bluuebunny/crossref_metadata_2025_split huggingface dataset:
SMAD4 mutations do not preclude epithelial–mesenchymal transition in colorectal cancer
Authors: Frey Patrick , Devisme Antoine , Rose Katja , Schrempp Monika , Freihen Vivien , Andrieux Geoffroy , Boerries Melanie , Hecht Andreas 
Published: December 2021

AbstractTransforming growth factor beta (TGFβ) superfamily signaling is a prime inducer of epithelial-mesenchymal transitions (EMT) that foster cancer cell invasion and metastasis, a major cause of cancer-related deaths. Yet, TGFβ signaling is frequently inactivated in human tumor entities including colorectal cancer (CRC) and pancreatic adenocarcinoma (PAAD) with a high proportion of mutations incapacitating SMAD4, which codes for a transcription factor (TF) central to canonical TGFβ and bone morphogenetic protein (BMP) signaling. Beyond its role in initiating EMT, SMAD4 was reported to crucially contribute to subsequent gene regulatory events during EMT execution. It is therefore widely assumed that SMAD4-mutant (SMAD4mut) cancer cells are unable to undergo EMT. Here, we scrutinized this notion and probed for potential SMAD4-independent EMT execution using SMAD4mut CRC cell lines. We show that SMAD4mut cells exhibit morphological changes, become invasive, and regulate EMT marker genes upon induction of the EMT-TF SNAIL1. Furthermore, SNAIL1-induced EMT in SMAD4mut cells was found to be entirely independent of TGFβ/BMP receptor activity. Global assessment of the SNAIL1-dependent transcriptome confirmed the manifestation of an EMT gene regulatory program in SMAD4mut cells highly related to established EMT signatures. Finally, analyses of human tumor transcriptomes showed that SMAD4 mutations are not underrepresented in mesenchymal tumor samples and that expression patterns of EMT-associated genes are similar in SMAD4mut and SMAD4 wild-type (SMAD4wt) cases. Altogether, our findings suggest that alternative TFs take over the gene regulatory functions of SMAD4 downstream of EMT-TFs, arguing for considerable plasticity of gene regulatory networks operating in EMT execution. Further, they establish that EMT is not categorically precluded in SMAD4mut tumors, which is relevant for their diagnostic and therapeutic evaluation.
The NSP14/NSP10 RNA repair complex as a Pan-coronavirus therapeutic target
Authors: Rona Gergely , Zeke Andras , Miwatani-Minter Bearach , de Vries Maren , Kaur Ramanjit , Schinlever Austin , Garcia Sheena Faye , Goldberg Hailey V. , Wang Hui , Hinds Thomas R. , Bailly Fabrice , Zheng Ning , Cotelle Philippe , Desmaële Didier , Landau Nathaniel R. , Dittmann Meike , Pagano Michele 
Published: December 2021

AbstractThe risk of zoonotic coronavirus spillover into the human population, as highlighted by the SARS-CoV-2 pandemic, demands the development of pan-coronavirus antivirals. The efficacy of existing antiviral ribonucleoside/ribonucleotide analogs, such as remdesivir, is decreased by the viral proofreading exonuclease NSP14-NSP10 complex. Here, using a novel assay and in silico modeling and screening, we identified NSP14-NSP10 inhibitors that increase remdesivir’s potency. A model compound, sofalcone, both inhibits the exonuclease activity of SARS-CoV-2, SARS-CoV, and MERS-CoV in vitro, and synergistically enhances the antiviral effect of remdesivir, suppressing the replication of SARS-CoV-2 and the related human coronavirus OC43. The validation of top hits from our primary screenings using cellular systems provides proof-of-concept for the NSP14 complex as a therapeutic target.
SET activation of nitroarenes by 2-azaallyl anions as a straightforward access to 2,5-dihydro-1,2,4-oxadiazoles
Authors: Zou Dong , Gan Lishe , Yang Fan , Wang Huan , Pu Youge , Li Jie , Walsh Patrick J. 
Published: December 2021

AbstractThe use of nitroarenes as amino sources in synthesis is challenging. Herein is reported an unusual, straightforward, and transition metal-free method for the net [3 + 2]-cycloaddition reaction of 2-azaallyl anions with nitroarenes. The products of this reaction are diverse 2,5-dihydro-1,2,4-oxadiazoles (>40 examples, up to 95% yield). This method does not require an external reductant to reduce nitroarenes, nor does it employ nitrosoarenes, which are often used in N–O cycloadditions. Instead, it is proposed that the 2-azaallyl anions, which behave as super electron donors (SEDs), deliver an electron to the nitroarene to generate a nitroarene radical anion. A downstream 2-azaallyl radical coupling with a newly formed nitrosoarene is followed by ring closure to afford the observed products. This proposed reaction pathway is supported by computational studies and experimental evidence. Overall, this method uses readily available materials, is green, and exhibits a broad scope.
Spin-neutral currents for spintronics
Authors: Shao Ding-Fu , Zhang Shu-Hui , Li Ming , Eom Chang-Beom , Tsymbal Evgeny Y. 
Published: December 2021

AbstractElectric currents carrying a net spin polarization are widely used in spintronics, whereas globally spin-neutral currents are expected to play no role in spin-dependent phenomena. Here we show that, in contrast to this common expectation, spin-independent conductance in compensated antiferromagnets and normal metals can be efficiently exploited in spintronics, provided their magnetic space group symmetry supports a non-spin-degenerate Fermi surface. Due to their momentum-dependent spin polarization, such antiferromagnets can be used as active elements in antiferromagnetic tunnel junctions (AFMTJs) and produce a giant tunneling magnetoresistance (TMR) effect. Using RuO2 as a representative compensated antiferromagnet exhibiting spin-independent conductance along the [001] direction but a non-spin-degenerate Fermi surface, we design a RuO2/TiO2/RuO2 (001) AFMTJ, where a globally spin-neutral charge current is controlled by the relative orientation of the Néel vectors of the two RuO2 electrodes, resulting in the TMR effect as large as ~500%. These results are expanded to normal metals which can be used as a counter electrode in AFMTJs with a single antiferromagnetic layer or other elements in spintronic devices. Our work uncovers an unexplored potential of the materials with no global spin polarization for utilizing them in spintronics.
High-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content
Authors: Granata Cesare , Caruana Nikeisha J. , Botella Javier , Jamnick Nicholas A. , Huynh Kevin , Kuang Jujiao , Janssen Hans A. , Reljic Boris , Mellett Natalie A. , Laskowski Adrienne , Stait Tegan L. , Frazier Ann E. , Coughlan Melinda T. , Meikle Peter J. , Thorburn David R. , Stroud David A. , Bishop David J. 
Published: December 2021

AbstractMitochondrial defects are implicated in multiple diseases and aging. Exercise training is an accessible, inexpensive therapeutic intervention that can improve mitochondrial bioenergetics and quality of life. By combining multiple omics techniques with biochemical and in silico normalisation, we removed the bias arising from the training-induced increase in mitochondrial content to unearth an intricate and previously undemonstrated network of differentially prioritised mitochondrial adaptations. We show that changes in hundreds of transcripts, proteins, and lipids are not stoichiometrically linked to the overall increase in mitochondrial content. Our findings suggest enhancing electron flow to oxidative phosphorylation (OXPHOS) is more important to improve ATP generation than increasing the abundance of the OXPHOS machinery, and do not support the hypothesis that training-induced supercomplex formation enhances mitochondrial bioenergetics. Our study provides an analytical approach allowing unbiased and in-depth investigations of training-induced mitochondrial adaptations, challenging our current understanding, and calling for careful reinterpretation of previous findings.
Find and cut-and-transfer (FiCAT) mammalian genome engineering
Authors: Pallarès-Masmitjà Maria , Ivančić Dimitrije , Mir-Pedrol Júlia , Jaraba-Wallace Jessica , Tagliani Tommaso , Oliva Baldomero , Rahmeh Amal , Sánchez-Mejías Avencia , Güell Marc 
Published: December 2021

AbstractWhile multiple technologies for small allele genome editing exist, robust technologies for targeted integration of large DNA fragments in mammalian genomes are still missing. Here we develop a gene delivery tool (FiCAT) combining the precision of a CRISPR-Cas9 (find module), and the payload transfer efficiency of an engineered piggyBac transposase (cut-and-transfer module). FiCAT combines the functionality of Cas9 DNA scanning and targeting DNA, with piggyBac donor DNA processing and transfer capacity. PiggyBac functional domains are engineered providing increased on-target integration while reducing off-target events. We demonstrate efficient delivery and programmable insertion of small and large payloads in cellulo (human (Hek293T, K-562) and mouse (C2C12)) and in vivo in mouse liver. Finally, we evolve more efficient versions of FiCAT by generating a targeted diversity of 394,000 variants and undergoing 4 rounds of evolution. In this work, we develop a precise and efficient targeted insertion of multi kilobase DNA fragments in mammalian genomes.
Revealing nano-scale lattice distortions in implanted material with 3D Bragg ptychography
Authors: Li Peng , Phillips Nicholas W. , Leake Steven , Allain Marc , Hofmann Felix , Chamard Virginie 
Published: December 2021

AbstractSmall ion-irradiation-induced defects can dramatically alter material properties and speed up degradation. Unfortunately, most of the defects irradiation creates are below the visibility limit of state-of-the-art microscopy. As such, our understanding of their impact is largely based on simulations with major unknowns. Here we present an x-ray crystalline microscopy approach, able to image with high sensitivity, nano-scale 3D resolution and extended field of view, the lattice strains and tilts in crystalline materials. Using this enhanced Bragg ptychography tool, we study the damage helium-ion-irradiation produces in tungsten, revealing a series of crystalline details in the 3D sample. Our results lead to the conclusions that few-atom-large ‘invisible’ defects are likely isotropic in orientation and homogeneously distributed. A partially defect-denuded region is observed close to a grain boundary. These findings open up exciting perspectives for the modelling of irradiation damage and the detailed analysis of crystalline properties in complex materials.
CRISPR-Cas9 effectors facilitate generation of single-sex litters and sex-specific phenotypes
Authors: Douglas Charlotte , Maciulyte Valdone , Zohren Jasmin , Snell Daniel M. , Mahadevaiah Shantha K. , Ojarikre Obah A. , Ellis Peter J. I. , Turner James M. A. 
Published: December 2021

AbstractAnimals are essential genetic tools in scientific research and global resources in agriculture. In both arenas, a single sex is often required in surplus. The ethical and financial burden of producing and culling animals of the undesired sex is considerable. Using the mouse as a model, we develop a synthetic lethal, bicomponent CRISPR-Cas9 strategy that produces male- or female-only litters with one hundred percent efficiency. Strikingly, we observe a degree of litter size compensation relative to control matings, indicating that our system has the potential to increase the yield of the desired sex in comparison to standard breeding designs. The bicomponent system can also be repurposed to generate postnatal sex-specific phenotypes. Our approach, harnessing the technological applications of CRISPR-Cas9, may be applicable to other vertebrate species, and provides strides towards ethical improvements for laboratory research and agriculture.
RIPK1 dephosphorylation and kinase activation by PPP1R3G/PP1γ promote apoptosis and necroptosis
Authors: Du Jingchun , Xiang Yougui , Liu Hua , Liu Shuzhen , Kumar Ashwani , Xing Chao , Wang Zhigao 
Published: December 2021

AbstractReceptor-interacting protein kinase 1 (RIPK1) is a key regulator of inflammation and cell death. Many sites on RIPK1, including serine 25, are phosphorylated to inhibit its kinase activity and cell death. How these inhibitory phosphorylation sites are dephosphorylated is poorly understood. Using a sensitized CRISPR whole-genome knockout screen, we discover that protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is required for RIPK1-dependent apoptosis and type I necroptosis. Mechanistically, PPP1R3G recruits its catalytic subunit protein phosphatase 1 gamma (PP1γ) to complex I to remove inhibitory phosphorylations of RIPK1. A PPP1R3G mutant which does not bind PP1γ fails to rescue RIPK1 activation and cell death. Furthermore, chemical prevention of RIPK1 inhibitory phosphorylations or mutation of serine 25 of RIPK1 to alanine largely restores cell death in PPP1R3G-knockout cells. Finally, Ppp1r3g−/− mice are protected from tumor necrosis factor-induced systemic inflammatory response syndrome, confirming the important role of PPP1R3G in regulating apoptosis and necroptosis in vivo.
Intrinsic cerebellar functional connectivity of social cognition and theory of mind in first-episode psychosis patients
Authors: Park Soo Hwan , Kim Taekwan , Ha Minji , Moon Sun-Young , Lho Silvia Kyungjin , Kim Minah , Kwon Jun Soo 
Published: December 2021

AbstractNeuroimaging studies have revealed how intrinsic dysconnectivity among cortical regions of the mentalizing network (MENT) and the mirror neuron system (MNS) could explain the theory of mind (ToM) deficit in schizophrenia patients. However, despite the concurrent involvement of the cerebellum with the cortex in social cognition, the dysfunction in intrinsic interplay between the cerebellar nodes of MENT/MNS and the cortex in schizophrenia patients remains unknown. Thus, we aimed to investigate whether resting-state cerebello–cortical dysconnectivity exists in first-episode psychosis (FEP) patients in relationship with their ToM deficit. A total of 37 FEP patients and 80 healthy controls (HCs) underwent resting-state functional magnetic resonance imaging. Using a priori-defined cerebellar seeds that functionally connect to the MENT (right crus II) and MNS (right crus I), we compared cerebello–cortical functional connectivities (FCs) in FEP patients and HCs. Correlations between cerebello–parietal connectivities and ToM performance were investigated in FEP patients. FEP patients showed hyperconnectivity between the right crus II and anterior cingulate gyrus and between the right crus I and supplementary motor area, bilateral postcentral gyrus, and right central/parietal operculum (CO/PO). Hypoconnectivity was found between the right crus II and left supramarginal gyrus (SMG) in FEP patients. FCs between the right crus II and left SMG and between the right crus I and right CO/PO were significantly correlated with ToM scores in FEP patients. In accordance with the “cognitive dysmetria” hypothesis, our results highlight the importance of cerbello-cortical dysconnectivities in understanding social cognitive deficits in schizophrenia patients.
Deep learning-based robust automatic non-invasive measurement of blood pressure using Korotkoff sounds
Authors: Chang Ji-Ho , Doh Il 
Published: December 2021

AbstractThis paper proposes a method that automatically measures non-invasive blood pressure (BP) based on an auscultatory approach using Korotkoff sounds (K-sounds). There have been methods utilizing K-sounds that were more accurate in general than those using cuff pressure signals only under well-controlled environments, but most were vulnerable to the measurement conditions and to external noise because blood pressure is simply determined based on threshold values in the sound signal. The proposed method enables robust and precise BP measurements by evaluating the probability that each sound pulse is an audible K-sound based on a deep learning using a convolutional neural network (CNN). Instead of classifying sound pulses into two categories, audible K-sounds and others, the proposed CNN model outputs probability values. These values in a Korotkoff cycle are arranged in time order, and the blood pressure is determined. The proposed method was tested with a dataset acquired in practice that occasionally contains considerable noise, which can degrade the performance of the threshold-based methods. The results demonstrate that the proposed method outperforms a previously reported CNN-based classification method using K-sounds. With larger amounts of various types of data, the proposed method can potentially achieve more precise and robust results.
Instability caused swimming of ferromagnetic filaments in pulsed field
Authors: Zaben Abdelqader , Kitenbergs Guntars , Cēbers Andrejs 
Published: December 2021

AbstractMagnetic filaments driven by external magnetic field are an interesting topic of research in-terms of the possible bio-medical applications. In this paper, we investigated the applicability of using ferromagnetic filaments as micro swimmers both experimentally and numerically. It was found that applying a pulse wave field profile with a duty cycle of 30$$\%$$
%
induced experimentally observable swimming, which is similar to the breast stroke of micro algae. Good agreement with numerical simulations was found. Moreover, for stable continuous swimming, an initial filament shape is required to avoid transition to the structurally preferred non-swimming S-like mode.
Interplay between eutrophication and climate warming on bacterial communities in coastal sediments differs depending on water depth and oxygen history
Authors: Seidel Laura , Broman Elias , Turner Stephanie , Ståhle Magnus , Dopson Mark 
Published: December 2021

AbstractCoastal aquatic systems suffer from nutrient enrichment, which results in accelerated eutrophication effects due to increased microbial metabolic rates. Climate change related prolonged warming will likely accelerate existing eutrophication effects, including low oxygen concentrations. However, how the interplay between these environmental changes will alter coastal ecosystems is poorly understood. In this study, we compared 16S rRNA gene amplicon based bacterial communities in coastal sediments of a Baltic Sea basin in November 2013 and 2017 at three sites along a water depth gradient with varying bottom water oxygen histories. The shallow site showed changes of only 1.1% in relative abundance of bacterial populations in 2017 compared to 2013, while the deep oxygen-deficient site showed up to 11% changes in relative abundance including an increase of sulfate-reducing bacteria along with a 36% increase in organic matter content. The data suggested that bacterial communities in shallow sediments were more resilient to seasonal oxygen decline, while bacterial communities in sediments subjected to long-term hypoxia seemed to be sensitive to oxygen changes and were likely to be under hypoxic/anoxic conditions in the future. Our data demonstrate that future climate changes will likely fuel eutrophication related spread of low oxygen zones.
Tropical bee species abundance differs within a narrow elevational gradient
Authors: Conrad Kristin M. , Peters Valerie E. , Rehan Sandra M. 
Published: December 2021

AbstractInsect pollination is among the most essential ecosystem services for humanity. Globally, bees are the most effective pollinators, and tropical bees are also important for maintaining tropical biodiversity. Despite their invaluable pollination service, basic distributional patterns of tropical bees along elevation gradients are globally scarce. Here, we surveyed bees at 100 m elevation intervals from 800 to 1100 m elevation in Costa Rica to test if bee abundance, community composition and crop visitor assemblages differed by elevation. We found that 18 of 24 bee species spanning three tribes that represented the most abundantly collected bee species showed abundance differences by elevation, even within this narrow elevational gradient. Bee assemblages at the two crop species tested, avocado and squash, showed community dissimilarity between high and low elevations, and elevation was a significant factor in explaining bee community composition along the gradient. Stingless bees (Tribe Meliponini) were important visitors to both crop species, but there was a more diverse assemblage of bees visiting avocado compared to squash. Our findings suggest that successful conservation of tropical montane bee communities and pollination services will require knowledge of which elevations support the highest numbers of each species, rather than species full altitudinal ranges.
Robust anticipation of continuous steering actions from electroencephalographic data during simulated driving
Authors: Di Liberto Giovanni M. , Barsotti Michele , Vecchiato Giovanni , Ambeck-Madsen Jonas , Del Vecchio Maria , Avanzini Pietro , Ascari Luca 
Published: December 2021

AbstractDriving a car requires high cognitive demands, from sustained attention to perception and action planning. Recent research investigated the neural processes reflecting the planning of driving actions, aiming to better understand the factors leading to driving errors and to devise methodologies to anticipate and prevent such errors by monitoring the driver’s cognitive state and intention. While such anticipation was shown fordiscretedriving actions, such as emergency braking, there is no evidence for robust neural signatures ofcontinuousaction planning. This study aims to fill this gap by investigating continuous steering actions during a driving task in a car simulator with multimodal recordings of behavioural and electroencephalography (EEG) signals. System identification is used to assess whether robust neurophysiological signatures emerge before steering actions. Linear decoding models are then used to determine whether such cortical signals can predict continuous steering actions with progressively longer anticipation. Results point to significant EEG signatures of continuous action planning. Such neural signals show consistent dynamics across participants for anticipations up to 1 s, while individual-subject neural activity could reliably decode steering actions and predict future actions for anticipations up to 1.8 s. Finally, we use canonical correlation analysis to attempt disentangling brain and non-brain contributors to the EEG-based decoding. Our results suggest that low-frequency cortical dynamics are involved in the planning of steering actions and that EEG is sensitive to that neural activity. As a result, we propose a framework to investigate anticipatory neural activity in realistic continuous motor tasks.