bluuebunny/crossref_metadata_2025_split huggingface dataset:
Medical Assistance in Dying (MAiD) as a Source of Liver Grafts: Honouring the Ultimate Gift
Authors: Ray Samrat , Torres-Hernandez Alejandro , Bleszynski Michael Sean , Parmentier Catherine , McGilvray Ian , Sayed Blayne Amir , Shwaartz Chaya , Cattral Mark , Ghanekar Anand , Sapisochin Gonzalo , Tsien Cynthia , Selzner Nazia , Lilly Leslie , Bhat Mamatha , Jaeckel Elmar , Selzner Markus , Reichman Trevor W. 
Published: December 2022

Objective:
To report the clinical outcomes of liver transplants from donors after medical assistance in dying (MAiD) versus donors after cardiac death (DCD) and deceased brain death (DBD).

Summary Background Data:
In North America, the number of patients needing liver transplants exceeds the number of available donors. In 2016, MAiD was legalized in Canada.

Methods:
All patients undergoing deceased donor liver transplantation at Toronto General Hospital between 2016 and 2021 were included in the study. Recipient perioperative and postoperative variables and donor physiological variables were compared among 3 groups.

Results:
Eight hundred seven patients underwent deceased donor liver transplantation during the study period, including DBD (n=719; 89%), DCD (n=77; 9.5%), and MAiD (n=11; 1.4%). The overall incidence of biliary complications was 6.9% (n=56), the most common being strictures (n=55;6.8%), highest among the MAiD recipients [5.8% (DBD) vs. 14.2% (DCD) vs. 18.2% (MAiD); P=0.008]. There was no significant difference in 1 year (98.4% vs. 96.4% vs. 100%) and 3-year (89.3% vs. 88.7% vs. 100%) (P=0.56) patient survival among the 3 groups. The 1- and 3- year graft survival rates were comparable (96.2% vs. 95.2% vs. 100% and 92.5% vs. 91% vs. 100%; P=0.37).

Conclusion:
With expected physiological hemodynamic challenges among MAiD and DCD compared with DBD donors, a higher rate of biliary complications was observed in MAiD donors, with no significant difference noted in short-and long-term graft outcomes among the 3 groups. While ethical challenges persist, good initial results suggest that MAiD donors can be safely used in liver transplantation, with results comparable with other established forms of donation.
Fibroblast Growth Factor 5 (FGF5) and Its Missense Mutant FGF5-H174 Underlying Trichomegaly: A Molecular Dynamics Simulation Investigation
Authors: Hoang Skyler H. 
Published: December 2022

AbstractThe missense mutation Y174H of FGF5 (FGF5-H174) had been associated with trichomegaly, characterized by abnormally long and pigmented eyelashes. The amino acid tyrosine (Tyr/Y) is conserved across many species, proposedly holding important characteristics for the functions of FGF5. One-microsecond molecular dynamics simulations along with protein-protein docking and residue interacting network analysis were employed to investigate the structural dynamics and binding mode of both wild-type (FGF5-WT) and its mutated counterpart (FGF5-Y174H). It was found that the mutation caused decreases in number of hydrogen bonds within the protein, sheet secondary structure, interaction of residues 174 with others, and number of salt-bridges. On the other hand, the mutation showed increases in solvent accessible surface area, number of hydrogen bonds between the protein and solvent, coil secondary structure, protein C-alpha backbone root mean square deviation, protein residue root mean square fluctuations, as well as occupied conformational space. In addition, protein-protein docking integrated with molecular dynamics simulations and molecular mechanics - Poisson-Boltzmann surface area (MM/PBSA) binding energy calculation demonstrated that the mutated variant possessed stronger binding affinity towards fibroblast growth factor receptor 1 (FGFR1). However, residue interaction network analysis demonstrated that the binding mode was drastically different from that of the FGF5-WT-FGFR1 complex. In conclusion, the missense mutation conferred more instability, stronger binding affinity towards FGFR1 but with distinctively altered binding mode or residue connectivity. These findings might help explain the decreased activation of FGFR1, underlying trichomegaly.
Range restricted old and young lineages show the southern Western Ghats to be both a museum and a cradle of diversity for woody plants
Authors: Gopal Abhishek , Bharti D. K. , Page Navendu , Dexter Kyle G. , Krishnamani Ramanathan , Kumar Ajith , Joshi Jahnavi 
Published: December 2022

AbstractThe Western Ghats (WG) mountain chain is a global biodiversity hotspot with high diversity and endemicity of woody plants. The latitudinal breadth of the WG offers an opportunity to determine the evolutionary drivers of latitudinal diversity patterns. We examined the spatial patterns of evolutionary diversity using complementary phylogenetic diversity and endemism measures. To examine if different regions of the WG serve as a museum or cradle of evolutionary diversity, we examined the distribution of 470 species based on distribution modelling and occurrence locations across the entire region. In accordance with the expectation, we found that the southern WG is both a museum and cradle of woody plant evolutionary diversity, as a higher proportion of both old and young evolutionary lineages are restricted to the southern WG. The diversity gradient is likely driven by high geo-climatic stability in the south and phylogenetic niche conservatism for moist and aseasonal sites. This is corroborated by persistent lineage nestedness at almost all evolutionary depths (10–135 million years), and a strong correlation of evolutionary diversity with drought seasonality, precipitation and topographic heterogeneity. Our results highlight the global value of the WG, demonstrating, in particular, the importance of protecting the southern WG – an engine of plant diversification and persistence.
FrustraPocket: A protein–ligand binding site predictor using energetic local frustration
Authors: Freiberger Maria I. , Clemente Camila M. , Valero Eneko , Pombo Jorge G. , Leonetti Cesar O. , Ravetti Soledad , Parra R. Gonzalo , Ferreiro Diego U. 
Published: December 2022

Proteins are evolved polymers that minimize their free energy upon folding to their native states. Still, many folded proteins display energetic conflict between residues in various regions that can be identified as highly frustrated, and these have been shown to be related to several physiological functions. Here we show that small-ligand binding sites are typically enriched in locally frustrated interactions in the unbound state. We built a tool using a simple machine learning algorithm named FrustraPocket that combines the notion of small-molecule binding pockets and the localization of clusters of highly frustrated interactions to identify potential protein-ligand binding sites solely from the unbound forms.Availability and implementation (github)https://github.com/CamilaClemente/FrustraPocket/Docker containerhttps://hub.docker.com/r/proteinphysiologylab/frustrapocket
Global and cell type-specific immunological hallmarks of severe dengue progression
Authors: Ghita Luca , Yao Zhiyuan , Xie Yike , Duran Veronica , Cagirici Halise Busra , Samir Jerome , Osman Ilham , Agudelo Rojas Olga Lucia , Sanz Ana Maria , Sahoo Malaya Kumar , Robinson Makeda L. , Gelvez Rosa Margarita , Bueno Nathalia , Luciani Fabio , Pinsky Benjamin A. , Montoya Jose G. , Estupiñan Cardenas Maria Isabel , Villar Centeno Luis Angel , Rojas Garrido Elsa Marina , Rosso Fernando , Quake Stephen R. , Zanini Fabio , Einav Shirit 
Published: December 2022

AbstractSevere dengue (SD) is a major cause of morbidity and mortality impacting approximately 5 million of the 400 million people infected with dengue virus (DENV) annually. To define DENV target cells and immunological hallmarks of SD progression in children’s blood, we integrated virus-inclusive single cell RNA-Seq 2 (viscRNA-Seq 2) with functional assays. Beyond myeloid cells, in natural infection, B cells harbor replicating DENV capable of infecting permissive cells. Alterations in cell type abundance, gene and protein expression and secretion, and cell-cell communications point towards increased migration and inflammation in SD progressors (SDp). Concurrently, antigen presenting cells from SDp demonstrate intact uptake, yet impaired interferon responses and antigen presentation, in part DENV-modulated. Increased activation, regulation, and exhaustion of effector responses and expansion of HLA-DR-expressing, possibly compensatory, adaptive-like NK cells also characterize SDp. These findings reveal DENV target cells in the human blood and provide insight into SD pathogenesis beyond antibody-mediated enhancement.
Reimagining Gene-Environment Interaction Analysis for Human Complex Traits
Authors: Miao Jiacheng , Song Gefei , Wu Yixuan , Hu Jiaxin , Wu Yuchang , Basu Shubhashrita , Andrews James S. , Schaumberg Katherine , Fletcher Jason M. , Schmitz Lauren L. , Lu Qiongshi 
Published: December 2022

AbstractIn this study, we introduce PIGEON—a novel statistical framework for quantifying and estimating polygenic gene-environment interaction (GxE) using a variance component analytical approach. Based on PIGEON, we outline the main objectives in GxE studies, demonstrate the flaws in existing GxE approaches, and introduce an innovative estimation procedure which only requires summary statistics as input. We demonstrate the statistical superiority of PIGEON through extensive theoretical and empirical analyses and showcase its performance in multiple analytic settings, including a quasi-experimental GxE study of health outcomes, gene-by-sex interaction for 530 traits, and gene-by-treatment interaction in a randomized clinical trial. Our results show that PIGEON provides an innovative solution to many long-standing challenges in GxE inference and may fundamentally reshape analytical strategies in future GxE studies.
Lacustrine speciation associated with chromosomal inversion in a lineage of riverine fishes
Authors: MacGuigan Daniel J. , Krabbenhoft Trevor J. , Harrington Richard C. , Wainwright Dylan K. , Backenstose Nathan J. C. , Near Thomas J. 
Published: December 2022

ABSTRACTGeographic isolation is the primary driver of speciation in many vertebrate lineages. This trend is exemplified by North American darters, a clade of freshwater fishes where nearly all sister species pairs are allopatric and separated by millions of years of divergence. One of the only exceptions is the Lake Waccamaw endemicEtheostoma perlongumand its riverine sister speciesE. maculaticeps,which have no physical barriers to gene flow. Here we show that lacustrine speciation ofE. perlongumis characterized by morphological and ecological divergence likely facilitated by a large chromosomal inversion. WhileEtheostoma perlongumis phylogenetically nested within the geographically widespreadE. maculaticeps, there is a sharp genetic and morphological break coinciding with the lake-river boundary in the Waccamaw River system. Despite recent divergence, an active hybrid zone, and ongoing gene flow, analyses using ade novoreference genome reveal a 9 Mb chromosomal inversion with elevated divergence betweenE. perlongumandE. maculaticeps.This region exhibits striking synteny with known inversion supergenes in two distantly related fish lineages, suggesting deep evolutionary convergence of genomic architecture. Our results illustrate that rapid, ecological speciation with gene flow is possible even in lineages where geographic isolation is the dominant mechanism of speciation.
Unraveling the effects of virtual reality overground walking on dynamic balance and postural control
Authors: Horsak Brian , Simonlehner Mark , Dumphart Bernhard , Siragy Tarique 
Published: December 2022

AbstractThis study analyzed the effects of walking freely in Virtual Reality (VR) compared to walking in the real-world on dynamic balance and postural control. For this purpose nine male and twelve female healthy participants underwent standard 3D gait analysis while walking randomly in a real laboratory and in a room-scale overground VR environment resembling the real laboratory. The VR was delivered to participants by a head-mounted-display which was operated wirelessly and calibrated to the real-world. Dynamic balance was assessed with three outcomes: the Margin of Stability (MOS) in the anteroposterior (AP-MOS) and mediolateral (ML-MOS) directions at initial-contact, the relationship between the mediolateral Center of Mass (COM) position and acceleration at mid-stance with subsequent step width, and trunk kinematics during the entire gait cycle. We observed increased mediolateral (ML) trunk linear velocity variability, an increased coupling of the COM position and acceleration with subsequent step width, and a decrease in AP-MOS while walking in VR, but no change in ML-MOS when walking in VR. We conclude that walking in VR results in a less reliable optical flow, indicated by increased mediolateral trunk kinematic variability, which seems to be compensated by the participants by slightly reweighing sensorimotor input and thereby consciously tightening the coupling between the COM and foot placement to avoid a loss of balance. Our results are particularly valuable for future developers who want to use VR to support gait analysis and rehabilitation.
3D chromatin interactions involvingDrosophilainsulators are infrequent but preferential and arise before TADs and transcription
Authors: Messina Olivier , Raynal Flavien , Gurgo Julian , Fiche Jean-Bernard , Pancaldi Vera , Nollmann Marcelo 
Published: December 2022

AbstractIn mammals, insulators contribute to the regulation of loop extrusion to organize chromatin into topologically associating domains. InDrosophilathe role of insulators in 3D genome organization is, however, under current debate. Here, we addressed this question by combining bioinformatics analysis and multiplexed chromatin imaging. We describe a class ofDrosophilainsulators enriched at regions forming preferential chromatin interactions genome-wide. Notably, most of these 3D interactions do not involve TAD borders. Multiplexed imaging shows that these interactions occur infrequently, and only rarely involve multiple genomic regions coalescing together in space in single cells. Finally, we show that non-border preferential 3D interactions enriched in this class of insulators arise before TADs and transcription duringDrosophiladevelopment. Our results are inconsistent with insulators forming stable hubs in single cells, and instead suggest that they fine-tune existing 3D chromatin interactions, providing an additional regulatory layer for transcriptional regulation.
Differentiation of leukocytes in bronchoalveolar lavage fluid samples using higher harmonic generation microscopy and deep learning
Authors: van Huizen L.M.G. , Blokker M. , Rip Y. , Veta M. , Kalverda K.A. , Bonta P.I. , Duitman J.W. , Groot M.L. 
Published: December 2022

AbstractIn many diseases such as interstitial lung diseases (ILDs), patient diagnosis relies on diagnostic analysis of bronchoalveolar lavage fluid (BALF) and biopsies. In BALF the differentiation of neutrophils, eosinophils, lymphocytes, and macrophages can contribute to diagnose the underlying ILD entity. To analyze the BALF standard cytological techniques are labor-intensive and time-consuming. Studies have shown promising cell identification performance on blood fractions analyzed by third harmonic generation (THG) and multiphoton excited autofluorescence (MPEF) microscopy. Here, we extend this to BALF samples, and we trained a deep learning algorithm for automated analysis on the image level against reference cytology. We imaged blood fractions from three healthy individuals and one asthma patients, and six BALFs from ILD patients. We determined the leukocyte characteristics in terms of cellular and nuclear morphology, and THG and MPEF signal intensity. A deep learning model was trained on both blood fractions and BALF 2D images was used to estimate the leukocyte ratios by using only the standard cytology differential cell ratios at the image-level as reference. The deep learning network has learned to identify individual cells and was able to provide a reasonable estimate of the leukocyte percentage, coming within a 2 to 10% margin in BALF samples in the hold-out testing set. We suggest that the performance of the combined label free imaging and AI analysis can be improved further by collecting 3D data and data of additional fluid samples of various ILD diseases and healthy samples, THG/MPEF microscopy in combination with deep learning is a promising technique for instant differentiation and quantification of leukocytes. Immediate feedback on leukocyte ratios will not only speed-up the diagnostic process but can also reduce costs, the workload and reduce inter-observer variations.
Polychrome labeling reveals skeletal triradiate and elongation dynamics and abnormalities in patterning cue-perturbed embryos
Authors: Descoteaux Abigail E. , Zuch Daniel T. , Bradham Cynthia A. 
Published: December 2022

AbstractThe larval skeleton of the sea urchinLytechinus variegatusis an ideal model system for studying skeletal patterning; however, our understanding of the etiology of skeletal patterning in sea urchin larvae is limited due to the lack of approaches to live-image skeleton formation. Calcium-binding fluorochromes have been used to study the temporal dynamics of bone growth and healing. To date, only calcein green has been used in sea urchin larvae to fluorescently label the larval skeleton. Here, we optimize labeling protocols for four other calcium-binding fluorochromes-alizarin red, xylenol orange, tetracycline, and calcein blue- and demonstrate that these fluorochromes can be used individually or in nested pulse-chase experiments to understand the temporal dynamics of skeletogenesis and patterning. Using this pulse-chase approach we reveal that the initiation of skeletogenesis begins around 15 hours post fertilization, which is earlier than previously thought. We also explore the timing of triradiate formation in embryos treated with a range of patterning perturbagens, and demonstrate that triradiates form late and asynchronously in embryos ventralized via treatment with either nickel at early gastrula stage or with chlorate from fertilization. Finally, we measure the extent of fluorochrome incorporation in triple-labeled embryos to determine the elongation rate of numerous skeletal elements throughout early skeletal patterning and compare this to the rate of skeletal growth in axitinib-treated embryos. We find that skeletal elements elongate much more slowly in axitinib-treated embryos, and that axitinib treatment is sufficient to induce abnormal orientation of the triradiates.HighlightsCalcium-binding fluorochromes selectively label the sea urchin larval skeletonPulsed, nested polychrome labeling offers temporal insight into skeletal patterningTriradiate formation is delayed and asynchronous in ventralized embryosVEGFR inhibition slows skeletal elongation and perturbs triradiate orientation
Investigating the folding dynamics of NS2B protein of Zika virus
Authors: Kumar Ankur , Kumar Prateek , Mishra Pushpendra Mani , Giri Rajanish 
Published: December 2022

AbstractNS2B protein of the Zika virus acts as a co-factor for NS3 protease where only the cytosolic domain of NS2B is sufficient for the protease activity. At the same time, NS2B also involves in remodeling the NS3 protease structure. In isolation, we previously proved the NS2B cytosolic domain (residues 49-95) as a disordered type peptide conformation. Further, this study investigated the overall dynamics of NS2B full-length protein. Our Alphafold2 structure modeling system revealed surprising similarities between selected flavivirus NS2B proteins. This similarity reflects that the NS2B protein across flavivirus is conserved fold-wise. The MD simulation of Zika virus NS2B full-length protein shows that the cytosolic domain as a part of full-length protein is a disorder region supporting our previous experimental finding, which suggests the disordered nature of the cytosolic domain in isolation. Since the cytosolic domain of NS2B is essential for protease activity, we have also investigated the folding and dynamics of the NS2B cytosolic domain (residues 49-95) that shows the disorder to alpha helix transition in TFE. On the other hand, in the presence of SDS, macromolecular crowder like ficoll and PEG do not induce secondary structural change. This dynamics study could have implications for some unknown folds of the NS2B protein.
An ESCRT grommet cooperates with a diffusion barrier to maintain nuclear integrity
Authors: Ader Nicholas R. , Chen Linda , Surovtsev Ivan V. , Chadwick William L. , Rodriguez Elisa C. , King Megan C. , Lusk C. Patrick 
Published: December 2022

ABSTRACTThe molecular mechanisms by which the endosomal sorting complexes required for transport (ESCRT) proteins contribute to the integrity of the nuclear envelope (NE) barrier are not fully defined. Here, we leveraged the single NE hole generated by mitotic extrusion of theSchizosaccharomyces pombespindle pole body (SPB) to reveal two modes of ESCRT function executed by distinct complements of ESCRT-III proteins, both depending on CHMP7/Cmp7. A grommet-like function is required to restrict the NE hole in anaphase B, while replacement of Cmp7 by a sealing module ultimately closes the NE in interphase. Without Cmp7, nucleocytoplasmic compartmentalization surprisingly remains intact despite NE discontinuities up to 550 nm, suggesting mechanisms to prevent diffusion through these holes. We implicate SPB proteins as key components of a diffusion barrier acting with Cmp7 in anaphase B. Thus, NE remodeling mechanisms cooperate with proteinaceous diffusion barriers beyond nuclear pore complexes to protect the nuclear compartment.
Human Airway Mucociliary Tissue Cultures Chronically Exposed to E-Cigarette Vapors Exhibit Altered Cell Populations and Increased Secretion of Immunomodulatory Cytokines
Authors: Manna Vincent J. , Dwyer Shannon , Pizutelli Vanessa , Caradonna Salvatore J. 
Published: December 2022

ABSTRACTVape-pens or electronic cigarettes (e-cigarettes) are handheld battery powered devices that use a vape-liquid to produce a vapor that is inhaled by the user. The active ingredients in commercial vape-liquids are commonly nicotine, tetrahydrocannabinol or cannabidiol. A consequence of the rise in e-cigarette usage was the 2019 emergence of a vaping-induced respiratory disease denoted ‘e-cigarette or vaping use-associated lung injury’ (EVALI). One of the suspected causes of EVALI is Vitamin E Acetate (VEA), which was found to be a diluent in certain illicit tetrahydrocannabinol vape-pens, whereas nicotine is commonly diluted in equal parts propylene glycol and vegetable glycerin (PG:VG). The prevalent use of e-cigarettes by both adult and young adult populations and the emergence of a novel illness has made understanding how e-cigarette vapors affect our respiratory tissues a public health concern. We have designed and produced a simple device that can operate commercial e-cigarettes and deliver the vapor to a chamber containing a standard cell culture multi-well plate. Here we utilize our device to investigate how human airway mucociliary tissue cultures respond after chronic exposure to vapors produced from either PG:VG or VEA. We note several differences between how PG:VG and VEA vapors interact with and alter airway tissue cultures and suggest potential mechanisms for how VEA-vapors can exacerbate EVALI symptoms. Our device combined with primary human airway tissue cultures make an economical and compact model system that allows for animal-free investigations into the acute and chronic consequences of e-cigarette vapors on primary respiratory cells.