bluuebunny/crossref_metadata_2025_split huggingface dataset:
Parkinson’s disease patients display a DNA damage signature in blood that is predictive of disease progression
Authors: Sproviero Daisy , Payán-Gómez César , Milanese Chiara , Sun Shixiang , Gyenis Akos , Delia Domenico , Lashley Tammaryn , Vijg Jan , Hoeijmakers Jan H.J. , Mastroberardino Pier G. 
Published: March 2024

AbstractAging is the main risk factor for Parkinson’s disease (PD), yet our understanding of how age-related mechanisms contribute to PD pathophysiology remains limited. We conducted a longitudinal analysis of the Parkinson’s Progression Markers Initiative cohort to investigate the involvement of DNA damage in PD. Our findings revealed that PD patients exhibit disrupted DNA repair pathways and biased suppression of longer transcripts, indicating the presence of age-related, transcription-stalling DNA damage. Notably, this DNA damage signature was only detected in patients with more severe motor symptom progression over a three-year period, suggesting its potential as a predictor of disease severity. We further validated this signature in independent PD cohorts and confirmed increased signs of DNA damage in dopamine neurons of the substantia nigra pars compacta through histopathological analysis of PD brains. Our study sheds light on an aging-related mechanism in PD pathogenesis and identifies markers of disease progression providing a readily applicable diagnostic platform to prognosticate disease progression.One Sentence SummaryParkinson’s disease patients display a DNA damage signature in blood that is predictive of disease progression.
Evaluation of intracochlear pressure and distribution during fluid application in cochlea models and human petrous bone
Authors: Kim R. , Riemann C. , Kilgué A. , Schleyer S. , Pfeiffer CJ , Scholtz LU. , Schürmann M. , Todt I. 
Published: March 2024

AbstractIntroductionThe important factor during the application of substances for an inner ear therapy is the atraumatic execution as well as a homogeneous distribution over the cochlea in a reasonable time frame. Since faster delivery can be obtained with higher pressure but, higher pressure will lead to traumatic execution, there are certain constrains for the delivery process. Because of this, an optimized procedure for intracochlear delivery is needed, which enables reduction of intracochlear pressure during perfusion in reasonable time.Hence, the aim of this study was to compare different techniques of substance application and their effects on intracochlear pressure in different models.Material and MethodsIntracochlear pressure was measured by fiberoptic pressure sensors in artificial cochlea models and in a human temporal bone. The pressure sensor was introduced into the inner ear models via an additional channel or the lateral arcade of the temporal bone.In all models the substance was applied by means of an inner ear catheter (MED-EL, Innsbruck, Austria) via the round window with methylene blue with or without second access to the cochlea (helicotrema/oval window).ResultsThe application of substances showed significant differences in intracochlear pressure and substance distribution at the same velocity between the models with and without second access.ConclusionUsing a second-hole technique leads to a faster homogeneous distribution, as well as a lower intracochlear pressure, which can be assumed to be an essential factor for hearing preservation during substance application.
Intron-loss in Kinetoplastea correlates with a non-functional EJC and loss of NMD factors
Authors: Gabiatti Bernardo Papini , Freire Eden Ribeiro , Odenwald Johanna , Holetz Fabiola , Carrington Mark , Kramer Susanne , Zoltner Martin 
Published: March 2024

ABSTRACTIn metazoans, mRNA quality is tightly monitored from transcription to translation. A key role lies with the exon junction complex (EJC) that is placed upstream of the exon-exon junction after splicing. The EJC inner core is composed of Magoh, Y14, eIF4AIII and BTZ and the outer core of proteins involved in mRNA splicing (CWC22), export (Yra1), translation (PYM) and non-sense mediated decay (NMD, UPF1/2/3). The protozoan parasiteTrypanosoma bruceiencodes only two genes with introns, but all mRNAs are processed bytrans-splicing. The presence of the three core EJC proteins and a potential BTZ homologue (Rbp25) in trypanosomes has been suggested as an adaptation of the EJC function to marktrans-spliced mRNAs.We analysed trypanosome EJC components and noticed major differences between eIF4AIII and Magoh/Y14: (i) whilst eIF4AIII is essential, knocking out both Magoh and Y14 elicits only a mild growth phenotype and does not affect processing, export or stability of the twocis-spliced mRNAs (ii) eIF4AIII localization is mostly nucleolar, with a minor proportion in the nucleoplasm and cytoplasm, while Magoh and Y14 are nucleolar and nucleoplasmic but excluded from the cytoplasm (iii) eIF4AIII associates with nucleolar proteins (including NOM1/Sgd1p) and the splicing factor CWC22, but not with Y14 or Magoh, while Magoh and Y14 associate with each other, but not with eIF4AIII, CWC22 or the nucleolar proteins. Our data argue against the presence of a functional EJC in trypanosomes, but rather indicate that eIF4AIII adopted non-EJC related, essential functions, while Magoh and Y14 became redundant.Trypanosomes also possess homologues to the NMD proteins UPF1 and UPF2. We found that depletion of UPF1 causes only a minor reduction in growth and detailed phylogenetic analyses show several independent losses of UPF1 and UPF2, as well as total loss of UPF3 in the Kinetoplastida group. The data indicate that UPF1-dependent NMD is not essential in trypanosomes consistent with the observation that the cells tolerate the presence of mRNAs with allele-specific, endogenous PTCs (premature termination codons).Altogether, our comprehensive analyses of conserved components provide no evidence for a canonical EJC or NMD pathway in (almost) intron-less trypanosomatids.
Neuronal activation affects the organization and protein composition of the nuclear speckles
Authors: Szczepankiewicz Andrzej Antoni , Parobczak Kamil , Zaręba-Kozioł Monika , Ruszczycki Błażej , Bijata Monika , Trzaskoma Paweł , Hajnowski Grzegorz , Holm-Kaczmarek Dagmara , Włodarczyk Jakub , Wilczyński Grzegorz Marek , Rędowicz Maria Jolanta , Magalska Adriana 
Published: March 2024

AbstractNuclear speckles, also known as interchromatin granule clusters (IGCs), are subnuclear domains highly enriched in proteins involved in transcription and mRNA metabolism and, until recently, have been regarded primarily as their storage and modification hubs. However, several recent studies on non-neuronal cell types indicate that nuclear speckles may directly contribute to gene expression as some of the active genes have been shown to associate with these structures.Neuronal activity is one of the key transcriptional regulators and may lead to the rearrangement of some nuclear bodies. Notably, the impact of neuronal activation on IGC/nuclear speckles organization and function remains unexplored. To address this research gap, we examined whether and how neuronal stimulation affects the organization of these bodies in granular neurons from the rat hippocampal formation. Our findings demonstrate that neuronal stimulation induces morphological and proteomic remodelling of the nuclear speckles under bothin vitroandin vivoconditions. Importantly, these changes are not associated with cellular stress or cell death but are dependent on transcription and splicing.
The lipid droplet protein DHRS3 is a regulator of melanoma cell state
Authors: Johns Eleanor , Ma Yilun , Louphrasitthipol Pakavarin , Peralta Christopher , Hunter Miranda V. , Raymond Jeremy H. , Molina Henrik , Goding Colin R. , White Richard M. 
Published: March 2024

SummaryLipid droplets are fat storage organelles composed of a protein envelope and lipid rich core. Regulation of this protein envelope underlies differential lipid droplet formation and function. In melanoma, lipid droplet formation has been linked to tumor progression and metastasis, but it is unknown whether lipid droplet proteins play a role. To address this, we performed proteomic analysis of the lipid droplet envelope in melanoma. We found that lipid droplet proteins were differentially enriched in distinct melanoma states; from melanocytic to undifferentiated. DHRS3, which converts all-trans-retinal to all-trans-retinol, is upregulated in the MITFLO/undifferentiated/neural crest-like melanoma cell state and reduced in the MITFHI/melanocytic state. Increased DHRS3 expression is sufficient to drive MITFHI/melanocytic cells to a more undifferentiated/invasive state. These changes are due to retinoic acid mediated regulation of melanocytic genes. Our data demonstrate that melanoma cell state can be regulated by expression of lipid droplet proteins which affect downstream retinoid signaling.
The Effects of Acute Coordinative vs. Acute Endurance Exercise on the Cortisol Concentration
Authors: Budde Henning , Wegner Mirko , Ahrens Christiane , Velasques Bruna , Ribeiro Pedro , Machado Sergio , Gronwald Thomas , Amatriain-Fernández Sandra , Schaffarczyk Marcelle , Mueller-Alcazar Anett 
Published: March 2024

ABSTRACTBackgroundPhysical exercise interventions can cause neuroendocrine activation, which in turn increases salivary cortisol concentrations. Until now there have been no studies comparing endurance and coordinative exercise.ObjectiveThe purpose of this study was to examine the effects of these different interventions with an intraindividual comparison.Methods61 students between 18 and 30 years of age were included and first completed a coordinative exercise and one week later an endurance exercise of the same intensity and length which was self-set on the first day, with a maximum heart rate of 64 - 76% (HRmax) over a period of 15 min. To measure changes in the hypothalamic-pituitary-adrenal axis (HPA-axis) activity, saliva samples were collected before (t1) and after exercise (t2 and t3).ResultsBaseline values of cortisol (t0) did not differ significantly between coordinative and endurance exercise, t(55) = .233,p= .816. Post hoc tests revealed that the cortisol values of the second coordinative vs. endurance time point,t(55) = 2.097,p= .040,d= .741, and third coordinative vs. endurance time point,t(55) = 3.004,p= .004,d= .735, differed significantly with large effect sizes.ConclusionThe results show for the first time that coordinative exercise produced a higher cortisol release than endurance exercise of the same intensity and duration. Interventions such as coordinative exercise require higher cognitive components resulting in stronger cortisol release than endurance exercise. Thus, the type of acute exercise is a psychophysiological factor in determining the neuroendocrine stress response.Key pointsCortisol is an important catabolic hormone when it comes to overtraining or burnout in an athlete. Our results show for the first time that acute coordinative exercise produces a higher cortisol release than endurance exercise of the same intensity and duration.
Does behavior mediate the effect of weather on SARS-CoV-2 transmission? Evidence from cell-phone data
Authors: Grover Elise N. , Buchwald Andrea G. , Ghosh Debashis , Carlton Elizabeth J. 
Published: March 2024

AbstractBackgroundThere is growing evidence that weather alters SARS-CoV-2 transmission, but it remains unclear what drives the phenomenon. One prevailing hypothesis is that people spend more time indoors in cooler weather, leading to increased spread of SARS-CoV-2 related to time spent in confined spaces and close contact with others. However, the evidence in support of that hypothesis is limited and, at times, conflicting.ObjectivesWe aim to evaluate the extent to which weather impacts COVID-19 via time spent away-from-home in indoor spaces, as compared to a direct effect of weather on COVID-19 hospitalization, independent of mobility.MethodsWe use a mediation framework, and combine daily weather, COVID-19 hospital surveillance, cellphone-based mobility data and building footprints to estimate the relationship between daily indoor and outdoor weather conditions, mobility, and COVID-19 hospitalizations. We quantify the direct health impacts of weather on COVID-19 hospitalizations and the indirect effects of weather via time spent indoors away-from-home on COVID-19 hospitalizations within five Colorado counties between March 4th2020 and January 31st2021.ResultsWe found evidence that changes in 12-day lagged hospital admissions were primarily via the direct effects of weather conditions, rather than via indirect effects by which weather changes time spent indoors away-from-home. Sensitivity analyses evaluating time at home as a mediator were consistent with these conclusions.DiscussionOur findings do not support the hypothesis that weather impacted SARS-CoV-2 transmission via changes in mobility patterns during the first year of the pandemic. Rather, weather appears to have impacted SARS-CoV-2 transmission primarily via mechanisms other than human movement. We recommend further analysis of this phenomenon to determine whether these findings generalize to current SARS-CoV-2 transmission dynamics and other seasonal respiratory pathogens.
Optimal Pair Matching Combined with Machine Learning Predicts that Omega-3 Fatty Acid Supplementation Markedly Reduces the Risk of Myocardial Infarction in African Americans
Authors: Sun Shudong , Hara Aki , Johnstone Laurel , Hallmark Brian , Lu Eric , Watkins Joseph C. , Thomson Cynthia A. , Schembre Susan M. , Sergeant Susan , Umans Jason , Yao Guang , Zhang Hao Helen , Chilton Floyd H. 
Published: March 2024

AbstractConflicting results from clinical trials have contributed to a lack of consensus about cardioprotective effects of omega-3 (n-3) highly unsaturated fatty acids (HUFA). Although the VITAL trial did not demonstrate an overall benefit of n-3 HUFA supplementation on composite cardiovascular disease (CVD) and cancer outcomes, the substantial enrollment of African Americans (AfAm) afforded a unique opportunity for a post-hoc analysis of racial differences in the supplementation response. We employed propensity score matching to address potential covariate imbalances between AfAm and European American (EuAm) participants in VITAL (N=3,766 participants). Using Kaplan-Meier curves and two machine learning methodologies, we found that n-3 HUFA supplementation was significantly associated with a reduced risk of myocardial infarction (MI) exclusively in the AfAm subgroup, as evidenced by an odds ratio of 0.17 (95% CI [0.048, 0.59]). These findings indicate a potential cardioprotective benefit of n-3 supplementation in AfAm, specifically in reducing MI risks; a risk not identified in EuAm. Further investigation of n-3 HUFA effects through a hypothesis-driven randomized clinical trial among AfAm is needed to test a race-specific response that may inform recommendations for n-3 HUFA supplementation.
FilamentID reveals the composition and function of metabolic enzyme polymers during gametogenesis
Authors: Hugener Jannik , Xu Jingwei , Wettstein Rahel , Ioannidi Lydia , Velikov Daniel , Wollweber Florian , Henggeler Adrian , Matos Joao , Pilhofer Martin 
Published: March 2024

SUMMARYGamete formation and subsequent offspring development often involve extended phases of suspended cellular development or even dormancy. How cells adapt to recover and resume growth remains poorly understood. Here, we visualized budding yeast cells undergoing meiosis by cryo-electron tomography (cryoET) and discovered elaborate filamentous assemblies decorating the nucleus, cytoplasm, and mitochondria. To determine filament composition, we developed a “Filament IDentification” (FilamentID) workflow that combines multiscale cryoET/cryo-electron microscopy (cryoEM) analyses of gently lysed cells. FilamentID identified the mitochondrial filaments as the conserved aldehyde dehydrogenase Ald4ALDH2and the nucleoplasmic/cytoplasmic filaments being composed of acetyl-CoA synthetase Acs1ACSS2. The near-native high-resolution structures revealed the mechanism underlying polymerization and enabled us to perturb filament formation. Acs1 polymerization facilitates the recovery of chronologically aged spores, and more generally, the cell cycle re-entry of starved cells. FilamentID is broadly applicable to characterize filaments of unknown identity in diverse cellular contexts.HIGHLIGHTSFilamentID: a multiscale imaging workflow to characterize cellular filaments of unknown compositionThe conserved aldehyde dehydrogenase Ald4ALDH2polymerizes into filament arrays within meiotic mitochondriaThe conserved acetyl-CoA synthetase Acs1ACSS2forms filament arrays in the nucleus and the cytoplasmMetabolites mediate Acs1 polymerization to store Acs1 in an inactive state in gametes and starved cellsAcs1 filament formation is required for efficient return to growth from starvation stress
A Systems Biology Analysis of Chronic Lymphocytic Leukemia
Authors: Pozzati Giulia , Zhou Jinrui , Hazan Hananel , Klement Giannoula Lakka , Siegelmann Hava T. , Rietman Edward A. , Tuszynski Jack A. 
Published: March 2024

AbstractWhole-genome sequencing has revealed that TP53, NOTCH1, ATM, SF3B1, BIRC3, ABL, NXF1, BCR, ZAP70 are often mutated in CLL, but not consistently across all CLL patients. This paper employs a statistical thermo-dynamics approach in combination with the systems biology of the CLL protein-protein interaction networks to identify the most significant participant proteins in the cancerous transformation. Betti number (a topology of complexity) estimates highlight a protein hierarchy, primarily in the Wnt pathway known for aberrant CLL activation. These individually identified proteins suggest a network-targeted strategy over single-target drug development. The findings advocate for a multi-target inhibition approach, limited to several key proteins to minimize side effects, thereby providing a foundation for designing therapies. This study emphasizes a shift towards a comprehensive, multi-scale analysis to enhance personalized treatment strategies for CLL, which could be experimentally validated using siRNA or small molecule inhibitors. The result is not just the identification of these proteins but their rank-order, offering a potent signal amplification in the context of the 20,000 proteins produced by the human body, thus providing a strategic basis for therapeutic intervention in CLL, underscoring the necessity for a more holistic, cellular, chromosomal, and genome-wide study to develop tailored treatments for CLL patients.Author SummaryChronic Lymphocytic Leukemia (CLL) is a unique and slowly progressing cancer affecting white blood cells, and research on CLL has highlighted the inconsistency of gene mutations across patients. Using a novel approach that merges statistical thermodynamics and systems biology, this research examines the CLL protein-protein interaction networks to pinpoint proteins integral to the onset of the disease. Betti number (a topology of complexity) estimates, which measure the importance of individual proteins when removed from the network, helped identify numerous potential therapeutic targets, notably within the Wnt signaling pathway, a pathway implicated in various cellular processes and known for its defective expression in CLL. The finding advocates for a multi-target inhibition approach, focusing on several key proteins to minimize side effects, thereby laying a foundation for designing more effective therapies for CLL. This paper emphasizes the potential benefits of a comprehensive study, spanning cellular to genome-wide scales, to design personalized treatments for CLL patients.
Proteome analysis provides insights into sex differences inHolothuria Scabra
Authors: Cheng Chuhang , Wu FeiFei , Xu Yizhi , Ren Chunhua , Chen Ting , Li Shella , Shen Peihong , Jiang Fajun 
Published: March 2024

AbstractSex-determining mechanism is still ambiguous for sea cucumberHolothuria scabrawhich only manifests gonochorism in gonad. In this study, proteomic analysis was employed to delineate sex-related proteins and genes in gonads ofH. scabra, subsequently validated through Quantitative real-time polymerase chain reaction (qRT-PCR). A total of 5,313 proteins were identified via proteome sequencing. Among these, 817 proteins exhibited expression in both the ovary and testis, with 445 proteins displaying up-regulation and 372 proteins showing down-regulation. Furthermore, 136 and 69 proteins were identified as ovary-specific and testis-specific Differentially Abundant Proteins (DAPs), respectively. For the validation of 75 DAP coding genes, 9 genes were considered to be reliable. Notably, 25 ovary-bias proteins enriched in ribosome pathway strongly indicated the crucial role of ribosome in ovary. And 5S/18S rRNA ratio inH. Scabramay have potencial to establish a nondestructive method to distinguish sexes unambiguously. This study serves to furnish novel evidence pertaining to sex differences inH. scabra.
Intron-lariat spliceosomes convert lariats to true circles: implications for intron transposition
Authors: Ares Manuel , Igel Haller , Katzman Sol , Donohue John P. 
Published: March 2024

AbstractRare, full length circular intron RNAs distinct from lariats have been reported in several species, but their biogenesis is not understood. We envision and test a hypothesis for their formation usingSaccharomyces cerevisiae, documenting full length and novel processed circular RNAs from multiple introns. Evidence implicates a previously undescribed catalytic activity of the intron-lariat spliceosome (ILS) in which the 3’-OH of the lariat tail (with optional trimming and adenylation by the nuclear 3’ processing machinery) attacks the branch, joining the intron 3’ end to the 5’ splice site in a 3’-5’ linked circle. Human U2 and U12 spliceosomes produce analogous full length and processed circles. Post-splicing catalytic activity of the spliceosome may promote intron transposition during eukaryotic genome evolution.
The magnitude of exercise-induced hypoalgesia can be improved and correlated with endogenous pain modulation following 4 weeks of treadmill running
Authors: Xu Zi-Han , An Nan , Xu Shuang , Wang Ru-Yun , Li Yue 
Published: March 2024

AbstractObjectiveWe aimed to investigate changes in pain perception, acute exercise-induced hypoalgesia (EIH), and endogenous pain modulation responses following 4-week treadmill running exercises of different intensities in healthy individuals.MethodsFifty-six healthy individuals included in this study. All participants were randomly assigned to three experimental groups (TRH, high intensity running, TRM, moderate intensity running and TRL, low intensity running). All participants performed 12 treadmill running sessions within 4 weeks at different intensities based on their target heart rate (THR). A running assessment was administered one week before running sessions. The magnitudes of EIH, conditioned pain modulation (CPM), and temporal summation (TS) responses following regular treadmill running were assessed. Pressure pain thresholds (PPT) or mechanical pain thresholds (MPT) were also determined following regular treadmill running.ResultsTreadmill running only induced acute EIH responses, with all pre-running PPT and MPT remaining unaltered. The acute EIH following each running sessions and CPM responses were also significantly improved in both the TRM and TRL groups, with TS score decreased in the TRM group.ConclusionsA 4-week low to moderate intensity treadmill running improved acute EIH response by enhancing endogenous pain modulation in healthy individuals. Future studies should consider sex, behavior, and physiological factors to provide a comprehensive understanding of the changes in EIH following regular exercises.