bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differentiation and Integration of Competing Memories: A Neural Network Model
Authors: Ritvo Victoria J. H. , Nguyen Alex , Turk-Browne Nicholas B. , Norman Kenneth A. 
Published: April 2023

AbstractWhat determines when neural representations of memories move together (integrate) or apart (differentiate)? Classic supervised learning models posit that, when two stimuli predict similar outcomes, their representations should integrate. However, these models have recently been challenged by studies showing that pairing two stimuli with a shared associate can sometimes cause differentiation, depending on the parameters of the study and the brain region being examined. Here, we provide a purely unsupervised neural network model that can explain these and other related findings. The model can exhibit integration or differentiation depending on the amount of activity allowed to spread to competitors — inactive memories are not modified, connections to moderately active competitors are weakened (leading to differentiation), and connections to highly active competitors are strengthened (leading to integration). The model also makes several novel predictions — most importantly, that when differentiation occurs as a result of this unsupervised learning mechanism, it will be rapid and asymmetric, and it will give rise to anticorrelated representations in the region of the brain that is the source of the differentiation. Overall, these modeling results provide a computational explanation for a diverse set of seemingly contradictory empirical findings in the memory literature, as well as new insights into the dynamics at play during learning.
Paradoxical increases in anterior cingulate cortex activity during nitrous oxide-induced analgesia reveal a signature of pain affect
Authors: Weinrich Jarret AP , Liu Cindy D , Jewell Madison E , Andolina Christopher R , Bernstein Mollie X , Benitez Jorge , Rodriguez-Rosado Sian , Braz Joao M , Maze Mervyn , Nemenov Mikhail I , Basbaum Allan I 
Published: April 2023

AbstractThe general consensus is that increases in neuronal activity in the anterior cingulate cortex (ACC) contribute to pain’s negative affect. Here, usingin vivoimaging of neuronal calcium dynamics in mice, we report that nitrous oxide, a general anesthetic that reduces pain affect, paradoxically, increases ACC spontaneous activity. As expected, a noxious stimulus also increased ACC activity. However, as nitrous oxide increases baseline activity, the relative change in activity from pre-stimulus baseline was significantly less than the change in the absence of the general anesthetic. We suggest that this relative change in activity represents a neural signature of the affective pain experience. Furthermore, this signature of pain persists under general anesthesia induced by isoflurane, at concentrations in which the mouse is unresponsive. We suggest that this signature underlies the phenomenon of connected consciousness, in which use of the isolated forelimb technique revealed that pain percepts can persist in anesthetized patients.
The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in aDrosophilamodel of Parkinson’s disease
Authors: Yi Shuanglong , Wang Linfang , Ho Margaret S. , Zhang Shiping 
Published: April 2023

AbstractParkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the motor deficits, selective loss of dopaminergic (DA) neurons, and the brain accumulation of α-synuclein (α-syn)-composed protein aggregates called Lewy bodies (LBs). Whereas dysfunction in the protein degradation pathway, like autophagy in neurons, has been demonstrated as a critical mechanism for eliminating protein aggregates in PD, how protein aggregates are eliminated in the other brain cell type, glia, is less well characterized. In the present study, we show that Atg9, the only transmembrane protein in the core autophagy pathway, is highly expressed inDrosophilaadult brain glia. Results from immunostaining and live-cell imaging analysis reveal that a significant portion of Atg9 localizes to the trans-Golgi network (TGN), autophagosomes, and lysosomes in glia; Atg9 is persistently in contact with these organelles. Lacking glialatg9reduces the number of omegasome and autophagosome and impairs autophagic substrate degradation, suggesting that glial Atg9 participates in the early steps of autophagy, hence the control of autophagic degradation. Importantly, loss of glialatg9induces parkinsonian symptoms inDrosophilaincluding progressive DA neuron loss and locomotion deficits. Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and PD. These results provide new insights on the underlying mechanism of PD.
A zinc finger transcription factor tunes social behaviors by controlling transposable elements and immune response in prefrontal cortex
Authors: Truby Natalie L. , Kim R. Kijoon , Silva Gabriella M. , Qu Xufeng , Picone Joseph A. , Alemu Rebecca , Neve Rachael L. , Cui Xiaohong , Liu Jinze , Hamilton Peter J. 
Published: April 2023

AbstractThe neurobiological origins of social behaviors are incompletely understood. Here we utilized synthetic biology approaches to reprogram the function of ZFP189, a transcription factor whose expression and function in the rodent prefrontal cortex was previously determined to be protective against stress-induced social deficits. We created novel synthetic ZFP189 transcription factors including ZFP189VPR, which activates the transcription of target genes and therefore exerts opposite functional control from the endogenous, transcriptionally repressive ZFP189WT. Upon viral delivery of these synthetic ZFP189 transcription factors to mouse prefrontal cortex, we observe that ZFP189-mediated transcriptional control promotes mature dendritic spine morphology on transduced pyramidal neurons. Interestingly, dysregulation of ZFP189-mediated transcription in this brain area, achieved by delivery of synthetic ZFP189VPR, precipitates social behavioral deficits in terms of social interaction, motivation, and the cognition necessary for the maintenance of social hierarchy, without other observable behavioral deficits. By performing RNA sequencing in virally manipulated prefrontal cortex tissues, we discover that ZFP189 transcription factors of opposing regulatory function have opposite influence on the expression of genetic transposable elements as well as genes that participate in immune functions. Collectively, this work reveals that ZFP189 function in the prefrontal cortex coordinates structural and transcriptional neuroadaptations necessary for social behaviors by binding transposable element-rich regions of DNA to regulate immune-related genes. Given the evidence for a co-evolution of social behavior and the brain immune response, we posit that ZFP189 may have evolved to augment brain transposon-associated immune function as a way of enhancing an animal’s capacity for functioning in social groups.
Cell type-specific responses to fungal infection in plants revealed by single-cell transcriptomics
Authors: Tang Bozeng , Feng Li , Ding Pingtao , Ma Wenbo 
Published: April 2023

SummaryPlant infection by microbial pathogens is a dynamic process. Here, we investigated the heterogeneity of plant responses in the context of pathogen location. A single-cell atlas ofArabidopsis thalianaleaves challenged by the fungusColletotrichumhigginsianum revealed cell type-specific gene expression that highlights an enrichment of intracellular immune receptors in vasculature cells. Using trajectory inference, we assigned cells that directly interacted with the invasive hyphae. Further analysis of cells at these infection sites revealed transcriptional plasticity based on cell type. A reprogramming of abscisic acid signalling was specifically activated in guard cells. Consistently, a contact-dependent stomatal closure was observed, possibly representing a defense response that anticipates pathogen invasive growth. We defined cell type-specific deployments of genes activating indole glucosinolate biosynthesis at the infection sites, and determined their contribution to resistance. This research highlights the spatial dynamics of plant response during infection and reveals cell type-specific processes and gene functions.
Behavior-relevant top-down cross-modal predictions in mouse neocortex
Authors: Han Shuting , Helmchen Fritjof 
Published: April 2023

AbstractAnimals rely on predicting their environment and the consequences of their actions to adapt to a constantly changing world. The predictive coding hypothesis proposes that the brain generates predictions and continuously compares them with bottom-up sensory inputs to guide behavior. However, how the brain reconciles conflicting top-down predictions and bottom-up sensory information during behavior remains unclear. To address this question, we simultaneously imaged neuronal populations in the mouse somatosensory cortex and the posterior parietal cortex during an auditory-cued texture discrimination task. After mice learnt the task with fixed tone-texture matching, mismatched pairing caused conflicting tone-based texture predictions and actual texture inputs. When top-down interaction was dominant, texture representations in both areas were modified and mice decided based on the predicted rather than actual texture, whereas dominant bottom-up interaction corrected the representations as well as behavioral choice. Our findings provide evidence for hierarchical predictive coding in the mouse neocortex and open new avenues for understanding higher cognitive functions.
Interrogation of dynamic glucose-enhanced MRI and fluorescence-based imaging reveals a perturbed glymphatic network in Huntington’s disease
Authors: Liu Hongshuai , Chen Lin , Zhang Chuangchuang , Liu Chang , Li Yuguo , Cheng Liam , Wei Zhiliang , Zhang Ziqin , Lu Hanzhang , van Zijl Peter C. M. , Iliff Jeffrey J. , Xu Jiadi , Duan Wenzhen 
Published: April 2023

ABSTRACTHuntington’s disease (HD) is a neurodegenerative disorder that presents with progressive motor, mental, and cognitive impairment leading to early disability and mortality. The accumulation of mutant huntingtin protein aggregates in neurons is a pathological hallmark of HD. The glymphatic system, a brain-wide perivascular network, facilitates the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF), supporting interstitial solute clearance including abnormal proteins from mammalian brains. In this study, we employed dynamic glucose-enhanced (DGE) MRI to measure D-glucose clearance from CSF as a tool to assess CSF clearance capacity to predict glymphatic function in a mouse model of HD. Our results demonstrate significantly diminished CSF clearance efficiency in premanifest zQ175 HD mice. The impairment of CSF clearance of D-glucose, measured by DGE MRI, worsened with disease progression. These DGE MRI findings in compromised glymphatic function in HD mice were further confirmed with fluorescence-based imaging of glymphatic CSF tracer influx, suggesting an impaired glymphatic function in premanifest stage of HD. Moreover, expression of the astroglial water channel aquaporin-4 (AQP4) in the perivascular compartment, a key mediator of glymphatic function, was significantly diminished in both HD mouse brain as well as postmortem human HD brain. Our data, acquired using a clinically translatable MRI approach, indicate a perturbed glymphatic network in the HD brain as early as in the premanifest stage. Further validation of these findings in clinical studies should provide insights into potential of glymphatic clearance as a HD biomarker and for glymphatic functioning as a disease-modifying therapeutic target for HD.
Systemic Proteome Phenotypes Reveal Defective Metabolic Flexibility in Mecp2 Mutants
Authors: Zlatic Stephanie A. , Werner Erica , Surapaneni Veda , Lee Chelsea E. , Gokhale Avanti , Singleton Kaela , Duong Duc , Crocker Amanda , Gentile Karen , Middleton Frank , Dalloul Joseph Martin , Liu William Li-Yun , Patgiri Anupam , Tarquinio Daniel , Carpenter Randall , Faundez Victor 
Published: April 2023

AbstractGenes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are systemic diseases that profoundly impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations inMECP2. Transcriptomes and proteomes of organs and brain regions fromMecp2-null mice as well as diverseMECP2-null male and female human cells were assessed. Widespread changes in the steady-state transcriptome and proteome were identified in brain regions and organs of presymptomaticMecp2-null male mice as well as mutant human cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular,Mecp2- andMECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid metabolism and mitochondrial pathways.MECP2mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations inMecp2/MECP2perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.
High-resolution structure of mammalian PI31–20S proteasome complex reveals mechanism of proteasome inhibition
Authors: Hsu Hao-Chi , Wang Jason , Kjellgren Abbey , Li Huilin , DeMartino George N. 
Published: April 2023

ABSTRACTProteasome-catalyzed protein degradation mediates and regulates critical aspects of many cellular functions and is an important element of proteostasis in health and disease. Proteasome function is determined in part by the types of proteasome holoenzymes formed between the 20S core particle that catalyzes peptide bond hydrolysis and any of multiple regulatory proteins to which it binds. One of these regulators, PI31, was previously identified as anin vitro20S proteasome inhibitor, but neither the molecular mechanism nor the possible physiologic significance of PI31-mediated proteasome inhibition has been clear. Here we report a high- resolution cryo-EM structure of the mammalian 20S proteasome in complex with PI31. The structure shows that two copies of the intrinsically-disordered carboxyl-terminus of PI31 are present in the central cavity of the closed-gate conformation of the proteasome and interact with proteasome catalytic sites in a manner that blocks proteolysis of substrates but resists their own degradation. The two inhibitory polypeptide chains appear to originate from PI31 monomers that enter the catalytic chamber from opposite ends of the 20S cylinder. We present evidence that PI31 can inhibit proteasome activity in mammalian cells and may serve regulatory functions for the control of cellular proteostasis.
Identification of overlapping and distinct mural cell populations during early embryonic development
Authors: Colijn Sarah , Nambara Miku , Stratman Amber N. 
Published: April 2023

AbstractMural cells are an essential perivascular cell population that associate with blood vessels and contribute to vascular stabilization and tone. In the embryonic zebrafish vasculature,pdgfrbandtaglnare commonly used as markers for identifying pericytes and vascular smooth muscle cells (vSMCs). However, the expression patterns of these markers used in tandem have not been fully described. Here, we used theTg(pdgfrb:Gal4FF; UAS:RFP)andTg(tagln:NLS-EGFP)transgenic lines to identify single- and double-positive perivascular populations in the cranial, axial, and intersegmental vessels between 1 and 5 days post-fertilization. From this comparative analysis, we discovered two novel regions oftagln-positive cell populations that have the potential to function as mural cell precursors. Specifically, we found that the hypochord— a reportedly transient structure—contributes totagln-positive cells along the dorsal aorta. We also identified a unique sclerotome-derived mural cell progenitor population that resides along the midline between the neural tube and notochord and contributes to intersegmental vessel mural cell coverage. Together, our findings highlight the variability and versatility of trackingpdgfrbandtaglnexpression in mural cells of the developing zebrafish embryo.Summary StatementDetailed analysis ofpdgfrb/taglnvascular expression patterns in embryonic zebrafish reveals novel regions oftagln-positive populations such as the hypochord and a mural cell progenitor population adjacent to the midline.
Manufacturers' emission reduction investment strategy under carbon cap-and-trade policy and uncertain low-carbon preferences
Authors: Xu Chunqiu , Liu Fengzhi , Zhou Yanjie , Dou Runliang , Feng Xuehao , Shen Bo 
Published: April 2023

PurposeThis paper aims to find optimal emission reduction investment strategies for the manufacturer and examine the effects of carbon cap-and-trade policy and uncertain low-carbon preferences on emission reduction investment strategies.Design/methodology/approachThis paper studied a supply chain consisting of one manufacturer and one retailer, in which the manufacturer is responsible for emission reduction investment. The manufacturer has two emission reduction investment strategies: (1) invest in traditional emission reduction technologies only in the production process and (2) increase investment in smart supply chain technologies in the use process. Then, three different Stackelberg game models are developed to explore the benefits of the manufacturer in different cases. Finally, this paper coordinates between the manufacturer and the retailer by developing a revenue-sharing contract.FindingsThe manufacturer's optimal emission reduction strategy is dynamic. When consumers' low-carbon preferences are low and the government implements a carbon cap-and-trade policy, the manufacturer can obtain the highest profit by increasing the emission reduction investment in the use process. The carbon cap-and-trade policy can encourage the manufacturer to reduce emissions only when the initial carbon emission is low. The emission reduction, order quantity and the manufacturer's profit increase with the consumers' low-carbon preferences. And the manufacturer can adjust the emission reduction investment according to the emission reduction cost coefficient in two processes.Originality/valueThis paper considers the investment of emission reduction technologies in different processes and provides theoretical guidance for manufacturers to make a low-carbon transformation. Furthermore, the paper provides suggestions for governments to effectively implement carbon cap-and-trade policy.
Preparedness and crisis‐driven policy change: COVID‐19, digital readiness, and information technology professionals in Canadian local government
Authors: Spicer Zachary , Lyons Joseph , Calvert Morgan 
Published: April 2023

AbstractThis article explores the pandemic‐induced transition to electronic municipal council meetings in Ontario, Canada as an instance of crisis‐driven policy change. Employing survey data of information technology (IT) professionals and a critical case study, this research probes the notion that crises, like pandemics, can not only create windows for policy change, but also draw attention to the many often overlooked operational elements of government, including the increasingly important policy role played by IT professionals.
The Multifaceted Role of Self‐Generated Question Asking in Curiosity‐Driven Learning
Authors: Kedrick Kara , Schrater Paul , Koutstaal Wilma 
Published: April 2023

AbstractCuriosity motivates the search for missing information, driving learning, scientific discovery, and innovation. Yet, identifying that there is a gap in one's knowledge is itself a critical step, and may demand that one formulate a question to precisely express what is missing. Our work captures the integral role of self‐generated questions during the acquisition of new information, which we refer to as active‐curiosity‐driven learning. We tested active‐curiosity‐driven learning using our “Curiosity Question & Answer Task” paradigm, where participants (N=135) were asked to generate questions in response to novel, incomplete factual statements and provided the opportunity to forage for answers. We also introduce new measures of question quality that express how well questions capture stimulus and foraging information. We hypothesized that active question asking should influence behavior across the stages of our task by increasing the probability that participants express curiosity, forage for answers, and remember what they had thereby discovered. We found that individuals who asked a high number of quality questions experienced elevated curiosity, were more likely to pursue missing information that was semantically related to their questions, and more likely to retain the information on a later cued recall test. Additional analyses revealed that curiosity played a predominant role in motivating participants to forage for missing information, and that both curiosity and satisfaction with the acquired information boosted memory recall. Overall, our results suggest that asking questions enhances the value of missing information, with important implications for learning and discovery of all forms.
Clinical development time is shorter for new anticancer drugs approved via accelerated approval in the US or via conditional approval in the EU
Authors: Demirci Ebru , Omes‐Smit Grace , Zwiers Alex 
Published: April 2023

AbstractThe US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) offer expedited regulatory approval programs for drugs with high potential patient value applicable at different stages leading to marketing authorization: (i) drug development (fast track designation (FTD), breakthrough therapy designation (BTD), regenerative medicine advanced therapy designation in the United States, and priority medicines scheme in the European Union), (ii) review of marketing authorization application (priority review in the United States and accelerated assessment in the European Union), (iii) approval of drug (accelerated approval in the United States and conditional approval in the European Union). Typical clinical development time of 76 new anticancer drugs, for which the EMA gave a positive opinion between January 2010 and December 2019, was 6.7 years: 5.8 years for small molecules and 7.7 years for biotechnology‐derived products. Drugs following only BTD (5.6 years) typically had a shorter clinical development time than drugs following only FTD (6.4 years) or both FTD and BTD (6.4 years), compared to drugs not following any expedited regulatory approval program at the drug development stage (7.7 years). Drugs following an expedited regulatory approval program at the stage of drug development and accelerated approval in the United States (FDA1 [4.5 years] and FDA3 [5.6 years]), and drugs following the standard procedure at the stage of drug development and conditional approval in the European Union (EMA5 [5.5 years] and EMA7 [4.5 years]) typically had a reduced clinical development time. These findings provide insight for the industry into combinations of expedited regulatory approval programs correlated with shorter clinical development time of new anticancer drugs.