bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a High-Performance Open-Source 3D Bioprinter
Authors: Tashman Joshua W. , Shiwarski Daniel J. , Feinberg Adam W. 
Published: September 2022

AbstractThe application of 3D printing to biological research has provided the tissue engineering community with a method for organizing cells and biological materials into complex 3D structures. While many commercial bioprinting platforms exist, they are expensive, ranging from $5,000 to over $500,000. This high cost of entry prevents many labs from incorporating 3D bioprinting into their research. Due to the open-source nature of desktop plastic 3D printers, an alternative option has been to convert low-cost plastic printers into bioprinters. Several open-source modifications have been described, but there remains a need for a user-friendly, step-by-step guide for converting a thermoplastic printer into a bioprinter using components with validated performance. Here we convert a low-cost 3D printer, the FlashForge Finder, into a bioprinter using our Replistruder 4 syringe pump and the Duet3D Duet 2 WiFi for total cost of less than $900. We demonstrate that the accuracy of the bioprinter’s travel is better than 35 µm in all three axes, and quantify fidelity by printing square lattice collagen scaffolds with average errors less than 2%. We also show high fidelity reproduction of clinical-imaging data by printing a scaffold of a human ear using collagen bioink. Finally, to maximize accessibility and customizability, all components we have designed for the bioprinter conversion are provided as open-source 3D models, along with instructions for further modifying the bioprinter for additional use cases, resulting in a comprehensive guide for the bioprinting field.
Huntingtin Over-Expression Does Not Alter Overall Survival in Murine Cancer Models
Authors: Chan Laura , Hill Austin , Lu Ge , Van Raamsdonk Jeremy , Gascoyne Randy D. , Hayden Michael R. , Leavitt Blair R. 
Published: September 2022

ABSTRACTA reduced incidence of various forms of cancer has been reported in Huntington’s disease (HD) patients and may be due to pro-apoptotic effects of mutant huntingtin. We tested this hypothesis by assessing the effects of huntingtin protein over-expression on survival in two murine cancer models. We generated yeast artificial chromosome (YAC) HD mice containing human huntingtin transgenes with various CAG tract lengths (YAC18, YAC72, YAC128) on either an Msh2 or p53 null background, which have increased cancer incidence. In both mouse models of cancer, the over-expression of either mutant or wild-type huntingtin had no significant effect on overall survival. These results do not support the hypothesis that mutant huntingtin expression is protective against cancer.
Treatment with anti-HER2 chimeric antigen receptor tumor-infiltrating lymphocytes (CAR-TILs) is safe and associated with antitumor efficacy in mice and companion dogs
Authors: Forsberg Elin MV , Riise Rebecca , Saellström Sara , Karlsson Joakim , Alsén Samuel , Bucher Valentina , Hemminki Akseli , Olofsson Bagge Roger , Ny Lars , Nilsson Lisa M , Rönnberg Henrik , Nilsson Jonas A 
Published: September 2022

AbstractPatients with metastatic melanoma have a historically poor prognosis, but recent advances in treatment options, including targeted therapy and immunotherapy, have drastically improved the outcomes for some of these patients. However, not all patients respond to available treatments, and around 50% of patients with metastatic cutaneous melanoma and almost all patients with metastases of uveal melanoma die of their disease. Thus, there is a need for novel treatment strategies for patients with melanoma that do not benefit from the available therapies. Chimeric antigen receptor-expressing T (CAR-T) cells are largely unexplored in melanoma. Traditionally, CAR-T cells have been produced by transducing blood-derived T cells with a virus expressing CAR. However, tumor-infiltrating lymphocytes (TILs) can also be engineered to express CAR, and such CAR-TILs could be dual-targeting. To this end, tumor samples and autologous TILs from metastasized human uveal and cutaneous melanoma were expanded in vitro and transduced with a lentiviral vector encoding an anti-HER2 CAR construct. When infused into patient-derived xenograft (PDX) mouse models carrying autologous tumors, CAR-TILs were able to eradicate melanoma, even in the absence of antigen presentation by HLA. To advance this concept to the clinic and assess its safety in an immune-competent and human-patient-like setting, we treated four companion dogs with autologous anti-HER2 CAR-TILs. We found that these cells were tolerable and showed signs of anti-tumor activity. Taken together, CAR-TIL therapy is a promising avenue for broadening the tumor-targeting capacity of TILs in patients with checkpoint immunotherapy-resistant melanoma.
Perturbation of Lipid Bilayers by Biomimetic Photoswitches Based on Cyclocurcumin
Authors: Delova Anastasiia , Losantos Raúl , Pecourneau Jérémy , Bernhard Yann , Mourer Maxime , Pasc Andreea , Monari Antonio 
Published: September 2022

ABSTRACTThe use of photoswitches which may be activated by suitable electromagnetic radiation is an attractive alternative to conventional photodynamic therapy. Here we report all atom molecular dynamics simulation of a biomimetic photoswitch derived from cyclocurcumin and experiencingE/Zphotoisomerization. In particular, we show that the two isomers interact persistently with a lipid bilayer modeling a cellular membrane. Furthermore, the interaction with the membrane is strongly dependent on the concentration and a transition between ordered or disordered arrangements of the photoswitches is observed. We also confirm that the structural parameters of the bilayer are differently affected by the two isomers, and hence can be modulated through photoswitching, offering interesting perspectives for future applications.TOC Graphic
The Chalcidoidea bush of life – a massive radiation blurred by mutational saturation
Authors: Cruaud Astrid , Rasplus Jean-Yves , Zhang Junxia , Burks Roger , Delvare Gérard , Fusu Lucian , Gumovsky Alex , Huber John T. , Janšta Petr , Mitroiu Mircea-Dan , Noyes John S. , van Noort Simon , Baker Austin , Böhmová Julie , Baur Hannes , Blaimer Bonnie B. , Brady Seán G. , Bubeníková Kristýna , Chartois Marguerite , Copeland Robert S. , Papilloud Natalie Dale-Skey , Dal Molin Ana , Dominguez Chrysalyn , Gebiola Marco , Guerrieri Emilio , Kresslein Robert L. , Krogmann Lars , Lemmon Emily Moriarty , Murray Elizabeth A. , Nidelet Sabine , Nieves-Aldrey José Luis , Perry Ryan K. , Peters Ralph S. , Polaszek Andrew , Sauné Laure , Torréns Javier , Triapitsyn Serguei , Tselikh Ekaterina V. , Yoder Matthew , Lemmon Alan R. , Woolley James B. , Heraty John M. 
Published: September 2022

ABSTRACTCapturing phylogenetic signal from a massive radiation can be daunting. The superfamily Chalcidoidea is an excellent example of a hyperdiverse group that has remained recalcitrant to phylogenetic resolution. Chalcidoidea are mostly parasitoid wasps that until now included 27 families, 87 subfamilies and as many as 500,000 estimated species. We combined 1007 exons obtained with Anchored Hybrid Enrichment with 1048 Ultra-Conserved Elements (UCEs) for 433 taxa including all extant families, over 95% of all subfamilies and 356 genera chosen to represent the vast diversity of the superfamily. Going back and forth between molecular results and our collective morphological and biological knowledge, we detected insidious bias driven by the saturation of nucleotide data and highlighted morphological convergences. Our final results are based on a concatenated analysis of the least saturated exons and UCE data sets (2054 loci, 284,106 sites). Our analyses support a sister relationship with Mymarommatoidea. Seven of the previously recognized families were not monophyletic, so foundations for a new classification are discussed. Biology appears potentially more informative than morphology, as illustrated by the elucidation of a clade of plant gall associates and a clade of taxa with planidial first-instar larvae. The phylogeny suggests a shift from smaller soft-bodied wasps to larger and more heavily sclerotized wasps. Deep divergences in Chalcidoidea coincide with an increase in insect families in the fossil record, and an early shift to phytophagy corresponds with the beginning of the “Angiosperm Terrestrial Revolution”. Our dating analyses suggest a Middle Jurassic origin of 174 Ma (167.3-180.5 Ma) and a crown age of 162.2 Ma (153.9–169.8 Ma) for Chalcidoidea. During the Cretaceous, Chalcidoidea underwent a rapid radiation in southern Gondwana with subsequent dispersals to the Northern Hemisphere. This scenario is discussed with regard to knowledge about host taxa of chalcid wasps, their fossil record, and Earth’s paleogeographic history.
Leadership in PhD (LeaP): a longitudinal leadership skill building program for underrepresented biomedical research trainees
Authors: Doles Mali D , Kang Ji Yun , Scholl Linda M , Doles Jason D 
Published: September 2022

AbstractIncreasing diversity in the biomedical research workforce is a critical national issue. Particularly concerning is the lack of representation at more advanced career stages/in leadership positions. While there are numerous institutional initiatives promoting professional research skills (i.e. grant writing, presenting, networking) for underrepresented (UR) PhD trainees, there are comparatively fewer opportunities for leadership development. We present a blueprint for Leadership in PhD (LeaP), a cohort-based program aiming to equip UR biomedical research trainees with skills to succeed as academic, industry, and community leaders. In contrast to intensive short-term programs or workshops, LeaP is a longitudinal 4-year experience with an emphasis on self-directed and experiential learning. First year trainees receive foundational didactic instruction on core leadership concepts coupled with facilitated peer discussions and one-on-one coaching support. We outline a program evaluation framework that assesses student learning, satisfaction, and program efficacy. Evaluation data from the inaugural year is presented and discussed.
Defining Cardiac Recovery at Single Cell Resolution
Authors: Amrute Junedh M. , Lai Lulu , Ma Pan , Koenig Andrew L. , Kamimoto Kenji , Bredemeyer Andrea , Shankar Thirupura S. , Kuppe Christoph , Kadyrov Farid F. , Schulte Linda J. , Stoutenburg Dylan , Kopecky Benjamin J. , Navankasattusas Sutip , Visker Joseph , Morris Samantha A. , Kramann Rafael , Leuschner Florian , Mann Douglas L. , Drakos Stavros G. , Lavine Kory J. 
Published: September 2022

AbstractRecovery of cardiac function is the ultimate goal of heart failure therapy. Unfortunately, cardiac recovery remains a rare and poorly understood phemomenon. Herein, we performed single nucleus RNA-sequencing (snRNA-seq) from non-diseased donors and heart failure patients. By comparing patients who recovered LV systolic function following LV assist device implantation to those who did not recover and donors, we defined the cellular and transcriptional landscape and predictors of cardiac recovery. We sequenced 40 hearts and recovered 185,881 nuclei with 13 distinct cell types. Using pseudobulk differential expression analysis to explicate cell specific signatures of cardiac recovery, we observed that recovered cardiomyocytes do not revert to a normal state, and instead, retain transcriptional signatures observed in heart failure. Macrophages and fibroblasts displayed the strongest signatures of recovery. While some evidence of reversion to a normal state was observed, many heart failure associated genes remained elevated and recovery signatures were predominately indicative of a biological state that was unique from donor and heart failure conditions. Acquisition of recovery states was associated with improved LV systolic function. Pro-inflammatory macrophages and inflammatory signaling in fibroblasts were identified as negative predictors of recovery. We identified downregulation of RUNX1 transcriptional activity in macrophages and fibroblasts as a central event associated with and predictive of cardiac recovery. In silico perturbation of RUNX1 in macrophages and fibroblasts recapitulated the transcriptional state of cardiac recovery. This prediction was corroborated in a mouse model of cardiac recovery mediated by BRD4 inhibition where we observed a decrease in macrophage and fibroblast Runx1 expression, diminished chromatin accessibility within peaks linked to the Runx1 locus, and acquisition of recovery signatures. These findings suggest that cardiac recovery is a unique biological state and identify RUNX1 as a possible therapeutic target to facilitate cardiac recovery.
Detecting stabilizing, directional, and disruptive patterns of anthropogenic species loss with general models of nonrandom extinction
Authors: Huron Nicholas A. , Hedges S. Blair , Helmus Matthew R. 
Published: September 2022

AbstractThe selective landscape that gave rise to Earth’s species has shifted in the Anthropocene. Humans have accelerated extinction pressures, making efforts to detect general non-random patterns of extinction increasingly important. Much research has focused on detecting which traits make some species more likely to go extinct, such as large body size and slow reproductive rate in animals, limited dispersal in vascular plants, and narrow habitat requirements in cacti. However, general models for such non-random extinction are lacking. Here, we adapt the three general models of natural selection to classify non-random extinction as directional, disruptive, or stabilizing extinction. We develop a quantitative method for testing which general extinction model best describes observed data and apply it to the Caribbean lizard genusLeiocephalusas a case study. We surveyed the literature for recorded last occurrence for extinct and threat status for extant species. Eight species have gone extinct and ten are predicted to go extinct soon. Past extinctions inLeiocephalusshowed directional extinction of large bodied species, while future-predicted extinctions exhibited a more complex extinction model similar to both random and stabilizing extinction with respect to body size. Similarly, future-predicted extinctions exhibited stabilizing extinction with respect to limb and tail lengths. Lizards with either very long or very short appendages are most likely to go extinct in the future. This shift from directional to stabilizing extinction forLeiocephalusis consistent with hunting, introduced predators, and habitat loss that first increased extinction pressure on the largest species and then extinction pressure on species that deviate from an adaptive peak centered on a generalist ground-lizard body plan. As adaptive optima shift in the Anthropocene, general models of non-random extinction are essential to developing a mature strategy for future successful conservation efforts.
High Resolution Imaging of the Osteogenic and Angiogenic Interface at the Site of Cranial Bone Defect Repair via Multiphoton Microscopy
Authors: Schilling Kevin , Zhai Yuankun , Zhou Zhuang , Zhou Bin , Brown Edward , Zhang Xinping 
Published: September 2022

ABSTRACTThe spatiotemporal blood vessel formation and specification at the osteogenic and angiogenic interface of cranial bone defect repair were examined utilizing a high-resolution multiphoton-based imaging platform in conjunction with advanced optical techniques that allow interrogation of the oxygen microenvironment and cellular energy metabolism in living animals. Our study demonstrates the dynamic changes of vessel types, i.e. arterial, venous and capillary vessel networks at the superior and dura periosteum of cranial bone defect, suggesting a differential coupling of the vessel type with osteoblast expansion and bone tissue deposition/remodeling during repair. Employing transgenic reporter mouse models that label distinct types of vessels at the site of repair, we further show that oxygen distributions in capillary vessels at the healing site are heterogeneous as well as time and location-dependent. The endothelial cells coupling to osteoblasts prefer glycolysis and are less sensitive to microenvironmental oxygen changes than osteoblasts. In comparison, osteoblasts utilize relatively more OxPhos and potentially consume more oxygen at the site of repair. Taken together, our study highlights the dynamics and functional significance of blood vessel types at the site of defect repair, opening up opportunities for further delineating the oxygen and metabolic microenvironment at the interface of bone tissue regeneration.
Ensemble Machine Learning to “Boost” Ubiquitination-sites Prediction
Authors: Mo Xiaoye , Jiang Xia 
Published: September 2022

ABSTRACTUbiquitination-site prediction is an important task because ubiquitination is a critical regulatory function for many biological processes such as proteasome degradation, DNA repair and transcription, signal transduction, endocytoses, and sorting. However, the highly dynamic and reversible nature of ubiquitination makes it difficult to experimentally identify specific ubiquitination sites. In this paper, we explore the possibility of improving the prediction of ubiquitination sites using ensemble machine learning methods including Random Forrest (RF), Adaptive Boosting (ADB), Gradient Boosting (GB), and eXtreme Gradient Boosting (XGB). By doing grid search with the four ensemble methods and six comparison non-ensemble learning methods including Naïve Base (NB), Logistic Regression (LR), Decision Trees (DT), Support Vector Machine (SVM), LASSO, and K-Nearest Neighbor (KNN), we find that all the four ensemble methods significantly outperform one or more non-ensemble methods included in this study. XGB outperforms three out of the six non-ensemble methods that we included; ADB and RF both outperform two of the six non-ensemble methods; GB outperforms one non-ensemble method. Comparing the four ensemble methods among themselves. GB performs the worst; XGB and ADB are very comparable in terms of prediction, but ADB beats XGB by far in terms of both the unit model training time and total running time. Both XGB and ADB tend to do better than RF in terms of prediction, but RF has the shortest unit model training time out of the three. In addition, we notice that ADB tends to outperform XGB when dealing with small-scale datasets, and RF can outperform either ADB or XGB when data are less balanced. Interestingly, we find that SVM, LR, and LASSO, three of the six non-ensemble methods included, perform comparably with all the ensemble methods. Based on this study, ensemble learning is a promising approach to ignificantly improving ubiquitination-site prediction using protein segment data.
Redox regulation of Kv7 channels through EF3 hand of calmodulin
Authors: Nuñez Eider , Jones Frederick , Muguruza-Montero Arantza , Urrutia Janire , Aguado Alejandra , Malo Covadonga , Bernardo-Seisdedos Ganeko , Domene Carmen , Millet Oscar , Gamper Nikita , Villarroel Alvaro 
Published: September 2022

ABSTRACTNeuronal KV7 channels, important regulators of cell excitability, are among the most sensitive proteins to reactive oxygen species. The S2S3 linker of the voltage sensor was reported as a site mediating redox modulation of the channels. Recent structural insights reveal potential interactions between this linker and the Ca2+-binding loop of the third EF-hand of calmodulin (CaM), which embraces an antiparallel fork formed by the C-terminal helices A and B. We found that precluding Ca2+ binding to the EF3 hand, but not to EF1, EF2 or EF4 hands, abolishes oxidation-induced enhancement of Kv7.4 currents. Monitoring FRET between helices A and B tagged with fluorescent proteins, we observed that S2S3 peptides cause a reversal of the signal in the presence of Ca2+, but have no effect in the absence of this cation or if the peptide is oxidized. The capacity of loading EF3 with Ca2+ is essential for this reversal of the FRET signal, whereas the consequences of obliterating Ca2+ binding to EF1, EF2 or EF4 are negligible. Furthermore, we show that EF3 is necessary and sufficient to translate Ca2+ signals to reorient the AB fork. Our data is consistent with the proposal that oxidation of cysteine residues in the S2S3 loop relieves Kv7 channels from a constitutive inhibition imposed by interactions between the EF3 hand of CaM which is necessary and sufficient for this signaling.SignificanceOxidation-dependent enhancement of the KV7/M-channels plays a cytoprotective role in neurons. Here, we show that calmodulin (CaM), the main protein that conveys information from transient intracellular Ca2+ oscillations, plays a critical role in oxidative signal transduction. The prevailing view is that the main role of the EF-hands is to respond to Ca2+ and that the two EF-hands of CaM in each lobe act in coordination during signaling. We find that EF3 by itself is sufficient and necessary for the oxidative response of Kv7 channel complex and for gating the Calcium Responsive Domain of Kv7 channels. In addition, the direction of EF3-dependent signaling can be reversed by protein-protein interactions with solvent exposed regions outside the target binding groove between EF-hands.
Evolutionary trajectories are contingent on mitonuclear interactions
Authors: Biot-Pelletier Damien , Bettinazzi Stefano , Gagnon-Arsenault Isabelle , Dubé Alexandre K. , Bédard Camille , Nguyen Tuc H. M. , Fiumera Heather L. , Breton Sophie , Landry Christian R. 
Published: September 2022

AbstractCritical mitochondrial functions, including cellular respiration, rely on frequently interacting components expressed from both the mitochondrial and nuclear genomes. The fitness of eukaryotic organisms depends on a tight collaboration between both genomes. In the face of an elevated rate of evolution in the mitochondrial genome, current models predict that maintenance of mitonuclear compatibility relies on compensatory evolution of the nuclear genome. Mitonuclear interactions would therefore exert an influence on evolutionary trajectories. One prediction from this model is that the same nuclear genomes but evolving with different mitochondrial haplotypes would follow distinct molecular paths towards higher fitness peaks. To test this prediction, we submitted 1344 populations derived from seven mitonuclear genotypes ofSaccharomyces cerevisiaeto more than 300 generations of experimental evolution in conditions that either select for a mitochondrial function, or that do not strictly require respiration for survival. Performing high-throughput phenotyping and whole-genome sequencing on independently evolved individuals isolated from endpoint populations, we identified numerous examples of gene-level evolutionary convergence among populations with the same mitonuclear background. Phenotypic and genotypic data on strains derived from this evolution experiment identify the nuclear genome and the environment as the main determinants of evolutionary divergence, but also show a modulating role for the mitochondrial genome exerted both directly and via interactions with the two other components. We finally recapitulated a subset of prominent loss-of-function alleles in the ancestral backgrounds and confirmed a generalized pattern of mitonuclear-specific and highly epistatic fitness effects. Together, these results demonstrate how mitonuclear interactions can dictate evolutionary divergence of populations with identical starting nuclear genotypes.