bluuebunny/crossref_metadata_2025_split huggingface dataset:
MNK inhibitor eFT508 (Tomivosertib) suppresses ectopic activity in human dorsal root ganglion neurons from dermatomes with radicular neuropathic pain
Authors: Li Yan , Uhelski Megan L. , North Robert Y. , Mwirigi Juliet M. , Tatsui Claudio E. , Cata Juan P. , Corrales German , Price Theodore J. , Dougherty Patrick M. 
Published: June 2023

AbstractSpontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in preclinical models and in patients suffering from this largely untreated disease. While many intracellular signaling mechanisms have been examined in preclinical models that drive this spontaneous activity (SA), none of these have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we show that inhibition of mitogen activated protein kinase interacting kinase (MNK) with eFT508 (25 nM) reverses SA in human sensory neurons associated with painful dermatomes. MNK inhibition in spontaneously active nociceptors decreased action potential amplitude and produced alterations in the magnitude of afterhyperpolarizing currents suggesting modification of Na+and K+channel activity downstream of MNK inhibition. The effects of MNK inhibition on SA took minutes to emerge and were reversible over time with eFT508 washout. MNK inhibition with eFT508 led to a profound loss of eIF4E Serine 209 phosphorylation, a specific target of the kinase, within 2 min of drug treatment, consistent with the rapid action of the drug on SA in electrophysiology experiments. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.Conflict of interestTJP is a co-founder of 4E Therapeutics, a company developing MNK inhibitors for neuropathic pain. The other authors declare no conflicts of interest.
AnEnterobacteriaceaebloom in aging animals is restrained by the gut microbiome
Authors: Choi Rebecca , Bodkhe Rahul , Pees Barbara , Kim Dan , Berg Maureen , Monnin David , Cho Juhyun , Narayan Vivek , Deller Ethan , Shapira Michael 
Published: June 2023

AbstractThe gut microbiome plays important roles in host function and health. Core microbiomes have been described for different species, and imbalances in their composition, known as dysbiosis, are associated with pathology. Changes in the gut microbiome and dysbiosis are common in aging, possibly due to multi-tissue deterioration, which includes metabolic shifts, dysregulated immunity, and disrupted epithelial barriers. However, the characteristics of these changes, as reported in different studies, are varied and sometimes conflicting. Using clonal populations ofC. elegansto highlight trends shared among individuals, and employing NextGen sequencing, CFU counts and fluorescent imaging to characterize age-dependent changes in worms raised in different microbial environments, we identified anEnterobacteriaceaebloom as a common denominator in aging animals. Experiments usingEnterobacter hormachei, a representative commensal, suggested that theEnterobacteriaceaebloom was facilitated by a decline in Sma/BMP immune signaling in aging animals and demonstrated its detrimental potential for increasing susceptibility to infection. However, such detrimental effects were context-dependent, mitigated by competition with commensal communities, highlighting the latter as determinants of healthy versus unhealthy aging, depending on their ability to restrain opportunistic pathobionts.
Laterality defect of the heart in non-teleost fish
Authors: Huijskes Myrte M. , Icardo José M. , Coolen Bram F. , Jensen Bjarke 
Published: June 2023

AbstractDextrocardia is a rare congenital malformation in humans in which most of the heart mass is positioned in the right hemithorax rather than on the left. The heart itself may be normal and dextrocardia is sometimes diagnosed during non-related explorations. A few reports have documented atypical positions of the cardiac chambers in farmed teleost fish. Here, we report the casual finding of a left-right mirrored heart ventricle in a 85 cm long spiny dogfish (Squalus acanthias) that was caught in the wild. Macroscopic observations showed an outflow tract originating from the left side of the ventricular mass, rather than from the right. Internal inspection revealed the normal structures, including a looped cavity on the inner curvature of which was a large trabeculation, or the bulboventricular fold. MRI data acquired at 0.7 mm isotropic resolution and subsequent 3D-modeling revealed the atrioventricular canal was to the right of the bulboventricular fold, rather than on the left. The atrium and sinus venosus had the normal midline position and gross shape. Spurred by finding of the left-right mirrored shark ventricle, we revisit our previously published material on farmed Adriatic sturgeon (Acipenser naccarii), a non-teleost bony fish. We found several alevins with inverted (L-loop) hearts, amounting to an approximate incidence of 1-2 %. Additionally, an adult sturgeon measuring 90 cm in length showed abnormal topology of the cardiac chambers, but normal position of the abdominal organs. In conclusion, left-right mirrored hearts, a setting that resembles human dextrocardia, can occur in both farmed and wild non-teleost fish.
Small Interactor of PKD2 (SIP), a novel PKD2-related single-pass transmembrane protein, is required for proteolytic processing and ciliary import ofChlamydomonasPKD2
Authors: Das Poulomi , Mekonnen Betlehem , Alkhofash Rama , Ingle Abha , Workman E. Blair , Feather Alec , Liu Peiwei , Lechtreck Karl F. 
Published: June 2023

AbstractInChlamydomonascilia, the ciliopathy-relevant TRP channel PKD2 is spatially compartmentalized into a distal region, in which PKD2 binds the axoneme and extracellular mastigonemes, and a smaller proximal region, in which PKD2 is more mobile and lacks mastigonemes. Here, we show that the two PKD2 regions are established early during cilia regeneration and increase in length as cilia elongate. In abnormally long cilia, only the distal region elongated whereas both regions adjusted in length during cilia shortening. In dikaryon rescue experiments, tagged PKD2 rapidly entered the proximal region of PKD2-deficient cilia whereas assembly of the distal region was hindered, suggesting that axonemal docking of PKD2 requiresde novociliary assembly. We identified Small Interactor of PKD2 (SIP), a small PKD2-related protein, as a novel component of the PKD2-mastigoneme complex. Insipmutants, stability and proteolytic processing of PKD2 in the cell body were reduced and PKD2-mastigoneme complexes were absent from mutant cilia. Like thepkd2andmst1mutants,sipswims with reduced velocity. Cilia of thepkd2mutant beat with normal frequency and bending pattern but were less efficient in moving cells supporting a passive role of the PKD2-SIP-mastigoneme complexes in increasing the effective surface ofChlamydomonascilia.
Aberrant cortical activity, functional connectivity, and neural assembly architecture after photothrombotic stroke in mice
Authors: Bandet Mischa V. , Winship Ian R. 
Published: June 2023

AbstractDespite substantial recent progress in mapping the trajectory of network plasticity resulting from focal ischemic stroke, there is mixed evidence for changes in neuronal excitability and activity within the peri-infarct cortex of mice. Most of these data have been acquired from anesthetized animals, acute tissue slices, or immunoassays on extracted tissue, and thus may not reflect cortical activity dynamics in the intact cortex of an awake animal. Here,in vivotwo- photon calcium imaging in awake, behaving mice was used to longitudinally track cortical activity, network functional connectivity, and neural assembly architecture for 2 months following photothrombotic stroke targeting the forelimb somatosensory cortex. This model is associated with sensorimotor recovery over the weeks following stroke, allowing us to relate network changes to behavior. Our data revealed spatially restricted but long-lasting alterations in somatosensory neural networks. Specifically, we demonstrate significant and long-lasting disruptions in neural assembly architecture concurrent with a deficit in functional connectivity between individual neurons. Reductions in neuronal spiking in peri-infarct cortex were transient but predictive of impairment in skilled locomotion measured in the tapered beam task. Notably, altered neural networks were highly localized, with assembly architecture and neural connectivity relatively unaltered a distance outside the peri-infarct cortex, even in regions demonstrated to be the site of functional remapping of the forelimb somatosensory representation in anaesthetized preparations. Thus, using longitudinal two photon microscopy in awake animals, these data show a complex spatiotemporal relationship between peri-infarct neuronal network function and behavioral recovery that is more nuanced than functional remapping in response to strong sensory stimulation under anesthesia.
Temporal Changes in The Proanthocyanidins to Anthocyanins Ratio During Dormancy Associate with Bloom Time Variations in Peach
Authors: Das Protiva Rani , Islam Md Tabibul , Liu Jianyang , Liu Zongrang , Dardick Chris , Sherif Sherif M. 
Published: June 2023

AbstractThis study provides a thorough exploration of the mechanisms regulating the onset of flowering in peach trees, a process principally governed by bud-dormancy. We applied untargeted metabolomics combined with a comprehensive series of molecular and biochemical experiments to scrutinize the variations in bloom times among different peach cultivars. The impact of exogenous chemical stimuli, specifically ethephon (ET) and abscisic acid (ABA), on bloom times was also evaluated. Our study revealed that the ET-induced delay in bloom time was associated with higher levels of proanthocyanidin (PA) compared to anthocyanins (ACNs) during endodormancy. Furthermore, fluctuations in the PA/ACNs ratio during dormancy demonstrated a strong correlation with the chill requirements and bloom dates of 12 distinct peach genotypes. The research further uncovers the crucial role of ABA in regulating the biosynthesis of PAs and ACNs during peach tree dormancy. Intriguingly, the exogenous application of ABA during endodormancy resulted in a reduction of PA content, leading to an earlier bloom time. We also observed variations in DAM gene expression between early- and late-blooming cultivars. The late-blooming cultivars exhibited higher transcript levels of DAM genes, elevated PA levels, and lower ABA levels compared to their early-blooming counterparts. Importantly, our study proposes PAs and ACNs as quantitative marker metabolites for endo- and ecodormancy phases. This innovative finding paves the way for developing more accurate chill and heat requirement models, thereby enabling a more precise understanding and projection of the impacts of global climate change on the phenology of tree fruit species.
Enhancing single-cell western blotting sensitivity using diffusive analyte blotting and antibody conjugate amplification
Authors: Long Mariia Alibekova , Benman William , Petrikas Nathan , Bugaj Lukasz J. , Hughes Alex J. 
Published: June 2023

AbstractWhile there are many techniques to achieve highly sensitive, multiplex detection of RNA and DNA from single cells, detecting protein contents often suffers from low limits of detection and throughput. Miniaturized, high-sensitivity western blots on single cells (scWesterns) are attractive since they do not require advanced instrumentation. By physically separating analytes, scWesterns also uniquely mitigate limitations to target protein multiplexing posed by affinity reagent performance. However, a fundamental limitation of scWesterns is their limited sensitivity for detecting low-abundance proteins, which arises from transport barriers posed by the separation gel against detection species. Here we address sensitivity by decoupling the electrophoretic separation medium from the detection medium. We transfer scWestern separations to a nitrocellulose blotting medium with distinct mass transfer advantages over traditional in-gel probing, yielding a 5.9-fold improvement in limit of detection. We next amplify probing of blotted proteins with enzyme-antibody conjugates which are incompatible with traditional in-gel probing to achieve further improvement in the limit of detection to 103molecules, a 520-fold improvement. This enables us to detect 85% and 100% of cells in an EGFP-expressing population using fluorescently tagged and enzyme-conjugated antibodies respectively, compared to 47% of cells using in-gel detection. These results suggest compatibility of nitrocellulose-immobilized scWesterns with a variety of affinity reagents — not previously accessible for in-gel use — for further signal amplification and detection of low abundance targets.
The molecular architecture of the desmosomal outer dense plaque by integrative structural modeling
Authors: Pasani Satwik , Menon Kavya S , Viswanath Shruthi 
Published: June 2023

AbstractDesmosomes mediate cell-cell adhesion and are prevalent in tissues under mechanical stress. However, their detailed structural characterization is not available. Here, we characterized the molecular architecture of the desmosomal outer dense plaque (ODP) using Bayesian integrative structural modelingviathe Integrative Modeling Platform. Starting principally from the structural interpretation of an electron cryo-tomogram, we integrated information from X-ray crystallography, an immuno-electron microscopy study, biochemical assays,in-silicopredictions of transmembrane and disordered regions, homology modeling, and stereochemistry information. The integrative structure was validated by information from imaging, tomography, and biochemical studies that were not used in modeling. The ODP resembles a densely packed cylinder with a PKP layer and a PG layer; the desmosomal cadherins and PKP span these two layers. Our integrative approach allowed us to localize disordered regions, such as N-PKP and PG-C. We refined previous protein-protein interactions between desmosomal proteins and provided possible structural hypotheses for defective cell-cell adhesion in several diseases by mapping disease-related mutations on the structure. Finally, we point to features of the structure that could confer resilience to mechanical stress. Our model provides a basis for generating experimentally verifiable hypotheses on the structure and function of desmosomal proteins in normal and disease states.Significance statementDesmosomes are cell-cell junctions that possess a hyper-adhesive property and are prevalent in tissues under mechanical stress. However, their detailed structural characterization has eluded experimental structural biologists so far. Here, we use an integrative approach that allows us to rigorously combine biochemical, biophysical, and cell biological data at multiple scales in order to determine the molecular architecture of the outer dense plaque region of desmosomes. We validate the structural model by several pieces of information not used to compute it. The model allows us to generate hypotheses on the desmosomal proteins in normal and disease states.
Transcriptional landscape of DTP-DTEP transition reveals DUSP6 as a driver of HER2 inhibitor tolerance via Neuregulin/HER3 axis
Authors: Momeny Majid , Tienhaara Mari , Chakroborty Deepankar , Sharma Mukund , Varjus Roosa , Merisaari Joni , Padzik Artur , Vogt Andreas , Paatero Ilkka , Kurppa Kari J. , Elenius Klaus , Laajala Teemu D. , Westermarck Jukka 
Published: June 2023

AbstractThe mechanisms promoting re-growth of dormant cancer cells under continuous tyrosine kinase inhibitor (TKI) therapy are poorly understood. Here we present transcriptional profiling of HER2+ breast cancer cells treated continuously with HER2 TKI (HER2i) therapy for 9 months. The data reveals specific gene regulatory programs associated with transition from dormant drug tolerant persister cells (DTPs) to proliferating DTEP (drug tolerant expanding persister) cells and eventually long-term resistance. Focusing on yet poorly understood phosphatases as determinants of therapy tolerance, expression of dual-specificity phosphatase DUSP6 was found inhibited in DTPs, but strongly induced upon re-growth of DTEPs. DUSP6 overexpression conferred apoptosis resistance whereas its pharmacological blockade prevented DTEP development under HER2i therapy. The DUSP6-driven HER2i tolerance was mediated by activation of neuregulin-HER3 axis, and consistent with the role of HER3 in widespread therapy tolerance, DUSP6 targeting also synergized with clinically used HER2i combination therapies.In vivo,pharmacological DUSP6 targeting induced synthetic lethal effect with HER2i in independent tumor models, and its genetic targeting reduced tumor growth in orthotopic brain metastasis model. Collectively this work provides first transcriptional landscape of DTP-DTEP transition under TKI therapy, and identify DUSP6 as a novel candidate therapy target to overcome widespread HER3-driven therapy resistance.
An information-theoretic quantification of the content of communication between brain regions
Authors: Celotto Marco , Bím Jan , Tlaie Alejandro , De Feo Vito , Lemke Stefan , Chicharro Daniel , Nili Hamed , Bieler Malte , Hanganu-Opatz Ileana L. , Donner Tobias H. , Brovelli Andrea , Panzeri Stefano 
Published: June 2023

AbstractQuantifying the amount, content and direction of communication between brain regions is key to understanding brain function. Traditional methods to analyze brain activity based on the Wiener-Granger causality principle quantify the overall information propagated by neural activity between simultaneously recorded brain regions, but do not reveal the information flow about specific features of interest (such as sensory stimuli). Here, we develop a new information theoretic measure termed Feature-specific Information Transfer (FIT), quantifying how much information about a specific feature flows between two regions. FIT merges the Wiener-Granger causality principle with information-content specificity. We first derive FIT and prove analytically its key properties. We then illustrate and test them with simulations of neural activity, demonstrating that FIT identifies, within the total information flowing between regions, the information that is transmitted about specific features. We then analyze three neural datasets obtained with different recording methods, magneto- and electro-encephalography, and spiking activity, to demonstrate the ability of FIT to uncover the content and direction of information flow between brain regions beyond what can be discerned with traditional anaytical methods. FIT can improve our understanding of how brain regions communicate by uncovering previously hidden feature-specific information flow.
Client assessments of their audit experiences: the role of experience quality, similarity and client participation
Authors: Sampet Jomjai , Sarapaivanich Naruanard , Ekasingh Erboon , Patterson Paul 
Published: June 2023

PurposeThis study examines how three psychological factors (i.e. perceived experience quality, perceived similarity and client participation) that impact client evaluations of their recent audit experiences influence client satisfaction and trustworthiness, which, in turn, affect advocacy in an small- and medium-sized enterprise (SME) context. Furthermore, the study investigates whether the influence of the three psychological factors on client satisfaction and trustworthiness is contingent on client expertise.Design/methodology/approachThe sample consisted of 744 SME executives from the following four regions: central, northern, eastern and southern Thailand. Data were collected using a survey questionnaire. Confirmatory factor analysis was conducted to ensure the reliability and validity of the scale before structural equation modeling was applied to analyze the data.FindingsThe results showed significant positive effects of the three psychological factors (perceived experience quality, perceived similarity and client participation) on client satisfaction and perceived trustworthiness. The moderating role of client expertise on the relationships is also found. More specifically, client expertise positively moderated the connections between experience quality and satisfaction, experience quality and trustworthiness and client participation and trustworthiness. Conversely, client expertise negatively moderated the similarity–satisfaction and similarity–trustworthiness relationships.Originality/valueThis study contributes to the audit literature by examining the role of psychological factor that impacts client satisfaction and perceived trustworthiness in the SME context. Moreover, the moderating role of client expertise is examined for the first time, providing new insights into the boundary condition of the relationship.
Microfinance's digital transformation for sustainable inclusion
Authors: Fersi Marwa , Boujelbéne Mouna , Arous Feten 
Published: June 2023

PurposeThe purpose of this paper is to evaluate the performance of Microfinance Institutions (MFIs) offering FinTech services. This study contributes to the existing literature on microfinance digitalization, financial inclusion and sustainable development. The study also takes into consideration a behavioral perspective through the efficiency evaluation process of MFIs offering FinTech services.Design/methodology/approachThe following study employs the Stochastic Frontier Analysis approach to estimate the operational and social efficiency scores of the 387 MFIs over the period 2005–2019. Then, it tries to consider factors influencing MFIs' efficiency and assess their effects. Hence, two separate models for operation and social efficiency introducing a set of factors, including FinTech proxies and overconfidence proxies, are tested. The first model for operational efficiency uses a random-effects estimator while the second one for social efficiency uses a fixed-effects estimator.FindingsThe results show that innovative MFIs have weaker averages of operational efficiency than non-innovative ones but higher averages of social efficiency. This was justified by the fact that innovative MFIs are more socially oriented. Further, findings of this study depict that the proxies of FinTech affect negatively the level of operational efficiency of MFIs. They also depict a negative relationship between FinTech proxies and the level of social efficiency. These results hold through robustness tests.Originality/valueThe highlight of this study is that it takes heed of the indirect effect of technological innovation on the efficiency of MFIs. It has been proved that it moderates the impact of managerial overconfidence (manifested by excessive risk-taking, viz., high levels of PAR30, LGR and NIM) on the level of both operational and social efficiencies.