bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interictal Spikes in Alzheimer’s Disease: Preclinical Evidence for Dominance of the Dentate Gyrus and Cholinergic Control by Medial Septum
Authors: Lisgaras Christos Panagiotis , Scharfman Helen E. 
Published: April 2023

ABSTRACTHIGHLIGHTSInterictal spikes (IIS) occur in 3 mouse lines with Alzheimer’s disease featuresIIS in all 3 mouse lines were most frequent during rapid eye movement (REM) sleepThe dentate gyrus showed larger IIS and earlier current sources vs. CA1 or cortexChemogenetic silencing of medial septum (MS) cholinergic neurons reduced IIS during REMMS silencing did not change REM latency, duration, number of bouts or theta powerInterictal spikes (IIS) are a common type of abnormal electrical activity in Alzheimer’s disease (AD) and preclinical models. The brain regions where IIS are largest are not known but are important because such data would suggest sites that contribute to IIS generation. Because hippocampus and cortex exhibit altered excitability in AD models, we asked which areas dominate the activity during IIS along the cortical-CA1-dentate gyrus (DG) dorso-ventral axis. Because medial septal (MS) cholinergic neurons are overactive when IIS typically occur, we also tested the novel hypothesis that silencing the MS cholinergic neurons selectively would reduce IIS.We used mice that simulate aspects of AD: Tg2576 mice, presenilin 2 (PS2) knockout mice and Ts65Dn mice. To selectively silence MS cholinergic neurons, Tg2576 mice were bred with choline-acetyltransferase (ChAT)-Cre mice and offspring were injected in the MS with AAV encoding inhibitory designer receptors exclusively activated by designer drugs (DREADDs). We recorded local field potentials along the cortical-CA1-DG axis using silicon probes during wakefulness, slow-wave sleep (SWS) and rapid eye movement (REM) sleep.We detected IIS in all transgenic or knockout mice but not age-matched controls. IIS were detectable throughout the cortical-CA1-DG axis and occurred primarily during REM sleep. In all 3 mouse lines, IIS amplitudes were significantly greater in the DG granule cell layer vs. CA1 pyramidal layer or overlying cortex. Current source density analysis showed robust and early current sources in the DG, and additional sources in CA1 and the cortex also. Selective chemogenetic silencing of MS cholinergic neurons significantly reduced IIS rate during REM sleep without affecting the overall duration, number of REM bouts, latency to REM sleep, or theta power during REM. Notably, two control interventions showed no effects.Consistent maximal amplitude and strong current sources of IIS in the DG suggest that the DG is remarkably active during IIS. In addition, selectively reducing MS cholinergic tone, at times when MS is hyperactive, could be a new strategy to reduce IIS in AD.
Supramolecular ‘catch-and-release’ strategy for bioorthogonal fluorogenic imaging across the visible spectrum
Authors: Sasmal Ranjan , Som Arka , Kumari Pratibha , Pahwa Meenakshi , Saha Nilanjana Das , Rao Sushma , Vasu Sheeba , Agasti Sarit S. 
Published: April 2023

AbstractFluorogenic probes that unmask fluorescence signals in response to a bioorthogonal reaction are a powerful new addition to biological imaging. They can provide significantly reduced background fluorescence and minimize non-specific signals, potentially allowing real-time high-contrast imaging without washing out excess fluorophores. While diverse classes of highly refined synthetic fluorophores are readily available now, their integration into a bioorthogonal fluorogenic scheme still necessitates another level of extensive design efforts and customized structural alterations to optimize quenching mechanisms for each given fluorophore scaffold. Herein, we present an easy-to-implement and highly generalizable supramolecular ‘catch-and-release’ strategy for generating an efficient bioorthogonal fluorogenic response from essentially any readily available fluorophores without further structural alterations. We designed this distinct strategy based on the macrocyclic cucurbit[7]uril (CB7) host, where a fluorogenic response is achieved by programming a guest displacement reaction from the macrocycle cavity. We used this strategy to rapidly generate fluorogenic probes across the visible spectrum from structurally diverse classes of fluorophore scaffolds, including coumarin, bodipy, rhodamine, and cyanine. These probes were applied to no-wash fluorogenic imaging of various target molecules in live cells and tissue with minimal background and no appreciable non-specific signal. Notably, the orthogonal reactivity profile of the system allowed us to pair this host-guest fluorogenic probe with the covalently clickable fluorogenic probe to achieve high-contrast super-resolution and multiplexed fluorogenic imaging in cells and tissue.
Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology
Authors: Castano Anna , Silvestre Margaux , Wells Carrow I. , Sanderson Jennifer L. , Ferrer Carla A. , Ong Han Wee , Liang Yi , Richardson William , Silvaroli Josie A. , Bashore Frances M. , Smith Jeffery L. , Genereux Isabelle M. , Dempster Kelvin , Drewry David H. , Pabla Navjot S. , Bullock Alex N. , Benke Tim A. , Ultanir Sila K. , Axtman Alison D. 
Published: April 2023

AbstractPathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD have indicated that CDKL5 kinase function is central to disease pathology.CDKL5encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further,Cdkl5knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces post-synaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated, key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity and human neuropathology.
Repurposing the atypical Type I-G CRISPR system for bacterial genome engineering
Authors: Shangguan Qilin , White Malcolm F 
Published: April 2023

AbstractThe CRISPR-Cas system functions as a prokaryotic immune system and is highly diverse, with six major types and numerous sub-types. The most abundant are type I CRISPR systems, which utilise a multi-subunit effector, Cascade, and a CRISPR RNA (crRNA) to detect invading DNA species. Detection leads to DNA loading of the Cas3 helicase-nuclease, leading to long range deletions in the targeted DNA, thus providing immunity against mobile genetic elements (MGE). Here, we focus on the type I-G system, a streamlined, 4- subunit complex with an atypical Cas3 enzyme. We demonstrate that Cas3 helicase activity is not essential for immunity against MGEin vivoand explore applications of theThioalkalivibrio sulfidiphilusCascade effector for genome engineering inEscherichia coli. Long range, bidirectional deletions were observed when thelacZgene was targeted. Deactivation of the Cas3 helicase activity dramatically altered the types of deletions observed, with small deletions flanked by direct repeats that are suggestive of microhomology mediated end joining. When donor DNA templates were present, both the wild-type and helicase deficient systems promoted homology-directed repair (HDR), with the latter system providing improvements in editing efficiency, suggesting that a single nick in the target site may promote HDR inE. coliusing the type I-G system. These findings open the way for further application of the type I-G CRISPR systems in genome engineering.
On growth and form of the mammary gland: Mesenchyme instructs growth while epithelium directs branching
Authors: Lan Qiang , Trela Ewelina , Lindström Riitta , Satta Jyoti , Kaczyńska Beata , Christensen Mona M. , Holzenberger Martin , Jernvall Jukka , Mikkola Marja L. 
Published: April 2023

AbstractMammary gland is a unique organ that undergoes dynamic alterations throughout a female’s reproductive life, making it an ideal model for developmental, stem cell and cancer biology research. Mammary gland development beginsin uteroand proceeds via a quiescent bud stage before the initial outgrowth and subsequent branching morphogenesis. How mammary epithelial cells transit from quiescence to an actively proliferating and branching tissue during embryogenesis and, importantly, how the branch pattern is determined remain largely unknown. Here we provide evidence indicating that epithelial cell proliferation, segregation into basal and luminal lineages that characterize the postnatal mammary duct, and onset of branching are independent processes, yet partially coordinated by the Eda signaling pathway. By performing heterotypic and heterochronic epithelial-mesenchymal recombination experiments between mammary and salivary gland tissues andex vivolive imaging, we demonstrate that unlike previously concluded, the mode of branching is an intrinsic property of the mammary epithelium while the growth pace and density of the mammary ductal tree are governed by the mesenchyme. Transcriptomic profiling andex vivoandin vivofunctional studies disclose that mesenchymal Wnt/ß-catenin signaling, and in particular IGF-1 downstream of it critically regulate mammary gland growth. These results underscore the general need to carefully decompose the different developmental processes producing branched organs.
The evolution of multi-component weapons in the superfamily of leaf-footed bugs
Authors: Miller Christine W. , Kimball Rebecca T. , Forthman Michael 
Published: April 2023

ABSTRACTSexually selected weapons, such as the antlers of deer, claws of crabs, and tusks of beaked whales, are strikingly diverse across taxa and even within groups of closely related species. Phylogenetic comparative studies have typically taken a simplified approach to investigating the evolution of weapon diversity, examining the gains and losses of entire weapons, major shifts in size or type, or changes in location. Less understood is how individual weapon components evolve and assemble into a complete weapon. We addressed this question by examining weapon evolution in the diverse, multi-component hind-leg and body weapons of leaf-footed bugs, Superfamily Coreoidea (Hemiptera: Heteroptera). Male leaf-footed bugs use their weapons to fight for access to mating territories. We used a large multilocus dataset comprised of ultraconserved element loci for 248 species and inferred evolutionary transitions among component states using ancestral state estimation. We found that weapons added components over time with some evidence of a cyclical evolutionary pattern — gains of components followed by losses and then gains again. Further, we found that certain trait combinations evolved repeatedly across the phylogeny. This work reveals the remarkable and dynamic evolution of weapon form in the leaf-footed bugs. It also highlights that multi-component weapons may be especially useful in providing insights into the evolutionary interplay of form and function.TEASER TEXTFor centuries, humans have been fascinated by the morphological weapons animals use to engage in battle. The diversity of sexually selected weapons is surprising, with considerable variation across even closely related groups of animals. Studies are needed that take a detailed view of the components that comprise weapons and the evolutionary assembly of these components into a complete structure. Here, we reconstruct the evolution of a multi-component weapon in a superfamily of insects. Male leaf-footed bugs use spiky, enlarged hind legs to wrestle over mating territories. We measured 15 putative weapon components across 248 species, using phylogenetic comparative analyses. We found that the number of weapon components generally increased over time, with many gains and losses of components along the way. We found that certain components were more likely to evolve with others, suggesting that specific trait combinations might be especially functional in battle. This work highlights that evolutionary studies of complex, multi-component weapons may be useful for reconstructing the evolutionary assembly of weapons and the interplay of form and function.
Disrupting microglial TGF-β signaling triggers region-specific pathology in the spinal cord
Authors: Zhu Keying , Min Jin-Hong , Joshua Vijay , Liu Yun , Pieber Melanie , Suerth Valerie , Sarlus Heela , Harris Robert , Lund Harald 
Published: April 2023

AbstractTransforming growth factor-β (TGF-β) signaling is critical for microglial maturation during development and the maintenance of microglial homeostasis in adulthood. It remains unclear whether regional susceptibilities to the loss of TGF-β signaling in microglia also exist, and the contributing factors have yet to be identified. We find that deletion ofTgfbr2on microglia leads to microglial activation and demyelination in mouse spinal cords, primarily in the dorsal column (DC).Tgfbr2-deficient microglia exhibit distinct transcriptomic changes, and those sorted from the DC display a more proinflammatory profile compared to those from the ventral column (VC) and grey matter (GM). Single nucleus RNA sequencing (snRNA-seq) of the spinal cord uncovers a microglial subtype that emerges exclusively followingTgfbr2deletion (termed TGFβ signaling-suppressed microglia, TSM), exhibiting high expression ofMmp12, Gpnmb, Lgals3, Mgll, and Alcam,predominantly located in the DC. Phenotypically, disruption of microglial TGF-β signaling results in behavioral deficits that are more severe in female and older mice, whereas young male mice are less affected. Mechanistically, we reveal a significantly higher level of TGF-β1/TGFBR2 in the spinal cords of normal older mice compared to the young mice, with the DC region richer in genes of the TGF-β signaling pathway than the VC and GM regions. This indicates that older mice and the DC region require more TGFβ1 to maintain tissue homeostasis and, reciprocally, are more responsive and sensitive to the disruption of TGF-β signaling in microglia. Herein, we report a demyelinating disease with region-specificity and its susceptibility to the loss of microglial TGF-β signaling with gender and age differences. Our findings contribute valuable information to our understanding of the importance of microglia in regulating myelin health, especially during the aging process.
RavA-ViaA linksVibrio choleraeCpx- and Zra2- envelope stress to antibiotic response
Authors: Krin Evelyne , Carvalho André , Lang Manon , Babosan Anamaria , Mazel Didier , Baharoglu Zeynep 
Published: April 2023

AbstractRavA-ViaA were reported to play a role in aminoglycoside sensitivity but the mechanisms remain elusive. Here, we performed competition and survival experiments to confirm that deletion ofravA-viaAincreases tolerance of the Gram-negative pathogenVibrio choleraeto low and high aminoglycoside concentrations, during aerobic growth. Using high throughput strategies in this species, we identify Cpx and Zra2 two-component systems as new partners of RavA-ViaA. We show that the aminoglycoside tolerance ofΔravviarequires the presence of these membrane stress sensing two-component systems. We propose that deletion of the RavA-ViaA function facilitates the response aminoglycosides because of a pre-activated state of Cpx and Zra2 membrane stress response systems. We also find an impact of these genes on polymyxin B sensitivity and vancomycin resistance, and we show that simultaneous inactivation ofravviafunction together with envelope stress response systems leads to outer membrane permeabilization. Vancomycin is mostly used for Gram-positive because of its low efficiency for crossing the Gram-negative outer membrane. Targeting of theravA-viaAoperon for inactivation could be a future strategy to allow uptake of vancomycin into multidrug resistant Gram-negative bacteria.
Leptin activation of dorsal raphe neurons inhibits feeding behavior
Authors: Maxwell N.D. , Smiley C.E. , Sadek A.T. , Loyo-Rosado F.Z. , Giles D.C. , Macht V.A. , Woodruff J.L. , Taylor D.L. , Wilson S.P. , Fadel J.R. , Reagan L.P. , Grillo C.A. 
Published: April 2023

AbstractLeptin is a homeostatic regulatory element that signals the presence of energy stores -in the form of adipocytes-which ultimately reduces food intake and increases energy expenditure. Similarly, serotonin (5-HT), a signaling molecule found in both the central and peripheral nervous systems, also regulates food intake. Here we use a combination of pharmacological manipulations, optogenetics, retrograde tracing, andin situhybridization, combined with behavioral endpoints to physiologically and anatomically identify a novel leptin-mediated pathway between 5-HT neurons in the dorsal raphe nucleus (DRN) and hypothalamic arcuate nucleus (ARC) that controls food intake. In this study, we show that microinjecting leptin directly into the DRN reduces food intake in male Sprague-Dawley rats. This effect is mediated by leptin-receptor expressing neurons in the DRN as selective optogenetic activation of these neurons at either their ARC terminals or DRN cell bodies also reduces food intake. Anatomically, we identified a unique population of serotonergic raphe neurons expressing leptin receptors that send projections to the ARC. Finally, by utilizingin vivomicrodialysis and high-performance liquid chromatography, we show that leptin administration to the DRN increases 5-HT efflux into the ARC. Overall, this study identifies a novel circuit for leptin-mediated control of food intake through a DRN-ARC pathway, utilizing 5-HT as a mechanism to control feeding behavior. Characterization of this new pathway creates opportunities for understanding how the brain controls eating behavior, as well as opens alternative routes for the treatment of eating disorders.Significance:Leptin and serotonin both play a vital role in the regulation of food intake, yet there is still uncertainty in how these two molecules interact to control appetite. The purpose of this study is to further understand the anatomical and functional connections between leptin receptor expressing neurons in the dorsal raphe nucleus, the main source of serotonin, and the arcuate nucleus of the hypothalamus, and how serotonin plays a role in this pathway to reduce food intake. Insight gained from this study will contribute to a more thorough understanding of the networks that regulate food intake, and open alternative avenues for the development of treatments for obesity and eating disorders.
Target Detection Modulates EEG Spectral Correlates of Memory Encoding
Authors: Broitman Adam W. , Swallow Khena M. 
Published: April 2023

AbstractThe current study investigates whether changes in scalp electroencephalographic (EEG) activity over time reflect the effects of target detection and divided attention on memory encoding. We recorded EEG activity in 61 young adults as they memorized lists of words either under full attention (single-task) or while performing a secondary task (dual-task). In both cases, colored squares appeared with each word. However, in the dual-task condition participants also pressed a button when the colored squares were in a predefined color (target) but made no response when the squares were in a different color (distractor). Subsequent memory effects in the alpha (8-12 Hz) and high gamma (50-100 Hz) frequency bands changed throughout the trial, and these effects differed across conditions. Prior to word presentation, high gamma activity was associated with encoding success in the target and single-task conditions, but not in the distractor conditions. In contrast, alpha band activity decreased following word presentation, and these decreases were greater for successfully encoded words in the target condition than in the distractor or single-task conditions. The results are consistent with the view that alpha and gamma activity reflect distinct neural processes which both contribute to memory formation, but are differentially sensitive to task demands and momentary shifts in attention.
Selective Vulnerability of Layer 5a Corticostriatal Neurons in Huntington’s Disease
Authors: Pressl Christina , Mätlik Kert , Kus Laura , Darnell Paul , Luo Ji-Dung , Paul Matthew R. , Weiss Alison R. , Liguore William , Carroll Thomas S. , Davis David A. , McBride Jodi , Heintz Nathaniel 
Published: April 2023

ABSTRACTThe properties of the cell types that are selectively vulnerable in Huntington’s disease (HD) cortex, the nature of somatic CAG expansions ofmHTTin these cells, and their importance in CNS circuitry have not been delineated. Here we employed serial fluorescence activated nuclear sorting (sFANS), deep molecular profiling, and single nucleus RNA sequencing (snRNAseq) to demonstrate that layer 5a pyramidal neurons are vulnerable in primary motor cortex and other cortical areas of HD donors. ExtensivemHTT-CAG expansions occur in vulnerable layer 5a pyramidal cells, and in Betz cells, layer 6a, layer 6b neurons that are resilient in HD. Retrograde tracing experiments in macaque brains identify the vulnerable layer 5a neurons as corticostriatal pyramidal cells. We propose that enhanced somaticmHTT-CAG expansion and altered synaptic function act together to cause corticostriatal disconnection and selective neuronal vulnerability in the HD cerebral cortex.
A generalizable computational mechanism underlying the interaction between momentary craving and decision-making
Authors: Kulkarni Kaustubh R. , Berner Laura A. , Rhoads Shawn A. , Fiore Vincenzo G. , Schiller Daniela , Gu Xiaosi 
Published: April 2023

ABSTRACTSubstance craving and maladaptive choices are intertwined across addictive disorders. However, the computational mechanisms connecting craving and decision-making remain elusive. Here, we tested a hypothesis that momentary craving and value-based decision-making influence each other during substance-related reinforcement learning. We measured momentary craving as two groups of human participants (alcohol drinkers and cannabis users; totaln=132) performed a reinforcement learning task in which they received group-specific addictive cue or monetary rewards. Using computational modeling, we found that, across both groups, momentary craving biased learning rate related to substance-associated prediction errors (RPEs), but not monetary RPEs. Additionally, expected values and RPEs jointly influenced elicited craving across reward types and participant groups. Alcohol and cannabis users also differed in the extent to which their craving and decision-making influenced each other, suggesting important computational divergence between the two groups. Finally, regressions incorporating model-derived parameters best predicted substance use severity in the alcohol, but not cannabis group, supporting the utility of using these model-based parameters in making clinical predictions for selective substance groups. Together, these findings provide a computational mechanism for the interaction between substance craving and maladaptive choices that is generalizable across addictive domains.