bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuron-specific protein expression at striatal excitatory synapses
Authors: Wang Yi-Zhi , Perez-Rosello Tamara , Surmeier D. James , Savas Jeffrey N. 
Published: March 2023

AbstractCombinatorial expression of postsynaptic proteins underlies synapse diversity within and between neuron types1-5. Thus, characterization of neuron-type-specific postsynaptic proteomes is key to obtaining a deeper understanding of discrete synaptic properties and how selective dysfunction manifests in synaptopathies6-9. To overcome the limitations associated with bulk measures of synaptic protein abundance6,10, we developed a biotin proximity protein tagging probe to characterize neuron-type-specific postsynaptic proteomesin vivo. We found Shank3 protein isoforms are differentially expressed by direct and indirect pathway spiny projection neurons (dSPNs and iSPNs). Studies in mice lacking Shank3 gene exons 13-16 revealed a robust postsynaptic proteome alteration in iSPNs. We report unexpected cell-type specific synaptic protein isoform expression which could play a key causal role in specifying synapse diversity and selective synapse dysfunction in synaptopathies.
The relationship between object-based spatial ability and virtual navigation performance
Authors: Garg Tanya , Velasco Pablo Fernández , Patai Zita Eva , Malcolm Charlotte P. , Kovalets Victor , Bohbot Veronique D. , Coutrot Antoine , Hegarty Mary , Hornberger Michael , Spiers Hugo J. 
Published: March 2023

AbstractSpatial navigation is a multi-faceted behaviour drawing on many different aspects of cognition. Visuospatial abilities, such as spatial working memory and mental rotation, in particular, may be key factors. A range of tests have been developed to assess visuospatial processing and memory, but how such tests relate to navigation ability remains unclear. This understanding is important to advance tests of navigation for disease monitoring in Alzheimer’s Disease, where disorientation is an early symptom. Here, we report the use of an established mobile gaming app, Sea Hero Quest, as a measure of navigation ability. We used three separate tests of navigation embedded in the game: wayfinding, path integration and spatial memory in a radial arm maze. In the same participants, we also collected measures of mental rotation (Mental Rotation Test), visuospatial processing (Design Organization Test) and visuospatial working memory (Digital Corsi). We found few strong correlations across our measures. Being good at wayfinding in a virtual navigation test does not mean an individual will rate themself as a confident navigator, be good at path integration, or have a superior memory in a radial arm maze. However, those good at wayfinding tend to perform well on the three visuospatial tasks examined here, and to also use a landmark strategy in the radial maze task. These findings help clarify the inter-relationships between different abilities supporting visuospatial and navigation skills.HighlightsThree navigation tests embedded in the game Sea Hero Quest were examined in relation to three object-based visuospatial tasks, and self-ratings of navigation ability and stress during navigation.No associations were observed among performance on wayfinding, path integration and radial arm maze levels of Sea Hero Quest.Object-based visuospatial abilities were selectively correlated with performance on wayfinding levels of Sea Hero Quest.Gameplay stress and navigation strategy were not associated with performance on Sea Hero Quest navigation tasks.
Rise of the Cybercrabs: how digital cloning in an integrated taxonomic framework can support deep-sea exploration
Authors: Reynaud Emmanuel G. , Gutierrez-Heredia Luis , Garbett Amy , Horn Esben , Carlsson Jens , Collins Patrick C. 
Published: March 2023

ABSTRACTTaxonomy has been a labour-intensive field of expertise based on hours of manual work and lengthy comments that are mainly bound to books and publications on a two-dimensional world. But every species described is a three-dimensional organism that needs to be seen, manipulated to be fully understood in its native shape. Nowadays, digital technology allows us to transform everyone in an avatar or a digital clone with ease, but collections do not provide many type specimens in a digital format. Here we present a simple approach used to study a specific deep-sea crabSegonzacia mesatlanticaand provide online digital taxonomy across four repository sites. This offers the possibility to describe, exchange digitally and analyse specimens in its full 3D, establish their taxonomy and share them widely on online databases as well as physically by additive manufacturing to duplicate them in collections and outreach activities. Using an integrated taxonomic approach that included the use of 3D type specimens and molecular barcoding we provide evidence that the genusSegonzaciamay be more diverse than previously understood
Choroid Plexus Modulates Subventricular Zone Adult Neurogenesis and Olfaction Through Secretion of Small Extracellular Vesicles
Authors: Liu Luke L. , Shannahan Jonathan , Zheng Wei 
Published: March 2023

SummaryThe choroid plexus (CP) in brain ventricles secrete cerebrospinal fluid (CSF) that bathes the adjacent subventricular zone (SVZ); the latter is the largest neurogenic region in adult brain harboring neural stem/progenitor cells (NSPCs) and supplies newborn neurons to the olfactory bulb (OB) for normal olfaction. We discovered the presence of a CP-SVZ regulatory (CSR) axis in which the CP, by secreting small extracellular vesicles (sEVs), regulated adult neurogenesis in the SVZ and maintained olfaction. The proposed CSR axis was supported by 1) differential neurogenesis outcomes in the OB when animals treated with intracerebroventricular (ICV) infusion of sEVs collected from the CP of normal or manganese (Mn)-poisoned mice, 2) progressively diminished SVZ adult neurogenesis in mice following CP-targeted knockdown of SMPD3 to suppress CP sEV secretion, and 3) compromised olfactory performance in these CP-SMPD3-knockdown mice. Collectively, our findings demonstrate the biological and physiological presence of this sEV-dependent CSR axis in adult brains.HighlightsCP-secreted sEVs regulate adult neurogenesis in the SVZ.CP-secreted sEVs modulate newborn neurons in the OB.Suppression of sEV secretion from the CP deteriorates olfactory performance.
FLT3 signaling inhibition preserves opioid analgesia while abrogating tolerance and hyperalgesia
Authors: Jouvenel Antoine , Tassou Adrien , Thouaye Maxime , Ruel Jérôme , Antri Myriam , Leyris Jean-Philippe , Paquet Aurore , Mallié Sylvie , Sar Chamroeum , Diouloufet Lucie , Sonrier Corinne , Daubeuf François , Bertin Juliette , Alves Stacy , Ventéo Stéphanie , Frossard Nelly , Carroll Patrick , Mechaly Ilana , Rognan Didier , Sokoloff Pierre , Dallel Radhouane , Delmas Patrick , Valmier Jean , Rivat Cyril 
Published: March 2023

AbstractOpioid analgesia is counteracted on chronic use by tolerance and hyperalgesia inducing dose escalation and life-threatening overdoses. Mu opiate receptors (MOR) expressed in primary sensory neurons were recently found to control tolerance and hyperalgesia, but the underlying mechanisms remained elusive. Here we show that genetic inactivation offms-like tyrosine kinase receptor 3 (FLT3) receptor in sensory neurons abrogates morphine tolerance and hyperalgesia by preventing MOR-induced hyperactivation of the cAMP signaling pathway and subsequent excitatory adaptive processes. Moreover, the specific FLT3 inhibitor BDT001 potentiates morphine analgesia in acute and chronic pain models, without aggravating morphine adverse effects, and reverses tolerance and hyperalgesia once installed. Thus, FLT3 appears as a key regulator of the MOR signaling pathway and its pharmacological blockade shows promise to enhance chronic opioid analgesic efficacy.
MBNL1 regulates programmed postnatal switching between regenerative and differentiated cardiac states
Authors: Bailey Logan R.J. , Bugg Darrian , Reichardt Isabella M. , Ortaç C. Dessirée , Gunaje Jagadambika , Johnson Richard , MacCoss Michael J. , Sakamoto Tomoya , Kelly Daniel P. , Regnier Michael , Davis Jennifer M. 
Published: March 2023

AbstractDiscovering determinants of cardiomyocyte maturity and the maintenance of differentiated states is critical to both understanding development and potentially reawakening endogenous regenerative programs in adult mammalian hearts as a therapeutic strategy. Here, the RNA binding protein Muscleblind-like 1 (MBNL1) was identified as a critical regulator of cardiomyocyte differentiated states and their regenerative potential through transcriptome-wide control of RNA stability. Targeted MBNL1 overexpression early in development prematurely transitioned cardiomyocytes to hypertrophic growth, hypoplasia, and dysfunction, whereas loss of MBNL1 function increased cardiomyocyte cell cycle entry and proliferation through altered cell cycle inhibitor transcript stability. Moreover, MBNL1-dependent stabilization of the estrogen-related receptor signaling axis was essential for maintaining cardiomyocyte maturity. In accordance with these data, modulating MBNL1 dose tuned the temporal window of cardiac regeneration, where enhanced MBNL1 activity arrested myocyte proliferation, and MBNL1 deletion promoted regenerative states with prolonged myocyte proliferation. Collectively these data suggest MBNL1 acts as a transcriptome-wide switch between regenerative and mature myocyte states postnatally and throughout adulthood.
Curved adhesions mediate cell attachment to soft matrix fibres in 3D
Authors: Zhang Wei , Lu Chih-Hao , Nakamoto Melissa L. , Tsai Ching-Ting , Roy Anish R. , Lee Christina E. , Yang Yang , Jahed Zeinab , Li Xiao , Cui Bianxiao 
Published: March 2023

AbstractMammalian cells adhere to the extracellular matrix (ECM) and sense mechanical cues through integrin-mediated adhesions1, 2. Focal adhesions and related structures are the primary architectures that transmit forces between the ECM and the actin cytoskeleton. Although focal adhesions are abundant when cells are cultured on rigid substrates, they are sparse in soft environments that cannot support high mechanical tensions3. Here, we report a new class of integrin-mediated adhesions, curved adhesions, whose formation is regulated by membrane curvature instead of mechanical tension. In soft matrices made of protein fibres, curved adhesions are induced by membrane curvatures imposed by the fibre geometry. Curved adhesions are mediated by integrin ɑVβ5 and are molecularly distinct from focal adhesions and clathrin lattices. The molecular mechanism involves a previously unknown interaction between integrin β5 and a curvature-sensing protein FCHo2. We find that curved adhesions are prevalent in physiologically relevant environments. Disruption of curved adhesions by knocking down integrin β5 or FCHo2 abolishes the migration of multiple cancer cell lines in 3D matrices. These findings provide a mechanism of cell anchorage to natural protein fibres that are too soft to support the formation of focal adhesions. Given their functional importance for 3D cell migration, curved adhesions may serve as a therapeutic target for future development.
Sex differences in anxiety and threat avoidance in GAD65 knock-out mice
Authors: Ulrich Michelle , Pollali Evangelia , Çalışkan Gürsel , Stork Oliver , Albrecht Anne 
Published: March 2023

AbstractAnxiety disorders have been linked to a disbalance of excitation and inhibition in a network of brain structures comprising frontal cortical regions, the amygdala and the hippocampus, among others. Recent imaging studies suggest sex differences in the activation of this anxiety network during the processing of emotional information. Rodent models with genetically altered ϒ-amino butyric acid (GABA) neurotransmission allow studying the neuronal basis of such activation shifts and their relation to anxiety endophenotypes, but to date sex effects have rarely been addressed. Using mice with a null mutation of the GABA synthetizing enzyme glutamate decarboxylase 65 (GAD65-/-), we started to compare anxiety-like behavior and avoidance in male vs. female GAD65-/- mice and their wildtype littermates. In an open field, female GAD65-/- mice displayed increased activity, while male GAD65-/- mice showed an increased adaptation of anxiety-like behavior over time. GAD65-/- mice of both sexes had a higher preference for social interaction partners, which was further heightened in male mice. In male mice higher escape responses were observed during an active avoidance task. Together, female mice showed more stable emotional responses despite GAD65 deficiency. To gain insights into interneuron function in network structures controlling anxiety and threat perception, fast oscillations (10-45 Hz) were measured inex vivoslice preparations of the anterior cingulate cortex (ACC). GAD65-/- mice of both sexes displayed increased gamma power in the ACC and a higher density of PV-positive interneurons, which are crucial for generating such rhythmic activity. In addition, GAD65-/- mice had lower numbers of somatostatin-positive interneurons in the basolateral amygdala and in the dorsal dentate gyrus especially in male mice, two key regions important for anxiety and active avoidance responses. Our data suggest sex differences in the configuration of GABAergic interneurons in a cortico-amygdala-hippocampal network controlling network activity patterns, anxiety and threat avoidance behavior.HighlightsRole of GABA in sex-specific anxiety endophenotypes demonstrated in GAD65-/- miceSex- and GAD65-dependent alterations in anxiety, social preference and avoidanceEnhanced in vitro gamma-beta oscillations in ACC slices of GAD65-/- miceIncreased parvalbumin(+) interneuron counts in ACC slices of GAD65-/- miceReduced somatostatin(+) interneuron counts in dorsal DG and BLA of male GAD65-/- miceGraphical Abstract
Coupling of Slack and NaV1.6 sensitizes Slack to quinidine blockade and guides anti-seizure strategy development
Authors: Yuan Tian , Wang Yifan , Jin Yuchen , Yang Hui , Xu Shuai , Zhang Heng , Chen Qian , Li Na , Ma Xinyue , Song Huifang , Peng Chao , Geng Ze , Dong Jie , Duan Guifang , Sun Qi , Yang Yang , Yang Fan , Huang Zhuo 
Published: March 2023

ABSTRACTQuinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidine’s blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6’s N-and C-termini binding to Slack’s C-terminus, and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slack’s C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of “Slack as an isolated target” for anti-epileptic drug discovery efforts, and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy.GRAPHICAL ABSTRACT
Evolution of chemosensory and detoxification gene families across herbivorous Drosophilidae
Authors: Pelaez Julianne N. , Gloss Andrew D. , Goldman-Huertas Benjamin , Kim Bernard , Lapoint Richard T. , Pimentel-Solorio Giovani , Verster Kirsten I. , Aguilar Jessica M. , Dittrich Anna C. Nelson , Singhal Malvika , Suzuki Hiromu C. , Matsunaga Teruyuki , Armstrong Ellie E. , Charboneau Joseph L.M. , Groen Simon C. , Hembry David H. , Ochoa Christopher J. , O’Connor Timothy K. , Prost Stefan , Zaaijer Sophie , Nabity Paul D. , Wang Jiarui , Rodas Esteban , Liang Irene , Whiteman Noah K. 
Published: March 2023

AbstractHerbivorous insects are exceptionally diverse, accounting for a quarter of all known eukaryotic species, but the genetic basis of adaptations that enabled this dietary transition remains poorly understood. Many studies have suggested that expansions and contractions of chemosensory and detoxification gene families – genes directly mediating interactions with plant chemical defenses – underlie successful plant colonization. However, this hypothesis has been challenging to test because the origins of herbivory in many lineages are ancient (>150 million years ago [mya]), obscuring genomic evolutionary patterns. Here, we characterized chemosensory and detoxification gene family evolution acrossScaptomyza,a genus nested withinDrosophilathat includes a recently derived (<15 mya) herbivore lineage of mustard (Brassicales) specialists and carnation (Caryophyllaceae) specialists, and several non-herbivorous species. Comparative genomic analyses revealed that herbivorousScaptomyzahave among the smallest chemosensory and detoxification gene repertoires across 12 drosophilid species surveyed. Rates of gene turnover averaged across the herbivore clade were significantly higher than background rates in over half of the surveyed gene families. However, gene turnover was more limited along the ancestral herbivore branch, with only gustatory receptors and odorant binding proteins experiencing strong losses. The genes most significantly impacted by gene loss, duplication, or changes in selective constraint were those involved in detecting compounds associated with feeding on plants (bitter or electrophilic phytotoxins) or their ancestral diet (yeast and fruit volatiles). These results provide insight into the molecular and evolutionary mechanisms of plant-feeding adaptations and highlight strong gene candidates that have also been linked to other dietary transitions inDrosophila.
Bioactive Natural Product Discovery via Deuterium Adduct Bioactivity Screening
Authors: Zill N.A. , Du Y. , Marinkovich S. , Gu D. , Seidel J. , Zhang W. 
Published: March 2023

AbstractThe discovery of bioactive natural products lies at the forefront of human medicine. The continued discovery of these molecules is imperative in the fight against infection and disease. While natural products have historically dominated the drug market, discovery in recent years has slowed significantly, partly due to limitations in current discovery methodologies. This work demonstrates a new workflow, Deuterium Adduct Bioactivity Screening (DABS), which pairs untargeted isotope labeling with whole cell binding assays for bioactive natural product discovery. DABS was validated and led to the discovery of a new isoprenyl guanidine alkaloid, zillamycin, which showed anti-cancer and anti-microbial activities. DABS thus represents a new workflow to accelerate discovery of natural products with a wide range of bioactive potential.
The Ribosome Profiling landscape of yeast reveals a high diversity in pervasive translation
Authors: Papadopoulos Chris , Arbes Hugo , Chevrollier Nicolas , Blanchet Sandra , Cornu David , Roginski Paul , Rabier Camille , Atia Safiya , Lespinet Olivier , Namy Olivier , Lopes Anne 
Published: March 2023

AbstractPervasive translation is a widespread phenomenon that plays an important role in de novo gene birth; however, its underlying mechanisms remain unclear. Based on multiple Ribosome Profiling (Ribo-Seq) datasets, we investigated the RiboSeq landscape of coding and noncoding regions of yeast. Therefore, we developed a representation framework which allows the visual representation and rational classification of the entire diversity of Ribo-Seq signals that could be observed in yeast. We show that if coding regions are restricted to specific areas of the Ribo-Seq landscape, noncoding regions are associated with a wide diversity of translation signals and, conversely, populate the entire yeast Ribo-Seq landscape. Specifically, we reveal that noncoding regions are associated with canonical translation signals, but also with non-canonical ones absent from coding regions, and which appear to be a hallmark of pervasive translation. Notably, we report thousands of translated noncoding ORFs among which, 251 led to detectable products with Mass Spectrometry while being characterized by a wide range of translation specificities. Overall, we show that pervasive translation is not random with noncoding ORF translation signals being consistent across Ribo-Seq experiments. Finally, we show that the translation signal of noncoding ORFs is not explained by features related to the emergence of function, but rather determined by the translation start codon and the codon distribution in their two alternative frames. Overall, our results enable us to propose a topology of the pervasive Ribo-Seq landscape of a species, and open the way to future comparative analyses of this translation landscape under different conditions.
Clec12a tempers inflammation while restricting expansion of a colitogenic commensal
Authors: Chiaro Tyson R. , Bauer Kaylyn M. , Ost Kyla S. , Stephen-Victor Emmanuel , Nelson Morgan C. , Hill Jennifer H. , Bell Rickesha , Harwood Morgan , Voth Warren , Jackson Taylor , Klag Kendra A , O’Connell Ryan M. , Zac Stephens W. , Round June L. 
Published: March 2023

SUMMARYRegulation of the microbiota is critical to intestinal health yet the mechanisms employed by innate immunity remain unclear. Here we show that mice deficient in the C-Type-lectin receptor, Clec12a developed severe colitis, which was dependent on the microbiota. Fecal-microbiota-transplantation (FMT) studies into germfree mice revealed a colitogenic microbiota formed within Clec12a-/-mice that was marked by expansion of the gram-positive organism,Faecalibaculum rodentium. Treatment withF. rodentiumwas sufficient to worsen colitis in wild-type mice. Macrophages within the gut express the highest levels of Clec12a. Cytokine and sequencing analysis in Clec12a-/-macrophages revealed heighten inflammation but marked reduction in genes associated with phagocytosis. Indeed, Clec12a-/-macrophages are impaired in their ability to uptakeF. rodentium.Purified Clec12a had higher binding to gram-positive organisms such asF. rodentium. Thus, our data identifies Clec12a as an innate immune surveillance mechanism to control expansion of potentially harmful commensals without overt inflammation.
Alamar Blue assay optimization to minimize drug interference and inter-assay viability
Authors: Dinh Mina N. , Hitomi Masahiro , Al-Turaihi Zahraa A. , Scott Jacob G. 
Published: March 2023

ABSTRACTAlamar Blue (AB) has become an increasingly popular reagent of choice for cell viability assays. We chose AB over other reagents such as MTT and Cell-Titer Glo due to its cost effectiveness and its ability to be a nondestructive assay. While analyzing the effect of osimertinib, an EGFR inhibitor on the non-small cell lung cancer cell line, PC-9, we noticed unexpected right-shifts of dose response curves as compared to the curve obtained by Cell Titer Glo assay. Here, we describe our modified AB assay method to avoid right shift right shift in dose response curve. Unlike some of the redox drugs that were reported to directly affected AB reading, osimertinib itself did not directly increase AB reading. Yet, the removal of the drug containing medium prior to AB addition eliminated falsely increased reading giving comparable dose response curve as the one determined by Cell Titer Glo assay. When a panel of 11 drugs were assessed, we found that this modified AB assay eliminated unexpected similar right shifts detected in other epidermal growth factor receptor (EGFR) inhibitors. We also found that plate-to-plate variability can be minimized by adding an appropriate concentration of rhodamine B solution to the assay plates to calibrate fluorimeter sensitivity. This calibration method also enables a continuous longitudinal assay to monitor cell growth or recovery from drug toxicity over time. Our new modified AB assay is expected to provide accuratein vitromeasurement of EGFR targeted therapies.