bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distinct functions for the paralogous RBM41 and U11/U12-65K proteins in the minor spliceosome
Authors: Norppa Antto J. , Chowdhury Iftekhar , van Rooijen Laura E. , Ravantti Janne J. , Snel Berend , Varjosalo Markku , Frilander Mikko J. 
Published: October 2023

ABSTRACTIn this work, we identify RBM41 as a novel unique protein component of the minor spliceosome. RBM41 has no previously recognized cellular function but has been identified as a paralog of the U11/U12-65K protein, a known unique component of the minor spliceosome that functions during the early steps of minor intron recognition as a component of the U11/U12 di-snRNP. We show that both proteins use their highly similar C-terminal RRMs to bind to 3’-terminal stem-loops in U12 and U6atac snRNAs with comparable affinity. Our BioID data indicate that the unique N-terminal domain of RBM41 is necessary for its association with complexes containing DHX8, an RNA helicase, which in the major spliceosome drives the release of mature mRNA from the spliceosome. Consistently, we show that RBM41 associates with excised U12-type intron lariats, is present in the U12 mono-snRNP, and is enriched in Cajal bodies, together suggesting that RBM41 functions in the post-splicing steps of the minor spliceosome assembly/disassembly cycle. This contrasts with the U11/U12-65K protein, which uses the N-terminal region to interact with U11 snRNP during the intron recognition step. Finally, we show that while RBM41 knockout cells are viable, they show alterations in the splicing of U12-type introns, particularly differential U12-type 3’ splice site usage. Together, our results highlight the role 3’-terminal stem-loop of U12 snRNA as a dynamic binding platform for the paralogous U11/U12-65K and RBM41 proteins, which function at distinct stages of minor spliceosome assembly/disassembly cycle.
Fitness landscape of substrate-adaptive mutations in evolved APC transporters
Authors: Karapanagioti Foteini , Atlason Úlfur Á. , Slotboom Dirk J. , Poolman Bert , Obermaier Sebastian 
Published: October 2023

AbstractThe emergence of new protein functions is crucial for the evolution of organisms. This process has been extensively researched for soluble enzymes, but it is largely unexplored for membrane transporters, even though the ability to acquire new nutrients from a changing environment requires evolvability of transport functions. Here, we demonstrate the importance of environmental pressure in obtaining a new activity or altering a promiscuous activity in members of the Amino acid-Polyamine-organoCation (APC)-type yeast amino acid transporters family. We identify APC members that have broader substrate spectra than previously described. Usingin vivoexperimental evolution, we evolve two of these transporter genes,AGP1andPUT4, towards new substrate specificities. Single mutations on these transporters are found to be sufficient for expanding the substrate range of the proteins, while retaining the capacity to transport all original substrates. Nonetheless, each adaptive mutation comes with a distinct effect on the fitness for each of the original substrates, illustrating a trade-off between the ancestral and evolved functions. Collectively, our findings reveal how substrate-adaptive mutations in membrane transporters contribute to fitness and provide insights into how organisms can use transporter evolution to explore new ecological niches.
Lipid discovery enabled by sequence statistics and machine learning
Authors: Christensen Priya M. , Martin Jonathan , Uppuluri Aparna , Joyce Luke R. , Wei Yahan , Guan Ziqiang , Morcos Faruck , Palmer Kelli L. 
Published: October 2023

AbstractBacterial membranes are complex and dynamic, arising from an array of evolutionary pressures. One enzyme that alters membrane compositions through covalent lipid modification is MprF. We recently identified thatStreptococcus agalactiaeMprF synthesizes lysyl-phosphatidylglycerol (Lys-PG) from anionic PG, and a novel cationic lipid, lysyl-glucosyl-diacylglycerol (Lys-Glc-DAG), from neutral glycolipid Glc-DAG. This unexpected result prompted us to investigate whether Lys-Glc-DAG occurs in other MprF-containing bacteria, and whether other novel MprF products exist. Here, we studied protein sequence features determining MprF substrate specificity. First, pairwise analyses identified several streptococ-cal MprFs synthesizing Lys-Glc-DAG. Second, a restricted Boltzmann machine-guided approach led us to discover an entirely new substrate for MprF inEnterococcus, diglucosyl-diacylglycerol (Glc2-DAG), and an expanded set of organisms that modify glycolipid substrates using MprF. Overall, we combined the wealth of available sequence data with machine learning to model evolutionary constraints on MprF sequences across the bacterial domain, thereby identifying a novel cationic lipid.
Initiation of a ZAKα-dependent Ribotoxic Stress Response by the Innate Immunity Endoribonuclease RNase L
Authors: Xi Jiajia , Snieckute Goda , Asthana Abhishek , Gaughan Christina , Bekker-Jensen Simon , Silverman Robert H. 
Published: October 2023

ABSTRACTRNase L is a regulated endoribonuclease in higher vertebrates that functions in antiviral innate immunity. Interferons induce OAS enzymes that sense double-stranded RNA of viral origin leading to synthesis of 2’,5’-oligoadenylate (2-5A) activators of RNase L. However, it is unknown precisely how RNase L inhibits viral infections. To isolate effects of RNase L from other effects of double-stranded RNA or virus, 2-5A was directly introduced into cells. Here we report that RNase L activation by 2-5A causes a ribotoxic stress response that requires the ribosome-associated MAP3K, ZAKα. Subsequently, the stress-activated protein kinases (SAPK) JNK and p38α are phosphorylated. RNase L activation profoundly altered the transcriptome by widespread depletion of mRNAs associated with different cellular functions, but also by SAPK-dependent induction of inflammatory genes. Our findings show that 2-5A is a ribotoxic stressor that causes RNA damage through RNase L triggering a ZAKα kinase cascade leading to proinflammatory signaling and apoptosis.HighlightsRNase L signals antiviral innate immunity from the ribosomeThe ribotoxic stress response requires the MAP3K ZAKαRNA cleavage leads to transcription of proinflammatory genesZAKα contributes to apoptosis downstream of RNase L activity
Polarity-dependent expression and localization of secretory glucoamylase mRNA in filamentous fungal cells
Authors: Morita Yuki , Takegawa Kaoru , Collins Brett M. , Higuchi Yujiro 
Published: October 2023

SUMMARYIn multinuclear and multicellular filamentous fungi little is known about how mRNAs encoding secreted enzymes are transcribed and localized spatiotemporally. To better understand this process we visualized mRNA encoding GlaA, a glucoamylase secreted in large amounts by the industrial filamentous fungusAspergillus oryzae, in living cells by the MS2 system. We found thatglaAmRNA was significantly transcribed and localized near the hyphal tip and septum, which are the sites of protein secretion. We also revealed thatglaAmRNA exhibits long-range dynamics in the vicinity of the endoplasmic reticulum (ER) in a manner that is dependent on the microtubule motor proteins kinesin-1 and kinesin-3, but independent of early endosomes. Moreover, we elucidated that the regulatory mechanisms ofglaAmRNA by stress granules and processing bodies were different under high temperature and ER stress. Collectively, this study uncovers a dynamic regulatory mechanism of mRNA encoding a secretory enzyme in filamentous fungi.
Parkinsonism Sac domain mutation in Synaptojanin-1 affects ciliary properties in iPSC-derived dopaminergic neurons
Authors: Rafiq Nisha Mohd , Fujise Kenshiro , Rosenfeld Martin Shaun , Xu Peng , Wu Yumei , De Camilli Pietro 
Published: October 2023

ABSTRACTSynaptojanin-1 (SJ1) is a major neuronal-enriched PI(4,5)P24- and 5-phosphatase implicated in the shedding of endocytic factors during endocytosis. A mutation (R258Q) that impairs selectively its 4-phosphatase activity causes Parkinsonism in humans and neurological defects in mice (SJ1RQKI mice). Studies of these mice showed, besides an abnormal assembly state of endocytic factors at synapses, the presence of dystrophic nerve terminals selectively in a subset of nigro-striatal dopamine (DA)-ergic axons, suggesting a special lability of DA neurons to the impairment of SJ1 function. Here we have further investigated the impact of SJ1 on DA neurons using iPSC-derived SJ1 KO and SJ1RQKI DA neurons and their isogenic controls. In addition to the expected enhanced clustering of endocytic factors in nerve terminals, we observed in both SJ1 mutant neuronal lines increased cilia length. Further analysis of cilia of SJ1RQDA neurons revealed abnormal accumulation of the Ca2+channel Cav1.3 and of ubiquitin chains, suggesting an impaired clearing of proteins from cilia which may result from an endocytic defect at the ciliary base, where a focal concentration of SJ1 was observed. We suggest that SJ1 may contribute to the control of ciliary protein dynamics in DA neurons, with implications on cilia-mediated signaling.
Design and selection of drug properties to increase the public health impact of next-generation seasonal malaria chemoprevention: a modelling study
Authors: Braunack-Mayer Lydia , Malinga Josephine , Masserey Thiery , Nekkab Narimane , Sen Swapnoleena , Schellenberg David , Tchouatieu André-Marie , Kelly Sherrie L , Penny Melissa A 
Published: October 2023

BackgroundSeasonal malaria chemoprevention (SMC) is recommended for disease control in settings with moderate to highPlasmodium falciparumtransmission and currently depends on administration of sulfadoxine-pyrimethamine with amodiaquine. However, poor regimenadherence and the increasedfrequencyof sulfadoxine-pyrimethamine resistant parasite mutations may threaten SMC’s effectiveness. We need guidance to de-risk the development of drug compounds for malaria prevention.MethodsWe combined an individual-based malaria transmission model that has explicit parasite growth with drug pharmacokinetic/pharmacodynamic models. We modelled SMC drug attributes for several possible modes-of-action, linked to their potential public health impact. Global sensitivity analyses identified trade-offs between drug elimination half-life, maximum killing effect, and SMC coverage, and optimisation identified minimum requirements to maximise malaria burden reductions.FindingsModel predictions show that preventing infection for the entire period between SMC cycles is more important than drug curative efficacy for clinical disease effectiveness outcomes, but similarly important for impact on prevalence. When four SMC cycles are deployed to children under five years with high levels of coverage (69% of children receiving all cycles), drug candidates require a duration of protection half-life of >23 days (elimination half-life >10 days) to achieve >75% clinical incidence and severe disease reductions (measured over the intervention period in the target population, compared with no intervention across a range of modelled scenarios). High coverage is critical to achieve these targets, requiring >60% of children received all SMC cycles and >90% of children at least one cycle regardless of the drug’s duration.InterpretationWhile efficacy is crucial for malaria prevalence reductions, chemoprevention development should select drug candidates for their duration of protection to maximise burden reductions, with the duration half-life determiningcycle timing. Explicitlydesigning or selectingdrug properties to increase communityuptake is paramount.FundingBill & Melinda Gates Foundation and the Swiss National Science Foundation.
Deletion of CD44 promotes adipogenesis by regulating PPARɣ and cell cycle-related pathways
Authors: Weng Xiong , Jiang Hao , Zhou Houjiang , Lin De , Wang Jing , Kang Li 
Published: October 2023

AbstractCD44, a cell surface adhesion receptor and stem cell biomarker, is recently implicated in chronic metabolic diseases. Ablation of CD44 ameliorates adipose tissue inflammation and insulin resistance in obesity. Here, we investigated cell type specific CD44 expression in human and mouse adipose tissue and further studied how CD44 in preadipocytes regulates adipocyte function. Using Crispr Cas9-mdediated gene deletion and lentivirus-mediated gene re-expression, we discovered that deletion of CD44 promotes adipocyte differentiation and adipogenesis, whereas re-expression of CD44 abolishes this effect and decreases insulin responsiveness and adiponectin secretion in 3T3-L1 cells. Mechanistically, CD44 does so via suppressingPpargexpression. Using quantitative proteomics analysis, we further discovered that cell cycle-regulated pathways were mostly decreased by deletion of CD44. Indeed, re-expression of CD44 moderately restored expression of proteins involved in all phases of the cell cycle. Our data suggest that CD44 plays a crucial role in regulating adipogenesis and adipocyte function possibly through regulating PPAR☐ and cell cycle-related pathways. This study provides evidence for the first time that CD44 expressed in preadipocytes plays key roles in regulating adipocyte function outside immune cells where CD44 is primarily expressed. Therefore, targeting CD44 in (pre)adipocytes may provide therapeutic potential to treat obesity-associated metabolic complications.
Influence of consumption experience on the behavior of craft beer consumers: beginner and experienced consumers
Authors: Haddad Felipe Furtini , Vieira Kelly Carvalho , Carneiro João de Deus Souza 
Published: October 2023

PurposeThis paper aims to identify the profiles of beginner and experienced consumers (BCs and ECs) of craft beer and evaluate their perception, knowledge and purchase intention.Design/methodology/approachA total of 291 craft beer consumers including 148 BCs and 143 ECs participated in the study, which was divided into 2 stages: quantitative research through a questionnaire and conjoint analysis.FindingsBCs are mostly female, with a lower age, income and consumption frequency, presented a shallower understanding of International Bitterness Units (IBU) and considered 7.0% alcohol by volume (ABV) as a high-relative value in craft beers. Otherwise, ECs are mostly men with a higher age and consumption frequency, and they don't consider 50 IBU as high bitterness. The results of conjoint analysis indicate that both groups of consumers attribute greater relative importance to ABV and nonalcoholic beers had lower purchase intentions. Finally, the authors show that beer with 30 IBU and 4.5% ABV is preferred by both BCs and ECs.Originality/valueThe authors' identification about the distinct behaviors of different groups of consumers, based on their consumption time of craft beer, as managerial implications for industries producing craft beer and, as a theoretical contribution, the authors have defined “BCs” and “ECs” based on the experiences with and durations of craft beer consumption.
A cross-national study of the emotional intelligence of young adults in the Middle East
Authors: Nassar Yahya Hayati , Alharballeh Siham , Dodeen Hamzeh Mohd 
Published: October 2023

PurposeThis study aimed to assess emotional intelligence (EI) among young adults across three Arab countries: Egypt, Jordan and the United Arab Emirates.Design/methodology/approachA total of 1884 university students participated from the three countries and completed the Schutte Self Report Emotional Intelligence Test (SSEIT). Data were validated by confirmatory factor analysis using SPSS AMOS version 29. Path analysis, t-tests and analyses of variance were performed to understand the influence of background variables on the EI of the study participants.FindingsThe results provide theoretical support for the SSEIT and the hypothesized relationship between managing personal and others' emotions. Although significant differences were found between participants in terms of gender and grade point average (GPA), no difference was found between participants based on nationality. The results of this study indicate the need to prioritize EI in young adults and other implications.Originality/valueThe importance of EI in individuals' daily lives cannot be overemphasized. However, scholarly insights into the state of EI in the Arab context are scarce.
How popular is a topic on social media? A multi-criteria decision-making framework based on user engagement
Authors: Güner Samet , Cebeci Halil Ibrahim , Aydemir Emrah 
Published: October 2023

PurposeSocial media is widely used to capture citizens' opinions and topics deemed important. The importance or interest social media users attribute to a topic is traditionally measured by tweet frequency. This approach is practical but overlooks other user engagement tools such as retweets, likes, quotes, and replies. As a result, it may lead to a misinterpretation of social media signals. This paper aims to propose a method that considers all user engagement indicators and ranks the topics based on the interest attributed by social media users.Design/methodology/approachA multi-criteria decision-making framework was proposed, which calculates the relative importance of user engagement tools using objective (information entropy) and subjective (Bayesian Best-Worst Method) methods. The results of the two methods are aggregated with a combinative method. Then, topics are ranked based on their user engagement levels using Multi-Objective Optimization by Ratio Analysis.FindingsThe proposed approach was used to determine citizens' priorities in transport policy, and the findings are compared with those obtained solely based on tweet frequency. The results revealed that the proposed multi-criteria decision-making framework generated more comprehensive and robust results.Practical implicationsThe proposed method provides a systematic way to interpret social media signals and guide institutions in making better policies, hence ensuring that the demands of users/society are properly addressed.Originality/valueThis study presents a systematic method to prioritize user preferences in social media. It is the first in the literature to discuss the necessity of considering all user engagement indicators and proposes a reliable method that calculates their relative importance.
Pilot effectiveness trial of Mood Lifters for individuals who self-report bipolar disorder
Authors: Pokowitz Elena Lauren , Menzies Cassandra , Votta Cecilia , Ye Haonan , O’Donnell Lisa , Deldin Patricia 
Published: October 2023

Purpose
Bipolar disorder is associated with poor mental and physical health outcomes, and therefore, it is crucial to research and develop effective interventions for this population (Grande et al., 2016). Unfortunately, research on the efficacy of current interventions shows only small improvements in symptoms and quality of life (Oud et al., 2016). Additionally, individuals with bipolar disorder face barriers to accessing care like social stigma, isolation and financial constraints (Blixen et al., 2016). This paper aims to introduce and examine the effectiveness of an accessible, peer-led group program, Mood Lifters (Votta and Deldin, 2022), in those who completed the program and also self-reported a diagnosis of bipolar disorder.

Design/methodology/approach
Mood Lifters is a 15-week, peer-led group program that approaches mental wellness from a biopsychosocial framework using strategies from a variety of evidence-based treatment methods (e.g. cognitive-behavioral therapy, dialectical behavior therapy, interpersonal psychotherapy, etc.). Participants meet once a week for 1 hour to review various mental health topics, including behavioral changes and insight into mood patterns. Individuals who participated in nonacademic groups in a company setting and self-reported a bipolar diagnosis were surveyed at the beginning and end of their program to measure various aspects of psychological functioning.

Findings
Results suggest that these individuals experienced significant improvements in depression, anxiety, social functioning and perceived stress, along with flourishing and positive and negative affect.

Originality/value
These findings are promising, given that bipolar disorder is historically difficult to treat (Grande et al., 2016). Based on this preliminary evidence, the authors have developed a Mood Lifters program specifically for individuals with bipolar disorder and are launching a randomized control clinical trial.
Automation in public sector jobs and services: a framework to analyze public digital transformation’s impact in a data-constrained environment
Authors: Bonomi Savignon Andrea , Zecchinelli Riccardo , Costumato Lorenzo , Scalabrini Fabiana 
Published: October 2023

Purpose
This study aims to estimate the value of the impact from digital transformation (DX) focusing on its automation effect, looking at the time and cost savings coming from the substitution effect with an adoption of digital technologies. For example, cloud and artificial intelligence technologies such as ChatGPT have the potential to change ways of working, substituting and replacing several of the tasks that are currently carried out by public administration (PA) employees and labor processes underpinning PA services.

Design/methodology/approach
The paper outlines a new framework to estimate the potential impact of DX on the public sector. The authors apply this framework to estimate the value of the impact of DX on the Italian PA, defining the latter by the collection of the value of its labor (i.e. PA workforce salaries) and by the collection of the value of its outputs (i.e. public services’ costs).

Findings
This study ultimately maps out the magnitude and trends of how likely the PA occupations and services could be substituted in a wider process of DX. To do this, the authors apply their framework to the Italian PA, and they triangulate secondary data collection, from official accounts of the Italian Ministry of Economics and the National Statistical Institute, with methodological antecedents from the UK Office for National Statistics and experts’ insights. Results provide a snapshot on the type and magnitude of PA jobs and services projected to be affected by automation over the next 10 years.

Originality/value
To the best of the authors’ knowledge, this paper provides for the first time an approach to estimate the value of the impact of DX on the public sector in a data-constrained environment – or in the lack of the required primary data. Once applied to the Italian PA, this approach provides a granular map of the automatability of each of the PA occupations and of the PA services. Finally, this paper mentions preliminary insights on potential challenges related to equity in public sector jobs and implications on recruitment processes.
Rethinking tourism: why and who?
Authors: Butler Richard 
Published: October 2023

PurposeThis study aims to discuss the idea of a rethinking of tourism, as proposed in the academic literature, in the wake of the coronavirus disease 2019 (COVID-19) pandemic, to evaluate the rationale for such a process and to consider by and for whom such a rethink should be undertaken.Design/methodology/approachThis is a viewpoint paper, interpreting the literature on the topic of refocusing and rethinking tourism in general and identifying issues arising from such arguments – in particular, the impact of such a process on tourists and their destinations.FindingsWhilst a rethink of tourism is appropriate and necessary in many respects, the rationale and goals of such a process need to be made specific and focussed rather than general and based on interest groups' preferences and beliefs.Originality/valueMuch of the discussion about rethinking tourism has focussed on what is perceived to be wrong with tourism by the various interest groups rather than what the goal and value of a refocus might be. This paper questions that approach and argues for change at local and specific levels rather than a sweeping and generalised approach.