excellent science'

Abstract: ABSTRACT The ubiquitously distributed ammonia-oxidizing archaea generate energy from ammonia and build cell mass from inorganic carbon sources, thereby contributing to both the global nitrogen and carbon cycles. However, little is known about the regulation of their predicted core carbon metabolism. A thermodynamic model for Nitrososphaera viennensis was developed to estimate the consumption of inorganic carbon in relation to ammonia consumed for energy and was tested experimentally by growing cells in carbon-limited and excess conditions. A combined proteomic and metabolomic approach to the experimental conditions revealed distinct metabolic adaptation depending on the amount of carbon supplied, either in a catalase or pyruvate background as a reactive oxygen species scavenger. Integration of protein and metabolite dynamics revealed a cellular strategy under carbon limitation to maintain a pool of amino acids and an upregulation of proteins necessary for translation initiation to stay primed for protein synthesis. The combination of modeling and functional genomics fills gaps in the understanding of the central metabolism and its regulation in a chemolithoautotrophic, ammonia-oxidizing archaeon, even in the absence of available genetic tools. IMPORTANCE Little is known about the regulation of carbon metabolism within ammonia-oxidizing archaea (AOA), a widespread clade that plays a critical role in the global nitrogen cycle while also fixing inorganic carbon. To address this missing knowledge, the soil AOA Nitrososphaera viennensis was subjected to various levels of inorganic carbon and analyzed via a systems biology approach to better understand how its core metabolism is regulated. The results demonstrate a strong dependence on the carbon fixation cycle and highlight key connection points between the core metabolic pathways. The analysis additionally revealed tight control on translational processes and elucidated unique cellular responses when the organism was exposed to either exogenous catalase or pyruvate to relieve oxidative stress from reactive oxygen species. The presented data highlight metabolic responses of N. viennensis and provide a better understanding of how the organism, and likely other AOA, respond to various environmental conditions.


Genome-wide meta-analysis of ascertainment and symptom structures of major depression in case-enriched and community cohorts

Mark J. Adams, Jackson G. Thorp, Bradley S. Jermy, Alex S. F. Kwong, Kadri Kõiv, Andrew D. Grotzinger, Michel G. Nivard, Sally Marshall, Yuri Milaneschi, Bernhard T. Baune, Bertram Müller-Myhsok, Brenda W. J. H. Penninx, Dorret I. Boomsma, Douglas F. Levinson, Gerome Breen, Giorgio Pistis, Hans J. Grabe, Henning Tiemeier, Klaus Berger, Marcella Rietschel, Patrik K. Magnusson, Rudolf Uher, Steven P. Hamilton, Susanne Lucae, Kelli Lehto, Qingqin S. Li, Enda M. Byrne, Ian B. Hickie, Nicholas G. Martin, Sarah E Medland, Naomi R. Wray, Elliot M. Tucker-Drob, Estonian Biobank Research Team, Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Cathryn M. Lewis, Andrew M McIntosh, Eske M. Derks

Division of Psychiatry, University of Edinburgh

National Institutes of Health, Medical Research Council, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Eesti Teadusagentuur, Wellcome Trust, European Research Council, National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care North West Coast

Abstract: AbstractBackgroundDiagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and etiological subtypes. There are several challenges to integrating symptom data from genetically informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data.MethodsWe conducted genome-wide association studies of major depressive symptoms in three cohorts that were enriched for participants with a diagnosis of depression (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts who were not recruited on the basis of diagnosis (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors.ResultsThe best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for the skip-structure in community cohorts (use of Depression and Anhedonia as gating symptoms).ConclusionThe results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analyzing genetic association data.


CRISPRthripsis: The Risk of CRISPR/Cas9-induced Chromothripsis in Gene Therapy

Mario Amendola, Mégane Brusson, Annarita Miccio

Agence Nationale de la Recherche under “Investissements d’avenir” program, “Appel à projets générique 2020”, European Research Council

Abstract: Abstract The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 nuclease system has allowed the generation of disease models and the development of therapeutic approaches for many genetic and non-genetic disorders. However, the generation of large genomic rearrangements has raised safety concerns for the clinical application of CRISPR/Cas9 nuclease approaches. Among these events, the formation of micronuclei and chromosome bridges due to chromosomal truncations can lead to massive genomic rearrangements localized to one or few chromosomes. This phenomenon, known as chromothripsis, was originally described in cancer cells, where it is believed to be caused by defective chromosome segregation during mitosis or DNA double-strand breaks. Here, we will discuss the factors influencing CRISPR/Cas9-induced chromothripsis, hereafter termed CRISPRthripsis, and its outcomes, the tools to characterize these events and strategies to minimize them.


Metaphoric Reference: A Real-Time Analysis

Bilingual Figurative Language Processing


Sugar


Memories of Violence: Hama 1982


Introduction


Legitimacy and International Rights Holding

The Law and Politics of International Legitimacy


Agent identity in economics


“Wait and See” versus “No Regrets”: Comparing the Costs of Economic Strategies


“Fraternalism permeates the atmosphere”


The Second World War: informal empire transformed, 1939–1945


Sappho and Epic


Floating exchange rates and the new interbloc protectionism: tariffs versus quotas


Righting Markets


Immunodeficiency in velo-cardio-facial syndrome


Cellular water relations of plants


Health-Health Trade-offs


Reflections on the revolution in France, and on the proceedings in certain societies in London relative to that event. In a letter intended to have been sent to a gentleman in Paris. By the Right Honourable Edmund Burke


Structural, linguistic and literary features


The Macroprudential Countercyclical Capital Buffer in Basel III

José A. Carrasco-Gallego, Margarita Rubio


Dark matter at the centres of galaxies


Historiography, Epic and the Textual Transmission of Imperial Values: Liudprand’sAntapodosisandDigenes Akrites

Reading in the Byzantine Empire and Beyond


A statistical narrative: Australia, 1800–2010

The Cambridge Economic History of Australia

Matthew Butlin, Robert Dixon, Peter J. Lloyd


The politics of free will inThe Blazing World


Prologue

American Identity and the Politics of Multiculturalism


The pessimistic human story

Faith and the Faithfulness of Jesus in Hebrews


The development of complex society in China


Turing and the development of computational complexity


Democracy and Patriarchy

The Rise of Gay Rights and the Fall of the British Empire


Investigating the Brain


Cyberattacks and international human rights law

Weapons under International Human Rights Law


EU primary law on services: fundamentals and delimitations

Services Liberalization in the EU and the WTO


Introduction

Public Participation and Legitimacy in the WTO


Index


Logical Truth, Logical Consequence, and Explosions!


Introduction

The Cambridge Companion to Slavery in American Literature


Flag Varieties and Schubert Polynomials

Equivariant Cohomology in Algebraic Geometry


The concept of number


Reviewing

The Cambridge Companion to Victorian Women's Writing


Digital Business Models


Persian Virtues


Introduction


Advocacy and Activism


Supporting individual researchers

The Royal Society and the Promotion of Science since 1960


Laws


Petrarch and the ancients


The misbegotten: long lineages, long branches and the interrelationships of Aotus, Callicebus and the saki–uacaris*

Evolutionary Biology and Conservation of Titis, Sakis and Uacaris

Alfred L. Rosenberger, Marcelo F. Tejedor


The archaeological record


The Bible and the emerging ‘scientific’ world-view


Toward a General Scaling Theory for Linking Traits, Stoichiometry, and Body Size to Ecosystem Function

Brian J. Enquist, Sean T. Michaletz, Andrew J. Kerkhoff


Interobserver agreement for neonatal seizure detection using multichannel <scp>EEG</scp>

Annals of Clinical and Translational Neurology

Nathan J. Stevenson, Robert R. Clancy, Sampsa Vanhatalo, Ingmar Rosén, Janet M. Rennie, Geraldine B. Boylan

Neonatal Brain Research Group Irish Centre for Fetal and Neonatal Translational Research University College Cork Cork Ireland

Wellcome Trust UK, Wellcome Trust UK, Science Foundation Ireland, Science Foundation Ireland, Science Foundation Ireland, Children's Hospital of Philadelphia Endowed Chair in Pediatric Neurology Research, Topiramate Research Fund, Finnish Academy, Sigrid Juselius Foundation

Abstract: AbstractObjectiveTo determine the interobserver agreement (IOA) of neonatal seizure detection using the gold standard of conventional, multichannel EEG.MethodsA cohort of full‐term neonates at risk of acute encephalopathy was included in this prospective study. The EEG recordings of these neonates were independently reviewed for seizures by three international experts. The IOA was estimated using statistical measures including Fleiss' kappa and percentage agreement assessed over seizure events (event basis) and seizure duration (temporal basis).ResultsA total of 4066 h of EEG recordings from 70 neonates were reviewed with an average of 2555 seizures detected. The IOA was high with temporal assessment resulting in a kappa of 0.827 (95% CI: 0.769–0.865; n = 70). The median agreement was 83.0% (interquartile range [IQR]: 76.6–89.5%; n = 33) for seizure and 99.7% (IQR: 98.9–99.8%; n = 70) for nonseizure EEG. Analysis of events showed a median agreement of 83.0% (IQR: 72.9–86.6%; n = 33) for seizures with 0.018 disagreements per hour (IQR: 0.000–0.090 per hour; n = 70). Observers were more likely to disagree when a seizure was less than 30 sec. Overall, 33 neonates were diagnosed with seizures and 28 neonates were not, by all three observers. Of the remaining nine neonates with contradictory EEG detections, seven presented with low total seizure burden.InterpretationThe IOA is high among experts for the detection of neonatal seizures using conventional, multichannel EEG. Agreement is reduced when seizures are rare or have short duration. These findings support EEG‐based decision making in the neonatal intensive care unit, inform EEG interpretation guidelines, and provide benchmarks for seizure detection algorithms.


Preventing mitochondrial reverse electron transport as a strategy for cardioprotection

Hiran A. Prag, Michael P. Murphy, Thomas Krieg

British Heart Foundation, Medical Research Council, Wellcome Trust

Abstract: AbstractIn the context of myocardial infarction, the burst of superoxide generated by reverse electron transport (RET) at complex I in mitochondria is a crucial trigger for damage during ischaemia/reperfusion (I/R) injury. Here we outline the necessary conditions for superoxide production by RET at complex I and how it can occur during reperfusion. In addition, we explore various pathways that are implicated in generating the conditions for RET to occur and suggest potential therapeutic strategies to target RET, aiming to achieve cardioprotection.


Expanding the repertoire of GalNAc analogues for cell-specific bioorthogonal tagging of glycoproteins

Abdul Zafar, Sandhya Sridhar, Ganka Bineva-Todd, Anna Cioce, Nadia Abdulla, Vincent Chang, Stacy A. Malaker, David S. Hewings, Benjamin Schumann

Chemical Glycobiology Laboratory, The Francis Crick Institute, NW1 1AT London, UK

Biotechnology and Biological Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council, Cancer Research UK, Cancer Research UK, Wellcome Trust, Engineering and Physical Sciences Research Council, National Institute of General Medical Sciences, National Science Foundation

Abstract: Demonstrating the use of azide-containing GalNAc analogues in conjunction with an engineered metabolic pathway to study glycosylation cell-specifically.


Physiologically‐based pharmacokinetic modelling of long‐acting injectable cabotegravir and rilpivirine in pregnancy

British Journal of Clinical Pharmacology

Shakir Atoyebi, Fazila Bunglawala, Nicolas Cottura, Sandra Grañana‐Castillo, Maiara Camotti Montanha, Adeniyi Olagunju, Marco Siccardi, Catriona Waitt

Abstract: AimsLong‐acting cabotegravir and rilpivirine have been approved to manage HIV in adults, but data regarding safe use in pregnancy are limited. Physiologically‐based pharmacokinetic (PBPK) modelling was used to simulate the approved dosing regimens in pregnancy and explore if Ctrough was maintained above cabotegravir and rilpivirine target concentrations (664 and 50 ng/mL, respectively).MethodsAn adult PBPK model was validated using clinical data of cabotegravir and rilpivirine in nonpregnant adults. This was modified by incorporating pregnancy‐induced metabolic and physiological changes. The pregnancy PBPK model was validated with data on oral rilpivirine and raltegravir (UGT1A1 probe substrate) in pregnancy. Twelve weeks' disposition of monthly and bimonthly dosing of long‐acting cabotegravir and rilpivirine was simulated at different trimesters and foetal exposure was also estimated.ResultsPredicted Ctrough at week 12 for monthly long‐acting cabotegravir was above 664 ng/mL throughout pregnancy, but below the target in 0.5% of the pregnant population in the third trimester with bimonthly long‐acting cabotegravir. Predicted Ctrough at week 12 for monthly and bimonthly long‐acting rilpivirine was below 50 ng/mL in at least 40% and over 90% of the pregnant population, respectively, throughout pregnancy. Predicted medians (range) of cord‐to‐maternal blood ratios were 1.71 (range, 1.55‐1.79) for cabotegravir and 0.88 (0.78‐0.93) for rilpivirine between weeks 38 and 40.ConclusionsModel predictions suggest that monthly long‐acting cabotegravir could maintain antiviral efficacy throughout pregnancy, but that bimonthly administration may require careful clinical evaluation. Both monthly and bimonthly long‐acting rilpivirine may not adequately maintain antiviral efficacy in pregnancy.


Inter-rater and intra-rater agreement of [99mTc]-labelled NM-01, a single-domain programmed death-ligand 1 (PD-L1) antibody, using quantitative SPECT/CT in non-small cell lung cancer

Daniel Johnathan Hughes, Gitasha Chand, Jessica Johnson, Damion Bailey, Kathryn Adamson, Vicky Goh, Gary J. R. Cook

Abstract: Abstract Background Immune checkpoint inhibitors, including those against programmed cell death protein-1 (PD-1) or its ligand (PD-L1), are routinely used to treat non-small cell lung cancer (NSCLC). PD-L1 is a validated prognostic and predictive immunohistochemical biomarker of anti-PD-1/PD-L1 therapy but displays temporospatial heterogeneity of expression. Non-invasive radiopharmaceutical techniques, including technetium-99m [99mTc]-labelled anti-PD-L1 single-domain antibody (NM-01) SPECT/CT, have the potential to improve the predictive value of PD-L1 assessment. This study aims to determine the inter- and intra-rater agreement of the quantitative measurement of [99mTc]NM-01 SPECT/CT in NSCLC. Methods Participants (n = 14) with untreated advanced NSCLC underwent [99mTc]NM-01 SPECT/CT at baseline (n = 3) or at baseline plus 9-week follow-up (n = 11). [99mTc]NM-01 uptake (of primary lung, lymph node, thoracic and distant metastases, and healthy reference tissues) was measured using SUVmax and malignant lesion-to-blood pool ratios with Siemens xSPECT Broad Quantification software by three independent raters. Intraclass correlation coefficients (ICC) were calculated and Bland–Altman plot analysis performed to determine inter- and intra-rater agreement. Results There was excellent inter-rater agreement of manual freehand SUVmax scores of primary lung tumour (T; n = 25; ICC 1.00; 95% CI 0.99–1.00), individual lymph node metastases (LN; n = 56; ICC 0.97; 95% CI 0.95–0.98), thoracic metastases (ThMet; n = 9; ICC 0.94; 95% CI 0.83–0.99) and distant metastases (DisMet; n = 21; ICC 0.91; 95% CI 0.83–0.96). The inter-rater ICCs of tumour-to-blood pool (T:BP), LN:BP, ThMet:BP and DisMet:BP measures of [99mTc]NM-01 uptake also demonstrated good or excellent agreement. Manual freehand scoring of T, LN, ThMet, DisMet and their ratios using [99mTc]NM-01 SPECT/CT following a 28-day interval was consistent for all raters with good or excellent intra-rater agreement demonstrated (ICCs range 0.86–1.00). Conclusion Quantitative assessment of [99mTc]NM-01 SPECT/CT in NSCLC, using SUVmax of malignant primary or metastatic lesions and their ratios with healthy reference tissues, demonstrated good or excellent inter- and intra-rater agreement in this study. Further validation with ongoing and future larger cohort studies is now warranted. Clinical trial registration ClinicalTrials.gov identifier no. NCT04436406 (registered 18th June 2020; available at https://clinicaltrials.gov/ct2/show/NCT04436406) and NCT04992715 (registered 5th August 2021; available at https://clinicaltrials.gov/ct2/show/NCT04992715).


The use of simultaneous stereo-electroencephalography and magnetoencephalography in localizing the epileptogenic focus in refractory focal epilepsy

Umesh Vivekananda, Chunyan Cao, Wei Liu, Jing Zhang, Fergus Rugg-Gunn, Matthew C Walker, Vladimir Litvak, Bomin Sun, Shikun Zhan

Department of Clinical and Experimental Epilepsy, UCL, Queen Square Institute of Neurology, London WC1N 3BG, UK

National Institute of Health Research, Epilepsy Research UK, Medical Research Council, Academy Medical Sciences, Wellcome Trust, National Natural Science Foundation of China

Abstract: Abstract Both magnetoencephalography and stereo-electroencephalography are used in presurgical epilepsy assessment, with contrasting advantages and limitations. It is not known whether simultaneous stereo-electroencephalography–magnetoencephalography recording confers an advantage over both individual modalities, in particular whether magnetoencephalography can provide spatial context to epileptiform activity seen on stereo-electroencephalography. Twenty-four adult and paediatric patients who underwent stereo-electroencephalography study for pre-surgical evaluation of drug-resistant focal epilepsy, were recorded using simultaneous stereo-electroencephalography–magnetoencephalography, of which 14 had abnormal interictal activity during recording. The 14 patients were divided into two groups; those with detected superficial (n = 7) and deep (n = 7) brain interictal activity. Interictal spikes were independently identified in stereo-electroencephalography and magnetoencephalography. Magnetoencephalography dipoles were derived using a distributed inverse method. There was no significant difference between stereo-electroencephalography and magnetoencephalography in detecting superficial spikes (P = 0.135) and stereo-electroencephalography was significantly better at detecting deep spikes (P = 0.002). Mean distance across patients between stereo-electroencephalography channel with highest average spike amplitude and magnetoencephalography dipole was 20.7 ± 4.4 mm. for superficial sources, and 17.8 ± 3.7 mm. for deep sources, even though for some of the latter (n = 4) no magnetoencephalography spikes were detected and magnetoencephalography dipole was fitted to a stereo-electroencephalography interictal activity triggered average. Removal of magnetoencephalography dipole was associated with 1 year seizure freedom in 6/7 patients with superficial source, and 5/6 patients with deep source. Although stereo-electroencephalography has greater sensitivity in identifying interictal activity from deeper sources, a magnetoencephalography source can be localized using stereo-electroencephalography information, thereby providing useful whole brain context to stereo-electroencephalography and potential role in epilepsy surgery planning.


Defining New Pathways to Manage the Ongoing Emergence of Bat Rabies in Latin America

Julio A. Benavides, William Valderrama, Sergio Recuenco, Wilson Uieda, Gerardo Suzán, Rafael Avila-Flores, Andres Velasco-Villa, Marilene Almeida, Fernanda A.G. de Andrade, Baldomero Molina-Flores, Marco Antonio Natal Vigilato, Julio Cesar Augusto Pompei, Paolo Tizzani, Jorge E. Carrera, Darcy Ibanez, Daniel G. Streicker

Departamento de Ecología y Biodiversidad, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago 8370146, Chile

Abstract: Rabies transmitted by common vampire bats (Desmodus rotundus) has been known since the early 1900s but continues to expand geographically and in the range of species and environments affected. In this review, we present current knowledge of the epidemiology and management of rabies in D. rotundus and argue that it can be reasonably considered an emerging public health threat. We identify knowledge gaps related to the landscape determinants of the bat reservoir, reduction in bites on humans and livestock, and social barriers to prevention. We discuss how new technologies including autonomously-spreading vaccines and reproductive suppressants targeting bats might manage both rabies and undesirable growth of D. rotundus populations. Finally, we highlight widespread under-reporting of human and animal mortality and the scarcity of studies that quantify the efficacy of control measures such as bat culling. Collaborations between researchers and managers will be crucial to implement the next generation of rabies management in Latin America.


Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism

Karl-Heinz Storbeck, Lina Schiffer, Elizabeth S Baranowski, Vasileios Chortis, Alessandro Prete, Lise Barnard, Lorna C Gilligan, Angela E Taylor, Jan Idkowiak, Wiebke Arlt, Cedric H L Shackleton

Department of Biochemistry, Stellenbosch University, Stellenbosch, South Africa

Wellcome Trust, Wellcome Trust, Medical Research Council, Medical Research Council, Diabetes UK, Academy of Medical Sciences UK

Abstract: AbstractSteroid biosynthesis and metabolism are reflected by the serum steroid metabolome and, in even more detail, by the 24-hour urine steroid metabolome, which can provide unique insights into alterations of steroid flow and output indicative of underlying conditions. Mass spectrometry–based steroid metabolome profiling has allowed for the identification of unique multisteroid signatures associated with disorders of steroid biosynthesis and metabolism that can be used for personalized approaches to diagnosis, differential diagnosis, and prognostic prediction. Additionally, steroid metabolome analysis has been used successfully as a discovery tool, for the identification of novel steroidogenic disorders and pathways as well as revealing insights into the pathophysiology of adrenal disease. Increased availability and technological advances in mass spectrometry–based methodologies have refocused attention on steroid metabolome profiling and facilitated the development of high-throughput steroid profiling methods soon to reach clinical practice. Furthermore, steroid metabolomics, the combination of mass spectrometry–based steroid analysis with machine learning–based approaches, has facilitated the development of powerful customized diagnostic approaches. In this review, we provide a comprehensive up-to-date overview of the utility of steroid metabolome analysis for the diagnosis and management of inborn disorders of steroidogenesis and autonomous adrenal steroid excess in the context of adrenal tumors.


11-Oxygenated Estrogens Are a Novel Class of Human Estrogens but Do not Contribute to the Circulating Estrogen Pool

Lise Barnard, Lina Schiffer, Renate Louw du-Toit, Jennifer A Tamblyn, Shiuan Chen, Donita Africander, Wiebke Arlt, Paul A Foster, Karl-Heinz Storbeck

Department of Biochemistry, Stellenbosch University, Matieland, South Africa

Academy of Medical Sciences, Wellcome Trust, National Research Foundation, National Institutes of Health, National Institutes of Health, University of Birmingham

Abstract: Abstract Androgens are the obligatory precursors of estrogens. In humans, classic androgen biosynthesis yields testosterone, thought to represent the predominant circulating active androgen both in men and women. However, recent work has shown that 11-ketotestosterone, derived from the newly described 11-oxygenated androgen biosynthesis pathway, makes a substantial contribution to the active androgen pool in women. Considering that classic androgens are the obligatory substrates for estrogen biosynthesis catalyzed by cytochrome P450 aromatase, we hypothesized that 11-oxygenated androgens are aromatizable. Here we use steroid analysis by tandem mass spectrometry to demonstrate that human aromatase generates 11-oxygenated estrogens from 11-oxygenated androgens in 3 different cell-based aromatase expression systems and in human ex vivo placenta explant cultures. We also show that 11-oxygenated estrogens are generated as a byproduct of the aromatization of classic androgens. We show that 11β-hydroxy-17β-estradiol binds and activates estrogen receptors α and β and that 11β-hydroxy-17β-estradiol and the classic androgen pathway-derived active estrogen, 17β-estradiol, are equipotent in stimulating breast cancer cell line proliferation and expression of estrogen-responsive genes. 11-oxygenated estrogens were, however, not detectable in serum from individuals with high aromatase levels (pregnant women) and elevated 11-oxygenated androgen levels (patients with congenital adrenal hyperplasia or adrenocortical carcinoma). Our data show that while 11-oxygenated androgens are aromatizable in vitro and ex vivo, the resulting 11-oxygenated estrogens are not detectable in circulation, suggesting that 11-oxygenated androgens function primarily as androgens in vivo.


Psychosocial factors, health behaviors and risk of cancer incidence: Testing interaction and effect modification in an individual participant data meta‐analysis

Maartje Basten, Kuan‐Yu Pan, Lonneke A. van Tuijl, Alexander de Graeff, Joost Dekker, Adriaan W. Hoogendoorn, Femke Lamers, Adelita V. Ranchor, Roel Vermeulen, Lützen Portengen, Adri C. Voogd, Jessica Abell, Philip Awadalla, Aartjan T. F. Beekman, Ottar Bjerkeset, Andy Boyd, Yunsong Cui, Philipp Frank, Henrike Galenkamp, Bert Garssen, Sean Hellingman, Martijn Huisman, Anke Huss, Melanie R. Keats, Almar A. L. Kok, Steinar Krokstad, Flora E. van Leeuwen, Annemarie I. Luik, Nolwenn Noisel, Yves Payette, Brenda W. J. H. Penninx, Ina Rissanen, Annelieke M. Roest, Judith G. M. Rosmalen, Rikje Ruiter, Robert A. Schoevers, David Soave, Mandy Spaan, Andrew Steptoe, Karien Stronks, Erik R. Sund, Ellen Sweeney, Emma L. Twait, Alison Teyhan, W. M. Monique Verschuren, Kimberly D. van der Willik, Mirjam I. Geerlings

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht and Utrecht University  Utrecht The Netherlands

KWF Kankerbestrijding, Medical Research Council, Wellcome Trust, National Institute on Aging, National Institute for Health and Care Research, ZonMw

Abstract: AbstractDepression, anxiety and other psychosocial factors are hypothesized to be involved in cancer development. We examined whether psychosocial factors interact with or modify the effects of health behaviors, such as smoking and alcohol use, in relation to cancer incidence. Two‐stage individual participant data meta‐analyses were performed based on 22 cohorts of the PSYchosocial factors and CAncer (PSY‐CA) study. We examined nine psychosocial factors (depression diagnosis, depression symptoms, anxiety diagnosis, anxiety symptoms, perceived social support, loss events, general distress, neuroticism, relationship status), seven health behaviors/behavior‐related factors (smoking, alcohol use, physical activity, body mass index, sedentary behavior, sleep quality, sleep duration) and seven cancer outcomes (overall cancer, smoking‐related, alcohol‐related, breast, lung, prostate, colorectal). Effects of the psychosocial factor, health behavior and their product term on cancer incidence were estimated using Cox regression. We pooled cohort‐specific estimates using multivariate random‐effects meta‐analyses. Additive and multiplicative interaction/effect modification was examined. This study involved 437,827 participants, 36,961 incident cancer diagnoses, and 4,749,481 person years of follow‐up. Out of 744 combinations of psychosocial factors, health behaviors, and cancer outcomes, we found no evidence of interaction. Effect modification was found for some combinations, but there were no clear patterns for any particular factors or outcomes involved. In this first large study to systematically examine potential interaction and effect modification, we found no evidence for psychosocial factors to interact with or modify health behaviors in relation to cancer incidence. The behavioral risk profile for cancer incidence is similar in people with and without psychosocial stress.


Inhibition of the glucocorticoid‐activating enzyme 11β‐hydroxysteroid dehydrogenase type 1 drives concurrent 11‐oxygenated androgen excess

Lina Schiffer, Imken Oestlund, Jacky L. Snoep, Lorna C. Gilligan, Angela E. Taylor, Alexandra J. Sinclair, Rishi Singhal, Adrian Freeman, Ramzi Ajjan, Ana Tiganescu, Wiebke Arlt, Karl‐Heinz Storbeck

Institute of Metabolism and Systems Research University of Birmingham  Birmingham UK

National Research Foundation, National Research Foundation, National Research Foundation, Academy of Medical Sciences, Wellcome Trust, Medical Research Council

Abstract: Abstract Aldo‐keto reductase 1C3 (AKR1C3) is a key enzyme in the activation of both classic and 11‐oxygenated androgens. In adipose tissue, AKR1C3 is co‐expressed with 11β‐hydroxysteroid dehydrogenase type 1 (HSD11B1), which catalyzes not only the local activation of glucocorticoids but also the inactivation of 11‐oxygenated androgens, and thus has the potential to counteract AKR1C3. Using a combination of in vitro assays and in silico modeling we show that HSD11B1 attenuates the biosynthesis of the potent 11‐oxygenated androgen, 11‐ketotestosterone (11KT), by AKR1C3. Employing ex vivo incubations of human female adipose tissue samples we show that inhibition of HSD11B1 results in the increased peripheral biosynthesis of 11KT. Moreover, circulating 11KT increased 2–3 fold in individuals with type 2 diabetes after receiving the selective oral HSD11B1 inhibitor AZD4017 for 35 days, thus confirming that HSD11B1 inhibition results in systemic increases in 11KT concentrations. Our findings show that HSD11B1 protects against excess 11KT production by adipose tissue, a finding of particular significance when considering the evidence for adverse metabolic effects of androgens in women. Therefore, when targeting glucocorticoid activation by HSD11B1 inhibitor treatment in women, the consequently increased generation of 11KT may offset beneficial effects of decreased glucocorticoid activation.


Loss of the Polyketide Synthase StlB Results in Stalk Cell Overproduction in Polysphondylium violaceum

Takaaki B Narita, Yoshinori Kawabe, Koryu Kin, Richard A Gibbs, Adam Kuspa, Donna M Muzny, Stephen Richards, Joan E Strassmann, Richard Sucgang, Kim C Worley, Pauline Schaap

School of Life Sciences, University of Dundee, United Kingdom

National Science Foundation, National Institutes of Health, Japanese Society for the Promotion of Science, Japanese Society for the Promotion of Science, European Molecular Biology Organisation, Wellcome Trust, European Research Council

Abstract: Abstract Major phenotypic innovations in social amoeba evolution occurred at the transition between the Polysphondylia and group 4 Dictyostelia, which comprise the model organism Dictyostelium discoideum, such as the formation of a new structure, the basal disk. Basal disk differentiation and robust stalk formation require the morphogen DIF-1, synthesized by the polyketide synthase StlB, the des-methyl-DIF-1 methyltransferase DmtA, and the chlorinase ChlA, which are conserved throughout Dictyostelia. To understand how the basal disk and other innovations evolved in group 4, we sequenced and annotated the Polysphondylium violaceum (Pvio) genome, performed cell type-specific transcriptomics to identify cell-type marker genes, and developed transformation and gene knock-out procedures for Pvio. We used the novel methods to delete the Pvio stlB gene. The Pvio stlB− mutants formed misshapen curly sorogens with thick and irregular stalks. As fruiting body formation continued, the upper stalks became more regular, but structures contained 40% less spores. The stlB− sorogens overexpressed a stalk gene and underexpressed a (pre)spore gene. Normal fruiting body formation and sporulation were restored in Pvio stlB− by including DIF-1 in the supporting agar. These data indicate that, although conserved, stlB and its product(s) acquired both a novel role in the group 4 Dictyostelia and a role opposite to that in its sister group.


A Comparative Analysis of Global Datasets and Initiatives for Urban Health and Sustainability

Jonathon Taylor, Andy Haines, James Milner, Mike Davies, Paul Wilkinson

Institute for Environmental Design and Engineering, University College London, Central House, 14 Upper Woburn Place, London WC1H 0NN, UK

Abstract: Globally, urban populations are growing rapidly, and in most cases their demands for resources are beyond current limits of sustainability. Cities are therefore critical for achieving national and international sustainability objectives, such as greenhouse gas reduction. Improving sustainability may also provide opportunities for urban population health co-benefits by reducing unhealthy exposures and behaviours. However, there is currently sparse empirical evidence on the degree to which city characteristics are associated with variations in health-related exposures, behaviours and sustainability. This paper examines the feasibility of aggregating empirical data relating to sustainability and health for global cities. An initial scoping review of existing English-language datasets and networks is performed. Resulting datasets are analysed for data types, collection method, and the distribution of contributing cities across climates, population sizes, and wealth. The review indicates datasets are populated using inconsistent methodologies and metrics and have poor overlap of cities between them. Data and organisations tend to be biased towards larger and wealthier cities, and concentrated in Europe and North America. Therefore, despite vast amounts of available data, limitations of reliability, representativeness, and disparate sources mean researchers are faced with significant obstacles when aggregating data to analyse the sustainability and health of globally representative samples of cities.


Structure and Properties of a Natural Competence-Associated Pilin Suggest a Unique Pilus Tip-Associated DNA Receptor

Mohd Zulkifli Salleh, Vijaykumar Karuppiah, Matthew Snee, Angela Thistlethwaite, Colin W. Levy, David Knight, Jeremy P. Derrick

Lydia Becker Institute of Immunology and Inflammation, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom

Terengganu State Government Foundation, Wellcome Trust

Abstract: Thermus thermophilus is a thermophilic bacterium which is capable of natural transformation, the uptake of external DNA with high efficiency. DNA uptake is thought to be mediated by a competence-associated pilus, which binds the DNA substrate and mediates its transfer across the outer membrane and periplasm. Here, we describe the structural and functional analysis of two pilins which are known to be essential for DNA uptake, ComZ and PilA2. ComZ adopts an unusual structure, incorporating a large β-solenoid domain into the pilin structural framework. We argue on structural grounds that this structure cannot readily be accommodated into the competence pilus fiber unless it is at the tip. We also show that ComZ binds DNA and identify two lysine residues which appear to be important for DNA binding. These results suggest a model in which ComZ and PilA2 form a tip-associated DNA receptor which mediates DNA uptake.