bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tau phosphorylation impedes functionality of protective tau envelopes
Authors: Siahaan Valerie , Weissova Romana , Lanska Eva , Karhanova Adela , Dostal Vojtech , Henriot Veronique , Janke Carsten , Libusova Lenka , Braun Marcus , Balastik Martin , Lansky Zdenek 
Published: March 2024

AbstractTau, an axonal microtubule-associated protein, is a critical regulator of microtubule function and stability. Tau interaction with microtubules is regulated by tau phosphorylation. Tau hyperphosphorylation is implicated in microtubule destabilization related to neurodegenerative disorders. How tau phosphorylation leads to microtubule destabilization is however unknown. Recently, it was shown that tau molecules on microtubules cooperatively assemble into cohesive layers termed envelopes. Tau envelopes protect microtubules against degradation by microtubule-severing enzymes, suggesting a functional link between envelopes and microtubule stability. Here we show that tau phosphorylation has deleterious effects on the microtubule-protective function of tau envelopes. Using reconstitution and live-cell experiments, we found that tau phosphorylation destabilizes tau envelopes and decreases their integrity, leading to reduced microtubule protection against microtubule-severing enzymes. Our data suggest that a perturbation of microtubule homeostasis linked to tau hyperphosphorylation in neurodegeneration, could be explained by the disassembly and impaired functionality of the tau envelopes.
Development of a ddPCR approach for the absolute quantification of soil microorganisms involved in atmospheric CO2fixation
Authors: Le Geay Marie , Mayers Kyle , Küttim Martin , Lauga Béatrice , Jassey Vincent E.J. 
Published: March 2024

AbstractCarbon fixing microorganisms (CFMs) play a crucial role in soil carbon (C) cycling contributing to carbon uptake and sequestration through various metabolic pathways. Despite their significance, quantification of the absolute abundance of CFMs in soils remains elusive. This study employed a digital droplet PCR (ddPCR) approach to quantify the abundance of key and emerging CFM pathways in fen and bog across different depths (0-15 cm). Targeting total prokaryotes (16S rRNAgene), oxygenic phototrophs (23S rRNAgene), aerobic anoxygenic phototrophic bacteria (AAnPB,pufMgene), and chemoautotrophs (cbbLgene), we optimized ddPCR conditions to achieve absolute quantification of these genes. Overall, our results revealed that oxygenic phototrophs were the most abundant CFMs, constituting 12% of total prokaryotic abundance, followed by chemoautotrophs (10%) and AAnPBs (9%). Fen exhibited higher gene concentrations than bog. Depth variations were also observed, differing between fen and bog for all genes. Our findings highlight the abundance of oxygenic phototrophs and chemoautotrophs in peatlands, challenging previous estimations that relied solely on oxygenic phototrophs for microbial CO2fixation assessments. Incorporating absolute gene quantification is crucial for a comprehensive understanding of microbial contributions to soil processes, shedding light on the intricate mechanisms of soil functioning in peatlands.
Differential warming at crown scale impact walnut primary growth onset and secondary growth rate
Authors: Dusart Nicolas , Moulia Bruno , Saudreau Marc , Serre Christophe , Charrier Guillaume , Hartmann Félix P. 
Published: March 2024

AbstractTrees are exposed to significant spatio-temporal thermal variations, which can induce intracrown discrepancies in the onset and dynamics of primary and secondary growth. In recent decades, an increase in late winter and early spring temperatures has been observed, potentially accelerating bud break, cambial activation and their potential coordination. Intracrown temperature heterogeneities could lead to asymmetric tree shapes unless there is a compensatory mechanism at the crown level.An original warming experiment was conducted on young Juglans regia trees in a greenhouse. From February to August, the average temperature difference during the day between warmed and control parts was 4°C. The warming treatment advanced the date of budbreak significantly, by up to 14 days. Warming did not alter secondary growth resumption but increased growth rates, leading to higher xylem cell production (twice as many) and to an increase in radial increment (+80% compared to control). Meristems resumptions were asynchronous without coordination in response to temperature. Buds on warmed branches began to swell two weeks prior to cambial division, which was one week earlier than on control branches. A difference in carbon and water remobilisation at the end of bud ecodormancy was noted under warming. Overall, our results argue for a lack of compensatory mechanisms at the crown scale, which may lead to significant changes in tree architecture in response to intra-crown temperature heterogeneities.Highlight: When tree are submitted to asymmetrical warming, it leads to early budbreak and enhanced cambial activity for warmed branches
The role of Kinesin-1 in neuronal dense core vesicle transport and lifespan regulation inC. elegans
Authors: Gavrilova Anna , Boström Astrid , Korabel Nickolay , Fedotov Sergei , Poulin Gino B. , Allan Victoria J. 
Published: March 2024

AbstractFast axonal transport is crucial for neuronal function and is driven by kinesins and cytoplasmic dynein. We investigated the role of the kinesin-1 motor complex in dense core vesicle (DCV) transport inC. elegans, using mutants in kinesin light chains (klc-1 andklc-2) and the kinesin motor subunit (unc-116) expressing anida-1::gfptransgene that labels DCVs in the ALA neuron. A reduced-functionunc-116(rf)mutation greatly impaired DCV transport in both directions. Aklc-2(rf)reduced-function mutation decreased DCV velocity in both directions and reduced the frequency of body bends during swimming. In contrast, theklc-1(-)null mutation had no effect on anterograde transport or swimming ability, but surprisingly it increased the speed of retrograde DCV transport. We also determined lifespan, finding thatklc-1(-)orklc-2(rf)single mutants were wild-type whereas theunc-116(rf),ida-1::gfpandunc-116(rf);ida-1::gfpstrains were short-lived. Strikingly, theida-1::gfptransgenic synergistically interact with eitherklcmutant to extend lifespan compared to wild-type and parental strains. Our findings suggest that kinesin-1 not only influences anterograde and retrograde DCV transport but also plays a role in regulating lifespan.
Establishing a national linked database for fetal alcohol spectrum disorder (FASD) in the UK: multi-method public and professional involvement to determine acceptability and feasibility
Authors: Harding Sarah K , Samways Beverley , Dillon Amy , Butcher Sandra , Boyd Andy , Mukherjee Raja , Cook Penny A. , McQuire Cheryl 
Published: March 2024

ABSTRACTObjectiveto conduct public and professional involvement work to establish stakeholder views on the feasibility, acceptability, key purposes, and design of a national linked longitudinal research database for fetal alcohol spectrum disorder (FASD) in the UK. MethodsFollowing stakeholder-mapping, we identified contributors through collaborator networks and online searches. We consulted with stakeholders using online workshops (one for adults with FASD [and their supporters] N=5; one for caregivers of people with FASD N=7), 1:1/small-team video calls/email communication twith clinicians, policymakers, data-governance experts, third-sector representatives, and researchers [N=35]), and one hybrid clinical workshop (N=17). Discussions covered data availability, benefits, challenges, and design preferences for a national pseudonymised linked database for FASD. We derived key themes from the notes and recordings collected across all involvement activities.ResultsOur tailored, multi-method approach generated high levels of stakeholder engagement. Stakeholders expressed strong support for a pseudonymised national linked database for FASD. Key anticipated benefits were the potential for: increased awareness and understanding of FASD, leading to better support; new insights into clinical profiles, leading to greater diagnostic efficiency; facilitating international collaboration; and increased knowledge of the long-term impacts of FASD on health, social care, education, economic and criminal justice outcomes. Policymakers noted clear alignment with contemporary FASD and digital transformation priorities. Given the rich data infrastructure established in the UK, stakeholders expressed that a national linked FASD database could be world-leading. Common stakeholder concerns were around privacy and data-sharing and the importance of retaining space for clinical judgement alongside insights gained from quantitative analyses.ConclusionsMulti-method and multidisciplinary public and professional involvement activities demonstrated the feasibility and acceptability of establishing a national linked database for FASD in the UK. Perceived benefits and challenges varied by stakeholder group, demonstrating that flexible, diverse, embedded stakeholder collaboration will be essential as we establish this database.
Sentence production and sentence repetition in autistic adolescents and young adults: Linguistic sensitivity to finiteness-marking
Authors: Girolamo Teresa , Ghali Samantha , Larson Caroline 
Published: March 2024

AbstractPurposeDespite the clinical utility of sentence production and sentence repetition to identify language impairment in autism, little is known about the extent to which these tasks are sensitive to potential dialectal variation. One promising method is strategic scoring (Oetting et al., 2016), which has good clinical utility for identifying language impairment in nonautistic school-age children across dialects of English. This report applies strategic scoring to analyze sentence repetition and sentence production in autistic adolescents and adults.MethodThirty-one diverse autistic adolescents and adults with language impairment (ALI;n=15) and without language impairment (ASD;n=16) completed the Formulated Sentences and Recalling Sentences subtests of the Clinical Evaluation of Language Fundamentals-5thEd (Wiig et al., 2013). Descriptive analyses and regression evaluated effects of scoring condition, group, and scoring condition by group on outcomes, as well as group differences in finiteness-marking across utterances and morphosyntactic structures.ResultsStrategic and unmodified item-level scores were essentially constant on both subtests and significantly lower in the ALI than the ASD group. Only group predicted item-level scores. Group differences were limited to: percent grammatical utterances on Formulated Sentences and percent production of overt structures combined on Sentence Repetition (ALI < ASD).DiscussionFindings support the feasibility of strategic scoring for sentence production and sentence repetition to identify language impairment and indicate that potential dialectal variation in finiteness-marking did not confound outcomes in this sample. To better understand the clinical utility of strategic scoring, replication with a larger sample varying in age and comparisons with dialect-sensitive measures are needed.
Very Long-term Longitudinal Follow-up of Heart Failure on the REMADHE Trial
Authors: Bocchi Edimar Alcides , Guimaraes Guilherme Veiga , Romero Cristhian Espinoza , Ayub Ferreira Silvia Moreira , Biselli Bruno , Chizzola Paulo Roberto , Munhoz Robinson Tadeu , Fukushima Julia Tizue , das Dores Cruz Fátima 
Published: March 2024

AbstractBackgroundHeart failure (HF) is associated with frequent hospitalization and worse prognosis. Prognosis factors and survival in very long-term follow-up have not been reported in HF. HF disease management programs(DMP) results are contradictory. DMP efficacy in very long-term follow-up is unknown. We studied the very long-term follow-up of up to 23.6 years and prognostic factors of HF in 412 patients under GDMT included in the REMADHE trial.MethodsThe REMADHE trial was a prospective, single-center, randomized trial comparing DMP versus usual care(C). The first patient was randomized on October 5, 1999. The primary outcome of this extended REMADHE was all-cause mortality.ResultsThe all-cause mortality rate was 88.3%. HF was the first cause of death followed by death at home. Mortality was higher in the first 6-year follow-up. The predictive variables in multivariate analysis associated with mortality were age ≥52 years (P=0.015), Chagas etiology (P=0.010), LVEF <45% (P=0.008), use of digoxin (P=0.002), functional class IV (P=0.01), increase in urea (P=0.03), and reduction of lymphocytes (P=0.005). In very long-term follow-up, DMP did not affect mortality in patients under GDMT. HF as a cause of death was more frequent in the C group. Chagas disease, LVEF <45%, and renal function were associated with different modes of death.ConclusionDMP was not effective in reducing very-long term mortality; however, the causes of death had changed. Our findings that age, LVEF, Chagas’ disease, functional class, renal function, lymphocytes, and digoxin use were associated with poor prognosis could influence future strategies to improve HF management.
In vivo Assembly of Bacterial Partition Condensates on Circular Supercoiled and Linear DNA
Authors: Sekkouri Alaoui Hicham , Quèbre Valentin , Delimi Linda , Rech Jérôme , Debaugny-Diaz Roxanne , Labourdette Delphine , Campos Manuel , Cornet François , Walter Jean-Charles , Bouet Jean-Yves 
Published: March 2024

SummaryIn bacteria, faithful DNA segregation of chromosomes and plasmids is mainly mediated by ParABS systems. These systems, consisting of a ParA ATPase, a DNA binding ParB CTPase, and centromere sitesparS, orchestrate the separation of newly replicated DNA copies and their intracellular positioning. Accurate segregation relies on the assembly of a high-molecular-weight complex, comprising a few hundreds of ParB dimers nucleated fromparSsites. This complex assembles in a multi-step process and exhibits dynamic liquid-droplet properties. Despite various proposed models, the complete mechanism for partition complex assembly remains elusive. This study investigates the impact of DNA supercoiling on ParB DNA binding profilesin vivo, using the ParABS system of the plasmid F. We found that variations in DNA supercoiling does not significantly affect any steps in the assembly of the partition complex. Furthermore, physical modeling, leveraging ChIP-seq data from linear plasmids F, suggests that ParB sliding is restricted to approximately 2-Kbp fromparS, highlighting the necessity for additional mechanisms beyond ParB sliding over DNA for concentrating ParB into condensates nucleated atparS. Lastly, explicit simulations of a polymer coated with bound ParB suggest a dominant role for ParB-ParB interactions in DNA compaction within ParB condensates.
Stable and Oscillatory Hypoxia Differentially Regulate Invasibility of Breast Cancer Associated Fibroblasts
Authors: Du Wenqiang , Novin Ashkan , Liu Yamin , Afzal Junaid , Liu Shaofei , Suhail Yasir , Kshitiz  
Published: March 2024

AbstractAs local regions in the tumor outstrip their oxygen supply, hypoxia can develop, affecting not only the cancer cells, but also other cells in the microenvironment, including cancer associated fibroblasts (CAFs). Hypoxia is also not necessarily stable over time, and can fluctuate or oscillate. Hypoxia Inducible Factor-1 is the master regulator of cellular response to hypoxia, and can also exhibit oscillations in its activity. To understand how stable, and fluctuating hypoxia influence breast CAFs, we measured changes in gene expression in CAFs in normoxia, hypoxia, and oscillatory hypoxia, as well as measured change in their capacity to resist, or assist breast cancer invasion. We show that hypoxia has a profound effect on breast CAFs causing activation of key pathways associated with fibroblast activation, but reduce myofibroblast activation and traction force generation. We also found that oscillatory hypoxia, while expectedly resulted in a “sub-hypoxic” response in gene expression, it resulted in specific activation of pathways associated with actin polymerization and actomyosin maturation. Using traction force microscopy, and a nanopatterned stromal invasion assay, we show that oscillatory hypoxia increases contractile force generation vs stable hypoxia, and increases heterogeneity in force generation response, while also additively enhancing invasibility of CAFs to MDA-MB-231 invasion. Our data show that stable and unstable hypoxia can regulate many mechnobiological characteristics of CAFs, and can contribute to transformation of CAFs to assist cancer dissemination and onset of metastasis.
CPT1A Mediates Radiation Sensitivity in Colorectal Cancer
Authors: Chen Zhenhui , Yu Lu , Zheng Zhihao , Wang Xusheng , Guo Qiqing , Chen Yuchuan , Zhang Yaowei , Zhang Yuqin , Xiao Jianbiao , Chen Keli , Fan Hongying , Ding Yi 
Published: March 2024

AbstractThe prevalence and mortality rates of colorectal cancer (CRC) are increasing worldwide. Radiation resistance hinders radiotherapy, a standard treatment for advanced CRC, leading to local recurrence and metastasis. Elucidating the molecular mechanisms underlying radioresistance in CRC is critical to enhance therapeutic efficacy and patient outcomes. Bioinformatic analysis and tumour tissue examination were conducted to investigate theCPT1AmRNA and protein levels in CRC and their correlation with radiotherapy efficacy. Furthermore, lentiviral overexpression and CRISPR/Cas9 lentiviral vectors, along within vitroandin vivoradiation experiments, were used to explore the effect of CPT1A on radiosensitivity. Additionally, transcriptomic sequencing, molecular biology experiments, and bioinformatic analyses were employed to elucidate the molecular mechanisms by which CPT1A regulates radiosensitivity. CPT1A was significantly downregulated in CRC and negatively correlated with responsiveness to neoadjuvant radiotherapy. Functional studies suggested that CPT1A mediates radiosensitivity, influencing reactive oxygen species (ROS) scavenging and DNA damage response. Transcriptomic and molecular analyses highlighted the involvement of the peroxisomal pathway. Mechanistic exploration revealed that CPT1A downregulates the FOXM1-SOD1/SOD2/CAT axis, moderating cellular ROS levels after irradiation and enhancing radiosensitivity. CPT1A downregulation contributes to radioresistance in CRC by augmenting the FOXM1-mediated antioxidant response. Thus, CPT1A is a potential biomarker of radiosensitivity and a novel target for overcoming radioresistance, offering a future direction to enhance CRC radiotherapy.
Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by suppressing super-enhancer-driven oncogenic transcription
Authors: Cigrang Max , Obid Julian , Nogaret Maguelone , Seno Léane , Ye Tao , Davidson Guillaume , Catez Philippe , Berico Pietro , Capelli Clara , Marechal Clara , Zachayus Amélie , Elly Clémence , Li Tsai-Kun , Compe Emmanuel , Avilés Pablo , Davidson Irwin , Egly Jean-Marc , Cuevas Carmen , Coin Frédéric 
Published: March 2024

AbstractThe dynamic cellular transitions exhibited by skin cutaneous melanoma (SKCM) cells present a significant challenge to current therapeutic approaches, emphasizing the critical need for innovative treatments. Lurbinectedin, a marine-derived compound belonging to the ecteinascidin family, has recently gained approval for the treatment of metastatic small-cell lung cancer (SCLC). In this study, we demonstrate the efficacy of lurbinectedin against SKCM cells, irrespective of their driver mutations or phenotypic states. Additionally, we have developed two novel derivatives of lurbinectedin, termed ecubectedin and PM54, both of which exhibit potent cytotoxic effects on SKCM cells. Moreover, these analogs demonstrate robust anti-tumor activity in melanoma xenograft models, including those resistant to current therapies, leading to prolonged animal survival. Mechanistically, our investigation reveals that these novel synthetic ecteinascidins markedly suppress oncogenic super-enhancer (SE)-mediated gene expression in SKCM cells through a multifaceted mechanism. They bind to and inhibit the activity of promoters of lineage-specific master transcription factors, as well as promoters of genes encoding ubiquitous transcription factors/coactivators, which are highly enriched at oncogenic SEs. These mechanisms likely synergize to disrupt the expression of cancer-promoting genes. Overall, our findings highlight the potential of synthetic ecteinascidins as promising therapeutics for cancers characterized by diverse transcriptional landscapes, particularly in cases where conventional therapeutic options have failed due to the heterogeneity of malignant cell population
MftG is crucial for ethanol metabolism of mycobacteria by linking mycofactocin oxidation to respiration
Authors: Graça Ana Patrícia , Nikitushkin Vadim , Ellerhorst Mark , Vilhena Cláudia , Klassert Tilman E. , Starick Andreas , Siemers Malte , Al-Jammal Walid K. , Vilotijevic Ivan , Slevogt Hortense , Papenfort Kai , Lackner Gerald 
Published: March 2024

AbstractMycofactocin is a redox cofactor essential for the alcohol metabolism of mycobacteria.. While the biosynthesis of mycofactocin is well established, the genemftG, which encodes an oxidoreductase of the glucose-methanol-choline superfamily, remained functionally uncharacterized. Here, we show that MftG enzymes are almost exclusively found in genomes containing mycofactocin biosynthetic genes and are present in 75% of organisms harboring these genes. Gene deletion experiments inMycolicibacterium smegmatisdemonstrated a growth defect of the ΔmftGmutant on ethanol as a carbon source, accompanied by an arrest of cell division reminiscent of mild starvation. Investigation of carbon and cofactor metabolism implied a defect in mycofactocin reoxidation. Cell-free enzyme assays and respirometry using isolated cell membranes indicated that MftG acts as a mycofactocin dehydrogenase shuttling electrons toward the respiratory chain. Transcriptomics studies also indicated remodeling of redox metabolism to compensate for a shortage of redox equivalents. In conclusion, this work closes an important knowledge gap concerning the mycofactocin system and adds a new pathway to the intricate web of redox reactions governing the metabolism of mycobacteria.