bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis for CFTR inhibition by CFTRinh-172
Authors: Young Paul , Levring Jesper , Fiedorczuk Karol , Blanchard Scott C. , Chen Jue 
Published: October 2023

ABSTRACTThe cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates electrolyte and fluid balance in epithelial tissues. Whereas activation of CFTR is vital to treating cystic fibrosis, selective inhibition of CFTR is a potential therapeutic strategy for secretory diarrhea and autosomal dominant polycystic kidney disease (ADPKD). Although several CFTR inhibitors have been developed by high-throughput screening, their modes of action remain elusive. In this study, we determined the structure of CFTR in complex with the inhibitor CFTRinh- 172 to 2.7 Å resolution by cryogenic electron microscopy (cryo-EM). We observe that CFTRinh- 172 binds inside the pore near transmembrane helix 8 (TM8), a critical structural element that links ATP hydrolysis with channel gating. Binding of CFTRinh-172 stabilizes a conformation in which the chloride selectivity filter is collapsed and the pore is blocked from the extracellular side of the membrane. Single molecule fluorescence resonance energy transfer (smFRET) experiments indicate that CFTRinh-172 inhibits channel gating without compromising nucleotide-binding domain (NBD) dimerization. Together, these data show that CFTRinh-172 acts as both a pore blocker and a gating modulator, setting it apart from typical ion channel inhibitors. The dual functionality of CFTRinh-172 reconciles previous biophysical observations and provides a molecular basis for its activity.Significance statementThe pathogenesis of secretory diarrhea and autosomal dominant polycystic kidney disease involves hyperactivation of the CFTR ion channel. CFTR inhibitors, including the small-molecule CFTRinh-172, have been developed as therapeutic candidates to treat these diseases. This study offers a structural understanding of CFTRinh-172’s mode of action, clarifying its dual inhibitory role as both a pore blocker and gating modulator. The molecular description of how CFTRinh-172 interacts with CFTR provides a structural foundation to its specificity and efficacy. Furthermore, the observation that CFTR inhibitors and potentiators both interact with TM8 strengthens the notion that this helix serves as an allosteric link between the ATPase site and the channel gate, and is therefore a hotspot for pharmacological modulation.
Computational mechanisms underlying motivation to earn symbolic reinforcers
Authors: Burk Diana C. , Taswell Craig , Tang Hua , Averbeck Bruno B. 
Published: October 2023

AbstractReinforcement learning (RL) is a theoretical framework that describes how agents learn to select options that maximize rewards and minimize punishments over time. We often make choices, however, to obtain symbolic reinforcers (e.g. money, points) that can later be exchanged for primary reinforcers (e.g. food, drink). Although symbolic reinforcers are motivating, little is understood about the neural or computational mechanisms underlying the motivation to earn them. In the present study, we examined how monkeys learn to make choices that maximize fluid rewards through reinforcement with tokens. The question addressed here is how the value of a state, which is a function of multiple task features (e.g. current number of accumulated tokens, choice options, task epoch, trials since last delivery of primary reinforcer, etc.), drives value and affects motivation. We constructed a Markov decision process model that computes the value of task states given task features to capture the motivational state of the animal. Fixation times, choice reaction times, and abort frequency were all significantly related to values of task states during the tokens task (n=5 monkeys). Furthermore, the model makes predictions for how neural responses could change on a moment-by-moment basis relative to changes in state value. Together, this task and model allow us to capture learning and behavior related to symbolic reinforcement.Significance statementSymbolic reinforcers, like money and points, play a critical role in our lives. Like rewards, symbolic reinforcers can be motivating and can even lead to compulsive behaviors like gambling addiction. However, we lack an understanding of how symbolic reinforcement can drive fluctuations in motivation. Here we investigated the effect of symbolic reinforcers on behaviors related to motivation during a token reinforcement learning task, using a novel reinforcement learning model and data from five monkeys. Our findings suggest that the value of a task state can affect willingness to initiate a trial, speed to choose, and persistence to complete a trial. Our model makes testable predictions for within trial fluctuations of neural activity related to values of task states.
Rapid generation of single-insertion transgenics by Tol2 transposition in zebrafish
Authors: Kalvaitytė Miglė , Gabrilavičiūtė Sofija , Balciunas Darius 
Published: October 2023

AbstractThe Tol2 transposable element is the most widely used transgenesis tool in zebrafish. However, its high activity almost always leads to multiple unlinked integrations of the transgenic cassette in F1fish. Each of these transgenes is susceptible to position effects from surrounding regulatory landscape, which can lead to altered expression and, consequently, activity. Scientists therefore must strike a balance between the need to maximize reproducibility by establishing single-insertion transgenic lines and the need to complete experiments within a reasonable timeframe. In this article, we introduce a simple competitive dilution strategy for rapid generation of single-insertion transgenics. By usingcry:BFPreporter plasmid as a competitor, we achieved a nearly fourfold reduction in the number of the transgene of interest(TgOI) integrations while simultaneously increasing the proportion of single-insertion F1generation transgenics to over 50%. We also observed variations inTgOIexpression among independent single-insertion transgenics, highlighting that the commonly used ubiquitousubbpromoter is susceptible to position effects. Wide application of our competitive dilution strategy will save time, reduce animal usage, and improve reproducibility of zebrafish research.SummaryCompetitive dilution of Tol2 transgenesis vectors facilitates isolation of single-insertion transgenic zebrafish lines in the F1generation, reducing animal usage, improving reproducibility, and saving time.
ECM-Focused Proteomic Analysis of Ear Punch Regeneration inAcomys Cahirinus
Authors: McCabe Maxwell C. , Okamura Daryl M. , Erickson Christopher B. , Perry Blair W. , Brewer Chris M. , Nguyen Elizabeth D. , Saviola Anthony J. , Majesky Mark W. , Hansen Kirk C. 
Published: October 2023

AbstractIn mammals, significant injury is generally followed by the formation of a fibrotic scar which provides structural integrity but fails to functionally restore damaged tissue. Spiny mice of the genusAcomysrepresent the first example of full skin autotomy in mammals.Acomys cahirinushas evolved extremely weak skin as a strategy to avoid predation and is able to repeatedly regenerate healthy tissue without scar after severe skin injury or full-thickness ear punches. Extracellular matrix (ECM) composition is a critical regulator of wound repair and scar formation and previous studies have suggested that alterations in its expression may be responsible for the differences in regenerative capacity observed betweenMus musculusandA. cahirinus, yet analysis of this critical tissue component has been limited in previous studies by its insolubility and resistance to extraction. Here, we utilize a 2-step ECM-optimized extraction to perform proteomic analysis of tissue composition during wound repair after full-thickness ear punches inA. cahirinusandM. musculusfrom weeks 1 to 4 post-injury. We observe changes in a wide range of ECM proteins which have been previously implicated in wound regeneration and scar formation, including collagens, coagulation and provisional matrix proteins, and matricryptic signaling peptides. We additionally report differences in crosslinking enzyme activity and ECM protein solubility betweenMusandAcomys.Furthermore, we observed rapid and sustained increases in CD206, a marker of pro-regenerative M2 macrophages, inAcomys,whereas little or no increase in CD206 was detected inMus.Together, these findings contribute to a comprehensive understanding of tissue cues which drive the regenerative capacity ofAcomysand identify a number of potential targets for future pro-regenerative therapies.
Uncovering DUB Selectivity Through Ion-Mobility-Based Assessment of Ubiquitin Chain Isomers
Authors: Shestoperova Elizaveta I. , Strieter Eric R. 
Published: October 2023

ABSTRACTUbiquitination is a reversible posttranslational modification that maintains cellular homeostasis and regulates protein turnover. Deubiquitinases (DUBs) are a large family of proteases that catalyze the removal of ubiquitin (Ub) along with the dismantling and editing of Ub chains. Assessing the activity and selectivity of DUBs is critical for defining physiological function. Despite numerous methods for evaluating DUB activity, none are capable of assessing activity and selectivity in the context of multicomponent mixtures of native, unlabeled ubiquitin conjugates. Here we report on an ion mobility (IM)-based approach for measuring DUB selectivity in the context of unlabeled mixtures of Ub chains. We show that IM-MS can be used to assess the selectivity of DUBs in a time-dependent manner. Moreover, using the branched Ub chain selective DUB UCH37/UCHL5 along with a mixture of Ub trimers, a strong preference for branched Ub trimers bearing K6 and K48 linkages is revealed. Our results demonstrate that IM coupled with mass spectrometry (IM-MS) is a powerful method for evaluating DUB selectivity under conditions more physiologically relevant than single component mixtures.
Tunneling nanotubes enable intercellular transfer in zebrafish embryos
Authors: Korenkova Olga , Liu Shiyu , Prlesi Inès , Pepe Anna , Albadri Shahad , Bene Filippo Del , Zurzolo Chiara 
Published: October 2023

SummaryTunneling nanotubes (TNTs) are thin intercellular connections facilitating the transport of diverse cargoes, ranging from ions to organelles. While TNT studies have predominantly been conducted in cell cultures, the existence of open-ended TNTs within live organisms remains unverified. Despite the observation of intercellular connections during embryonic development across various species, their functional role has not been confirmed. In this study, we performed mosaic labeling of gastrula cells in zebrafish embryos to demonstrate the coexistence of TNT-like structures alongside other cellular protrusions. These embryonic TNT-like connections exhibited similar morphology to TNTs described in cell culture, appeared to have similar formation mechanisms and could be induced by Eps8 overexpression and CK666 treatment. Most notably, to classify them as TNTs, we demonstrated their capability to transfer both soluble cargoes and organelles, which is a defining feature of open-ended TNTs. This study marks the first demonstration of functional TNTs in a living embryo.
Light-load performance optimization for LLC resonant converter
Authors: Yao Xuliang , Han Xiao , Liao Yuefeng , Wang Jingfang 
Published: October 2023

Purpose
This study aims to solve the problem that under light-load conditions, the output voltage regulation capability is lost due to the fact that the voltage gain of the LLC resonant converter does not decrease with the increase of the switching frequency.

Design/methodology/approach
In this paper, the impedance model considering the parasitic parameters of the primary and secondary sides is calculated under light-load conditions, the limitations of the previous method are explained and a new circuit improvement is proposed.

Findings
In this paper, an improved circuit is proposed, and the impedance Bode plot is used to verify that the circuit can effectively improve the voltage gain problem under light-load conditions. Finally, the experimental results verify the effectiveness of the proposed circuit through comparison with traditional solutions and circuits.

Originality/value
In this paper, the impedance model considering the parasitic parameters of the primary and secondary sides is calculated, the limitations of the previous method are explained and a new circuit improvement is proposed. When compared with the previous method, the proposed circuit improvement can suppress the voltage gain increase that occurs when the switching frequency increases to a certain level.
Mirroring digital content marketing framework: capturing providers’ perspectives through stimuli assessment and behavioural engagement response
Authors: Filipovic Jelena , Arslanagic-Kalajdzic Maja 
Published: October 2023

Purpose
This study aims to propose a novel mirroring digital content marketing (MDCM) framework that extends the current consumer-based digital content marketing (DCM) framework to encompass the provider’s perspective. Relying on the stimulus–organism–response theory, the authors posit that content stimuli influence behavioural engagement responses that, respectively, mirror the motives and self-reported engagement from the consumer-based DCM.

Design/methodology/approach
To empirically verify the provider side of the MDCM framework, the authors used one newsletter and one matching website with corresponding 117 weekly data points. Data were drawn from three sources for six countries: newsletter content stimuli, newsletter performance indicators and Google Analytics metrics on matching website performance. OLS and panel regressions were used to analyse the data and generate results.

Findings
The results show that content stimuli do explain the behavioural engagement responses of consumers recorded by the provider. However, the effects of the different stimuli are inconsistent: functional stimuli have both positive and negative effects, while social stimuli positively impact the behavioural engagement response. The authors further show that the newsletter engagement response influences subsequent engagement responses across channels (e.g. via the linked news media website).

Research limitations/implications
Further research definitely needs to empirically verify the connection between two sides of the MDCM framework. As proposed by authors, provider-based stimuli are corresponding to the consumer-based motivations, however, which stimuli are triggering which motivations and how they can consequently be translated to both consumer- and provider-based behavioural engagement is still an open question. Different theoretical lenses could be taken in the usage of MDCM framework.

Practical implications
Our observations are relevant for marketers that want to use certain stimuli in their digital content, in particular a content introduced in the newsletter and the website. The authors show that stimuli are indeed related to the behavioural engagement response of consumers and that various stimuli impact engagement differently. Furthermore, the recommendations for the marketing managers of news media are to use priming across the platforms in their Web communication strategies.

Originality/value
This study proposes and empirically tests the provider side of the MDCM framework across two news media channels, focusing on behavioural engagement responses.
Speak up to speed up innovation: servant leadership triggered innovative work behavior mediated through voice behavior
Authors: Khan Muhammad Mumtaz , Mubarik Muhammad Shujaat , Ahmed Syed Saad , Islam Tahir 
Published: October 2023

Purpose
This study aims to unfurl the mediating role of facets of voice behavior. The study also unearths the relationship between servant leadership and voice behavior.

Design/methodology/approach
The data were collected from follower manager dyads in two waves of data collection initiated after the completion of the preceding wave. The final sample size obtained was 312.

Findings
The study found servant leadership to be related to innovative work behavior and facets of voice behavior. The study also found promotive voice behavior and preventive voice behavior to be related to the innovative work behavior of employees. The study found promotive voice behavior and prohibitive voice behavior work as parallel mediators linking servant leadership to the innovative work behavior of employees.

Originality/value
To the best of the authors’ knowledge, this study is the first to unearth mediation linking servant leadership to innovative work behavior through both facets of voice behavior.
A bibliometric analysis of wine economics and business research: insights, trends, and future directions
Authors: Ruggeri Giordano , Corsi Stefano , Mazzocchi Chiara 
Published: October 2023

Purpose
This study aims to provide a comprehensive overview of the academic landscape in wine economics and business research over the past decades, capturing and analysing the literature through rigorous bibliometric methodologies. The study is intended as a foundational resource for academics, policymakers and industry stakeholders interested in the evolving scholarly discourse within the wine industry.

Design/methodology/approach
The authors analyse data from over 3,200 papers in the field of wine economics and business published between 1990 and 2022, sourced from Scopus. Various bibliometric indicators are applied, including publication and citation counts, and methods like keyword and co-citation analyses were used to map out the thematic and intellectual landscape.

Findings
The study reveals the escalating global relevance of wine economics and business research and identifies prominent papers and authors, influential countries and leading journals. The analysis reveals a dynamic shift in academic focus. Initially concentrating on foundational inquiries in the 1990s, research evolved to encompass complex themes such as e-commerce, wine tourism, sustainability and global crises. The study emphasises the adaptability and resilience of the wine supply chain and anticipates future research areas.

Originality/value
This study presents a comprehensive bibliometric analysis of the expanding body of research in wine economics and business, using data from over 3,200 documents published between 1990 and 2022. It uniquely combines different advanced bibliometric tools to provide a multifaceted overview of wine economics and business research.
Research on the mechanism of digital transformation to improve enterprise environmental performance
Authors: Xie Jiaping , Zhang Tingting , Zhao Junjie 
Published: October 2023

PurposeBased on the background of enterprise digital transformation, this paper aims to examine the impact of digitization on the cooperative behavior and environmental performance of green technology innovation.Design/methodology/approachBy constructing a model of quantity competition between the two enterprises, this paper examines the impact of digitization on the cooperative behavior and environmental performance of green technology innovation from the micro level. It uses Shanghai and Shenzhen A-share-listed companies as research samples. An unbalanced panel data set from 2011 to 2018 was constructed to empirically test the effect of digital transformation on the environmental performance of enterprises.FindingsThe findings reveal the following. First, digital transformation can significantly improve the environmental performance of enterprises. Second, green technological innovation sharing plays an intermediary role between digital transformation and enterprise environmental performance. Third, when the level of digitization is high, the sharing effect of green technology innovation brought about by digital technology is stronger and enterprises tend to carry out cooperative green technology innovation. Lastly, the level of development of regional science and technology finance plays a positive regulatory role in digital transformation and enterprise environmental performance.Originality/valueThis paper first proposes that green technology innovation-sharing is an important mechanism that can significantly improve enterprises' environmental performance. The authors empirically examine the mechanism and analyze the heterogeneity of the impact of digitalization level on enterprises' environmental performance. The authors also discuss the moderating effect of regional technology and finance development levels on the relationship between digitalization and enterprises' environmental performance.
Genoa, former church of Saints Gerolamo and Francesco Saverio and former university library: conservation, reuse and enhancement proposals
Authors: Musso Stefano Francesco , Franco Giovanna 
Published: October 2023

PurposeThis article sets out to show how principles and questions about method that underlie a way of interpreting the discipline of conservation and restoration can find results in research and studies, aiming at achieving even conscious reuse process. The occasion is the very recent research performed on the former Church of Saints Gerolamo and Francesco Saverio in Genoa, Italy, the Jesuit church annexed to the 17th-century College of the order. It is a small Baroque jewel in the heart of the ancient city, former University Library and actually abandoned, forgotten for years, inaccessible and awaiting a new use.Design/methodology/approachThe two-year work carried out on the monumental building was conducted according to a study and research methodology developed and refined over the years within the activities of the School of Specialisation in Architectural Heritage and Landscape of the University of Genoa. It is a multidisciplinary and rigorous approach, which aims to train high-level professionals, up-to-date and aware of the multiple problems that interventions on existing buildings, especially of a monumental nature, involve.FindingsThe biennal study has been carried out within the activities of the Post-Graduate Programme in Architectural Heritage and Landscape of the University of Genoa. The work methodology faces the challenges of the contemporary complexity, raised by the progressive broadening of the concept of cultural “heritage” and by the problems of its conservation, its active safeguard and its reuse: safety in respect of seismic risk, fire and hydro geological instability, universal accessibility – cognitive, physical and alternative – resource efficiency, comfort and savings in energy consumption, sustainability, communication and involvement of local communities and stakeholders.Originality/valueThe goals of the work were the following: understanding of the architectural heritage, through the correlated study of its geometries, elements and construction materials, surfaces, structures, spaces and functions; understanding of the transformations that the building has undergone over time, relating the results of historical reconstructions from indirect sources and those of direct archaeological analysis; assessment of the state of conservation of the building recognising phenomena of deterioration, damage, faults and deficits that affect materials, construction elements, systems and structures; identification of the causes and extent of damage, faults and deficits, assessing the vulnerability and level of exposure of the asset to the aggression of environmental factors and related risks; evaluation of the compatibility between the characteristics of the available spaces, the primary needs of conservation, the instance of regeneration and possible new uses; the definition of criteria and guidelines for establishing the planning of conservation, restoration and redevelopment interventions.