bluuebunny/crossref_metadata_2025 huggingface dataset:
Is the Atlantic a Source for Decadal Predictability of Sea‐Level Rise in Venice?
Authors: Zanchettin D. , Rubinetti S. , Rubino A.
Published: September 2022

Sea‐level rise is one of the most critical consequences of global warming, with potentially vast impacts on coastal environments and societies. Sea‐level changes are spatially and temporally heterogeneous on multiannual‐to‐multidecadal timescales. Here, we demonstrate that the observed rate of winter sea‐level rise in the Italian city of Venice contains significant multidecadal fluctuations, including interdecadal periods of near‐zero trend. Previous literature established a connection between the local sea‐level trend in Venice and over the broad subpolar and eastern North Atlantic. We demonstrate that for multidecadal variations in sea‐level trend such connection holds only since the mid‐20th Century. Such multidecadal sea‐level fluctuations relate to North Atlantic sea‐surface temperature changes described by the Atlantic multidecadal variability, or AMV. The link is explained by combined effect of AMV‐linked steric variations in the North Atlantic propagating in the Mediterranean Sea, and large‐scale atmospheric circulation anomalies over the North Atlantic with a local effect on sea level in Venice. We discuss the implications of such variability for near‐term predictability of winter sea‐level changes in Venice. Combining available sea‐level projections for Venice with a scenario of imminent AMV cooling yields a slowdown in the rate of sea‐level rise in Venice, with the possibility of mean values remaining even roughly constant in the next two decades as AMV effects contrast the expected long‐term sea‐level rise. Acknowledging, understanding, and communicating this multidecadal variability in local sea‐level rise is crucial for management and protection of this world‐class historical site.
Self‐Adaptive Multi‐Objective Climate Policies Align Mitigation and Adaptation Strategies
Authors: Carlino Angelo , Tavoni Massimo , Castelletti Andrea
Published: September 2022

Intensifying climate change impacts can divert the economic resources away from emission reduction toward adaptation to reduce rising damages, jeopardizing temperature stabilization within safe levels. Indeed, the traditional static welfare‐maximizing climate policy design leads to a conflict between mitigation and adaptation, invalidating the recently established consistency of cost‐benefit analysis with the Paris Agreement's targets. Here, we show that this tension can be resolved by integrating multi‐objective optimization and feedback control in the Dynamic Integrated Climate Economy model to design self‐adaptive climate policies trading off welfare maximization with the Paris Agreement compliance. These policies allow adjusting against uncertainty as information on the socio‐climatic system accumulates, thus representing the policy‐making process more realistically. We show that, the costs being the same as in traditional methods, warming above 2°C and the probability of overshooting can be drastically reduced, emphasizing the need for integrating adaptation and mitigation strategies and the value of embracing a self‐adaptive, multi‐objective perspective.
Widespread "Forever Chemicals" in Subsurface Environments
Authors: Wang Dengjun , Lyu Xueyan
Published: October 2022

Massive use of materials containing per- and polyfluoroalkyl substances in commercial and industrial sectors has led to their widespread occurrence in subsurface environments.
Greenland Interannual Ice Mass Variations Detected by GRACE Time‐Variable Gravity
Authors: Li Zhen , Chao Benjamin Fong , Zhang Zizhan , Jiang Liming , Wang Hansheng
Published: September 2022

To better understand the impact of climate forcing on Greenland ice sheet (GrIS), we study the GrIS mass variations on the interannual timescale as observed by the satellite mission of Gravity Recovery and Climate Experiment (GRACE). By employing the method of empirical orthogonal function) analysis, we find: (a) That the GrIS interannual mass variations are significantly correlated with the Pacific Decadal Oscillation, suggesting a connection to the changes of the Icelandic Low (a permanent low‐pressure system) related to PDO; (b) An East‐West Costal Dipole related to precipitation anomaly subjects to the North Atlantic Oscillation; (c) Certain contribution of the Atlantic Multidecadal Oscillation to GrIS mass variations in the form of temperature and runoff anomalies.
Impact of Grids and Dynamical Cores in CESM2.2 on the Surface Mass Balance of the Greenland Ice Sheet
Authors: Herrington Adam R. , Lauritzen Peter H. , Lofverstrom Marcus , Lipscomb William H. , Gettelman Andrew , Taylor Mark A.
Published: September 2022

Six different configurations, a mixture of grids and atmospheric dynamical cores available in the Community Earth System Model, version 2.2 (CESM2.2), are evaluated for their skill in representing the climate of the Arctic and the surface mass balance of the Greenland Ice Sheet (GrIS). The finite‐volume dynamical core uses structured, latitude‐longitude grids, whereas the spectral‐element dynamical core is built on unstructured meshes, permitting grid flexibility such as quasi‐uniform grid spacing globally. The 1°–2° latitude‐longitude and quasi‐uniform unstructured grids systematically overestimate both accumulation and ablation over the GrIS. Of these 1°–2° grids, the latitude‐longitude grids outperform the quasi‐uniform unstructured grids because they have more degrees of freedom to represent the GrIS. Two Arctic‐refined meshes, with 1/4° and 1/8° refinement over Greenland, were developed for the spectral‐element dynamical core and are documented here as newly supported configurations in CESM2.2. The Arctic meshes substantially improve the simulated clouds and precipitation rates in the Arctic. Over Greenland, these meshes skillfully represent accumulation and ablation processes, leading to a more realistic GrIS surface mass balance. As CESM is in the process of transitioning away from conventional latitude‐longitude grids, these new Arctic‐refined meshes improve the representation of polar processes in CESM by recovering resolution lost in the transition to quasi‐uniform grids, albeit at increased computational cost.
Refined Tectonic Evolution of the Betic‐Rif Orogen Through Integrated 3‐D Microstructural Analysis and Sm‐Nd Dating of Garnet Porphyroblasts
Authors: Aerden Domingo G. A. M. , Farrell Thomas P. , Baxter Ethan F. , Stewart Emily M. , Ruiz‐Fuentes Alejandro , Bouybaouene Mohamed
Published: September 2022

High‐resolution microstructural analysis of porphyroblast inclusion trails integrated with Sm‐Nd garnet geochronology has provided new insight into the tectonic history of the Betic‐Rif orogen. Three principal age groups of porphyroblasts are demonstrated with distinctly oriented inclusion‐trails. Inclusion‐trail curvature axes or “FIA” (Foliation Inflexion/Intersection Axes) are shown to represent “fossilized” crenulation axes from which a succession of different crustal shortening directions can be deduced. The regional consistency of microstructural orientations and their geometric relationship with multiple sets of macroscopic folds reveal the composite character of the Gibraltar Arc formed by a superposition of different folding directions and associated lineations. Bulk‐garnet ages of 35–22 Ma obtained from five micaschist samples of the Alpujarride‐Sebtide complex (ASC) and of 35–13 Ma from four micaschists of the Nevado‐Filabride complex (NFC) allow to deduce NNE‐SSW directed shortening in the Late Eocene changing to NW‐SE shortening in the early Oligocene, alternating with suborthogonal NE‐SW shortening during the Miocene. These directions can be related to a major swing in the direction of relative Africa‐Iberia plate‐motion known from kinematic modeling of magnetic seafloor anomalies, and subsequent dynamic interference between plate convergence and suborthogonal “tectonic escape” of the Alboran Domain. Coupled to previously established P‐T‐t paths, the new garnet ages support a common tectono‐metamorphic evolution of the ASC and NFC as laterally equivalent orogenic domains until, in the Miocene, the second became re‐buried under the first.
Engineered magnetic plant biobots for nerve agent removal
Authors: Song Su-Jin , Mayorga-Martinez Carmen C. , Huska Dalibor , Pumera Martin
Published: September 2022

Biohybrid micro/nanorobots that integrate biological entities with artificial nanomaterials have shown great potential in the field of biotechnology. However, commonly used physical hybridization approaches can lead to blockages and damage to biological interfaces, impeding the optimal exploitation of natural abilities. Here, we show that magnetically propelled plant biobots (MPBs), employing tomato-callus cultivation engineering in the presence of Fe3O4nanoparticles (NPs), are capable of active movement and directional guidance under a transversal rotating magnetic field. The Fe3O4NPs were transported through the cell growth media and then taken up into the plant tissue cells (PTCs), imparting the plant biobot with magnetic function. Moreover, Fe ions support the growth of callus cells, resulting in nanoparticle incorporation and enabling faster growth and structurally compact texture. The magnetic plant biobots demonstrated rapid and efficient removal of chlorpyrifos (approximately 80%), a hazardous nerve gas agent that causes severe acute toxicity, and recovery using an external magnetic field. The eco-friendly plant biobots described here demonstrate their potential in biomedical and environmental applications.
Synergistic interplay between photoisomerization and photoluminescence in a light-driven rotary molecular motor
Authors: Toyoda Ryojun , Hoang Nong V. , Moghaddam Kiana Gholamjani , Crespi Stefano , Pooler Daisy R. S. , Faraji Shirin , Pshenichnikov Maxim S. , Feringa Ben L.
Published: September 2022

Photoactuators and photoluminescent dyes utilize light to perform mechanical motion and undergo spontaneous radiation emission, respectively. Combining these two functionalities in a single molecule would benefit the construction of advanced molecular machines. Due to the possible detrimental interaction between the two light-dependent functional parts, the design of hybrid systems featuring both functions in parallel remains highly challenging. Here, we develop a light-driven rotary molecular motor with an efficient photoluminescent dye chemically attached to the motor, not compromising its motor function. This molecular system shows efficient rotary motion and bright photoluminescence, and these functions can be addressed by a proper choice of excitation wavelengths and solvents. The moderate interaction between the two parts generates synergistic effects, which are beneficial for lower-energy excitation and chirality transfer from the motor to the photoluminescent dye. Our results provide prospects towards photoactive multifunctional systems capable of carrying out molecular rotary motion and tracking its location in a complex environment.
Cement substitution with secondary materials can reduce annual global CO2 emissions by up to 1.3 gigatons
Authors: Shah Izhar Hussain , Miller Sabbie A. , Jiang Daqian , Myers Rupert J.
Published: September 2022

Population and development megatrends will drive growth in cement production, which is already one of the most challenging-to-mitigate sources of CO2 emissions. However, availabilities of conventional secondary cementitious materials (CMs) like fly ash are declining. Here, we present detailed generation rates of secondary CMs worldwide between 2002 and 2018, showing the potential for 3.5 Gt to be generated in 2018. Maximal substitution of Portland cement clinker with these materials could have avoided up to 1.3 Gt CO2-eq. emissions (~44% of cement production and ~2.8% of anthropogenic CO2-eq. emissions) in 2018. We also show that nearly all of the highest cement producing nations can locally generate and use secondary CMs to substitute up to 50% domestic Portland cement clinker, with many countries able to potentially substitute 100% Portland cement clinker. Our results highlight the importance of pursuing regionally optimized CM mix designs and systemic approaches to decarbonizing the global CMs cycle.
Decarbonization will lead to more equitable air quality in California
Authors: Zhu Shupeng , Mac Kinnon Michael , Carlos-Carlos Andrea , Davis Steven J. , Samuelsen Scott
Published: September 2022

Air quality associated public health co-benefit may emerge from climate and energy policies aimed at reducing greenhouse gas (GHG) emissions. However, the distribution of these co-benefits has not been carefully studied, despite the opportunity to tailor mitigation efforts so they achieve maximum benefits within socially and economically disadvantaged communities (DACs). Here, we quantify such health co-benefits from different long-term, low-carbon scenarios in California and their distribution in the context of social vulnerability. The magnitude and distribution of health benefits, including within impacted communities, is found to varies among scenarios which reduce economy wide GHG emissions by 80% in 2050 depending on the technology- and fuel-switching decisions in individual end-use sectors. The building electrification focused decarbonization strategy achieves ~15% greater total health benefits than the truck electrification focused strategy which uses renewable fuels to meet building demands. Conversely, the enhanced electrification of the truck sector is shown to benefit DACs more effectively. Such tradeoffs highlight the importance of considering environmental justice implications in the development of climate mitigation planning.
Magnetization switching in polycrystalline Mn3Sn thin film induced by self-generated spin-polarized current
Authors: Xie Hang , Chen Xin , Zhang Qi , Mu Zhiqiang , Zhang Xinhai , Yan Binghai , Wu Yihong
Published: September 2022

Electrical manipulation of spins is essential to design state-of-the-art spintronic devices and commonly relies on the spin current injected from a second heavy-metal material. The fact that chiral antiferromagnets produce spin current inspires us to explore the magnetization switching of chiral spins using self-generated spin torque. Here, we demonstrate the electric switching of noncollinear antiferromagnetic state in Mn3Sn by observing a crossover from conventional spin-orbit torque to the self-generated spin torque when increasing the MgO thickness in Ta/MgO/Mn3Sn polycrystalline films. The spin current injection from the Ta layer can be controlled and even blocked by varying the MgO thickness, but the switching sustains even at a large MgO thickness. Furthermore, the switching polarity reverses when the MgO thickness exceeds around 3 nm, which cannot be explained by the spin-orbit torque scenario due to spin current injection from the Ta layer. Evident current-induced switching is also observed in MgO/Mn3Sn and Ti/Mn3Sn bilayers, where external injection of spin Hall current to Mn3Sn is negligible. The inter-grain spin-transfer torque induced by spin-polarized current explains the experimental observations. Our findings provide an alternative pathway for electrical manipulation of non-collinear antiferromagnetic state without resorting to the conventional bilayer structure.
A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin
Authors: Qiu Deyun , Pei Jinxin V. , Rosling James E. O. , Thathy Vandana , Li Dongdi , Xue Yi , Tanner John D. , Penington Jocelyn Sietsma , Aw Yi Tong Vincent , Aw Jessica Yi Han , Xu Guoyue , Tripathi Abhai K. , Gnadig Nina F. , Yeo Tomas , Fairhurst Kate J. , Stokes Barbara H. , Murithi James M. , Kümpornsin Krittikorn , Hasemer Heath , Dennis Adelaide S. M. , Ridgway Melanie C. , Schmitt Esther K. , Straimer Judith , Papenfuss Anthony T. , Lee Marcus C. S. , Corry Ben , Sinnis Photini , Fidock David A. , van Dooren Giel G. , Kirk Kiaran , Lehane Adele M.
Published: September 2022

Diverse compounds target thePlasmodium falciparumNa+pump PfATP4, with cipargamin and (+)-SJ733 the most clinically-advanced. In a recent clinical trial for cipargamin, recrudescent parasites emerged, with most having a G358S mutation in PfATP4. Here, we show that PfATP4G358Sparasites can withstand micromolar concentrations of cipargamin and (+)-SJ733, while remaining susceptible to antimalarials that do not target PfATP4. The G358S mutation in PfATP4, and the equivalent mutation inToxoplasma gondiiATP4, decrease the sensitivity of ATP4 to inhibition by cipargamin and (+)-SJ733, thereby protecting parasites from disruption of Na+regulation. The G358S mutation reduces the affinity of PfATP4 for Na+and is associated with an increase in the parasite’s resting cytosolic [Na+]. However, no defect in parasite growth or transmissibility is observed. Our findings suggest that PfATP4 inhibitors in clinical development should be tested against PfATP4G358Sparasites, and that their combination with unrelated antimalarials may mitigate against resistance development.
FtsN maintains active septal cell wall synthesis by forming a processive complex with the septum-specific peptidoglycan synthases in E. coli
Authors: Lyu Zhixin , Yahashiri Atsushi , Yang Xinxing , McCausland Joshua W. , Kaus Gabriela M. , McQuillen Ryan , Weiss David S. , Xiao Jie
Published: September 2022

FtsN plays an essential role in promoting the inward synthesis of septal peptidoglycan (sPG) by the FtsWI complex during bacterial cell division. How it achieves this role is unclear. Here we use single-molecule tracking to investigate FtsN’s dynamics during sPG synthesis in E. coli. We show that septal FtsN molecules move processively at ~9 nm s−1, the same as FtsWI molecules engaged in sPG synthesis (termed sPG-track), but much slower than the ~30 nm s−1 speed of inactive FtsWI molecules coupled to FtsZ’s treadmilling dynamics (termed FtsZ-track). Importantly, processive movement of FtsN is exclusively coupled to sPG synthesis and is required to maintain active sPG synthesis by FtsWI. Our findings indicate that FtsN is part of the FtsWI sPG synthesis complex, and that while FtsN is often described as a “trigger” for the initiation for cell wall constriction, it must remain part of the processive FtsWI complex to maintain sPG synthesis activity.
Near-infrared-laser-navigated dancing bubble within water via a thermally conductive interface
Authors: Hu Man , Wang Feng , Chen Li , Huo Peng , Li Yuqi , Gu Xi , Chong Kai Leong , Deng Daosheng
Published: September 2022

Precise manipulation of droplets or bubbles hosts a broad range of applications for microfluidic devices, drug delivery, and soft robotics. Generally the existing approaches via passively designing structured surfaces or actively applying external stimuli, inherently confine their motions within the planar or curved geometry at a slow speed. Consequently the realization of 3D manipulation, such as of the underwater bubbles, remains challenging. Here, during the near-infrared-laser impacting on water, by simply introducing a thermally conductive interface, we unexpectedly observe a spontaneously bouncing bubble with hundreds-of-micrometer diameter at tens-of-Hertz frequency. The unique formation of temperature inversion layer in our system generates the depth-dependent thermal Marangoni force responsible for the bouncing behavior. Both the scaling analysis and numerical simulation agree with observations quantitatively. Furthermore, by controlling the navigation speed of the laser beam, the bubble not only shows excellent steerability with velocity up to 40 mm/s, but also exhibits distinctive behaviors from bouncing to dancing within water. We demonstrate the potential applications by steering the bubble within water to specifically interact with tiny objects, shedding light on the fabrication of bubble-based compositions in materials science and contamination removal in water treatment.
Chiral molecular imprinting-based SERS detection strategy for absolute enantiomeric discrimination
Authors: Arabi Maryam , Ostovan Abbas , Wang Yunqing , Mei Rongchao , Fu Longwen , Li Jinhua , Wang Xiaoyan , Chen Lingxin
Published: September 2022

Chiral discrimination is critical in environmental and life sciences. However, an ideal chiral discrimination strategy has not yet been developed because of the inevitable nonspecific binding entity of wrong enantiomers or insufficient intrinsic optical activities of chiral molecules. Here, we propose an “inspector” recognition mechanism (IRM), which is implemented on a chiral imprinted polydopamine (PDA) layer coated on surface-enhanced Raman scattering (SERS) tag layer. The IRM works based on the permeability change of the imprinted PDA after the chiral recognition and scrutiny of the permeability by an inspector molecule. Good enantiomer can specifically recognize and fully fill the chiral imprinted cavities, whereas the wrong cannot. Then a linear shape aminothiol molecule, as an inspector of the recognition status is introduced, which can only percolate through the vacant and nonspecifically occupied cavities, inducing the SERS signal to decrease. Accordingly, chirality information exclusively stems from good enantiomer specific binding, while nonspecific recognition of wrong enantiomer is curbed. The IRM benefits from sensitivity and versatility, enabling absolute discrimination of a wide variety of chiral molecules regardless of size, functional groups, polarities, optical activities, Raman scattering, and the number of chiral centers.
A shuttling-based two-qubit logic gate for linking distant silicon quantum processors
Authors: Noiri Akito , Takeda Kenta , Nakajima Takashi , Kobayashi Takashi , Sammak Amir , Scappucci Giordano , Tarucha Seigo
Published: September 2022

Control of entanglement between qubits at distant quantum processors using a two-qubit gate is an essential function of a scalable, modular implementation of quantum computation. Among the many qubit platforms, spin qubits in silicon quantum dots are promising for large-scale integration along with their nanofabrication capability. However, linking distant silicon quantum processors is challenging as two-qubit gates in spin qubits typically utilize short-range exchange coupling, which is only effective between nearest-neighbor quantum dots. Here we demonstrate a two-qubit gate between spin qubits via coherent spin shuttling, a key technology for linking distant silicon quantum processors. Coherent shuttling of a spin qubit enables efficient switching of the exchange coupling with an on/off ratio exceeding 1000, while preserving the spin coherence by 99.6% for the single shuttling between neighboring dots. With this shuttling-mode exchange control, we demonstrate a two-qubit controlled-phase gate with a fidelity of 93%, assessed via randomized benchmarking. Combination of our technique and a phase coherent shuttling of a qubit across a large quantum dot array will provide feasible path toward a quantum link between distant silicon quantum processors, a key requirement for large-scale quantum computation.
Probabilistic computing using Cu0.1Te0.9/HfO2/Pt diffusive memristors
Authors: Woo Kyung Seok , Kim Jaehyun , Han Janguk , Kim Woohyun , Jang Yoon Ho , Hwang Cheol Seong
Published: September 2022

A computing scheme that can solve complex tasks is necessary as the big data field proliferates. Probabilistic computing (p-computing) paves the way to efficiently handle problems based on stochastic units called probabilistic bits (p-bits). This study proposes p-computing based on the threshold switching (TS) behavior of a Cu0.1Te0.9/HfO2/Pt (CTHP) diffusive memristor. The theoretical background of the p-computing resembling the Hopfield network structure is introduced to explain the p-computing system. P-bits are realized by the stochastic TS behavior of CTHP diffusive memristors, and they are connected to form the p-computing network. The memristor-based p-bit is likely to be ‘0’ and ‘1’, of which probability is controlled by an input voltage. The memristor-based p-computing enables all 16 Boolean logic operations in both forward and inverted operations, showing the possibility of expanding its uses for complex operations, such as full adder and factorization.
Near-infrared phosphorescent carbon dots for sonodynamic precision tumor therapy
Authors: Geng Bijiang , Hu Jinyan , Li Yuan , Feng Shini , Pan Dengyu , Feng Lingyan , Shen Longxiang
Published: September 2022

Theranostic sonosensitizers with combined sonodynamic and near infrared (NIR) imaging modes are required for imaging guided sonodynamic therapy (SDT). It is challenging, however, to realize a single material that is simultaneously endowed with both NIR emitting and sonodynamic activities. Herein, we report the design of a class of NIR-emitting sonosensitizers from a NIR phosphorescent carbon dot (CD) material with a narrow bandgap (1.62 eV) and long-lived excited triplet states (11.4 μs), two of which can enhance SDT as thermodynamically and dynamically favorable factors under low-intensity ultrasound irradiation, respectively. The NIR-phosphorescent CDs are identified as bipolar quantum dots containing both p- and n-type surface functionalization regions that can drive spatial separation of e−–h+ pairs and fast transfer to reaction sites. Importantly, the cancer-specific targeting and high-level intratumor enrichment of the theranostic CDs are achieved by cancer cell membrane encapsulation for precision SDT with complete eradication of solid tumors by single injection and single irradiation. These results will open up a promising approach to engineer phosphorescent materials with long-lived triplet excited states for sonodynamic precision tumor therapy.
Household transmission of SARS-CoV-2 Omicron variant of concern subvariants BA.1 and BA.2 in Denmark
Authors: Lyngse Frederik Plesner , Kirkeby Carsten Thure , Denwood Matthew , Christiansen Lasse Engbo , Mølbak Kåre , Møller Camilla Holten , Skov Robert Leo , Krause Tyra Grove , Rasmussen Morten , Sieber Raphael Niklaus , Johannesen Thor Bech , Lillebaek Troels , Fonager Jannik , Fomsgaard Anders , Møller Frederik Trier , Stegger Marc , Overvad Maria , Spiess Katja , Mortensen Laust Hvas
Published: September 2022

SARS coronavirus 2 (SARS-CoV-2) continues to evolve and new variants emerge. Using nationwide Danish data, we estimate the transmission dynamics of SARS-CoV-2 Omicron subvariants BA.1 and BA.2 within households. Among 22,678 primary cases, we identified 17,319 secondary infections among 50,588 household contacts during a 1–7 day follow-up. The secondary attack rate (SAR) was 29% and 39% in households infected with Omicron BA.1 and BA.2, respectively. BA.2 was associated with increased susceptibility of infection for unvaccinated household contacts (Odds Ratio (OR) 1.99; 95%–CI 1.72-2.31), fully vaccinated contacts (OR 2.26; 95%–CI 1.95–2.62) and booster-vaccinated contacts (OR 2.65; 95%–CI 2.29–3.08), compared to BA.1. We also found increased infectiousness from unvaccinated primary cases infected with BA.2 compared to BA.1 (OR 2.47; 95%–CI 2.15–2.84), but not for fully vaccinated (OR 0.66; 95%–CI 0.57–0.78) or booster-vaccinated primary cases (OR 0.69; 95%–CI 0.59–0.82). Omicron BA.2 is inherently more transmissible than BA.1. Its immune-evasive properties also reduce the protective effect of vaccination against infection, but do not increase infectiousness of breakthrough infections from vaccinated individuals.
Inositol hexakisphosphate is required for Integrator function
Authors: Lin Min-Han , Jensen Madeline K. , Elrod Nathan D. , Huang Kai-Lieh , Welle Kevin A. , Wagner Eric J. , Tong Liang
Published: September 2022

Integrator is a multi-subunit protein complex associated with RNA polymerase II (Pol II), with critical roles in noncoding RNA 3′-end processing and transcription attenuation of a broad collection of mRNAs. IntS11 is the endonuclease for RNA cleavage, as a part of the IntS4-IntS9-IntS11 Integrator cleavage module (ICM). Here we report a cryo-EM structure of theDrosophilaICM, at 2.74 Å resolution, revealing stable association of an inositol hexakisphosphate (IP6) molecule. The IP6binding site is located in a highly electropositive pocket at an interface among all three subunits of ICM, 55 Å away from the IntS11 active site and generally conserved in other ICMs. We also confirmed IP6association with the same site in human ICM. IP6binding is not detected in ICM samples harboring mutations in this binding site. Such mutations or disruption of IP6biosynthesis significantly reduced Integrator function in snRNA 3′-end processing and mRNA transcription attenuation. Our structural and functional studies reveal that IP6is required for Integrator function inDrosophila, humans, and likely other organisms.
Crowding results from optimal integration of visual targets with contextual information
Authors: Cicchini Guido Marco , D’Errico Giovanni , Burr David Charles
Published: September 2022

Crowding is the inability to recognize an object in clutter, usually considered a fundamental low-level bottleneck to object recognition. Here we advance and test an alternative idea, that crowding, like predictive phenomena such as serial dependence, results from optimizing strategies that exploit redundancies in natural scenes. This notion leads to several testable predictions: crowding should be greatest for unreliable targets and reliable flankers; crowding-induced biases should be maximal when target and flankers have similar orientations, falling off for differences around 20°; flanker interference should be associated with higher precision in orientation judgements, leading to lower overall error rate; effects should be maximal when the orientation of the target is near that of the average of the flankers, rather than to that of individual flankers. Each of these predictions were supported, and could be simulated with ideal-observer models that maximize performance. The results suggest that while crowding can affect object recognition, it may be better understood not as a processing bottleneck, but as a consequence of efficient exploitation of the spatial redundancies of the natural world.
Single cell and spatial transcriptomic analyses reveal microglia-plasma cell crosstalk in the brain during Trypanosoma brucei infection
Authors: Quintana Juan F. , Chandrasegaran Praveena , Sinton Matthew C. , Briggs Emma M. , Otto Thomas D. , Heslop Rhiannon , Bentley-Abbot Calum , Loney Colin , de Lecea Luis , Mabbott Neil A. , MacLeod Annette
Published: September 2022

Human African trypanosomiasis, or sleeping sickness, is caused by the protozoan parasiteTrypanosoma bruceiand induces profound reactivity of glial cells and neuroinflammation when the parasites colonise the central nervous system. However, the transcriptional and functional responses of the brain to chronicT. bruceiinfection remain poorly understood. By integrating single cell and spatial transcriptomics of the mouse brain, we identify that glial responses triggered by infection are readily detected in the proximity to the circumventricular organs, including the lateral and 3rdventricle. This coincides with the spatial localisation of both slender and stumpy forms ofT. brucei. Furthermore, in silico predictions and functional validations led us to identify a previously unknown crosstalk between homeostatic microglia andCd138+plasma cells mediated by IL-10 and B cell activating factor (BAFF) signalling. This study provides important insights and resources to improve understanding of the molecular and cellular responses in the brain during infection with African trypanosomes.
Reducing data dimension boosts neural network-based stage-specific malaria detection
Authors: Preißinger Katharina , Kellermayer Miklós , Vértessy Beáta G. , Kézsmárki István , Török János
Published: September 2022

Although malaria has been known for more than 4 thousand years1, it still imposes a global burden with approx. 240 million annual cases2. Improvement in diagnostic techniques is a prerequisite for its global elimination. Despite its main limitations, being time-consuming and subjective, light microscopy on Giemsa-stained blood smears is still the gold-standard diagnostic method used worldwide. Autonomous computer assisted recognition of malaria infected red blood cells (RBCs) using neural networks (NNs) has the potential to overcome these deficiencies, if a fast, high-accuracy detection can be achieved using low computational power and limited sets of microscopy images for training the NN. Here, we report on a novel NN-based scheme that is capable of the high-speed classification of RBCs into four categories—healthy ones and three classes of infected ones according to the parasite age—with an accuracy as high as 98%. Importantly, we observe that a smart reduction of data dimension, using characteristic one-dimensional cross-sections of the RBC images, not only speeds up the classification but also significantly improves its performance with respect to the usual two-dimensional NN schemes. Via comparative studies on RBC images recorded by two additional techniques, fluorescence and atomic force microscopy, we demonstrate that our method is universally applicable for different types of microscopy images. This robustness against imaging platform-specific features is crucial for diagnostic applications. Our approach for the reduction of data dimension could be straightforwardly generalised for the classification of different parasites, cells and other types of objects.
Exosomal telomerase transcripts reprogram the microRNA transcriptome profile of fibroblasts and partially contribute to CAF formation
Authors: Likonen Daniela , Pinchasi Maria , Beery Einat , Sarsor Zinab , Signorini Lorenzo Federico , Gervits Asia , Sharan Roded , Lahav Meir , Raanani Pia , Uziel Orit
Published: September 2022

It is now well accepted that cancer cells change their microenvironment from normal to tumor-supportive state to provide sustained tumor growth, metastasis and drug resistance. These processes are partially carried out by exosomes, nano-sized vesicles secreted from cells, shuttled from donor to recipient cells containing a cargo of nucleic acids, proteins and lipids. By transferring biologically active molecules, cancer-derived exosomes may transform microenvironmental cells to become tumor supportive. Telomerase activity is regarded as a hallmark of cancer. We have recently shown that the transcript of human telomerase reverse transcriptase (hTERT), is packaged in cancer cells derived- exosomes. Following the engulfment of the hTERT transcript into fibroblasts, it is translated into a fully active enzyme [after assembly with its RNA component (hTERC) subunit]. Telomerase activity in the recipient, otherwise telomerase negative cells, provides them with a survival advantage. Here we show that exosomal telomerase might play a role in modifying normal fibroblasts into cancer associated fibroblasts (CAFs) by upregulating $$\mathrm{\alpha }$$
α
SMA and Vimentin, two CAF markers. We also show that telomerase activity changes the transcriptome of microRNA in these fibroblasts. By ectopically expressing microRNA 342, one of the top identified microRNAs, we show that it may mediate the proliferative phenotype that these cells acquire upon taking-up exosomal hTERT, providing them with a survival advantage.
Exosomal miRNA-21 from Toxoplasma gondii-infected microglial cells induces the growth of U87 glioma cells by inhibiting tumor suppressor genes
Authors: Jung Bong-Kwang , Song Hyemi , Shin Hyejoo , Chai Jong-Yil
Published: September 2022

Toxoplasma gondii is an intracellular protozoan parasite that can modulate the microenvironment of infected hosts and is known to be associated with the incidence of brain tumor growth. In this study, we suggested that the exosomal microRNA-21 derived from Toxoplasma infection would contribute to the growth of brain tumors. Exosomes of BV2 microglial cells infected with Toxoplasma were characterized and confirmed internalization to U87 glioma cells. Exosomal miRNA expression profiles were analyzed using microRNA array and miR-21A-5p associated with Toxoplasma and tumor sorted. We also examined the mRNA level of tumor-associated genes in U87 glioma cells by changing the level of miR-21 within exosomes and the effects of exosomes on the proliferation of human U87 glioma cells. Expression of miRNA-21 was increased and anti-tumorigenic genes (FoxO1, PTEN, and PDCD4) were decreased in exosomes within T. gondii-infected U87 glioma cells. Toxoplasma-infected BV2-derived exosomes induced proliferation of U87 glioma cells. The exosomes induced the growth of U87 cells in a mouse tumor model. We suggest that the increased exosomal miR-21 from Toxoplasma-infected BV2 microglial cells may play an important role as a cell growth promotor of U87 glioma cells through a down-regulation of anti-tumorigenic genes.
Identification of hydantoin based Decaprenylphosphoryl-β-d-Ribose Oxidase (DprE1) inhibitors as antimycobacterial agents using computational tools
Authors: Mali Suraj N. , Pandey Anima , Bhandare Richie R. , Shaik Afzal B.
Published: September 2022

Tuberculosis (TB) is one of the emerging infectious diseases in the world. DprE1 (Decaprenylphosphoryl-β-d-ribose 2′-epimerase), an enzyme accountable for mycobacterial cell wall synthesis was the first drug gable target based on discoveries of inhibitors via HTS (high throughput screening). Since then, many literature reports have been published so far enlightening varieties of chemical scaffolds acting as inhibitors of DprE1. Herein, in our present study, we have developed statistically robust GA-MLR (genetic algorithm multiple linear regression), atom-based as well as field based-3D-QSAR models. Both atom-based as well as field based-3D-QSAR models (internally as well as externally validated) were obtained with robust Training set, R2 > 0.69 and Test set, Q2 > 0.50. We have also developed top ranked 5 point hypothesis AAAHR_1 among 14 CPHs (common pharmacophore hypotheses). We found that our dataset molecule had more docking score (XP mode = − 9.068 kcal/mol) than the standards isoniazid and ethambutol; when docked into binding pockets of enzyme 4P8C with Glide module. We further queried our best docked dataset molecule 151 for ligand based virtual screening using “SwissSimilarity” platform. Among 9 identified hits, we found ZINC12196803 had best binding energies and docking score (docking score = − 9.437 kcal/mol, MMGBSA dgBind = − 70.508 kcal/mol). Finally, our molecular dynamics studies for 1.2–100 ns depicts that these complexes are stable. We have also carried out in-silico ADMET predictions, Cardiac toxicity, ‘SwissTargetPredictions’ and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding energy calculations for further explorations of dataset as well as hit molecules. Our current studies showed that the hit molecule ZINC12196803 may enlighten the path for future developments of DprE1 inhibitors.
Influence of electrode potential, pH and NAD+ concentration on the electrochemical NADH regeneration
Authors: Aamer Emad , Thöming Jorg , Baune Michael , Reimer Nicholas , Dringen Ralf , Romero Manuela , Bösing Ingmar
Published: September 2022

Electrochemical NAD+ reduction is a promising method to regenerate NADH for enzymatic reactions. Many different electrocatalysts have been tested in the search for high yields of the 1,4-isomer of NADH, the active NADH, but aside from electrode material, other system parameters such as pH, electrode potential and educt concentration also play a role in NADH regeneration. The effect of these last three parameters and the mechanisms behind their influence on NADH regeneration was systematically studied and presented in this paper. With percentages of active NADH ranging from 10 to 70% and faradaic efficiencies between 1 and 30%, it is clear that all three system parameters drastically affect the reaction outcome. As a proof of principle, the NAD+ reduction in the presence of pyruvate and lactate dehydrogenase was performed. It could be shown that the electrochemical NADH regeneration can also be done successfully in parallel to enzymatically usage of the regenerated cofactor.
Environment is associated with chytrid infection and skin microbiome richness on an amphibian rich island (Taiwan)
Authors: Schmeller Dirk S. , Cheng Tina , Shelton Jennifer , Lin Chun-Fu , Chan-Alvarado Alan , Bernardo-Cravo Adriana , Zoccarato Luca , Ding Tzung-Su , Lin Yu-Pin , Swei Andrea , Fisher Matthew C. , Vredenburg Vance T. , Loyau Adeline
Published: September 2022

Growing evidence suggests that the origins of the panzootic amphibian pathogens Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal) are in Asia. In Taiwan, an island hotspot of high amphibian diversity, no amphibian mass mortality events linked to Bd or Bsal have been reported. We conducted a multi-year study across this subtropical island, sampling 2517 individuals from 30 species at 34 field sites, between 2010 and 2017, and including 171 museum samples collected between 1981 and 2009. We analyzed the skin microbiome of 153 samples (6 species) from 2017 in order to assess any association between the amphibian skin microbiome and the probability of infection amongst different host species. We did not detect Bsal in our samples, but found widespread infection by Bd across central and northern Taiwan, both taxonomically and spatially. Museum samples show that Bd has been present in Taiwan since at least 1990. Host species, geography (elevation), climatic conditions and microbial richness were all associated with the prevalence of infection. Host life-history traits, skin microbiome composition and phylogeny were associated with lower prevalence of infection for high altitude species. Overall, we observed low prevalence and burden of infection in host populations, suggesting that Bd is enzootic in Taiwan where it causes subclinical infections. While amphibian species in Taiwan are currently threatened by habitat loss, our study indicates that Bd is in an endemic equilibrium with the populations and species we investigated. However, ongoing surveillance of the infection is warranted, as changing environmental conditions may disturb the currently stable equilibrium.
GnRH agonist-triggering ovulation in women with advanced age
Authors: Rahav Koren Roni , Miller Netanella , Moran Rimon , Decter Dean , Berkowitz Arie , Haikin Herzberger Einat , Wiser Amir
Published: September 2022

This study evaluates the effect of GnRH agonist (GnRHa) trigger for ovulation induction among women with advanced maternal age (AMA). This is a retrospective study performed at a single assisted reproductive technology centre, 2012 to 2020. A total of 306 patients with 515 IVF cycles who were triggered with GnRHa for Ovum Pick Up (OPU), were divided into two groups according to maternal age: age ≥ 40 and age < 40. The groups were compared for demographics, stimulation parameters of IVF treatment and IVF treatment outcomes. The patients in the age < 40 group were approximately 10 years younger than the patients in the age ≥ 40 group (31 ± 5.4 vs. 41.5 ± 1.3 years, p < 0.001). The age ≥ 40 group had significantly higher mean E2/retrieved oocytes ratio, compared to the age < 40 group (310.3 ± 200.6 pg/ml vs. 239 ± 168.2 pg/ml, p = 0.003), and a lower mean MII/retrieved oocyte (35 ± 37.8 vs. 43.4 ± 35.9, p = 0.05, respectively). Multivariable logistic regression analysis for E2/retrieved oocytes demonstrated that age < 40 and total dose of gonadotropins were significant variables. In conclusion, GnRHa for ovulation triggering in high responder patients prior to OPU appears to be a good option for AMA. However, this population is characterized by different parameters of ovarian response that require further evaluation.
Insight into the pulmonary molecular toxicity of heated tobacco products using human bronchial and alveolar mucosa models at air–liquid interface
Authors: Rahman Mizanur , Irmler Martin , Introna Micol , Beckers Johannes , Palmberg Lena , Johanson Gunnar , Upadhyay Swapna , Ganguly Koustav
Published: September 2022

Heated tobacco products (HTP) are novel nicotine delivery products with limited toxicological data. HTP uses heating instead of combustion to generate aerosol (HTP-smoke). Physiologically relevant human bronchial and alveolar lung mucosa models developed at air–liquid interface were exposed to HTP-smoke to assess broad toxicological response (n = 6–7; ISO puffing regimen; compared to sham; non-parametric statistical analysis; significance: p < 0.05). Elevated levels of total cellular reactive oxygen species, stress responsive nuclear factor kappa-B, and DNA damage markers [8-hydroxy-2′-deoxyguanosine, phosphorylated histone H2AX, cleaved poly-(ADP-Ribose) polymerase] were detected in HTP-smoke exposed bronchial and/or alveolar models. RNA sequencing detected differential regulation of 724 genes in the bronchial- and 121 genes in the alveolar model following HTP-smoke exposure (cut off: p ≤ 0.01; fold change: ≥ 2). Common enriched pathways included estrogen biosynthesis, ferroptosis, superoxide radical degradation, xenobiotics, and α-tocopherol degradation. Secreted levels of interleukin (IL)1ꞵ and IL8 increased in the bronchial model whereas in the alveolar model, interferon-γ and IL4 increased and IL13 decreased following HTP-smoke exposure. Increased lipid peroxidation was detected in HTP-smoke exposed bronchial and alveolar models which was inhibited by ferrostatin-1. The findings form a basis to perform independent risk assessment studies on different flavours of HTP using different puffing topography and corresponding chemical characterization.
Simultaneous monitoring of mouse grip strength, force profile, and cumulative force profile distinguishes muscle physiology following surgical, pharmacologic and diet interventions
Authors: Munier Joseph J. , Pank Justin T. , Severino Amie , Wang Huan , Zhang Peixiang , Vergnes Laurent , Reue Karen
Published: September 2022

Grip strength is a valuable preclinical assay to study muscle physiology in disease and aging by directly determining changes in muscle force generation in active laboratory mice. Existing methods to statistically evaluate grip strength, however, have limitations in the power and scope of the physiological features that are assessed. We therefore designed a microcontroller whose serial measure of resistance-based force enables the simultaneous readout of (1) peak grip strength, (2) force profile (the non-linear progress of force exerted throughout a standard grip strength trial), and (3) cumulative force profile (the integral of force with respect to time of a single grip strength trial). We hypothesized that muscle pathologies of different etiologies have distinct effects on these parameters. To test this, we used our apparatus to assess the three muscle parameters in mice with impaired muscle function resulting from surgically induced peripheral pain, genetic peripheral neuropathy, adverse muscle effects induced by statin drug, and metabolic alterations induced by a high-fat diet. Both surgically induced peripheral nerve injury and statin-associated muscle damage diminished grip strength and force profile, without affecting cumulative force profile. Conversely, genetic peripheral neuropathy resulting from lipin 1 deficiency led to a marked reduction to all three parameters. A chronic high-fat diet led to reduced grip strength and force profile when normalized to body weight. In high-fat fed mice that were exerted aerobically and allowed to recover for 30 min, male mice exhibited impaired force profile parameters, which female mice were more resilient. Thus, simultaneous analysis of peak grip strength, force profile and cumulative force profile distinguishes the muscle impairments that result from distinct perturbations and may reflect distinct motor unit recruitment strategies.