bluuebunny/crossref_metadata_2025_split huggingface dataset:
LUC7 proteins define two major classes of 5’ splice sites in animals and plants
Authors: Kenny Connor J. , McGurk Michael P. , Schüler Sandra , Cordero Aidan , Laubinger Sascha , Burge Christopher B. 
Published: December 2022

AbstractMutation or deletion of the U1 snRNP-associated factor LUC7L2 is associated with myeloid neoplasms, and knockout of LUC7L2 alters cellular metabolism. Here, we uncover that members of the LUC7 protein family differentially regulate two major classes of 5’ splice sites (5’SS) and broadly regulate mRNA splicing in both human cell lines and leukemias withLUC7L2copy number variation. We describe distinctive 5’SS features of exons impacted by the three human LUC7 paralogs: LUC7L2 and LUC7L enhance splicing of “right-handed” 5’SS with stronger consensus matching on the intron side of the near-invariant /GU, while LUC7L3 enhances splicing of “left-handed” 5’SS with stronger consensus matching upstream of the /GU. We validated our model of sequence-specific 5’SS regulation both by mutating splice sites and swapping domains between human LUC7 proteins. Evolutionary analysis indicates that the LUC7L2/LUC7L3 subfamilies diverged before the divergence of animals and plants. Analysis ofArabidopsis thalianamutants confirmed that plant LUC7 orthologs possess specificity similar to their human counterparts, indicating that 5’SS regulation by LUC7 proteins is deeply conserved.
Deep Learning and Single Cell Phenotyping for Rapid Antimicrobial Susceptibility Testing
Authors: Zagajewski Aleksander , Turner Piers , Feehily Conor , El Sayyed Hafez , Andersson Monique , Barrett Lucinda , Oakley Sarah , Stracy Mathew , Crook Derrick , Nellåker Christoffer , Stoesser Nicole , Kapanidis Achillefs N. 
Published: December 2022

AbstractThe rise of antimicrobial resistance (AMR) is one of the greatest public health challenges, already causing up to 1.2 million deaths annually and rising. Current gold-standard antimicrobial susceptibility tests (ASTs) are low-throughput and can take up to 48 hours, with implications for patient care. We present advances towards a novel, rapid AST, based on the deep-learning of single-cell specific phenotypes directly associated with antimicrobial susceptibility inEscherichia coli. Our models can reliably (80% single-cell accuracy) classify untreated and treated susceptible cells, across a range of antibiotics and phenotypes - including phenotypes not visually distinct to a trained, human observer. Applying models trained on lab-reference susceptible strains to clinical isolates ofE. colitreated with ciprofloxacin, we demonstrate our models reveal significant (p<0.001) differences between resistant and susceptible populations, around a fixed treatment level. Conversely, deploying on cells treated with a range of ciprofloxacin concentrations, we show single-cell phenotyping has the potential to provide equivalent information to a 24-hour growth AST assay, but in as little as 30 minutes.
Using drivers and transmission pathways to identify SARS-like coronavirus spillover risk hotspots
Authors: Muylaert Renata L. , Wilkinson David A , Kingston Tigga , D’Odorico Paolo , Rulli Maria Cristina , Galli Nikolas , John Reju Sam , Alviola Phillip , Hayman David T. S. 
Published: December 2022

AbstractThe emergence of SARS-like coronaviruses is a multi-stage process from wildlife reservoirs to people. Here we characterize multiple drivers—landscape change, host distribution, and human exposure—associated with the risk of spillover of SARS-like coronaviruses to help inform surveillance and mitigation activities. We consider direct and indirect transmission pathways by modeling four scenarios with livestock and mammalian wildlife as potential and known reservoirs before examining how access to healthcare varies within clusters and scenarios. We found 19 clusters with differing risk factor contributions within a single country (N=9) or transboundary (N=10). High-risk areas were mainly closer (11-20%) rather than far (<1%) from healthcare. Areas far from healthcare reveal healthcare access inequalities, especially Scenario 3, which includes wild mammals as secondary hosts. China (N=2) and Indonesia (N=1) had clusters with the highest risk. Our findings can help stakeholders in land use planning integrating healthcare implementation and One Health actions.
Deep divergence and genomic diversification of gut symbionts of neotropical stingless bees
Authors: Sarton-Lohéac Garance , da Silva Carlos Gustavo Nunes , Mazel Florent , Baud Gilles , de Bakker Vincent , Das Sudip , Chazli Yassine El , Ellegaard Kirsten , Garcia-Garcera Marc , Glover Natasha , Liberti Joanito , Marçal Lorena Nacif , Prasad Aiswarya , Somerville Vincent ,   SAGE class 2019-2020 and 2020-2021, Bonilla-Rosso Germán , Engel Philipp 
Published: December 2022

AbstractSocial bees harbor conserved gut microbiota that may have been acquired in a common ancestor of social bees and subsequently co-diversified with their hosts. However, most of this knowledge is based on studies on the gut microbiota of honey bees and bumble bees. Much less is known about the gut microbiota of the third and most diverse group of social bees, the stingless bees. Specifically, the absence of genomic data from their microbiota presents an important knowledge gap in understanding the evolution and functional diversity of the social bee microbiota. Here we combined community profiling with culturing and genome sequencing of gut bacteria from six neotropical stingless bee species from Brazil. Phylogenomic analyses show that most stingless bee gut isolates form deep-branching sister clades of core members of the honey bee and bumble bee gut microbiota with conserved functional capabilities, confirming the common ancestry and ecology of their microbiota. However, our bacterial phylogenies were not congruent with those of the host indicating that the evolution of the social bee gut microbiota was not driven by strict co-diversification, but included host switches and independent symbiont gain and losses. Finally, as reported for the honey bee and bumble bee microbiota, we find substantial genomic divergence among strains of stingless bee gut bacteria suggesting adaptation to different host species and glycan niches. Our study offers first insights into the genomic diversity of the stingless bee microbiota, and highlights the need for broader samplings to understand the evolution of the social bee gut microbiota.ImportanceStingless bees are the most diverse group of the corbiculate bees and represent important pollinator species throughout the tropics and subtropics. They harbor specialized microbial communities in their gut that are related to those found in honey bees and bumble bees and that are likely important for bee health. Few bacteria have been cultured from the gut of stingless bees which has prevented characterization of their genomic diversity and functional potential. Here, we established cultures of major community members of the gut microbiota of six stingless bee species and sequenced their genomes. We find that most stingless bee isolates belong to novel bacterial species distantly related to those found in honey bees and bumble bees and encoding similar functional capabilities. Our study offers a new perspective on the evolution of the social bee gut microbiota and presents the basis to characterize the symbiotic relationships between gut bacteria and stingless bees.
Modulation of the E-cadherin in human cells infectedin vitrowithCoxiella burnetii
Authors: Osman Ikram Omar , Mezouar Soraya , Belhaouari-Brahim Djamal , Mege Jean-Louis , Devaux Christian Albert 
Published: December 2022

AbstractHigh concentration of soluble E-cadherin (E-cad) was previously found in sera from Q fever patients. Here, BeWo cells which express a high concentration of E-cad were used as anin vitromodel to investigate the expression and function of E-cad in response to infection byCoxiella burnetii, the etiological agent of Q fever. Infection of BeWo cells withC. burnetiileads to a decrease in the number of BeWo cells expressing E-cad at their membrane. A shedding of soluble E-cad was associated with the post-infection decrease of membrane-bound E-cad. The modulation of E-cad expression requires bacterial viability and was not found with heat-inactivatedC. burnetii. Moreover, the intracytoplasmic cell concentration of β-catenin (β-cat), a ligand of E-cad, was reduced after bacterial infection, suggesting that the bacterium induces modulation of the E-cad/β-cat signaling pathway andCDH1andCTNNB1genes transcription. Finally, several genes operating the canonical Wnt-Frizzled/β-cat pathway were overexpressed in cells infected withC. burnetii. This was particularly evident with the highly virulent strain ofC. burnetii, Guiana. Our data demonstrate that infection of BeWo cells by liveC. burnetiimodulates the E-cad/β-cat signaling pathway.
At Which Low Amplitude Modulated Frequency Do Infants Best Entrain? A Frequency Tagging Study
Authors: Ives James , Labendzki Pierre , Perapoch Amadó Marta , Greenwood Emily , Viswanathan Narain , Northrop Tom , Wass Sam 
Published: December 2022

AbstractPrevious infant entrainment research has shown neural entrainment to a wide range of stimuli and amplitude modulated frequencies. However, it is unknown if infants neurally entrain more strongly to some frequencies more than others, and to which low amplitude modulated frequency infants show the strongest entrainment. The current study seeks to address this by testing the neural entrainment of N=23 4–6-month-old infants and N=22 control group adult caregivers while they listened to a range of sinusoidally amplitude modulated beep stimuli at rest (no sound), 2, 4, 6, 8, 10 and 12 Hz. Analysis examined differences across power and phase, regions of interest predetermined by previous literature and by segmented time windows. Results showed that the strongest entrainment was at 2Hz for both adult and infant participants; that there was no significant difference in power and phase, entrainment was occipital temporal and slightly left fronto-central in adults and right fronto-central and left occipito-temporal in infants, leading to some regions of interest used in previous studies being significant in infants and all regions of interest being significant in adults. Segmenting by time window did not show any significant increase or decrease in entrainment over time, but longer time windows showed a stronger entrainment response. In conclusion, it is important to choose appropriate stimulation frequencies when investigating entrainment between stimulation frequencies or across ages; whole head recording is recommended to see the full extent of activation; there is no preference on power vs phase analyses; and longer recordings show stronger effects.Author Contribution StatementIves, J., conceptualisation, data collection and curation, formal analysis, methodology, writing – original draft; Labendzki, P., data collection and curation, formal analysis, writing – review & editing; Perapoch Amadó, M., data collection and curation, writing – review & editing; Greenwood, E., data collection and curation, participant recruitment, writing – review & editing; Viswanathan, N., data collection and curation, writing – review & editing; Northrop, T., data collection and curation, participant recruitment, writing – review & editing; Wass, S., conceptualisation, funding acquisition, methodology, project administration, supervision, writing – review & editing.Highlights2Hz amplitude modulation stimulation showed the strongest neural entrainmentWe discuss power vs phase analyses of infant and adult frequency tagging responsesWe illustrate topographic differences in adult and infant neural responses
Adult born hippocampal granule cells promote pattern separation by bidirectionally modulating the remapping of place and cue cells
Authors: Tuncdemir Sebnem N. , Grosmark Andres D. , Chung Hannah , Luna Victor M. , Lacefield Clay O. , Losonczy Attila , Hen Rene 
Published: December 2022

AbstractThe hippocampal dentate gyrus (DG) exhibits a unique form of neural plasticity that results from continuous integration of adult born neurons, referred to as ‘adult neurogenesis’. Recent studies have proposed that adult neurogenesis promotes the ability to encode new memories without interference from previously stored memories that share similar features, through a neural computation known as pattern separation. However, due to lack ofin vivophysiological evidence, the manner in which adult neurogenesis contributes to pattern separation remains unknown. Here, we investigate the contribution of functionally integrated yet immature adult born granule cells (iGCs) to DG computations by examining how chronic ablation or acute chemogenetic silencing of iGCs affects the activity of mature granule cells (mGCs) usingin vivo2-photon Ca2+imaging. In both cases we observed altered remapping of mGCs but in opposite directions depending on their tuning selectivity. Rather than broadly modulating the activity of all mGCs, iGCs promote the remapping of place cells but limit the remapping of mGCs representing sensory cues (cue cells). We propose that these properties of iGCs explain their role in pattern separation because they promote the formation of non-overlapping representations for identical sensory cues encountered in different locations. Conversely, the absence of iGCs shifts the DG network to a state dominated by sensory cue information, a situation that is consistent with the overgeneralization often observed in anxiety disorders such as PTSD.
Inhibitory gating of thalamocortical inputs onto rat gustatory insular cortex
Authors: Haley Melissa S. , Fontanini Alfredo , Maffei Arianna 
Published: December 2022

ABSTRACTIn the rat primary gustatory cortex (GC), a subregion of the larger insular cortex, neurons display time-varying neural responses to gustatory stimuli. GC taste responses are dramatically reduced following inactivation of the gustatory thalamus, the parvicellular region of the ventral posteromedial thalamic nucleus (VPMpc). Pharmacological inactivation of VPMpc also has a profound effect on GC spontaneous activity. This indicates that the projection from VPMpc plays a crucial role in GC taste processing as well as in the control of its state. How VPMpc afferents engage GC circuits and drive neuronal ensembles to effectively code tastant identity, as well as modulate the overall state of the GC network, remains unclear. To investigate the synaptic properties and organization of VPMpc afferents in GC, we employed a circuit-breaking optogenetic approach, stimulating VPMpc terminal fields while performing whole-cell patch clamp recordings from GC neurons in rat acute slices. Informed by previous studies of thalamocortical inputs to other sensory cortices, we hypothesized that VPMpc-GC synapses have laminar- and cell-specific properties that gate sensory input, conferring computationally flexibility to how taste information is processed in GC. We found that VPMpc-GC synapses are strongly gated by the activity regime of VPMpc afferents, as well as by feedforward and feedback inhibition onto VPMpc terminals. These results provide novel insight into the circuit underpinning of GC responsiveness to incoming thalamocortical activity.SIGNIFICANCE STATEMENTWe report that the input from the primary taste thalamus to the primary gustatory cortex (GC) shows distinct properties compared to primary thalamocortical synapses onto other sensory areas. VPMpc afferents in GC make synapses with excitatory neurons distributed across all cortical layers and display frequency-dependent short-term plasticity to repetitive stimulation, thus they do not fit the classic distinction between drivers and modulators typical of other sensory thalamocortical circuits. Feedforward inhibition gates thalamocortical activation and provides local corticothalamic feedback via presynaptic ionotropic and metabotropic GABA receptors. The connectivity and inhibitory control of thalamocortical synapses support the time-varying response dynamics to taste stimuli observed in GC neuronsin vivo.
Spontaneous activation of cortical somatosensory networks depresses their excitability in preterm human neonates
Authors: Whitehead Kimberley , Rupawala Mohammed , Laudiano-Dray Maria Pureza , Meek Judith , Olhede Sofia , Fabrizi Lorenzo 
Published: December 2022

AbstractIntroductionThe activity of the developing cortex is characteristically discontinuous where sudden high amplitude bursts interrupt periods of quiescent background. While the functional importance of this activity is clear, its aetiology is not known. Here, we hypothesise that this alternating pattern arises because of “refractoriness” of cortical networks following spontaneous activation.MethodsTo test this hypothesis, we assessed whether spontaneous activity in sensory networks depressed their excitability by measuring the impact of ongoing activity on the response to an external sensory stimulus. We recorded cortical activity before and after mechanical tactile stimulation of hands and feet in 35 preterm infants of median 32 weeks post-menstrual age.ResultsMechanical stimulation evoked wideband energy increases with two distinct peaks within the delta and alpha-beta band. The delta activity engaged extended cortical areas, while the faster activity engaged local somatotopically specific areas. By then characterising the spectro-spatial properties of the spontaneous activity preceding stimulation, we showed that baseline energy with a distribution and spectral profile similar to that of somatosensory-evoked activity dampened the energy changes elicited by touching the body.DiscussionSensory-evoked activity in preterm human neonates likely represents the coordinated activation of extended (tangential) and local (e.g. columnar) cortical aggregates. The occurrence of spontaneous cortical events in the same cortical regions depresses their excitability preventing their immediate re-engagement. This “refractoriness” offers the first etiological explanation to the cyclical burst-quiescence pattern typical of preterm cortical activity.
Local angiogenic interplay of Vegfc/d and Vegfa drives brain region-specific development of fenestrated capillaries
Authors: Parab Sweta , Card Olivia A. , Chen Qiyu , Buck Luke D. , Quick Rachael E. , Horrigan William F. , Levkowitz Gil , Vanhollebeke Benoit , Matsuoka Ryota L. 
Published: December 2022

ABSTRACTFenestrated and blood-brain barrier (BBB)-forming endothelial cells constitute major brain capillaries, and this vascular heterogeneity is crucial for region-specific neural function and brain homeostasis. How these capillary types emerge in a brain region-specific manner and subsequently establish intrabrain vascular heterogeneity remains unclear. Here, we show a core angiogenic mechanism critical for fenestrated brain capillary development via a comparative analysis of the zebrafish choroid plexuses (CPs) and circumventricular organs (CVOs), demonstrating capillary-type-selective vascularization mechanisms. We found that zebrafish deficient for Gpr124, Reck, or Wnt7aa exhibit severely-impaired BBB angiogenesis without any apparent defect in fenestrated capillary formation in the CPs and CVOs. Conversely, simultaneous genetic loss of various Vegf combinations revealed remarkable heterogeneity of endothelial requirements for Vegfs-dependent angiogenesis within and across these organs, identifying unexpected interplay of Vegfc/d and Vegfa in fenestrated brain capillary formation. Expression analysis and paracrine activity-deficientvegfcmutant characterization suggest that endothelial cells and non-neuronal specialized cell types present in the CPs and CVOs are major sources of Vegfs responsible for regionally-restricted angiogenic interplay. Thus, local presentations and interplay of Vegfc/d and Vegfa control brain region-specific emergence of fenestrated capillaries, providing insight into fenestrated capillary formation in other organs and also how intra-organ vascular heterogeneity arises.
Pain and cognitive performance in adults with multiple sclerosis: A systematic review
Authors: Brown Fraser S , Glasmacher Stella A , Taylor Daniel , Jenkins Ruth , Chandran Siddharthan , Gillespie David , Foley Peter 
Published: December 2022

AbstractIntroductionPain and cognitive dysfunction are separately known to be important manifestations of multiple sclerosis (MS). Although pain is a complex subjective phenomenon with affective and cognitive aspects, it is not known if people with MS reporting pain are at greater risk of reduced performance in objective tests of cognition. The presence or direction of any association remains to be clarified, as do the roles of confounders such as fatigue, medication and mood.MethodsWe conducted a systematic review of studies examining the relationship between pain and objectively measured cognition in adults with confirmed MS, according to a pre-registered protocol (PROSPERO 42020171469). We carried out searches in MEDLINE, Embase and PsychInfo. We evaluated the role of potential confounders (medication, depression, anxiety, fatigue and sleep) and described findings by eight pre-specified cognitive domains.Results11 studies (n=3714, range 16 to 1890 participants per study) were included in the review. Four studies included longitudinal data. Nine studies identified a relationship between pain and objectively measured cognitive performance. In seven of these studies, higher pain scores were associated with poorer cognitive performance. However, no evidence was available for some cognitive domains. Heterogeneous study methodology precluded meta-analysis. Studies infrequently controlled for the specified confounders. Most studies were judged to be at risk of bias.DiscussionSeveral studies, but not all, identified a negative relationship between pain severity and objectively measured cognitive performance. Our ability to further characterise this relationship is limited by study design and lack of evidence in many cognitive domains. Future studies should better establish this relationship and delineate the neurological substrate underpinning it.
TMPRSS2 is essential for SARS-CoV-2 Beta and Omicron infection
Authors: Metzdorf Kristin , Jacobsen Henning , Greweling-Pils Marina C. , Hoffmann Markus , Lüddecke Tatjana , Miller Felicitas , Melcher Lars , Kempf Amy M. , Nehlmeier Inga , Bruder Dunja , Widera Marek , Ciesek Sandra , Pöhlmann Stefan , Čičin-Šain Luka 
Published: December 2022

AbstractThe COVID-19 pandemic remains a global health threat and novel antiviral strategies are urgently needed. SARS-CoV-2 employs the cellular serine protease TMPRSS2 for entry into lung cells and TMPRSS2 inhibitors are being developed for COVID-19 therapy. However, the SARS-CoV-2 Omicron variant, which currently dominates the pandemic, prefers the endo/lysosomal cysteine protease cathepsin L over TMPRSS2 for cell entry, raising doubts whether TMPRSS2 inhibitors would be suitable for treatment of patients infected with the Omicron variant. Nevertheless, the contribution of TMPRSS2 to spread of SARS-CoV-2 in the infected host is largely unclear. Here, we show that loss of TMPRSS2 strongly reduced the replication of the Beta variant in nose, trachea and lung of C57BL mice and protected the animals from weight loss and disease. Infection of mice with the Omicron variant did not cause disease, as expected, but again TMPRSS2 was essential for efficient viral spread in the upper and lower respiratory tract. These results identify a key role of TMPRSS2 in SARS-CoV-2 Beta and Omicron infection and highlight TMPRSS2 as an attractive target for antiviral intervention.