bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue-scale dynamic mapping of Hematopoietic Stem Cells and supportive niche cells in the fetal liver
Authors: Helbling Patrick M. , Vijaykumar Anjali , Gomariz Alvaro , Zerkatje Thomas , Zielińska Karolina A. , Loosli Kathrin , Isringhausen Stephan , Nagasawa Takashi , Roeder Ingo , Manz Markus G. , Yokomizo Tomomasa , Nombela-Arrieta César 
Published: September 2023

SummaryThe fetal liver (FL) plays a fundamental role in the ontogeny of the hematopoietic system, by transiently providing a fertile microenvironment for the maturation, proliferation and expansion of fetal hematopoietic progenitors, as well as definitive hematopoietic stem cells (HSCs). Nonetheless, the cellular make up and identity of HSC niches in the FL remain poorly described. Here we employed a combination of 3D quantitative microscopy, bulk mRNA-seq, flow cytometry and cell-specific reporter models, to dissect the spatiotemporal dynamics of putative niche cells and HSCs in the FL microenvironment. We find that at peak stages of FL hematopoiesis, pro-hematopoietic cytokines are promiscuously expressed by endothelial, mesenchymal cells and most prominently by hepatoblasts. These multicellular consortia of parenchymal/stromal cells are spatially predominant in the FL, thus providing unrestricted access to supportive factors throughout the entire tissue. Accordingly, in these early phases HSCs are found scattered across the parenchyma not displaying obvious spatial biases within the broad microanatomy of the FL, but exhibiting clustering behaviors. This highly conducive microenvironment is transient and gets rapidly remodeled through hepatoblast differentiation and sterile inflammatory signaling, leading to the downregulation of hematopoietic factors and the contraction of supportive niches, which temporarily coincide with the exit of HSCs towards emergent BM tissues.
Growth factor-induced desialylation for the fast control of endocytosis
Authors: MacDonald Ewan , Forrester Alison , Valades-Cruz Cesar A. , Madsen Thomas D. , Hetmanski Joseph H. R. , Dransart Estelle , Ng Yeap , Godbole Rashmi , Shp Ananthan Akhil , Leconte Ludovic , Chambon Valérie , Ghosh Debarpan , Pinet Alexis , Bhatia Dhiraj , Lombard Bérangère , Loew Damarys , Larson Martin R. , Leffler Hakon , Lefeber Dirk J. , Clausen Henrik , Caswell Patrick , Shafaq-Zadah Massiullah , Mayor Satyajit , Weigert Roberto , Wunder Christian , Johannes Ludger 
Published: September 2023

SummaryIt is commonly assumed that the glycan makeup of glycoproteins that reach the cell surface is final and static. Here, we challenge this notion by the discovery of a molecular switch that induces acute and reversible changes of glycans on the plasma membrane. We demonstrate that within minutes, the epidermal growth factor triggers the galectin-driven endocytosis of cell surface glycoproteins, such as integrins, that are key regulators of cell adhesion and migration. The onset of this process, mediated by the Na+/H+antiporter NHE-1 and the neuraminidases Neu1/3, requires the pH-triggered enzymatic removal of sialic acids whose presence otherwise prevents galectin binding. Desialylated glycoproteins are then retrogradely transported to the Golgi apparatus where their glycan makeup is reset, and their function is repurposed to regulate EGF-dependent invasive cell migration. Glycosylation at the cell surface thereby emerges as a dynamic and reversible regulatory post-translational modification that controls a highly adaptable trafficking pathway.
Serial attentional resource allocation during parallel feature value tracking
Authors: Merkel Christian , Burgmann Luise , Bartsch Mandy V. , Schoenfeld Mircea A. , Hopf Jens-Max 
Published: September 2023

AbstractThe visual system has evolved the ability to track features like color and orientation in parallel. This property aligns with the specialization of processing these feature dimensions in the visual cortex. But what if we ask to track changing feature-values within the same feature dimension? Parallel tracking would then have to share the same cortical representation, which would set strong limitations on tracking performance. We address this question by measuring the precision of color representations when human observers track the color of two superimposed dot clouds that simultaneously change color along independent trajectories in color-space. We find (1) that tracking precision is highly imbalanced between streams. (2) Tracking precision changes over time by alternating between streams at a rate of ∼1Hz. These observations suggest that, while parallel color tracking is possible, it is highly limited, essentially allowing for only one color-stream to be tracked with precision at a given time.
Fast updating feedback from piriform cortex to the olfactory bulb relays multimodal reward contingency signals during rule-reversal
Authors: Trejo Diego Hernandez , Ciuparu Andrei , da Silva Pedro Garcia , Velasquez Cristina M. , Rebouillat Benjamin , Gross Michael D. , Davis Martin B. , Muresan Raul C. , Albeanu Dinu F. 
Published: September 2023

AbstractWhile animals readily adjust their behavior to adapt to relevant changes in the environment, the neural pathways enabling these changes remain largely unknown. Here, using multiphoton imaging, we investigated whether feedback from the piriform cortex to the olfactory bulb supports such behavioral flexibility. To this end, we engaged head-fixed mice in a multimodal rule-reversal task guided by olfactory and auditory cues. Both odor and, surprisingly, the sound cues triggered cortical bulbar feedback responses which preceded the behavioral report. Responses to the same sensory cue were strongly modulated upon changes in stimulus-reward contingency (rule reversals). The re-shaping of individual bouton responses occurred within seconds of the rule-reversal events and was correlated with changes in the behavior. Optogenetic perturbation of cortical feedback within the bulb disrupted the behavioral performance. Our results indicate that the piriform-to-olfactory bulb feedback carries reward contingency signals and is rapidly re-formatted according to changes in the behavioral context.
HIV co-infection is associated with reducedMycobacterium tuberculosistransmissibility in sub-Saharan Africa
Authors: Windels Etthel M. , Wampande Eddie M. , Joloba Moses L. , Boom W. Henry , Goig Galo A. , Cox Helen , Hella Jerry , Borrell Sonia , Gagneux Sebastien , Brites Daniela , Stadler Tanja 
Published: September 2023

AbstractPersons living with HIV are known to be at increased risk of developing tuberculosis (TB) disease upon infection withMycobacterium tuberculosis(Mtb). However, it has remained unclear how HIV co-infection affects subsequentMtbtransmission from these patients. Here, we customized a Bayesian phylodynamic framework to estimate the effects of HIV co-infection on theMtbtransmission dynamics from sequence data. We applied our model to fourMtbgenomic datasets collected in sub-Saharan African countries with a generalized HIV epidemic. Our results confirm that HIV co-infection is a strong risk factor for developing active TB. Additionally, we demonstrate that HIV co-infection is associated with a reduced effective reproductive number for TB. Stratifying the population by CD4+ T-cell count yielded similar results, suggesting that, in this context, CD4+ T-cell count is not a better predictor ofMtbtransmissibility than HIV infection status. Together, our genome-based analyses complement observational household studies, and firmly establish the negative association between HIV co-infection andMtbtransmissibility.Author summaryMany sub-Saharan African countries have seen a considerable rise in TB incidence since the introduction of HIV, suggesting a strong interaction between HIV and TB epidemics. HIV infection is recognized as an important risk factor for developing TB, but the contribution of HIV-infected TB patients to furtherMtbtransmission is poorly understood. In this study, we analyzed four sets ofMtbgenomic sequences collected in different countries, including sequences from HIV-negative and HIV-positive TB patients. We applied a phylodynamic model to these sequences, aimed at inferring transmission dynamics within and between different host populations. While our findings support that HIV is a strong risk factor for TB, we show that HIV-positive TB patients generate a significantly lower number of secondary TB cases than HIV-negative patients. This suggests that HIV-positive patients often act as sinks inMtbtransmission chains, while HIV-negative patients are a major source of transmission.
Behaviorally irrelevant feature matching increases neural and behavioral working memory readout
Authors: Karabay Aytaç , Wolff Michael J. , Ruuskanen Veera , Akyürek Elkan G. 
Published: September 2023

AbstractThere is an ongoing debate about whether working memory (WM) maintenance relies on persistent activity and/or short-term synaptic plasticity. This is a challenging question, because neuroimaging techniques in cognitive neuroscience measure activity only. Recently, neural perturbation techniques have been developed to tackle this issue, such as visual impulse perturbation or “pinging”, which reveals (un)attended WM content during maintenance. There are contrasting explanations of how pinging reveals WM content, which is central to the debate. Pinging could reveal mnemonic representations by perturbing content-specific networks or by increasing the neural signal-to-noise ratio of active neural states. Here we tested the extent to which the neural impulse response is patterned by the WM network, by presenting two different impulse stimuli. If the impulse interacts with WM networks, the WM-specific impulse response should be enhanced by physical overlap between the initial memory item and the subsequent external perturbation stimulus. This prediction was tested in a working memory task by matching or mismatching task-irrelevant spatial frequencies between memory items and impulse stimuli, as well as probes. Matching probe spatial frequency with memory items resulted in faster behavioral response times and matching impulse spatial frequency with memory items increased the specificity of the neural impulse response as measured from EEG. Matching spatial frequencies did neither result in globally stronger neural responses nor in a larger decrease in trial-to-trial variability compared to mismatching spatial frequencies. The improved neural and behavioural readout of irrelevant feature matching provide evidence that impulse perturbation interacts directly with the memory representations.
Streptococcus mutansinhibits the growth ofEnterococcusvia the non-ribosomal cyclic peptide mutanobactin
Authors: Robertson Ethan B. , Willett Julia L. E. 
Published: September 2023

AbstractEnterococcus faecalisis a Gram-positive commensal bacterium in the gastrointestinal tract and an opportunistic pathogen. Enterococci are a leading cause of nosocomial infections, treatment of which is complicated by intrinsic and acquired antibiotic resistance mechanisms. Additionally,E. faecalishas been associated with various oral diseases, and it is frequently implicated in the failure of endodontic treatment. For establishment and persistence in a microbial community,E. faecalismust successfully compete against other bacteria. Streptococcal species play an important role in the establishment of the oral microbiome and co-exist withEnterococcusin the small intestine, yet the nature of interactions betweenE. faecalisand oral streptococci remains unclear. Here, we describe a mechanism by whichStreptococcus mutansinhibits the growth ofE. faecalisand other Gram-positive pathogens through the production of mutanobactin, a cyclic lipopeptide. Mutanobactin is produced by a polyketide synthase–nonribosomal peptide synthetase hybrid system encoded by themublocus. Mutanobactin-producingS. mutansinhibits planktonic and biofilm growth ofE. faecalisand is also active against otherEnterococcusspecies andStaphylococcus aureus. Mutanobactin damages the cell envelope ofE. faecalis, similar to other lipopeptide antibiotics like daptomycin.E. faecalisresistance to mutanobactin is mediated by the virulence factor gelatinase, a secreted metalloprotease. Our results highlight the anti-biofilm potential of the microbial natural product mutanobactin, provide insight into howE. faecalisinteracts with other organisms in the human microbiome, and demonstrate the importance of studyingE. faecalisdynamics within polymicrobial communities.SignificanceEntercoccus faecalisis a leading cause of hospital-acquired infections, treatment of which is complicated by virulence factors, biofilm formation, and antibiotic resistance. Here, we demonstrate the antibiotic and anti-biofilm activity of mutanobactin, a cyclic lipopeptide produced byStreptococcus mutans, againstEnterococcusandStaphylococcusspp., including vancomycin-resistant Enterococci (VRE). Similar to other lipopeptides, mutanobactin damages the bacterial cell envelope.E. faecalismay overcome antagonism from mutanobactin through production of gelatinase, a secreted protease and prevalent virulence factor. Our results demonstrate the antibiotic and anti-biofilm potential of mutanobactin and highlight the role of bacterial proteases in resistance to bacteria- and host-derived antimicrobial compounds.
Hyperexcitability in humanMECP2null neuronal networks manifests as calcium-dependent reverberating super bursts
Authors: Pradeepan Kartik S , McCready Fraser P , Wei Wei , Khaki Milad , Zhang Wenbo , Salter Michael W , Ellis James , Martinez-Trujillo Julio 
Published: September 2023

ABSTRACTRett syndrome (RTT) patients show abnormal developmental trajectories including loss of language and repetitive hand movements but also have signs of cortical hyperexcitability such as seizures. RTT is predominantly caused by mutations inMECP2and can be modelled in vitro using human stem cell-derived neurons.MECP2null excitatory neurons are smaller in soma size and have reduced synaptic connectivity but are also hyperexcitable, due to higher input resistance, which increases the chance to evoke action potentials with a given depolarized current. Few studies examine how single neuron activity integrates into neuronal networks during human development. Paradoxically, networks ofMECP2null neurons show a decrease in the frequency of bursting patterns consistent with synaptic hypoconnectivity, but no hyperexcitable network events have been reported. Here, we show thatMECP2null neurons have an increase in the frequency of a network event described as reverberating super bursts (RSBs) relative to isogenic controls. RSBs can be mistakenly called as a single long duration burst by standard burst detection algorithms. However, close examination revealed an initial large amplitude network burst followed by high frequency repetitive low amplitude mini-bursts. Using a custom burst detection algorithm, we unfolded the multi-burst structure of RSBs revealing thatMECP2null networks increased the total number of bursts relative to isogenic controls. Application of the Ca2+chelator EGTA-AM selectively eliminated RSBs and rescued the network burst phenotype relative to the isogenic controls. Our results indicate that during early development,MECP2null neurons are hyperexcitable and produce hyperexcitable networks. This may predispose them to the emergence of hyper-synchronic states that potentially translate into seizures. Network hyperexcitability is dependent on asynchronous neurotransmitter release driven by pre-synaptic Ca2+and can be rescued by EGTA-AM to restore typical network dynamics.HIGHLIGHTSReverberating super-bursts (RSBs) follow a stereotypic form of a large initial network burst followed by several smaller amplitude high-frequency mini-bursts.RSBs occur more often inMECP2null excitatory networks.MECP2null excitatory networks with increased RSBs show a hyperexcitable network burst phenotype relative to isogenic controls.The calcium chelator, EGTA-AM, decreases RSBs and rescues the dynamics ofMECP2null hyperexcitable networks.
The Interactome of DUX4 Reveals Multiple Activation Pathways
Authors: Slavin Moriya , Zohar Keren , Claus Clothilde , Schneidman-Duhovny Dina , Linial Michal , Coppée Frédérique , Kalisman Nir 
Published: September 2023

AbstractThe ectopic expression of the DUX4 protein in muscle cells is the underlying cause of Facioscapulohumeral Muscular Dystrophy (FSHD). DUX4 is a potent transcription factor that activates a large number of genes in a dysregulated manner, but the direct protein interactions involved in this activation are only partially known. Here, we tailored an affinity purification and mass spectrometry (AP-MS) analysis to the unique features and functions of DUX4, to provide a more complete view of its interactome. We also obtained and verified all-atom models for two of the major interactions by employing cross-linking and mass spectrometry (CL-MS), computational modeling, and guided mutation studies. We find that DUX4 interacts strongly with two homologous transcription activators, PTOV1 and MED25, in addition to the previously characterized CBP/p300. The interaction with the PTOV1/MED25 domain involves the wrapping of the last thirty residues of the DUX4 activation region around the domain in a very extensive interface. Hence, DUX4 has the capacity to both open the chromatin and directly recruit the Mediator complex. DUX4 also binds to all members of the RFPL4 family, which are among the strongest genes it activates. These interactions are mediated through a hitherto unrecognized motif in the DUX4 disordered linker region. This feedback mechanism suggests that DUX4 may be inhibited by its own activation products, and explains its typical pulsed expression profile. We also found SIX1 and the AP-2 complex as strong DUX4 C-terminal interactors. A separate analysis of interactions involving the N-terminal of DUX4 revealed enrichment of proteins that are involved in DNA repair following double-strand breaks. Overall, these findings reveal new activation pathways for DUX4, which may be modulated in future strategies to control its toxicity. This study also showcases the synergy between CL-MS and deep-learning based modeling for the structural elucidation of challenging protein-protein interactions.
The Microtubule Severing Protein UNC-45A Counteracts the Microtubule Straightening Effects of Taxol
Authors: Hoshino Asumi , Clemente Valentino , Shetty Mihir , Castle Brian , Odde David , Bazzaro Martina 
Published: September 2023

AbstractUNC-45A is the only known ATP-independent microtubule (MT) severing protein. Thus, it severs MTs via a novel mechanism.In vitroand in cells UNC-45A-mediated MT severing is preceded by the appearance of MT bends. While MTs are stiff biological polymers, in cells, they often curve, and the result of this curving can be breaking off. The contribution of MT severing proteins on MT lattice curvature is largely undefined. Here we show that UNC-45A curves MTs. Usingin vitrobiophysical reconstitution and TIRF microscopy analysis, we show that UNC-45A is enriched in the areas where MTs are curved versus the areas where MTs are straight. In cells, we show that UNC-45A overexpression increases MT curvature and its depletion has the opposite effect. We also show that this effect occurs is independent of actomyosin contractility. Lastly, we show for the first time that in cells, Paclitaxel straightens MTs, and that UNC-45A can counteracts the MT straightening effects of the drug.Significance:Our findings reveal for the first time that UNC-45A increases MT curvature. This hints that UNC-45A-mediated MT severing could be due to the worsening of MT curvature and provide a mechanistic understanding of how this MT-severing protein may act. UNC-45A is the only MT severing protein expressed in human cancers, including paclitaxel-resistant ovarian cancer. Our finding that UNC-45A counteracts the paclitaxel-straightening effects of MTs in cells suggests an additional mechanism through which cancer cells escape drug treatment.
Cerebellar granule cell migration and folia development requires Mllt11/Af1q/Tcf7c
Authors: Blommers Marley , Stanton-Turcotte Danielle , Witt Emily A. , Heidari Mohsen , Iulianella Angelo 
Published: September 2023

ABSTRACTThe organization of neurons into distinct layers, known as lamination, is a common feature of the nervous system. This process, which arises from the direct coupling of neurogenesis and neuronal migration, plays a crucial role in the development of the cerebellum, a structure exhibiting a distinct folding cytoarchitecture with cells arranged in discrete layers. Disruptions to neuronal migration can lead to various neurodevelopmental disorders, highlighting the significance of understanding the molecular regulation of lamination. Here we report a role Mllt11/Af1q/Tcf7c (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q, also known as Mllt11 transcriptional cofactor 7; henceforth referred to Mllt11) in the migration of cerebellar granule cells (GCs). We now show that Mllt11 plays a role in both tangential and radial migration of GCs. Loss ofMllt11led to an accumulation of GC precursors in the Rhombic Lip region and a reduction in the number of GCs successfully populating developing folia. Consequently, this results in smaller folia and an overall reduction in cerebellar size. Furthermore, analysis of the anchoring centers reveals disruptions in the perinatal folia cytoarchitecture, including alterations in the Bergmann glia fiber orientation and reduced infolding of the Purkinje cell plate. Lastly, we demonstrate that Mllt11 interacts with Non-muscle Myosin IIB (NMIIB) and regulates its expression. We propose the dysregulation of NMIIB underlies altered GC migratory behavior. Taken together, the findings reported herein demonstrate a role for Mllt11 in regulating neuronal migration within the developing cerebellum, which is necessary for its proper neuroanatomical organization.
Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology
Authors: Han Feng , Lee JiaQie , Chen Xi , Ziontz Jacob , Ward Tyler , Landau Susan M , Baker Suzanne L , Harrison Theresa M , Jagust William J ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2023

AbstractAmyloid-β (Aβ) and tau deposition constitute Alzheimer’s disease (AD) neuropathology. Cortical tau deposits first in the entorhinal cortex and hippocampus and then propagates to neocortex in an Aβ-dependent manner. Tau also tends to accumulate earlier in higher-order association cortex than in lower-order primary sensory-motor cortex. While previous research has examined the production and spread of tau, little attention has been paid to its clearance. Low-frequency (<0.1 Hz) global brain activity during the resting state is coupled with cerebrospinal fluid (CSF) flow and potentially reflects glymphatic clearance. Here we report that tau deposition in subjects with evaluated Aβ, accompanied by cortical thinning and cognitive decline, is strongly associated with decreased coupling between CSF flow and global brain activity. Substantial modulation of global brain activity is also manifested as propagating waves of brain activation between higher- and lower-order regions, resembling tau spreading. Together, the findings suggest an important role of resting-state global brain activity in AD tau pathology.One Sentence SummaryResting-state global brain activity affects tau deposition through the potential involvement of a glymphatic clearance function.