bluuebunny/crossref_metadata_2025_split huggingface dataset:
The prostate cancer therapy enzalutamide compared with abiraterone acetate/prednisone impacts motivation for exploration, spatial learning and alters dopaminergic transmission in aged castrated mice
Authors: Nicola Celeste , Dubois Martine , Campart Cynthia , Sagheer Tareq Al , Desrues Laurence , Schapman Damien , Galas Ludovic , Lange Marie , Joly Florence , Castel Hélène 
Published: April 2021

ABSTRACTCognitive side effects after cancer treatment, threatening quality of life (QoL) and adherence to treatments, now constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are next generation therapy (NGT) administered with androgen deprivation therapy to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment have been recently reported. We developed a behavioral 17 months-aged and castrated mouse model receivingper osAAP or ENZ during 5 days per week for six consecutive weeks. After behavioral tests, brain and plasma were collected for immunohistochemical studies. The objective was to elucidate the impact of NGT on spontaneous activity, cognitive functions and emotional reactivity, as well as neurobiological functions. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH+-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus, highlighted ENZ-induced dopaminergic regulation whithin the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory or behavioral flexibility performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN+-neurons in the dorsal hippocampus. These results establish the consequences of the mCRPC treatment ENZ in aged castrated mouse motivation to exploration and cognition, of particular importance for future management of patients elderly postrate cancer patients and their QoL.
NRPS-gene disruption in the apple-pathogen,Neonectria ditissima
Authors: Vélëz Heriberto , Bourras Salim , Garkava-Gustavsson Larisa , Dalman Kerstin 
Published: April 2021

AbstractApple production in Sweden and elsewhere is being threaten by the fungus,Neonectria ditissima, which causes a disease known as Fruit Tree Canker. The disease can cause extensive damages and the removal of diseased-wood and heavily infected trees can be laborious and expensive. Currently, there is no way to eradicate the fungus from infected trees and our knowledge of the infection process is limited. Thus, in order to target and modify genes efficiently, the genetic transformation technique developed forN. ditissimaback in 2003 was modified. We report on the upgraded protocol and show that protoplasts were viable, able to uptake foreign DNA, and able to regenerate back into a mycelial colony, either as targeted gene-disruption mutants or as ectopic mutants expressing GFP.
The monitoring system is attuned to others’ actions during dyadic motor
interactions
Authors: Moreau Quentin , Tieri Gaetano , Era Vanessa , Aglioti Salvatore Maria , Candidi Matteo 
Published: April 2021

Abstract
Successful interpersonal motor interactions necessitate the simultaneous
monitoring of our own and our partner’s actions. To characterize the dynamics of
the action monitoring system for tracking self and other behaviors during dyadic
synchronous interactions, we combined EEG recordings and immersive Virtual
Reality in two tasks where participants were asked to coordinate their actions
with those of a Virtual Partner (VP). The two tasks differed in the features to
be monitored: the Goal task required participants to
predict and monitor the VP’s reaching goal; the
Spatial task required participants to predict and
monitor the VP’s reaching trajectory. In both tasks, the VP performed unexpected
movement corrections to which the participant needed to adapt. By comparing the
neural activity locked to the detection of unexpected changes in the VP action
(other-monitoring) or to the participants’ action-replanning (self-monitoring),
we show that during interpersonal interactions the monitoring system is more
attuned to others’ than to one’s own actions. Additionally, distinctive neural
responses to VP’s unexpected goals and trajectory corrections were found: goal
corrections were reflected both in early fronto-central and later posterior
neural responses while trajectory deviations from the expected movement were
reflected only in later and posterior responses. Since these responses were
locked to the partner’s behavior and not to one’s own, our results indicate that
during interpersonal interactions the action monitoring system is dedicated to
evaluating the partner’s movements. Hence, our results reveal an eminently
social role of the monitoring system during motor interactions.

Significance Statement
Non-verbal synchronous interpersonal interactions require the
monitoring of both our actions and those of our partners. Understanding
the neural underpinnings of this ability with a focus on the dynamics
between self- and other-monitoring is fundamental to the comprehension
of social coordination. By combining EEG and immersive Virtual Reality
we demonstrate that the monitoring system is more attuned to others’
actions than to our own. In two tasks, we show that the neural activity
associated with unexpected corrections in the goal or the trajectory of
an action are locked to the partner’s actions rather than to the
participants’ subsequent adaptation. This pattern of results highlights
a social mode adopted by the monitoring system to handle motor
interactions.
Evaluation of efficacy-versusaffinity-driven agonism with biased GLP-1R ligands P5 and exendin-F1
Authors: Marzook Amaara , Chen Shiqian , Pickford Phil , Lucey Maria , Wang Yifan , Corrêa Ivan R , Broichhagen Johannes , Hodson David J , Salem Victoria , Rutter Guy A , Tan Tricia M , Bloom Stephen R , Tomas Alejandra , Jones Ben 
Published: April 2021

AbstractThe glucagon-like peptide-1 receptor (GLP-1R) is an important regulator of glucose homeostasis and has been successfully targeted for the treatment of type 2 diabetes. Recently described biased GLP-1R agonists with selective reductions in β-arrestinversusG protein coupling show improved metabolic actionsin vivo. However, two prototypical G protein-favouring GLP-1R agonists, P5 and exendin-F1, are reported to show divergent effects on insulin secretion. In this study we aimed to resolve this discrepancy by performing a side-by-side characterisation of these two ligands across a variety ofin vitroandin vivoassays. Exendin-F1 showed reduced acute efficacyversusP5 for several readouts, including recruitment of mini-G proteins, G protein-coupled receptor kinases (GRKs) and β-arrestin-2. Maximal responses were also lower for both GLP-1R internalisation and the presence of active GLP-1R-mini-Gscomplexes in early endosomes with exendin-F1 treatment. In contrast, prolonged insulin secretionin vitroand sustained anti-hyperglycaemic efficacy in mice were both greater with exendin-F1 than with P5. We conclude that the particularly low acute efficacy of exendin-F1 and associated reductions in GLP-1R downregulation appear to be more important than preservation of endosomal signalling to allow sustained insulin secretion responses. This has implications for the ongoing development of affinity-versusefficacy-driven biased GLP-1R agonists as treatments for metabolic disease.
Necrosis-induced apoptosis promotes regeneration inDrosophilawing imaginal discs
Authors: Klemm Jacob , Stinchfield Michael J. , Harris Robin E. 
Published: April 2021

AbstractRegeneration is a complex process that requires a coordinated genetic response to tissue loss. Signals from dying cells are crucial to this process and are best understood in the context of regeneration following programmed cell death, like apoptosis. Conversely, regeneration following unregulated forms of death such as necrosis have yet to be fully explored. Here we have developed a method to investigate regeneration following necrosis using theDrosophilawing imaginal disc. We show that necrosis stimulates regeneration at an equivalent level to that of apoptosis-mediated cell death and activates a similar response at the wound edge involving localized JNK signaling. Unexpectedly however, necrosis also results in significant apoptosis far from the site of ablation, which we have termed necrosis-induced apoptosis (NiA). This apoptosis occurs independent of changes at the wound edge and importantly does not rely on JNK signaling. Furthermore, we find that blocking NiA limits proliferation and subsequently inhibits regeneration, suggesting that tissues damaged by necrosis can activate programmed cell death at a distance from the injury to promote regeneration.
Establishment of a Patient-Derived, Magnetic Levitation-Based, 3D Spheroid Granuloma Model for Human Tuberculosis
Authors: Kotze Leigh A. , Beltran Caroline G.G. , Lang Dirk , Loxton Andre G. , Cooper Susan , Meiring Maynard , Glanzmann Brigitte , Kinnear Craig , Walzl Gerhard , du Plessis Nelita 
Published: April 2021

ABSTRACTTuberculous granulomas that develop in response toMycobacterium tuberculosis(M.tb) infection are highly dynamic entities shaped by the host immune response and disease kinetics. Within this microenvironment, immune cell recruitment, polarization and activation is driven not only by co-existing cell types and multi-cellular interactions, but also byM.tb-mediated changes involving metabolic heterogeneity, epigenetic reprogramming and rewiring of the transcriptional landscape of host cells. There is an increased appreciation of thein vivocomplexity, versatility and heterogeneity of the cellular compartment that constitutes the tuberculosis (TB) granuloma, and the difficulty in translating findings from animal models to human disease. Here we describe a novel biomimeticin vitro3-dimentional (3D) human lung granuloma model, resembling early “innate” and “adaptive” stages of the TB granuloma spectrum, and present results of histological architecture, host transcriptional characterization, mycobacteriological features, cytokine profiles and spatial distribution of key immune cells. A range of manipulations of immune cell populations in these granulomas will allow the study of host/pathogen pathways involved in the outcome of infection, as well as pharmacological interventions.IMPORTANCETuberculosis is a highly infectious disease, with granulomas as its hallmark. Granulomas play an important role in the control of M.tb infection and as such are crucial indicators for our understanding of host resistance to TB. Correlates of risk and protection to M.tb are still elusive, and the granuloma provides the perfect environment in which to study the immune response to infection and broaden our understanding thereof; however, human granulomas are difficult to obtain, and animal models are costly and do not always faithfully mimic human immunity. In fact, most TB research is conducted in vitro on immortalized or primary immune cells and cultured in 2D on flat, rigid plastic, which does not reflect in vivo characteristics. We have therefore conceived a 3D, human in vitro granuloma model which allows researchers to study features of granuloma-forming diseases, in an 3D structural environment resembling in vivo granuloma architecture and cellular orientation.
γδT Cells Are Required for CD8+T Cell Response to Vaccinia Viral Infection
Authors: Dai Rui , Huang Xiaopei , Yang Yiping 
Published: April 2021

AbstractVaccinia virus (VV) is the most studied member of the poxvirus family, is responsible for the successful elimination of smallpox worldwide, and has been developed as a vaccine vehicle for infectious diseases and cancer immunotherapy. We have previously shown that the unique potency of VV in the activation of CD8+T cell response is dependent on efficient activation of the innate immune system through Toll-like receptor (TLR)-dependent and -independent pathways. However, it remains incompletely defined what regulate CD8+T cell response to VV infection. In this study, we showed that γδT cells play an important role in promoting CD8+T cell response to VV infection. We found that γδT cells can directly present viral antigens in the context MHC-I for CD8+T cell activation to VVin vivo, and we further demonstrated that cell-intrinsic MyD88 signaling in γδT cells is required for activation of γδT cells and CD8+T cells. These results illustrate a critical role for γδT cells in the regulation of adaptive T cell response to viral infection and may shed light on the design of more effective vaccine strategies based on manipulation of γδT cells.ImportanceTargeting the immune systems has powerful potentials to treat many disorders, such as some cancers and viral infections. By understanding how the immune system responds to model infections, we can better determine strategies to manipulate our immune systems. Vaccinia virus is responsible for the worldwide elimination of smallpox and produces one of the longest immune responses known in humans. We know from previous findings that NK cells are required for initial immune response and CD8+T cells are required for the elimination of the virus. How CD8+T cells are activated in response to Vaccinia virus is not fully understood. This manuscript found that γδT cells activate CD8+T cells in response to Vaccinia virus infection through MyD88 pathway
IGF2BP2 Promotes Cancer Progression by Degrading the RNA Transcript Encoding a v-ATPase Subunit
Authors: Latifkar A. , Wang F. , Mullmann J.J. , Fernandez I.R. , Ling L. , Fischbach C. , Weiss R.S. , Lin H. , Cerione R.A. , Antonyak M.A. 
Published: April 2021

AbstractInsulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) binds to various RNA transcripts and promotes cancer progression, although little is known regarding its regulation. Here we show IGF2BP2 is a substrate of the deacetylase and tumor suppressor sirtuin 1 (SIRT1) and regulates the expression of the vacuolar ATPase subunit ATP6V1A. SIRT1 down-regulation in aggressive cancers leads to increased acetylation of IGF2BP2 which recruits the XRN2 nuclease to degrade the ATP6V1A transcript, decreasing its expression. This impairs lysosomal function and results in the production of a secretome that enhances cancer cell proliferation and metastasis. These findings describe a previously unrecognized role for IGF2BP2 in the degradation of an mRNA transcript essential for lysosomal function and highlight how its sirtuin-regulated acetylation state can have significant biological and disease consequences.One Sentence SummaryAcetylation of the RNA binding protein IGF2BP2, upon down-regulation of SIRT1, leads to degradation of the transcript encoding ATP6V1A and impaired lysosomal function in aggressive cancer cells.
Deficiency of the paternally inherited geneMagel2alters the development of separation-induced vocalization and maternal behavior in mice
Authors: Bosque Ortiz Gabriela M. , Santana Gustavo M. , Dietrich Marcelo O. 
Published: April 2021

AbstractThe behavior of offspring results from the combined expression of maternal and paternal genes. Genomic imprinting silences some genes in a parent-of-origin specific manner, a process that, among all animals, occurs only in mammals. How genomic imprinting affects the behavior of mammalian offspring, however, remains poorly understood. Here, we studied how the loss of the paternally inherited geneMagel2in mouse pups affects the emission of separation-induced ultrasonic vocalizations (USV). Using quantitative analysis of more than one hundred thousand USVs, we characterized the rate of vocalizations as well as their spectral features from postnatal days 6 to 12 (P6-P12), a critical phase of mouse development during which pups fully depend on the mother for survival. Our analyses show thatMagel2deficient offspring emit separation-induced vocalizations at lower rates and with altered spectral features. We also show that dams display altered behavior towards their ownMagel2deficient offspring. In a test to compare the retrieval of two pups, dams retrieve wildtype control pups first and faster thanMagel2deficient offspring. These results suggest that the loss ofMagel2impairs the expression of separation-induced vocalization in pups as well as maternal behavior, both of which support the pups’ growth and development.
Naturalistic audio-movies reveal common spatial organization across “visual” cortices of different blind individuals
Authors: Musz Elizabeth , Loiotile Rita , Chen Janice , Bedny Marina 
Published: April 2021

AbstractOccipital cortices of different sighted people contain analogous maps of visual information (e.g., foveal vs. peripheral space). In congenital blindness, “visual” cortices enhance responses to nonvisual stimuli. Do deafferented visual cortices of different blind people represent common informational maps? We leverage a naturalistic stimulus paradigm and inter-subject pattern similarity analysis to address this question. Blindfolded sighted (S, n=22) and congenitally blind (CB, n=22) participants listened to three auditory excerpts from movies; a naturalistic spoken narrative; and matched degraded auditory stimuli (i.e., shuffled sentences and backwards speech) while undergoing fMRI scanning. In a parcel-based whole brain analysis, we measured the spatial activity patterns evoked by each unique, ten-second segment of each auditory clip. We then compared each subject’s spatial pattern to that of all other subjects in the same group (CB or S) within and across segments. In both blind and sighted groups, segments of meaningful auditory stimuli produced distinctive patterns of activity that were shared across individuals. Crucially, only in the CB group, this segment-specific, cross-subject pattern similarity effect emerged in visual cortex, but only for meaningful naturalistic stimuli and not backwards speech. These results suggest that spatial activity patterns within deafferented visual cortices encode meaningful, segment-level information contained in naturalistic auditory stimuli, and that these representations are spatially organized in a similar fashion across blind individuals.Significance StatementRecent neuroimaging studies show that the so-called “visual” cortices activate during non-visual tasks in people who are born blind. Do the visual cortices of people who are born blind develop similar representational maps? While congenitally blind individuals listened to naturalistic auditory stimuli (i.e., sound clips from movies), distinct timepoints within each stimulus elicited unique spatial activity patterns in visual cortex, and these patterns were shared across different people. These findings suggest that in blindness, the visual cortices encode meaningful information embedded in naturalistic auditory signals in a spatially distributed manner, and that a common representational map can emerge in visual cortex independent of visual experience.
Genome-wide association study reveals candidate genes for flowering time in cowpea (Vigna unguiculata[L.] Walp)
Authors: Paudel Dev , Dareus Rocheteau , Rosenwald Julia , Muñoz-Amatriaín María , Rios Esteban F. 
Published: April 2021

AbstractCowpea (Vigna unguiculata[L.] Walp., diploid, 2n= 22) is a major crop used as a protein source for human consumption as well as a quality feed for livestock. It is drought and heat tolerant and has been bred to develop varieties that are resilient to changing climates. Plant adaptation to new climates and their yield are strongly affected by flowering time. Therefore, understanding the genetic basis of flowering time is critical to advance cowpea breeding. The aim of this study was to perform genome-wide association studies (GWAS) to identify marker trait associations for flowering time in cowpea using single nucleotide polymorphism (SNP) markers. A total of 367 accessions from a cowpea minicore collection were evaluated in Ft. Collins, CO in 2019 and 2020, and 292 accessions were evaluated in Citra, FL in 2018. These accessions were genotyped using the Cowpea iSelect Consortium Array that contained 51,128 SNPs. GWAS revealed seven reliable SNPs for flowering time that explained 8-12% of the phenotypic variance. Candidate genes includingFT, GI, CRY2, LSH3, UGT87A2, LIF2, andHTA9that are associated with flowering time were identified for the significant SNP markers. Further efforts to validate these loci will help to understand their role in flowering time in cowpea, and it could facilitate the transfer of some of this knowledge to other closely related legume species.
Diverse ATPase proteins in mobilomes constitute a large potential sink for prokaryotic host ATP
Authors: Shim Hyunjin , Shivram Haridha , Lei Shufei , Doudna Jennifer A. , Banfield Jillian F. 
Published: April 2021

AbstractProkaryote mobilome genomes rely on host machineries for survival and replication. Given that mobile genetic elements (MGEs) derive their energy from host cells, we investigated the diversity of ATP-utilizing proteins in MGE genomes to determine whether they might be associated with proteins that could suppress related host proteins that consume host energy. A comprehensive search of 353 huge phage genomes revealed that up to 9% of the proteins have ATPase domains. For example, ATPase proteins constitute ~3% of the genomes of Lak phages with ~550 kbp genomes that occur in the microbiomes of humans and other animals. Statistical analysis shows the number of ATPase proteins increases linearly with genome length, consistent with a large sink for host ATP during replication of megaphages. Using metagenomic data from diverse environments, we found 505 mobilome proteins with ATPase domains fused to diverse functional domains. Among these composite ATPase proteins, 61.6% have known functional domains that could contribute to host energy diversion during the mobilome life cycle. As many have domains that are known to interact with nucleic acids and proteins, we infer that numerous ATPase proteins are used during replication and for protection from host immune systems. We found a set of uncharacterized ATPase proteins with nuclease and protease activities, displaying unique domain architectures that are energy intensive based on the presence of multiple ATPase domains. In many cases, these composite ATPase proteins genomically co-localize with small proteins in genomic contexts that are reminiscent of toxin-antitoxin systems and phage helicase-antibacterial helicase systems. Small proteins that function as inhibitors may be a common strategy for control of cellular processes, thus could inspire the development of new nucleic acid and protein manipulation tools, with diverse biotechnological applications.