bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-molecule live imaging of subunit interactions and exchange within cellular regulatory complexes
Authors: Graham Thomas G.W. , Dugast-Darzacq Claire , Dailey Gina M. , Weng Britney , Darzacq Xavier , Tjian Robert 
Published: June 2024

SummaryCells are built from vast networks of competing molecular interactions, most of which have been impossible to monitor in vivo. We recently devised a new strategy, proximity-assisted photoactivation (PAPA), to detect these interactions at single-molecule resolution in live cells. Here we apply PAPA to visualize the network of interactions that regulate the central transcription elongation factor P-TEFb. PAPA between multiple pairs of endogenous proteins, combined with fast single-molecule tracking (fSMT), revealed that inactive P-TEFb within the 7SK ribonucleoprotein complex is largely unbound to chromatin, that this complex dissociates within minutes of treatment with a P-TEFb kinase inhibitor, and that heterogeneous ribonucleoproteins (hnRNPs) bind 7SK concomitant with P-TEFb release. Unlike 7SK-bound P-TEFb, P-TEFb associated with the coactivator BRD4 exhibited increased binding to chromatin. Our results address longstanding questions about a key transcriptional regulator and demonstrate that PAPA-fSMT can probe subunit interactions and exchange within endogenous regulatory complexes in live cells.
The Alzheimer’s disease geneSORL1regulates lysosome function in human microglia
Authors: Mishra Swati , Morshed Nader , Sindhu Sonia , Kinoshita Chizuru , Stevens Beth , Jayadev Suman , Young Jessica E. 
Published: June 2024

AbstractTheSORL1gene encodes the sortilin related receptor protein SORLA, a sorting receptor that regulates endo-lysosomal trafficking of various substrates. Loss of function variants inSORL1are causative for Alzheimer’s disease (AD) and decreased expression of SORLA has been repeatedly observed in human AD brains.SORL1is highly expressed in the central nervous system, including in microglia, the tissue resident immune cells of the brain. Loss of SORLA leads to enlarged lysosomes in hiPSC-derived microglia like cells (hMGLs). However, how SORLA deficiency contributes to lysosomal dysfunction in microglia and how this contributes to AD pathogenesis is not known. In this study, we show that loss of SORLA results in decreased lysosomal degradation and lysosomal enzyme activity due to altered trafficking of lysosomal enzymes in hMGLs. Phagocytic uptake of fibrillar amyloid beta 1-42 and synaptosomes is increased in SORLA deficient hMGLs, but due to reduced lysosomal degradation, these substrates aberrantly accumulate in lysosomes. An alternative mechanism of lysosome clearance, lysosomal exocytosis, is also impaired inSORL1deficient microglia, which may contribute to an altered immune response. Overall, these data suggest that SORLA has an important role in proper trafficking of lysosomal hydrolases in hMGLs, which is critical for microglial function. This further substantiates the microglial endo-lysosomal network as a potential novel pathway through whichSORL1may increase AD risk and contribute to development of AD. Additionally, our findings may inform development of novel lysosome and microglia associated drug targets for AD.
Hepatocyte-derived extracellular vesicles regulate liver regeneration after partial hepatectomy
Authors: McGinn Mina , Rabender Christopher , Mikkelsen Ross , Yakovlev Vasily 
Published: June 2024

AbstractWhile significant progress has been made in understanding different aspects of liver regeneration, the molecular mechanisms responsible for the initiation and termination of cell proliferation in the liver after massive loss or injury of liver tissue remain unknown. The loss of liver mass affects tissue-specific mitogenic inhibitors in the blood, which in turn regulate the proliferation of remaining hepatocytes and liver regeneration. Although well described in a number of publications, which inhibitory substances or “sensor molecules” control the regeneration mechanisms to properly maintain liver size remain unknown. Extracellular vesicles (EVs) are nano-sized, membrane-limited structures secreted by cells into the extracellular space. Their proposed role is stable intercellular carriers of proteins and RNAs, mostly micro-RNA, from secreted to recipient cells. Taken up by the recipient cells, EVs can significantly modulate their biological functions. In the present study, usingin vivoandin vitromodels, we demonstrate that hepatocyte proliferation and liver regeneration are regulated by EVs secreted by hepatocytes into the bloodstream. This regulation is carried out through a negative feedback mechanism, which explains the very precise regeneration of liver tissue after massive damage. We also demonstrate that an essential component of this mechanism is RNA carried by hepatocyte-derived EVs. These findings open up a new and unexplored area of biology regarding the mechanisms involved in the homeostasis regulation of various constantly renewing tissues by maintaining the optimal size and correct ratio between differentiating and proliferating cells.
Glycogen homeostasis and mtDNA expression require motor neuron to muscle TGFβ/Activin Signaling inDrosophila
Authors: Bretscher Heidi , O’Connor Michael B. 
Published: June 2024

SummaryMaintaining metabolic homeostasis requires coordinated nutrient utilization between intracellular organelles and across multiple organ systems. Many organs rely heavily on mitochondria to generate (ATP) from glucose, or stored glycogen. Proteins required for ATP generation are encoded in both nuclear and mitochondrial DNA (mtDNA). We show that motoneuron to muscle signaling by the TGFβ/Activin family member Actβ positively regulates glycogen levels duringDrosophiladevelopment. Remarkably, we find that levels of stored glycogen are unaffected by altering cytoplasmic glucose catabolism. Instead, Actβ loss reduces levels of mtDNA and nuclearly encoded genes required for mtDNA replication, transcription and translation. Direct RNAi mediated knockdown of these same nuclearly encoded mtDNA expression factors also results in decreased glycogen stores. Lastly, we find that expressing an activated form of the type I receptor Baboon in muscle restores both glycogen and mtDNA levels inactβmutants, thereby confirming a direct link between Actβ signaling, glycogen homeostasis and mtDNA expression.Key PointsThe Drosophila TGFβ family member Actβ signals from motor neuron to muscle positively regulating glycogen levelsActβ positively regulates nuclearly encoded factors required for mtDNA expressionGenes involved in mtDNA expression directly regulate glycogen storesExpressing an activated receptor in muscle restores glycogen and mtDNA inactβmutantsAbstract Figure
Type I interferon responses contribute to immune protection against mycobacterial infection
Authors: Szydlo-Shein Andrea , Sanz-Magallón Duque de Estrada Blanca , Rosenheim Joshua , Turner Carolin T. , Chandran Aneesh , Tsaliki Evdokia , Lipman Marc C. I. , Kunst Heinke , Pollara Gabriele , Elks Philip M. , Levraud Jean-Pierre , Payne Elspeth M. , Noursadeghi Mahdad , Tomlinson Gillian S. 
Published: June 2024

AbstractType I interferon responses have been considered detrimental to host protection in tuberculosis (TB). We provide novel data to challenge this paradigm, derived from transcriptional profiling of human in vivo immune responses to discover associations with radiographic disease severity in pulmonary TB, combined with mechanistic studies to test causality for observed associations using a zebrafish larval mycobacterial infection model. Type I interferon activity in tissue samples from the site of a standardised mycobacterial challenge, the tuberculin skin test, was associated with less severe human TB disease. Abrogation of type I interferon signalling, by CRISPR-mediated mutagenesis ofstat2, led to increased burden and dissemination ofMycobacterium marinuminfection in zebrafish larvae. The mechanism for increased severity of mycobacterial infection in zebrafish involves reduced recruitment of myeloid cells required to restrict bacterial growth. Our data support a clear host protective role for type I interferon responses in mycobacterial infection, with potential applications for risk-stratification of adverse outcomes and development of a host-directed therapy to mitigate against severe disease.
“Transcriptomic Profiling Unveils Novel Therapeutic Options for Drug-Resistant Temporal Lobe Epilepsy”
Authors: Sánchez-Jiménez Patricia , Alonso-Guirado Lola , Cerrada-Gálvez Laura , Elizalde-Horcada Marcos , Granero-Cremades Inmaculada , Maietta Paolo , Gómez-Martín Antonio , Abad-Santos Francisco , Torres-Díaz Cristina Virginia , de Toledo Maria , Frade-Porto Natalia , Gonzalez-Tarno Patricia , Pulido Paloma , Ovejero-Benito María C. 
Published: June 2024

ABSTRACTBackgroundEpilepsy drug treatments fail in 25-30% of patients, who then develop drug resistance. Temporal lobe epilepsy is the most prevalent subtype associated with drug resistance. Classical drug discovery is a long and extremely costly process with a high rate of failure in clinical trials. Drug repurposing is a more cost- and time-effective strategy. Hence, the main objective of this study is to propose drug candidates for the treatment of drug-resistant temporal lobe epilepsy (DR-TLE) through drug repurposing based on transcriptomic profiling.MethodsTotal RNA-sequencing (RNA-Seq) was performed on 45 formalin-fixed paraffin-embedded (FFPE) hippocampi of DR-TLE patients and 36 FFPE hippocampi of post-mortem biobank donors. RNA-Seq was carried out in an Illumina NovaSeq 6000 platform in 100bp paired-end. Drug repurposing based on transcriptomic analysis top candidates was performed against these databases: Pandrugs2, PharmOmics, DGIdb, ToppGene, L1000CDS2and Connectivity Map.ResultsWe found 887 genes differentially expressed between DR-TLE patients and post-mortem controls. We observed 74 potential drug candidates in at least two independent databases. Of these, we selected only the 11 which can cross the blood-brain barrier: cobimetinib, panobinostat, melphalan, rucaparib, alectinib, ponatinib, danazol, carboplatin, vandetanib, erlotinib, and gefitinib. After analyzing their safety and efficacy profile based on previous publications, we provide a list of the top 5 candidates.ConclusionsWe therefore propose erlotinib, danazol, rucaparib, ponatinib, and panobinostat as potential therapies for DR-TLE based on differential RNA-Seq profiling.
The Impact of Instructions on Individual Prioritization Strategies in a Dual-Task Paradigm for Listening Effort
Authors: Kestens Katrien , Lepla Emma , Vandoorne Flore , Ceuleers Dorien , Van Goylen Louise , Keppler Hannah 
Published: June 2024

ABSTRACTIntroductionThis study examined the impact of instructions on the prioritization strategy employed by individuals during a listening effort dual-task paradigm.MethodsThe dual-task paradigm consisted of a primary speech understanding task in different listening conditions and a secondary visual memory task, both performed separately (baseline) and simultaneously (dual-task). Twenty-three normal-hearing participants (mean age: 36.8 years; 14 females) were directed to prioritize the primary speech understanding task in the dual-task condition, whereas another twenty-three (matched for age, gender, and education level) received no specific instructions regarding task priority. Both groups performed the dual-task paradigm twice (mean interval: 14.8 days). Patterns of dual-task interference were assessed by plotting the dual-task effect of the primary and secondary task against each other. Fisher’s exact tests were used to assess whether there was an association between interference patterns and group (non-prioritizing and prioritizing) across all listening conditions and test sessions.ResultsNo statistically significant association was found between the pattern of dual-task interference and the group to which the participants belong for any of the listening conditions and test sessions. Descriptive analysis revealed no consistent strategy use within individuals across listening conditions and test sessions, suggesting a lack of a uniform approach regardless of the given instructions.ConclusionProviding prioritization instructions was insufficient to ensure that an individual will mainly focus on the primary task and consistently adhere to this strategy across listening conditions and test sessions. These results raised reservations about the current usage of dual-task paradigms for listening effort.
Modulation of Microtubule Dynamics by Monovalent Ions
Authors: Fernandes Simon , Aumeier Charlotte 
Published: June 2024

ABSTRACTThe microtubule cytoskeleton is a dynamic network essential for many cellular processes, influenced by physicochemical factor such as temperature, pH, dimer concentration and ionic environment. In this study, we used in vitro reconstitution assays to examine the effects of four monovalent ions (Na+, K+, Cl-, and Ac-) on microtubule dynamics, uncovering distinct effects for each ion. Na+was found to increase microtubule dynamicity by raising catastrophe frequency, polymerization and depolymerization speeds, ultimately reducing microtubule lifetime by 80 %. Conversely, Ac boosts microtubule nucleation and stabilizes microtubules by increasing rescue frequency and preventing breakages, resulting in longer microtubules with extended lifetimes. Cl-appeared to potentiate the effects of Na+, while K+had minimal impact on microtubule dynamic parameters. These findings demonstrate that Na+and Ac-have opposing effects on microtubule dynamics, with Na+destabilizing and Ac-stabilizing the microtubule structure. This ionic impact is mainly through modulation of tubulin-tubulin interactions rather than affecting the hydrolysis rate. In conclusion, ion identity plays a crucial role in modulating microtubule dynamics. Understanding the ionic environment is essential for microtubule-related research, as it significantly influences microtubule behavior, stability, and interactions with other proteins.SIGNIFICANCE STATEMENTThe microtubule cytoskeleton is vital for cellular processes and influenced by temperature, pH, dimer concentration, and ionic environment. Understanding how these physicochemical factors regulate microtubule polymerization is crucial for elucidating microtubule dynamics and stability. Our in vitro reconstitution assays reveal that Na+and Ac-ions have opposing effects on microtubule dynamics. Na+increases dynamicity by raising catastrophe frequency and reducing lifetime by 80 %, while Ac-enhances nucleation and stability, resulting in longer microtubules. Cl-potentiates the effects of Na+, and K+has minimal impact. Our findings highlight that ion identity crucially modulates microtubule dynamics, significantly influencing stability and interactions.
CCDC32 stabilizes clathrin-coated pits and drives their invagination
Authors: Yang Ziyan , Yang Changsong , Xu Peiliu , Han Lu , Li Yueping , Peng Linyuan , Wei Xiangying , Schmid Sandra L. , Svitkina Tatyana , Chen Zhiming 
Published: June 2024

AbstractClathrin-mediated endocytosis (CME) is essential for maintaining cellular homeostasis. Previous studies have reported more than 50 CME accessory proteins; however, the mechanism driving the invagination of clathrin-coated pits (CCPs) remains elusive. Quantitative live cell imaging reveals that CCDC32, a poorly characterized endocytic accessory protein, regulates CCP stabilization and is required for efficient CCP invagination. CCDC32 interacts with the α-appendage domain (AD) of AP2 via its coiled-coil domain to exert this function. Furthermore, we showed that the clinically observed nonsense mutations in CCDC32, which result in the development of cardio-facio-neuro-developmental syndrome (CFNDS), inhibit CME by abolishing CCDC32-AP2 interactions. Overall, our data demonstrates the function and molecular mechanism of a novel endocytic accessory protein, CCDC32, in CME regulation.Significance StatementClathrin-mediated endocytosis (CME) happens via the initiation, stabilization, and invagination of clathrin-coated pits (CCPs). In this study, we used a combination of quantitative live cell imaging, ultrastructure electron microscopy and biochemical experiments to show that CCDC32, a poorly studied and functional ambiguous protein, acts as an important endocytic accessory protein that regulates CCP stabilization and invagination. Specifically, CCDC32 exerts this function via its interactions with AP2, and the coiled-coil domain of CCDC32 and the α-appendage domain (AD) of AP2 are essential in mediating CCDC32-AP2 interactions. Importantly, we demonstrate that clinically observed loss-of-function mutations in CCDC32 lose AP2 interaction capacity and inhibit CME, resulting in the development of cardio-facio-neuro-developmental syndrome (CFNDS).
Is US farm sector debt underestimated? Evidence from equipment lending
Authors: Briggeman Brian , Byers Luke , Ifft Jennifer , Kuhns Ryan , Miller Noah , Yu Jisang 
Published: June 2024

PurposeThe growth of lending from nontraditional lenders may pose challenges for official US Department of Agriculture (USDA) farm sector debt estimates, but it is difficult to find data to assess official estimates. The purpose of this study is to examine whether debt provided by nontraditional lenders is accurately accounted for in official estimates.Design/methodology/approachWe compare traditional and nontraditional lending data from farm equipment lien collateral values and the USDA Agricultural Resource Management Survey (ARMS). After analyzing trends in equipment lending implied by farm equipment lien data and ARMS, we estimate whether changes in farm equipment lien values predict changes in equipment debt reported in ARMS and whether lender type influences that relationship.FindingsWe find that credit provided by nontraditional lenders is likely underreported in ARMS. Our econometric model shows that equipment debt volumes for nontraditional lenders are consistently lower than traditional loan volumes in ARMS across a variety of model specifications. We also find that an increase in lien values for nontraditional lenders is less likely to predict an increase in ARMS equipment debt volumes than an increase for traditional lenders.Practical implicationsOfficial farm sector debt estimates may not fully account for nontraditional lenders.Originality/valueThis study demonstrates how the growth of nontraditional lending poses challenges for estimating US farm sector debt. We evaluate farm sector debt estimates and advance knowledge of the role of nontraditional lenders in farm equipment credit provision. The farm equipment lien dataset provides a rich source of novel data for research on local and national equipment debt and investment.
Chilean national policy councils: a heterogeneous type of public organization for governance
Authors: Cevallos Rodrigo A. 
Published: June 2024

PurposeThis article aims to explore, characterize and discuss the notion of the National Policy Councils (NPCs) as public organizations for governance in Chilean public management.Design/methodology/approachA subset of active NPCs of the Chilean public management was identified, characterized and analyzed following previously used schemes.FindingsThe results showcase heterogeneity in the design of NPCs, with differences among several key features. Proposed explanations for this heterogeneity are an evolutionary approach and the fuzziness of the concept. These notions are relevant outcomes for the academic discussion and the practical implementation of NPCs.Originality/valueThe novelty of this research is based on assessing NPCs of different policy domains in an intra-country analysis by comparing their main features and configuration to determine if NPCs could be understood and treated as a unique type of public organization.
Green Lean Six Sigma in the food industry: a systematic literature review
Authors: McDermott Olivia , Moloney Cian , Noonan John , Rosa Angelo 
Published: June 2024

PurposeThe current paper aims to discuss the implementation of Green Lean Six Sigma (GLSS) in the food industry to improve sustainable practices. The focus is more specifically on dairy processors to ascertain the current state of the literature and aid future research direction.Design/methodology/approachUtilising a systematic literature review (SLR), the paper addresses various terms and different written forms in the literature. The study characterises the current deployment of GLSS in the food industry and explains the reported benefits of this approach.FindingsGLSS, a concept that has yet to be fully explored in the food industry, as in other sectors, holds significant potential to enhance the food industry’s sustainability practices. The dairy sector, a subsector of the food industry known for its high greenhouse gas emissions, is a prime candidate for the application of GLSS. In instances where it has been applied, GLSS has demonstrated its effectiveness in improving sustainability, reducing waste, lowering greenhouse gas emissions and minimising water usage. However, the specific tools used and the model for GLSS implementation are areas that require further study, as they have the potential to revolutionise food industry operations and reduce their environmental impacts.Practical implicationsBenchmarking of this research by the food industry sector and by academics can aid understanding of the practical application of GLSS tools and aid implementation of these practices to evolve the dairy processing sector in the next decade as sustainability champions in the sector.Originality/valueThis study extensively analyses GLSS in the food industry, with a particular focus on dairy processors.
Revisiting mindsets for careers research: what we know, what we don’t and why we should care
Authors: Keating Lauren A. 
Published: June 2024

PurposeBy virtue of affecting how people perceive and respond to challenges, mindsets are conceivably consequential for, though relatively under-studied, in careers research. This paper thereby highlights the importance of bridging the mindsets and careers literature.Design/methodology/approachI review literature describing the ontology of mindsets, before reviewing what is currently known about mindsets in the careers domain. This is followed by theorizing about mindset dynamics in pressing career challenges, and providing avenues for future research.FindingsI outline some of the major implications of fixed and growth mindsets as they (potentially) relate to career-relevant cognitions, emotions and behaviors. I also formulate an agenda for future research with regard to what we study, who we study and how we, as scholars, can study mindsets in careers.Originality/valueThis review enables looking back on the state of mindsets and careers research. The theorizing herein about mindset dynamics in careers also invites scholars to look toward exciting research possibilities about how mindsets can shape careers in ways not yet realized.