bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aging impairs astrocytes in the human cerebral cortex
Authors: Popov Alexander , Brazhe Nadezda , Morozova Kseniia , Yashin Konstantin , Bychkov Maxim , Nosova Olga , Sutyagina Oksana , Brazhe Alexey , Parshina Evgenia , Li Li , Medyanik Igor , Korzhevskii Dmitry E , Shenkarev Zakhar , Lyukmanova Ekaterina , Verkhratsky Alexei , Semyanov Alexey 
Published: November 2022

AbstractHow aging affects cellular components of the human brain active milieu remains largely unknown. We analyzed astrocytes and neurons in the neocortical access tissue of younger (22 - 50 years) and older (51 - 72 years) adult patients who underwent glioma resection. Aging decreased the amount of reduced mitochondrial cytochromes in astrocytes but not neurons. The total amount of protein was decreased in astrocytes and increased in neurons. Aged astrocytes showed morphological dystrophy quantified by the decreased length of branches, decreased volume fraction of leaflets, and shrinkage of the anatomical domain. Dystrophy correlated with the loss of gap junction coupling between astrocytes and increased input resistance. Aging was accompanied by the upregulation of glial fibrillary acidic protein (GFAP) and downregulation of membrane-cytoskeleton linker Ezrin associated with leaflets. No significant changes in neuronal excitability or spontaneous inhibitory postsynaptic signaling were observed. Thus, brain aging is associated with the impaired morphological presence and mitochondrial malfunction of astrocytes, but not neurons.
Rab8, Rab11, and Rab35 coordinate lumen and cilia formation during Zebrafish Left-Right Organizer development
Authors: Aljiboury Abrar A. , Ingram Eric , Krishnan Nikhila , Ononiwu Favour , Pal Debadrita , Manikas Julie , Taveras Christopher , Hall Nicole A. , Da Silva Jonah , Freshour Judy , Hehnly Heidi 
Published: November 2022

ABSTRACTAn essential process duringDanio rerio’sleft-right organizer (Kupffer’s Vesicle, KV) development is for the majority of developing KV cells to form a motile cilium that extend into the KV lumen. Left-right beating of motile cilia within the KV lumen directs fluid flow to establishment the embryo’s left-right axis. However, when KV cells start to form cilia and how cilia formation is coordinated with KV lumen formation has not been examined. We identified that nascent KV cells form cilia at their centrosomes at random intracellular positions that then move towards a forming apical membrane containing cystic fibrosis transmembrane conductance regulator (CFTR). Using optogenetic clustering approaches, we found that Rab35 positive membranes recruit Rab11 to modulate CFTR delivery to the apical membrane, which is required for lumen opening, and subsequent cilia extension into the lumenal cavity. Once the intracellular cilia reach the CFTR positive apical membrane, Arl13b-positive cilia extend and elongate in a Rab8 dependent manner into the forming lumen once the lumen reaches an area of 300 μm2. These studies demonstrate the need to acutely coordinate Rab8, Rab11, and Rab35-mediated membrane trafficking events to ensure appropriate timing in lumen and cilia formation during KV development.
DAT Val559 Mice Exhibit Compulsive Behavior Under Devalued Reward Conditions Accompanied by Cellular and Pharmacological Changes
Authors: Stewart Adele , Davis Gwynne L. , Areal Lorena B. , Rabil Maximilian J. , Tran Vuong , Mayer Felix P. , Blakely Randy D. 
Published: November 2022

AbstractIdentified across multiple psychiatric disorders, the dopamine (DA) transporter (DAT) Ala559Val substitution triggers non-vesicular, anomalous DA efflux (ADE), perturbing DA neurotransmission and behavior. We have shown that DAT Val559 mice display a waiting impulsivity and changes in cognitive performance associated with enhanced reward motivation. Here, utilizing a within-subject, lever-pressing paradigm designed to bias the formation of goal-directed or habitual behavior, we demonstrate that DAT Val559 mice modulate their nose-poke behavior appropriately to match context, but demonstrate a perseverative checking behavior. Although DAT Val559 mice display no issues with the cognitive flexibility required to acquire and re-learn a visual pairwise discrimination task, devaluation of reward evoked habitual reward seeking in DAT Val559 mutants in operant tasks regardless of reinforcement schedule. The direct DA agonist apomorphine also elicits locomotor stereotypies in DAT Val559, but not WT mice. Our observation that dendritic spine density is increased in the dorsal medial striatum (DMS) of DAT Val559 mice speaks to an imbalance in striatal circuitry that might underlie the propensity of DAT Val559 mutants to exhibit compulsive behaviors when reward is devalued. Thus, DAT Val559 mice represent a model for dissection of how altered DA signaling perturbs circuits that normally balance habitual and goal-directed behaviors.
Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule regulation
Authors: Pinzi Luca , Conze Christian , Bisi Nicolo , Torre Gabriele Dalla , Monteiro-Abreu Nanci , Trushina Nataliya I. , Soliman Ahmed , Krusenbaum Andrea , Dolouei Maryam Khodaei , Hellwig Andrea , Christodoulou Michael S. , Passarella Daniele , Bakota Lidia , Rastelli Giulio , Brandt Roland 
Published: November 2022

ABSTRACTTauopathies such as Alzheimer’s disease are characterized by the aggregation and increased phosphorylation of the microtubule-associated protein tau. The pathological changes in tau are closely linked to neurodegeneration, making tau a prime candidate for intervention. However, the multiple facets of tau function and the lack of cellular tauopathy models that could support mechanism-based drug development hampers progress. Here we report the development of a live-cell imaging approach to quantitatively monitor pathological changes of human tau as it interacts with axonal microtubules. We show that a full-length aggregation-prone tau construct exhibits reduced interaction with microtubules as it increasingly aggregates. Through chemoinformatic analyses, we identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that inhibit tau aggregation and modulate tau phosphorylation. We found that PHOX15 restores the physiological microtubule interaction of aggregation-prone tau in neurons and inhibits the first phase of tau aggregationin vitro. Furthermore, we report that PHOX15 inhibits the tau kinases GSK3β and Cdk5, alters the kinome activity of model neurons, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and indicate that the binding of PHOX15 in one of the channels reduces the protofilament’s ability to adopt a PHF-like conformation. The data show that our imaging approach provides a useful tool for identifying compounds that modulate tau-microtubule interaction in axons. We demonstrate that a polypharmacological approach to simultaneously treat tau aggregation and tau phosphorylation is able to restore physiological microtubule regulation, identifying PHOX15 as a promising drug candidate to counteract tau-induced neurodegeneration.
A new polymodal gating model of the proton-activated chloride channel
Authors: Zhao Piao , Tang Cheng , Yang Yuqin , Xiao Zhen , Perez-Miller Samantha , Zhang Heng , Luo Guoqing , Liu Hao , Li Yaqi , Liao Qingyi , Yang Fan , Dong Hao , Khanna Rajesh , Liu Zhonghua 
Published: November 2022

AbstractThe proton-activated chloride (PAC) channel plays critical roles in ischemic neuron death, but its activation mechanisms remain elusive. Here, we interrogated PAC channel gating using its unique bidirectional modulator C77304 as a pharmacological probe. C77304 activated the PAC channel by acting on its proton gating, while simultaneously inhibiting channel activity at higher doses, through interaction with two modulatory sites with different affinities and state-dependence. Excitingly, we revealed that PAC undergoes intrinsic proton gating-independent voltage activation, which was defined by an ion-flux gating mechanism. Scanning-mutagenesis and molecular dynamics simulation confirmed that E181, E257, and E261 in human PAC form the primary proton sensors, as alanine mutations eliminated the channel’s proton gating while sparing the voltage-dependent gating. This proton sensing mechanism was basically conserved among orthologous PAC channels. Collectively, our data unveils the polymodal gating and proton sensing mechanisms in the PAC channel which may inspire potential drug development.
A novel anti-cancer therapy with nuclear export inhibitor Selinexor in combination with oncolytic myxoma virus
Authors: Rahman Masmudur M. , van Oosterom Fleur , Enow Junior Ayuk , Hossain Maksuda , Gutierrez-Jensen Ami D. , Cashen Mackenzie , Everts Anne , Lowe Kenneth , Kilbourne Jacquelyn , Daggett-Vondras Juliane , Karr Timothy L. , McFadden Grant 
Published: November 2022

AbstractOncolytic viruses exploited for cancer therapy are developed to selectively infect, replicate, and kill cancer cells to stop tumor growth. However, in some cancer cells, oncolytic viruses are often limited in completing their full replication cycle, making progeny virions, and/or spread in the tumor bed due to the heterogeneous cell types within the tumor bed. Here we report that nuclear export pathway regulates oncolytic myxoma virus (MYXV) infection and cytoplasmic viral replication in a subclass of human cancer cell types where virus replication is restricted. Inhibition of CRM1/XPO-1 nuclear export pathway with nuclear export inhibitors can overcome this restriction by trapping restriction factors in the nucleus and allow significantly enhanced virus replication and killing of human cancer cells. Furthermore, knockdown of CRM1/XPO-1 significantly enhanced MYXV replication in restrictive human cancer cells and reduced the formation of anti-viral granules associated with RNA helicase DHX9. Bothin vitroandin vivo, we demonstrate that the approved CRM1 inhibitor drug Selinexor enhances the replication of MYXV and cell killing of diverse human cancer cells. In the xenograft tumor model in NSG mice, combination therapy with Selinexor plus MYXV significantly reduced tumor burden and enhanced the survival of animals. Additionally, we performed global scale proteomic analysis of nuclear and cytosolic proteins in human cancer cells to identify the host and viral proteins that are upregulated or downregulated by different treatments. These results for the first time indicate that Selinexor in combination with oncolytic MYXV can be used as potential new anti-cancer therapy
Neotelomere formation by human telomerase
Authors: Kinzig Charles G. , Zakusilo George , Takai Kaori K. , de Lange Titia 
Published: November 2022

SummaryThe maintenance of genome integrity requires that telomerase action be limited to telomeres and not convert DSBs into neotelomeres. Using the breakpoint sequence from an apparent germline neotelomere formation event, we developed an assay to detect and quantify telomeric repeat addition at Cas9-programmed DSBs in human cells. The data show that telomerase can add telomeric repeats to DSBs and that this process can generate functional neotelomeres. Neotelomere formation is increased when telomerase is overexpressed, suggesting that in most human cells, low (or absent) telomerase activity limits the deleterious effects of de novo telomere addition. We show that neotelomere formation at DSBs is inhibited by long-range resection and the accompanying activation of ATR signaling. Our findings reveal that telomerase can cause genome instability by generating neotelomeres at DSBs. We propose that neotelomere formation can promote tumorigenesis by ending detrimental breakage-fusion-bridge cycles in cancer cells whose genome alterations engender dicentric chromosomes.
Intermediate Gray Matter Interneurons in the Lumbar Spinal Cord Play a Critical and Necessary Role in Coordinated Locomotion
Authors: Kuehn Naëmi , Schwarz Andreas , Beretta Carlo Antonio , Schwarte Yvonne , Schmitt Francesca , Motsch Melanie , Weidner Norbert , Puttagunta Radhika 
Published: November 2022

AbstractLocomotion is a complex task involving excitatory and inhibitory circuitry in spinal gray matter. While genetic knockouts examine the function of unique spinal interneuron (SpIN) subtypes, the phenotype of combined premotor interneuron loss remains to be explored. We modified a kainic acid lesion to damage intermediate gray matter (laminae V-VII) in the lumbar spinal enlargement (spinal L2-L4) in female rats. A thorough, tailored behavioral evaluation revealed deficits in gross hindlimb function, skilled walking, coordination, balance and gait two-weeks post-injury. Using a Random Forest algorithm, we combined these behavioral assessments into a highly predictive binary classification system which strongly correlated with structural deficits in the rostro-caudal axis. Machine-learning quantification confirmed interneuronal damage to laminae V-VII in spinal L2-L4 correlates with hindlimb dysfunction. White matter damage and lower motoneuron loss did not correlate with behavioral deficits. Animals do not regain lost sensorimotor function three months after injury, indicating that natural recovery of the spinal cord cannot compensate for loss of laminae V-VII neurons. As spinal cord injuries are often located at spinal enlargements, this research lays the groundwork for new neuroregenerative therapies to replace these lost neuronal pools vital to sensorimotor function.HighlightsFunctional deficits in coordination, balance, rhythmic walking and gait follow two weeks after a lumbar (L2-L4) intermediate (V-VII) gray matter spinal cord injury in ratsDeficits correlate with neuronal loss in laminae V-VII in spinal levels L2-L4 but do not correlate with lower motoneuron loss or white matter damage nor do animals show signs of sensory dysfunction due to spinal cord injuryCoordination deficits remain after three months, indicating that natural recovery cannot compensate for this interneuronal lossNewly developed machine-learning models non-invasively fully classify injured animals by functional readouts equivalent to time-intensive endpoint histological analysis
Training students in inter- and transdisciplinary sustainability education: nurturing cross-faculty staff commitment and continuous community collaboration
Authors: Tijsma Geertje , Horn Annemarie , Urias Eduardo , Zweekhorst Marjolein B.M. 
Published: November 2022

Purpose
To properly address complex sustainability issues, higher education institutes (HEIs), such as universities, need to implement innovative educational programmes that adhere to transdisciplinary principles. This study aims to contribute to the understanding of how to do so across and beyond a university.

Design/methodology/approach
This study presents a module comprising two courses, the first of which centres on the identification of sustainability issues in student-led multi-actor dialogue sessions and the second on addressing those sustainability issues through interdisciplinary collaboration among master’s students who are at the same time also working on their own thesis. The authors conducted continuous evaluations during the first two pilot years, including community (partners), faculty and student perspectives.

Findings
The authors found that the module was successful in training students for inter- and transdisciplinarity. Moreover, high levels of commitment were observed from a diverse range of students and faculty across one HEI as well as positive responses from the community (partners) involved in the module. Further improvements of the module rely on active buy-in from programme directors and ensuring continuous collaboration throughout the co-creation process by streamlining the translation of the issues into manageable research projects with specific research questions.

Practical implications
This study provides inspiration and lessons on how to implement university-wide inter- and transdisciplinary module into higher education.

Originality/value
The module is innovative in combining university-wide and interdisciplinary learning with and transdisciplinary learning through long-term, co-creational collaboration within and beyond the university.
Who does it better and why? Empirical analysis of public-private partnership in infrastructure in Asia-Pacific
Authors: Sharma Chandan 
Published: November 2022

PurposeThis research has two primary goals: first, to develop a composite index that evaluates the degree to which Asian–Pacific economies are prepared to engage in public–private partnerships (PPPs), and second, to investigate the factors that have been most influential in the formation of PPP arrangements in the nations' infrastructure over the course of the period 1995–2016.Design/methodology/approachThe study constructs sectoral and overall index of possible determinants of PPP. Subsequently, it examines each constructed index's role in PPP investment. The author also conducted a panel data analysis to understand the role of each of the potential determinants on PPP projects and investments. This paper analyzes the author’s empirical models using a range of cross-section and panel estimators, including Poisson, zero-inflated Poisson and fixed effect.FindingsThe study’s results based on cross-section analysis suggest that regulatory and institution quality, institutional arrangement and regulatory frameworks, financial market development and macroeconomic stability positively impact investment in PPP. Moreover, the results depict that financial market development has the most substantial impact on PPP investment, followed by macroeconomic stability and prior experience with PPPs. The panel data analysis shows that per-capita income, financial development, inflation, debt, resource import and fuel export are crucial determinants of PPP in Asian–Pacific economies.Practical implicationsGovernments of the countries should promptly amend the important policies outlined in this study and adopt a more robust strategy to foster a competitive PPP environment. This will aid in maintaining transparency and gaining the confidence of investors. The study’s findings may assist policymakers in focusing on specific areas in need of improvement. Social welfare and industrialization are ultimately enhanced by the formulation of such policies and by attracting additional infrastructure investment.Originality/valueThis is the first attempt to rank countries on the basis of PPP enablers. Unlike previous studies, this study examines the role of a large number of indicators in determining PPP investment and projects in cross-section as well as panel data framework. The study also investigates the effects of PPP specific provisions and rules. Furthermore, the focus is specifically on Asian–Pacific countries, which are a mix of third-world, emerging, developing and developed countries. Focusing on Asia–Pacific is also crucial because the region is home to most of the world's population, and the region's infrastructure outcomes significantly impact their lives.
Up, up and away! The metaphor of verticality and the moderating role of regulatory focus in price assessments
Authors: Costa Marconi Freitas da , Angelo Claudio Felisoni de , Farias Salomão Alencar de 
Published: November 2022

PurposeThe purpose of this study is to analyze the effects of the metaphor of verticality on how individuals assess prices, having regulatory focus as a moderator of this relationship.Design/methodology/approachTwo experiments were conducted with a 2 × 2 between-subjects design (metaphor of verticality: physically higher vs physically lower × regulatory focus: promotion vs prevention). The second study performed moderated mediation by incorporating the self-esteem variable.FindingsThe results show that the treatment group consisting of prevention-focused individuals who consider themselves physically higher assessed prices according to what was proposed for the study compared to the group consisting of promotion-focused individuals who consider themselves physically lower. Participants in Treatment Group 1 attributed the lowest prices to products, demanded more significant discounts to go to another store searching for a product and considered the prices more unfair.Originality/valueThe primary contribution of this study is to reveal that the position of one's body on the vertical axis influences their thoughts and, therefore, their decision-making in the scope of products and services prices. Moreover, regulatory focus can attenuate such effects.
Total factor productivity change in China's grain production sector: 1980–2018
Authors: Zheng Zhihao , Cheng Shen , Henneberry Shida R. 
Published: November 2022

AbstractThis study analyses changes in total factor productivity (TFP) of grains as an aggregate commodity and major grain crops including rice, wheat, and corn, using pooled provincial and time‐series data from 1980 to 2018 for China. Results show that the growth of TFP in the grain sector was driven by technical improvements. Moreover, the grain output and wheat production benefited more from TFP growth, whereas the growth in the usage of inputs drove the growth in rice and corn production. Findings also indicate that the laissez‐faire market‐oriented policy led to a dramatic fall in output while the intervention‐led policy resulted in a substantial rise in output, but neither of them fostered the growth of productivity. Conversely, the incentive‐led policy in a market‐oriented environment that raised the comparative profitability in grain production promoted the growth in both output and productivity in the grain sector. As the comparative advantage shifts away from agriculture in China, an appropriate support is thus necessary to stimulate farmers' incentive in growing grain crops.
Influence of high‐pressure processing on nutritional composition and bioactive compounds of Phaseolus coccineus L
Authors: Redondo‐Cuenca Araceli , Pedrosa Mercedes Martín , Sanz Ma Dolores Tenorio , Alvarado López Alejandra N. , Garcia‐Alonso Alejandra 
Published: November 2022

AbstractThe influence of high‐pressure processing (HPP) prior to cooking on nutritional composition and bioactive compounds content of four varieties of Phaseolus coccineus L. was studied. Cooking and HPP+C increased the protein content. However, minerals, total carbohydrates, ciceritol and α‐galactosides were reduced. Fat was not affected by cooking but decreased after HPP+C. For dietary fiber, the behavior observed was different depending on the sample and the treatment applied. HPP+C could be considered a good processing technology to retain the advantageous lower myo‐inositol phosphates isoforms and supply prebiotic oligosaccharides. The trypsin inhibitors activity was lower in the cooked and HPP+C samples; however, there were no significant differences between both thermal treatments. Thus, HPP+C reduced cooking time and preserving or improving the nutritional composition of the beans and their bioactive compounds content.