bluuebunny/crossref_metadata_2025_split huggingface dataset:
Right Ex-situ split grafts for adult liver transplantation - A Multicenter Benchmarking Analysis
Authors: Boulanger Natacha , Muller Xavier , Dondero Federica , Golse Nicolas , Goumard Claire , Breton Antoine , Sepulveda Ailton , Allard Marc-Antoine , Savier Eric , Dokmak Safi , Pittau Gabriella , Ciacio Oriana , Salloum Chady , Perdigão Fabiano , Rousseau Géraldine , Lim Chetana , Rossignol Guillaume , Vibert Eric , Sa Cunha Antonio , Mohkam Kayvan , Azoulay Daniel , Adam René , Scatton Olivier , Lesurtel Mickael , Cherqui Daniel , Soubrane Olivier , Mabrut Jean Yves 
Published: June 2024

Objective:
To analyse outcomes after adult right ex-situ split graft liver transplantations (RSLT) and compare with available outcome benchmarks from whole liver transplantation (WLT).

Summary Background Data:
Ex-situ SLT may be a valuable strategy to tackle the increasing graft shortage. Recently established outcome benchmarks in WLT offer a novel reference to perform a comprehensive analysis of results after ex-situ RSLT.

Methods:
This retrospective multicenter cohort study analyzes all consecutive adult SLT performed using right ex-situ split grafts from 01.01.2014 to 01.06.2022. Study endpoints included 1 year graft and recipient survival, overall morbidity expressed by the comprehensive complication index (CCI©) and specific post-LT complications. Results were compared to the published benchmark outcomes in low-risk adult WLT scenarii.

Results:
In 224 adult right ex-situ SLT, 1y recipient and graft survival rates were 96% and 91.5%, within the WLT benchmarks. The 1y overall morbidity was also within the WLT benchmark (41.8 CCI points vs. <42.1). Detailed analysis, revealed cut surface bile leaks (17%, 65.8% Grade IIIa) as a specific complication without a negative impact on graft survival. There was a higher rate of early hepatic artery thrombosis (HAT) after SLT, above the WLT benchmark (4.9% vs. ≤4.1%), with a significant impact on early graft but not patient survival.

Conclusion:
In this multicentric study of right ex-situ split graft LT, we report 1-year overall morbidity and mortality rates within the published benchmarks for low-risk WLT. Cut surface bile leaks and early HAT are specific complications of SLT and should be acknowledged when expanding the use of ex-situ SLT.
Tumor-intrinsic and Cancer-associated Fibroblast Subtypes Independently Predict Outcomes in Pancreatic Cancer
Authors: Lee Jaewon J. , Kearney Joseph F. , Trembath Hannah E. , Hariharan Arthi , LaBella Michelle E. , Kharitonova Elena V. , Chan Priscilla S. , Morrison Ashley B. , Cliff Ashley , Meyers Michael O. , Kim Hong Jin , Rashid Naim U. , Peng Xianlu L. , Yeh Jen Jen 
Published: June 2024

Objective:
To assess the utility of tumor-intrinsic and cancer-associated fibroblast (CAF) subtypes of pancreatic ductal adenocarcinoma (PDAC) in predicting response to neoadjuvant therapy (NAT) and overall survival (OS).

Background:
PDAC remains a deadly disease with limited treatment options, and both the tumor as well as the microenvironment play an important role in pathogenesis. Gene expression–based tumor-intrinsic subtypes (classical and basal-like) have been shown to predict outcomes, but tumor microenvironment subtypes are still evolving.

Methods:
RNA-sequencing was performed on 114 deidentified resected PDAC tumors. Clinical data were collected by retrospective chart review. Single sample classifiers were used to determine classical and basal-like subtypes as well as tumor-permissive permCAF and tumor-restraining restCAF subtypes. Survival was analyzed using the log-rank test.

Results:
Patients who received NAT had an increase in OS, with a median survival of 27.9 months compared with 20.1 months for those who did not receive NAT, but the difference did not reach statistical significance (hazard ratio: 0.64, P=0.076). Either tumor-intrinsic or CAF subtypes alone were associated with OS regardless of NAT or no NAT, and patients with classical or restCAF subtypes had the best outcomes. When evaluated together, patients with the classical-restCAF subtype had the best OS and basal-permCAF the worst OS (P<0.0001). Patients undergoing NAT with the classical-restCAF subtype demonstrated the longest OS compared with the other groups (P=0.00041).

Conclusions:
CAF subtypes have an additive effect over tumor-intrinsic subtypes in predicting survival with or without neoadjuvant FOLFIRINOX in PDAC. Molecular subtyping of both tumor and CAF compartments of PDAC may be important steps in selecting first-line systemic therapy.
Cardiometabolic health, cortical thickness, and neurotransmitter systems: a large-scale multivariate study
Authors: Nicolaisen-Sobesky Eliana , Maleki Balajoo Somayeh , Mahdipour Mostafa , Mihalik Agoston , Hoffstaedter Felix , Mourao-Miranda Janaina , Tahmasian Masoud , Eickhoff Simon B. , Genon Sarah 
Published: June 2024

SummaryThere is a recognized link between risk factors for non-communicable diseases and brain health. However, the specific effects that they have on brain health are still poorly understood, preventing its implementation in clinical practice. For instance, the association between such risk factors and cortical thickness (CT) has been primarily explored using univariate/bivariate methods and global/lobar measures of CT and has yielded inconsistent results. In this work, we aim to study the relationship between risk factors for non-communicable diseases and CT. In addition, we adopt a systems-level perspective to understand such relationship, by integrating several brain features including brain structure and function as well as neurotransmitter systems.Here, we analyzed latent dimensions linking a broad set of risk factors for non-communicable diseases to parcel-wise CT across the whole cortex (including raw, proportional, and brain size- corrected measures). We used a multivariate approach (regularized canonical correlation analysis (RCCA)) embedded in a machine learning framework that allows to capture inter- individual variability and to assess the generalizability of the model. The brain patterns (captured in association with risk factors) were characterized from a multi-level perspective, by comparing them with patterns of brain structure, function, and neurotransmitter systems. Analyses were performed separately in women (n=3685, 46-81 years) and in age-matched men (n=3685, 46-81 years) to avoid sex-bias on the results.We found one significant latent dimension (women: rrange=0.25-0.30, p=0.005-0.005; men: rrange=0.31-0.34, p=0.005-0.005), capturing variability in cardiometabolic health, including physical activity, body morphology/composition, basal metabolic rate, and blood pressure. This cardiometabolic health dimension was linked to a CT axis of inter-individual variability from the insula and cingulate cortex to occipital and parietal areas. Interestingly, this brain pattern was associated with the binding potentials of several neurotransmitter systems, including serotoninergic, dopaminergic, cholinergic, and GABAergic systems. Of note, this latent dimension was similar across sexes and across CT measures (raw, proportional, and brain-size corrected).We observed a robust, multi-level and multivariate link between cardiometabolic health, CT, and neurotransmitter systems. These findings support the urgency of further investigation into the interaction between brain health and physical health and contributes to the challenge to the classical conceptualization of neuropsychiatric and physical illnesses as categorical entities. Therefore, regular monitoring of cardiometabolic risk factors may reduce their adverse effects on brain health and prevent the development of brain diseases.
Isolating Poroelastic and Viscoelastic Mechanisms of Soft Tissues and Hydrogels Through Sequential Microscale Indentation Testing: New Applications of Indentation Theory for Microscale Characterization
Authors: Zahin Muhtadi Munawar , Al Barghouthi Abeer , Dickerson Darryl A. 
Published: June 2024

AbstractSoft hydrated materials, including biological tissues and hydrogels, exhibit complex time-dependent mechanical behaviors due to their poroelastic and viscoelastic properties. These properties often manifest on overlapping time scales, making it challenging to isolate the individual contributions of poroelasticity and viscoelasticity to the overall mechanical response. This study presents a novel semi-analytical model for characterizing these properties through sequential microscale load relaxation indentation testing. By extending existing theories, we developed a poroviscoelastic framework that enables the deconvolution of poroelastic and viscoelastic effects. Using this model to fit sequential microscale indentation data, we characterized porcine heart and liver tissues, as well as collagen and GelMA hydrogels, revealing distinct differences in their poroelastic and viscoelastic parameters. Our findings demonstrate that this approach not only provides rapid and detailed insights into the mechanical properties at the microscale but also offers significant advantages over traditional methods in terms of speed, computational efficiency, and practicality. This methodology has broad implications for advancing the understanding of tissue mechanics and the design of biomimetic materials for tissue engineering applications.Statement of SignificanceThis study introduces a novel approach to understanding the mechanical behavior of soft hydrated materials, like tissues and hydrogels. This study introduces a semi-analytical model to describe the time dependent behavior and a practical approach to distinguish between poroelasticity and viscoelasticity at the microscale. By providing this model along with a rapid and efficient characterization method, our approach enhances understanding of time-dependent mechanical behaviors critical for soft tissue mechanics and biomaterials design.
4G cloning: rapid gene assembly for expression of multisubunit protein complexes in diverse hosts
Authors: Taschner Michael , Dickinson Joe Bradley , Roisné-Hamelin Florian , Gruber Stephan 
Published: June 2024

AbstractMulti-subunit protein complexes are at the heart of many cellular processes, and studying their biochemical activities and structuresin vitrorequires their reconstitution by recombinant expression and purification. Obtaining targets at sufficient purity and scale typically requires the screening of several protein variants and expression hosts. Existing cloning strategies allow to produce constructs for co-expression of proteins, but are often time-consuming, labour-intensive, host-specific, or involving error-prone assembly steps. Here we present a unique set of vectors together with a novel assembly strategy designed to overcome these limitations. It allows for the generation of expression constructs for multi-subunit protein complexes for various hosts in a single cloning step. Its modular nature allows the system to be easily extended to target additional expression hosts or to include new tags or regulatory sequences. As a proof of principle, we present the parallel construction of expression vectors for several Structural Maintenance of Chromosomes (SMC) complexes, allowing us to devise strategies for the recombinant production of these targets in bacteria, insect cells, and human cells, respectively. This work will help laboratories working on protein complexes to streamline their workflow, increase their productivity and improve the quality of the purified material.
Co-Contraction Embodies Uncertainty: An Optimal Feedforward Strategy for Robust Motor Control
Authors: Berret Bastien , Verdel Dorian , Burdet Etienne , Jean Frédéric 
Published: June 2024

AbstractDespite our environment is often uncertain, we generally manage to generate stable motor behaviors. While reactive control plays a major role in this achievement, proactive control is critical to cope with the substantial noise and delays that affect neuromusculoskeletal systems. In particular, muscle co-contraction is exploited to robustify feedforward motor commands against internal sensorimotor noise as was revealed by stochastic optimal open-loop control modeling. Here, we extend this framework to neuromusculoskeletal systems subjected to random disturbances originating from the environment. The analytical derivation and numerical simulations predict a singular relationship between the degree of uncertainty in the task at hand and the optimal level of anticipatory co-contraction. This prediction is confirmed through a single-joint pointing task experiment where an external torque is applied to the wrist near the end of the reaching movement with varying probabilities across blocks of trials. We conclude that uncertainty calls for impedance control via proactive muscle co-contraction to stabilize behaviors when reactive control is insufficient for task success.Author summaryThis work presents a computational framework for predicting how humans modulate muscle co-contraction to cope with uncertainties of different origins. In our neuromusculoskeletal system, uncertainties have both internal (sensorimotor noise) and external (environmental randomness) origins. The present study focuses on the latter type of uncertainty, which had not been dealt with systematically previously despite its importance in everyday life. Therefore, we thoroughly investigated how random disturbances occurring with some probability in a motor task shape the feedforward control of mechanical impedance through muscle co-contraction. Here we provide theoretical, numerical and experimental evidence that the optimal level of co-contraction steeply increases with the uncertainty of our environment. These findings show that muscle co-contraction embodies uncertainty and optimally mitigates its consequences on task execution when feedback control is insufficient due to sensory noise and delays.
Glycosaminoglycans act as activators of peptidylarginine deiminase 4
Authors: Bereta Grzegorz P. , Bielecka Ewa , Marzec Karolina , Pijanowski Łukasz , Biela Artur , Wilk Piotr , Kamińska Marta , Nowak Jakub , Wątor Elżbieta , Grudnik Przemysław , Kowalczyk Dominik , Kozieł Joanna , Mydel Piotr , Poręba Marcin , Kantyka Tomasz 
Published: June 2024

AbstractPeptidylarginine deiminase 4 (PAD4) is a citrullinating enzyme that is gathering increasing attention due to its possible involvement in physiological processes as well as in the pathogenesis of diseases like rheumatoid arthritis or thrombosis. PAD4 is activated by calcium ions, but the details of this mechanism are elusive, because in the human body, Ca2+concentrations are too low for full activity. Given that glycosaminoglycans (GAGs) are also implicated in the development and progression of rheumatoid arthritis, we investigated the activation of PAD4 by GAGs using heparin as a model. We employed activity assays, chromatography techniques, molecular interaction measurements (MST and SPR), FACS, and immunocytochemistry to demonstrate the activation of PAD4 by GAGs. Our data show that PAD4 binds heparin with high affinity and forms high molecular weight complexes with heparin, consistent with heparin-bound tetramer formation. Heparin activates PAD4 by increasing the enzyme’s Ca2+affinity threefold. We also show that the effectiveness of activation with heparin depends on the length of GAG used and its negative charge. Direct measurement of heparin binding to PAD4 confirmed tight interaction with nanomolar affinity. Mutagenesis of regions likely responsible for heparin binding showed that dimerization of PAD4 is necessary for efficient activation, but the distinct binding site was not determined as interaction with heparin likely occurs over larger surface of PAD4. Furthermore, we show that other GAG family members, including heparan and chondroitin sulphates, are also able to activate PAD4. We also found that disturbed production of GAGs by CHO cells results in reduced PAD4 binding efficiency. Finally, heparin induces NETosis in hPMNs in concentration-dependent manner, as measured by the release of DNA and citrullination of histone H3. In summary, we identify the first natural coactivator of PAD4, which is present in all individuals, potentially explaining the regulation of PAD4 activity in physiological conditions, and providing new insight into the development of rheumatoid arthritis and other PAD4-related diseases.
One N-glycan regulates natural killer cell antibody-dependent cell-mediated cytotoxicity and modulates Fc γ receptor IIIa / CD16a structure
Authors: Kremer Paul G. , Lampros Elizabeth A. , Blocker Allison M. , Barb Adam W. 
Published: June 2024

AbstractBoth endogenous antibodies and a subset of antibody therapeutics engage Fc gamma receptor (FcγR)IIIa / CD16a to stimulate a protective immune response. Increasing the FcγRIIIa/IgG1 interaction improves the immune response and thus represents a strategy to improve therapeutic efficacy. FcγRIIIa is a heavily glycosylated receptor and glycan composition affects antibody-binding affinity. Though our laboratory previously demonstrated that natural killer (NK) cell N-glycan composition affected the potency of one key protective mechanism, antibody-dependent cell-mediated cytotoxicity (ADCC), it was unclear if this effect was due to FcγRIIIa glycosylation. Furthermore, the structural mechanism linking glycan composition to affinity and cellular activation remained undescribed. To define the role of individual amino acid and N-glycan residues we measured affinity using multiple FcγRIIIa glycoforms. We observed stepwise affinity increases with each glycan truncation step with the most severely truncated glycoform displaying the highest affinity. Removing the N162 glycan demonstrated its predominant role in regulating antibody-binding affinity, in contrast to four other FcγRIIIa N-glycans. We next evaluated the impact of the N162 glycan on NK cell ADCC. NK cells expressing the FcγRIIIa V158 allotype exhibited increased ADCC following kifunensine treatment to limit N-glycan processing. Notably, an increase was not observed with cells expressing the FcγRIIIa V158 S164A variant that lacks N162 glycosylation, indicating the N162 glycan is required for increased NK cell ADCC. To gain structural insight into the mechanisms of N162 regulation, we applied a novel protein isotope labeling approach in combination with solution NMR spectroscopy. FG loop residues proximal to the N162 glycosylation site showed large chemical shift perturbations following glycan truncation. These data support a model for the regulation of FcγRIIIa affinity and NK cell ADCC whereby composition of the N162 glycan stabilizes the FG loop and thus the antibody-binding site.
White adipose tissue remodeling in Little Brown Myotis (Myotis lucifugus) with white-nose syndrome
Authors: Pannkuk Evan L. , Moore Marianne S. , Bansal Shivani , Kumar Kamendra , Suman Shubhankar , Howell Daryl , Kath Joseph A. , Kurta Allen , Reeder DeeAnn M. , Field Kenneth A. 
Published: June 2024

AbstractWhite-nose syndrome (WNS) is a fungal wildlife disease of bats that has caused precipitous declines in certain Nearctic bat species. A key driver of mortality is premature exhaustion of fat reserves, primarily white adipose tissue (WAT), that bats rely on to meet their metabolic needs during winter. However, the pathophysiological and metabolic effects of WNS have remained ill-defined. To elucidate metabolic mechanisms associated with WNS mortality, we infected a WNS susceptible species, the Little Brown Myotis (Myotis lucifugus), withPseudogymnoascus destructans(Pd) and collected WAT biopsies for histology and targeted lipidomics. These results were compared to the WNS-resistant Big Brown Bat (Eptesicus fuscus). A similar distribution in broad lipid class was observed in both species, with ∼60% of total WAT consisting of triacylglycerides (TAGs). We found several baseline differences in WAT chemical composition between species.M. lucifugusWAT had significantly higher levels of measured TAGs (∼30%). Higher lipid levels inE. fuscusWAT were primarily sphingomyelins and glycerophosphoethanolamines (PEs), along with glycerophospholipids (GPs) dominated by unsaturated or monounsaturated moieties and n-6 (18:2, 20:2, 20:3, 20:4) fatty acids. These differences betweenM. lucifugusandE. fuscusmay indicate dietary differences that lead to differential “fuel” reserves that are available during torpor. FollowingPd-infection, we found that perturbation to WAT reserves occurs inM. lucifugus, but not in the resistantE. fuscus. A total of 36 GPs (primarily PEs) were higher inPd-infectedM. lucifugus, indicating perturbation to the WAT structural component. In addition to changes in lipid chemistry, smaller adipocyte sizes and increased extracellular matrix deposition was observed inPd-infectedM. lucifugus. This is the first study to describe WAT lipidomic composition of bats with different susceptibilities to WNS and highlights that recovery from WNS may require repair from adipose remodeling in addition to replenishing depot fat during spring emergence.
Differential Effects of Haloperidol on Neural Oscillations During Wakefulness and Sleep
Authors: Gallo Diego , Cavelli Matias , Castro-Zaballa Santiago , Castro-Nin Juan Pedro , Pascovich Claudia , Torterolo Pablo , González Joaquín 
Published: June 2024

AbstractThe electrical activity of the brain, characterized by its frequency components, reflects a complex interplay between periodic (oscillatory) and aperiodic components. These components are associated with various neurophysiological processes, such as the excitation-inhibition balance (aperiodic activity) or interregional communication (oscillatory activity). However, we do not fully understand whether these components are truly independent or if different neuromodulators modulate them in different ways. The dopaminergic system has a critical role for cognition and motivation, being a potential modulator of these power spectrum components. To improve our understanding of these questions, we investigated the differential effects of this system on these components using electrocorticogram recordings in cats, which show clear oscillations and aperiodic 1/f activity. Specifically, we focused on the effects of haloperidol (a D2 receptor antagonist) on oscillatory and aperiodic dynamics during wakefulness and sleep. By parameterizing the power spectrum into these two components, our findings reveal a state-dependent modulation of oscillatory activity by the D2 receptor across the brain. Surprisingly, aperiodic activity was not significantly affected and exhibited inconsistent changes across the brain. This suggests a nuanced interplay between neuromodulation and the distinct components of brain oscillations, providing insights into the selective regulation of oscillatory dynamics in awake states.