bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipid Aging Clocks as predictive and prognostic biomarker in cancer and inflammaging
Authors: Unfried Maximilian , Cazenave-Gassiot Amaury , Bischof Evelyne , Holcapek Michal , Scheibye-Knudsen Morten , Wenk Markus R. , Gruber Jan , Kennedy Brian K. 
Published: September 2024

AbstractLipids are a heterogenous class of molecules involved in signaling, cell structure and energy storage. Lipid metabolism is dysregulated in aging and aging-related diseases such as cancer, metabolic disorders, and neurodegeneration. In this study, we developed a biological age predictor – a Lipid Aging Clock - based on human serum lipidome data of pancreatic ductal adenocarcinoma (PDAC) patients, that has a Pearson correlation coefficient of 0.81 to chronological age with a median absolute error of 4.5 years. This shows that it is possible to build aging clocks measuring aging from pathological cohorts.We find that LipidAgeAcceleration is increased in both PDAC and pancreatitis, indicating that these pancreatic conditions accelerate aging or that individuals with age acceleration or more likely to acquire them (or both). Furthermore, the lipid age clock is predictive of PDAC survival, where positive accelerated Lipid Age is associated with an 86% higher mortality risk. Among the lipid species associated with LipidAgeAcceleration, Ceramides, Sphingomyelins and Glycerophosphocholines, have statistically significant hazard ratios, and directly impact increased mortality. Pathway analysis of lipid species selected by the lipid clock further identifies age-dependent dysregulation of specific lipid pathways, including Sphingolipid, Glycerolipid, Glycerophospholipid metabolism, and steroid biosynthesis. Sphingolipid metabolism is significantly dysregulated in both aging and PDAC, connecting aging dynamics and cancer mortality. Moreover, sphingolipids are involved in inflammatory processes, and therefore the lipid aging clock could be, at least in part, reflecting inflammaging and is likely influenced by age-related alterations to the immune system. In summary, our work shows that lipid alterations are a robust biological age predictor with utility in cancer and aging research, as well as in predicting disease-associated outcomes.
A Machine Learning Approach to Predict Cognitive Decline in Alzheimer’s Disease Clinical Trials
Authors: Nallapu Bhargav T. , Petersen Kellen K. , Qian Tianchen , Demirsoy Idris , Ghanbarian Elham , Davatzikos Christos , Lipton Richard B. , Ezzati Ali ,   Alzheimer’s Disease Neuroimaging Initiative
Published: September 2024

AbstractBackgroundOf persons randomized to the placebo arm of Alzheimer’s Disease (AD) treatment trials, 40% do not show cognitive decline over 80 weeks of follow-up. Identifying and excluding these individuals from both arms of randomized clinical trials (RCTs) of AD has the potential to increase power to detect treatment effects.ObjectivesWe aimed to develop machine learning-based predictive models to identify persons unlikely to show decline on placebo treatment over 80 weeks.MethodWe used the data from 1072 patients with mild dementia and biomarker evidence of amyloid burden from the placebo arm of EXPEDITION3 trial. Participants were identified as those who demonstrated Clinically Meaningful Cognitive Decline (CMCD, change in ADAS-Cog≥3) or Cognitive Stable (CS, change in ADAS-Cog<3) at final visit of the trial (week 80). Machine learning-based classifiers were trained to classify participants into CMCD vs. CS groups using combinations of demographics, neuropsychological tests (NP) and biomarkers, including APOE4 genotype and volumetric MRI. The results were developed in 70% of the EXPEDITION3 placebo sample (EXPtrain) using 5-fold cross-validation. Trained models were then used to classify the participants in an internal validation sample (EXPvalid)and an external matched sample from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) study.ResultParticipants selected from the EXPEDITION3 trial were on average 72.7(±7.7) years old, 59% were female. CMCD was observed in 55.8% of participants of EXPEDITION3 at final visit. In the independent validation sample within the EXPEDITION3 data, all the models showed high sensitivity and modest specificity. Positive predictive values (PPVs) of models were at least 11% higher than base prevalence of CMCD observed at the end of the trial. The subset of matched ADNI participants (ADNIAD) were on average 74.5(±6.4) years old and 46% female. The models that were validated in ADNIADalso showed high sensitivity, modest specificity and PPVs of at least 15% higher than the base prevalence in ADNIAD.ConclusionOur results indicate that predictive models have the potential to improve the design of AD trials through selective inclusion criteria for participants expected to decline and exclusion of those expected to remain stable.
Oxidative stress and PARP activation in the lungs is an early event in COVID-19 pneumonia
Authors: Juhász Péter , Bohus Péter , Sipos Adrienn , Curtin Nicola , Méhes Gábor , Bai Péter 
Published: September 2024

AbstractOxidative stress and poly(ADP-ribosyl)ation (PARylation) leads to tissue damage and inflammation in multiple lung diseases, likely in COVID-19. In a previous study we evidenced PARylation in multiple pulmonary cell types in patients who died of COVID-19, but not in patients who died of non-COVID-19 causes. We extended these observations in this retrospective immunohistochemical study by enlarging and stratifying the study population. We showed that pulmonary PARylation and oxidative stress peaked in the exudative and then decreased in the proliferative phase. Pulmonary oxidative stress and PARylation correlated with the serum markers of liver and kidney damage, oxygen transport, tissue hypoxia, lymphocytopenia, blood clotting and disseminated intravascular coagulation. Most correlations between PARylation and serum chemistry readouts were identified in the exudative phase. PARylation correlated with viral load and with the oxidative stress in the tissues, however, correlation between viral load and oxidative stress was marginal suggesting that oxidative stress and the presence of SARS-CoV-2 can independently induce PARylation. In males the time of hospitalization (time to death) was inversely correlated with pulmonary PARylation. Furthermore, males, died of COVID-19, were ∼15 years younger than females, however, there was no difference in pulmonary oxidative stress and PARylation between genders at death. Taken together, pulmonary PARylation and oxidative stress manifests early, in the exudative phase of COVID-19 and PARylation contributes to worse clinical outcome for males. These results suggest repurposing pharmacological PARP inhibitors for acute COVID-19 to counteract tissue damage.
Advancing Early Warning Systems for Malaria: Progress, Challenges, and Future Directions - A Scoping Review
Authors: Mategula Donnie , Gichuki Judy , Barnes Karen I , Giorgi Emanuele , Terlouw Dianne Jannete 
Published: September 2024

ABSTRACTBackgroundMalaria Early Warning Systems(EWS) are predictive tools that often use climatic and environmental variables to forecast malaria risk and trigger timely interventions. Despite their potential benefits, the development and implementation of malaria EWS face significant challenges and limitations. We reviewed the current evidence on malaria EWS, including their settings, methods, performance, actions, and evaluation.MethodsWe conducted a comprehensive literature search using keywords related to EWS and malaria in various databases and registers. We included primary research and programmatic reports focused on developing and implementing Malaria EWS. We extracted and synthesized data on the characteristics, outcomes, and experiences of Malaria EWS.ResultsAfter reviewing 5,535 records, we identified 30 studies from 16 countries that met our inclusion criteria. The studies varied in their transmission settings, from pre-elimination to high burden, and their purposes, ranging from outbreak detection to resource allocation. The studies employed various statistical and machine-learning models to forecast malaria cases, often incorporating environmental covariates such as rainfall and temperature. The most common mode used is the time series model. The performance of the models was assessed using measures such as the Akaike Information Criterion( AIC), Root Mean Square Error (RMSE), and adjusted R squared(R2). The studies reported actions and responses triggered by EWS predictions, such as vector control, case management, and health education. The lack of standardized criteria and methodologies limited the evaluation of EWS impact.ConclusionsThis review provides a comprehensive overview of the current status of Malaria EWS, highlighting the progress, challenges, and gaps in the field. The review informs and guides policymakers, researchers, and practitioners in enhancing EWS and malaria control strategies. The review also underscores the need for further research on the integration, sustainability, and evaluation of Malaria EWS usage and harmonized methods to ease review.
Population genomics ofMacrophominaspp. reveals cryptic host specialization and evidence for meiotic recombination
Authors: Pennerman K.K. , Goldman P. , Dilla-Ermita C.J. , Ramos G. , Jaime J.H. , Lopez-Hernandez J. , Ramos J. , Aviles M. , Borrero C. , Gomez A.O. , Neal J.M. , Chilvers M. , Ortiz V. , Stukenbrock E.H. , Goldman G.H. , Mengitsu A. , Lopez-Nicora H.D. , Sacher G.O. , Vaghefi N. , Kiss L. , Benz J.P. , Machado A.R. , Seijo T.E. , Peres N.A. , Martin F.N. , Broome J.C. , Ivors K. , Cole G. , Knapp S. , McFarlane D.J. , Mattner S.W. , Gambardella M. , Henry P.M. 
Published: September 2024

AbstractKnowledge of the factors structuring populations of pathogenic fungi is fundamental to disease management efforts and basic biology. High-quality short-read sequence data were obtained for 463Macrophominaspp. isolates collected from 91 host plant species and soil in 23 countries. Analyses revealed high diversity, admixture, and equal mating type ratios suggesting on-going recombination. Although most tested isolates could asymptomatically colonize strawberry, only isolates from a single phylogroup caused disease. In addition to strawberry, evidence for host specialization was discovered for soybean, demonstrating this broad host range pathogen contains phylogroups with cryptic specialization. Geography × isolate genotype associations were weak, suggesting these species were frequently trafficked between regions. Re-analysis using genomic data supported current species boundaries, and new molecular markers were designed to specifically identify each species. Contrary to expectations,M. phaseolinashould be considered a species with both specialist and generalist populations for which meiosis can increase genetic diversity.
Revealing the co-existence of written and spoken language coding neural populations in the left-ventral occipitotemporal cortex
Authors: Wang Shuai , Dubarry Anne-Sophie , Chanoine Valérie , Sein Julien , Anton Jean-Luc , Nazarian Bruno , Mercier Manuel R. , Trébuchon Agnès , Pattamadilok Chotiga 
Published: September 2024

AbstractReading relies on the ability to map written symbols with speech sounds. The left ventral occipitotemporal cortex (left-vOT) plays a crucial role in this process. Through the automatization of the mapping ability, this specific part of the ventral visual pathway (a.k.a., the Visual Word Form Area) progressively becomes specialized in written word recognition. Yet, despite its key role in reading, the area also responds to speech. This observation raises questions about the actual nature of neural representations encoded in the left-vOT and, therefore, the underlying mechanism of the cross-modal responses. Here, we addressed this issue by applying fine-grained analyses of within- and cross-modal repetition suppression effects (RSEs) and Multi-Voxel Pattern Analyses in fMRI and sEEG experiments. Convergent evidence across analysis methods and protocols showed significant RSEs and successful decoding in both within-modal visual and auditory conditions suggesting that subpopulations of neurons within the left-vOT distinctly encode written and spoken language inputs. This functional organization of neural populations enables the area to respond to speech input directly and indirectly, i.e., after speech sounds are converted to orthographic representations. The finding opens further discussions on how the human brain may be prepared and adapted for an acquisition of a complex ability such as reading.Significance StatementLearning to read generates new functional responses in neurons in the left ventral visual pathway. Soon after reading acquisition, these neurons become specialized in processing known scripts, thus leading to the functional designation of the “Visual Word Form Area” (VWFA). However, controversies remain regarding the nature of neural representations encoded in this “reading” region, as its activation to speech is also reported. We investigate the neural mechanism(s) underlying these bimodal responses using within and cross-modal repetition suppression and decoding protocols. fMRI and sEEG experiments provided converging evidence indicating that, despite its specialization in reading, VWFA also contained subpopulations of neurons that encode speech. This functional organization could reveal why neurons at this anatomical location are ideal for reading acquisition.
Identification of M-Sec as a unique cellular regulator of CSF-1 receptor activation
Authors: Abdelnaser Randa A. , Hiyoshi Masateru , Takahashi Naofumi , Eltalkhawy Youssef M. , Mizuno Hidenobu , Kimura Shunsuke , Hase Koji , Ohno Hiroshi , Monde Kazuaki , Ono Akira , Suzu Shinya 
Published: September 2024

ABSTRACTFms, the CSF-1 receptor encoding tyrosine kinase, is essential for tissue macrophage development, and the therapeutic target for many tumors. However, it is not completely understood how Fms activation is regulated. Here, we identify the cellular protein M-Sec as a unique regulator of Fms. In macrophages, Fms forms large aggregates via unknown mechanisms. We found that the inhibition or knockdown of reduced Fms aggregate formation and functional response of macrophages to CSF-1, which was consistent with reduced Fms activation after CSF-1 stimulation. When expressed in 293 cells, M-Sec augmented Fms aggregate formation and CSF-1-induced Fms activation. CSF-1 and M-Sec bind the cellular phosphatidylinositol 4,5-biphosphate (PIP2). The removal of PIP2-binding motif of Fms or M-Sec, or the depletion of cellular PIP2 reduced Fms aggregate formation. Moreover, M-Sec altered cellular distribution of PIP2. Since CSF-1-induced dimerization of Fms is critical for its activation, our findings suggest that M-Sec augments large Fms aggregate formation via PIP2, which brings Fms monomers close to each other and enables the efficient dimerization and activation of Fms in response to CSF-1.
Physical mechanism reveals bacterial slowdown above a critical number of flagella
Authors: Tătulea-Codrean Maria , Lauga Eric 
Published: September 2024

AbstractNumerous studies have explored the link between bacterial swimming and the number of flagella, a distinguishing feature of motile multiflagellated bacteria. We revisit this open question using augmented slender-body theory simulations, in which we resolve the full hydrodynamic interactions within a bundle of helical filaments rotating and translating in synchrony. Unlike previous studies, our model considers the full torque-speed relationship of the bacterial flagellar motor, revealing its significant impact on multiflagellated swimming. Because the viscous load per motor decreases with flagellar number, the bacterial flagellar motor (BFM) transitions from the high-load to the low-load regime at a critical number of filaments, leading to bacterial slowdown as further flagella are added to the bundle. We explain the physical mechanism behind the observed slowdown as an interplay between the load-dependent generation of torque by the motor, and the load-reducing cooperativity between flagella, which consists of both hydrodynamic and non-hydrodynamic components. The theoretically predicted critical number of flagella is remarkably close to the values reported for the model organismEscherichia coli. Our model further predicts that the critical number of flagella increases with viscosity, suggesting that bacteria can enhance their swimming capacity by growing more flagella in more viscous environments, consistent with empirical observations.
Targeted protein degradation in lysosome utilizing naturally produced bifunctional antibodies with high levels of mannose 6-phosphate glycans
Authors: Hedman Andrew C. , Liu Shou , Srnak Jennifer A. , Marcinczyk Riley N. , Do Stephanie , Lyons Linda M. , Kornfeld Stuart , Do Hung , Liu Lin 
Published: September 2024

ABSTRACTNovel antibodies have been created for targeted degradation of extracellular and membrane proteins in the lysosome. The mechanism of degradation of target proteins for these antibodies has involved either chemical conjugation of synthetic mannose 6-phosphate (M6P) or engineered bispecific antibodies. Currently, recombinant antibodies cannot be produced with naturally phosphorylated N-glycans. Here, we report the development of a novel platform technology for producing bifunctional therapeutic antibodies with high levels of M6P-bearing glycans directly from producing cells. The antibodies designated asphosphorylatedN-glycosylated peptidechimericantibodies (PNCA) maintain their affinity for antigens with concurrent high affinity binding to cell surface cation-independent mannose-6-phosphate receptors that facilitate internalization and delivery of antibody/antigen complexes to lysosomes for efficient degradation of both target extracellular soluble and membrane proteins. This PNCA approach provides a simple, scalable, and viable approach for producing naturally phosphorylated bifunctional antibodies from production cell lines for targeted protein degradation in lysosomes.
LPA3: Pharmacodynamic differences between lysophosphatidic acid and oleoyl-methoxy glycerophosphothionate. Biased agonism, two sites
Authors: Solís K. Helivier , Romero-Ávila M. Teresa , Rincón-Heredia Ruth , Martínez-Morales Juan Carlos , García-Sáinz J. Adolfo 
Published: September 2024

AbstractLysophosphatidic acid (LPA) and oleoyl-methoxy glycerophosphothionate (OMPT) increased LPA3phosphorylation; OMPT being considerably more potent than LPA. OMPT was also more potent than LPA to activate ERK 1/2. In contrast, to increase intracellular calcium OMPT was less effective than LPA.LPA-induced LPA3-β-arrestin 2 interaction was fast and robust, whereas that induced by OMPT was only detected at 60 min of incubation. LPA- and OMPT-induced receptor internalization was fast but that of OMPT was more marked. LPA-induced internalization was blocked by Pitstop 2, whereas OMPT-induced receptor internalization was partially inhibited by Pitstop 2 and Filipin and entirely by the combination of both. The data again indicate differences in the actions of these agonists.When LPA-stimulated cells were rechallenged with 1 µM LPA, hardly any response was detected, i.e., a “refractory” state was induced. However, if OMPT was used as the second stimulus, a conspicuous and robust response was observed. These data again suggest the possibility that two binding sites for these agonists might exist in the LPA3receptor, one showing a very high affinity for OMPT and another, likely shared by LPA and OMPT (structural analogs) with lower affinity.One sentence summaryOMPT, oleoyl-methoxy glycerophosphothionate, a biased agonits interacting with an additional binding site in LPA3receptors.
Sustainable practices in last-mile logistics of small Brazilian e-retailers: an analysis using an MCDM approach
Authors: Bonilla Maria Alejandra M. , Da Silva Bruna Simões , Schmitt Max Bogo , Bouzon Marina 
Published: September 2024

PurposeThe objective is to contribute to the development of strategies through the identification of sustainability practices. Thus, the research has a twofold objective: to unveil sustainability practices integrated into last-mile logistics activities by e-commerce retailers, analyze the interrelations among these practices and categorize them based on their significance for small Brazilian e-commerce retailers.Design/methodology/approachA literature mapping was conducted to identify sustainability practices in last-mile activities adopted by e-retailers, leading to the proposal of a meta-model. A total of 67 articles are part of the final sample. Subsequently, the study applied the Decision-Making Trial and Evaluation Laboratory (DEMATEL) multicriteria decision-making technique to structure the research problem through cause-and-effect analysis among practices, aiming to prioritize critical practices.FindingsThe results indicate a strong dependence on economic practices to enable sustainability in last-mile logistics. In the economic dimension of sustainability, operating costs and quality of services are effect variables and achieved the highest relation concerning the other practices.Research limitations/implicationsThe article provides theoretical contributions by addressing two complementary areas of knowledge: Stakeholder Theory and Sustainability, also aligning with Global Reporting Initiative (GRI) guidelines. In practical terms, it stands out for offering valuable insights into the implementation of sustainable strategies by identifying economic, environmental and social practices in last-mile logistics, particularly within the context of small businesses in the e-retail segment.Practical implicationsThe results help e-retailers re-evaluate last-mile logistics processes from a sustainability perspective. This study aims to fill the knowledge gap in the current literature on adopting sustainable practices in small e-commerce retail firms.Social implicationsConsidering that one of the pillars of sustainability is a commitment to social development, this study contributes to understanding the view of small e-retailers on the independent goods delivery workers responsible for the delivery of goods.Originality/valueThe originality of this research lies in identifying economic, social and environmental sustainability practices adopted by e-retailers in last-mile logistics processes. Additionally, the study focuses on the small-scale e-commerce retail segment, an area that has been little explored in the Brazilian context. Lastly, the proposed meta-model contributes to addressing practices from the perspective of Stakeholder Theory and the Sustainability approach.