bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptive anti-tumor immunity is orchestrated by a population of CCL5-producing tissue-resident NK cells
Authors: Kirchhammer Nicole , Trefny Marcel P , Natoli Marina , Brücher Dominik , Smith Sheena N , Werner Franziska , Koch Victoria , Schreiner David , Bartoszek Ewelina , Buchi Mélanie , Schmid Markus , Breu Daniel , Hartmann K Patricia , Zaytseva Polina , Thommen Daniela S , Läubli Heinz , Böttcher Jan P , Stanczak Michal A , Kashyap Abhishek S , Plückthun Andreas , Zippelius Alfred 
Published: May 2021

AbstractT cell-directed cancer immunotherapy often fails to generate lasting tumor control. Harnessing additional effectors of the immune response against tumors may strengthen the clinical benefit of immunotherapies. Here, we demonstrate that therapeutic targeting of the IFNγ-IL-12 pathway relies on the ability of a population of tissue-resident NK (trNK) cells to orchestrate an anti-tumor microenvironment. Particularly, utilizing an engineered adenoviral platform, we show that paracrine IL-12 enhances functional DC-CD8 T cell interactions to generate adaptive anti-tumor immunity. This effect depends on the abundance of trNK cells and specifically their capacity to produce the cDC1-chemoattractant CCL5. Failure to respond to IL-12 and other IFNγ-inducing therapies such as immune checkpoint blockade in tumors with low trNK cell infiltration could be overcome by intra-tumoral delivery of CCL5. Our findings reveal a novel barrier for T cell-focused therapies and offer mechanistic insights into how T cell-NK cell-DC crosstalk can be enhanced to promote anti-tumor immunity and overcome resistance.SignificanceWe identified the lack of CCL5-producing, tissue-resident NK (trNK) cells as a barrier to T cell-focused therapies. While IL-12 induces anti-tumoral DC-T cell crosstalk in trNK cellrichtumors, resistance to IL-12 or anti-PD-1 in trNK cellpoortumors can be overcome by the additional delivery of CCL5.
A deep-learning-based toolbox for Automated Limb Motion Analysis (ALMA) in murine models of neurological disorders
Authors: Aljovic Almir , Zhao Shuqing , Chahin Maryam , de la Rosa del Val Clara , Van Steenbergen Valerie , Kerschensteiner Martin , Bareyre Florence M 
Published: May 2021

AbstractIn neuroscience research, the refined analysis of rodent locomotion is complex and cumbersome, and access to the technique is limited because of the necessity for expensive equipment. In this study, we implemented a new deep-learning-based toolbox for Automated Limb Motion Analysis (ALMA) that requires only basic behavioral equipment and an inexpensive camera. The ALMA toolbox enables the unbiased and comprehensive analyses of locomotor kinematics and paw placement and can be applied to neurological conditions affecting the brain and spinal cord. We demonstrated that the ALMA toolbox can (1) robustly track the evolution of locomotor deficits after spinal cord injury, (2) sensitively detect locomotor abnormalities after traumatic brain injury, and (3) correctly predict disease onset in a multiple sclerosis model. We, therefore, established a broadly applicable automated and standardized approach that requires minimal financial and time commitments to facilitate the comprehensive analysis of locomotion in rodent disease models.
Oligodendrocyte precursor cells guide the migration of cortical interneurons by unidirectional contact repulsion
Authors: Lepiemme Fanny , Mazzucchelli Gabriel , Silva Carla G. , Nguyen Laurent 
Published: May 2021

AbstractThe cerebral cortex is built by neural cells that migrate away from their birthplace. In the forebrain, ventrally-derived oligodendrocyte precursor cells (vOPCs) travel tangentially together with cortical interneurons (cINs) to reach the cortex. After birth, vOPCs form transient synapses with cINs before engaging later into myelination. Here we tested whether these populations interact during embryogenesis while migrating. By coupling histological analysis of mouse genetic models with live imaging, we showed that, while responding to the chemokine Cxcl12, vOPCs and cINs occupy mutually-exclusive forebrain territories. Moreover, vOPCs depletion selectively disrupts the migration and distribution of cINs. At the cellular level, we found that by promoting unidirectional contact-repulsion (UCoRe) of cINs, vOPCs steer their migration away from blood vessels and contribute to their allocation to proper migratory streams. UCoRe is thus an efficient strategy to spatially control the competition for a shared chemoattractant, thereby allowing cINs to reach proper cortical territories.
Genetic tools for the stable overexpression of circular RNAs
Authors: Mecozzi Nicol , Nenci Arianna , Vera Olga , Falzone Aimee , DeNicola Gina M. , Karreth Florian A. 
Published: May 2021

AbstractCircular RNAs (circRNAs) are a class of non-coding RNAs that feature a covalently closed ring structure formed through backsplicing. circRNAs are broadly expressed and contribute to biological processes through a variety of functions. Standard gain-of-function and loss-of-function approaches to study gene functions have significant limitations when studying circRNAs. Overexpression studies in particular suffer from the lack of efficient genetic tools. While mammalian expression plasmids enable transient overexpression of circRNAs in cultured cells, most cell biological studies require long-term ectopic expression. Here we report the development and characterization of genetic tools enabling stable circRNA overexpressionin vitroandin vivo. We demonstrated that circRNA expression constructs can be delivered to cultured cells via transposons, whereas lentiviral vectors have limited utility for the delivery of circRNA constructs. We further showed that circRNA transposons can be supplied to mouse livers via hydrodynamic tail vein injection, resulting in ectopic circRNA expression in a hepatocellular carcinoma mouse model. Furthermore, we generated genetically engineered mice harboring circRNA expression constructs. We demonstrate that this approach enables constitutive, global circRNA overexpression as well as inducible circRNA expression directed specifically to melanocytes in a melanoma mouse model. Overall, these tools expand the genetic toolkit available for the functional characterization of circRNAs of interest.
Late-in-life treadmill-training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts
Authors: Cho Jae Min , Ly Kellsey , Ramous Caroline , Thompson Lauren , Hansen Michele , Mattera Maria Sara de Lima Coutinho , Pires Karla Maria , Ferhat Maroua , Whitehead Kevin J , Carter Kandis , Buffolo Márcio , Ghosh Rajeshwary , Park Seul-Ki , Boudina Sihem , Symons J David 
Published: May 2021

ABSTRACT AND KEYWORDSThere is evidence for a progressive decline of protein quality control mechanisms during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy (referred to as autophagy) is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs adult mice. As expected, 24-month old male C57BL/6J mice (old) exhibited : (i) repressed autophagosome formation and protein aggregate accumulation in the heart; (ii) systolic and diastolic dysfunction; and (iii) reduced exercise capacity, vs. 8-month old (adult) mice (all p< .05). Separate cohorts of 21 month old mice completed a 3-month progressive resistance treadmill-running program (old-ETR) that improved (all < .05) : (i) body composition; (ii) exercise capacity; and (iii) soleus muscle citrate synthase activity, vs. age-matched mice that did not train (old-SED). Importantly, (iv) protein expression of autophagy markers indicated trafficking of the autophagosome to the lysosome increased, (v) protein aggregate clearance improved, and (vi) overall function was enhanced (all p<0.05), in hearts from old-ETR vs. old- SED mice. Dietary maneuvers and pharmacological interventions shown to elevate basal autophagy are reported to mitigate / reverse age-associated cardiac dysfunction. Here we show the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and overall function in mouse hearts.
Predicting phenotypes from genetic, environment, management, and historical data using CNNs
Authors: Washburn Jacob D. , Cimen Emre , Ramstein Guillaume , Reeves Timothy , O’Briant Patrick , McLean Greg , Cooper Mark , Hammer Graeme , Buckler Edward S. 
Published: May 2021

AbstractPredicting phenotypes from genetic (G), environmental (E), and management (M) conditions is a long-standing challenge with implications to agriculture, medicine, and conservation. Most methods reduce the factors in a dataset (feature engineering) in a subjective and potentially oversimplified manner. Convolutional Neural Networks (CNN) can overcome this by allowing the data itself to determine which factors are most important. CNN models were developed for predicting agronomic yield from a combination of replicated trials and historical yield survey data. The results were more accurate than standard methods when tested on heldout G, E, and M data (r=0.5 vs r=0.4), and performed slightly worse than standard methods when only G was held out (r=0.74 vs r=0.78). Pre-training on historical data increased accuracy by 1-36% compared to trial data alone. Saliency map analysis indicated the CNN has “learned” to prioritize many factors of known agricultural importance.
Metapopulations with habitat modification
Authors: Miller Zachary R. , Allesina Stefano 
Published: May 2021

AbstractAcross the tree of life, organisms modify their local environment, rendering it more or less hospitable for other species. Despite the ubiquity of these processes, simple models that can be used to develop intuitions about the consequences of widespread habitat modification are lacking. Here we extend the classic Levins’ metapopulation model to a setting where each of n species can colonize patches connected by dispersal, and when patches are vacated via local extinction, they retain a “memory” of the previous occupant—modeling habitat modification. While this model can exhibit a wide range of dynamics, we draw several overarching conclusions about the effects of modification and memory. In particular, we find that any number of species may potentially coexist, provided that each is at a disadvantage when colonizing patches vacated by a conspecific. This notion is made precise through a quantitative stability condition, which provides a way to unify and formalize existing conceptual models. We also show that when patch memory facilitates coexistence, it generically induces a positive relationship between diversity and robustness (tolerance of disturbance). Our simple model provides a portable, tractable framework for studying systems where species modify and react to a shared landscape.
An Efficient Method to Quantify Structural Distributions in Heterogeneous cryo-EM Datasets
Authors: Gu Hanlin , Wang Wei , Unarta Ilona Christy , Zeng Wenqi , Sheong Fu Kit , Cheung Peter Pak-Hang , Liu Song , Yao Yuan , Huang Xuhui 
Published: May 2021

AbstractCryogenic Electron Microscopy (cryo-EM) preserves the ensemble of protein conformations in solution and thus provide a promising way to characterize conformational changes underlying protein functions. However, it remains challenging for existing software to elucidate distributions of multiple conformations from a heterogeneous cryo-EM dataset. We developed a new algorithm: Linear Combinations of Template Conformations (LCTC) to obtain distributions of multiple conformations from cryo-EM datasets. LCTC assigns 2D images to the template 3D structures obtained by Multi-body Re-finement of RELION via a novel two-stage matching algorithm. Specifically, an initial rapid assignment of experimental 2D images to template 2D images was applied based on auto-correlation functions of image contours that can efficiently remove the majority of irrelevant 2D images. This is followed by pixel-pixel matching of images with fewer number of 2D images, which can accurately assign the 2D images to the template images. We validate the LCTC method by demonstrating that it can accurately reproduce the distributions of 3Thermus aquaticus(Taq) RNA polymerase (RNAP) structures with different degrees of clamp opening from a simulated cryo-EM dataset, in which the correct distributions are known. For this dataset, we also show that LCTC greatly outperforms clustering-based Manifold Embedding and Maximum Likelihood-based Multi-body Re-finement algorithms in terms of reproducing the structural distributions. Lastly, we also successfully applied LCTC to reveal the populations of various clamp-opening conformations from an experimentalEscherichia coliRNAP cryo-EM dataset. Source code is available athttps://github.com/ghl1995/LCTC.
Cooperativity of catalytic and lectin-like domain ofT. congolensetrans-sialidase modulates its catalytic activity
Authors: Waespy Mario , Gbem Thaddeus T. , Kumar Nilima Dinesh , Mani Shanmugam Solaiyappan , Rosenau Jana , Dietz Frank , Kelm Sørge 
Published: May 2021

AbstractTrans-sialidases (TS) represent a multi-gene family of unusual enzymes, which catalyse the transfer of terminal sialic acids from sialoglycoconjugates to terminal galactose orN-acetylgalactosamine residues of oligosaccharides without the requirement of CMP-Neu5Ac, the activated Sia used by typical sialyltransferases. Most work on trypanosomal TS has been done on enzymatic activities of TS fromT. cruzi(causing Chagas disease in Latin America), subspecies ofT. brucei, (causing human sleeping sickness in Africa) andT. congolense(causing African Animal Trypanosomosis in livestock). Previously, we demonstrated thatT. congolenseTS (TconTS) lectin domain (LD) binds to several carbohydrates, such as 1,4-β-mannotriose.To investigate the influence of TconTS-LD on enzyme activities, we firstly performedin silicoanalysis on structure models of TconTS enzymes. Findings strongly supports the potential of domain swaps between TconTS without structural disruptions of the enzymes overall topologies. Recombinant domain swapped TconTS1a/TS3 showed clear sialidase and sialic acid (Sia) transfer activities, when using fetuin and lactose as Sia donor and acceptor substrates, respectively. While Sia transfer activity remained unchanged from the level of TconTS1a, hydrolysis was drastically reduced. Presence of 1,4-β-mannotriose during TS reactions modulates enzyme activities favouring trans-sialylation over hydrolysis.In summary, this study provides strong evidence that TconTS-LDs play pivotal roles in modulating enzyme activity and biological functions of these and possibly other TS, revising our fundamental understanding of TS modulation and diversity.
Comparative chromatin accessibility upon BDNF-induced neuronal activity delineates neuronal regulatory elements
Authors: Ibarra Ignacio L. , Ratnu Vikram S. , Gordillo Lucia , Hwang In-Young , Mariani Luca , Weinand Kathryn , Hammarén Henrik M. , Bulyk Martha L. , Savitski Mikhail M. , Zaugg Judith B. , Noh Kyung-Min 
Published: May 2021

AbstractNeuronal activity induced by brain-derived neurotrophic factor (BDNF) triggers gene expression, which is crucial for neuronal survival, differentiation, synaptic plasticity, memory formation, and neurocognitive health. However, its role in chromatin regulation is unclear. Here, using temporal profiling of chromatin accessibility and transcription in mouse primary cortical neurons upon either BDNF stimulation or depolarization (KCl), we identify features that define BDNF-specific chromatin-to-gene expression programs. Enhancer activation is an early event in the regulatory control of BDNF-treated neurons, where the bZIP motif-binding Fos protein pioneered chromatin opening and cooperated with co-regulatory transcription factors (Homeobox, EGRs, and CTCF) to induce transcription. Deleting cis-regulatory sequences decreased BDNF-mediated Arc expression, a regulator of synaptic plasticity. BDNF-induced accessible regions are linked to preferential exon usage by neurodevelopmental disorder-related genes and heritability of neuronal complex traits, which were validated in human iPSC-derived neurons. Thus, we provide a comprehensive view of BDNF-mediated genome regulatory features using comparative genomic approaches to dissect mammalian neuronal activity.
Retrosplenial and hippocampal synchrony during retrieval of old memories in macaques
Authors: Hussin A.T. , Abbaspoor S. , Hoffman K.L. 
Published: May 2021

SUMMARYTo understand the neural activity behind recollections of the distant past, we recorded from the hippocampus and retrosplenial cortex of macaques as they retrieved year-old and newly-acquired object-scene associations. Year-old memoranda preferentially evoked retrosplenial sigma oscillations (10-15 Hz), and phase-locking between RSC and eye movements during retrieval. In contrast, gamma-band retrosplenial-hippocampal synchrony was stronger during retrieval of new items. Primate retrosplenial oscillations may therefore guide retrieval of visuospatial events long past.
Ecological network analysis of watershed meta-ecosystems: A new perspective on quantifying the integrated watershed ecosystem
Authors: Yang Haile 
Published: May 2021

AbstractA watershed is an integrated ecosystem. In different disciplines, a watershed has been described as a geomorphic unit, a hydrological unit, an ecological unit, or a socio-economic unit and has been quantitatively described using different indicator systems. Until now, no general indicator system has existed that could quantitatively describe the geomorphic features, hydrologic features, ecological features and socio-economic features of an integrated watershed ecosystem (IWE) simultaneously. Here, we proposed a quantitative descriptive framework for an IWE (QDFIWE). This QDFIWE involved three steps: (1) constructing a watershed meta-ecosystem (WME) based on the hierarchical system of the watershed; (2) constructing flow networks based on the WME; and (3) identifying the holistic properties (such as spatial throughput, spatial organization and spatial resilience) of the WME through analyzing its flow networks based on ecological network analysis (ENA). Then, we applied this method to study the geomorphic topological structure, geomorphic spatial structure, natural water resource system and integrated water resource system of the Yangtze River basin. The results suggested that based on the QDFIWE, (1) one could construct different WMEs and corresponding flow networks for different requirements; (2) one could obtain time series of the holistic properties of an IWE to analyze its evolution; (3) one could compare, classify and cluster any number of IWEs through identifying their holistic properties according to similar strategies; and (4) one could determine or create more indicators, which could provide additional information, based on the holistic properties of an IWE. This study demonstrates that the QDFIWE is a general method of quantifying the holistic properties of all subsystems of an IWE simultaneously. Thus, the method can improve the understanding of the IWE.
Implicit adaptation to mirror-reversal is in the correct coordinate system but the wrong direction
Authors: Wang Tianhe , Taylor Jordan A. 
Published: May 2021

AbstractLearning in visuomotor adaptation tasks is the result of both explicit and implicit processes. Explicit processes, operationalized as re-aiming an intended movement to a new goal, account for the lion’s share of learning while implicit processes, operationalized as error-dependent learning that gives rise to aftereffects, appear to be highly constrained. The limitations of implicit learning are highlighted in the mirror-reversal task, where implicit corrections act in opposition to performance. This is surprising given the mirror-reversal task has been viewed as emblematic of implicit learning. One potential confound of these studies is that both explicit and implicit processes were allowed to operate concurrently, which may interact, potentially in opposition. Therefore, we sought to further characterized implicit learning in a mirror-reversal task with a clamp design to isolate implicit learning from explicit strategies. We confirmed that implicit adaptation is in the wrong direction for mirror-reversal and operates as if the perturbation were a rotation, and only showed a moderate attenuation after three days of training. This result raised the question of whether implicit adaptation blindly operates as though perturbations were a rotation. In a separate experiment, which directly compared a mirror-reversal and a rotation, we found that implicit adaptation operates in a proper coordinate system for different perturbations: adaptation to a mirror-reversal and rotational perturbation is more consistent with Cartesian and polar coordinate systems, respectively. It remains an open question why implicit process would be flexible to the coordinate system of a perturbation but continue to be directed inappropriately.Public Significance StatementPatients with severe amnesia can improve their performance from day to day in mirror-reversal tasks. These findings led, in part, to the codification of explicit and implicit processes in classic theories regarding the taxonomy of memory systems, with motor learning resting firmly in the branch of implicit memory. However, recent evidence has shown that explicit processes also play an important role in motor learning. What’s more, these studies have found that implicit learning doesn’t operate in a useful way in the mirror-reversal task. In the present study, we further examine this puzzling behavior of implicit learning in a mirror-reversal task using a design that can isolate implicit processes from explicit strategies. We clearly showed that the implicit system adapts in the wrong direction for a mirror-reversal, acting as if the perturbation were a rotation. Surprisingly, however, we found that although adaptation is in the wrong direction, the implicit system is sensitive to a particular coordinate system. These findings further challenge the flexibility of this implicit adaptation process in motor learning.