bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cortical structure of neural synchrony and information flow during transition from wakefulness to light non-rapid eye movement sleep
Authors: Fan Joline M. , Kudo Kiwamu , Verma Parul , Ranasinghe Kamalini G. , Morise Hirofumi , Findlay Anne M. , Vossel Keith , Kirsch Heidi E. , Raj Ashish , Krystal Andrew D. , Nagarajan Srikantan S. 
Published: March 2022

ABSTRACTSleep is a highly stereotyped phenomenon, requiring robust spatial and temporal coordination of neural activity. How the brain coordinates neural activity with sleep onset can provide insight into the physiological functions subserved by sleep and pathologic phenomena associated with sleep onset. We quantified whole-brain network changes in synchrony and information flow during the transition from wake to non-rapid eye movement (NREM) sleep using magnetoencephalography imaging in healthy subjects. In addition, we performed computational modeling to infer excitatory and inhibitory properties of local neural activity. The sleep transition was identified to be encoded in spatially and temporally specific patterns of local and long-range neural synchrony. Patterns of information flow revealed that mesial frontal regions receive hierarchically organized inputs from broad cortical regions upon sleep onset. Finally, biophysical neural mass modeling demonstrated spatially heterogeneous properties of cortical excitation-to-inhibition from wake to NREM. Together, these findings reveal whole-brain corticocortical structure in the sleep-wake transition and demonstrate the orchestration of local and long-range, frequency-specific cortical interactions that are fundamental to sleep onset.
The Anti-Burkholderia Lasso Peptide Ubonodin Co-Opts the Siderophore Receptor PupB for Cellular Entry
Authors: Do Truc , Thokkadam Alina , Leach Robert , Link A. James 
Published: March 2022

ABSTRACTNew antibiotics are needed as bacterial infections continue to be a leading cause of death. Notorious among antibiotic-resistant bacteria is the Burkholderia cepacia complex (Bcc), which infects cystic fibrosis patients, causing lung function decline. We recently discovered a novel ribosomally synthesized and post-translationally modified peptide (RiPP), ubonodin, with potent activity against several Burkholderia pathogens. Ubonodin inhibits RNA polymerase, but only select Bcc strains were susceptible, indicating that having a conserved cellular target does not guarantee activity. Given the cytoplasmic target, we speculate that cellular uptake of ubonodin determines susceptibility. Here, we report a new outer membrane siderophore receptor, PupB, that is required for ubonodin uptake in B. cepacia. Loss of PupB renders B. cepacia resistant to ubonodin, whereas expressing PupB sensitizes a resistant strain. Thus, outer membrane transport is the major determinant of ubonodin’s spectrum of activity. We also show that PupB is activated by a TonB protein and examine a transcriptional pathway that further regulates PupB. Finally, we elucidate the complete cellular uptake pathway for ubonodin by also identifying its inner membrane transporter in B. cepacia. Our work unravels central steps in the mechanism of action of ubonodin and establishes a general framework for dissecting RiPP function.
Parental age at conception on mouse lemur’s offspring longevity: sex-specific maternal effects
Authors: Martine Perret , Aude Anzereay 
Published: March 2022

AbstractParental age at conception often influences offspring’s longevity, a phenomenon referred as the “Lansing effect” described in large variety of organisms. But, the majority of the results refer to the survival of juveniles, mainly explained by an inadequate parental care by the elderly parents, mostly the mothers. Studies on the effect of parental age on offspring’s longevity in adulthood remain few, excepted in humans for whom effects of parental age are variable according to statistical models or socioeconomic environments. In a small primate which the longevity reaches up to 12 years, we investigated the effects of parental age at conception on the longevity of offspring (N = 278) issued from parents with known longevity. None of the postnatal parameters, including body mass, influenced offspring’s longevity. Mothers’ age at conception significantly affected offspring’s longevity in males but not females. By contrast, fathers’ age at conception did not influence offspring’s longevity. When considering the age of the breeding pairs at conception, the older the mother, the lower the longevity of male offspring with a minimum when the father was aged. No such correlation was observed for female offspring. Lastly, the longevity of female offspring was significantly positively related to the longevity of both parents. Compared with current studies, the surprisingly minor effect of fathers ‘age and the major impact of mothers’ age on male offspring survival, despite favourable conditions, were discussed in relation with the highly seasonal reproduction in mouse lemurs.
Activation of targetable inflammatory immune signaling is seen in Myelodysplastic Syndromes with SF3B1 mutations
Authors: Choudhary Gaurav S , Pellagatti Andrea , Agianian Bogos , Smith Molly A , Bhagat Tushar D , Gordon-Mitchell Shanisha , Pandey Sanjay , Shah Nishi , Aluri Srinivas , Schwartz Leya , Steeples Violetta , Booher Robert N , Ramachandra Murali , Samson Maria Elena , Carbajal Milagros , Pradhan Kith , Bowman Teresa V. , Pillai Manoj M , Will Britta , Wickrema Amittha , Shastri Aditi , Bradley Robert , Martell Robert , Steidl Ulrich G. , Gavathiotis Evripidis , Boultwood Jacqueline , Starczynowski Daniel T. , Verma Amit 
Published: March 2022

AbstractBackgroundMutations in the SF3B1 splicing factor are commonly seen in Myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML), yet the specific oncogenic pathways activated by missplicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood.MethodsRNA-seq data from SF3B1 mutant samples was analyzed and functional roles of IRAK4 isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in pre-clinical models of MDS/AMLResultsRNA-seq splicing analysis of innate immune mediators in SF3B1 mutant MDS samples revealed retention of full-length exon 6 of interleukin-1 receptor-associated kinase 4 (IRAK4), a critical downstream mediator that links the Myddosome to inflammatory NF-kB activation. Exon 6 retention leads to a longer isoform, encoding a protein (IRAK4-Long) that contains the entire death domain and kinase domain, leading to maximal activation of NF-kB. Cells with wild-type SF3B1 contain smaller IRAK4 isoforms that are targeted for proteosomal degradation. Expression of IRAK4-Long in SF3B1 mutant cells induces TRAF6 activation leading to K63-linked ubiquitination of CDK2, associated with a block in hematopoietic differentiation. Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models.ConclusionsSF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models.
Serotonin sensing by microglia conditions the proper development of neuronal circuits and of social and adaptive skills
Authors: Albertini Giulia , D’Andrea Ivana , Druart Mélanie , Béchade Catherine , Nieves-Rivera Nayadoleni , Etienne Fanny , Le Magueresse Corentin , Rebsam Alexandra , Heck Nicolas , Maroteaux Luc , Roumier Anne 
Published: March 2022

AbstractThe proper maturation of emotional and sensory circuits requires a fine tuning of serotonin (5-HT) level during early postnatal development. Consistently, dysfunctions of the serotonergic system have been associated with neurodevelopmental psychiatric diseases, including autism spectrum disorders (ASD). However, the mechanisms underlying the developmental effects of 5-HT remain partially unknown, one obstacle being the action of 5-HT on different cell types.Here, we focused on microglia, which play a role in brain wiring refinement, and we investigated whether the control of these cells by 5-HT is relevant for neurodevelopment and spontaneous behaviors. Since the main 5-HT sensor in microglia is the 5-HT2B receptor subtype, we prevented 5-HT signaling specifically in microglia by conditionally invalidating Htr2b gene in these cells. We observed that abrogating the serotonergic control of microglia neonatally impacts the phagolysosomal compartment of these cells and their proximity to synapses, and perturbs neuronal circuits maturation. Furthermore, this early ablation of microglial 5-HT2B receptors leads to adult hyperactivity in a novel environment and behavioral defects in sociability and flexibility. Importantly, we show that these behavioral alterations result from a developmental effect, since they are not observed when microglial Htr2b invalidation is induced later, at P30 onward.Thus, a primary alteration of 5-HT sensing in microglia, during a critical time window between birth and P30, is sufficient to impair social and flexibility skills. This link between 5-HT and microglia may explain the association between serotonergic dysfunctions and behavioral traits, like impaired sociability and inadaptability to novelty, which are prominent in several psychiatric disorders such as ASD.
Longitudinal dynamics of microvascular recovery after acquired cortical injury
Authors: Lin Xiaoxiao , Chen Lujia , Jullienne Amandine , Zhang Hai , Salehi Arjang , Hamer Mary , Holmes Todd , Obenaus Andre , Xu Xiangmin 
Published: March 2022

AbstractAcquired brain injuries due to trauma damage cortical vasculature, which in turn impairs blood flow to injured tissues. There are reports of vascular morphological recovery following traumatic brain injury (TBI), but the remodeling process has not been examined longitudinally in detail after injury in vivo. Understanding the dynamic processes that influence recovery is thus critically important. We evaluated the longitudinal and dynamic microvascular recovery and remodeling up to 2 months post injury using live brain miniscope and 2-photon microscopic imaging. The new imaging approaches captured dynamic morphological and functional recovery processes at high spatial and temporal resolution in vivo. Vessel painting documented the initial loss and subsequent temporal morphological vascular recovery at the injury site. Miniscopes were used to longitudinally image the temporal dynamics of vascular repair in vivo after brain injury in individual mice across each cohort. We observe near-immediate nascent growth of new vessels in and adjacent to the injury site that peaks between 14-21 days post injury. 2-photon microscopy confirms new vascular growth and further demonstrates differences between cortical layers after cortical injury: large vessels persist in deeper cortical layers (>200 μm), while superficial layers exhibit a dense plexus of fine (and often non-perfused) vessels displaying regrowth. Functionally, blood flow increases mirror increasing vascular density. Filopodia development and endothelial sprouting is measurable within 3 days post injury that rapidly transforms regions devoid of vessels to dense vascular plexus in which new vessels become increasingly perfused. Within 7 days post injury, blood flow is observed in these nascent vessels. Behavioral analysis reveals improved vascular modulation after 9 days post injury, consistent with vascular regrowth. We conclude that morphological recovery events are closely linked to functional recovery of blood flow to the compromised tissues, which subsequently leads to improved behavioral outcomes.
Single-cell transcriptome profiles ofDrosophila fruitless-expressing neurons from both sexes
Authors: Palmateer Colleen M , Artikis Catherina , Brovero Savannah G , Friedman Benjamin , Gresham Alexis , Arbeitman Michelle N 
Published: March 2022

AbstractDrosophila melanogasterreproductive behaviors are orchestrated byfruitlessneurons. We performed single-cell RNA-sequencing onfru P1pupal neurons. Uniform Manifold Approximation and Projection (UMAP) clustering generates an atlas containing 113 clusters. While the male and female neurons overlap in UMAP space, more than half the UMAP clusters have sex-differences in neuron number, and nearly all clusters display sex-differential expression. Based on an examination of enriched marker genes, we annotate clusters as circadian clock neurons, mushroom body Kenyon cell neurons, neurotransmitter- and/or neuropeptide-producing, and those that expressdoublesex. Enriched marker gene analyses also shows that genes that encode members of the immunoglobulin superfamily of cell adhesion molecules, transcription factors, neuropeptides, neuropeptide receptors, and Wnts have unique patterns of enriched expression across the clusters.In vivospatial gene-expression links to the UMAP clusters are provided. A functional analysis offru P1circadian neurons shows they have dimorphic roles in sleep/activity and period length. Given that most clusters are comprised of male and female neurons indicates that the sexes havefru P1neurons with common gene expression programs. Sex-specific expression is overlaid on this program, to build the potential for vastly different sex-specific behaviors.
Triosephosphate export from chloroplasts regulates flavonoid biosynthesis and permits high light acclimation through the inactivation of SnRK1
Authors: Zirngibl Max-Emanuel , Araguirang Galileo Estopare , Kitashova Anastasia , Jahnke Kathrin , Rolka Tobias , Kühn Christine , Nägele Thomas , Richter Andreas S. 
Published: March 2022

AbstractPlants evolved multiple strategies to cope with rapid changes in the environment. During high light acclimation, biosynthesis of photoprotective flavonoids, such as anthocyanins, is induced. However, the exact nature of the signal and downstream factors for high light induction of flavonoid biosynthesis (FB) are still under debate. Here we show that carbon-fixation in chloroplasts, subsequent export of photosynthates by TRIOSEPHOSPHATE/PHOSPHATE TRANSLOCATOR (TPT), and the rapid increase in cellular sugar contents permit the transcriptional activation of FB during high light acclimation. In combination with genetic and physiological analysis, targeted and whole transcriptome gene expression studies showed that reactive oxygen species and phytohormones play only a minor role for rapid HL-induction of the anthocyanin branch of FB. In addition to FB, sugar-responsive genes were late-repressed or induced intpt-2in the course of the high light treatment and a significant overlap with transcripts regulated by SNF1-RELATED PROTEIN KINASE 1 (SnRK1) was found. Analysis of mutants with increased and repressed SnRK1 activity revealed that inactivation of SnRK1 is required for the rapid induction of FB during high light acclimation. Our study underlines the central role of chloroplasts as sensors for environmental changes and emphasizes the vital function of sugar-signalling in plant acclimation, even beyond the regulation of FB.
An easily modifiable conjugative plasmid for studying horizontal gene transfer
Authors: Wang Qinqin , Olesen Asmus Kalckar , Maccario Lorrie , Sørensen Søren J. , Madsen Jonas Stenløkke 
Published: March 2022

AbstractHorizontal gene transfer is an important mechanism in bacterial evolution and can occur at striking frequencies when mediated by mobile genetic elements. Conjugative plasmids are mobile genetic elements that are main drivers of horizontal transfer and a major facilitator in the spread of antibiotic resistance genes. However, conjugative plasmid models that readily can be genetically modified with the aim to study horizontal transfer are not currently available. The aim of this study was to develop a conjugative plasmid model where the insertion of gene cassettes such as reporter genes (e.g., fluorescent proteins) or antibiotic resistance genes would be efficient and convenient. For that, we introduced a single attTn7 site into the conjugative broad-host-range IncP-1 plasmid pKJK5 in a non-disruptive manner. Furthermore, a version with lower transfer rate and a non-conjugative version of pKJK5-attTn7 were also constructed. The advantage of having the attTn7 sites is that genes of interest can be introduced in a single step with very high success rate using the Tn7 transposition system. In addition, larger genetic fragments can be inserted. To illustrate the efficacy of the constructed pKJK5 plasmids, they were complimented with sfgfp in addition to seven different β-lactamase genes representing the four known classes of β-lactamases.
Clinical application of tumour-in-normal contamination assessment from whole genome sequencing
Authors: Mitchell Jonathan , Milite Salvatore , Bartram Jack , Walker Susan , Volkova Nadezda , Yavorska Olena , Zarowiecki Magdalena , Chalker Jane , Thomas Rebecca , Vago Luca , Sosinsky Alona , Caravagna Giulio 
Published: March 2022

AbstractThe unexpected contamination of normal samples with tumour cells reduces variant detection sensitivity, compromising downstream analyses in canonical tumour-normal analyses. Leveraging whole-genome sequencing data available at Genomics England, we develop a tool for normal sample contamination assessment, which we validate in silico and against minimal residual disease testing. From a systematic review of 771 patients with haematological malignancies and sarcomas, we find contamination across a range of cancer clinical indications and DNA sources, with highest prevalence in saliva samples from acute myeloid leukaemia patients, and sorted CD3+ T-cells from myeloproliferative neoplasms. Further exploration reveals 108 hotspot mutations in genes associated with haematological cancers at risk of being subtracted by standard variant calling pipelines. Our work highlights the importance of contamination assessment for accurate somatic variants detection in research and clinical settings, especially with large-scale sequencing projects being utilised to deliver accurate data from which to make clinical decisions for patient care.
The lateral intraparietal area preferentially supports stimulus selection in directed tasks compared to undirected free behavior
Authors: Johnston W. Jeffrey , Tetrick Stephanie M. , Freedman David J. 
Published: March 2022

AbstractOur reactions to the sensory world depend on context. For instance, explicit directions to search for a particular object or feature will induce a different treatment of the sensory world than exploration without a fixed goal. To understand how we navigate the sensory world, it is necessary to understand how both directed search and undirected exploration are produced by the brain. The lateral intraparietal area (LIP) in the posterior parietal cortex has an established role in visual stimulus selection. However, most studies of LIP’s role in stimulus selection focus primarily on highly trained, directed tasks, in which animals are given explicit cues as to which stimulus they should select. Here, we compare neural activity in LIP across two tasks. In one task, the animal is given an explicit direction to select one of two natural images from an array; in the other, the animal is allowed to choose an image freely based on their innate preferences. We find that LIP reliably encodes the eye movement prior to its execution only in the directed task, while the eye movement encoding in the undirected task emerges significantly later. Further, LIP’s encoding of the image’s behavioral relevance emerges after the decision in both tasks. These results indicate that LIP preferentially supports stimulus selection in highly trained and directed behaviors, as opposed to free behavior.
Floating EMG Sensors and Stimulators Wirelessly Powered and Operated by Volume Conduction for Networked Neuroprosthetics
Authors: Becerra-Fajardo Laura , Krob Marc Oliver , Minguillon Jesus , Rodrigues Camila , Welsch Christine , Tudela-Pi Marc , Comerma Albert , Oliveira Barroso Filipe , Schneider Andreas , Ivorra Antoni 
Published: March 2022

AbstractBackgroundImplantable neuroprostheses consisting of a central electronic unit wired to electrodes benefit thousands of patients worldwide. However, they present limitations that restrict their use. Those limitations, which are more adverse in motor neuroprostheses, mostly arise from their bulkiness and the need to perform complex surgical implantation procedures. Alternatively, it has been proposed the development of distributed networks of intramuscular wireless microsensors and microstimulators that communicate with external systems for analyzing neuromuscular activity and performing stimulation or controlling external devices. This paradigm requires the development of miniaturized implants that can be wirelessly powered and operated by an external system. To accomplish this, we propose a wireless power transfer (WPT) and communications approach based on volume conduction of innocuous high frequency (HF) current bursts. The currents are applied through external textile electrodes and are collected by the wireless devices through two electrodes for powering and bidirectional digital communications. As these devices do not require bulky components for obtaining power, they may have a flexible threadlike conformation, facilitating deep implantation by injection.MethodsWe report the design and evaluation of advanced prototypes based on the above approach. The system consists of an external unit, floating semi-implantable devices for sensing and stimulation, and a bidirectional communications protocol. The devices are intended for their future use in acute human trials to demonstrate the distributed paradigm. The technology is assayed in vitro using an agar phantom, and in vivo in hindlimbs of anesthetized rabbits.ResultsThe semi-implantable devices were able to power and bidirectionally communicate with the external unit. Using 13 commands modulated in innocuous 3 MHz HF current bursts, the external unit configured the sensing and stimulation parameters, and controlled their execution. Raw EMG was successfully acquired by the wireless devices at 1 ksps.ConclusionsThe demonstrated approach overcomes key limitations of existing neuroprostheses, paving the way to the development of distributed flexible threadlike sensors and stimulators. To the best of our knowledge, these devices are the first based on WPT by volume conduction that can work as EMG sensors and as electrical stimulators in a network of wireless devices.