bluuebunny/crossref_metadata_2025_split huggingface dataset:
Jag1 represses Notch activation in lateral supporting cells and inhibits an outer hair cell fate in the medial compartment of the developing cochlea
Authors: de Haan Sandra , Corbat Agustin A. , Cederroth Christopher R. , Autrum Lisa G. , Hankeova Simona , Driver Elizabeth C. , Canlon Barbara , Kelley Matthew W. , Andersson Emma R. 
Published: February 2024

AbstractNotch signaling regulates both inner and middle ear morphogenesis and establishes a strict pattern of sensory cells in the organ of Corti in the mammalian cochlea. Patients with Alagille syndrome have impaired Notch signaling (∼94% withJAG1mutations) resulting in sensorineural and conductive hearing loss. Here, we investigate the function of Jag1-mediated Notch activation in cochlear patterning and signaling using the Jag1 “Nodder” (Jag1Ndr/Ndr) mouse model of Alagille syndrome.Jag1Ndr/Ndrmice exhibited severe vestibular and auditory deficits and a dose-dependent increase in ectopic inner hair cells and a reduction in outer hair cells. Single cell RNA sequencing of the organ of Corti demonstrated a global dysregulation of genes associated with inner ear development and deafness. Analysis of individual cell types indicated a novel role for Jag1 in repressing Notch activation in lateral supporting cells and revealed a function for Jag1 in gene regulation and development of outer hair cells. Additionally, “outer hair cell-like” SLC26A5 (Prestin) positive cells were present in the medial compartment and pillar cell region ofJag1Ndr/Ndrmice and exhibited location-dependent expression of the inner hair cell fate-regulatorTbx2, revisiting the potency ofTbx2in driving inner hair cell commitment in “outer hair cell-like” cells in the Jag1-mutant IHC compartment. Our data reveals a novel role for Jag1 in repressing Notch activation in lateral supporting cells and highlights involvement for Notch signaling in inner versus outer hair cell specification and positioning.
Characterization of ribosome stalling and no-go mRNA decay stimulated by the Fragile X protein, FMRP
Authors: Scarpitti MaKenzie R. , Pastore Benjamin , Tang Wen , Kearse Michael G. 
Published: February 2024

ABSTRACTLoss of functional fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) and is the leading monogenic cause of autism spectrum disorders and intellectual disability. FMRP is most notably a translational repressor and is thought to inhibit translation elongation by stalling ribosomes as FMRP-bound polyribosomes from brain tissue are resistant to puromycin and nuclease treatment. Here, we present data showing that the C-terminal non-canonical RNA-binding domain of FMRP is essential and sufficient to induce puromycin-resistant mRNA•ribosome complexes. Given that stalled ribosomes can stimulate ribosome collisions and no-go mRNA decay (NGD), we tested the ability of FMRP to drive NGD of its target transcripts in neuroblastoma cells. Indeed, FMRP and ribosomal proteins, but not PABPC1, were enriched in isolated nuclease-resistant disomes compared to controls. Using siRNA knockdown and RNA-seq, we identified 16 putative FMRP-mediated NGD substrates, many of which encode proteins involved in neuronal development and function. Increased mRNA stability of the putative substrates was also observed when either FMRP was depleted or NGD was prevented via RNAi. Taken together, these data support that FMRP stalls ribosomes and can stimulate NGD of a select set of transcripts in cells, revealing an unappreciated role of FMRP that would be misregulated in FXS.
Pia-FLOW: Deciphering hemodynamic maps of the pial vascular connectome and its response to arterial occlusion
Authors: Glück Chaim , Zhou Quanyu , Droux Jeanne , Chen Zhenyue , Glandorf Lukas , Wegener Susanne , Razansky Daniel , Weber Bruno , El Amki Mohamad 
Published: February 2024

AbstractThe pial vasculature is the sole source of blood supply to the neocortex. The brain is contained within the skull, a vascularized bone marrow with a unique anatomical connection to the brain. Recent developments in tissue clearing have enabled unprecedented mapping of the entire pial and calvarial vasculature. However, what are the absolute flow rates values of those vascular networks? This information cannot accurately be retrieved with the commonly used bioimaging methods. Here, we introduce Pia-FLOW, a new approach based on large-scale fluo-rescence localization microscopy, to attain hemodynamic imaging of the whole murine pial and calvarial vasculature at frame rates up to 1000 Hz and spatial resolution reaching 5.4 µm. Using Pia-FLOW, we provide detailed maps of flow velocity, direction and vascular diameters which can serve as ground-truth data for further studies, advancing our understanding of brain fluid dynamics. Furthermore, Pia-FLOW revealed that the pial vascular network functions as one unit for robust allocation of blood after stroke.
Npbwr1signaling mediates fast antidepressant action
Authors: Stein Gregor , Aly Janine S. , Lange Lisa , Manzolillo Annamaria , Riege Konstantin , Brancato Anna , Hübner Christian A. , Turecki Gustavo , Hoffmann Steve , Engmann Olivia 
Published: February 2024

AbstractChronic stress is a major risk factor for depression, a leading cause of disability and suicide. Because current antidepressants work slowly, have common side effects, and are only effective in a minority of patients, there is an unmet need to identify the underlying molecular mechanisms. Here, we reveal the receptor for neuropeptides B and W,Npbwr1, as a key regulator of depressive-like symptoms.Npbwr1is increased in the nucleus accumbens of chronically stressed mice and postmortem in patients diagnosed with depression. Using viral-mediated gene transfer, we demonstrate a causal link betweenNpbwr1, dendritic spine morphology, the biomarkerBdnf, and depressive-like behaviors. Importantly, microinjection of the synthetic antagonist ofNpbwr1, CYM50769, rapidly ameliorates depressive-like behavioral symptoms and altersBdnflevels. CYM50769 is selective, well tolerated, and shows effects up to 7 days after administration of a single dose. In summary, these findings drastically advance our understanding of mood and chronic stress and warrant further investigation of CYM50769 as a potential fast-acting antidepressant.
Functional Connectivity Differences in Distinct Dentato-Cortical Networks in Alzheimer’s Disease and Mild Cognitive Impairment
Authors: Herrejon Ivan A. , Jackson T. Bryan , Hicks Tracey H. , Bernard Jessica A. ,   Alzheimer’s Disease Neuroimaging Initiative
Published: February 2024

AbstractRecent research has implicated the cerebellum in Alzheimer’s disease (AD), and cerebro-cerebellar network connectivity is emerging as a possible contributor to symptom severity. The cerebellar dentate nucleus (DN) has parallel motor and non-motor sub-regions that project to motor and frontal regions of the cerebral cortex, respectively. These distinct dentato-cortical networks have been delineated in the non-human primate and human brain. Importantly, cerebellar regions prone to atrophy in AD are functionally connected to atrophied regions of the cerebral cortex, suggesting that dysfunction perhaps occurs at a network level. Investigating functional connectivity (FC) alterations of the DN is a crucial step in understanding the cerebellum in AD and in mild cognitive impairment (MCI). Inclusion of this latter group stands to provide insights into cerebellar contributions prior to diagnosis of AD. The present study investigated FC differences in dorsal (dDN) and ventral (vDN) DN networks in MCI and AD relative to cognitively normal participants (CN) and relationships between FC and behavior. Our results showed patterns indicating both higher and lower functional connectivity in both dDN and vDN in AD compared to CN. However, connectivity in the AD group was lower when compared to MCI. We argue that these findings suggest that the patterns of higher FC in AD may act as a compensatory mechanism. Additionally, we found associations between the individual networks and behavior. There were significant interactions between dDN connectivity and motor symptoms. However, both DN seeds were associated with cognitive task performance. Together, these results indicate that cerebellar DN networks are impacted in AD, and this may impact behavior. In concert with the growing body of literature implicating the cerebellum in AD, our work further underscores the importance of investigations of this region. We speculate that much like in psychiatric diseases such as schizophrenia, cerebellar dysfunction results in negative impacts on thought and the organization therein. Further, this is consistent with recent arguments that the cerebellum provides crucial scaffolding for cognitive function in aging. Together, our findings stand to inform future clinical work in the diagnosis and understanding of this disease.
Targeted Degradation of METTL3 Against Acute Myeloid Leukemia and Gastric Cancer
Authors: Hwang Kyubin , Bae Juhyeon , Jhe Yoo-Lim , Kim Jungmin , Cheong Jae-Ho , Sim Taebo 
Published: February 2024

ABSTRACTAccumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancer types, either dependent or independent of its m6A methyl transferase activity. We have designed proteolysis-targeting chimeras (PROTACs) targeting METTL3 and identifiedKH12as a potent METTL3 degrader. Treatment ofKH12on MOLM-13 cells causes more than 80% degradation of METTL3 with a half-maximal degradation concentration (DC50) of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition,KH12reverses differentiation and possesses anti-proliferative effects surpassing the reported inhibitors in MOLM-13 cells. Furthermore,KH12significantly suppresses the growth of various gastric cancer (GC) cells, where the m6A-independent activity of METTL3 plays a crucial role in tumorigenesis. The anti-GC effect ofKH12was further confirmed in patient-derived organoids (PDOs). This study highlights the therapeutic potential of targeted degradation of epitranscriptomic writer METTL3 as an anti-cancer strategy.
PPARγ mediated enhanced lipid biogenesis fuelsMycobacterium tuberculosisgrowth in a drug-tolerant hepatocyte environment
Authors: Sarkar Binayak , Singh Jyotsna , Yadav Mohit , Sharma Priya , Sharma Raman Deep , Singh Shweta , Chandramouli Aakash , Mehdiratta Kritee , Kumar Ashwani , Kamat Siddhesh S. , Ghorpade Devram S. , Mohanty Debasisa , Kumar Dhiraj , Gokhale Rajesh S. 
Published: February 2024

AbstractMycobacterium tuberculosis(Mtb) infection of the lungs, besides producing prolonged cough with mucus, also causes progressive fatigue and cachexia with debilitating loss of muscle mass. While anti-tuberculosis (TB) drug therapy is directed toward eliminating bacilli, the treatment regimen ignores the systemic pathogenic derailments that probably dictate TB-associated mortality and morbidity. Presently, it is not understood whether Mtb spreads to metabolic organs and brings about these impairments. Here we show that Mtb creates a replication-conducive milieu of lipid droplets in hepatocytes by upregulating transcription factor PPARγ and scavenging lipids from the host cells. In hepatocytes, Mtb shields itself against the common anti-TB drugs by inducing drug-metabolizing enzymes. Infection of the hepatocytes in thein vivoaerosol mice model can be consistently observed post-week 4 along with enhanced expression of PPARγ and drug-metabolizing enzymes. Moreover, histopathological analysis indeed shows the presence of Mtb in hepatocytes along with granuloma-like structures in human biopsied liver sections. Hepatotropism of Mtb during the chronic infectious cycle results in immuno-metabolic dysregulation that could magnify local and systemic pathogenicity, altering clinical presentations.
Attentional guidance through object associations in visual cortex
Authors: Lerebourg Maëlle , de Lange Floris P. , Peelen Marius V. 
Published: February 2024

AbstractEfficient behavior requires the rapid attentional selection of task-relevant objects. Preparatory activity of target-selective neurons in visual cortex is thought to support attentional selection, guiding spatial attention and favoring processing of target-matching input. However, naturalistic searches are often guided by non-targets, including target-associated “anchor” objects. For instance, when looking for a pen, we may direct our attention to the office desk on which we expect to find it. Here, using fMRI and eyetracking in a context-guided search task, we tested whether preparatory activity in visual cortex reflected the target, the guiding anchor object, or both. Participants learned associations between targets and anchors, reversing across two scene contexts, before searching for these targets. Participants’ first fixations were reliably guided by the associated anchor. Preparatory activity in lateral occipital cortex (LOC), and right intraparietal sulcus (IPS), represented the target-associated anchor rather than the target. These results shed light on the neural basis of context-guided search in structured environments.
Solaris: a panel of bright and sensitive hybrid voltage indicators for imaging membrane potential in cultured neurons
Authors: Yang Junqi , Zhu Siyan , Yang Luming , Peng Luxin , Han Yi , Hayward Rebecca Frank , Park Pojeong , Hu Dachao , Cohen Adam E. , Zou Peng 
Published: February 2024

AbstractDynamic changes in the membrane potential underlie neuronal activities. Fluorescent voltage indicators allow optical recording of electrical signaling across a neuronal population with cellular precision and at millisecond-level temporal resolution. Here we report the design and characterization of a chemigenetic hybrid voltage indicator, Solaris, in which a circularly permuted HaloTag is inserted into the first extracellular loop ofAcetabulariarhodopsin. Solaris is compatible with fluorogenic HaloTag ligands JF525, JF549, JF552, JF585, and JF635. The most sensitive conjugate, Solaris585, has more than 2-fold higher voltage sensitivity than the spectrally similar Voltron2585(ΔF/F0= -28.1 ± 1.3% versus -12.3 ± 0.7% per action potential in cultured neurons). Solaris585supports the measurement of optogenetically evoked spike activity or dual-color imaging in conjunction with green-emitting calcium or glutamate indicators. Solaris indicators are also applicable to fluorescence lifetime imaging, which probes the absolute membrane potential. This new hybrid voltage indicator is a valuable tool for imaging neuronal electrophysiological activities in cultured cells with substantially improved dynamic range compared to previous hybrid indicators.
Cell lipotypes localization in brain by mass spectrometry imaging
Authors: Martínez-Gardeazabal Jonatan , Moreno-Rodríguez Marta , Llorente-Ovejero Alberto , Gonález de San Román Estibaliz , Lombardero Laura , de Tena Iker Bengoetxea , Sustacha Juan , Matute Carlos , Manuel Iván , Bonifazi Paolo , Rodríguez-Puertas Rafael 
Published: February 2024

AbstractThe study investigates brain lipid super-specialisation by defining characteristic spectral lipotypic profiles for the five primary cerebral cell-types. Utilizing a computational approach, the research visualizes the anatomical distribution of these profiles with high spatial resolution in brain tissues. This method unveils cellular stereotypic lipidic signatures within the CNS, providing a new framework for exploring the physiological roles of lipids in diverse cell-types present in brain or in any other tissue.
Notch-signaling is required for mediating between two pattern forming processes during head regeneration inHydrapolyps
Authors: Steichele Mona , Sauermann Lara , Pan Qin , Moneer Jasmin , de la Porte Alexandra , Heß Martin , Mercker Moritz , Strube Catharina , Flaswinkel Heinrich , Jenewein Marcell , Böttger Angelika 
Published: February 2024

AbstractHydrapolyps regenerate lost body parts, including the head. In addition,Hydrahead tissue has organizer properties thus being able to recruit body column tissue from a host polyp to produce ectopic hydranths after transplantation. These pattern forming processes involve Notch- and Wnt/β-catenin-signaling.Hydrahead regeneration consists of two parts, hypostome/organizer and tentacle development. Previous work had shown that the Notch inhibitor DAPT blocks hypostome regeneration and organizer formation, but not the appearance of tentacle genes and tentacle tissue. Here we show that the β-catenin inhibitor iCRT14 blocks tentacle regeneration, but not regeneration of hypostome and organizer tissue. Using RT-qPCR gene expression analyzes during head regeneration we found that DAPT inhibitsHyWnt3- andHyBMP2/4expression and expression of transcriptional repressor genes includingCnGsc,Sp5andHyHes,while increasing expression ofHyBMP5/8band thec-fos-related geneHyKayak.ICRT14 blocks expression of the tentacle specification factorHyAlx,but not expression ofHyWnt3. Thus, in accordance with regeneration of two head structures we find two signaling and gene expression modules withHyWnt3andHyBMP4part of a hypostome/organizer module, andBMP5/8,HyAlxand β-catenin part of a tentacle module. We conclude that Notch functions as an inhibitor of tentacle production to allow regeneration of hypostome/head organizer. Furthermore, withHyKayakwe present a candidate target gene for HvNotch induced repressor genes. Using siRNA and the Fos/Jun-inhibitor T5224 we show that HyKayak attenuates the expression ofHyWnt3.Finally, Notch signaling was not required for head regeneration of fresh water polyps ofCraspedacusta. Polyps ofCraspedacustado not have tentacles and thus, after head removal only regenerate a hypostome with a crescent of nematocytes around the mouth opening. This corroborates the idea that Notch-signaling mediates between two pattern forming processes duringHydrahead regeneration.
Circadian regulation of endoplasmic reticulum calcium response in cultured mouse astrocytes
Authors: Ryu Ji Eun , Shim Kyu-Won , Roh Hyun Woong , Park Minsung , Lee Jae-Hyung , Kim Eun Young 
Published: February 2024

AbstractThe circadian clock, an internal time-keeping system orchestrates 24-hour rhythms in physiology and behavior by regulating rhythmic transcription in cells. Astrocytes, the most abundant glial cells, play crucial roles in central nervous system (CNS) functions, but the impact of the circadian clock on astrocyte functions remains largely unexplored. In this study, we identified 412 circadian rhythmic transcripts in cultured mouse cortical astrocytes through RNA sequencing. Gene Ontology analysis indicated that genes involved in Ca2+homeostasis are under circadian control. Notably,Herpud1(Herp) exhibited robust circadian rhythmicity at both mRNA and protein levels, a rhythm disrupted in astrocytes lacking the circadian transcription factor, BMAL1. HERP regulated endoplasmic reticulum (ER) Ca2+release by modulating the degradation of inositol 1,4,5-trisphosphate receptors (ITPRs). ATP-stimulated ER Ca2+release varied with the circadian phase, being more pronounced at subjective night phase, likely due to the rhythmic expression of ITPR2. Correspondingly, ATP-stimulated cytosolic Ca2+increases were heightened at the subjective night phase. This rhythmic ER Ca2+response led to circadian phase-dependent variations in the phosphorylation of Connexin 43 (Ser368) and gap junctional communication. Given the role of gap junction channel (GJC) in propagating Ca2+signals, we suggest that this circadian regulation of ER Ca2+responses could affect astrocytic modulation of synaptic activity according to the time of day. Overall, our study enhances the understanding of how the circadian clock influences astrocyte function in the CNS, shedding light on their potential role in daily variations of brain activity and health.
Triplex real-time PCR ZKIR-T assay for simultaneous detection of theKlebsiella pneumoniaespecies complex and identification ofK. pneumoniaesensu stricto
Authors: Ligowska-Marzęta Małgorzata , Barbier Elodie , Rodrigues Carla , Piveteau Pascal , Schrøder Hansen Dennis , Hartmann Alain , Nielsen Eva Møller , Brisse Sylvain 
Published: February 2024

AbstractKlebsiella pneumoniaespecies complex (KpSC) members, including the most important speciesK. pneumoniae(phylogroup Kp1 of the KpSC), are important opportunistic pathogens which display increasing rates of antimicrobial resistance worldwide. As they are widespread in food and the environment, there is a need for fast, sensitive and reliable methods to detect KpSC members in complex matrices. Previously, the ZKIR real-time PCR assay was developed to detect all KpSC members without distinction. Given that Kp1 is the clinically most significant phylogroup of the KpSC, here we aimed to simultaneously identify Kp1 while detecting all KpSC members. Three TaqMan probes were developed and used: thezkirP1 probe to detect phylogroups Kp1 to Kp5 and Kp7; thezkirP2 probe to detect phylogroup Kp6; and the Kp1 probe to specifically identify this phylogroup. The new assay was tested on a total of 95 KpSC and 19 non-KpSC strains from various sources, representing the different phylogroups as defined by whole genome sequencing. The results showed almost complete specificity, as the expected PCR results were obtained for 112 (98%) strains. The new triplex real-time PCR assay, called ZKIR-T, enables detection of all KpSC taxa while discriminating Kp1, which will be useful for rapid screening and to focus downstream analyses on chosen phylogroups of the KpSC.ImportanceThe pathogens of theKlebsiella pneumoniaespecies complex are widespread in food and animals and are amongst the main pathogens responsible for multidrug resistant infections in humans. In this study, we developed a highly sensitive detection assay that enables detection of this group of bacteria, with the simultaneous identification of the most common and clinically important species. This triplex one-reaction assay was shown to be highly sensitive and precise, enabling fast screening of varied samples for the presence of KpSC andK. pneumoniae sensu stricto.
Aperiodic and Hurst EEG exponents across early human brain development: a systematic review
Authors: Stanyard R. A. , Mason D. , Ellis C. , Dickson H. , Short R. , Batalle D. , Arichi T. 
Published: February 2024

AbstractIn electroencephalographic (EEG) data, power-frequency slope exponents (1/fβ) can provide non-invasive markers ofin vivoneural activity excitation-inhibition (E:I) balance. E:I balance may be altered in neurodevelopmental conditions; hence, understanding how 1/fβevolves across infancy/childhood has implications for developing early assessments/interventions. This systematic review (PROSPERO-ID: CRD42023363294) explored the early maturation (0-26yrs) of resting-state EEG 1/fmeasures (aperiodic [AE], power law [PLE] and Hurst [HE] exponents), including studies containing ≥1 1/fmeasures and ≥10 typically developing participants. Five databases (including Embase and Scopus) were searched during March 2023. Forty-two studies were identified (Nparticipants=3478). Risk of bias was assessed using the Quality Assessment with Diverse Studies tool. Narrative synthesis of HE data suggests non-stationary EEG activity occurs throughout development. Age-related trends were complex, with rapid decreases in AEs during infancy and heterogenous changes thereafter. Regionally, AE maxima shifted developmentally, potentially reflecting spatial trends in maturing brain connectivity. This work highlights the importance of further characterising the development of 1/fmeasures to better understand how E:I balance shapes brain and cognitive development.