bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroadaptive Events In Adult Offspring Induced By Perinatal Chronic Stimulation Of The Renin‐Angiotensin System (RAS)
Authors: Macchione Ana Fabiola , Dadam Florencia , Antunes‐Rodrigues Jose , Vivas Laura 
Published: November 2023

Studies of last decades give evidence of the important role of the perinatal environment in the developing systems being able to result in permanent changes of the physiology and the metabolism of the new individual. Evidences from our and other laboratories indicate that mechanisms and circuits involved in the hydrosaline balance may be vulnerable to perinatal programming effects. This hydroelectrolytic‐programming may be given by intrauterine and/or postnatal environment alterations.In this work, the programming model utilized was the chronic stimulation of RAS given by the partial aortic ligation (PAL) in dams before the matting and along the gestation and lactation. Water and sodium intake patterns and neuronal activity (Fos‐ir, Fos‐immunostaining) were investigated in adult offspring subject to a sodium depletion made with Furosemide (40mg/kg, sc) and low sodium diet [F/LSD]. Maternal fluid intake, plasma electrolyte levels and plasma renin activity (PRA) were also studied at weaning in mothers and female offspring. The perinatal programming groups (PP) were: i) PAL/hypertonic sodium solution/water [PAL]; ii) sham surgery/hypertonic sodium solution/water [Sh‐Na] and iii) only water [Sh‐W]. The PP started one week before mating and finished at weaning.PAL‐dams showed an increased PRA levels and water and total fluid intakes, and a diminished in osmolality levels without being altered their natremia levels. The two last results probably were a consequence of the dipsogenic effect of the PAL model. In contrast, PAL‐pups showed an increase in natremia and osmolality levels. Possibly, this plasma osmolyte accumulation in PAL pups may be origin by renal immaturity that leads to a deficient excretory function unable of eliminated the excess of circulating sodium.A decrease in water and sodium intake was observed in adult PAL‐offspring subject to F/LSD. This behaviour was accompanied by an increase in the number of Fos‐ir cells in the dorsal raphe nucleus. Because this nucleus is part of a circuit that tonically inhibits fluid intake, it is possible to assume that the decreased fluid intake in PAL‐offspring may be due to a desensitization of this nucleus, preventing the normal triggering of the fluid ingestion response induced by F/LSD. These data shown neuroadaptive events, probably such as a consequence of long‐term perinatal programming processes that affect reception of signals and activity of brain circuits involved in hydrosaline homeostasis and in fluid intake regulation.Support or Funding InformationThis work was supported by ANPCyT, CONICET, MinCyT and SECyT.
Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) Quantitative Proteomic Analysis Identifies Potential Therapeutic Targets of Berberine for Experimental Colitis
Authors: Li Yanhong , Bian Zhaoxiang 
Published: November 2023

Background and AimsBerberine has been proved to have beneficial effects against ulcerative colitis (UC) with unknown targets. The changes of protein profile in pathogenesis‐targeted colon have been proposed as an ideal material to uncover the therapeutic targets of drug for UC.MethodsThe colons were collected from water control mice, three cycles of DSS‐induced colitis mice, and berberine‐treated colitis mice. Isobaric tags for relative and absolute quantitation (iTRAQ)‐based quantification proteomics was conducted to investigate the colon proteins whose abundance were changed.ResultsA total of 167 proteins that exhibited changes in abundance between berberine‐treated and DSS‐treated control mice were identified, including mast cell protease 2 (Mcpt2), eosinophil cationic protein 1 (Ear1), calcium‐activated chloride channel regulator 1 (Clca1), apolipoprotein A‐I (Apoa1), 60S ribosomal protein L19 (Rpl19) and 60S ribosomal protein L18 (Rpl18). Importantly, the observed changes in the abundance of these six proteins in the two groups of animals were supported in another quantitative evaluation of the individual colon using a multiple reaction monitor (MRM) assay.ConclusionsThus, the quantitative target analysis demonstrated Mcpt2, Ear1, Clca1, Apoa1, Rpl19 and Rpl18 are potential therapeutic target of berberine for UC.Support or Funding InformationThis work was supported by grant from the Municipal Science and Technology Program of Shenzhen (Basic Research Fund [2015]1342).
NMR Mapping of the Allosteric Network in the Oncogenic Protein Kinase A Chimera Dnajb1‐PRKACA
Authors: Karamafrooz Adak N , Li Geoffrey N , Simon Sanford M , Taylor Susan S , Veglia Gianluigi N 
Published: November 2023

Protein Kinase A (PKA) is a well‐known member of the serine‐threonine protein kinase superfamily. PKA signaling is involved in the control of a wide variety of cellular processes from metabolism to ion channel activation, cell growth and differentiation, gene expression and apoptosis. Recent genomic studies have identified a chimeric fusion of the catalytic subunit of cAMP‐dependent Protein Kinase A (PKA) with the DNAJB1 chaperone on the N‐terminus (DNAJB1‐PRKACA) as a single driver for the progression of Fibrolamellar Hepatocellular Carcinoma (FL‐HCC). Previous X‐ray studies show a compact structure of the chimeric kinase, with the DNAJB1 moiety tucked onto the core of the enzyme. In contrast, our NMR studies show that the enzyme's core and the DNAJB1 appendix move independently and that these conformational dynamics affect the binding of the endogenous inhibitor peptide PKI. Additionally, the conformational dynamics of DNAJB1 also affect the allosteric cooperativity of the enzyme, which is a central property for substrate affinity and catalysis. These structural and dynamic dysfunctions may be correlated to the aberrant cellular function of this kinase and progression of FL‐HCC.Support or Funding InformationNIH
Mechanical untying of the smallest knotted protein from different pulling axis using optical tweezers.
Authors: Rivera Maira , Bustamante Andrés , Hao Yuxin , Maillard Rodrigo A , Baez Mauricio 
Published: November 2023

Knotted polypeptides constitute a group of proteins whose backbone chain entangles in the folded state. The folding mechanism of knotted protein is complex, involving multiple intermediate states. Therefore, it is difficult to determine experimentally the thermodynamic and kinetic barriers associated with threading the polypeptide chain. To address this problem, we used optical tweezers to study the folding mechanism of MJ0366, the smallest protein containing a shallow trefoil knot. Specifically, we mechanically manipulated the knotted protein from different pulling directions to either tighten the knot upon unfolding or to untie the protein from different points of its structure. When the knot was tightened in force‐ramp experiments, we observed single unfolding and refolding transitions characterized by unimodal force distributions, and an accompanying change in contour length (Lc = 24 ± 3 nm) consistent with the expected theoretical value. Moreover, in constant‐force experiments, we observed that the protein oscillates between two states, whose frequency of interconversion showed a linear dependence with force. These observations suggest a two‐state folding mechanism when the trefoil knot remains in the polypeptide chain. However, when the knot is untied by keeping the C‐termini free to thread, the protein unfolds in either one or two transitions and at forces higher than those observed when pulling from the N and C termini. Moreover, 50% of the unfolding transitions have a Lc shorter than the expected value, suggesting that the protein can be trapped in a misfolded state during its refolding process. When the knot is untied by keeping both N‐ and C‐termini free to thread, we observed a single unfolding force distribution with the expected Lc for this construct. However, the refolding process could not be characterized because it occurs at forces below the resolution limit (<1 pN). Our results suggest that when the knot remains in the unfolded state, the folding landscape have a smooth and funneled shape. However, when the knotted protein has to overcome the threading process this energy landscape becomes rough.Support or Funding InformationFondecyt 1151274, CONICYT fellowship No 21130254 and CONICYT fellowship No 21150966.
The Structure and Function of VE‐cadherin in Endothelial Cells
Authors: Wary Anita L , Sreedhar Siva 
Published: November 2023

Endothelial cells, cells that line the blood vessels, are responsible for transporting the flow of blood to tissues for the purpose of oxygenating and supplying nutrients. These cells are connected, side‐to‐side, by adherens junctions (AJs). The proteins responsible for keeping AJs together are the adhesion molecules called VE‐cadherins. The York Community High School MSOE Center for BioMolecular Modeling SMART Team used 3‐D modeling and printing technology to examine structure‐function relationships of these proteins. Each VE‐cadherin is composed of five extracellular domains, a transmembrane domain, and a cytoplasmic domain. Each domain is made up of a seven stranded beta barrel fold. One such strand is called the A strand, and this strand, in the EC1 domain, allows for two VE‐cadherins from two adjacent endothelial cells to connect together. This formation of cell‐cell adhesion between the two VE‐cadherins is due to heterophilic interaction. Disruption of VE‐cadherin‐mediated cell‐cell adhesion results in increased permeability of the endothelial cells which can cause edema and hemorrhages. There are several factors that can disrupt this VE‐cadherin‐VE‐cadherin cell adhesion event, such as bacterial infection‐induced sepsis. In the presence of an optimal concentration of calcium and magnesium, however, VE‐cadherin molecules are able to promote a type of paracellular pathway that mediates the passage of hormones, oxygen, and nutrients. VE‐cadherin is an integral protein that functions as an adhesion zipper for endothelial cells; therefore, without these adhesion molecules, the endothelium will not be able to work as a selective barrier.Support or Funding InformationCenter for BioMolecular Modeling, Milwaukee School of Engineering
Insight into Parkinson's Disease from Yeasts: Evidence for sumoylation as a protective factor against alpha‐synuclein toxicity
Authors: Jones Paul , Thomas Rosemary , Ganev Yoan , Roman Alex , Marshall Morgan , Lipkin Galina , Ong Emily , DebBurman Shubhik 
Published: November 2023

Parkinson's disease (PD) is a neurodegenerative disorder linked to the loss of dopaminergic neurons in the midbrain. A key pathological marker of PD is the presence of Lewy bodies, which are mainly composed of misfolded alpha‐synuclein protein. Alpha‐synuclein is a highly post‐translationally modified protein. While the contributions of phosphorylation and nitration of alpha‐synuclein as aids to PD pathology is well studied, less is known about sumoylation, which is proposed to be neuroprotective based on limited studies. The majority of sumoylation takes place on the lysine‐96 and lysine‐102 sites of alpha‐synuclein and it increases the protein's solubility. The goal of this research was to better understand the role of sumoylation in regulating alpha‐synuclein toxicity, and we performed four studies towards it. First, we evaluated the effects of blocking sumoylation on alpha‐synuclein in budding and fission yeast models for PD and found that alpha‐synuclein becomes more aggregated and toxic and localized less at the plasma membrane. Second, we evaluated the effects altering sumoylation pathways by using yeast strains with reduced (ulp1ts) or excessive sumoylation (smt3ts), and found that alpha‐synuclein aggregates more with reduced sumoylation, but becomes less toxic with increased sumoylation. Third, we asked how altering phosphorylation of alpha‐synuclein would alter sumoylation's protective role and found that blocking phosphorylation reduced alpha‐synuclein toxicity. Finally, we evaluated whether blocking sumoylation on familial PD mutant versions of alpha‐synuclein would exacerbate its toxicity; preliminary studies suggest that exacerbation for some, but not all mutants. In the future, we will conduct further studies to understand how sumoylation affects other variants and modifications of alpha‐synuclein.Support or Funding InformationNeuroscience Program and Biology Department, Lake Forest College, Lake Forest, IL 60045
Bdellovibrio’sPrey-Independent Growth is Fuelled by Amino Acids as a Carbon Source
Authors: Herencias C , Rivero-Buceta MV , Salgado S , Baquero F , del Campo R , Nogales J , Prieto MA 
Published: November 2023

ABSTRACTIdentifying the nutritional requirements and growth conditions of microorganisms is crucial for determining their applicability in industry and understanding their role in clinical ecology. Predatory bacteria such asBdellovibrio bacteriovorushave emerged as promising tools for combating infections by human bacterial pathogens due to their natural killing features.Bdellovibrio’slifecycle occurs inside prey cells, using the cytoplasm as a source of nutrients and energy. However, this lifecycle supposes a challenge when determining the specific uptake of metabolites from the prey to complete the growth inside cells, a process that has not been completely elucidated. Here, following a model-based approach we illuminate the ability ofBdellovibrio bacteriovorusto replicate DNA, increase biomass, and generate adenosine triphosphate (ATP) in an amino acid-based rich media in the absence of prey, keeping intact its predatory capacity. In this culture, we determined the main carbon sources used and their preference, being glutamate, serine, aspartate, isoleucine, and threonine. This study offers new insights into the role of predatory bacteria in natural environments and establishes the basis for developing newBdellovibrioapplications using appropriate metabolic and physiological methodologies.
Adaptive functions correlate with evoked neurotransmitter release in SYT1-associated neurodevelopmental disorder
Authors: Park Paul Y. , Bleakley Lauren E. , Saraya Nadia , Al-Jawahiri Reem , Eck Josefine , Aloi Marc A. , Melland Holly , Baker Kate , Gordon Sarah L. 
Published: November 2023

AbstractPathogenic missense variants in the essential synaptic vesicle protein synaptotagmin-1 (SYT1) cause a neurodevelopmental disorder that is characterised by motor delay and intellectual disability, hyperkinetic movement disorder, episodic agitation, and visual impairments. SYT1 is the presynaptic calcium sensor that both triggers and drives synchronous neurotransmitter release. We have previously shown that pathogenic variants around the calcium-sensing region of the critical C2B domain decrease synaptic vesicle exocytosis in neurons. Here we show that recently identified variants within the facilitatory C2A domain of the protein (L159R, T196K, E209K, E219Q), as well as additional variants in the C2B domain (M303V, S309P, Y365C, G369D), share this underlying pathogenic mechanism, causing a graded and variant-dependent dominant-negative impairment in exocytosis. We establish that the extent of disruption to exocytosisin vitrocorrelates with neurodevelopmental impacts of this disorder. Specifically, the severity of motor and communication impairments exhibited by individuals harbouring these variants correlates with multiple measures of exocytic impairment. Together, this suggests that there is a genotype-function-phenotype relationship in SYT1-associated neurodevelopmental disorder, centring impaired evoked neurotransmitter release as a common pathogenic driver of this disorder. Moreover, this points toward a direct link between control of neurotransmitter release and development of adaptive functions, and provides a tractable target for therapeutic amelioration.
Cross-Comparison of Gut Metagenomic Profiling Strategies
Authors: Gulyás Gábor , Kakuk Balázs , Dörmő Ákos , Járay Tamás , Prazsák István , Csabai Zsolt , Henkrich Miksa Máté , Boldogkői Zsolt , Tombácz Dóra 
Published: November 2023

ABSTRACTA critical issue in microbiome research is the selection of reliable laboratory and bioinformatics pipelines. In the absence of generally accepted technical benchmarks and evaluation standards, comparing data generated by different studies becomes challenging. In this work, we carried out the most comprehensive study to date on this topic. We encompassed every stage of processing, from DNA extraction to computational assessment. We adopted four procedures for DNA purification, six for library construction, three for sequencing, and five for bioinformatics. Additionally, we used datasets published by others to corroborate our results. We introduced a software tool that distinctively delivers consistent results, irrespective of sample or dataset origins. This study underscores the importance of methodological optimization at the outset of research projects to ensure the reliability of results and their comparability with findings from other studies. Additionally, this study provides an optimized robust pipeline for gut microbiome analysis.
Tuning of granulopoietic signaling byde novodesigned agonists
Authors: Ullrich Timo , Pollmann Christoph , Ritter Malte , Haaf Jérémy , Aghaallaei Narges , Tesakov Ivan , El-Riz Maya , Maksymenko Kateryna , Hatskovska Valeriia , Kandabarau Sergey , Klimiankou Maksim , Lengerke Claudia , Welte Karl , Hernandez-Alvarez Birte , Müller Patrick , Lupas Andrei , Piehler Jacob , Skokowa Julia , ElGamacy Mohammad 
Published: November 2023

AbstractEnhancing cytokine-based therapies by systematically tuning how an agonist associates its receptor is emerging as a powerful new concept in drug discovery. Here, we report the design and characterization of agonists that tune the granulocyte-colony stimulating factor receptor (G-CSFR) activity, which is central for the proliferation and granulocytic differentiation of hematopoietic stem cells. Using design agonists, we study the impact of varying the receptor-binding affinity and dimerization geometry on receptor association, downstream signaling, and cellular response. Hence, we achieved agonists with altered signaling specificities that are hyper-thermostable, can outcompete the native ligand (G-CSF), and bias granulopoietic differentiation over triggering proliferation. Furthermore, the design agonists differentially modulate the kinetics and amplitudes of signal transduction pathways, and gene expression patterns. Unlike G-CSF, they achieve selective activation of gene sets with hematopoietic functions with minimal unwanted effects on immunomodulatory signaling. These findings demonstrate the potential of dissecting the complex G-CSFR signaling, and open up ways for new therapeutic applications for designed cytokines.Graphical abstract
Mandatory annual report filings of private companies – why late or missing?
Authors: Laidroo Laivi , Küttim Merle , Rumma Kirsti , Siimann Paavo , Avarmaa Mari 
Published: November 2023

PurposeThis study explores the causes of delayed mandatory annual report filings of private companies in Estonia.Design/methodology/approachThe authors use an online survey targeting companies that had submitted annual reports for 2017 late (late-filers) or failed to submit these by July 2020 (non-filers). The responses of 492 late-filers and 122 non-filers are analysed with exploratory factor analysis, Mann–Whitney U-Test and logistic regression.FindingsAnnual report filing decisions of both, late-filers and non-filers, are strongly driven by administrative costs attached to the preparation and submission of reports with non-filers perceiving these to be significantly greater. The relevance of other disclosure-related costs and benefits remains similar for both late-filers and non-filers. While proprietary and privacy concerns remain rather unimportant, benefits of timely disclosure, in the form of access to financing and possibilities to continue ordinary business activities, remain important disclosure timing drivers.Practical implicationsPolicy interventions should focus on preventive measures that hinder companies' ordinary business activities in case of non-compliance to reporting deadlines. Monetary sanctions can be used to strengthen the desired behaviour alongside broader clarification of the purpose of mandatory reporting and available exemptions.Originality/valueThe authors propose an empirically testable comprehensive one-period model of disclosure timing decisions of private companies differentiating late-filers and non-filers. The authors address the limitations of previous studies through a survey that allows the authors to draw direct inferences about the trade-offs between different decision drivers and the motivations behind managers' disclosure timing decisions.
Development and validation of the Digital Health Acceptability Questionnaire
Authors: Haydon Helen M , Major Taylor , Kelly Jaimon T , Catapan Soraia de C , Caffery Liam J , Smith Anthony C , Gallegos-Rejas Victor , Thomas Emma E , Banbury Annie , Snoswell Centaine L 
Published: November 2023

Summary: Acceptability (of healthcare services) is an important construct that lacks a consistent definition within research. Addressing this issue, a systematic review led to the Theoretical Framework of Acceptability. In this study, we describe the development (based on the Theoretical Framework of Acceptability) and validation of the Digital Health Acceptability Questionnaire. Nineteen items aligning with the Theoretical Framework of Acceptability were developed. Two versions of the questionnaire measuring telehealth acceptability by telephone ( N = 644) and videoconference appointment ( N = 425), were administered to a nationally representative survey of consumers in Australia. Two exploratory factor analyses (Oblimin rotation) were conducted for each scale (telephone/videoconference). Two-factor solutions (5 items each) were found for both (telephone/videoconference) acceptability questionnaires: (a) attitude toward the service as a means to address healthcare needs and affective attitude and (b) individual capacity and effort to use telehealth. Before rotation, Factor 1 of the telephone scale (α = 0.92) measured 56.18% of the variance and Factor 2 (α = 0.86) measured 14.17%. Factor 1 of the videoconference scale (α = 0.90) measured 56.68% of the variance and Factor 2 (α = 0.85) measured 10.63%. The full10-item acceptability questionnaire showed excellent internal consistency (telephone: α = 0.91 and videoconference: α = 0.92). The 2-dimensional Digital Health Acceptability Questionnaire is a brief survey based on research evidence and validated in a large Australian sample.